Jump to content

All Activity

This stream auto-updates     

  1. Earlier
  2. It is estimated that more than 330 million people currently suffer from Dry Eye Syndrome worldwide. Although often misunderstood, the complex disease can even lead to a chronic vision threatening disorder, conjunctivochalasis (CCh). Certain modern day conveniences are thought to be a cause in the increase of the condition, with extended viewing of digital screens, laser eye surgery, exposure to air conditioning and increased life expectancy to blame for the growing incidence. LO2A Eye Drops Artificial tear preparation, presented in sterile, uni-dose vials to minimize risk of infection and contamination. LO2A is currently registered and marketed by its inventor in Germany and Switzerland for the treatment of Dry Eye Syndrome ("Dry Eye"), in Hungary for the treatment of Dry Eye and Conjunctivochalasis ("CCh") and in the Netherlands for the treatment of Dry Eye and Sjögren’s Syndrom. LO2A was developed by Prof. Shabtay Dikstein (School of Pharmacy, Hebrew U. – 1990s), as substitute for natural tears, to lubricate and protect ocular surface tissues. Well-established safety profile over more than 10 years of sales in Europe through local distributors, with no material known side effects. Preservative-free (Preservatives have recognized potential for irritation and sensitization; can damage the ocular surface and cornea) Can be used with any contact lenses Anti-irritant properties Non-Newtonian viscosity profile Available in uni-dose and future multi-dose form Wize Pharma holds exclusive marketing & distribution rights in US, ROW(*), Ukraine & Israel Sold by the inventor as: Hylan® – Germany, the Netherlands Lacrycon® – Switzerland Conheal® – Hungary Dry Eye Syndrome ("Dry Eye") Multifactorial disease of the tear and ocular surface resulting in discomfort, visual disturbance and tear film instability with potential damage to the ocular surface.* Tear layer protects the surface of the eye, providing nutrition Injury is a dynamic process, resulting in change in tear composition & symptoms of burning, redness, blurred vision, etc. Dry Eye is the most frequent symptom treated by ophthalmologists Epidemiological studies show dry eye will occur in 14-33% of population. Market size in 2014 est. + $2.5B, increasing steadily every year. Increase in incidence with age and other factor Conjunctivochalasis (CCh) Conjunctivochalasis (CCh) is a complication of dry eye Aseptic, chronic inflammation of the conjunctiva; on a background of dry eye syndrome Common age-related eye condition over 50; increases in frequency & severity with age Also markedly increased in people wearing contact lenses, regardless of age Appears in one third of dry eye patients Inflammation condition is sustained; not spontaneously reversible Severe CCh (Stage 3) can only be treated by invasive surgical treatment, which can cause considerable discomfort Sjögren’s Syndrome Sjögren’s syndrome is a chronic long-term auto-immune disease The patient's white blood cells attack the saliva and tear glands, leading to dry mouth and eyes While Sjögren’s syndrome can develop at any age, the majority of patients are diagnosed after the age of 40 with 90% of patients female There are approximately 4,000,000 people in the USA and 500,000 in the UK with Sjögren’s Syndrome
  3. Study Confirms Urgent, Unmet Needs in Childhood-Onset Lupus Experts identify lupus nephritis and neuropsychiatric disease among highest research priority areas. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) and Lupus Foundation of America (LFA) conducted a first-of-its-kind, multidisciplinary research effort on childhood-onset lupus to assess research priorities for addressing this life-threatening disease. Results from the study, “Research Priorities in Childhood-Onset Lupus: Results of a Multidisciplinary Prioritization Exercise” published in Pediatric Rheumatology, conclude that the highest areas needing research in childhood lupus are nephritis, clinical trials, biomarkers, neuropsychiatric disease, and refractory skin disease. The study also revealed a strong need for multidisciplinary collaboration moving forward. When asked which sub-specialties in addition to rheumatology should collaborate in childhood lupus research, 92% suggested collaborating with nephrologists, 73% with dermatologists, and 68% with mental health specialists. Children with lupus have more pervasive and life-threatening organ involvement compared to adults with lupus, and an estimated 6,000 US children and adolescents are currently living with the disease which has few treatment options and no cure. Over 250 members of CARRA, Midwestern Pediatric Nephrology Consortium (MWPNC) and Pediatric Dermatology Research Alliance (PeDRA) Connective Tissue Disease Group participated in the study. Click image to view larger Inflammation of the Kidneys Nephritis (inflammation of the kidneys) was identified as the number one research priority. Up to 80% of children with lupus develop nephritis, which increases risk of kidney failure, cardiovascular disease and death. Lupus nephritis (LN) requires prolonged therapy, often with toxic medications, and complex treatment plans. Although there have been many advances over the last several decades and many people with lupus can enjoy good health and normal activities, LN is still a driving factor in increased complications, hospitalizations and mortality rates, especially in children versus adults with lupus. Cognitive Impairment Lupus commonly affects the brain in children and can cause strokes as well as severely impair the ability to think through tasks. Neuropsychiatric disease (involvement of the nervous system) was also identified as a top challenge for clinicians and researchers treating children with lupus. Neuropsychiatric complications can have substantial negative impact on cognitive development, educational and vocational outcomes in children and adolescents with lupus. Up to 65% of children with lupus develop neuropsychiatric involvement over the course of their disease, with up to 85% developing neuropsychiatric involvement in the first two years from diagnosis.1 The burden, ranging from missed school or even school failure to major challenges with treatment adherence, can have an enormous impact on a child’s psychological development and quality of life. Today, the treatment of childhood lupus is generally extrapolated from adult clinical trials data and optimal drug dosing, duration of therapy and outcomes measurement may differ for pediatric patients. Specific to nephritis and neuropsychiatric disease, important focus areas across all lupus experts were determining best treatments, biomarkers/pathophysiology, drug discovery/novel treatments, understanding long term outcomes, and refining provider reported quality measures. Of note, understanding long term outcomes was ranked highly important across every research area. “This study underscores the urgency for childhood lupus research. We are committed to investing in this area, and our partnership with CARRA as leaders in this field will bolster our progress as we work together to elevate childhood lupus research,” said Stevan Gibson, President and CEO, Lupus Foundation of America. “The findings from the study offer a roadmap to guide future research endeavors, so that the scope and devastation of lupus in children aligns with received funding.” “This is the first published research prioritization effort among experts in childhood lupus, which highlights the lack of evidence that exists specific to this disease. There are important differences between adults and children, and significant knowledge gaps limit our understanding of the best treatments and long term outcomes in children with lupus,” said Aimee Hersh, Chair of the CARRA Systemic Lupus Erythematosus Committee. “This multidisciplinary approach to identifying research priorities emphasizes the need for collaboration for childhood lupus care and research. The results from this exercise will help set a research agenda moving forward.” The study, Research Priorities in Childhood-Onset Lupus: Results of a Multidisciplinary Prioritization Exercise, appears in Pediatric Rheumatology. Systemic Lupus Erythematosus in Children and Adolescents, Pediatric Clinics of North America, Volume 59, Issue 2, April 2012 https://www.lupus.org/news/study-confirms-urgent-unmet-needs-in-childhoodonset-lupus
  4. Rheumatology, the journal of the British Society for Rheumatology, is offering free access (through December 31) to its ten most highly cited papers of 2017 and 2018. https://academic.oup.com/rheumatology/pages/highly_cited_articles Highly Cited Articles Rheumatology publishes a wide range of high quality original scientific papers with a focus on basic, clinical, and translational research in rheumatology. Ten of the highest cited papers published in 2017 and 2018 can be explored below for free until the end of December 2019. The worldwide incidence and prevalence of systemic lupus erythematosus: a systematic review of epidemiological studies Frances Rees, Michael Doherty, Matthew J Grainge, Peter Lanyon, Weiya Zhang The spectrum of giant cell arteritis and polymyalgia rheumatica: revisiting the concept of the disease Christian Dejaco, Christina Duftner, Frank Buttgereit, Eric L. Matteson, Bhaskar Dasgupta Secukinumab sustains improvement in signs and symptoms of psoriatic arthritis: 2 year results from the phase 3 FUTURE 2 study Iain B McInnes, Philip J Mease, Christopher T Ritchlin, Proton Rahman, Alice B Gottlieb, et al. The British Society for Rheumatology guideline for the management of systemic lupus erythematosus in adults Caroline Gordon, Maame-Boatemaa Amissah-Arthur, Mary Gayed, Sue Brown, Ian N. Bruce, et al. The effect of ethnicity and genetic ancestry on the epidemiology, clinical features and outcome of systemic lupus erythematosus Myles J. Lewis, Ali S. Jawad A longitudinal cohort study of the anti-synthetase syndrome: increased severity of interstitial lung disease in black patients and patients with anti-PL7 and anti-PL12 autoantibodies Iago Pinal-Fernandez, Maria Casal-Dominguez, Julio A. Huapaya, Jemima Albayda, Julie J. Paik, et al. Nicotine drives neutrophil extracellular traps formation and accelerates collagen-induced arthritis Jaejoon Lee, Ayala Luria, Christopher Rhodes, Harini Raghu, Nithya Lingampalli, et al. What drives osteoarthritis?—synovial versus subchondral bone pathology Thomas Hügle, Jeroen Geurts The British Society for Rheumatology Guideline for the Management of Gout Michelle Hui, Alison Carr, Stewart Cameron, Graham Davenport, Michael Doherty, et al. More severe disease and slower recovery in younger patients with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase-associated autoimmune myopathy Eleni Tiniakou, Iago Pinal-Fernandez, Thomas E. Lloyd, Jemima Albayda, Julie Paik, et al.
  5. A stay-at-home August. Our little dog, Lucy, has been ill and we daren’t risk travel. Yet there are upsides to our August at home. London is different, tourists outnumber commuters, seats in trains, peace over Brexit while the ‘remainers’ take their August break in Provence. No conferences or medical meetings, though September promises to be busy, with our own annual Hughes Syndrome patients’ meeting fully subscribed (we plan another in March next year). Also, there is the 13th international antiphospholipid conference in Manchester. This biannual conference has grown and grown. The first conference, which we organised at Hammersmith Hospital in 1984 (a year after our original papers on the syndrome in 1983) attracted, I think, 47 attendees! This year, the conference returns to England for the first time – to Manchester and organised by my friend Prof. Ian Bruce. As before, the abstracts of the papers will be published in the journal ‘LUPUS. I also hope to provide a summary for our charity website ghic.world/ Patient of the month Leg pain Mrs SR, aged 55, previously well, suffered from acute pain and swelling in her left calf. She had been on an organised walk the day before and at first attributed the pain to muscle spasm. The following day the pain and discomfort spread to the other leg and with it, a darkish discolouration in the right toes. Mrs SR’s GP arranged for an urgent appointment at the nearest vascular clinic. The initial findings suggested two separate problems, a probable DVT (deep vein thrombosis) in the left leg and more seriously, an arterial clot in the right leg. Mrs SR was admitted for further investigation. To cut a long story short, Mrs SR underwent arterial surgery to remove the artery obstruction and was treated with Warfarin anticoagulation. Further investigation showed a surprisingly normal arterial tree. A slight mitral valve leak was found, but thought not to be significant. Slowly, painfully, the ischaemic big toe healed. Further tests? Routine blood tests were essentially normal, including blood sugar, cholesterol and screens for malignancy and infection. Further history Mrs SR mentioned to the houseman that her sister suffered from Lupus. Lupus tests were negative,.but the houseman (a locum) had heard of Antiphospholipid Syndrome – a cousin of Lupus – and ran the blood tests. All three tests positive, strongly positive. The whole clinical picture (possibly including the cardiac valve leak) fitted the diagnosis. Treatment: long term Warfarin, probably at high level. Outlook good, provided the patient kept a careful watch over her anticoagulant control. What is this patient teaching us? To suffer both a venous thrombosis as well as an arterial thrombosis certainly suggests Hughes Syndrome. (Most other clotting disorders cause venous thrombosis only). Oddly, there were no other obvious precipitating factors or clues (except perhaps the leaky valve). Wrong! There was a clue. A strong one. Mrs SR had a strong family history of auto-immune diseases – Lupus and now possibly Hughes Syndrome (and maybe more). The more we seek, the more we find genetic linkages within the growing autoimmunity world family. (Prof G Hughes', The London Lupus Centre)
  6. 10 Challenges in Treating Lupus 10 most important challenges in treating patients with SLE. (©Blueringmedia,AdobeStock) Gregory M. Weiss, M.D. June 13, 2019 We have come a long way since the introduction of glucocorticoids for the treatment of systemic lupus erythematosus (SLE). A one-year survival rate of 50 percent has become a 10-year survival of 90 percent due to advances in treatment. Even with improved treatment and prognosis several challenges remain in the management of SLE. In this article, we highlight the 10 most important challenges in treating patients with SLE as outlined by Laurent Arnaud, M.D., Ph.D., of Strasbourg, France, in a review published in Lupus Science & Medicine earlier this year. 1) Treat to target favoring disease remission (or low disease activity) In 2016, a large international panel sought to define remission in systemic lupus erythematosus (SLE). The panel was able to agree on three principles: Remission should be a durable state. A validated index should be used. Distinction should be made between remission on and off therapy. While at the same time the Asia Pacific Lupus Collaboration developed a Low Disease Activity State index, the challenge remains to validate whether these definitions are predictive of outcomes and ultimately used as targets in treat-to-target management of SLE. 2) Limiting the use of glucocorticoids While glucocorticoids have played a major role in the improvement of systemic lupus erythematosus (SLE) prognosis, a large number of patients never discontinue glucocorticoids. Glucocorticoid dose predicts its overall exposure which can increase the risk of damage accrual even at low doses. Several challenges exist with regards to glucocorticoid treatment in SLE: Using a low dose glucocorticoid or a glucocorticoid free regimen should be discussed as a major target. Glucocorticoid management should be addressed as an important concern in future research with glucocorticoid tapering schemes, glucocorticoid-related adverse events, damage accrual and cumulative glucocorticoid doses being examined. Glucocorticoid doses should be managed using more objective tools such as the glucocorticoid cumulative dose, follow-up of disease activity and damage, and recording of glucocorticoid-related adverse events. 3) Deriving more comprehensive tools for the evaluation of disease activity Do to multiple organs being involved in systemic lupus erythematosus (SLE), it is difficult to define disease activity as a whole. While several tools have been developed to assess the overall activity of the disease, in most cases the clinician has to form a judgment with regard to whether each manifestation is due to SLE or some other cause. The authors believe that a more objective and reproducible measure of disease activity is needed and may include biomarkers and utilization of modern technology such as deep machine learning. 4) Developing more effective and better tolerated drugs While drug therapy in systemic lupus erythematosus (SLE) has improved, several gaps remain in the care of SLE patients such as the progression of lupus nephritis to end-stage kidney disease. For example, in lupus nephritis, a significant proportion of patients still progress towards end-stage kidney disease. “Our group has recently published a systematic review (in the Annals of Rheumatic Diseases) of 74 targeted therapies for SLE, showing that we may expect great changes in the therapeutic tools available for SLE treatment,” the authors wrote. “We believe that current challenges are shifting from whether some new drugs will be available to the identification of the best strategy for the selection of the most adequate drug (or drug combination) at the patient level, to warrant a positive balance between efficacy and side effects. The need to investigate biomarkers that would allow adequate prediction of response to therapy remains high, but when solved will allow a more rational selection of the optimal pharmacological agent within the broad pipeline of targeted therapies for SLE.” These current challenges are shifting from whether new drugs will be available to identifying the best strategy for the selection of the most adequate drug, or drug combination, at the patient level. Identifying strong biomarkers will allow a more rational selection of the optimal pharmacological agent. 5) Dissecting the heterogeneity of the disease at the molecular and genetic level Both environmental and genetic factors play roles in the development and exacerbation of systemic lupus erythematosus (SLE). To date, a large number of nucleotide polymorphisms have been implicated in SLE however none of them have utility on their own in the diagnosis or treatment of patients. An important challenge will be to develop an optimal genetic model for patients’ sub-stratification using multiomics to better personalize medicine for patients with SLE 6) Identifying relevant biomarkers for individualized treatment Matching the right treatment to the individual patient remains a challenge in SLE. Traditional markers such as anti-double-stranded-DNA fall short and should give way to multiomics, which utilize high-throughput tools such as next-generation sequencing and computerization of data, to open the door for an integrated and personalized treatment approach. Non-coding RNAs, owing to being tissue-specific regulators of gene expression, may emerge as important makers of flares in SLE. It remains a challenge to develop a holistic approach to SLE, a challenge that will require a specialized interface between all providers. 7) Managing fertility and pregnancy Pregnancy remains a significant challenge in women with systemic lupus erythematosus (SLE). We as clinicians have to improve the outcomes of pregnancy in patients with aPL and/or anti-SSA/B antibodies. The overall prognosis of pregnancy in SLE is better when the disease has been in remission for at least six months, or one year for nephritis with a low organ damage score. Strong predictors of complications during pregnancy with SLE include: Active SLE at the time of conception and/or positivity for lupus anticoagulant or triple positivity, use of antihypertensive treatments, and low platelet count. Finally, clinicians should be aware that pregnancy complications can mimic SLE flares and anti-phospholipid antibodies can lead to both maternal and fetal adverse events. Managing comorbidities Late cardiovascular morbidity and mortality have increased along with overall systemic lupus erythematosus (SLE) patient survival. One challenge here is that measures validated for determining cardiovascular disease risk are based on North American populations and may not be adapted from the general population to patients with SLE. Infections remain an serious comorbidity with SLE. Vaccines should be used provided immunosuppressive therapy does not contraindicate use. Osteoporosis can be significant in SLE patients especially with glucocorticoid treatment. Anti-osteoporotic treatment should be considered. 9) Improving the network of care More light should be shed on rare diseases like systemic lupus erythematosus (SLE). We need to improve early diagnosis while limiting diagnosis uncertainty. Training of new clinicians should included recognition of rare diseases and education should be provided to practicing caregivers, patients, and their families alike. Global awareness should be the goal. 10) Favoring a holistic approach All aspects of the patient with SLE should be addressed. Patient reported outcome measures can facilitate holistic treatment and lead to better quality of life. Just as organ damage is a concern, so should fatigue, depression, pain, sleep disturbance and obesity be. Better trials are needed in an effort to find non-pharmacological interventions aimed at treating the whole patient. Finally, individual factors such as race, smoking, and socioeconomic background should be taken into consideration when developing a plan for patients with SLE. REFERENCE Renaud Felten, Flora Sagez, Pierre-Edouard Gavand, et al. “10 most important contemporary challenges in the management of SLE.” Lupus Science & Medicine 2019;6:e000303. DOI:10.1136/ lupus-2018-000303 https://www.rheumatologynetwork.com/lupus/10-challenges-treating-lupus
  7. Pregnant SLE Patients Discontinue Meds When They Shouldn't (©SydaProductionsShutterStock.com) Gregory M. Weiss, M.D. August 7, 2019 Lupus, Modern Medicine News, News, Rheumatology Recent evidence shows that pregnant women with systemic lupus erythematosus (SLE) often discontinue their lupus medications during pregnancy despite recommendations to continue them. The findings, reported by Mary A. De Vera, M.D., of the University of British Columbia, appear in the July 16 online issue of Lupus. “Considering the patterns of medication use seen in this study, it appears that expectant mothers with SLE would benefit from having a discussion with their care providers about how to manage their disease during their pregnancy, which medications are safe to take, and which should be avoided,” the authors wrote. “Knowing medication use in pregnant women with SLE is key to understanding how to support patients with family planning and pregnancy decisions.” Since lupus primarily affects women in their childbearing years, pregnancy can be a time fraught with risk and complications such as stillbirth, preterm labor and miscarriage. A significant portion of pregnant women with systemic lupus erythematosus will experience flares late in the pregnancy or after the birth. While concerns over taking medications during pregnancy exist, it is recommended that women with lupus continue their antimalarial drugs like hydroxychloroquine throughout gestation and during breast-feeding, according to GR de Jesus, et al. writing in the July 12, 2015 online issue of Autoimmune Diseases. The authors of the Lupus study sought to characterize the frequency of use of anti-malarial drugs, immunosuppressants and other medications, before, during and after pregnancy with particular interest on discontinuation of antimalarials and immunosuppressants during pregnancy. THE STUDY This was a population-based study of 284 women with systemic lupus erythematosus and 376 pregnancies. They were assessed for the discontinuation of antimalarials and immunosuppressants. Use of other lupus medications were also recorded. Rates of antimalarial use and azathioprine during the study period were 33.2 percent and 11.4 percent respectively. The authors further found that 26.3 percent of pregnancies in lupus patients were exposed to glucocorticosteroids and 23.7 percent to non-steroidal anti-inflammatory drugs. Pre-pregnancy antimalarial use stood at 36.2 percent, which dropped to 19.1 percent during the first trimester, 16.7 percent in the second, and held relatively steady at 17 percent in the third. Use rebounded to 31.1 percent after delivery. Pre-Pregnancy azathioprine was used by 11.7 percent, which dropped to 6.6 percent in the first trimester, 6.4 percent during the second, 6.9 percent in the third and rose to 10.4 percent after delivery. 33.2 percent of patients were exposed to glucocorticosteroids before pregnancy, 14.9 percent in the first trimester, 13.3 percent in the second trimester, 19.7 percent in the third trimester and 25.3 percent after delivery. 34.8 percent were exposed to NSIADs before pregnancy and 19.1 percent after pregnancy. Antimalarials were discontinued at a rate of 28.9 percent in the 12 months preceding pregnancy and 9.7 percent during pregnancy from the first trimester to the second and 26 percent from the second trimester to the third. Having had more children was associated with discontinuing antimalarials before pregnancy and time since lupus diagnosis was associated with higher odds of discontinuing antimalarials during pregnancy. Azathioprine was discontinued at a rate of 29.2 percent before pregnancy, 8.0 percent from the first to the second trimester and 9.1 percent from the second to third. Take-home points for clinicians and final thoughts The high rates of discontinuation, in particular antimalarial treatment underscore the disconnect between the recommended treatment for lupus during pregnancy and the reality. “As these findings conflict with the afore- mentioned recommendations regarding the continued use of antimalarials during SLE pregnancies, they suggest the importance of educating women with SLE who are pregnant or planning to become pregnant on the benefits and risks of medications during pregnancy,” the authors write. Compliance is a serious concern. Strong evidence and concise recommendations are useless if patients are not following the treatment plan. The responsibility rests with the clinician to disseminate the knowledge pregnant women need to make the right choices about continuing their medication regimen when both systemic lupus erythematosus and pregnancy coincide. REFERENCE Zusman, E. Z., Sayre, E. C., Aviña-Zubieta, J. A., & De Vera, M. A. (2019). “Patterns of medication use before, during and after pregnancy in women with systemic lupus erythematosus: a population-based cohort study.” Lupus. July 16, 2019 https://doi.org/10.1177/0961203319863111 https://www.rheumatologynetwork.com/lupus/pregnant-sle-patients-discontinue-meds-when-they-shouldnt
  8. Pregnant SLE Patients Discontinue Meds When They Shouldn't (©SydaProductionsShutterStock.com) Gregory M. Weiss, M.D. August 7, 2019 Lupus, Modern Medicine News, News, Rheumatology Recent evidence shows that pregnant women with systemic lupus erythematosus (SLE) often discontinue their lupus medications during pregnancy despite recommendations to continue them. The findings, reported by Mary A. De Vera, M.D., of the University of British Columbia, appear in the July 16 online issue of Lupus. “Considering the patterns of medication use seen in this study, it appears that expectant mothers with SLE would benefit from having a discussion with their care providers about how to manage their disease during their pregnancy, which medications are safe to take, and which should be avoided,” the authors wrote. “Knowing medication use in pregnant women with SLE is key to understanding how to support patients with family planning and pregnancy decisions.” Since lupus primarily affects women in their childbearing years, pregnancy can be a time fraught with risk and complications such as stillbirth, preterm labor and miscarriage. A significant portion of pregnant women with systemic lupus erythematosus will experience flares late in the pregnancy or after the birth. While concerns over taking medications during pregnancy exist, it is recommended that women with lupus continue their antimalarial drugs like hydroxychloroquine throughout gestation and during breast-feeding, according to GR de Jesus, et al. writing in the July 12, 2015 online issue of Autoimmune Diseases. The authors of the Lupus study sought to characterize the frequency of use of anti-malarial drugs, immunosuppressants and other medications, before, during and after pregnancy with particular interest on discontinuation of antimalarials and immunosuppressants during pregnancy. THE STUDY This was a population-based study of 284 women with systemic lupus erythematosus and 376 pregnancies. They were assessed for the discontinuation of antimalarials and immunosuppressants. Use of other lupus medications were also recorded. Rates of antimalarial use and azathioprine during the study period were 33.2 percent and 11.4 percent respectively. The authors further found that 26.3 percent of pregnancies in lupus patients were exposed to glucocorticosteroids and 23.7 percent to non-steroidal anti-inflammatory drugs. Pre-pregnancy antimalarial use stood at 36.2 percent, which dropped to 19.1 percent during the first trimester, 16.7 percent in the second, and held relatively steady at 17 percent in the third. Use rebounded to 31.1 percent after delivery. Pre-Pregnancy azathioprine was used by 11.7 percent, which dropped to 6.6 percent in the first trimester, 6.4 percent during the second, 6.9 percent in the third and rose to 10.4 percent after delivery. 33.2 percent of patients were exposed to glucocorticosteroids before pregnancy, 14.9 percent in the first trimester, 13.3 percent in the second trimester, 19.7 percent in the third trimester and 25.3 percent after delivery. 34.8 percent were exposed to NSIADs before pregnancy and 19.1 percent after pregnancy. Antimalarials were discontinued at a rate of 28.9 percent in the 12 months preceding pregnancy and 9.7 percent during pregnancy from the first trimester to the second and 26 percent from the second trimester to the third. Having had more children was associated with discontinuing antimalarials before pregnancy and time since lupus diagnosis was associated with higher odds of discontinuing antimalarials during pregnancy. Azathioprine was discontinued at a rate of 29.2 percent before pregnancy, 8.0 percent from the first to the second trimester and 9.1 percent from the second to third. Take-home points for clinicians and final thoughts The high rates of discontinuation, in particular antimalarial treatment underscore the disconnect between the recommended treatment for lupus during pregnancy and the reality. “As these findings conflict with the afore- mentioned recommendations regarding the continued use of antimalarials during SLE pregnancies, they suggest the importance of educating women with SLE who are pregnant or planning to become pregnant on the benefits and risks of medications during pregnancy,” the authors write. Compliance is a serious concern. Strong evidence and concise recommendations are useless if patients are not following the treatment plan. The responsibility rests with the clinician to disseminate the knowledge pregnant women need to make the right choices about continuing their medication regimen when both systemic lupus erythematosus and pregnancy coincide. REFERENCE Zusman, E. Z., Sayre, E. C., Aviña-Zubieta, J. A., & De Vera, M. A. (2019). “Patterns of medication use before, during and after pregnancy in women with systemic lupus erythematosus: a population-based cohort study.” Lupus. July 16, 2019 https://doi.org/10.1177/0961203319863111 https://www.rheumatologynetwork.com/lupus/pregnant-sle-patients-discontinue-meds-when-they-shouldnt
  9. SLE Breakthrough Finds a Link Between Microbial Translocation and Autoantibodies (©AysezgicmeliShutterstock.com) Gregory M. Weiss, M.D. August 7, 2019 Lupus, Modern Medicine News, News, Rheumatology A previously unknown direct relationship has been found between microbial translocation from the gastrointestinal tract and autoantibody levels in patients with systemic lupus erythematosus. The findings by, Gary Gilkeson, M.D., and Wei Jiang, M.D., of the Medical University of South Carolina in Charleston, appear in the May 20 online issue of Arthritis and Rheumatology. The authors state, “An understanding of the mechanism of autoantibody induction in systemic lupus erythematosus (SLE) can lead to the development of therapeutic targets that prevent autoantibody production thereby slowing disease onset, mitigating downstream inflammation and reducing tissue damages.” Systemic lupus erythematosus is a chronic autoimmune mediated inflammatory disease that results from a loss of tolerance to the patient’s own antigens leading to autoantibody production. It is known that genetic factors influence the development of lupus leading to clustering of the disease within families. The source of autoantibody production in systemic lupus erythematosus remains elusive and is likely multifactorial with genetic, environmental, immunologic, and hormonal factors contributing to development of the disease. Recent research has implicated increased intestinal permeability in the pathogenesis of autoimmune disease. While under normal conditions the gastrointestinal tract serves as a barrier to environmental antigens, however, in certain disease states, this barrier may be compromised allowing translocation of gut microbes into the bloodstream. The authors sought to determine the role of microbial translocation in systemic lupus erythematosus. They examined lupus patients and their first-degree relatives comparing them to healthy controls. Two cohorts were included in the study. The first group consisted of 18 unrelated healthy control subjects and 18 first-degree relatives of systemic lupus erythematosus patients. The second included 19 healthy controls and 21 lupus patients. Plasma autoantibodies and lipopolysaccharide levels were measured and DNA bacterial DNA was extracted from plasma to determine if translocation had occurred. From the bacterial DNA microbiome species was determined. Auto-antigen array demonstrated higher plasma levels of a large spectrum of autoantibodies in systemic lupus erythematosus patients and first-degree relatives of lupus patients compared to healthy controls. Four representative lupus-related IgG autoantibodies including anti-double stranded DNA, anti-nucleosome, anti-single stranded DNA and anti-chromatin were increased in lupus patients and first-degree relatives compared to healthy control subjects. Compared to unrelated healthy control subjects, systemic lupus erythematosus patients and parents or children who were first-degree relatives had increased microbial translocation as evidenced by plasma lipopolysaccharide levels. First-degree relatives of lupus patients but not lupus patients themselves had decreased intestinal species diversity when compared to healthy controls. Take-home points and final thoughts First-degree relatives of systemic lupus erythematosus patients also have significantly elevated levels of lupus related autoantibodies. Increased levels of lipopolysaccharide in these patients are consistent with prior research linking infection, bacterial translocation and autoimmunity. The authors state, “The increased translocation of bacterial products into the systemic circulation from the permeable mucosa suggests that insights into autoimmune pathology can be gained from studying the circulating microbiome as opposed to other sites.” In a letter to the editor the authors discuss why they believe bacterial diversity was decreased in relatives but not in lupus patients themselves. They found after reanalyzing the data that diversity differences did not occur within a specific racial group but did between different races. They point out that, “while race may play a role in differences in circulating microbiome diversity, additional studies are needed to confirm this hypothesis.” Systemic lupus erythematosus is a very complex disease with an etiology that has remained elusive. The authors have discovered a possible infectious cause of lupus that could lead to focus on intestinal integrity and possibly uncover medications that we are using that compromise gut barrier. While the discovery of bacterial translocation in lupus opens the door for future investigation into preventing this from happening, the sheer number of different possible causes for systemic lupus erythematosus remains daunting. With continued efforts like those of the authors, we take important steps toward understanding lupus in the hopes of improving the quality of life of those who suffer from it. REFERENCE Elizabeth Ogunrinde, Zejun Zhou, Zhenwu Luo, et al. "A link between plasma microbial translocation, microbiome, and autoantibody development in first-degree relatives of systemic lupus erythematosus patients." Arthritis and Rheumatology. 2019 May 20. doi: 10.1002/art.40935 https://www.rheumatologynetwork.com/lupus/sle-breakthrough-finds-link-between-microbial-translocation-and-autoantibodies?rememberme=1&elq_mid=8392&elq_cid=1830808&GUID=9D824BFE-EF27-47A3-BAE0-900DC34C90C7
  10. Take the Right Shots for Lupus! August 15, 2019 While August is when we savor the last weeks of summer, it is also the time to look ahead and prepare for fall. In recognition of National Immunization Month, our Chief Scientific Officer Dr. Teodora Staeva provides background on vaccines and relays government recommendations for which are safe for people with lupus. “Vaccines help to develop immunity, in other words protect against disease, by imitating an infection,” notes Dr. Staeva. “Most vaccines contain small amounts of the germs (or parts of them) that cause disease but are either killed or weakened. The vaccine prompts the immune system to produce T cells and antibodies against these germs, and thus allows the body to learn how to fight these microbes in the future. However, several rounds of vaccination are often required to achieve optimal protection.” Currently there are four main types of vaccines. Live-attenuated vaccines use the weakened (attenuated) form of the virus so that it does not cause serious illness in individuals with healthy immune systems. Vaccines with live viruses are generally NOT recommended for people with lupus. Inactivated vaccines are made by killing the germ while making the vaccine. These are considered safe and effective for people with lupus. Subunit or purified antigen vaccines use only specific pieces of the germ. Thus, they give a very robust immune response targeted to key portions of the microbe. Generally, these vaccines can be used widely, including on people with weakened immune systems. Toxoid vaccines use a toxin (harmful product) made by the germ that causes a disease. They create immunity to the parts of the germ that cause a disease instead of the germ itself. That means the immune response is targeted to the toxin instead of the whole germ. “People with lupus are at greater risk for infections due to immunosuppression, so vaccines are very important,” noted Dr. Staeva. “But speak to your doctor before getting any vaccine to determine which are right for you and when.” _________________________________________________________________________ Recommendations from the U.S. Department of Health & Human Services (HHS), Office of Women’s Health: People with lupus typically can get the following vaccines that do not contain live viruses: The flu shot (not nasal spray which contains a live form of the flu virus) Pneumonia vaccine Human papillomavirus (HPV) vaccine Tetanus, diphtheria, and acellular pertussis (Td/Tdap) vaccine Vaccines with live viruses that may not be safe for people with lupus, include: Nasal spray vaccine for the flu Varicella (chickenpox) vaccine Herpes Zoster (Shingles) vaccine Measles, Mumps, Rubella (MMR) vaccine Live typhoid vaccine (oral) Sources: U.S. Department of Health & Human Services, Office of Women’s Health https://www.lupusresearch.org/take-the-right-shots-for-lupus/
  11. July 2019 22 July 2019 by Professor Graham R V Hughes MD FRCP This week, we held the 33rd annual “Ten Topics in Rheumatology” meeting in London. Organised by Professor Chris Edwards and his team from the London Lupus Centre – Professor David D’Cruz, Professor Munther Khamashta and Dr Arvind Kaul, it was a full house of 300 doctors from far and wide, including one from New Zealand. For me, it was a fantastic 2 days – the usual formula of top international speakers, short presentations and the most up-to-date reviews. Congratulations to Chris and the team. I took part in a session arranged by Professor Khamashta called “kerbside consults” – a series of cases (of Hughes Syndrome) with questions posed by the audience, as well as 3 experts – Cathy Nelson-Piercy (Consultant Obstetric Physician at St Thomas’ Hospital) and David D’Cruz (my colleague at the London Lupus Centre) and myself. One of the 4 cases presented by Professor Khamashta covered a number of aspects and I will use this case for my July blog. Patient of the Month Miss G.L., a 25 year old secretary, developed an acute deep vein thrombosis of the leg at the age of 23. There had been no prior clues to the diagnosis apart from a past history of frequent pre-menstrual headaches. She had never smoked or taken oestrogen-containing drugs. There was no family history of thrombosis or auto-immune disease. However, her tests for antiphospholipid antibodies (aPL) were positive – strongly positive, and “triple-positive” (all three of the currently used aPL tests – aCL, LA and anti-β2 GP1 – were positive at high level). She was treated with Warfarin. Interestingly, the headaches which had been frequent (though ‘livable’) disappeared. The Warfarin continued, perhaps longer than usual, for a year. Miss G.L. raised two topics – marriage “in a year or two” and pregnancy, and the second concerning horse riding. She asked whether it was now safe to stop the Warfarin, prior to taking up horse riding again, or at least to convert to aspirin. What would you do? Perhaps not surprisingly, the three experts gave rather differing opinions. The first agreed with a change to aspirin. After all, this was a venous thrombosis and not arterial, and the risk of re-thrombosis on aspirin was small. The second expert discussed pregnancy. The treatment of pregnancy in Hughes Syndrome was becoming almost standardised worldwide, with low molecular weight heparin, plus or minus aspirin being first choice. The warfarin, if continued, could be changed to heparin as soon as the pregnancy test became positive. The third expert focused more on the primary thrombosis. This young woman in the prime of her life was at high risk unless treated. Although not universally accepted, a number of studies have suggested that “triple positive” aPL patients (aCL, LA and anti-β2 GP1 positive) have much stronger tendency to re-thrombose. Although Warfarin has a bad press, and interacts with many foods and drinks, it has three big pluses. Firstly, unlike many other anti-clotting treatments, its therapeutic dose can be closely controlled (many Hughes Syndrome patients living normal lives with the help of self-testing INR machines). Secondly, current experience suggests that Warfarin may be superior to newer anticoagulants (‘NOACS’) in severe APS (though admittedly, Miss G.L’s thrombosis was venous). The third specialist admitted that many of his Warfarin patients took part in horse riding (and other ‘contact’ sports) but he did recognise that, for some, the risk was too great. His rather brutal opinion was “keep the Warfarin, sell the horse”. PROFESSOR GRAHAM R V HUGHES MD FRCP Head of The London Lupus Centre London Bridge Hospital https://ghic.world/blog/july-2019
  12. Entry Requirements for Lupus Nephritis Clinical Trials Exclude Majority of Patients in UK Registry, Study Says JULY 10, 2019 BY IQRA MUMAL IN NEWS. Click Here to receive Lupus News via e-mail How clinical trials into lupus nephritis define their requirements for patient eligibility are too strict, leaving many people with active and severe disease ineligible for participation, according to a study that looked at six lupus trials and how well their “inclusion and exclusion criteria” matched patients in a large U.K. registry. Its researchers reported that a majority of registry patients, 50.6%, would not have been enrolled under published entry requirements. These findings were presented at the recent 2019 European Congress of Rheumatology(EULAR 2019), in a poster titled “How Well Do Clinical Trials Represent Real World Lupus Nephritis Patients?” Lupus nephritis (inflammation of the kidneys) can be a serious complication of systemic lupus erythematosus (SLE). The standard of care for lupus nephritis is treatment using glucocorticoids or conventional immunosuppressants. Rituxan (rituximab), an antibody that dampens some immune cells, has been used off-label to treat some with lupus nephritis, but has not shown efficacy across several clinical trials. Finding better treatments for these people requires clinical studies that determine safety and effectiveness. But stringent requirements for trial participation, often done to ensure patient homogeneity in the group studied, can result in criteria that does not accurately reflect real-world patients, the study notes. Researchers set out to evaluate clinical trial criteria for lupus nephritis by determining how closely they reflected a general population. They reviewed six recently published clinical trials involving these patients. Then they compared inclusion and exclusion criteria common across the trials to patients with active lupus nephritis in a U.K.-wide database of SLE patients called the BILAG-Biologics Register (BILAG-BR). Inclusion criteria define the characteristics that potential participants must have to be in a study, while exclusion criteria define those that disqualify from participation. The registry showed 259 people with active lupus nephritis, corresponding to 28.9% of its population. Among them, 230 had been treated with Rituxan, while the 29 others were given standard of care. Analysis showed that 70 people (30.4%) in the Rituxan group and 10 (34.5%) in the standard-of-care group that would not meet all inclusion criteria common to the six trials. The requirement that patients most often missed was not having a urine protein/creatinine ratio below 100 mg/mmol. This would exclude people with more severe kidney impairment. A majority, 118 patients or 51.3%, in the Rituxan group and six patients (20.7%) in standard-of-care also met one or more common exclusion criteria for the trials. Most often, the excluding criteria was active disease in the central nervous system and low levels of antibodies implying an immune system disorder (hypogammaglobulinaemia). Overall, more than half of registry patients (50.6%) with active lupus nephritis would not satisfy all inclusion and exclusion criteria, and likely be ineligible for clinical trial entry, the study found. Among patients deemed ineligible, those in the Rituxan group were younger (mean age, 36) compared to those given standard of care (mean age, 49). Most were also minorities (non-Caucasian) and female. “In a large national cohort of active LN [lupus nephritis] we found that 50.6% of patients would not be eligible for clinical trial entry using published entry criteria,” the researchers wrote. “This poses significant implications on the study of LN treatment in patients with more severe disease. When designing clinical trials, the stringency of eligibility criteria should be reviewed in order to provide greater representation of the target disease population,” they concluded. https://lupusnewstoday.com/2019/07/10/entry-criteria-for-lupus-nephritis-trials-exclude-majority-patients-in-uk-registry-study-finds/?utm_source=LUP+NEws+E-mail+List&utm_campaign=4dbb72aad6-RSS_WEEKLY_EMAIL_CAMPAIGN_US&utm_medium=email&utm_term=0_50dac6e56f-4dbb72aad6-71887989
  13. Medtronic Partners With Tel Aviv-Based Stroke Detection Startup Viz.ai by Meir Orbach / CTech An MRI of the human brain. Photo: Wikimedia Commons. CTech – Dublin-headquartered medical device maker Medtronic has signed a partnership agreement with stroke detection startup Viz.ai, the latter announced Monday. As part of the agreement, Medtronic will distribute Viz.ai’s technology in the US. The financial details of the agreement were not disclosed. Viz.ai develops deep learning and artificial intelligence-powered technology that can analyze brain scans and automatically transfer the information to a doctor to ensure the most immediate treatment for strokes. Viz.ai’s system connects to a hospital CT scanner and alerts the stroke specialist if a suspected large vessel occlusion (LVO) stroke has been identified, sending the radiological images directly to their smartphone. Based in San Francisco and Tel Aviv, Viz.ai was founded in 2016 after one of its founders, David Golan, suffered a brain event. The company has raised approximately $29 million to date. This is not Medtronic’s first dip in the Israeli tech pool. In September 2018, Medtronic acquired Israel-based surgical robotics company Mazor Robotics for $1.34 billion in cash. Earlier that year, it acquired medical visualization company Visionsense for $65 million. https://www.algemeiner.com/2019/07/22/medtronic-partners-with-tel-aviv-based-stroke-detection-startup-viz-ai/
  14. Understanding the Role of Polyautoimmunity in Rheumatic Diseases (©Zerbor,Shutterstock.com) Linda Peckel July 16, 2019 Rheumatology, Autoimmune Diseases, Modern Medicine News, News, Rheumatoid Arthritis An estimated 5 percent of the world’s population is diagnosed with one of a group of heterogeneous autoimmune rheumatic diseases (ARDs) including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjogren’s syndrome (SS). Not only do these diseases share mechanisms and risk factors, they are often comorbid conditions recognized as polyautoimmune (PolyA) manifestations of the same underlying dysfunction. Patients with SLE are frequently positive for anti-rheumatoid factor (RF) and less often for anti-citrullinated protein antibodies associated with RA, although less than 10% are diagnosed with concomitant SLE/RA, known as rhupus. Another 10% of SLE patients are recognized to have antiphospholipid syndrome (APS) although up to 54% have been shown to carry antibodies. Other PolyA’s may include SLE/hypothyroidism, RA/autoimmune thyroid disease (AITD), and concomitant symptoms of SS with SLE, AITD, or systemic sclerosis (SSc). According to studies by Gonzalez and colleagues (the most recent of which is published in the Journal of Autoimmunity)1 , 2 patterns of PolyA have emerged: 1) Overt PolyA, which reflects more than one well-defined ARD in a single patient, and 2) Latent PolyA, in which underlying patterns of autoantibodies are identified that do not correspond to the main diagnosis, and may be predictive of 1 or more additional ARDs. The authors conducted a cross-sectional cluster analysis of patients with the most common ARDs for antibody and cytokine patterns in a cohort of 187 individuals with diagnoses of SLE, RA, SSc, and SS (n = 70, 51, 35, and 31). They found that the frequency of PolyA did not differ across all 4 ARDs, although SLE and SS were associated with a younger age of onset. Rheumatoid factor and CCP3 were identified in 84.3% and76.5% of patients with RA, who also had the highest levels of Interleukin (IL)-6, interferon (IFN)-α, and IL-12/23p40 cytokines. Antinuclear antibodies (ANAs) were most prevalent in patients with SSc (97% positive) and SLE patients (71.4%), with distinctive patterns of additional antibodies and cytokines to each disease. The study revealed six main PolyA clusters involving the 4 ARDs that may provide biomarkers useful for diagnosis of current disease as well as prediction of other ARDs over time. The authors suggested that particular attention should be paid to latent PolyA, and to the strong association of IL-12/23p40 to 3 of the 6 cluster groups. REFERENCE 1. Molano-González N, Rojas M, Monsalve DM. "Cluster analysis of autoimmune rheumatic diseases based on autoantibodies. New insights for polyautoimmunity." J Autoimmun 2019;98:24-32. https://www.rheumatologynetwork.com/rheumatology/understanding-role-polyautoimmunity-rheumatic-diseases?rememberme=1&elq_mid=7781&elq_cid=1830808&GUID=9D824BFE-EF27-47A3-BAE0-900DC34C90C7
  15. Fatigue in Patients with Lupus is Real Fatigue in patients with systemic lupus erythematosus (SLE) has been linked to anti-NR2 antibodies, which responds to treatment with belimumab, a study shows. (©ArtemidaPsy,Shutterstock.com) Whitney J. Palmer June 24, 2019 Lupus, Rheumatology, Women's Health Patients with systemic lupus erythematosus (SLE) who have higher levels of antibodies to the receptor in the brain associated with memory and learning also experience more severe levels of fatigue, new research shows. The results, published in a recent issue of Annals of Rheumat ic Diseases, identifies a link between fatigue—one of the most challenging symptoms patients with systemic lupus erythematosus face—and the presence of anti-NR2, a brain-reacting antibody. “The presence of anti-NR2 antibodies in patients with lupus with fatigue is a helpful diagnostic tool and may offer a major approach in the therapeutic management of this important disabling symptom in patients with lupus,” said Andreas Schwarting, M.D., a rheumatologist, immunologist, and medical director at the University Medical Center of the Johannesburg-Gutenberg University Mainz in Germany. Elevated levels of anti-NR2 have been reported in 25 percent to 38 percent of patients with lupus, they said, so these findings could affect a substantial number of patients. To determine the impact of these autoantibodies, researchers analyzed blood samples from 426 patients with lupus. They also assessed fatigue severity using a self-reporting questionnaire. The findings found that patients with higher anti-NR2 levels experienced the more significant impacts of fatigue, including motoric and cognitive fatigue. Researchers found no correlation between anti-NR2 levels and renal function, erythrocyte sedimentation rate, or C-reactive protein. Study results also showed belimumab effectively relieved fatigue. Patients receiving belimumab for six months to 36 months saw a significant decline in their levels of anti-NR2 antibodies, as well as a clinically significant drop in their fatigue scores. Overall, investigators said, the findings could directly impact patient care. “The results of our study offer a sustained clinical advantage: to add an objective measurement of fatigue in lupus patients to a subjective questionnaire,” they said. “Anti-NMDAR antibodies should be identified routinely for patients with lupus suffering from fatigue.” REFERENCE Schwarting A, Mockel T, Lutgendorf F, et al. "Fatigue in SLE: diagnostic and pathogenic impact of anti-N-methyl-D-aspartate receptor (NMDAR) autoantibodies." Annals of Rheumatic Diseases(2019), doi: 10.1136/annrheumdis-2019-215098. https://www.rheumatologynetwork.com/lupus/fatigue-patients-lupus-real?rememberme=1&elq_mid=7437&elq_cid=1830808&GUID=9D824BFE-EF27-47A3-BAE0-900DC34C90C7
  16. Fracture Risk is High in Lupus Patients with systemic lupus erythematosus (SLE) are at an increased risk for fractures, new research shows. The risk is particularly high among patients with lupus nephritis. (©PollapatChirawongShutterstock.com) Whitney J. Palmer June 24, 2019 Lupus, Joint/Bone Health, News, Rheumatology Patients with systemic lupus erythematosus (SLE) are at an increased risk for fractures, new research shows. The risk is particularly high among patients with lupus nephritis. In a study published in a recent issue of Arthritis & Rheumatology, investigators foiund that patients with lupus nephritis were far more likely to break a bone than patients who do not have lupus. “Patients with lupus nephritis may be at particularly high risk of fracture due to secondary or tertiary hyperparathyroidism and vitamin D deficiency,” said study author Sara Tedeschi, M.D., MPH, a rheumatology fellow at Brigham and Women’s Hospital. To assess fracture risk, researchers examined medical records for 47,709 lupus patients, including 9,449 patients who also had lupus nephritis. They identified pelvic, wrist, hip, and humeral fractures and compared these records to those of 190,836 patients without lupus. According to results, all lupus patients had a two-fold higher risk for any fracture compared to patients without lupus. Lupus nephritis patients have a three-fold risk over non-lupus patients and a 1.6-fold increase over lupus patients. However, findings did indicate that African American patients with lupus experienced a lower fracture risk than other study participants. When examining risk for specific types of fractures, investigators found lupus patients were at high risk for hip and pelvic fracture compared to patients without lupus. The risk was also elevated, though not as much, for humerus and wrist fractures. Researchers also discovered younger lupus patients had a 2.3-times higher fracture risk than younger patients who didn’t have lupus. Lupus patients over age 50 had a two-fold fracture risk increase. Less than half of patients with lupus received glucocorticoid treatment, indicating use of this medication was only responsible for some increased fracture risk. Ultimately, investigators said, these results reinforce the importance of identifying high-risk patients who have lupus and lupus nephritis to monitor them and provide for fracture prevention. REFERENCE Tedeschi S, Kim S, Guan H, Grossman J, Costenbader K. "Comparative Fracture Risks Among United States Medicaid Enrollees With and Those Without Systemic Lupus Erythematosus." Arthritis & Rheumatology (2019), doi: 10.1002/art.40818 https://www.rheumatologynetwork.com/lupus/fracture-risk-high-lupus?rememberme=1&elq_mid=7437&elq_cid=1830808&GUID=9D824BFE-EF27-47A3-BAE0-900DC34C90C7
  17. A severe autoimmune condition may be triggered by 'good' gut bacteria HEALTH 18 June 2019 Source: https://www.newscientist.com/article/2206861-a-severe-autoimmune-condition-may-be-triggered-by-good-gut-bacteria/ Sometimes ‘good’ gut microbes can turn bad NOBEASTSOFIERCE/SCIENCE PHOTO LIBRARY By Jessica Hamzelou The billions of bacteria that line our guts have evolved with us, and play a crucial role in our digestion, physical and mental health. But bacteria that seem beneficial for most people can cause harm in others: they can trigger an autoimmune disease in vulnerable people. That’s what Martin Kriegel, an immunologist at Yale University, and his colleagues found when they studied people with antiphospholipid syndrome (APS), an autoimmune disorder in which a person’s own immune system attacks a protein that plays a key role in blood thinning. People with the syndrome are at risk of clots, strokes and miscarriages, and it can be fatal. “Young people can suddenly die if they have this,” says Kriegel. He wondered if, by chance, any gut bacteria might express a protein similar to the one that can trigger APS, and so be attacked by the immune system of people with the syndrome. When his team screened microbiome databases they found a match: Roseburia intestinalis, a species of bacteria that is thought to improve gut health. “It’s probably random due to the sheer number of molecules in the microbiome,” says Kriegel. Read more: Autoimmune disorder lupus may be triggered by body’s bacteria The team then looked at immune system activity in the gut of people with APS and people without the condition. While R. intestinalis was present at similar levels in the guts of all people examined, the bacteria seemed to be causing inflammation in people with APS. These individuals also made antibodies to attack the bacteria – which looked very similar to the antibodies they made to attack their own proteins. In experiments with mice, Kriegel’s team also found that, in animals genetically prone to developing APS, a dose of R. intestinalis could trigger the syndrome, with lethal outcomes. This all suggests that R. intestinalis can inadvertently trigger APS in people genetically predisposed to develop the syndrome, says Kriegel. “It could be that a bug that is beneficial for one disease is detrimental for another,” says Kriegel. A person’s genes and lifestyle could potentially influence which way the relationship will go. Kriegel hopes that the microbiome could offer new treatment approaches for people with autoimmune diseases like APS. Theoretically, once a person has been diagnosed with the disease, removing the microbe from their gut microbiome might help prevent future clots, he says. Journal reference: Cell Host & Microbe , DOI: 10.1016/j.chom.2019.05.003
  18. Gut Bacteria May Cause Antiphospholipid Syndrome, LRA-Funded Study Shows June 18, 2019 A common type of bacteria living in the gut may spark a common lupus complication called antiphospholipid syndrome, a study partly funded by the Lupus Research Alliance shows. Antiphospholipid syndrome can lead to blood clots and miscarriages. Led by Dr. Martin Alexander Kriegel of Yale School of Medicine, the research may also help explain why patients’ symptoms recur. The immune system makes a mistake in lupus and produces proteins called antibodies that damage the kidneys, joints, and other parts of the body. Close to half of people with lupus have antiphospholipid antibodies that target molecules in the outer layer of the body’s cells. Researchers think that in patients with lupus, the immune system tries to destroy molecules from healthy cells because they look like molecules from bacteria. Dr. Kriegel and colleagues found that a tiny organism called Roseburia intestinalis, which is one of the most common bacteria in the intestines, may cause some of these attacks. The researchers found that these bacteria contain parts of molecules that are very much like the parts of a blood protein targeted in patients with antiphospholipid syndrome. They discovered that patients with antiphospholipid syndrome make antibodies that hone in on the same piece of the bacterium as in the blood protein and that these antibodies correlate with each other. When the scientists gave the bacterium to mice prone to lupus, the animals showed signs of antiphospholipid syndrome. “Our results suggest that Roseburia intestinalis may be a chronic trigger for antiphospholipid syndrome,” says Dr. Kriegel. “Because the bacteria are so common and stable in the human gut, they may keep sparking attacks by the immune system and cause patients’ symptoms to return again and again. Dr. Kriegel and his colleagues revealed their findings in the journal Cell Host & Microbe. “The microbiome is of great interest in lupus, and we are excited to see Dr. Kriegel’s results fulfill the promise of his LRA grant,” noted Kenneth M. Farber, President and CEO, Lupus Research Alliance. “This work points to a new approach to treating antiphospholipid syndrome, a dangerous complication of lupus.” https://www.lupusresearch.org/gut-bacteria-may-cause-antiphospholipid-syndrome-lra-funded-study-shows/ Full Press Release from Yale University:
  19. APRIL 23, 2019 BY ALANA KESSLER More and more I am humbled at the connection between the microbiome and immunity. We are continuing to learn daily how our health is connected with the relationship we have with the world around us and how we process our environment. I personally have someone in my circle with systemic lupus erythematosus (SLE) and was privy to the manner in which it wreaked havoc on her life. She expressed to me that this “invisible illness” created a sense of shame and despair in the way it can feel like it steals the life from you. Science is making strong headway in understanding the onset and progression of SLE. The ideology of the holistic body as a cause and treatment of disease is becoming more and more mainstream and can’t be ignored, especially in a disease that affects multiple organ systems with a variety of symptoms and manifestations. A recent study strongly linked lupus to imbalances in the gut microbiome — the delicate balance of bacteria that live in the gut — which we know is affected by both diet and lifestyle factors. Food is so important, but so is managing life from a place that doesn’t trigger the sympathetic nervous system’s flight or fight response. When we do live from a place of stress, the hormones secreted can put extra pressure on the adrenals and eventually contribute to the slow decline of immunity due to gut microbiome imbalances secondary to nervous system overstimulation. The role diet plays in SLE is two-fold. Because lupus is an autoimmune disease by nature, understanding the root cause is just as important as treating the debilitating symptomsbecause it can influence the progression of the disease. In a 2018 article published in the Journal of Experimental and Therapeutic Medicine, the authors reported, “The outstanding role that food plays is sustained not only by its nutritional value, but also by its capacity to modify the structure and function of the gut microbiota.” Below are some helpful diet guidelines to support a healthy gut microbiome and reduce inflammation: With a stable disease, a diet rich in polyunsaturated fatty acids and anti-inflammatory omega-3 fatty acids can help prevent inflammation. Food sources include fish oil, olive oil, flaxseed oil, salmon, tuna, sardines, and herring. Krill oil, which is an algae, is considered superior, and flaxseed has been shown to aid in renal function. Moderate protein intake to support renal function Fiber from phytoestrogens and vegetables has been shown to decrease metabolic syndrome and inflammation, but water intake must be adequate to avoid nutrient malabsorption. Adequate vitamin C, E, and A from sources such as orange juice, tangerines, papaya, and broccoli, carrots, pumpkins, sweet potatoes, and liver B complex helps with fat metabolism and clinical symptoms, and can be found in red meat, fortified cereals, chicken, nuts, eggs, bananas, and avocados. Decreasing the amount of the minerals zinc (found in milk, soybeans, and spinach) and sodium (less than 3 grams per day) in the diet can relieve symptoms. Increase selenium for improved adrenal function. Sources are found in nuts, whole cereal, and eggs. Curcumin (turmeric) Ultimately, personalization of the diet is important for anyone managing SLE. The overarching conclusion is that a general low-calorie diet with an emphasis on antioxidant-supporting phytonutrients, essential fatty acids, fiber, and limited processed and refined foods will stimulate the body’s natural healing response and help reverse and hopefully prevent future outbreaks and flare-ups. *** Alana Kessler, MS, RD, CDN, E-RYT, is a registered dietitian, nutritionist, weight management expert, and an accredited member of the CDR (Commission on Dietetic Registration) and the American Dietetic Association. She is also a yoga and meditation teacher, Ayurveda specialist, and the founder of the New York City-based fully integrated mind, body, and spirit urban sanctuary, BE WELL. Alana’s BE WELL ARC System and Method Mapping technique is a holistic multi-disciplinary approach to health and wellness that blends Eastern and clinical Western diet and lifestyle support to effect long-lasting behavior change. A graduate of NYU with a BA and MS in clinical nutrition, Alana is dedicated to helping others learn how to nourish themselves, create balance, and understand their true nature through nutrition, yoga, and inner wellness. She leads Yin Yoga workshops and trainings as well as wellness retreats at international locations. Her health, fitness, and lifestyle expertise has been featured in Aaptiv.com, Droz.com, EatThis.com, RD.com, Redbook, WomensHealthmag.com, and Vogue. For more information, visit her website at bewellbyak.com. https://lupusnewstoday.com/2019/04/23/diet-recommendations-manage-lupus-nutritionists-view/
  20. JUNE 6, 2019 BY DARLA GAY IN COLUMNS, LEARNING TO LIVE WITH LUPUS - A COLUMN BY DARLA GAY. Click Here to receive Lupus News via e-mail What is an anti-inflammatory diet? An anti-inflammatory diet is designed to reduce the inflammation in your body. Certain foods are known to contribute to inflammation, but it can also develop as a result of too much stress and too little exercise. It also leads to conditions such as arthritis, depression, lupus, and irritable bowel syndrome. Adopting an anti-inflammatory diet can help with these diseases and others such as Crohn’s, heart disease, diabetes, and Hashimoto’s. It can also help control obesity. Since I have several of these issues, I have been reading a lot about this lately. I have come up with the following lists of things to add to or remove from my current diet. Foods to add: Eating more of these will help lower the inflammation in my body: • Fruits such as apples, oranges, cherries, blueberries, blackberries, and strawberries • Dark green vegetables such as collard greens, spinach, and kale • Other veggies like broccoli, cauliflower, and sweet potatoes • Beans • Nuts such as walnuts, pecans, and almonds • Whole grains like oats and brown rice • Dark chocolate • Healthy oils like extra-virgin olive oil and coconut oil • Foods high in omega-3 fatty acids like oily fish (salmon, herring, and mackerel), flaxseed, and soybeans Foods to remove: These foods cause inflammation and need to be eliminated from my diet: • Dairy products such as ice cream, cheese, butter, and milk • Omega-6 fatty acids such as corn, sunflower, and vegetable oils • Refined carbs in pasta and white bread • Processed meat such as sausage, hot dogs, and lunchmeat • Fried foods • Gluten • Refined sugar and artificial sweeteners • Salt What I can expect from this diet Reducing the inflammation in my body should help with joint pain, fatigue, and weight gain. It can lower my risk for depression, heart disease, and diabetes. It will also help keep my blood sugar and cholesterol in check. Making a lifestyle change For me, the key to making these changes permanent is to consider them a lifestyle change rather than a diet. I am going to post my lists on the refrigerator so I can refer to them often. I’m lactose intolerant and never have milk or ice cream, so giving them up will be easy. Pasta and sweets are a different story. I know that gluten-free pasta is available, as well as noodles made from zucchini and squash, so I’ll have to give those a try. I get headaches from artificial sweeteners such as aspartame and sucralose. In the past, those were the only options for people wanting to replace refined sugar. Now, there are a lot of newer options I can try, such as Swerve and monk fruit. I am looking forward to experimenting with these in my current recipes. As long as I don’t feel like I’m being deprived of an entire category, such as sweets, I’ll be able to adapt to this new way of eating. I love trying new recipes, so this gives me a good excuse to buy a few more cookbooks. *** Note: Lupus News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Lupus News Today, or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to lupus. https://lupusnewstoday.com/2019/06/06/anti-inflammatory-diet-help-symptoms/?utm_source=LUP+NEws+E-mail+List&utm_campaign=bd77092c86-RSS_THURSDAY_EMAIL_CAMPAIGN_NON-US&utm_medium=email&utm_term=0_50dac6e56f-bd77092c86-71887989
  21. Treatment with Tofacitinib Helps Relieve Arthritis and Rash Symptoms in Lupus Patients, Study Shows lupusnewstoday.com/2019/05/31/tofacitinib-relieve-arthritis-skin-rash-symptoms-sle/ Ana PenaMay 31, 2019 Tofacitinib tablets, a medicine approved to treat rheumatoid and psoriatic arthritis, may work for lessening signs and symptoms of arthritis and skin rash in people with systemic lupus erythematosus (SLE), a small study has found. These findings were reported in the letter “Successful treatment of arthritis and rash with tofacitinib in systemic lupus erythematosus: the experience from a single centre” that was published in the journal Annals of Rheumatic Diseases. Tofacitinib is marketed by Pfizer with the brand name Xeljanz for treating rheumatoid and psoriatic arthritis in adults who have failed treatment with methotrexate or other disease-modifying anti-rheumatic drugs (DMARDs). The medicine also has been approved to help manage inflammation in adults with ulcerative colitis, another chronic inflammatory condition. It blocks the activity of certain janus kinases (JAK) enzymes, which are critical for the activity of the immune system. By targeting JAKs, tofacitinib inhibits the activity of several signaling molecules, including interferons and interleukins known to have a role in SLE development and progression. Clinical data collected from rheumatoid arthritis patients indicates that tofacitinib can act quickly to reduce inflammation, as corticosteroids do, but without the side effects of steroids. Tofacitinib has been used off-label to treat SLE in some patients, but there is still very little data about the effectiveness and safety of this treatment for lupus. That’s why a group of researchers at the Peking Union Medical College Hospital in China evaluated tofacitinib’s effectiveness in a group of 10 lupus patients seen at the center. Nine women and one man received 5 mg of tofacitinib two times a day, and were followed by the team for at least four weeks and up to one year. At each follow-up visit, patients were monitored for disease activity with laboratory tests, such as measurement of anti-dsDNA antibodies and complement C3 levels, and by using scoring systems commonly used in clinics — SLE Disease Activity Index-2000 (SLEDAI-2K) and physician’s global assessment (PGA). Within one year, tofacitinib yielded a quick resolution of arthritis in all four patients who had such symptoms, and promoted significant relief in skin rash in six of nine participants. All those patients who experienced improvements achieved clinical remission of arthritis or skin rash. Tofacitinib’s effectiveness for rash, however, was more uncertain. In two patients, the medicine improved symptoms only partially or not at all. And another patient even experienced a flare during the follow-up period. Despite the rapid benefit seen for disease activity, SLE blood markers remained unchanged during the study. This agrees with prior tests reported for a different JAK inhibitor, baricitinib (sold in the U.S as Olumiant), in lupus patients and animal models. Two patients experienced treatment-related adverse events. One had herpes varicella zoster (shingles) and the other had alopecia (spot baldness). Both continued on tofacitinib, but their dosage was tapered and they ended up achieving disease remission. Based on these findings the team believes that “tofacitinib can rapidly improve the symptoms and signs of arthritis and partially improve skin rash in patients with SLE, sparing steroid to reach [clinical remission].” In view of the small number of patients studied and the variable periods of follow-up for each of them, researchers stress that more studies are needed to confirm tofacitinib’s effectiveness and define its specific indication in patients with SLE.
  22. www.medscape.com Management of Inflammatory Rheumatic Conditions in the Elderly Clément Lahaye; Zuzana Tatar; Jean-Jacques Dubost; Anne Tournadre; Martin Soubrier Rheumatology. 2019;58(5):748-764. Abstract and Introduction Abstract The number of elderly people with chronic inflammatory rheumatic diseases is increasing. This heterogeneous and comorbid population is at particular risk of cardiovascular, neoplastic, infectious and iatrogenic complications. The development of biotherapies has paved the way for innovative therapeutic strategies, which are associated with toxicities. In this review, we have focused on the scientific and therapeutic changes impacting the management of elderly patients affected by RA, SpA or PsA. A multidimensional health assessment resulting in an integrated therapeutic strategy was identified as a major research direction for improving the management of elderly patients. Introduction As a result of increasing life expectancy, risk transition and improved quality of care, the number of people living with at least one chronic disease is increasing.[1] Chronic inflammatory rheumatic diseases (IRDs) affect 2–3% of the general population, involving a non-negligible proportion of elderly subjects. Almost one-third of RA patients are >60 years of age, and elderly patients with IRDs are at particular risk for cardiovascular, neoplastic and infectious complications. Furthermore, IRD in the elderly may have a distinct clinical and biological presentation, with differing responses to treatment. These features reflect the physiological changes (e.g. immunosenescence and alterations in pharmacokinetics) and comorbidities (diabetes, obesity, renal failure, etc.) associated with ageing, which vary widely from one individual to another.[2,3]Multimorbidity and polypharmacy, both of which are common in the elderly, are well-known risk factors for adverse drug reactions (ADRs) and interactions.[4] In parallel with this epidemiological evolution, a new class of maintenance therapy agents known as biologics, which comprise specific antibodies with immunomodulating properties, has emerged, thereby expanding the therapeutic arsenal hitherto containing DMARDs, such as MTX, and anti-inflammatory drugs. Paradoxically, elderly patients have mostly been left out of new therapeutic opportunities. Randomized controlled trials and prospective cohorts primarily recruit healthy or single-disease volunteers rather than elderly and comorbid patients.[5] Thus, the extrapolation of findings to real-life elderly patients may be compromised. Against this background, the novel mechanisms of action of biologics and paucity of literature specifically pertaining to the elderly have raised concerns about the safety of these new drugs, leading to more conventional therapeutic regimens in this population. Hypothesis and Search Strategy Several hypotheses guided our study: biologic treatments could benefit both older and younger people; physiological and pathological ageing associated with comorbidities, as well as co-treatment, could partly explain the risk of serious adverse events (AEs) (e.g. infection, cancer, neoplasia, fractures) observed with treatment; and beyond the specific treatments (DMARDs), a more global care strategy could improve outcomes, such as health related quality of life (HR-QoL) and autonomy. We searched PubMed's MEDLINE and the Web of Science database for studies published over the past 10 years. The search ended in October 2017. Keywords elderly, ageing, aged, recommendations or guidelines were combined with RA, SpA or PsA. The search was limited to articles published in English. The reference lists of relevant articles and conference proceedings were searched manually. In this overview, we focus on the therapeutic progress impacting the management of elderly with RA, spondyloarthropathy (SP) and PsA, highlighting gaps in the literature concerning this growing, but under-studied, population RA Specificities of Initial Presentation in the Elderly Most studies refer to older subjects without specifying whether the disease appeared after 60 years of age (elderly-onset RA, EORA) or at a younger age (young-onset RA, YORA). For this overview, the term EORA will be reserved for studies specifying an old age of onset. EORA has specific clinical and biological characteristics. The female predominance is less marked, disease onset more abrupt, morning stiffness prolonged and constitutional symptoms more severe than in YORA.[6] The differential diagnosis with PMR or microcrystalline arthritis is more challenging due to common proximal joint involvement.[7] EORA is associated with increased MRI-detected inflammation, but this effect of age is similar in controls, supporting the hypothesis of a general and non-disease-specific effect of age on MRI inflammation, possibly related to immunosenescence.[8] Higher IL-6 and lower TNFα levels have been observed in EORA compared with YORA.[9] In the elderly population, high levels of TNFα are associated with an increased risk of hospitalization and death at 1 year.[10] EORA patients often present with higher DAS 28 and Ratingen scores at diagnosis,[11] increased inflammation and disability[12–14] and a greater number of comorbidities,[12] but less RF and ACPA positivity.[15] Age and Treatment Effectiveness Due to the lack of specific studies in the elderly, conventional synthetic DMARDs (csDMARDs) in combination with glucocorticoids (GCs) constitute the initial treatment for RA, as in younger subjects.[16,17] As the reference csDMARD, MTX remains the gold standard in EORA management. The rare studies investigating its efficacy in the elderly have not revealed decreased effectiveness of csDMARDs compared with YORA. Pooled data from 11 MTX clinical trials involving 496 RA patients revealed no effect of age or renal impairment on MTX efficacy.[18] In the Swedish Farmacotherapy (SWEFOT) trial, higher age was associated with an increased likelihood of EULAR response to MTX in patients with new-onset RA.[19] A retrospective series of 90 RA patients showed no impact of age on the efficacy of LEF.[20] Despite widespread use of GCs, particularly in elderly RA patients,[21] initial dosage, optimal treatment duration, tapering strategies and the timing and frequency of administration remain largely empirical.[22] Expert reports advocate as low a dose and as short a duration as possible, a fortiori in elderly and fragile subjects.[17] Numerous studies have documented the effectiveness of biotherapies (mainly TNFα inhibitors, TNFi) in EORA (). In several registries, TNFi were found to be slightly less effective in patients aged >65 years in terms of improvements in disease activity,[23–25] radiographic damage,[15] functional recovery[26] and HR-QoL.[27] However, some registries have shown no effect of age on the response to TNFi[28] or radiological progression after 5 years of treatment.[11] Moreover, randomized controlled trials have demonstrated that the benefits in terms of clinical response and radiographic progression when adding etanercept (ETA),[29,30]infliximab or adalimumab[31] to MTX for RA treatment are maintained in the elderly population compared with subjects aged <65 years. In a post hoc study of the open-label period of three studies concerning ETA in RA, there were no substantial differences in efficacy for ETN patients ≥65 vs <65 years.[32] Table 1. The efficacy and safety of boDMARDs in elderly RA patients References Design Efficacy Tolerance Bathon et al.[29] Subset analysis (age ≥65 years vs age <65 years) of four randomized controlled clinical studies (n = 1353) or two long-term extensions (n = 1049) studying ETA in DMARD-resistant or late stage RA ERA tended to have somewhat less robust ACR responses to treatment than younger subjects. A similar slowing in radiographic progression after 1 year of ETA was observed in both age groups Rates of SAE tended to be higher in ERA than YRA, but are equivalent to placebo- or MTX-treated ERA Hyrich et al.[28] Register of RA patients starting ETA (n = 1267) or INF (n = 1612). Mean age 55 (12) years Age did not predict EULAR response or remission with either drug at 6 months No assessment Setoguchi et al. [58] Cohort (mean age 70 years) comparing 1152 patients on boDMARDs with 7306 patients on MTX No assessment boDMARD patients showed no difference in haematological malignancies or solid tumour incidence compared with MTX users Tutuncu et al. [59] Register of 2101 patients with EORA (after 60 years of age) were matched on the basis of disease duration with 2101 patients with YORA (between 40 and 60 years of age) No assessment Toxicities related to treatment with ETA, INF, ADA, KIN or other DMARDs were similar in the EORA and YORA groups Genevay et al. [23] Longitudinal population-based cohort, including 1227 YRA <65 years of age and 344 ERA >65 years of age starting anti-TNF therapy (mean follow-up 22 months) Mean change in DAS 28 scores at 2 years (–0.65 vs–0.58) was identical in ERA and YRA. HAQ score improved significantly less in ERA (–0.02) than in YRA (–0.1) due to the lack of improvement after 75 years of age Drug discontinuation rates were identical in all age groups. Cancer was significantly more frequent in ERA than YRA (7.1 vs 0%; P <0.05) Schneeweiss et al. [55] Cohort of 15 597 RA patients initiating DMARD therapy (TNF antagonists: 469) >65 years of age (mean age 76.5 years) No assessment The rate of serious infections among initiators of anti-TNF therapy was equivalent to that of MTX initiators (RR = 1.0; 95% CI: 0.6, 1.7) Askling et al.[60] Cohort of 6366 RA patients starting anti-TNF therapy were compared with a biologics-naïve RA cohort (n = 61 160) regarding the medium-term risks of cancer (up to 6 years) No assessment No overall elevation of cancer risk was associated with TNF therapy, regardless of follow-up time or age (<50, 51–74, >75 years) Köller et al.[31] Pooled data from two randomized, controlled, double-blind trials including patients with early RA using ADA or INF + MTX (788) or MTX alone (448), classified by quartiles of age, with the highest age group comprising 61–82 years After 1 year of MTX + TNF inhibitor therapy, improvement of a composite disease activity index, assessment of physical function and radiographic progression were similar across all age quartiles No assessment McDonald et al. [61] Cohort of 20 357 veterans with RA, including 3661 patients treated with boDMARDs (mean age 59.3 years) No assessment Unlike use of anti-TNF, increased age was an independent risk factor for herpes zoster Radovits et al. [62] Register of 730 RA patients, categorized into three age groups (<45, 45–65 and >65 years) at initiation of anti-TNF. Longitudinal analysis of DAS 28 during the first year of treatment Elderly patients had fewer EULAR good responses and remission and less improvement in disease activity and physical functioning than younger patients Drug survival, co-medication use and tolerance were comparable between the three age groups Filippini et al.[27] Observational cohort including 1114 RA patients treated with anti-TNF therapy (311 age ≥65 years and 803 age <65 years) and followed up to 3 years Decreases in DAS 28 and ESR were comparable, but the EULAR response was somewhat lower in the ERA. HAQ scores were higher at baseline with less improvement after treatment in ERA Anti-TNFα therapy was discontinued by 42% of ERA and 36.6% of YRA SAEs, infection and overall cancer were higher among ERA Hetland et al.[25] Register of 2326 RA patients beginning boDMARDs (median age 57 years). Treatment responses were assessed after 6 and 12 months Older age and initial low functional status were negative predictors of a clinical response and remission during anti-TNF treatment of RA No assessment Amari et al.[63] Cohort of 20 648 veterans with RA (mean age 63 years), including 4088 patients treated with anti-TNFs No assessment Age (per decade, HR = 1.23; 95% CI: 1.09, 1.38) and anti-TNF use (compared with csDMARDs, HR = 1.42; 95% CI: 1.24, 1.63) were risk factors for developing NMSC Galloway et al. [52] Prospective observational study assessing the risk of severe infection between 11 798 and 3598 csDMARD-treated RA patients stratified by age (<55, 55–64, 65–74 and >75 years) No assessment The crude rate of infection increased markedly with age. The increased risk of SI associated with anti-TNF therapy (+20% compared with csDMARDs) was equivalent in elderly and younger patients Lane et al.[53] Cohort of 20 814 veterans (mean age 63 years) with RA, including 3796 anti-TNF-treated patients. Rate of hospitalization for SI was compared with csDMARD users (mean follow-up 2.7 years) No assessment In multivariate analysis, unlike csDMARD use, anti-TNF use was associated with hospitalization for infection (HR = 1.24; 95% CI: 1.02, 1.50) Curtis et al.2012 [54] Prospective cohort of 11 657 RA patients (mean age 61.9 years) initiating anti-TNF therapy. The observed 1-year rates of infection were compared with a predicted infection risk score estimated in the absence of anti-TNF exposure No assessment The rate of SI for anti-TNF agents was increased incrementally by a fixed absolute difference irrespective of age (above vs below 65 years) Herrinton et al. [64] Cohort of 46 424 patients with selected autoimmune diseases. Mortality was compared between new anti-TNF users and similar new csDMARDs users No assessment Anti-TNF therapy was associated with a reduction in mortality among RA patients with ≥2 co-morbid conditions (aHR = 0.87; 95% CI: 0.77, 0.99), or age ≥75 years Toh et al.[57] Retrospective study of 3485 RA patients (mean age 57.9 years) who initiated INF or ETA. Rate of SI or opportunistic infections during the first year was compared between infliximab initiators and etanercept initiators No assessment Rate of SI per 100 person-years was 5.4 (95% CI: 3.8, 7.5) in patients <65 years and 16.0 (95% CI: 10.4, 23.4) in patients ≥65 years during the first 3 months following treatment initiation. The increased risk of SI associated with infliximab compared with etanercept in young subjects disappeared in patients >65 years of age Dreyer et al.[65] Register of RA patients (mean age 58 years). The incidence of cancer in patients treated with (n = 3347) or without TNF inhibitors (n = 3812) was evaluated over a mean follow-up of 2.5 years No assessment TNF antagonist-treated patients did not exhibit an increased risk of overall cancer (HR = 1.02; 95% CI: 0.80, 1.30) compared with non-treated patients, even >65 years of age (HR = 1.10; 95% CI: 0.80, 1.50) Payet et al.[34] Prospective register of 1709 RA patients (including 191 aged ≥75 years and 417 aged 65–74 years) aiming to compare the efficacy and safety of RTX as a function of patient age Patients aged 65–75 years were more likely to be good responders than non-responders at 1 year of follow-up than patients age ≥75 years (OR = 3.81, 95% CI: 1.14, 12.79). After the sixth month, the decrease in DAS 28 score was less marked in the population aged >75 years than in the group aged <50 years At 24 months, no significant difference was shown among the groups for SAE or RTX discontinuation rates. The reasons for discontinuation (inefficacy, AE) were the same in all four groups. Infections were more common in the elderly Wu et al.[66] Nationwide cohort of RA patients in Taiwan including 4426 treated with biologics and 17 704 matched patients taking csDMARDs only, with a median follow-up of 3 years aiming to compare the SIRs of cancer No assessment Incidence of cancer was reduced in biologic users in almost all subsets of study subjects, especially among those aged >60 (HR = 0.56; 95% CI: 0.40, 0.79), with disease duration >10 years (HR = 0.43; 95% CI: 0.24, 0.77). However, there was an increased risk for haematological cancers in the biologics cohort (SIR = 4.64; 95% CI: 2.65, 7.53) Pers et al.[38] Retrospective study of 222 RA patients (including 61 aged ≥65 years) aiming to assess the safety and efficacy of TCZ in daily practice considering two age groups: <65 years (<65) and ≥65 years After 6 months, the ERA less often reached remission (27.8 vs45.6%; P = 0.02) or good EULAR response (40.7 vs 61.0%; P < 0.01) compared with YRA Drug maintenance for TCZ and adverse event discontinuation rates were similar between the two age groups Sekiguchi et al. [14] Prospective cohort of 277 RA patients with high or moderate disease activity receiving ABA as an initial boDMARD to differentiate predictive factors of sustained clinical remission between YRA and ERA Clinical remission was similarly achieved between ERA (at 24 and 48 weeks in 35.1 and 36.5%) and YRA (34.9 and 43.4% at 24 and 48 weeks) No significant differences in the treatment withdrawal rates owing to adverse events depending on age Lahaye et al.[35] Prospective registry of 1017 RA patients (including 103 ≥75 years and 215 between 65 and 74 years) to study the effect of age on the risk–benefit balance of ABA with a 2-year follow-up The EULAR response (good or moderate) and remission rate were not significantly different according to age. At 6 months, the very elderly had a significantly lower likelihood of a good response than the very young (OR = 0.15, 95% CI: 0.03, 0.68). The decrease in DAS 28-ESR over the 24-month follow-up period did not differ by age Increasing age was associated with a higher rate of discontinuation for AE, especially SIs (per 100 patient-years: 1.73 in very young, 4.65 in intermediates, 5.90 in elderly, 10.38 in very elderly; P < 0.001) Kawashima et al. [56] Retrospective study of 183 RA patients over the age of 65 years treated with bo or csDMARDs over a 3-year observation period to determine the risk factors of SI No assessment The incidence rate of SI per 100 person-years was not significantly different between biologics-treated (8.0; 95% CI: 4.7, 13.5) and non-biologic DMARD-treated patients (6.3; 95% CI: 4.1, 9.5, P = 0.78). Prednisolone was associated with SI only in biologics-treated patients at 1–4 mg/day, and in both groups at >5 mg/day Curtis et al.[39] Pooled data from five phase 3 trials and separately from two open-label long-term extension studies concerning RA patients who received tofacitinib or placebo (phase 3 only), with/without csDMARDs, aiming to compare efficacy and safety outcomes between older (aged ≥65 years, 1136/7213) and younger patients In phase 3 trials, at 3 months, probability ratios for ACR responses and HAQ-DI improvement from baseline ≥0.22 favoured tofacitinib (5 and 10 mg BID). ACR responses were similar in ERA and YRA, but HAQ-DI ≥0.22 appeared to be somewhat lower for older tofacitinib-treated patients than for YRA Compared with YRA, ERA treated with 5 mg BID were more exposed to SAEs (IR = 17.6; 95% CI: 14.1, 21.9 vs 8.4; 95% CI: 7.4, 9.6), SI (IR = 3.9; 95% CI: 2.5, 6.0 vs 2.4; 95% CI: 1.9, 3.0) and discontinuation due to AEs [IR = 9.2 (95% CI: 7.0, 12.3) vs 6.0 (95% CI: 5.2, 7.0)]. This risk signal was similar with the 10 mg BID dosage ABA: abatacept; ADA: adalimumab; aHR: adjusted hazard ratio; BID: bis in die; boDMARD: biologic originator DMARD; csDMARD: conventional synthetic DMARD; EORA: elderly-onset RA; ERA: elderly RA patients; ETA: etanercept; IR: incidence rate; HR: hazard ratio; INF: infliximab; KIN: kineret; NMSC: non-melanoma skin cancer; OR: odds ratio; RR: risk ratio; RTX: rituximab; SAE: serious adverse event; SI: severe infection; SIR: standardized incidence ratio; TCZ: tocilizumab; YORA: younger-onset RA; YRA: Young RA patients. Data on other biologics are scarce and inconsistent. Regarding rituximab, a prospective study found no effect of age on changes in DAS 28 at 8 months,[33] whereas in the French registry, patients aged >75 years were less likely to be good responders at 1 year.[34] Sekiguchi et al.[14] revealed no difference between YORA and EORA in achieving remission with abatacept as the initial DMARD, yet the functional remission rate was lower in elderly patients. These data are consistent with the Japanese and French registries, in which there was no age-related difference in effectiveness, respectively, 1 and 2 years after introducing abatacept.[35,36] Matsuda et al. showed as much benefit of abatacept in the elderly as in the younger patients regarding HR-QoL, disease activity and reduction of GC dose.[37] A retrospective study assessing tocilizumab in RA patients found a significantly decreased number of elderly patients with good EULAR response and remission at 6 months.[38] Concerning oral Janus kinase inhibitors, patients aged >65 years had similar response rates to patients aged <65 years after 3 months of tofacitinib and baricitinib for moderate to severe RA in a pooled analysis of phase 3 trials.[39,40] Age and Adverse Drug Reactions As both RA and ageing are associated with cardiovascular disease, malignancies, osteoporosis and infection, it may be difficult to determine the extent to which treatment is responsible for the occurrence of complications.[41] Older subjects are more susceptible to infectious complications, with most studies reporting a 2- to 3-fold higher risk of serious infections for those aged >65 years.[42] MTX has been associated with serious AEs, such as major infections, hepatic failure, bone marrow depression and inflammatory pneumonitis. In a Canadian population-based study, increasing age was associated with an increased tendency towards MTX discontinuation in newly diagnosed RA patients.[43] As kidney failure and hypoalbuminaemia both increase the risk of severe MTX toxicity, a dose adjustment is often necessary in the elderly.[18,44,45] In a retrospective series of 90 LEF-treated RA patients (monotherapy or combination therapy) with 2 years of follow-up, the AEs and survival rates of LEF were equivalent between patients aged ≤65 years and those aged >65 years.[20] However, hypertension and unintentional weight loss related to LEF are of particular concern in the elderly.[46] Regarding TNFi, several studies have pointed out high infection risk in the elderly () particularly in cases of high comorbidity, elevated disease severity markers and previous infection.[42] In retrospective cohorts of RA patients treated with biologic originator DMARDs (boDMARDs), though drug discontinuation appeared similar between age groups; discontinuation was related mainly to AEs (specifically infections) in the elderly, whereas drug ineffectiveness was the main reason for treatment discontinuation in younger patients.[47–50] In a registry of RA patients treated with conventional DMARDs or TNFi, multivariate analysis revealed that TNFi use (risk ratio (RR) = 2.37; 95% CI: 1.11, 5.05; P = 0.026) and age (by decade RR = 1.82; 95% CI: 1.32, 2.52; P = 0.00031) were significant independent risk factors for serious infections.[51] A moderately increased absolute risk of serious infection has been reported after the introduction of TNFi, with no difference between age categories.[23,52–54]However, after multivariate adjustment for age, sex and comorbidities, most of the studies did not find an increased risk of serious infection associated with the initiation of TNFi therapy compared with non-biologic comparators,[55] even upon long-term follow-up[29,30,56] and irrespective of the inhibitor.[57] Table 1. The efficacy and safety of boDMARDs in elderly RA patients References Design Efficacy Tolerance Bathon et al.[29] Subset analysis (age ≥65 years vs age <65 years) of four randomized controlled clinical studies (n = 1353) or two long-term extensions (n = 1049) studying ETA in DMARD-resistant or late stage RA ERA tended to have somewhat less robust ACR responses to treatment than younger subjects. A similar slowing in radiographic progression after 1 year of ETA was observed in both age groups Rates of SAE tended to be higher in ERA than YRA, but are equivalent to placebo- or MTX-treated ERA Hyrich et al.[28] Register of RA patients starting ETA (n = 1267) or INF (n = 1612). Mean age 55 (12) years Age did not predict EULAR response or remission with either drug at 6 months No assessment Setoguchi et al. [58] Cohort (mean age 70 years) comparing 1152 patients on boDMARDs with 7306 patients on MTX No assessment boDMARD patients showed no difference in haematological malignancies or solid tumour incidence compared with MTX users Tutuncu et al. [59] Register of 2101 patients with EORA (after 60 years of age) were matched on the basis of disease duration with 2101 patients with YORA (between 40 and 60 years of age) No assessment Toxicities related to treatment with ETA, INF, ADA, KIN or other DMARDs were similar in the EORA and YORA groups Genevay et al. [23] Longitudinal population-based cohort, including 1227 YRA <65 years of age and 344 ERA >65 years of age starting anti-TNF therapy (mean follow-up 22 months) Mean change in DAS 28 scores at 2 years (–0.65 vs–0.58) was identical in ERA and YRA. HAQ score improved significantly less in ERA (–0.02) than in YRA (–0.1) due to the lack of improvement after 75 years of age Drug discontinuation rates were identical in all age groups. Cancer was significantly more frequent in ERA than YRA (7.1 vs 0%; P <0.05) Schneeweiss et al. [55] Cohort of 15 597 RA patients initiating DMARD therapy (TNF antagonists: 469) >65 years of age (mean age 76.5 years) No assessment The rate of serious infections among initiators of anti-TNF therapy was equivalent to that of MTX initiators (RR = 1.0; 95% CI: 0.6, 1.7) Askling et al.[60] Cohort of 6366 RA patients starting anti-TNF therapy were compared with a biologics-naïve RA cohort (n = 61 160) regarding the medium-term risks of cancer (up to 6 years) No assessment No overall elevation of cancer risk was associated with TNF therapy, regardless of follow-up time or age (<50, 51–74, >75 years) Köller et al.[31] Pooled data from two randomized, controlled, double-blind trials including patients with early RA using ADA or INF + MTX (788) or MTX alone (448), classified by quartiles of age, with the highest age group comprising 61–82 years After 1 year of MTX + TNF inhibitor therapy, improvement of a composite disease activity index, assessment of physical function and radiographic progression were similar across all age quartiles No assessment McDonald et al. [61] Cohort of 20 357 veterans with RA, including 3661 patients treated with boDMARDs (mean age 59.3 years) No assessment Unlike use of anti-TNF, increased age was an independent risk factor for herpes zoster Radovits et al. [62] Register of 730 RA patients, categorized into three age groups (<45, 45–65 and >65 years) at initiation of anti-TNF. Longitudinal analysis of DAS 28 during the first year of treatment Elderly patients had fewer EULAR good responses and remission and less improvement in disease activity and physical functioning than younger patients Drug survival, co-medication use and tolerance were comparable between the three age groups Filippini et al.[27] Observational cohort including 1114 RA patients treated with anti-TNF therapy (311 age ≥65 years and 803 age <65 years) and followed up to 3 years Decreases in DAS 28 and ESR were comparable, but the EULAR response was somewhat lower in the ERA. HAQ scores were higher at baseline with less improvement after treatment in ERA Anti-TNFα therapy was discontinued by 42% of ERA and 36.6% of YRA SAEs, infection and overall cancer were higher among ERA Hetland et al.[25] Register of 2326 RA patients beginning boDMARDs (median age 57 years). Treatment responses were assessed after 6 and 12 months Older age and initial low functional status were negative predictors of a clinical response and remission during anti-TNF treatment of RA No assessment Amari et al.[63] Cohort of 20 648 veterans with RA (mean age 63 years), including 4088 patients treated with anti-TNFs No assessment Age (per decade, HR = 1.23; 95% CI: 1.09, 1.38) and anti-TNF use (compared with csDMARDs, HR = 1.42; 95% CI: 1.24, 1.63) were risk factors for developing NMSC Galloway et al. [52] Prospective observational study assessing the risk of severe infection between 11 798 and 3598 csDMARD-treated RA patients stratified by age (<55, 55–64, 65–74 and >75 years) No assessment The crude rate of infection increased markedly with age. The increased risk of SI associated with anti-TNF therapy (+20% compared with csDMARDs) was equivalent in elderly and younger patients Lane et al.[53] Cohort of 20 814 veterans (mean age 63 years) with RA, including 3796 anti-TNF-treated patients. Rate of hospitalization for SI was compared with csDMARD users (mean follow-up 2.7 years) No assessment In multivariate analysis, unlike csDMARD use, anti-TNF use was associated with hospitalization for infection (HR = 1.24; 95% CI: 1.02, 1.50) Curtis et al.2012 [54] Prospective cohort of 11 657 RA patients (mean age 61.9 years) initiating anti-TNF therapy. The observed 1-year rates of infection were compared with a predicted infection risk score estimated in the absence of anti-TNF exposure No assessment The rate of SI for anti-TNF agents was increased incrementally by a fixed absolute difference irrespective of age (above vs below 65 years) Herrinton et al. [64] Cohort of 46 424 patients with selected autoimmune diseases. Mortality was compared between new anti-TNF users and similar new csDMARDs users No assessment Anti-TNF therapy was associated with a reduction in mortality among RA patients with ≥2 co-morbid conditions (aHR = 0.87; 95% CI: 0.77, 0.99), or age ≥75 years Toh et al.[57] Retrospective study of 3485 RA patients (mean age 57.9 years) who initiated INF or ETA. Rate of SI or opportunistic infections during the first year was compared between infliximab initiators and etanercept initiators No assessment Rate of SI per 100 person-years was 5.4 (95% CI: 3.8, 7.5) in patients <65 years and 16.0 (95% CI: 10.4, 23.4) in patients ≥65 years during the first 3 months following treatment initiation. The increased risk of SI associated with infliximab compared with etanercept in young subjects disappeared in patients >65 years of age Dreyer et al.[65] Register of RA patients (mean age 58 years). The incidence of cancer in patients treated with (n = 3347) or without TNF inhibitors (n = 3812) was evaluated over a mean follow-up of 2.5 years No assessment TNF antagonist-treated patients did not exhibit an increased risk of overall cancer (HR = 1.02; 95% CI: 0.80, 1.30) compared with non-treated patients, even >65 years of age (HR = 1.10; 95% CI: 0.80, 1.50) Payet et al.[34] Prospective register of 1709 RA patients (including 191 aged ≥75 years and 417 aged 65–74 years) aiming to compare the efficacy and safety of RTX as a function of patient age Patients aged 65–75 years were more likely to be good responders than non-responders at 1 year of follow-up than patients age ≥75 years (OR = 3.81, 95% CI: 1.14, 12.79). After the sixth month, the decrease in DAS 28 score was less marked in the population aged >75 years than in the group aged <50 years At 24 months, no significant difference was shown among the groups for SAE or RTX discontinuation rates. The reasons for discontinuation (inefficacy, AE) were the same in all four groups. Infections were more common in the elderly Wu et al.[66] Nationwide cohort of RA patients in Taiwan including 4426 treated with biologics and 17 704 matched patients taking csDMARDs only, with a median follow-up of 3 years aiming to compare the SIRs of cancer No assessment Incidence of cancer was reduced in biologic users in almost all subsets of study subjects, especially among those aged >60 (HR = 0.56; 95% CI: 0.40, 0.79), with disease duration >10 years (HR = 0.43; 95% CI: 0.24, 0.77). However, there was an increased risk for haematological cancers in the biologics cohort (SIR = 4.64; 95% CI: 2.65, 7.53) Pers et al.[38] Retrospective study of 222 RA patients (including 61 aged ≥65 years) aiming to assess the safety and efficacy of TCZ in daily practice considering two age groups: <65 years (<65) and ≥65 years After 6 months, the ERA less often reached remission (27.8 vs45.6%; P = 0.02) or good EULAR response (40.7 vs 61.0%; P < 0.01) compared with YRA Drug maintenance for TCZ and adverse event discontinuation rates were similar between the two age groups Sekiguchi et al. [14] Prospective cohort of 277 RA patients with high or moderate disease activity receiving ABA as an initial boDMARD to differentiate predictive factors of sustained clinical remission between YRA and ERA Clinical remission was similarly achieved between ERA (at 24 and 48 weeks in 35.1 and 36.5%) and YRA (34.9 and 43.4% at 24 and 48 weeks) No significant differences in the treatment withdrawal rates owing to adverse events depending on age Lahaye et al.[35] Prospective registry of 1017 RA patients (including 103 ≥75 years and 215 between 65 and 74 years) to study the effect of age on the risk–benefit balance of ABA with a 2-year follow-up The EULAR response (good or moderate) and remission rate were not significantly different according to age. At 6 months, the very elderly had a significantly lower likelihood of a good response than the very young (OR = 0.15, 95% CI: 0.03, 0.68). The decrease in DAS 28-ESR over the 24-month follow-up period did not differ by age Increasing age was associated with a higher rate of discontinuation for AE, especially SIs (per 100 patient-years: 1.73 in very young, 4.65 in intermediates, 5.90 in elderly, 10.38 in very elderly; P < 0.001) Kawashima et al. [56] Retrospective study of 183 RA patients over the age of 65 years treated with bo or csDMARDs over a 3-year observation period to determine the risk factors of SI No assessment The incidence rate of SI per 100 person-years was not significantly different between biologics-treated (8.0; 95% CI: 4.7, 13.5) and non-biologic DMARD-treated patients (6.3; 95% CI: 4.1, 9.5, P = 0.78). Prednisolone was associated with SI only in biologics-treated patients at 1–4 mg/day, and in both groups at >5 mg/day Curtis et al.[39] Pooled data from five phase 3 trials and separately from two open-label long-term extension studies concerning RA patients who received tofacitinib or placebo (phase 3 only), with/without csDMARDs, aiming to compare efficacy and safety outcomes between older (aged ≥65 years, 1136/7213) and younger patients In phase 3 trials, at 3 months, probability ratios for ACR responses and HAQ-DI improvement from baseline ≥0.22 favoured tofacitinib (5 and 10 mg BID). ACR responses were similar in ERA and YRA, but HAQ-DI ≥0.22 appeared to be somewhat lower for older tofacitinib-treated patients than for YRA Compared with YRA, ERA treated with 5 mg BID were more exposed to SAEs (IR = 17.6; 95% CI: 14.1, 21.9 vs 8.4; 95% CI: 7.4, 9.6), SI (IR = 3.9; 95% CI: 2.5, 6.0 vs 2.4; 95% CI: 1.9, 3.0) and discontinuation due to AEs [IR = 9.2 (95% CI: 7.0, 12.3) vs 6.0 (95% CI: 5.2, 7.0)]. This risk signal was similar with the 10 mg BID dosage ABA: abatacept; ADA: adalimumab; aHR: adjusted hazard ratio; BID: bis in die; boDMARD: biologic originator DMARD; csDMARD: conventional synthetic DMARD; EORA: elderly-onset RA; ERA: elderly RA patients; ETA: etanercept; IR: incidence rate; HR: hazard ratio; INF: infliximab; KIN: kineret; NMSC: non-melanoma skin cancer; OR: odds ratio; RR: risk ratio; RTX: rituximab; SAE: serious adverse event; SI: severe infection; SIR: standardized incidence ratio; TCZ: tocilizumab; YORA: younger-onset RA; YRA: Young RA patients. Compared with TNFi therapy-naïve subjects, patients on TNFi therapy are more susceptible to tuberculosis reactivation, usually affecting extrapulmonary sites (pericardium, gastrointestinal, bone or lymph nodes).[67] Age >60 years for RA, history of tuberculosis and daily GC use ≥5 mg were significant risk factors for this complication.[68,69] In addition, ageing RA patients are at particular risk of herpes zoster (HZ) infection. The incidence of HZ infection appears to be similar after initiating csDMARD or TNFi therapy, regardless of the inhibitor that is used.[70] Age and GC use are additional risk factors.[56,57] As a representative of the emerging class of Janus kinase inhibitors, tofacitinib seems to increase the risk of opportunistic infections such as tuberculosis and HZ infection.[71] Thus, the ACR recommends the HZ vaccine for all RA patients aged ≥50 years, before the introduction of boDMARDs due to it being a live vaccine.[72] Though data on other biologics are scarce, they suggest an increased risk of infection (). Concerning abatacept, two cohorts found no significant differences in treatment withdrawal rates due to AEs depending on age.[14,37] This outcome differed from the French registry, in which increasing age was associated with a higher AE-induced treatment discontinuation rate, especially in regards to severe infections.[35] In a Japanese registry, the elderly abatacept-treated group (>69.5 years) demonstrated higher incidence rate of discontinuation due to AEs in patients without concomitant use of MTX.[36] Concerning rituximab, even if one prospective study showed no effect of age on ADRs and serious ADRs,[33] other studies with long-term follow-up revealed that age >65 years is associated with a higher incidence of discontinuation rates due to serious ADR[73] or infections compared with age <65 years.[34] In a retrospective study pertaining to tocilizumab use in RA patients, drug maintenance was similar between elderly and younger RA patients. No differences were found according to age class.[38] In a pooled analysis pertaining to three randomized controlled trials and two open label extensions in tofacitinib-treated patients with moderate to severe RA, serious infections and AE-induced discontinuations are more common after 65 years of age.[39] Similar results were observed with baracitinib.[74] In addition to differences in the mode of action among DMARDs, the differing infectious risks may reflect an incomplete adjustment for infection risk factors in elderly RA patients (e.g. diabetes, malnutrition). Table 1. The efficacy and safety of boDMARDs in elderly RA patients References Design Efficacy Tolerance Bathon et al.[29] Subset analysis (age ≥65 years vs age <65 years) of four randomized controlled clinical studies (n = 1353) or two long-term extensions (n = 1049) studying ETA in DMARD-resistant or late stage RA ERA tended to have somewhat less robust ACR responses to treatment than younger subjects. A similar slowing in radiographic progression after 1 year of ETA was observed in both age groups Rates of SAE tended to be higher in ERA than YRA, but are equivalent to placebo- or MTX-treated ERA Hyrich et al.[28] Register of RA patients starting ETA (n = 1267) or INF (n = 1612). Mean age 55 (12) years Age did not predict EULAR response or remission with either drug at 6 months No assessment Setoguchi et al. [58] Cohort (mean age 70 years) comparing 1152 patients on boDMARDs with 7306 patients on MTX No assessment boDMARD patients showed no difference in haematological malignancies or solid tumour incidence compared with MTX users Tutuncu et al. [59] Register of 2101 patients with EORA (after 60 years of age) were matched on the basis of disease duration with 2101 patients with YORA (between 40 and 60 years of age) No assessment Toxicities related to treatment with ETA, INF, ADA, KIN or other DMARDs were similar in the EORA and YORA groups Genevay et al. [23] Longitudinal population-based cohort, including 1227 YRA <65 years of age and 344 ERA >65 years of age starting anti-TNF therapy (mean follow-up 22 months) Mean change in DAS 28 scores at 2 years (–0.65 vs–0.58) was identical in ERA and YRA. HAQ score improved significantly less in ERA (–0.02) than in YRA (–0.1) due to the lack of improvement after 75 years of age Drug discontinuation rates were identical in all age groups. Cancer was significantly more frequent in ERA than YRA (7.1 vs 0%; P <0.05) Schneeweiss et al. [55] Cohort of 15 597 RA patients initiating DMARD therapy (TNF antagonists: 469) >65 years of age (mean age 76.5 years) No assessment The rate of serious infections among initiators of anti-TNF therapy was equivalent to that of MTX initiators (RR = 1.0; 95% CI: 0.6, 1.7) Askling et al.[60] Cohort of 6366 RA patients starting anti-TNF therapy were compared with a biologics-naïve RA cohort (n = 61 160) regarding the medium-term risks of cancer (up to 6 years) No assessment No overall elevation of cancer risk was associated with TNF therapy, regardless of follow-up time or age (<50, 51–74, >75 years) Köller et al.[31] Pooled data from two randomized, controlled, double-blind trials including patients with early RA using ADA or INF + MTX (788) or MTX alone (448), classified by quartiles of age, with the highest age group comprising 61–82 years After 1 year of MTX + TNF inhibitor therapy, improvement of a composite disease activity index, assessment of physical function and radiographic progression were similar across all age quartiles No assessment McDonald et al. [61] Cohort of 20 357 veterans with RA, including 3661 patients treated with boDMARDs (mean age 59.3 years) No assessment Unlike use of anti-TNF, increased age was an independent risk factor for herpes zoster Radovits et al. [62] Register of 730 RA patients, categorized into three age groups (<45, 45–65 and >65 years) at initiation of anti-TNF. Longitudinal analysis of DAS 28 during the first year of treatment Elderly patients had fewer EULAR good responses and remission and less improvement in disease activity and physical functioning than younger patients Drug survival, co-medication use and tolerance were comparable between the three age groups Filippini et al.[27] Observational cohort including 1114 RA patients treated with anti-TNF therapy (311 age ≥65 years and 803 age <65 years) and followed up to 3 years Decreases in DAS 28 and ESR were comparable, but the EULAR response was somewhat lower in the ERA. HAQ scores were higher at baseline with less improvement after treatment in ERA Anti-TNFα therapy was discontinued by 42% of ERA and 36.6% of YRA SAEs, infection and overall cancer were higher among ERA Hetland et al.[25] Register of 2326 RA patients beginning boDMARDs (median age 57 years). Treatment responses were assessed after 6 and 12 months Older age and initial low functional status were negative predictors of a clinical response and remission during anti-TNF treatment of RA No assessment Amari et al.[63] Cohort of 20 648 veterans with RA (mean age 63 years), including 4088 patients treated with anti-TNFs No assessment Age (per decade, HR = 1.23; 95% CI: 1.09, 1.38) and anti-TNF use (compared with csDMARDs, HR = 1.42; 95% CI: 1.24, 1.63) were risk factors for developing NMSC Galloway et al. [52] Prospective observational study assessing the risk of severe infection between 11 798 and 3598 csDMARD-treated RA patients stratified by age (<55, 55–64, 65–74 and >75 years) No assessment The crude rate of infection increased markedly with age. The increased risk of SI associated with anti-TNF therapy (+20% compared with csDMARDs) was equivalent in elderly and younger patients Lane et al.[53] Cohort of 20 814 veterans (mean age 63 years) with RA, including 3796 anti-TNF-treated patients. Rate of hospitalization for SI was compared with csDMARD users (mean follow-up 2.7 years) No assessment In multivariate analysis, unlike csDMARD use, anti-TNF use was associated with hospitalization for infection (HR = 1.24; 95% CI: 1.02, 1.50) Curtis et al.2012 [54] Prospective cohort of 11 657 RA patients (mean age 61.9 years) initiating anti-TNF therapy. The observed 1-year rates of infection were compared with a predicted infection risk score estimated in the absence of anti-TNF exposure No assessment The rate of SI for anti-TNF agents was increased incrementally by a fixed absolute difference irrespective of age (above vs below 65 years) Herrinton et al. [64] Cohort of 46 424 patients with selected autoimmune diseases. Mortality was compared between new anti-TNF users and similar new csDMARDs users No assessment Anti-TNF therapy was associated with a reduction in mortality among RA patients with ≥2 co-morbid conditions (aHR = 0.87; 95% CI: 0.77, 0.99), or age ≥75 years Toh et al.[57] Retrospective study of 3485 RA patients (mean age 57.9 years) who initiated INF or ETA. Rate of SI or opportunistic infections during the first year was compared between infliximab initiators and etanercept initiators No assessment Rate of SI per 100 person-years was 5.4 (95% CI: 3.8, 7.5) in patients <65 years and 16.0 (95% CI: 10.4, 23.4) in patients ≥65 years during the first 3 months following treatment initiation. The increased risk of SI associated with infliximab compared with etanercept in young subjects disappeared in patients >65 years of age Dreyer et al.[65] Register of RA patients (mean age 58 years). The incidence of cancer in patients treated with (n = 3347) or without TNF inhibitors (n = 3812) was evaluated over a mean follow-up of 2.5 years No assessment TNF antagonist-treated patients did not exhibit an increased risk of overall cancer (HR = 1.02; 95% CI: 0.80, 1.30) compared with non-treated patients, even >65 years of age (HR = 1.10; 95% CI: 0.80, 1.50) Payet et al.[34] Prospective register of 1709 RA patients (including 191 aged ≥75 years and 417 aged 65–74 years) aiming to compare the efficacy and safety of RTX as a function of patient age Patients aged 65–75 years were more likely to be good responders than non-responders at 1 year of follow-up than patients age ≥75 years (OR = 3.81, 95% CI: 1.14, 12.79). After the sixth month, the decrease in DAS 28 score was less marked in the population aged >75 years than in the group aged <50 years At 24 months, no significant difference was shown among the groups for SAE or RTX discontinuation rates. The reasons for discontinuation (inefficacy, AE) were the same in all four groups. Infections were more common in the elderly Wu et al.[66] Nationwide cohort of RA patients in Taiwan including 4426 treated with biologics and 17 704 matched patients taking csDMARDs only, with a median follow-up of 3 years aiming to compare the SIRs of cancer No assessment Incidence of cancer was reduced in biologic users in almost all subsets of study subjects, especially among those aged >60 (HR = 0.56; 95% CI: 0.40, 0.79), with disease duration >10 years (HR = 0.43; 95% CI: 0.24, 0.77). However, there was an increased risk for haematological cancers in the biologics cohort (SIR = 4.64; 95% CI: 2.65, 7.53) Pers et al.[38] Retrospective study of 222 RA patients (including 61 aged ≥65 years) aiming to assess the safety and efficacy of TCZ in daily practice considering two age groups: <65 years (<65) and ≥65 years After 6 months, the ERA less often reached remission (27.8 vs45.6%; P = 0.02) or good EULAR response (40.7 vs 61.0%; P < 0.01) compared with YRA Drug maintenance for TCZ and adverse event discontinuation rates were similar between the two age groups Sekiguchi et al. [14] Prospective cohort of 277 RA patients with high or moderate disease activity receiving ABA as an initial boDMARD to differentiate predictive factors of sustained clinical remission between YRA and ERA Clinical remission was similarly achieved between ERA (at 24 and 48 weeks in 35.1 and 36.5%) and YRA (34.9 and 43.4% at 24 and 48 weeks) No significant differences in the treatment withdrawal rates owing to adverse events depending on age Lahaye et al.[35] Prospective registry of 1017 RA patients (including 103 ≥75 years and 215 between 65 and 74 years) to study the effect of age on the risk–benefit balance of ABA with a 2-year follow-up The EULAR response (good or moderate) and remission rate were not significantly different according to age. At 6 months, the very elderly had a significantly lower likelihood of a good response than the very young (OR = 0.15, 95% CI: 0.03, 0.68). The decrease in DAS 28-ESR over the 24-month follow-up period did not differ by age Increasing age was associated with a higher rate of discontinuation for AE, especially SIs (per 100 patient-years: 1.73 in very young, 4.65 in intermediates, 5.90 in elderly, 10.38 in very elderly; P < 0.001) Kawashima et al. [56] Retrospective study of 183 RA patients over the age of 65 years treated with bo or csDMARDs over a 3-year observation period to determine the risk factors of SI No assessment The incidence rate of SI per 100 person-years was not significantly different between biologics-treated (8.0; 95% CI: 4.7, 13.5) and non-biologic DMARD-treated patients (6.3; 95% CI: 4.1, 9.5, P = 0.78). Prednisolone was associated with SI only in biologics-treated patients at 1–4 mg/day, and in both groups at >5 mg/day Curtis et al.[39] Pooled data from five phase 3 trials and separately from two open-label long-term extension studies concerning RA patients who received tofacitinib or placebo (phase 3 only), with/without csDMARDs, aiming to compare efficacy and safety outcomes between older (aged ≥65 years, 1136/7213) and younger patients In phase 3 trials, at 3 months, probability ratios for ACR responses and HAQ-DI improvement from baseline ≥0.22 favoured tofacitinib (5 and 10 mg BID). ACR responses were similar in ERA and YRA, but HAQ-DI ≥0.22 appeared to be somewhat lower for older tofacitinib-treated patients than for YRA Compared with YRA, ERA treated with 5 mg BID were more exposed to SAEs (IR = 17.6; 95% CI: 14.1, 21.9 vs 8.4; 95% CI: 7.4, 9.6), SI (IR = 3.9; 95% CI: 2.5, 6.0 vs 2.4; 95% CI: 1.9, 3.0) and discontinuation due to AEs [IR = 9.2 (95% CI: 7.0, 12.3) vs 6.0 (95% CI: 5.2, 7.0)]. This risk signal was similar with the 10 mg BID dosage ABA: abatacept; ADA: adalimumab; aHR: adjusted hazard ratio; BID: bis in die; boDMARD: biologic originator DMARD; csDMARD: conventional synthetic DMARD; EORA: elderly-onset RA; ERA: elderly RA patients; ETA: etanercept; IR: incidence rate; HR: hazard ratio; INF: infliximab; KIN: kineret; NMSC: non-melanoma skin cancer; OR: odds ratio; RR: risk ratio; RTX: rituximab; SAE: serious adverse event; SI: severe infection; SIR: standardized incidence ratio; TCZ: tocilizumab; YORA: younger-onset RA; YRA: Young RA patients. Among pharmacological risk factors for infection, the use of GCs plays a predominant role. Oral GC at doses ≥5 mg prednisone-equivalent are associated with a dose-dependent increase in serious infection risk, which is still present up to 2 years after discontinuing treatment.[55,56,67] Moreover, low GC doses (1–4 mg/day) have been shown to be associated with serious infections in biologics-treated patients, but not in non-biologic DMARD-treated patients.[56] Specific studies on the benefit/risk balance of GCs in the elderly will be particularly useful. Elderly patients are at particular risk for cancer, and RA is associated with an overall increased incidence of cancer, especially Hodgkin's and non-Hodgkin's lymphoma,[75] and non-melanoma skin cancers.[76] Moreover, elderly RA patients who develop cancer have a higher mortality rate than subjects without RA after controlling for other comorbidities.[77] As biotherapies are suspected to play a role in carcinogenesis and tumour progression, cancer risk during boDMARDs treatment have been observed in numerous studies, with discordant results, particularly due to the disparate methodologies used (follow-up period, comparator, cancer type, etc.).[78,79] Notably, increased crude rates of cancer have been reported in EORA vsYORA patients undergoing TNFi treatment[23] or other biotherapies.[35] However, most of the studies did not reveal an increased overall cancer risk using TNFi[60,65,79,80] or other biologics[58,66] compared with csDMARDs in elderly patients. Although specific risks of haematological cancers[66] and non-melanoma skin cancer[63,81] have been reported in TNFi-treated patients compared with biologic-naïve patients, these studies were not specific to older subjects. Current knowledge advocates the monitoring of increased cancer risk in elderly patients, starting at diagnosis and continued a fortiori prior to and after biotherapy initiation. RA is associated with an increased risk of early cardiovascular diseases.[82,83] Due to inflammatory mediators playing a role in the pathogenesis of cardiovascular diseases, TNFi were expected to exert a protective effect.[82] Though such a benefit was observed in a younger patient population,[84] elderly patients receiving TNFi exhibited a higher hospitalization rate for heart failure (HF) than patients on MTX,[85] but without increased mortality.[64] In a retrospective US cohort of RA patients, TNFi were associated with higher acute myocardial infarction risk compared with abatacept.[86] However, in another American database of RA patients starting TNFi or boDMARD treatment after MTX use, there was no elevation in HF risk among users of inhibitors, irrespective of prior HF. Oral GCs were associated with a dose-dependent increase in HF risk.[78] Due to chronic inflammation, functional limitation and associated treatments, especially GCs, RA is associated with an increased risk of both fracture and sarcopenia. Besides traditional risk factors, such as low BMI or oral GC use, RA duration >10 years is associated with an elevated risk of hip fracture.[87] Due to the specific risk linked to prolonged GC use,[88] the ACR has established lifestyle and pharmacological recommendations for preventing and treating GC-induced osteoporosis.[89] Place of the Elderly in the Recommendations The 2015 Guidelines of the ACR and 2016 EULAR recommendations do not include recommendations regarding the elderly.[16,72] However, comorbidities and safety issues should be taken into account when therapeutic adjustments are required. Specific EULAR recommendations reaffirm the relevance of managing the higher cardiovascular disease risk, not only in patients with RA, but also in those with SA or PsA. The necessity of using NSAIDs and GCs sparingly has also been stressed,[90] but recommendations concerning GC use in elderly RA patients are lacking.[22] SpA and PsA Specificities of Initial Presentation in the Elderly Only 5% of SP patients are >50 years of age. These late-onset SP cases may present distinctive characteristics: constitutional signs, cervical involvement, predominant peripheral arthropathy of the upper and lower limbs and more frequently mixed forms, namely axial and peripheral joint disease.[91–93] Data on elderly patients mostly concern PsA, which occurs in 6–42% of psoriasis. Although arthritis may precede the onset of psoriasis by many years, the common scenario is that the onset of psoriasis is 10 years before PsA.[94] PsA has a more severe onset and more destructive outcome in the elderly than in younger subjects.[95] Elderly-onset PsA patients are characterized by higher rates of fatigue, pain scores, comorbid diseases and acute phase reactants and less dactylitis and nail involvement than young-onset PsA.[96] PsA is associated with increased mortality, most commonly with cardiovascular causes.[97] PsA, as well as ageing and tobacco use, is an independent risk factor of subclinical atherosclerosis (explored by intima–media thickness).[98] Patients with AS also exhibit a higher risk of myocardial infarction and stroke,[99] but no specific study has addressed elderly patients. Yet, screening for cardiovascular risk factors by physicians proves insufficient,[100] resulting in under-treatment.[101] PsA patients exhibit a higher risk of opportunistic infections and haematological cancer[102] than matched controls, partly linked to immunosenescence.[103] In the CORRONA registry, the adjusted incidences of overall malignancy and cancer subtypes, including non-melanoma skin cancer and lymphoma, were similar in PsA and RA patients, increasing with age, without a significant difference between csDMARD and boDMARD cases.[104] PsA also potentiates the risk of osteopenia, osteoporosis and pathological fractures in the elderly.[105] Age and Treatment Effectiveness Therapeutic efficacy and safety data in elderly PsA patients are limited ().[106,107] The efficacy of csDMARDs could be lower than that of boDMARDs in the elderly.[108] Biologics and conventional systemic therapies appear to be as effective in the elderly as in adult patients with moderate-to-severe Pso.[109–111] In a conflicting study involving 146 consecutive PsA patients initially undergoing TNFi treatment, age inversely correlated with minimal disease activity at 3 months.[112] Most authors reported a favourable risk/benefit ratio for long-term use of TNFi therapy in elderly Pso patients.[110,113,114] Table 2. The efficacy and safety of boDMARDs in elderly patients with SpA and PsA References Design Efficacy Tolerance Militello et al. [111] Post hoc analysis of two large phase 3 randomized placebo trials of etanercept in psoriasis including 77 elderly (≥65 years old) and 1158 younger patients The elderly and young patients did not differ with regard to the number of patients reaching PASI 50 or PASI 75 at week 12 and at any of the three dosing regimens. Both the elderly and young had similar improvement in quality of life (DLQI) with therapy Although dropout rates were similar at week 12, there was a significant increase in SAE in the elderly group across all cohorts. These events were not associated with treatment Menter et al. [110] A phase 3 randomized controlled evaluation of adalimumab with every other week dosing in 1212 patients with moderate to severe psoriasis. Post hocsubgroup analyses were conducted to determine factors associated with adalimumab efficacy PASI 75 score responses at week 16 were uniformly strong across subgroups, including age, 10-kg weight intervals, BMI and PsA history groups Older patients (≥65 years), tended to respond as well as younger patients Adalimumab had an acceptable safety profile and was well tolerated at week 16 regardless of the presence of comorbidities Iervolino et al. [112] A prospective cohort of 146 consecutive patients with PsA eligible for TNF inhibitor therapy was used to identify predictors of early minimal disease activity at 3 months Age (OR = 0.896, P = 0.003) and BASFI (OR = 0.479, P = 0.007) inversely predicted, whereas CRP (OR = 1.78, P = 0.018) directly predicted, achievement of minimal disease activity at 3 months No assessment Esposito et al. [114] Retrospective analysis of 89 patients with plaque-type psoriasis and PsA (n = 62) aged ≥65 years undergoing subcutaneous administration of ETA or ADA aiming to evaluate the long-term efficacy and safety profile In patients with PsA treated with ETA, the mean DAS44-ESR score decreased from 5.80 to 2.29 after 12 weeks and to 0.89 at 3 years, and the mean Pain-VAS score from 75.10 to 19.47 at week 12 and to 3.15 at 3 years. In patients with PsA treated with ADA, the mean DAS44-ESR score decreased from 3.43 to 2.45 after 12 weeks and to 1.44 at 3 years, and the mean Pain-VAS score from 71.30 to 35.91 at week 12 and to 18.26 at 3 years The survival rate after 3 years of treatment was 75.40 and 60.71% for ETA- and ADA-treated patients, respectively. Safety profiles of the two treatments were similar. Loss of efficacy was the major cause of treatment interruption. Injection site reactions, weight gain of ≥5 kg and upper respiratory tract infections were the most common adverse events Hayashi et al. [117] Retrospective study of 24 patients with moderate to severe plaque psoriasis aged >65 years (mean, 73.1 years) aiming to evaluate the efficacy and safety profile of UST (at weeks 0 and 4, and then every 12 weeks) over a 1-year period PASI 75 responses were 56.5% at week 16, 59.1% at week 28 and 60.0% at week 52 The mean DLQI score decreased from 7.8 (6.0) to 2.5 (3.4) at week 16, and 1.2 (1.7) at 1 year One patient developed a mild urinary tract infection, but no serious infection was reported during the 1-year treatment. Two patients developed arthritis and improved after switching to ADA Piaserico et al. [108] Prospective registry with 187 elderly patients with psoriasis (PsA 26%) receiving a new treatment with csDMARDs or boDMARDs At week 12 of therapy, PASI 75 was lower with traditional drugs (49, 27, 46 and 31% for MTX, acitretin, ciclosporin and PUVA, respectively) than with boDMARDs (64, 65, 93, 57 and 100% for etanercept, adalimumab, infliximab, efalizumab and ustekinumab, respectively) The rate of adverse events was 0.12, 0.32, 1.4 and 0.5 per patient-year in the MTX, acitretin, ciclosporin and PUVA groups, respectively. Etanercept was associated with a lower rate of adverse events compared with other boDMARDs (0.11 vs0.35, 0.19, 0.3 and 0.26 for etanercept, adalimumab, infliximab, efalizumab and ustekinumab, respectively) Medina et al. [115] Registry of psoriatic patients treated with systemic therapy including 175 elderly (≥65 years old) and 1618 younger patients. Adverse event rates were compared taking into account exposure to classic or biologic drugs No assessment SAEs were more common in elderly (drug group-adjusted HR = 3.2; 95% CI: 2.0, 5.1). Age-adjusted HR of all adverse events was lower for patients exposed to boDMARDs compared with csDMARDs (HR = 0.7; 95% CI: 0.6, 0.7) Garber et al.[109] Retrospective cohort of psoriatic patients including 48 elderly (≥65 years old) and 146 adult (18–64 years old) patients There was no significant difference in S-MAPA improvement at 12 weeks between the two cohorts when treated with biologics or conventional systemics. Within the elderly cohort, there was no significant difference in the efficacy of biologics vsconventional systemics at any time point For both boDMARDs and csDMARDs, there was no significant intergroup difference in the rate of adverse events or infection. Elderly patients had a higher rate of adverse events with csDMARDs than with boDMARDs (P = 0.033) Megna et al.[118] Retrospective study of 22 patients with psoriasis aged ≥65 years treated with UST at weeks 0 and 4, and then every 12 weeks for at least 2 years PASI 75 was reached in 63.6% (n= 14), 86.4% (n = 19) and 90.9% (n = 20) of patients after 28, 52 and 100 weeks, respectively Over 2 years, no cases of serious infections were reported; only two mild adverse events were registered (one liver enzyme elevation and one hyperglycaemia) ADA: adalimumab; BASFI: Bath Ankylosing Spondylitis Functionnal Index; DLQI: Dermatology Life Quality Index; boDMARD: biologic originator DMARD; csDMARD: conventional synthetic DMARD; ETA: etanercept; HR: hazard ratio; OR: odds ratio; PASI: Psoriasis Area and Severity Index; PUVA: Psoralen and UltraViolet A; SAE: serious adverse event; SI: severe infection; S-MAPA: Simple-Measure for Assessing Psoriasis Activity; UST: ustekinumab. Age and Adverse Drug Reactions Data concerning the effect of age on the occurrence of AEs, including infection rates for both biologics and conventional systemic treatments, appear to be inconsistent,[103,109,115] whereas conventional systemic treatments are more frequently discontinued in the elderly due to AEs compared with biologics. Similar to RA, TNFi exhibit an increased risk of reactivating latent tuberculosis in Pso patients, thereby requiring adequate screening and prevention strategies.[116] In AS, the risk of tuberculosis is elevated during TNFi therapy, and BMI <22 kg/m2 is a significant risk factor in this complication.[68] In a large-scale US cohort, the use of TNFi was not associated with increased mortality in patients with Pso, PsA or AS compared with non-biologic therapies, regardless of the drug used, even after 75 years.[64] In the DANBIO registry, patients on TNFi therapy for PsA or AS did not exhibit an increased incidence of cancer compared with TNFi-naïve patients, regardless of age.[65] Recently, ustekinumab has exhibited adequate efficacy and safety.[117,118] In the Psoriasis Longitudinal Assessment Registry (38% of PsA), long-term (≥12 months) treatment with a TNFi, but not MTX and ustekinumab, seemed to increase the risk of malignancy.[119] However, larger sample sizes and longer observation duration will be required to confirm the safer profile of ustekinumab compared with other TNFi in elderly Pso patients. Despite the limited data on biologic drugs (), biologics seem to be an effective and safe alternative to conventional systemic agents in the elderly PsA population. Table 2. The efficacy and safety of boDMARDs in elderly patients with SpA and PsA References Design Efficacy Tolerance Militello et al. [111] Post hoc analysis of two large phase 3 randomized placebo trials of etanercept in psoriasis including 77 elderly (≥65 years old) and 1158 younger patients The elderly and young patients did not differ with regard to the number of patients reaching PASI 50 or PASI 75 at week 12 and at any of the three dosing regimens. Both the elderly and young had similar improvement in quality of life (DLQI) with therapy Although dropout rates were similar at week 12, there was a significant increase in SAE in the elderly group across all cohorts. These events were not associated with treatment Menter et al. [110] A phase 3 randomized controlled evaluation of adalimumab with every other week dosing in 1212 patients with moderate to severe psoriasis. Post hocsubgroup analyses were conducted to determine factors associated with adalimumab efficacy PASI 75 score responses at week 16 were uniformly strong across subgroups, including age, 10-kg weight intervals, BMI and PsA history groups Older patients (≥65 years), tended to respond as well as younger patients Adalimumab had an acceptable safety profile and was well tolerated at week 16 regardless of the presence of comorbidities Iervolino et al. [112] A prospective cohort of 146 consecutive patients with PsA eligible for TNF inhibitor therapy was used to identify predictors of early minimal disease activity at 3 months Age (OR = 0.896, P = 0.003) and BASFI (OR = 0.479, P = 0.007) inversely predicted, whereas CRP (OR = 1.78, P = 0.018) directly predicted, achievement of minimal disease activity at 3 months No assessment Esposito et al. [114] Retrospective analysis of 89 patients with plaque-type psoriasis and PsA (n = 62) aged ≥65 years undergoing subcutaneous administration of ETA or ADA aiming to evaluate the long-term efficacy and safety profile In patients with PsA treated with ETA, the mean DAS44-ESR score decreased from 5.80 to 2.29 after 12 weeks and to 0.89 at 3 years, and the mean Pain-VAS score from 75.10 to 19.47 at week 12 and to 3.15 at 3 years. In patients with PsA treated with ADA, the mean DAS44-ESR score decreased from 3.43 to 2.45 after 12 weeks and to 1.44 at 3 years, and the mean Pain-VAS score from 71.30 to 35.91 at week 12 and to 18.26 at 3 years The survival rate after 3 years of treatment was 75.40 and 60.71% for ETA- and ADA-treated patients, respectively. Safety profiles of the two treatments were similar. Loss of efficacy was the major cause of treatment interruption. Injection site reactions, weight gain of ≥5 kg and upper respiratory tract infections were the most common adverse events Hayashi et al. [117] Retrospective study of 24 patients with moderate to severe plaque psoriasis aged >65 years (mean, 73.1 years) aiming to evaluate the efficacy and safety profile of UST (at weeks 0 and 4, and then every 12 weeks) over a 1-year period PASI 75 responses were 56.5% at week 16, 59.1% at week 28 and 60.0% at week 52 The mean DLQI score decreased from 7.8 (6.0) to 2.5 (3.4) at week 16, and 1.2 (1.7) at 1 year One patient developed a mild urinary tract infection, but no serious infection was reported during the 1-year treatment. Two patients developed arthritis and improved after switching to ADA Piaserico et al. [108] Prospective registry with 187 elderly patients with psoriasis (PsA 26%) receiving a new treatment with csDMARDs or boDMARDs At week 12 of therapy, PASI 75 was lower with traditional drugs (49, 27, 46 and 31% for MTX, acitretin, ciclosporin and PUVA, respectively) than with boDMARDs (64, 65, 93, 57 and 100% for etanercept, adalimumab, infliximab, efalizumab and ustekinumab, respectively) The rate of adverse events was 0.12, 0.32, 1.4 and 0.5 per patient-year in the MTX, acitretin, ciclosporin and PUVA groups, respectively. Etanercept was associated with a lower rate of adverse events compared with other boDMARDs (0.11 vs0.35, 0.19, 0.3 and 0.26 for etanercept, adalimumab, infliximab, efalizumab and ustekinumab, respectively) Medina et al. [115] Registry of psoriatic patients treated with systemic therapy including 175 elderly (≥65 years old) and 1618 younger patients. Adverse event rates were compared taking into account exposure to classic or biologic drugs No assessment SAEs were more common in elderly (drug group-adjusted HR = 3.2; 95% CI: 2.0, 5.1). Age-adjusted HR of all adverse events was lower for patients exposed to boDMARDs compared with csDMARDs (HR = 0.7; 95% CI: 0.6, 0.7) Garber et al.[109] Retrospective cohort of psoriatic patients including 48 elderly (≥65 years old) and 146 adult (18–64 years old) patients There was no significant difference in S-MAPA improvement at 12 weeks between the two cohorts when treated with biologics or conventional systemics. Within the elderly cohort, there was no significant difference in the efficacy of biologics vsconventional systemics at any time point For both boDMARDs and csDMARDs, there was no significant intergroup difference in the rate of adverse events or infection. Elderly patients had a higher rate of adverse events with csDMARDs than with boDMARDs (P = 0.033) Megna et al.[118] Retrospective study of 22 patients with psoriasis aged ≥65 years treated with UST at weeks 0 and 4, and then every 12 weeks for at least 2 years PASI 75 was reached in 63.6% (n= 14), 86.4% (n = 19) and 90.9% (n = 20) of patients after 28, 52 and 100 weeks, respectively Over 2 years, no cases of serious infections were reported; only two mild adverse events were registered (one liver enzyme elevation and one hyperglycaemia) ADA: adalimumab; BASFI: Bath Ankylosing Spondylitis Functionnal Index; DLQI: Dermatology Life Quality Index; boDMARD: biologic originator DMARD; csDMARD: conventional synthetic DMARD; ETA: etanercept; HR: hazard ratio; OR: odds ratio; PASI: Psoriasis Area and Severity Index; PUVA: Psoralen and UltraViolet A; SAE: serious adverse event; SI: severe infection; S-MAPA: Simple-Measure for Assessing Psoriasis Activity; UST: ustekinumab. Place of the Elderly in the Recommendations Three recommendation sets for PsA management have been published in the past 2 years.[120–122] Though no reference has been made to age, the impact of disease on pain, function, HR-QoL and other potentially related conditions (e.g. cardiovascular disease, malignancy, osteoporosis), as well as drug-related risks, should be considered in order to determine individualized targets. All guidelines recommend multidisciplinary and multispecialty assessment and management. In the UK guidelines of the British Association of Dermatologists concerning Pso, age, history and comorbid conditions should be considered when choosing the optimal biologic therapy, with no more details given.[123] Ways to Improve Care of the Elderly Limit Inappropriate Prescribing The lack of specific studies triggers fears of side effects or insufficient disease control by both the patient and prescriber, leading to innovative therapeutic strategies being least used in the elderly.[75] This results in an underuse of DMARDs, especially the biologics, at the cost of an excessive use of old treatments with uncertain risk/benefit balance (NSAIDs, GCs).[11,13,59,124,125]Though effective and inexpensive, GCs are potentially responsible for hypertension, insulin resistance, weight gain, osteoporosis, fractures, infections, gastric ulcers, adrenal suppression and mortality,[88] and NSAIDs can promote drug interactions, renal failure, cardiovascular events and gastrointestinal bleeding.[126] However, specific data in the elderly population are rare, and ongoing studies such as GLORIA (risk benefit of low dose steroids in elderly RA patients,[127]) will be needed to clarify the place of these molecules in elderly management. Even though the prescription of boDMARDs has progressed in RA over the last decade, the use of these drugs remains less common in elderly patients,[13,59,124,125,128–132] despite comparable or even higher disease severity and activity.[24] Other common characteristics found in the elderly are associated with a lower likelihood of boDMARD initiation, including less education,[133] low income and living alone.[134] Elderly psoriasis patients tend to be treated with biologics less frequently than younger patients.[103,109,115] Even with an equivalent or higher severity of PsA, the elderly tend to be treated less with TNFi than young patients.[96] As in other chronic diseases, polypharmacy is particularly frequent in IRD and can promote drug–drug interactions, ADRs and non-adherence.[135] Moreover, in the elderly, polypharmacy is also associated with cognitive impairment, falls and malnutrition.[136] Various strategies have been developed to minimize inappropriate prescribing in multimorbid older people, such as prescriber education in geriatric pharmacotherapy, routine application of STOPP/START (screening tool for older people's prescriptions/screening tool to alert to right treatment) criteria, electronic prescribing and close liaison between clinical pharmacists and physicians.[137] Look for Comorbidities to Refine the Prognosis The elderly population is characterized by great heterogeneity. Thus, comorbidities and functional limitations are not only determinants of poor HR-QoL, dependency and excess mortality in the elderly,[138–140] but are relevant prognostic factors in the treatment response. Yun et al. reported that use of antidepressants, narcotics or GCs at a dose >7.5 mg at baseline in Medicare RA patients was associated with lower biologic effectiveness (TNFi and abatacept).[141] The biologic effectiveness was greater among non-disabled persons compared with disabled patients (RR = 18; 95% CI: 1.08, 1.28). These results are consistent with data from other studies showing that disability, low functional status and concomitant GC use are inversely associated with the clinical response to treatment with TNFi.[25,28] Other studies have revealed an inverse relationship between the number of comorbid conditions and the probability of attaining remission.[124,129] In addition to lower efficacy, comorbidities and functional impairment are associated with more side effects. Renal insufficiency has been known for a long time to be a major determinant of MTX toxicity[18] due to impaired MTX elimination.[142] In a registry of 309 MTX-treated patients (first DMARD), the HAQ score (odds ratio = 1.84; 95% CI: 1.12, 3.01) was significantly associated with AEs at 1 year.[143] In retrospective cohorts of boDMARD-treated patients, the presence of comorbidities such as chronic pulmonary disease,[48,51] renal diseases[144] or diabetes mellitus[145] was associated with certain AEs, particularly infectious disease, whereas low functional status and concomitant GC use (>5 mg prednisolone per day) were associated with a higher incidence of AEs.[144,145] In the German biologics registry RABBIT, comorbidities and persistent, highly active disease (mean DAS 28 score >5.1) were significantly associated with increased mortality, even in patients >65 years of age.[146] A Comprehensive Assessment Serving a Global Strategy A comprehensive geriatric assessment is a systematic, multidimensional and multidisciplinary approach designed to collect data regarding the medical, nutritional, thymic, social and functional status of elderly patients. This assessment has proven very useful for building an integrated and personalized therapeutic project including pharmacological and non-pharmacological interventions, while preserving HR-QoL and autonomy and limiting mortality.[147] In particular, screening and preventing depression, denutrition and mobility limitations are efficacious ways of improving the HR-QoL and survival of the elderly. A meta-analysis of 72 studies including 13 189 RA patients revealed that depression is highly prevalent (between 15 and 35% according to the type of criteria used), even if older patients seem to be at lower risk than younger subjects.[148] In a German longitudinal database, depression was present in 22% of the 1072 elderly RA patients (mean age 72 years), and dementia, cancer, osteoporosis, hypertension and diabetes were associated with a higher risk of developing depression.[149] Moreover, depression is associated with increased global mortality in RA,[150] suicide death in RA and PsA,[151] and reduced likelihood of joint remission in RA and PsA.[152,153] However, anti-depressants are frequently associated with side effects and have inconstant benefits in pain management or functional status.[154] More specific studies would be needed to evaluate the interest of pharmacological and non-pharmacological treatment for depressed elderly.[155] Rheumatoid cachexia is characterized by an involuntary reduction in lean body mass (LBM) associated with normal or even increased fat mass,[156] and is observed in 26–71% of RA patients.[157] Low muscle function is often related to this low LBM, defining sarcopenia.[158] As bone and muscle are critically linked, low LBM and higher fat mass are associated with osteopenia, even after adjusting for age, race, gender and height.[159,160] Major fractures and sarcopenia are essential prognostic issues in the elderly for both HR-QoL and mortality.[161–163] In RA, the negative effect of low lean mass on walking speed is potentialized by ageing, depression, pain, cumulative GC exposure and non-treatment with DMARDs.[164] Adequate control of disease activity in combination with appropriate physical exercise and increased calcium/vitamin D and protein intake are efficient strategies for controlling rheumatoid cachexia, cardiovascular risk and risk of fracture, and preserving autonomy.[156,165,166] Thus, all types of physical activities, including walking or aerobic and strengthening exercises, have exhibited modest benefit in cardiovascular risk, disease-related outcomes, inflammation and HR-QoL in IRD, but without significant side effects.[167,168] Concerning nutritional intervention, the effects of antioxidant-rich and omega-3 fatty acid-rich diets (e.g. Mediterranean diets) are inconsistent.[169] A high dose omega-3 regimen (3–5 g/day) has been shown to improve disease-related activity markers in RA.[170] Restrictive diets and fasting, although potentially effective on disease activity in healthy middle-aged patients, could be particularly deleterious in the aged subject and must be avoided. Thus, no study has been conducted specifically with elderly subjects. Towards new Study Designs to Support Specific Recommendations Although current studies are more interested in the elderly population, they continue to evaluate the benefits of interventions using tools best adapted to younger patients. Regarding the elderly, the actual value given to clinical/biological/radiological criteria for activity seems rather disproportionate. The clinical relevance of therapeutic strategies should be assessed by their impact on HR-QoL, autonomy and mortality related to cardiovascular diseases or cancers. This will require broader criteria and longer-term assessments. These new evaluation criteria should then be considered in management strategies, which currently almost exclusively consider the IRD activity criteria.[16] Recent therapeutic developments have occurred rapidly, particularly when considering non-TNFi biologics. Their precise place among the therapeutic strategies needs to be re-evaluated: as second-line after relapse or as first-line in patients at risk of complications with conventional treatments. This issue appears to be particularly relevant for frail comorbid subjects. Therefore, further studies will be required to validate the most effective therapeutic strategies to best adapt the existing recommendations and guidelines. Conclusion In conclusion, IRD management in the elderly is a permanent challenge due to wide heterogeneity in terms of autonomy and comorbidity, several specificities in terms of the clinical presentation and treatment response, and a scarcity of specific literature pertaining to this patient population. Based on an increasing amount of data, biologic treatments appear to be useful tools for controlling disease activity and reducing iatrogenicity in severe IRD, even in the elderly population, limiting the use of more dangerous systemic drugs, such as GCs and NSAIDs. However, elderly patients often remain deprived of effective therapies, primarily due to age. A multidimensional health assessment should be performed in order to build up an integrated therapeutic strategy. Sidebar Rheumatology key Messages Elderly inflammatory rheumatic disease patients should be provided with individualized care. A multimodal evaluation could improve the quality of care for elderly IRD patients. Studies of elderly care are necessary to develop specific recommendations in IRD. References GBD Risk Factors Collaborators. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 2015;388:1659–724. Franceschi C, Bonafe` M, Valensin S et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 2000;908:244–54. McElhaney JE, Effros RB. Immunosenescence: what does it mean to health outcomes in older adults? Curr Opin Immunol 2009;21:418–24. Bressler R, Bahl JJ. Principles of drug therapy for the elderly patient. Mayo Clin Proc 2003;78:1564–77. Grimes DA, Schulz KF. Bias and causal associations in observational research. Lancet 2002;359:248–52. Soubrier M, Mathieu S, Payet S, Dubost J-J, Ristori J-M. Elderly-onset rheumatoid arthritis. Joint Bone Spine 2010;77:290–6. El-Labban AS, Abo Omar HAS, El-Shereif RR, Ali F, El-Mansoury TM. Pattern of young and old onset rheumatoid arthritis (YORA and EORA) among a group of Egyptian patients with rheumatoid arthritis. Clin Med Insights Arthritis Musculoskelet Disord 2010;3:25–31. Nieuwenhuis WP, Mangnus L, Steenbergen V, et al. Older age is associated with more MRI-detected inflammation in hand and foot joints. Rheumatology 2016;55:2212–9. Chen D-Y, Hsieh T-Y, Chen Y-M et al. Proinflammatory cytokine profiles of patients with elderly-onset rheumatoid arthritis: a comparison with younger-onset disease. Gerontology 2009;55:250–8. de Gonzalo-Calvo D, de Luxán-Delgado B, Martınez-Camblor P et al. Chronic inflammation as predictor of 1-year hospitalization and mortality in elderly population. Eur J Clin Invest 2012;42:1037–46. Mueller RB, Kaegi T, Finckh A et al. Is radiographic progression of late-onset rheumatoid arthritis different from young-onset rheumatoid arthritis? Results from the Swiss prospective observational cohort. Rheumatology 2014;53:671–7. Innala L, Berglin E, Möller B et al. Age at onset determines severity and choice of treatment in early rheumatoid arthritis: a prospective study. Arthritis Res Ther 2014;16:R94. Huscher D, Sengler C, Gromnica-Ihle E et al. Clinical presentation, burden of disease and treatment in youngonset and late-onset rheumatoid arthritis: a matched-pairs analysis taking age and disease duration into account. Clin Exp Rheumatol 2013;31:256–62. Sekiguchi M, Fujii T, Matsui K et al. Differences in predictive factors for sustained clinical remission with abatacept between younger and elderly patients with biologic-naive rheumatoid arthritis: results from the ABROAD Study. J Rheumatol 2016;43:1974–83. Krams T, Ruyssen-Witrand A, Nigon D et al. Effect of age at rheumatoid arthritis onset on clinical, radiographic, and functional outcomes: the ESPOIR cohort. Joint Bone Spine 2016;83:511–5. Smolen JS, Landewé R, Bijlsma J et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis 2017;76:960–77. Strehl C, Bijlsma JWJ, de Wit M et al. Defining conditions where long-term glucocorticoid treatment has an acceptably low level of harm to facilitate implementation of existing recommendations: viewpoints from an EULAR task force. Ann Rheum Dis 2016;75:952–7. Rheumatoid Arthritis Clinical Trial Archive Group. The effect of age and renal function on the efficacy and toxicity of methotrexate in rheumatoid arthritis. J Rheumatol 1995;22:218–23. Saevarsdottir S, Wallin H, Seddighzadeh M et al. Predictors of response to methotrexate in early DMARD naive rheumatoid arthritis: results from the initial openlabel phase of the SWEFOT trial. Ann Rheum Dis 2011;70:469–75. Alivernini S, Mazzotta D, Zoli A, Ferraccioli G. Leflunomide treatment in elderly patients with rheumatoid or psoriatic arthritis: retrospective analysis of safety and adherence to treatment. Drugs Aging 2009;26:395–402. Black RJ, Joseph RM, Brown B et al. Half of U.K. patients with rheumatoid arthritis are prescribed oral glucocorticoid therapy in primary care: a retrospective drug utilization study. Arthritis Res Ther 2015;17:375. Palmowski Y, Buttgereit T, Dejaco C et al. ''Official view'' on glucocorticoids in rheumatoid arthritis: a systematic review of international guidelines and consensus statements. Arthritis Care Res 2017;69:1134. Genevay S, Finckh A, Ciurea A et al. Tolerance and effectiveness of anti-tumor necrosis factor alpha therapies in elderly patients with rheumatoid arthritis: a populationbased cohort study. Arthritis Rheum 2007;57:679–85. Radovits BJ, Fransen J, Eijsbouts A, van Riel PLCM, Laan RFJM. Missed opportunities in the treatment of elderly patients with rheumatoid arthritis. Rheumatology 2009;48:906–10. Hetland ML, Christensen IJ, Tarp U et al. Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry. Arthritis Rheum 2010;62:22–32. Filippini M, Bazzani C, Atzeni F et al. Effects of anti-TNF alpha drugs on disability in patients with rheumatoid arthritis: long-term real-life data from the Lorhen Registry. Biomed Res Int 2014;2014:416892. Filippini M, Bazzani C, Favalli EG et al. Efficacy and safety of anti-tumour necrosis factor in elderly patients with rheumatoid arthritis: an observational study. Clin Rev Allergy Immunol 2010;38:90–6. Hyrich KL, Watson KD, Silman AJ, Symmons DPM. Predictors of response to anti-TNF-α therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology 2006;45:1558–65. Bathon JM, Fleischmann RM, Van der Heijde D et al. Safety and efficacy of etanercept treatment in elderly subjects with rheumatoid arthritis. J Rheumatol 2006;33:234–43. Fleischmann R, Iqbal I. Risk: benefit profile of etanercept in elderly patients with rheumatoid arthritis, ankylosing spondylitis or psoriatic arthritis. Drugs Aging 2007;24:239–54. Köller MD, Aletaha D, Funovits J et al. Response of elderly patients with rheumatoid arthritis to methotrexate or TNF inhibitors compared with younger patients. Rheumatology 2009;48:1575–80. Edwards CJ, Roshak K, Bukowski JF, Pedersen R, Thakur M, Marshall L, Jones H. Efficacy of etanercept in elderly patients with rheumatoid arthritis [abstract]. Arthritis Rheumatol 2017;69 (suppl 10). http://acrabstracts.org/abstract/efficacy-of-etanercept-in-elderly-patients-withrheumatoid-arthritis/ (2 December 2017, date last accessed). Wendler J, Burmester GR, Sörensen H et al. Rituximab in patients with rheumatoid arthritis in routine practice (GERINIS): six-year results from a prospective, multicentre, non-interventional study in 2,484 patients. Arthritis Res Ther 2014;16:R80. Payet S, Soubrier M, Perrodeau E et al. Efficacy and safety of rituximab in elderly patients with rheumatoid arthritis enrolled in a French Society of Rheumatology Registry. Arthritis Care Res 2014;66:1289–95. Lahaye C, Soubrier M, Mulliez A et al. Effectiveness and safety of abatacept in elderly patients with rheumatoid arthritis enrolled in the French Society of Rheumatology's ORA registry. Rheumatology 2016;55:874–82. Takahashi N, Kojima T, Asai S et al. Being elderly is not a predictive factor of discontinuation of abatacept due to adverse events in rheumatoid arthritis patients with concomitant methotrexate: a retrospective observational study based on data from a Japanese Multicenter Registry Study [abstract]. Arthritis Rheumatol 2017;69 (suppl 10). http://acrabstracts.org/abstract/being-elderly-is-not-apredictive-factor-of-discontinuation-of-abatacept-due-toadverse-events-in-rheumatoid-arthritis-patients-with-concomitant-methotrexate-a-retrospective-observationalstudy-based/ (7 January 2018, date last accessed). Matsuda M, Asanuma YF, Kouzu N, Mimura T. Analysis of the efficacy, safety and continuation rate of abatacept in elderly patients with rheumatoid arthritis [abstract]. Arthritis Rheumatol 2017;69 (suppl 10). http://acrabstracts.org/abstract/analysis-of-the-efficacy-safety-andcontinuation-rate-of-abatacept-in-elderly-patients-withrheumatoid-arthritis/ (7 January 2018, date last accessed). Pers Y-M, Schaub R, Constant E et al. Efficacy and safety of tocilizumab in elderly patients with rheumatoid arthritis. Joint Bone Spine 2015;82:25–30. Curtis JR, Schulze-Koops H, Takiya L et al. Efficacy and safety of tofacitinib in older and younger patients with rheumatoid arthritis. Clin Exp Rheumatol 2017;35:390–400. Fleischmann R, Alam J, Arora V et al. Safety and efficacy of baricitinib in elderly patients with rheumatoid arthritis. RMD Open 2017;3:e000546. van Onna M, Boonen A. The challenging interplay between rheumatoid arthritis, ageing and comorbidities. BMC Musculoskelet Disord 2016;17:184. Widdifield J, Bernatsky S, Paterson JM et al. Serious infections in a population-based cohort of 86,039 seniors with rheumatoid arthritis. Arthritis Care Res 2013;65:353–61. Bernatsky S, Ehrmann Feldman D. Discontinuation of methotrexate therapy in older patients with newly diagnosed rheumatoid arthritis: analysis of administrative health databases in Québec, Canada. Drugs Aging 2008;25:879–84. Alarcón GS, Kremer JM, Macaluso M et al.; Methotrexate-Lung Study Group. Risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis. A multicenter, case-control study. Ann Intern Med 1997;127:356–64. Kent PD, Luthra HS, Michet C. Risk factors for methotrexate-induced abnormal laboratory monitoring results in patients with rheumatoid arthritis. J Rheumatol 2004;31:1727–31. Baker JF, Sauer BC, Cannon GW et al. Changes in body mass related to the initiation of disease-modifying therapies in rheumatoid arthritis. Arthritis Rheumatol 2016;68:1818–27. Cho S-K, Sung Y-K, Kim D et al. Drug retention and safety of TNF inhibitors in elderly patients with rheumatoid arthritis. BMC Musculoskelet Disord 2016;17:333. Murota A, Kaneko Y, Yamaoka K, Takeuchi T. Safety of biologic agents in elderly patients with rheumatoid arthritis. J Rheumatol 2016;43:1984–8. Kawai VK, Grijalva CG, Arbogast PG et al. Changes in cotherapies after initiation of disease-modifying antirheumatic drug therapy in patients with rheumatoid arthritis. Arthritis Care Res 2011;63:1415–24. Busquets N, Tomero E, Descalzo MÁ et al. Age at treatment predicts reason for discontinuation of TNF antagonists: data from the BIOBADASER 2.0 registry. Rheumatology 2011;50:1999–2004. Komano Y, Tanaka M, Nanki T et al. Incidence and risk factors for serious infection in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors: a report from the Registry of Japanese Rheumatoid Arthritis Patients for Longterm Safety. J Rheumatol 2011;38:1258–64. Galloway JB, Hyrich KL, Mercer LK et al. Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly. Rheumatology 2011;50:124–31. Lane MA, McDonald JR, Zeringue AL et al. TNF-α antagonist use and risk of hospitalization for infection in a national cohort of veterans with rheumatoid arthritis. Medicine 2011;90:139–45. Curtis JR, Xie F, Chen L et al. Use of a disease risk score to compare serious infections associated with anti-tumor necrosis factor therapy among high- versus lower-risk rheumatoid arthritis patients. Arthritis Care Res 2012;64:1480–9. Schneeweiss S, Setoguchi S, Weinblatt ME et al. Antitumor necrosis factor alpha therapy and the risk of serious bacterial infections in elderly patients with rheumatoid arthritis. Arthritis Rheum 2007;56:1754–64. Kawashima H, Kagami S, Kashiwakuma D et al. Longterm use of biologic agents does not increase the risk of serious infections in elderly patients with rheumatoid arthritis. Rheumatol Int 2017;37:369–76. Toh S, Li L, Harrold LR et al. Comparative safety of infliximab and etanercept on the risk of serious infections: does the association vary by patient characteristics? Pharmacoepidemiol Drug Saf 2012;21:524–34. Setoguchi S, Solomon DH, Weinblatt ME et al. Tumor necrosis factor alpha antagonist use and cancer in patients with rheumatoid arthritis. Arthritis Rheum 2006;54:2757–64. Tutuncu Z, Reed G, Kremer J, Kavanaugh A. Do patients with older-onset rheumatoid arthritis receive less aggressive treatment? Ann Rheum Dis 2006;65:1226–9. Askling J, van Vollenhoven RF, Granath F et al. Cancer risk in patients with rheumatoid arthritis treated with anti-tumor necrosis factor α therapies: does the risk change with the time since start of treatment? Arthritis Rheum 2009;60:3180–9. McDonald JR, Zeringue AL, Caplan L et al. Herpes zoster risk factors in a national cohort of veterans with rheumatoid arthritis. Clin Infect Dis 2009;48:1364–71. Radovits BJ, Kievit W, Fransen J et al. Influence of age on the outcome of antitumour necrosis factor alpha therapy in rheumatoid arthritis. Ann Rheum Dis 2009;68:1470–3. Amari W, Zeringue AL, McDonald JR et al. Risk of nonmelanoma skin cancer in a national cohort of veterans with rheumatoid arthritis. Rheumatology 2011;50:1431–9. Herrinton LJ, Liu L, Chen L et al. Association between anti-TNF-α therapy and all-cause mortality. Pharmacoepidemiol Drug Saf 2012;21:1311–20. Dreyer L, Mellemkjær L, Andersen AR et al. Incidences of overall and site specific cancers in TNFα inhibitor treated patients with rheumatoid arthritis and other arthritides – a follow-up study from the DANBIO Registry. Ann Rheum Dis 2013;72:79–82. Wu C-Y, Chen D-Y, Shen J-L et al. The risk of cancer in patients with rheumatoid arthritis taking tumor necrosis factor antagonists: a nationwide cohort study. Arthritis Res Ther 2014;16:449. Dixon WG, Hyrich KL, Watson KD et al. Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR). Ann Rheum Dis 2010;69:522–8. Kim HW, Park JK, Yang J-A et al. Comparison of tuberculosis incidence in ankylosing spondylitis and rheumatoid arthritis during tumor necrosis factor inhibitor treatment in an intermediate burden area. Clin Rheumatol 2013;33:1307–12. Lim CH, Chen H-H, Chen Y-H et al. The risk of tuberculosis disease in rheumatoid arthritis patients on biologics and targeted therapy: a 15-year real world experience in Taiwan. PLoS One 2017;12:e0178035. Winthrop KL, Baddley JW, Chen L et al. Association between the initiation of anti-tumor necrosis factor therapy and the risk of herpes zoster. J Am Med Assoc 2013;309:887–95. Winthrop KL. The emerging safety profile of JAK inhibitors in rheumatic disease. Nat Rev Rheumatol 2017;13:234–43. Singh JA, Saag KG, Bridges SL et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol 2016;68:1–26. Vassilopoulos D, Delicha EM, Settas L et al. Safety profile of repeated rituximab cycles in unselected rheumatoid arthritis patients: a long-term, prospective real-life study. Clin Exp Rheumatol 2016;34:893–900. Fleischmann R, Alam J, Arora V et al. Safety and efficacy of baricitinib in elderly patients with rheumatoid arthritis. RMD Open 2017;3:e000546. Wolfe F, Michaud K. Biologic treatment of rheumatoid arthritis and the risk of malignancy: analyses from a large US observational study. Arthritis Rheum 2007;56:2886–95. Raaschou P, Simard JF, Holmqvist M, Askling J; for the ARTIS Study Group. Rheumatoid arthritis, anti-tumour necrosis factor therapy, and risk of malignant melanoma: nationwide population based prospective cohort study from Sweden. BMJ 2013;346:f1939. Nayak P, Luo R, Elting L, Zhao H, Suarez-Almazor ME. Impact of rheumatoid arthritis on the mortality of elderly patients who develop cancer: a population-based study. Arthritis Care Res 2017;69:75–83. Solomon DH, Mercer E, Kavanaugh A. Observational studies on the risk of cancer associated with TNFInhibitors in RA: a review of their methodologies and results. Arthritis Rheum 2012;64:21–32. Haynes K, Beukelman T, Curtis JR et al. Tumor necrosis factor α inhibitor therapy and cancer risk in chronic immune-mediated diseases. Arthritis Rheum 2013;65:48–58. Askling J, Fahrbach K, Nordstrom B et al. Cancer risk with tumor necrosis factor alpha (TNF) inhibitors: meta-analysis of randomized controlled trials of adalimumab, etanercept, and infliximab using patient level data. Pharmacoepidemiol Drug Saf 2011;20:119–30. Raaschou P, Simard JF, Asker Hagelberg C, Askling J; ARTIS Study Group. Rheumatoid arthritis, anti-tumour necrosis factor treatment, and risk of squamous cell and basal cell skin cancer: cohort study based on nationwide prospectively recorded data from Sweden. BMJ 2016;352:i262. Crowson CS, Liao KP, Davis JM et al. Rheumatoid arthritis and cardiovascular disease. Am Heart J 2013;166:622–8.e1. Lindhardsen J, Ahlehoff O, Gislason GH et al. The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: a Danish nationwide cohort study. Ann Rheum Dis 2011;70:929–34. Barnabe C, Martin B-J, Ghali WA. Systematic review and meta-analysis: anti-tumor necrosis factor α therapy and cardiovascular events in rheumatoid arthritis. Arthritis Care Res 2011;63:522–9. Setoguchi S, Schneeweiss S, Avorn J et al. Tumor necrosis factor-alpha antagonist use and heart failure in elderly patients with rheumatoid arthritis. Am Heart J 2008;156:336–41. Zhang J, Xie F, Yun H et al. Comparative effects of biologics on cardiovascular risk among older patients with rheumatoid arthritis. Ann Rheum Dis 2016;75:1813–8. van Staa TP, Geusens P, Bijlsma JWJ, Leufkens HGM, Cooper C. Clinical assessment of the long-term risk of fracture in patients with rheumatoid arthritis. Arthritis Rheum 2006;54:3104–12. Bijlsma JWJ, Buttgereit F. Adverse events of glucocorticoids during treatment of rheumatoid arthritis: lessons from cohort and registry studies. Rheumatology 2016;55:ii3–5. Buckley L, Guyatt G, Fink HA et al. 2017 American College of Rheumatology Guideline for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res 2017;69:1095–110. Agca R, Heslinga SC, Rollefstad S et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis 2017;76:17–28. Dubost JJ, Sauvezie B. Late onset peripheral spondyloarthropathy. J Rheumatol 1989;16:1214–7. Toussirot E. Late-onset ankylosing spondylitis and spondylarthritis: an update on clinical manifestations, differential diagnosis and pharmacological therapies. Drugs Aging 2010;27:523–31. Montilla C, Del Pino-Montes J, Collantes-Estevez E et al. Clinical features of late-onset ankylosing spondylitis: comparison with early-onset disease. J Rheumatol 2012;39:1008–12. Gladman D, Antoni C, Mease P, Clegg D, Nash P. Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann Rheum Dis 2005;64:ii14–7. Punzi L, Pianon M, Rossini P, Schiavon F, Gambari PF. Clinical and laboratory manifestations of elderly onset psoriatic arthritis: a comparison with younger onset disease. Ann Rheum Dis 1999;58:226–9. Kobak S, Yildiz F, Karaarslan A, Semiz H, Orman M. Characteristics of Turkish patients with elderly onset psoriatic arthritis: a retrospective cohort study. Medicine 2017;96:e7833. Arumugam R, McHugh NJ. Mortality and causes of death in psoriatic arthritis. J Rheumatol Suppl 2012;89:32–5. Ibáñez-Bosch R, Restrepo-Velez J, Medina-Malone M et al. High prevalence of subclinical atherosclerosis in psoriatic arthritis patients: a study based on carotid ultrasound. Rheumatol Int 2017;37:107–12. Mathieu S, Pereira B, Soubrier M. Cardiovascular events in ankylosing spondylitis: an updated meta-analysis. Semin Arthritis Rheum 2015;44:551–5. Parsi KK, Brezinski EA, Lin T-C, Li C-S, Armstrong AW. Are patients with psoriasis being screened for cardiovascular risk factors? A study of screening practices and awareness among primary care physicians and cardiologists. J Am Acad Dermatol 2012;67:357–62. Kimball AB, Szapary P, Mrowietz U et al. Underdiagnosis and undertreatment of cardiovascular risk factors in patients with moderate to severe psoriasis. J Am Acad Dermatol 2012;67:76–85. Hagberg KW, Li L, Peng M et al. Rates of cancers and opportunistic infections in patients with psoriatic arthritis compared with patients without psoriatic arthritis. J Clin Rheumatol 2016;22:241–7. Balato N, Patruno C, Napolitano M et al. Managing moderate-to-severe psoriasis in the elderly. Drugs Aging 2014;31:233–8. Gross R, Schwartzman-Morris J, Krathen M et al. A comparison of malignancy incidence among psoriatic and rheumatoid arthritis patients in a large US cohort. Arthritis Rheumatol 2014;66:1472–81. Kathuria P, Gordon KB, Silverberg JI. Association of psoriasis and psoriatic arthritis with osteoporosis and pathological fractures. J Am Acad Dermatol 2017;76:1045–53.e3. Grozdev IS, Van Voorhees AS, Gottlieb AB et al. Psoriasis in the elderly: from the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol 2011;65:537–45. Wong JW, Koo JYM. The safety of systemic treatments that can be used for geriatric psoriasis patients: a review. Dermatol Res Pract 2012;2012:367475. Piaserico S, Conti A, Lo Console F et al. Efficacy and safety of systemic treatments for psoriasis in elderly patients. Acta Derm Venereol 2014;94:293–7. Garber C, Plotnikova N, Au S, Sorensen EP, Gottlieb A. Biologic and conventional systemic therapies show similar safety and efficacy in elderly and adult patients with moderate to severe psoriasis. J Drugs Dermatol 2015;14:846–52. Menter A, Gordon KB, Leonardi CL, Gu Y, Goldblum OM. Efficacy and safety of adalimumab across subgroups of patients with moderate to severe psoriasis. J Am Acad Dermatol 2010;63:448–56. Militello G, Xia A, Stevens SR, Van Voorhees AS. Etanercept for the treatment of psoriasis in the elderly. J Am Acad Dermatol 2006;55:517–9. Iervolino S, Di Minno MND, Peluso R et al. Predictors of early minimal disease activity in patients with psoriatic arthritis treated with tumor necrosis factor-α blockers. J Rheumatol 2012;39:568–73. Chiricozzi A, Pavlidis A, Dattola A et al. Efficacy and safety of infliximab in psoriatic patients over the age of 65. Expert Opin Drug Saf 2016;15:1459–62. Esposito M, Giunta A, Mazzotta A et al. Efficacy and safety of subcutaneous anti-tumor necrosis factoralpha agents, etanercept and adalimumab, in elderly patients affected by psoriasis and psoriatic arthritis: an observational long-term study. Dermatology 2012;225:312–9. Medina C, Carretero G, Ferrandiz C et al. Safety of classic and biologic systemic therapies for the treatment of psoriasis in elderly: an observational study from national BIOBADADERM registry. J Eur Acad Dermatol Venereol 2015;29:858–64. Perlmutter A, Mittal A, Menter A. Tuberculosis and tumour necrosis factor-alpha inhibitor therapy: a report of three cases in patients with psoriasis. Comprehensive screening and therapeutic guidelines for clinicians. Br J Dermatol 2009;160:8–15. Hayashi M, Umezawa Y, Fukuchi O et al. Efficacy and safety of ustekinumab treatment in elderly patients with psoriasis. J Dermatol 2014;41:974–80. Megna M, Napolitano M, Balato N et al. Efficacy and safety of ustekinumab in a group of 22 elderly patients with psoriasis over a 2-year period. Clin Exp Dermatol 2016;41:564–6. Fiorentino D, Ho V, Lebwohl MG et al. Risk of malignancy with systemic psoriasis treatment in the Psoriasis Longitudinal Assessment Registry. J Am Acad Dermatol 2017;77:845–54.e5. Gossec L, Smolen JS, Ramiro S et al. European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update. Ann Rheum Dis 2016;75:499–510. Coates LC, Kavanaugh A, Mease PJ et al. Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2015. Treatment Recommendations for Psoriatic Arthritis. Arthritis Rheumatol 2016;68:1060–71. Smolen JS, Schöls M, Braun J et al. Treating axial spondyloarthritis and peripheral spondyloarthritis, especially psoriatic arthritis, to target: 2017 update of recommendations by an international task force. Ann Rheum Dis 2018;77:3–17. Smith CH, Jabbar-Lopez ZK, Yiu ZZ et al. British Association of Dermatologists guidelines for biologic therapy for psoriasis 2017. Br J Dermatol 2017;177:628–636. Ranganath VK, Maranian P, Elashoff DA et al. Comorbidities are associated with poorer outcomes in community patients with rheumatoid arthritis. Rheumatology 2013;52:1809–17. Morsley K, Kilner T, Steuer A. Biologics prescribing for rheumatoid arthritis in older patients: a single-center retrospective cross-sectional study. Rheumatol Ther 2015;2:165–72. Soubrier M, Rosenbaum D, Tatar Z et al. Vascular effects of nonsteroidal antiinflammatory drugs. Joint Bone Spine 2013;80:358–62. The glucocorticoid low-dose outcome in rheumatoid arthritis study. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02585258 (6 January 2018, date last accessed). Harrold LR, Peterson D, Beard AJ, Gurwitz JH, Briesacher BA. Time trends in medication use and expenditures in older patients with rheumatoid arthritis. Am J Med 2012;125:937.e9–15. Martin WJ, Shim M, Paulus HE et al. Older age at rheumatoid arthritis onset and comorbidities correlate with less Health Assessment Questionnaire-Disability Index and Clinical Disease Activity Index response to etanercept in the RADIUS 2 registry. J Clin Rheumatol Pract Rep Rheum Musculoskelet Dis 2014;20:301–5. Ng B, Chu A, Khan MM. A retrospective cohort study: 10-year trend of disease-modifying antirheumatic drugs and biological agents use in patients with rheumatoid arthritis at Veteran Affairs Medical Centers. BMJ Open 2013;3:e002468. Jones B, Hassan I, Maksymowych WP, Yacyshyn E. Biologic DMARD prescribing patterns in elderly patients with rheumatoid arthritis [abstract]. Arthritis Rheumatol 2017;69 (suppl 10). http://acrabstracts.org/abstract/biologic-dmard-prescribing-patterns-in-elderly-patientswith-rheumatoid-arthritis/ (7 January 2018, date last accessed). George MD, Sauer B, Teng MSCC et al. Predictors of earlier biologic initiation among patients with rheumatoid arthritis starting methotrexate [abstract]. Arthritis Rheumatol 2017;69 (suppl 10): http://acrabstracts.org/abstract/predictors-of-earlier-biologic-initiation-amongpatients-with-rheumatoid-arthritis-starting-methotrexate/ (7 January 2018, date last accessed). Putrik P, Ramiro S, Lie E et al. Less educated and older patients have reduced access to biologic DMARDs even in a country with highly developed social welfare (Norway): results from Norwegian cohort study NORDMARD. Rheumatology 2016;55:1217–24. Yelin E, Tonner C, Kim SC et al. Sociodemographic, disease, health system, and contextual factors affecting the initiation of biologic agents in rheumatoid arthritis: a longitudinal study. Arthritis Care Res 2014;66:980–9. van den Bemt BJF, Zwikker HE, van den Ende CHM. Medication adherence in patients with rheumatoid arthritis: a critical appraisal of the existing literature. Expert Rev Clin Immunol 2012;8:337–51. Shah BM, Hajjar ER. Polypharmacy, adverse drug reactions, and geriatric syndromes. Clin Geriatr Med 2012;28:173–86. Lavan AH, Gallagher PF, O'Mahony D. Methods to reduce prescribing errors in elderly patients with multimorbidity. Clin Interv Aging 2016;11:857–66. Kojima G, Iliffe S, Morris RW et al. Frailty predicts trajectories of quality of life over time among British community-dwelling older people. Qual Life Res 2016;25:1743–50. Lee I-C, Chiu Y-H, Lee C-Y. Exploration of the importance of geriatric frailty on health-related quality of life. Psychogeriatrics 2016;16:368–75. Fu WW, Fu TS, Jing R, McFaull SR, Cusimano MD. Predictors of falls and mortality among elderly adults with traumatic brain injury: a nationwide, population-based study. PLoS One 2017;12:e0175868. Yun H, Xie F, Delzell E et al. The comparative effectiveness of biologics among older adults and disabled rheumatoid arthritis patients in the Medicare population. Br J Clin Pharmacol 2015;80:1447–57. Bressolle F, Bologna C, Kinowski J, Sany J, Combe B. Effects of moderate renal insufficiency on pharmacokinetics of methotrexate in rheumatoid arthritis patients. Ann Rheum Dis 1998;57:110–3. Hider SL, Silman AJ, Thomson W et al. Can clinical factors at presentation be used to predict outcome of treatment with methotrexate in patients with early inflammatory polyarthritis? Ann Rheum Dis 2009;68:57–62. Strangfeld A, Eveslage M, Schneider M et al. Treatment benefit or survival of the fittest: what drives the timedependent decrease in serious infection rates under TNF inhibition and what does this imply for the individual patient? Ann Rheum Dis 2011;70:1914–20. Iwanaga N, Arima K, Terada K et al. Risk factors of adverse events during treatment in elderly patients with rheumatoid arthritis: an observational study. Int J Rheum Dis 2017;20:346–52. Listing J, Kekow J, Manger B et al. Mortality in rheumatoid arthritis: the impact of disease activity, treatment with glucocorticoids, TNFα inhibitors and rituximab. Ann Rheum Dis 2015;74:415–21. Tikkanen P, Lönnroos E, Sipilä S et al. Effects of comprehensive geriatric assessment-based individually targeted interventions on mobility of pre-frail and frail community-dwelling older people. Geriatr Gerontol Int 2015;15:80–8. Matcham F, Rayner L, Steer S, Hotopf M. The prevalence of depression in rheumatoid arthritis: a systematic review and meta-analysis. Rheumatology 2013;52:2136–48. Drosselmeyer J, Jacob L, Rathmann W, Rapp MA, Kostev K. Depression risk in patients with late-onset rheumatoid arthritis in Germany. Qual Life Res 2017;26:437–43. Ang DC, Choi H, Kroenke K, Wolfe F. Comorbid depression is an independent risk factor for mortality in patients with rheumatoid arthritis. J Rheumatol 2005;32:1013–9. Ogdie A, Maliha S, Shin D et al. Cause-specific mortality in patients with psoriatic arthritis and rheumatoid arthritis. Rheumatology 2017;56:907. Miwa Y, Takahashi R, Ikari Y et al. Clinical characteristics of rheumatoid arthritis patients achieving functional remission with six months of biological DMARDs treatment. Intern Med 2017;56:903–6. Michelsen B, Kristianslund EK, Sexton J et al. Do depression and anxiety reduce the likelihood of remission in rheumatoid arthritis and psoriatic arthritis? Data from the prospective multicentre NOR-DMARD study. Ann Rheum Dis 2017;76:1906–10. Richards BL, Whittle SL, Buchbinder R. Antidepressants for pain management in rheumatoid arthritis. Cochrane Database Syst Rev 2011;(11):CD008920. Holvast F, Massoudi B, Oude Voshaar RC, Verhaak PFM. Non-pharmacological treatment for depressed older patients in primary care: a systematic review and meta-analysis. PLoS One 2017;12:e0184666. Rajbhandary R, Khezri A, Panush RS. Rheumatoid cachexia: what is it and why is it important? J Rheumatol 2011;38:406–8. El Maghraoui A, Sadni S, Rezqi A et al. Does rheumatoid cachexia predispose patients with rheumatoid arthritis to osteoporosis and vertebral fractures? J Rheumatol 2015;42:1556–62. Cruz-Jentoft AJ, Baeyens JP, Bauer JM et al. Sarcopenia: European consensus on definition and diagnosis. Age Ageing 2010;39:412–23. He H, Liu Y, Tian Q et al. Relationship of sarcopenia and body composition with osteoporosis. Osteoporos Int 2016;27:473–82. Verschueren S, Gielen E, O'Neill TW et al. Sarcopenia and its relationship with bone mineral density in middleaged and elderly European men. Osteoporos Int 2013;24:87–98. Adachi JD, Adami S, Gehlbach S et al. Impact of prevalent fractures on quality of life: baseline results from the global longitudinal study of osteoporosis in women. Mayo Clin Proc 2010;85:806–13. Landi F, Cruz-Jentoft AJ, Liperoti R et al. Sarcopenia and mortality risk in frail older persons aged 80 years and older: results from ilSIRENTE study. Age Ageing 2013;42:203–9. Smith T, Pelpola K, Ball M, Ong A, Myint PK. Pre-operative indicators for mortality following hip fracture surgery: a systematic review and meta-analysis. Age Ageing 2014;43:464–71. Lusa AL, Amigues I, Kramer HR, Dam T-T, Giles JT. Indicators of walking speed in rheumatoid arthritis: relative influence of articular, psychosocial, and body composition characteristics. Arthritis Care Res 2015;67:21–31. Masuko K. Rheumatoid cachexia revisited: a metabolic co-morbidity in rheumatoid arthritis. Front Nutr 2014;1:20. Abizanda P, López MD, Garcıa VP et al. Effects of an oral nutritional supplementation plus physical exercise intervention on the physical function, nutritional status, and quality of life in frail institutionalized older adults: the ACTIVNES Study. J Am Med Dir Assoc 2015;16:439.e9–16. Karapolat H, Akkoc Y, Sari I et al. Comparison of groupbased exercise versus home-based exercise in patients with ankylosing spondylitis: effects on Bath Ankylosing Spondylitis Indices, quality of life and depression. Clin Rheumatol 2008;27:695–700. Metsios GS, Stavropoulos-Kalinoglou A, Kitas GD. The role of exercise in the management of rheumatoid arthritis. Expert Rev Clin Immunol 2015;11:1121–30. Semerano L, Julia C, Aitisha O, Boissier M-C. Nutrition and chronic inflammatory rheumatic disease. Joint Bone Spine 2017;84:547–52. Gioxari A, Kaliora AC, Marantidou F, Panagiotakos DP. Intake of ω-3 polyunsaturated fatty acids in patients with rheumatoid arthritis: a systematic review and metaanalysis. Nutr Burbank 2018;45:114–24.e4. Funding No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Rheumatology. 2019;58(5):748-764. © 2019 Oxford University Press https://www.medscape.com/viewarticle/912757?src=wnl_edit_tpal&uac=60604BR&impID=1971757&faf=1
  23. Gene Changes Key to Successful Pregnancy in Lupus April 29, 2019 Pregnant women with lupus are more likely to suffer complications than those who don’t. Lupus Research Alliance Scientific Advisory Board members Dr. Virginia Pascual, Professor at Weill Cornell Medicine; and Dr. Jane Salmon, Collette Kean Research Professor at Hospital for Special Surgery, and their colleagues asked if testing the blood, of pregnant women with lupus, using advanced technologies could identify, early in pregnancy, lupus patients at high risk for complications. Their new paper in the Journal of Experimental Medicine shows that during uncomplicated pregnancy in both healthy and lupus women some genes that incite the immune system become less active. These changes may make the immune system less aggressive and reduce the odds that it will attack the fetus. However, women with lupus who had pregnancy complications, including preeclampsia, did not show the desirable decrease in these immune signatures. Doctors came up with the term “lupus” because they thought the disease’s skin inflammation looked liked a wolf’s bite. The study “supports the idea that in some cases, pregnancy can ‘tame the wolf.’” Drs. Timothy Niewold and Shilpi Mehta-Lee wrote in a commentary on the paper. They note that the findings may enable doctors to identify patients with lupus who are susceptible to pregnancy complications and need careful monitoring To the immune system, a fetus developing in the womb resembles a foreign invader. Normally during pregnancy, the mother’s immune system develops what researchers call tolerance and avoids attacking the fetus. But when patients with lupus become pregnant, their immune system may be less likely to develop tolerance to the fetus, leading to complications such as preeclampsia, premature birth, and even death of the fetus. In the new study, Dr. Pascual and colleagues compared 92 pregnant women with lupus to 43 pregnant women who didn’t have the disease. The researchers obtained blood samples from the women during and shortly after their pregnancies. To detect the earliest changes associated with pregnancy onset, the scientists also analyzed blood from patients undergoing assisted reproductive technology. The researchers evaluated the patients’ immune system by measuring the activity of different genes that help determine how strongly it responds to potential threats. For a subset of these study participants, the investigators also examined the types of cells that are producing the specific immune responses. Early in pregnancy, the activity of key genes decreased in women who didn’t have lupus, probably increasing their tolerance to the developing baby. The researchers saw similar changes in women with lupus who had successful pregnancies. However, the immune system of women with lupus who went on to develop complications was not turned down. Their immune system might be more likely to attack the fetus or prevent its proper development. This inability to turn down the immune activity appears to be a risk factor for adverse pregnancy outcomes in lupus. Testing for these changes in gene activity might pinpoint patients with lupus who are more likely to develop pregnancy complications and who needs careful monitoring and specific therapeutic intervention to improve the outcome. https://www.lupusresearch.org/gene-changes-key-to-successful-pregnancy-in-lupus/
  24. Discovery may help explain why women get autoimmune diseases far more often than men April 19, 2019 , University of Michigan Stark differences in the presence of autoimmune antibodies and immune factors in the blood (top) and kidneys (bottom) of mice that produced excess VGLL3 (left column) compared with healthy mice (right column). Credit: University of Michigan It's one of the great mysteries of medicine, and one that affects the lives of millions of people: Why do women's immune systems gang up on them far more than men's do, causing nine times more women to develop autoimmune diseases such as lupus? Part of the answer, it turns out, may lie in the skin. New evidence points to a key role for a molecular switch called VGLL3. Three years ago, a team of University of Michigan researchers showed that women have more VGLL3 in their skin cells than men. Now, working in mice, they've discovered that having too much VGLL3 in skin cells pushes the immune system into overdrive, leading to a "self-attacking" autoimmune response. Surprisingly, this response extends beyond the skin, attacking internal organs too. Writing in JCI Insight, the team describes how VGLL3 appears to set off a series of events in skin that trigger the immune system to come running—even when there's nothing to defend against. "VGLL3 appears to regulate immune response genes that have been implicated as important to autoimmune diseases that are more common in women, but that don't appear to be regulated by sex hormones," says Johann Gudjonsson, M.D., Ph.D., who led the research team and is a professor of dermatology at the U-M Medical School. "Now, we have shown that over-expression of VGLL3 in the skin of transgenic mice is by itself sufficient to drive a phenotype that has striking similarities to systemic lupus erythematosus, including skin rash, and kidney injury." Effects of excess VGLL3 Gudjonsson worked with co-first authors Allison Billi, M.D., Ph.D., and Mehrnaz Gharaee-Kermani, Ph.D., and colleagues from several U-M departments, to trace VGLL3's effects. They found that extra VGLL3 in skin cells changed expression levels of a number of genes important to the immune system. Expression of many of the same genes is altered in autoimmune diseases like lupus. The gene expression changes caused by excess VGLL3 wreaked havoc in the mice. Their skin becomes scaly and raw. Immune cells abound, filling the skin and lymph nodes. The mice also produce antibodies against their own tissues, including the same antibodies that can destroy the kidneys of lupus patients. The researchers don't yet know what causes female skin cells to have more VGLL3 to begin with. It may be that over evolutionary time females have developed stronger immune systems to fight off infections—but at the cost of increased risk for autoimmune disease if the body mistakes itself for an invader. The researchers also don't know what triggers might set off extra VGLL3 activity. But they do know that in men with lupus, the same VGLL3 pathway seen in women with lupus is activated. Many of the current therapies for lupus, like steroids, come with unwanted side effects, from increased infection risk to cancer. Finding the key factors downstream of VGLL3 may identify targets for new, and potentially safer, therapies that could benefit patients of both sexes. Lupus, which affects 1.5 million Americans, can cause debilitating symptoms, and current broad-based treatment with steroids can make patients far more vulnerable to infections and cancer. Patients' role in future research Their colleague and senior coauthor Michelle Kahlenberg, M.D., of the U-M Division of Rheumatology, is now recruiting patients with lupus for a study sponsored by U-M's A. Alfred Taubman Medical Research Institute that could provide answers to these questions and more. Billi, a resident in dermatology, notes that when she speaks with patients who come to Michigan Medicine's dermatology clinics for treatment of the skin problems lupus can cause, she has to acknowledge the limits of current treatment. Even so, she says, patients are eager to take part in studies by contributing skin and DNA samples that could lead to new discoveries about their condition. "Many patients are frustrated that they've had to try multiple therapies, and still nothing is working well," she says. "To be able to tell them that we're working on a mouse that has the same disease as them, and that we need their help, brings out their motivation and interest in research. They know that it's a long game, and they're in for it." More information: Allison C. Billi et al, The female-biased factor VGLL3 drives cutaneous and systemic autoimmunity, JCI Insight (2019). DOI: 10.1172/jci.insight.127291 Provided by University of Michigan The female-biased factor VGLL3 drives cutaneous and systemic autoimmunity Allison C. Billi,1 Mehrnaz Gharaee-Kermani,2 Joseph Fullmer,1 Lam C. Tsoi,1,3,4,5 Brett D. Hill,6 Dennis Gruszka,7 Jessica Ludwig,7 Xianying Xing,1 Shannon Estadt,2,8 Sonya J. Wolf,2,8 Syed Monem Rizvi,6 Celine C. Berthier,9 Jeffrey B. Hodgin,10 Maria A. Beamer,1Mrinal K. Sarkar,1 Yun Liang,1 Ranjitha Uppala,1,8 Shuai Shao,1,11 Chang Zeng,1 Paul W. Harms,1,10 Monique E. Verhaegen,1 John J. Voorhees,1 Fei Wen,6 Nicole L. Ward,7 Andrzej A. Dlugosz,1,12 J. Michelle Kahlenberg,2,3 and Johann E. Gudjonsson1,3 First published April 18, 2019 - More info Abstract Autoimmune disease is 4 times more common in women than men. This bias is largely unexplained. Female skin is “autoimmunity prone,” showing upregulation of many proinflammatory genes, even in healthy women. We previously identified VGLL3 as a putative transcription cofactor enriched in female skin. Here, we demonstrate that skin-directed overexpression of murine VGLL3 causes a severe lupus-like rash and systemic autoimmune disease that involves B cell expansion, autoantibody production, immune complex deposition, and end-organ damage. Excess epidermal VGLL3 drives a proinflammatory gene expression program that overlaps with both female skin and cutaneous lupus. This includes increased B cell–activating factor (BAFF), the only current biologic target in systemic lupus erythematosus (SLE); IFN-κ, a key inflammatory mediator in cutaneous lupus; and CXCL13, a biomarker of early-onset SLE and renal involvement. Our results demonstrate that skin-targeted overexpression of the female-biased factor VGLL3 is sufficient to drive cutaneous and systemic autoimmune disease that is strikingly similar to SLE. This work strongly implicates VGLL3 as a pivotal orchestrator of sex-biased autoimmunity. Introduction Autoimmune disease is common, can be deadly, and affects women disproportionately. The prevalence of systemic lupus erythematosus (SLE) is 9 times higher among women than men, and many other autoimmune diseases show similar profound female skewing (1). However, the cause of this female bias remains elusive. Previous work has focused primarily on the influence of sex hormones, yet female bias in autoimmunity is observed even prior to puberty and following menopause (2), indicating alternative mechanisms at play. As most autoimmune diseases remain incurable, investigating the causes of autoimmunity is critical, and the drivers of female-biased autoimmunity are logical targets. We previously identified the conserved putative transcription cofactor vestigial like family member 3 (VGLL3) as a candidate female-biased immune regulator (3). VGLL3 is more abundant in the epidermis of women than men and shows female-specific nuclear localization, suggesting a role in sex-biased transcriptional regulation. In cell culture, VGLL3 knockdown decreased expression of select female-biased immune transcripts, including B cell–activating factor (BAFF, also known as TNFSF13B), the target of the only currently approved biologic therapy for SLE. Intriguingly, men who have SLE showed loss of sex-specific regulation of VGLL3, demonstrating upregulation and nuclear localization of VGLL3 in inflamed skin (3). This suggested that VGLL3 may govern a key upstream regulatory program promoting autoimmunity, but this hypothesis had yet to be explored. Results Human and murine VGLL3 share 87% sequence homology, including an identical putative transcription cofactor domain (Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.127291DS1). Similar to human women, female mice showed 2.8-fold higher Vgll3 expression than male mice in the skin (P = 0.053) (Supplemental Figure 1B), suggesting conserved sex-biased dynamics. To test for a causative role for cutaneous VGLL3 in promoting autoimmune disease, we generated transgenic mice overexpressing Vgll3 under the control of the bovine keratin 5 (K5) promoter (Figure 1A), which drives gene expression primarily in the epidermis but also in some other stratified squamous epithelia (4). Levels of Vgll3, as shown by quantitative reverse transcription PCR (qRT-PCR), in transgenic skin varied both across and within founder lines, with transgenic mice generally showing 5- to 50-fold expression relative to WT mice, and no consistent variation by sex (data not shown). Compared with WT mice, these K5-Vgll3–transgenic mice showed increased epidermal VGLL3 staining, with conspicuous nuclear localization (Figure 1B) analogous to human VGLL3 distribution in affected skin of patients with SLE (3). Transgenic pups were indistinguishable from WT pups at birth. Within 6–12 weeks of life, they began developing progressive skin thickening and scaling prominently involving the face and ears, common sites for human discoid lupus erythematosus (DLE) lesions (Figure 1C and Supplemental Figure 1C). No consistent skin phenotypic variation by sex was noted among transgenic littermates (data not shown). Figure 1 Overexpression of VGLL3 in the epidermis produces a skin phenotype with gross and histologic features of cutaneous lupus. (A) Transgenic (TG) cassette. The bovine keratin 5 (K5) promoter drives polycistronic expression of the full-length mouse VGLL3 and mCherry red fluorescent protein linked by an internal ribosome entry site (IRES). β-glob, rabbit β-globin intronic sequence; pA, polyadenylation signal. (B) Detection of VGLL3 protein (red) by immunofluorescence (IF) in skin of female WT and TG mice. Scale bar: 20 μm. Images are representative of sections from 3 WT and 3 TG animals examined. (C) Left: WT mouse compared with age-matched TG mouse with lupus-like skin rash. Right: Bright-field and fluorescence images of WT and lesional TG tail skin. Scale bar: 2 mm. (D) H&E staining of WT and TG volar skin sections, demonstrating epidermal hyperplasia, basal cell vacuolization, apoptotic keratinocytes (arrowhead, magnified on inset), and dermal inflammatory infiltrate. Scale bar: 20 μm. (E) TUNEL (red) staining of WT and TG tail skin sections. Scale bar: 50 μm. (F) Periodic acid–Schiff staining of WT and TG dorsal skin sections. Arrowheads indicate subtle basement membrane thickening. Scale bar: 20 μm. (G) Detection of IgG and complement factor C3 by IF in WT and TG nonlesional neck skin. Scale bar: 50 μm. In E–G, images are representative of sections from 3 WT and 3 TG animals examined. Histologically, early skin lesions showed epidermal thickening and focal interface dermatitis, an inflammatory reaction pattern seen in cutaneous lupus (Figure 1D and Supplemental Figure 1, D and E). TUNEL staining confirmed increased keratinocyte apoptosis (Figure 1E), subtle basement membrane thickening was evident on periodic acid–Schiff (PAS) staining (Figure 1F), and direct immunofluorescence (IF) revealed IgG and C3 deposition at the dermal-epidermal junction (Figure 1G all are characteristic features of cutaneous lupus in humans. To examine the effects of VGLL3 that were driving this lupus-like cutaneous phenotype, we evaluated WT mice and robustly expressing transgenic mice by qRT-PCR for transcript levels of a panel of proinflammatory and lupus-related factors. Many of these transcripts showed significant elevation in transgenic mice (Figure 2A and Supplemental Figure 2A), including Tnfsf13b (encoding BAFF); IFN-κ (Ifnk), the predominant type I IFN in cutaneous lupus (5); and Cxcl13, a biomarker of early-onset SLE, heightened disease activity, and renal involvement (6). IF studies of key VGLL3-regulated factors (Figure 2B) corroborated our qRT-PCR findings. Thus, epidermal VGLL3 overexpression drives immunological gene dysregulation, similar to what we previously observed in the skin of healthy women (3). Figure 2 Overexpression of VGLL3 in the epidermis recapitulates the autoimmunity-prone genetic signature of human female skin. (A) Detection of Vgll3 and enriched immune transcripts versus example nonenriched transcript Ifnb (IFN-β) by quantitative reverse transcription PCR (qRT-PCR) in skin of WT (n = 3) and TG mice (n = 2) with high Vgll3 expression (more than tenfold WT average). Horizontal bars represent the mean. *P < 0.05 by 2-tailed Student’s t test. (B) Detection of VGLL3 targets CXCL13 (top, red) and IFN-κ (bottom, green) by IF in WT and TG skin. Blue, DNA. Scale bar: 20 μm. Images are representative of sections from 3 WT and 3 TG animals examined. (C) Literature-based network analysis of genes differentially expressed in nonlesional, normal-appearing TG skin relative to WT skin by RNA-seq. (D) Expression in nonlesional TG versus WT skin of genes dysregulated (dysreg) in discoid lupus erythematosus (DLE; P = 4.0 × 10–10) or subacute cutaneous lupus erythematosus (SCLE; P = 2.3 × 10–8) versus all genes. x axis, log2 fold change (FC) in TG versus WT. See Methods for additional statistical details. For a broader examination of VGLL3 effects, we performed RNA-seq of normal-appearing dorsal skin from WT and transgenic mice to identify differentially expressed genes (transgenic DEGs) (Supplemental Table 1). Results largely affirmed our qRT-PCR data (Supplemental Figure 2B) and revealed that the panel of transcripts examined in Supplemental Figure 2B represent only a fraction of the VGLL3-regulated transcripts identified in transgenic mice. Of the 120 gene ontology terms significantly enriched (FDR ≤ 10%) among transgenic DEGs, nearly half were related to immunological processes (Supplemental Figure 2C). Importantly, these included multiple key pathways involved in SLE pathogenesis, such as IFN responses. Literature-based network analysis of transgenic DEGs revealed additional nodes of autoimmune pathogenesis (Figure 2C). To further explore our hypothesis that female-biased VGLL3 expression in human skin drives gene changes that may predispose women to autoimmunity, we compared transgenic DEGs with the set of genes upregulated in healthy human female skin relative to male skin (3) and found a significant overlap (P = 0.032). To evaluate for a direct effect of VGLL3 overexpression in keratinocytes of our mouse model, we cultured primary keratinocytes from WT and transgenic mouse tails and performed RNA-seq. Genes differentially expressed in transgenic keratinocytes also demonstrated enrichment for immunological gene ontology terms, such as immune response (P = 6.8 × 10–9) and cytokine activity (P = 1.2 × 10–8), and showed even more significant overlap with female-biased genes (P = 4.0 × 10–7). Thus, epidermal overexpression of VGLL3 is a prominent driver of immunological dysregulation and sex-biased gene expression in keratinocytes. We then compared our mouse skin RNA-seq results to transcriptomic data from skin of cutaneous lupus patients (7). Genes dysregulated in lesional skin of patients with DLE or subacute cutaneous lupus erythematosus (SCLE) were overrepresented among transgenic DEGs (DLE, P = 1.1 × 10–13; SCLE, P = 5.0 × 10–9) and showed widespread upregulation in transgenic mice (Figure 2D), revealing a shared pattern of gene dysregulation in skin of K5-Vgll3–transgenic mice and lupus patients. Together, these in vivo data demonstrate that VGLL3 overexpression in the epidermis is sufficient to drive a female-biased gene expression signature with dysregulation of pathways implicated in human autoimmune disease. Immunohistochemistry of K5-Vgll3–transgenic skin revealed a mixed inflammatory infiltrate (Figure 3). T and B cells were increased, as were DCs, which promote lymphocyte expansion, autoantibody production by B cells, and tissue damage in SLE (8). Flow cytometry of cells isolated from skin corroborated these findings, demonstrating increased plasmacytoid DCs, as well as IgM+ and IgG+ cells, consistent with B cell expansion (Supplemental Figure 3). Neutrophils were also elevated, consistent with the neutrophilic inflammation noted on some lesional sections (Supplemental Figure 1F) and observed in a significant subset of cutaneous lupus manifestations (9). These results illustrate that epidermal overexpression of VGLL3 results in a cutaneous phenotype with gross, histologic, and inflammatory features of cutaneous lupus. Figure 3 Overexpression of VGLL3 in the epidermis causes skin inflammation with features of cutaneous lupus. Detection of the indicated cell markers by immunohistochemistry in WT and TG ear sections. Ki67, cell proliferation marker; MECA, mouse endothelial cell antigen. Scale bar: 50 μm. Images are representative of sections from 4 WT and 4 TG animals examined. To further interrogate the inflammatory response in the K5-Vgll3–transgenic mouse, we analyzed skin-draining lymph nodes, spleen, and ear tissue from WT and transgenic mice with mass cytometry (CyTOF) using a 37-marker panel (Supplemental Figure 4 and Supplemental Table 2). Transgenic mice showed significant lymphadenopathy and splenomegaly (Figure 4A), features common in SLE and some lupus mouse models (10, 11). CyTOF data visualized using the dimensional reduction tool viSNE (12) showed expansion of B cell populations that were most prominent in skin-draining lymph nodes (Figure 4B and Supplemental Figure 4). Key populations emerging from CyTOF are highlighted in a SPADE tree (13) (Figure 4, C–E, and Supplemental Figure 5). B cells were significantly overrepresented in transgenic lymph nodes (q = 6.2 × 10–4; blue circles in Figure 4D) and spleen (q = 0.024). Together, these findings suggest that skin-directed VGLL3 overexpression drives a systemic inflammatory response with B cell expansion. Figure 4 Skin-directed VGLL3 overexpression drives a systemic inflammatory response with B cell expansion. (A) Left: Representative images of WT and TG skin-draining lymph nodes (LN) and spleens. Right: LN and spleen weights represented as a percentage of total body weight. Error bars represent mean ± SEM. **P < 0.01 by 2‑tailed Student’s t test (LN, n = 6 WT and 3 TG; spleen, n = 8 WT and 8 TG). (B) CyTOF data derived from a single experiment consisting of 3 age- and sex-matched WT and TG mice visualized by viSNE. Left: viSNE maps depicting expression of select markers. Each dot is a cell. Color reflects the level of expression of marker from low (blue) to high (red). Right: Contour plot of viSNE maps colored by density of cells isolated from the specified tissues in WT and TG mice. Here, color reflects cell density from low (blue) to high (red). Data shown correspond to 1 WT and 1 TG mouse that are representative of the experiment. LN and spleen data represent approximately 20,000 CD45+ live singlets per sample. Ear skin samples represent all recorded CD45+ live singlets (WT, 262 and TG, 264) for each sample. The complete viSNE analysis for all markers and samples for the experiment can be found in Supplemental Figure 4. Data are representative of 2 independent CyTOF experiments. (C) SPADE tree of LN samples depicted in B. Node size represents the number of cells in the population derived from the experiment represented in B and Supplemental Figure 4B. Mϕ, macrophage; Neut, neutrophil; Tγδ, γ δ T cell. (D) Percentage dot plot showing the proportion of each cell type in aggregated WT and TG lymph node samples for the CyTOF experiment. Colors correspond to the populations indicated in C and E. (E) Heatmap showing marker expression of the SPADE populations specified in Cacross aggregated LN, spleen, and skin samples included in the CyTOF experiment. Q val, q values for differential detection in WT versus TG LN. †q = 6.2 × 10–4, significantly upregulated in TG LN. Peripheral blood mononuclear cells (PBMCs) of patients with SLE show altered gene expression, with prominent dysregulation of genes in IFN and cytokine signaling pathways that likely contributes to systemic inflammation (14). Evaluating gene expression in blood of WT versus K5-Vgll3–transgenic mice, we observed a significantly higher effect size for genes whose human orthologs are dysregulated in blood of SLE patients (P = 1.6 × 10–22) (Figure 5A and Supplemental Table 3), indicating a shared pattern of gene dysregulation in circulating immune cells of K5-Vgll3–transgenic mice and patients with SLE. Figure 5 Mice with skin-directed VGLL3 overexpression develop manifestations of systemic autoimmune disease. (A) Differential expression in WT (n = 4) and TG (n = 4) mouse blood of genes dysregulated in SLE peripheral blood mononuclear cells (aqua) versus all genes (peach). (B) Detection at 1:50 dilution of circulating antinuclear antibodies (Ig) by indirect IF in HEp-2 cells in WT, TG, and positive control (+ control, aged NZM2328) serum. In total, 7 TG and 3 WT animals were evaluated; all TG mouse sera showed positive autoantibody staining at a dilution of 1:25 or higher, whereas all WT mouse sera were negative. (C) Detection of circulating anti–double-stranded DNA antibodies (α-dsDNA) by ELISA. Error bars represent mean ± SEM. ***P = 0.0005 by 2-tailed Student’s t test. n = 6 WT and 6 TG. (D) Detection of IgG (red) and complement factor C3 (green) by IF in WT and TG glomeruli. Blue, DNA. Scale bar: 20 μm. Images are representative of glomeruli visualized on sections from 6 WT and 6 TG animals examined. 0 of 6 WT and 6 of 6 transgenic mice scored positive for renal immune complex deposition. Finally, we investigated whether the B cell expansion of the K5-Vgll3 mouse was associated with autoantibody production. Autoantibodies are integral to pathogenesis of SLE and associated with increased risk of progression from cutaneous to systemic lupus (15). Commonly used SLE classification systems include their detection as a diagnostic criterion. By indirect IF of HEp-2 cells, antinuclear antibodies were detected in sera of transgenic mice with developed phenotypes (Figure 5B). A homogeneous pattern of nuclear staining was observed, which is commonly found in SLE patients. Anti–double-stranded DNA (anti-dsDNA) antibodies, which are a specific marker for SLE and fluctuate with disease activity (16), were abundant in sera of transgenic mice (Figure 5C). As anti-dsDNA antibodies are pathogenic to the kidney (17), we examined kidneys of transgenic mice and found IgG and C3 deposition in glomeruli (Figure 5D). Most transgenic mice were harvested by 4–5 months of age due to the severity of the skin phenotype, limiting time for evolution of fulminant nephritis; nonetheless, examination of the transgenic kidneys revealed a subtle trend toward increased inflammation relative to WT kidneys (P = 0.20; Supplemental Figure 6, A and B). As expected based on the mild histology, significant proteinuria was not detected (P = 0.19; Supplemental Figure 6C). Thus, skin-directed VGLL3 overexpression stimulates development of lupus-specific anti-dsDNA autoantibodies that results in immune complex deposition in the kidney, the purported initiating event in development of lupus nephritis (17). Discussion Female sex alone carries a greater risk for developing SLE than any genetic or environmental factor identified to date (18). Previously, we determined that women express an autoimmunity-prone genetic signature in their skin. We hypothesized that this program was driven by the putative transcription cofactor VGLL3, which is upregulated and nuclear localized in the skin of healthy women and SLE patients of both sexes (3). Here, we establish that skin-directed overexpression of murine VGLL3 is sufficient to drive an autoimmunity-prone transcriptional signature similar to that observed in female skin, causing inflammation and activation of type I IFN signaling that mimics cutaneous lupus. Intriguingly, although VGLL3 overexpression in our model was restricted by the bovine K5 promoter to keratinocytes and some other squamous epithelia (4), K5-Vgll3–transgenic mice developed systemic inflammation, with B cell activation and autoantibody production that culminated in renal immune complex deposition analogous to that seen in lupus nephritis. Thus, overexpression of a single female-biased gene is sufficient to trigger cutaneous autoimmune disease accompanied by a systemic autoimmune response with striking similarities to SLE. This includes development of anti-dsDNA antibodies, whose presence constitutes an independent risk factor for lupus nephritis (19), and detection of immune complexes in the skin and kidneys. A growing body of evidence suggests that, in autoimmune disease pathogenesis, the initial break in self-tolerance — the inciting “first hit” — occurs at epithelial surfaces. In rheumatoid arthritis, localized mucosal tissue damage may lead to posttranslational modification of peptides, resulting in formation of anti-citrullinated peptide antibodies (20), autoantibodies that often precede the onset of disease and in susceptible individuals may incite it (21). In antinuclear antibody–associated diseases, such as SLE and other connective tissue diseases, the first hit may occur in the skin. In patients with SLE, clearance of apoptotic cells is impaired (22). Insults, such as ultraviolet light, which induces immunological activation and apoptosis of keratinocytes, cause release of endogenous nuclear antigens. Presence of these autoantigens results in elaboration of cytokines and immune cell recruitment, and cytotoxic inflammation perpetuates their release, with resulting accumulation and possible entry into circulation as proinflammatory microparticles. Inflammation in the skin may therefore prime or exacerbate antinuclear antigen-focused autoimmunity. There are sparse data suggesting that treatment of cutaneous lupus may prevent progression to SLE (23). The results herein demonstrate that cutaneous disease may be sufficient to trigger a break in self-tolerance with evolution of systemic autoimmune disease. These findings are complemented by reports in mice describing evolution of SLE-like disease with development of anti-dsDNA antibodies and immune complex nephritis in response to epidermal IFN-γ overexpression (24, 25). Further study of the IFN-γ epidermal overexpression and K5-Vgll3 lupus mouse models may reveal that treatment of cutaneous lupus is sufficient to ameliorate or even prevent progression to systemic disease. If so, this could prompt a paradigm shift in our understanding of the pathogenesis of SLE. Our results do not distinguish a principal pathway promoting autoimmunity in the K5-Vgll3–transgenic mouse. As the VGLL3-regulated factor IFN-κ is the predominant type I IFN in cutaneous lupus (5), this presents a parsimonious explanation; however, VGLL3 alters the expression of genes that act in multiple independent inflammatory pathways, and the lupus-like phenotype of the K5-Vgll3–transgenic mouse may represent the cumulative manifestation of widespread immunological VGLL3-induced dysregulation. This is reflected in the diverse inflammatory pathways activated in the skin of transgenic mice (Figure 2C), many of which have key roles in autoimmunity: MHC class I, antigen binding, cytokine activation, humoral immune responses, cellular response to IFN, and regulation of T cell–mediated cytotoxicity (26). The significant overlap of VGLL3 targets with genes dysregulated in female skin suggests that the transgenic mouse phenotype represents a fully developed autoimmune disease of which female-biased autoimmunity is the forme fruste. Additional studies of the component inflammatory pathways in the K5-Vgll3 lupus model are required to dissect the pathogenesis further. Finally, one of the principal challenges of treating lupus is disease heterogeneity. Broad immunosuppressants address disease in a majority of patients but carry serious risks of infection and malignancy that contribute substantially to morbidity and mortality. In contrast, narrower agents, such as belimumab, the biologic therapy that targets BAFF, are effective only in a subset of patients where presumably the disease is driven more heavily by the targeted autoimmune pathway. As VGLL3 appears to be not only constitutively active in women but also turned on in men with SLE (3), targeting VGLL3 may prove beneficial in patients of both sexes. Additionally, the low levels of VGLL3 in healthy men suggest that it may be amenable to depletion without adverse effects. Given stimulation of diverse inflammatory pathways — including those involving type I IFN and BAFF — observed in the K5-Vgll3–transgenic mouse, VGLL3 depletion may successfully treat more subgroups within this heterogeneous patient population. In conclusion, our data support the assertion that enrichment of VGLL3 in female skin primes women for autoimmunity. This positions VGLL3 as a master orchestrator of sex bias in autoimmune disease, providing potentially novel avenues for future research and therapeutic development. Methods Mice, primary keratinocyte isolation, and culture The K5-Vgll3-IRES-tdTomato–transgenic (K5-Vgll3–transgenic) cassette was generated as follows. The Vgll3-IRES-mCherry insert was synthesized de novo by GenScript and subcloned into the pBK5 vector, in which the bovine K5 promoter drives expression primarily in epidermis but also in some other stratified squamous epithelia (4). Of note, expression of this specific promoter has been reported to be absent in thymus and spleen (4, 27), indicating no significant expression in the immune cells therein. The Vgll3 coding sequence was taken from NCBI reference sequence NM_028572.1. The mCherry coding sequence was taken from GenBank (accession AY678264, nt 1–711) (28). Following sequence verification, the transgenic cassette was isolated by restriction enzyme digest, purified, and injected into C57BL/6 mouse oocytes at the University of Michigan Transgenic Core. Founders were identified by PCR using the following PCR primers: forward, 5′-ATCGTGCCAAGTGTGGGCTTCGATACA-3′ (located in the Vgll3 coding sequence), reverse, 5′-CACATTGCCAAAAGACGGCAATATGG-3′ (located in the IRES) and were crossed with C57BL/6J breeders (The Jackson Laboratory) to establish transgenic lines. Transgene-positive offspring were screened for cutaneous phenotypes. Nine independent founder lines were generated that demonstrated spontaneous development of cutaneous phenotypes; progeny of 6 additional independent founders either failed to develop phenotypes or were harvested for experimental purposes prior to development of phenotypes. Phenotypes observed were overall fairly uniform and typically involved alopecia and ulceration that progressed with age, often necessitating euthanasia; transgenic animals from 6 independent founder lines are pictured at time of euthanasia in Supplemental Figure 1C. Transgenic mice were observed scratching and excessively barbering, and some transgenic animals were noted to be excessively barbering nontransgenic littermates. K5-Vgll3–transgenic mouse skin harvested from multiple sites was evaluated by fluorescent microscopy of transgenic mCherry to verify epidermal transgene expression (tail, Figure 1C). For RNA-seq analysis of nonlesional (posterior dorsal) skin and blood, 4 transgenic animals representing 3 independent founder lines were included (see below for associated methods). For RNA-seq analysis of transgenic and WT primary keratinocytes, all animals were from a single litter representing 1 founder line to enable simultaneous isolation, culture, and harvest. RNA‑seq analysis of transgenic nonlesional skin and primary keratinocytes confirmed significant Vgll3 mRNA overexpression relative to WT skin and primary keratinocytes, respectively. qRT-PCR also confirmed significant Vgll3 mRNA overexpression, although the variation and upper limit of Vgll3overexpression was greater (generally 5- to 50-fold), possibly due to increase in epidermal thickness. Consistent with prior reports of absent expression in lymphoreticular organs (4, 27), RNA-seq analysis of K5-Vgll3–transgenic blood showed no Vgll3 upregulation that would be suggestive of leakage of transgene expression in immune cells (data not shown). Given the overall similarity in phenotype and gene expression changes noted by RNA-seq analysis of nonlesional skin of 3 different founder lines, multiple founder lines were included throughout the manuscript, including in qRT-PCR analyses. Primary keratinocytes were isolated as previously described from tails of 3 WT and 3 transgenic 23-day-old weanlings from a single litter (29) with the following change: skin was incubated for 1.5 hours at 37°C rather than overnight at 4°C. Cells were expanded in culture for 3 days and harvested for RNA using Buffer RLT (Qiagen) per the manufacturer’s protocol. Tissue collection For harvest of tissues for generating RNA and frozen or paraffin sectioning, transgenic mice and WT controls were euthanized at 8 weeks of age or older. Whole blood was obtained by cardiac stick and RNA was isolated using the Mouse RiboPure-Blood RNA Isolation Kit (Thermo Fisher Scientific) or TriPure Isolation Reagent (MilliporeSigma) per the manufacturer’s protocols. Nonlesional posterior dorsal skin was removed by punch biopsy. Ears were removed in entirety. Skin from the indicated sites was otherwise harvested and processed as previously described (30). For harvest of tissues for mass cytometry (CyTOF) and flow cytometry, sex-matched transgenic and WT littermates were sacrificed at 8 weeks of age or older. Ears, spleen, and skin-draining (cervical and inguinal) lymph nodes were removed in entirety. The ear and dorsal skin samples were minced with a sterile razor and transferred to 18 ml RPMI (Gibco) containing 10% fetal calf serum (Atlanta Biologicals) and 1% Penicillin-Streptomycin (Gibco) (hereafter, RPMI complete media). To each sample, 2 ml of a skin digestion solution consisting of Hanks’ Balanced Salt Solution (Gibco) with 1 mg/ml DNAse I (MilliporeSigma), 1 mg/ml Hyaluronidase type V (MilliporeSigma), and 5 mg/ml Collagenase type IV (MilliporeSigma) was added. Samples were rotated for 2 hours at 37°C to digest. Following digestion, samples were filtered through a 40-μm cell strainer, washed with fresh RPMI complete media, and incubated on ice. Spleens and lymph nodes (4 lymph nodes combined for each animal) were weighed before being ground through a 70-μm cell strainer and suspended in RPMI complete media. For spleen samples, media were removed, and cells were incubated in RBC lysis buffer (Invitrogen) for 2 minutes. Lysis buffer was removed, and spleen samples were resuspended in fresh RPMI complete media. qRT-PCR RNA was converted to cDNA using a High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems). qRT-PCR was performed in technical duplicates for the biological replicate numbers indicated in the figure legends using TaqMan Universal PCR Master Mix (Applied Biosystems). TaqMan primer sets and probes were purchased from Applied Biosystems by Life Technologies and are listed in Supplemental Table 4. All values were normalized to the housekeeping gene 18S. All qRT-PCR data are presented with y axis log2-scaled and autolog numbered. RNA-seq and gene expression analyses Stranded mRNA libraries were prepared from nonlesional (posterior dorsal) skin, cultured keratinocytes, and whole blood from age- and sex-matched WT and transgenic mice (2 male and 2 female each) using the TruSeq RNA library prep kit (Illumina) and sequenced on the Illumina HiSeq 4000 sequencer at the University of Michigan DNA Sequencing Core. Data were quality controlled and analyzed using the pipeline described previously for RNA-seq analysis, including adapter trimming (31), read mapping, and quantification of gene expression (32). We used the GENCODE release m18 (GRCm38) from mouse. We filtered for average abundance of ≥1 read per gene across all samples. DESeq was used for expression normalization. Generalized linear regression was used for differential expression analysis using negative binomial distribution to model the count data (33). FDR was used to control the multiple testing. DEGs were defined as having FDR ≤ 10% and with |log2fold change| ≥ 1 (Supplemental Tables 1 and 3). For Supplemental Figure 2B, data are presented with y axis after log2 scaling and autologing of numbers for ease of comparison to qPCR data. Software‑extracted literature‑based network analysis was performed using Genomatix Pathway System Software. For identification of genes dysregulated in DLE and SCLE, microarray data from 26 DLE and 23 SCLE lesional skin biopsies and 7 normal skin biopsies (GEO GSE81071) were utilized to identify genes that are differentially expressed in DLE and SCLE skin (termed dysregulated in text to avoid confusion with transgenic DEGs) at the FDR ≤ 10% and with |log2fold change| ≥ 1 threshold. For identification of genes dysregulated in blood of SLE patients, RNA-seq data from whole blood of 99 SLE and 18 healthy control patients were analyzed as above and used to identify genes that were differentially expressed in blood of SLE patients (termed dysregulated in text to avoid confusion with transgenic DEGs). We performed analysis only for genes expressed in at least 20% of the normal samples. For investigation of target overlap with DLE and SCLE skin and SLE blood, only genes with identical names in mouse and human were included. Histology and immunostaining Hematoxylin (Surgipath, 3801540) and eosin (Surgipath, 3801600) staining was performed per standard protocols. Epidermal thickness was quantified on the H&E-stained sections using Adobe Photoshop. For each animal, approximately 100 measurements were taken from 8 different fields of view for each section analyzed. Epidermal thickness was measured from the stratum basale to stratum granulosum, excluding the stratum corneum and hair follicles for each animal. IF to detect VGLL3 and target proteins was performed as follows. For CXCL13 detection, formalin-fixed, paraffin-embedded tissue sections were deparaffinized, rehydrated, and heated at 95°C for 20 minutes in pH 6 antigen retrieval buffer. Slides were blocked and incubated with goat anti-mouse CXCL13 antibody (R&D System, AF470-SP) overnight at 4°C. For VGLL3 and IFN-κ detection, cryosections were subjected to acetone fixation. Slides were blocked and incubated with rabbit anti-mouse VGLL3 antibody (St. John’s Laboratory, STJ115228) or sheep anti-mouse IFN-κ antibody (R&D System, AF5206), respectively. All slides were then incubated with biotinylated secondary antibodies (Vector Laboratories) as appropriate, incubated with fluorochrome-conjugated streptavidin (Streptavidin, Alexa Fluor 488 conjugate [Thermo Fisher Scientific, S32354] or Streptavidin, Alexa Fluor 594 conjugate [Life Technologies, S32356]) as appropriate and mounted. Images were acquired using Zeiss Axioskop 2 microscope and analyzed by SPOT software V.5.1. PAS staining of paraffin sections was performed using the Periodic acid–Schiff (PAS) staining system (MilliporeSigma) per the manufacturer’s instructions (see procedure 395). TUNEL staining of paraffin sections was performed using the In Situ Cell Death Detection Kit, TMR red (Roche). Slides were mounted with ProLong Gold Antifade Mountant with DAPI (Thermo Fisher Scientific). IF of immune complex components was performed as follows. Slides with tissue cryosections were dried for 1 hour at 37°C, incubated in 4% paraformaldehyde for 20 minutes, and blocked. C3-FITC (ICL, GC3-90F-Z) and IgG-Texas Red-X (Thermo Fisher Scientific, T-862) goat anti-mouse antibodies were then added, and slides were incubated at 4°C for 1 hour. Hoechst stain (BD Biosciences, 561906) was added. Slides were dried and mounted using ProLong Gold Antifade Mountant (Thermo Fisher Scientific). Images were captured as above. For renal immune complex deposition, 10 glomeruli were assessed for each mouse, and mice were considered positive if more than one glomerulus demonstrated deposition of C3 and IgG. Immunohistochemistry of frozen sections was performed as previously described (30) using antibodies specific for CD4 (BD Biosciences, 550280), CD8a (BD Biosciences, 550281), CD11c (BD Biosciences, 550283), CD19 (BD Biosciences, 550284), F4/80 (eBioscience, 14-4801-82), Ki-67 (DAKO, M7249), and MECA-32 (Developmental Studies Hybridoma Bank, MECA-32-s). Antibodies were detected using either rabbit anti-rat IgG biotinylated (Vector Laboratories), goat anti-rabbit IgG biotinylated (Vector Laboratories), or rabbit anti-hamster IgG biotinylated (Southern Biotech) secondary antibodies, amplified with Avidin/Biotinylated Enzyme Complex (Vector Laboratories), and visualized using the enzyme substrate diaminobenzidine (Vector Laboratories). Slides were counterstained with hematoxylin. Images were captured using a Leica DM L82 microscope with an attached QImaging MicroPublisher 3.3 Mega Pixel camera and Q-capture Pro software. For detection of antinuclear antibodies, serum was taken undiluted, diluted 1:25, or diluted 1:50 and used for indirect IF on Kallestad HEp-2 Slides (Bio-Rad) with FITC goat anti-mouse Ig antibody (BD Biosciences) as the detection reagent. Imaging was performed as for IF above. Mass cytometry (CyTOF) Stimulation. Tissue was harvested and cell suspensions were prepared as above. All samples were then stimulated for 3 hours at 37°C in RPMI complete media with 5 ng/ml phorbol 12-myristate 13-acetate (MilliporeSigma), 1 μg/ml ionomycin (MilliporeSigma), 3 μg/ml Golgistop with Brefeldin A (BioLegend), and 0.67 μl/ml BD GolgiStop Protein Transport Inhibitor with Monensin (Thermo Fisher Scientific), and then incubated on ice until staining. Antibody conjugation with lanthanide metal. The lanthanide metals (Fluidigm) were conjugated to the antibodies using the Maxpar Antibody Labeling Kit (Fluidigm) per the manufacturer’s instructions. Briefly, 2.5 mM Maxpar polymer was preloaded with lanthanide metal at 37°C for 1 hour and buffer exchanged to conjugation buffer using a 3 K Nanosep Centrifugal Device (Pall Life Sciences). The antibody was partially reduced using TCEP at 37°C for 30 minutes and buffer exchanged to conjugation buffer using an Amicon Ultra 0.5-ml 50-kDa Centrifugal Filter Concentrator (MilliporeSigma). The lanthanide-loaded polymer was conjugated to partially reduced antibody following overnight incubation at room temperature. The unbound metal was removed from the metal-tagged antibody by washing with wash buffer in a 50-kDa concentrator. The final concentration of metal-tagged antibody was determined by measuring the absorbance at 280 nm against the wash buffer. See Supplemental Table 2 for the antibodies. Staining of cells with metal-tagged antibodies. Cell-ID Cisplatin-195Pt and Cell-ID Intercalator Iridium-191/193 (Fluidigm) were used to identify live cells. The cells were washed once with prewarmed serum-free media by pelleting at 300 g for 5 minutes at room temperature and stained with 1.25 μM live/dead stain (Cell-ID Cisplatin-195Pt diluted in serum-free media from 500 mM stock) at room temperature for 5 minutes. Free cisplatin was quenched by washing the cells with serum-containing media. CyPBS (1× PBS without heavy metal contaminants, prepared from 10 × PBS stock [Invitrogen] in deionized distilled Milli-Q water [MilliporeSigma]) was used to prepare CyFACS buffer (CyPBS containing 0.1% BSA, 2 mM EDTA and 0.05% sodium azide). The cells were then washed with CyFACS buffer and incubated with TruStain FcX (anti-mouse CD16/32, Biolegends) for 10 minutes at room temperature to block the Fc receptors. For cells surface marker staining, the metal-tagged antibody cocktail was made in CyFACS buffer and added to the cells in the presence of TruStain FcX (BioLegend) and incubated on ice for 60 minutes. Following cell surface marker staining, the cells were washed twice with CyFACS buffer and fixed with 1.6% paraformaldehyde in CyPBS for 20 minutes at room temperature. The cells were then washed and stored overnight at 4°C in CyFACS buffer. The following day, the cells were pelleted at 800 g for 5 minutes and permeabilized with eBioscience permeabilization buffer (Thermo Fisher Scientific) for 30 minutes at room temperature. The cells were then stained with intracellular staining metal-tagged antibody cocktail (made in eBioscience permeabilization buffer) at room temperature for 60 minutes. Following intracellular staining, the cells were washed once with permeabilization buffer and twice with CyFACS buffer and stained with 62.5 nM Cell-ID Intercalator Iridium-191/193 (diluted in 1.6% paraformaldehyde in PBS from 500 μM stock) at room temperature for 40 minutes or left at 4°C until ready for acquisition on CyTOF. CyTOF analysis of samples stained with metal-tagged antibodies. The samples were acquired using CyTOF Helios system (Fluidigm). The system was maintained and tuned according to the manufacturer’s instructions. In addition, internal vendor-set calibration was performed before acquiring samples. The fixed cells were washed twice with CyPBS and deionized distilled Milli-Q water and filtered through a 40-μM cell strainer. EQ Four Element Calibration Beads (Fluidigm) were added at the recommended concentration to the samples before acquisition on CyTOF. The samples were acquired on CyTOF at approximately 50–300 events/s. After acquisition, the instrument software applied a signal correction algorithm based on the calibration bead signal to correct for any temporal variation in detector sensitivity. CyTOF data analysis Total events were gated to remove noncellular events (negative for DNA intercalator), dead cells (uptake of cisplatin), and doublets (event length greater than 25). A viSNE was performed using combined lymph node (~20,000 events/sample), spleen (~20,000 events/sample), and ear (between 262 and 1234 events/sample) samples using Cytobank (34). All antibody channels were included in the viSNE analysis except for IL-17f, as it was suspected this marker was staining nonspecifically (37 included markers). The viSNE run was performed with 2000 iterations, a perplexity of 30, and a θ of 0.5. A spanning-tree progression analysis of density-normalized events (SPADE) clustering algorithm was performed on the same events used in the viSNE analysis using the Cytobank platform (13). As with the viSNE analysis, all antibody channels were included except for IL-17f, as we suspected this marker was staining nonspecifically (37 included markers). After some experimentation, it was found that 50 nodes with 100% event downsampling gave an adequate resolution of cellular subsets. SPADE nodes were manually bubbled based on defined phenotypic markers of major cellular populations (summarized in Figure 4E). Samples were compared based on the percentage of total cells from that sample contained within a bubble or individual node. Flow cytometry WT and transgenic ear tissue was harvested and cell suspensions were prepared as above. Cells were resuspended in blocking reagent of 1% BSA (Fisher Bioreagents) and 1% Horse Serum (Corning) in PBS. Antibody master mixes were prepared using antibodies specific for IgG-PerCP (BioLegend, 405334), IgM-APC (BioLegend, 406509), PDCA-1-APC (BioLegend, 127016), Cd11c-Pacific Blue (BioLegend, 117322), F4/80-Pacific Blue (BioLegend, 123124), and Ly-6G-PE (BioLegend, 127606) and added to each sample. Samples were incubated at room temperature in a dark environment for 45 minutes, washed with PBS, and resuspended in 4% paraformaldehyde in PBS (Affymetrix). Flow cytometry was performed with a BD LSR II (BD Biosciences). After manual gating to exclude dead cells and debris, data corresponding to all remaining cells were analyzed and visualized using FlowJo software (Tree Star). Detection of autoantibodies Anti–dsDNA antibodies were detected in serum using the Mouse anti-dsDNA IgG2a ELISA Kit (Alpha Diagnostic International) according to manufacturer’s instructions. Renal pathology scoring Kidneys from 4 WT and 4 transgenic animals were analyzed. A semiquantitative scoring system (0, no involvement; 0.5, minimal involvement of <10% per section; 1, mild involvement of 10%–30% of section; 2, moderate involvement of 31%–60% of section; and 3, severe involvement >60% of section) was used to assess 13 different parameters of activity and chronicity: mesangial hypercellularity, mesangial deposits, mesangial sclerosis, endocapillary cellular infiltrate, subepithelial deposits, subendothelial deposits, capillary thrombi, capillary sclerosis, cellular crescents, organized crescents, synechiae, tubular atrophy, and interstitial fibrosis. An activity and chronicity index was generated by compiling scores from groups of related parameters. For activity, mesangial hypercellularity, mesangial deposits, endocapillary cellular infiltrate, and cellular crescents were considered; for chronicity, interstitial fibrosis, tubular atrophy, organized crescents, and capillary sclerosis were considered. Analysis of urine albumin/creatinine ratio Urine from 8 WT and 5 transgenic animals was analyzed. Urine was collected from animals within 1 week of euthanasia. Technical duplicates were performed for every sample. To calculate albumin-to-creatinine ratios, urinary albumin was measured using the Albuwell M Kit (Exocell) and urinary creatinine using the QuantiChrom Creatinine Assay Kit (BioAssay Systems), both according to the manufacturer’s protocol. Data availability RNA-seq data have been deposited in GEO (GSE128453). CyTOF data have been made publically available in FlowReposity under repository ID FR‑FCM‑Z2Y6 (35). Statistics qRT-PCR data were tested for statistical significance using 2-tailed Student’s t test assuming homoscedasticity. Significance was defined as P ≤ 0.05. RNA-seq data were tested for normality, and statistical significance was calculated using a 2-tailed Student’s t test, Mann-Whitney U test, or Friedman’s test, as appropriate. For CyTOF data, statistical analysis on the bubbled SPADE populations was performed using Prism 8.0 (GraphPad). P values were computed using unpaired Student’s t tests assuming homoscedasticity. P values were considered discoveries if they fell below an FDR of 10% using the 2-stage step-up method of Benjamini, Krieger, and Yekutieli (36). Study approval Procedures involving the care and the use of mice in this study were reviewed and approved by the University of Michigan Institutional Animal Care and Use Committee (protocol PRO00006657). Author contributions ACB, MGK, MEV, AAD, JMK, and JEG conceived the study and designed experiments; LCT, BDH, and CCB developed computational methods and analyzed the data; MGK, JF, DG, JL, XX, SE, SJW, SMR, JBH, YL, PWH, and MEV conducted the experiments; and ACB, JMK, and JEG wrote the paper with input from all authors, including MAB, MKS, RU, SS, CZ, JJV, FW, and NLW. Supplemental material View Supplemental data View Supplemental Table 1 View Supplemental Table 3 Acknowledgments This work was supported by the A. Alfred Taubman Medical Research Institute’s Taubman Institute Innovation Projects program (to JEG, JMK, LCT, and FW), the Parfet Emerging Scholar Award (to JMK), and the Frances and Kenneth Eisenberg Emerging Scholar Award (to JEG); the University of Michigan Babcock Endowment Fund (to LCT and JEG); the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH (5T32AR007197-40 to ACB; K01AR072129 to LCT; R01-AR071384 to JMK; R01-AR069071 to JEG; and P50-AR070590, R01-AR062546, R01-AR063437, and R01-AR073196 to NLW); the Office of the Director of the NIH (S10-OD020053 to FW); a Rogel Cancer Center Support Grant (NIH P30-CA046592 to BDH, SMR, and FW); the National Science Foundation (1511720, 1645229, and 1653611 to FW); a Rheumatology Research Foundation Innovative Research Award (to JMK); the Dermatology Foundation (to LCT); the Arthritis National Research Foundation (to LCT); and the National Psoriasis Foundation (to LCT and NLW). Footnotes Conflict of interest: The authors have declared that no conflict of interest exists. Copyright: © 2019 American Society for Clinical Investigation Reference information: JCI Insight. 2019;4(8):e127291. https://doi.org/10.1172/jci.insight.127291. References Fish EN. The X-files in immunity: sex-based differences predispose immune responses. Nat Rev Immunol. 2008;8(9):737–744. View this article via: PubMed CrossRef Google Scholar Tedeschi SK, Bermas B, Costenbader KH. Sexual disparities in the incidence and course of SLE and RA. Clin Immunol. 2013;149(2):211–218. View this article via: PubMed CrossRef Google Scholar Liang Y, et al. A gene network regulated by the transcription factor VGLL3 as a promoter of sex-biased autoimmune diseases. Nat Immunol. 2017;18(2):152–160. View this article via: PubMed Google Scholar Ramírez A, Bravo A, Jorcano JL, Vidal M. Sequences 5’ of the bovine keratin 5 gene direct tissue- and cell-type-specific expression of a lacZ gene in the adult and during development. Differentiation. 1994;58(1):53–64. View this article via: PubMed Google Scholar Sarkar MK, et al. Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa. Ann Rheum Dis. 2018;77(11):1653–1664. View this article via: PubMed CrossRef Google Scholar Ezzat M, El-Gammasy T, Shaheen K, Shokr E. Elevated production of serum B-cell-attracting chemokine-1 (BCA-1/CXCL13) is correlated with childhood-onset lupus disease activity, severity, and renal involvement. Lupus. 2011;20(8):845–854. View this article via: PubMed CrossRef Google Scholar Liu J, Berthier CC, Kahlenberg JM. Enhanced Inflammasome Activity in Systemic Lupus Erythematosus Is Mediated via Type I Interferon-Induced Up-Regulation of Interferon Regulatory Factor 1. Arthritis Rheumatol. 2017;69(9):1840–1849. View this article via: PubMed CrossRef Google Scholar Teichmann LL, Ols ML, Kashgarian M, Reizis B, Kaplan DH, Shlomchik MJ. Dendritic cells in lupus are not required for activation of T and B cells but promote their expansion, resulting in tissue damage. Immunity. 2010;33(6):967–978. View this article via: PubMed CrossRef Google Scholar Ribero S, Sciascia S, Borradori L, Lipsker D. The Cutaneous Spectrum of Lupus Erythematosus. Clin Rev Allergy Immunol. 2017;53(3):291–305. View this article via: PubMed CrossRef Google Scholar Cohen PL, Eisenberg RA. Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease. Annu Rev Immunol. 1991;9:243–269. View this article via: PubMed CrossRef Google Scholar Andrews BS, et al. Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. J Exp Med. 1978;148(5):1198–1215. View this article via: PubMed CrossRef Google Scholar Amir el-AD , et al. viSNE enables visualization of high dimensional single-cell data and reveals phenotypic heterogeneity of leukemia. Nat Biotechnol. 2013;31(6):545–552. View this article via: PubMed CrossRef Google Scholar Qiu P, et al. Extracting a cellular hierarchy from high-dimensional cytometry data with SPADE. Nat Biotechnol. 2011;29(10):886–891. View this article via: PubMed CrossRef Google Scholar Rai R, Chauhan SK, Singh VV, Rai M, Rai G. RNA-seq Analysis Reveals Unique Transcriptome Signatures in Systemic Lupus Erythematosus Patients with Distinct Autoantibody Specificities. PLoS One. 2016;11(11):e0166312. View this article via: PubMed CrossRef Google Scholar Wieczorek IT, Propert KJ, Okawa J, Werth VP. Systemic symptoms in the progression of cutaneous to systemic lupus erythematosus. JAMA Dermatol. 2014;150(3):291–296. View this article via: PubMed CrossRef Google Scholar ter Borg EJ, Horst G, Hummel EJ, Limburg PC, Kallenberg CG. Measurement of increases in anti-double-stranded DNA antibody levels as a predictor of disease exacerbation in systemic lupus erythematosus. A long-term, prospective study. Arthritis Rheum. 1990;33(5):634–643. View this article via: PubMed CrossRef Google Scholar Raz E, Brezis M, Rosenmann E, Eilat D. Anti-DNA antibodies bind directly to renal antigens and induce kidney dysfunction in the isolated perfused rat kidney. J Immunol. 1989;142(9):3076–3082. View this article via: PubMed Google Scholar Voskuhl R. Sex differences in autoimmune diseases. Biol Sex Differ. 2011;2(1):1. View this article via: PubMed CrossRef Google Scholar Moroni G, et al. The value of a panel of autoantibodies for predicting the activity of lupus nephritis at time of renal biopsy. J Immunol Res. 2015;2015:106904. View this article via: PubMed Google Scholar Catrina AI, Deane KD, Scher JU. Gene, environment, microbiome and mucosal immune tolerance in rheumatoid arthritis. Rheumatology (Oxford). 2016;55(3):391–402. View this article via: PubMed Google Scholar England BR, Thiele GM, Mikuls TR. Anticitrullinated protein antibodies: origin and role in the pathogenesis of rheumatoid arthritis. Curr Opin Rheumatol. 2017;29(1):57–64. View this article via: PubMed CrossRef Google Scholar Kuhn A, et al. Accumulation of apoptotic cells in the epidermis of patients with cutaneous lupus erythematosus after ultraviolet irradiation. Arthritis Rheum. 2006;54(3):939–950. View this article via: PubMed CrossRef Google Scholar James JA, et al. Hydroxychloroquine sulfate treatment is associated with later onset of systemic lupus erythematosus. Lupus. 2007;16(6):401–409. View this article via: PubMed CrossRef Google Scholar Carroll JM, Crompton T, Seery JP, Watt FM. Transgenic mice expressing IFN-gamma in the epidermis have eczema, hair hypopigmentation, and hair loss. J Invest Dermatol. 1997;108(4):412–422. View this article via: PubMed CrossRef Google Scholar Seery JP, Carroll JM, Cattell V, Watt FM. Antinuclear autoantibodies and lupus nephritis in transgenic mice expressing interferon gamma in the epidermis. J Exp Med. 1997;186(9):1451–1459. View this article via: PubMed CrossRef Google Scholar Tsokos GC, Lo MS, Costa Reis P, Sullivan KE. New insights into the immunopathogenesis of systemic lupus erythematosus. Nat Rev Rheumatol. 2016;12(12):716–730. View this article via: PubMed CrossRef Google Scholar Wang Y, et al. Chronic skin-specific inflammation promotes vascular inflammation and thrombosis. J Invest Dermatol. 2012;132(8):2067–2075. View this article via: PubMed CrossRef Google Scholar Shaner NC, Campbell RE, Steinbach PA, Giepmans BN, Palmer AE, Tsien RY. Improved monomeric red, orange and yellow fluorescent proteins derived from Discosoma sp. red fluorescent protein. Nat Biotechnol. 2004;22(12):1567–1572. View this article via: PubMed CrossRef Google Scholar Lichti U, Anders J, Yuspa SH. Isolation and short-term culture of primary keratinocytes, hair follicle populations and dermal cells from newborn mice and keratinocytes from adult mice for in vitro analysis and for grafting to immunodeficient mice. Nat Protoc. 2008;3(5):799–810. View this article via: PubMed CrossRef Google Scholar Johnston A, et al. Keratinocyte overexpression of IL-17C promotes psoriasiform skin inflammation. J Immunol. 2013;190(5):2252–2262. View this article via: PubMed CrossRef Google Scholar Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30(15):2114–2120. View this article via: PubMed CrossRef Google Scholar Anders S, Pyl PT, Huber W. HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31(2):166–169. View this article via: PubMed CrossRef Google Scholar Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550. View this article via: PubMed CrossRef Google Scholar Kotecha N, Krutzik PO, Irish JM. Web-based analysis and publication of flow cytometry experiments. Curr Protoc Cytom. 2010;Chapter 10:Unit10.17. View this article via: PubMed Google Scholar Spidlen J, Breuer K, Rosenberg C, Kotecha N, Brinkman RR. FlowRepository ‑ A Resource of Annotated Flow Cytometry Datasets Associated with Peer‑reviewed Publications. Cytometry A. 2012;81(9):727–731. Benjamini Y, Krieger AM, Yekutieli D. Adaptive linear step-up procedures that control the false discovery rate. Biometrika. 2006;93(3):491–507. View this article via: CrossRef Google Scholar
  25. APS: What Rheumatologists Should Know about Hughes Syndrome February 17, 2016 • By Graham R.V. Hughes, MD, FRCP. The problem that dogs the work of all of those treating patients with antiphospholipid syndrome (APS) is the apparent lack of knowledge of the syndrome, both by the general public, as well as by swaths of the medical fraternity. You Might Also Like Put Hughes Syndrome on Your Radar New Assays May Help in the Diagnosis & Management of Antiphospholipid Syndrome Why Antiphospholipid Antibody Syndrome Should Be On Your Radar Explore this issue February 2016 Perhaps it was ever thus—a syndrome less than 40 years old could be described as new, but a syndrome that is common, touches all branches of medicine and, above all, that is potentially treatable, surely deserves wider recognition. Some of the difficulties derive from the complex clinical nature of APS: the half diagnoses, such as the migraine patient’s diagnostic pathway, which stops at “migraine”; the “atypical angina” in a 40-year-old woman that goes no further than “atypical angina”; the second or third miscarriage that is accepted as one of nature’s misfortunes; or, especially, the memory loss in that same 40 year old who goes undiagnosed. And most troublesome, the common failure to appreciate the limitations of antiphospholipid (aPL) testing and the vital, pivotal concept of sero­negative APS. The story of APS has, for me, been an incredible journey, from the early days in the late 1970s and early 1980s, followed by the original series of publications describing the clinical features and antibody studies resulting in our description of the anti-cardiolipin syndrome and later, to the (still technically not totally correct) anti-phospholipid syndrome.1-8 In the Third International Antiphospholipid Conference in 1994 in Leuven, Belgium, my colleagues honored me by naming the syndrome, Hughes syndrome. Thirty years on, there is still great satisfaction in diagnosing and treating APS patients with such discordant-seeming features as cataplexy and stillbirth, avascular hip necrosis and vertigo, or abdominal angina and multiple fractures—to give examples from recent clinics. Why the Brain? For me, APS/Hughes syndrome is very much a neurological condition. Brain function does seem to be especially targeted—the more APS patients one sees, the wider and wider the neuropsychiatric ripples spread. There have, of course, been many promising lines of research into the pathogenesis of cerebral APS, and many mechanisms have been proposed, ranging from platelet activation, induction of tissue factor, disruption of the annexin A5 anticoagulant shield, endothelial activation and, of course, alteration of the permeability of the blood–brain barrier and direct binding to neuronal cell surfaces, some harking back to earlier forays by Bluestein, Denburg and ourselves into possible cross-reactivity between anti-lymphocyte antibodies and brain.9-13 Interactions between brain and clotting process have a long history, including the observation that the coagulation mechanism within the central nervous system has a number of differences from that found in other organs—the brain’s endothelium expressing little thrombomodulin, for example. Whatever the mechanism, it’s difficult to avoid the observation that treatment with anticoagulation (e.g., with low molecular weight [LMW] heparin) often dramatically reverses the symptoms, including the migraine, the memory difficulties and the chorea. Such observations suggest that the brain pathology in many cases might not be so much infarction, but might relate more to “sludging” of the blood supply and impaired oxygenation. Migraine & Stroke “Did you suffer from headaches as a teenager?” “Yes, doctor. They were almost weekly for a time. They went away for a few years, but they came back with a vengeance now. They run in my family.” So speaks the 30-year-old female patient with APS (the male members of the family appear less often in APS clinics). This is such an important diagnostic clue in the assessment of a patient with possible APS. Yet despite many years of experience of APS, there are surprisingly few data assessing the true role of APS in the wider world of migraine. There are so many reasons to study the association—the response to anticoagulation—usually good, often striking—the study of siblings and other family members of migraine/APS patients. And above all else, the links now being reported between migraine and stroke. Like migraine, stroke is one of the recognized complications of APS/Hughes syndrome. Figures as high as 1 in 5 young strokes (under 45) having positive aPL tests have been reported.14-19 However, as with migraine, recognition of aPL in the etiology of stroke is, in general, still poor. For example, childhood stroke—well recognized clinically—is a prime target for aPL studies. Some years ago, the U.K. government launched a major stroke initiative, educating the public about the symptoms, signs and treatment of stroke. The antiphospholipid syndrome wasn’t on the list. Seizures In 1985, we observed that in lupus patients, seizures were more common in those patients with positive aPL tests.20 Since then, it has become clear that epilepsy, in all its forms, is an important accompaniment of APS. So much so, that in one study of idiopathic epilepsy in teenagers, 1 in 5 was found to be aPL positive.21 The initial midwife or obstetrician’s screening should include a simple questionnaire to rule out APS. The ramifications of these observations are many. Let me give two clinical examples: Firstly, temporal lobe epilepsy in APS may be under-recognized. One of my patients, a woman with classical APS, became an EEG technician. During her training she used four of her siblings as guinea pigs. Three had abnormal temporal lobe activity. It’s interesting to see how often a family history of epilepsy crops up in the history taking of patients with APS. The second clinical anecdote has been published elsewhere.22 A 42-year-old patient had a past history of mild lupus. However, her major problem—and one with a significant impact on her busy life—was recurrent seizures, both petit mal and grand mal, the latter requiring specialist care and the combination of a number of anti-epileptic drugs. During her stay in London, she developed a DVT (she was found to be aPL positive), and routine anticoagulation with warfarin was started. An immediate and unexpected bonus was a marked reduction in the frequency and severity of the seizures, requiring far less aggressive anti-epileptic treatment. Memory Loss Possibly the commonest manifestation of APS is memory loss. Often, the problem only sees the light of day when the patient is asked about the symptom. So many patients confess to worries about Alzheimer’s. To date, detailed clinical studies are few and far between. From time to time, and, it must be said, in a fairly desultory fashion, we have carried out psychometric testing on selected APS patients—and the results have often been surprising. Even more so, given the striking improvement seen in memory tests when anticoagulation is commenced.23 Multiple Sclerosis In view of the prominence of neurological features, including visual disturbance and fluctuating myelopathy, seen in APS, it is not surprising that a number of cases are diagnosed as MS.24,25 The subject is far from straightforward. Some in neurology declare that positive aPL tests are, in fact, sometimes seen in classical MS. I would prefer to turn the picture around. Such patients, at least some, may be APS first and MS second. Although anecdotally a number of such cases respond to anticoagulation, in others the response is, at best, borderline. Uthman has recently reviewed the fairly substantial literature on APS vs. MS.26 Other Neurological Features These include balance problems (a number of cases presenting as Meniere’s), chorea (sometimes severe),27,28 anosmia, sleep disturbance (including cataplexy and narcolepsy) and, recently, autonomic disturbance with a series of cases of POTS (postural orthostatic tachycardia syndrome).29 One of the questions on which there is debate is the prevalence of psychiatric manifestations. It has been my view that acute psychosis has been more a feature of lupus than APS, but in this I may be wrong. One of my patients, a woman with APS and OCD (obsessive compulsive disorder), improved with anticoagulation treatment. Interestingly, her teenage son, also a patient with OCD (and aPL positive), found the neuropsychiatric manifestations were far less prominent when aspirin treatment was started. Not the Brain Bone & joints—Have you suffered any fractures? A question not perhaps part of the routine history taking in APS patients. And yet, spontaneous bone fracture is becoming well recognized following the report of 27 spontaneous metatarsal fractures by Dr. Shirish Sangle in APS patients.30 Anecdotal reports suggest that (ischemic) bone fractures may be an important manifestation of the disease: My colleague, Professor Munther Khamashta, has a Hughes syndrome patient with normal DEXA and parathyroid studies who has had 57 spontaneous fractures. Clearly, this is an important area for clinical research. Likewise, avascular necrosis (AVN) hip pain is not uncommon in our APS patients. MRI has shown early AVN in some cases with no other risk factors, such as steroids. My clinical impression is that the hip pain often improves when heparin or warfarin is started. Heart—A major concern is the presence of angina and other cardiac symptoms in APS. Despite a few early reports of myocardial ischemia and coronary thrombosis, it’s only in recent years that publications revealing a high frequency of these complications have increased in frequency. Two examples are the research of Greco et al showing a relatively high prevalence of positive aPL tests in patients with cardiac ischemia, and the striking observation that women smokers on the pill who were aPL positive had a relative risk of 22 times for the development of myocardial infarction.31,32 The cardiac links are increased by the reporting of an association with cardiac syndrome X, angina with normal coronary angiographs.33 It’s a fair bet that aPL testing will become a standard in the cardiology clinic, especially in symptomatic women under 40. GI tract & liver—Since we made our observations on focal stenotic lesions in various arteries, including celiac and mesenteric arteries, we have focused more on symptoms of abdominal angina in patients with aPL/APS.34 This is a difficult condition to quantify, but we have seen a number of cases in whom clopidogrel or heparin has resulted in improvement (sometimes marked) in post-prandial pain. Although liver involvement in lupus is rare, abnormal liver function tests in APS are seen frequently. Although these can presage serious liver thrombosis, such as Budd-Chiari syndrome or the HELLP syndrome in pregnancy warning of impending catastrophic APS, more commonly, they have a more benign prognosis.35,36 One very positive case history: Back in the early 1980s, I saw a teenage girl with a DVT, positive aPL and Budd-Chiari syndrome. Prognosis poor? Thirty-plus years on, she remains well—on careful lifelong warfarin managed by her physicians in Portugal. Goldblatt’s disease, the kidney & APS—Renal artery stenosis, seen on a clear background of otherwise normal arteries, can mimic Goldblatt’s early observations on the development of hypertension in animals with experimentally occluded renal arteries. The discovery of renal artery stenosis localized lesions by Sangle led to similar findings in other vessels, leading to theories about localized thrombotic/endothelial pathology.37 Skin: livedo reticularis, an enigma—Although skin ulcers, dilated veins and subungual splinter hemorrhages are well-known sequelae of skin thrombosis in APS, livedo reticularis has an aura of mystery.38,39 Diagnostically, its presence is an important clue in patients suspected of having Hughes syndrome—including seronegative APS. Looking back over some of the conditions mentioned in this article—MS, migraine, multiple fractures, memory problems—for example, one wonders whether careful noting of the presence or absence of livedo might prove significant in the differential diagnosis of these conditions. One thing is certain: The presence of livedo adds an extra dimension to the severity of the clinical picture. Pregnancy Of course, the headline story of the syndrome is in pregnancy, where the success rate of healthy deliveries in aPL-positive pregnancies has soared from under 15% to over 90%. Without a doubt, diagnosis and treatment of these cases has been a significant advance in the world of obstetrics.40 Sadly, all of us working with APS have looked after aPL-positive patients (some of whom had suffered early miscarriages) who lost a baby late in the pregnancy. Stillbirth. Two years ago, The Times of London published a lead article titled, “The Stillbirth Scandal,” highlighting the poor stillbirth figures in the U.K.41 Yet some cases of stillbirth in the aPL-positive women could have been prevented. For example, a recent study from Utah found that aPL pregnancies had a three- to fivefold increased odds of stillbirth.42 Would more routine aPL testing in pregnancy help? Cost considerations apply. Miscarriage is common, and there are numerous causes. Thus, the current recommendation is to reserve testing for those women with three or more miscarriages. This does seem harsh. Perhaps a simple screening process might help. I have suggested that part of the initial midwife or obstetrician’s screening should include a simple three-part questionnaire: Have you had a thrombosis? Are you a migraine sufferer? Do you have a family history of autoimmune disease (i.e., lupus, RA, multiple sclerosis, thyroid disease)? I am sure that such a simple questionnaire might help identify a small at-risk group. In most centers, once the mother and baby are safely sent home, there is no long-term follow-up. Yet often, APS patients presenting at, say, the age of 40 with a thrombotic problem, give a past history of miscarriage 20 years earlier. In an ideal world, women with recurrent miscarriage deserve regular long-term follow-up. But the world is far from ideal. Lupus & APS The early clinical studies of APS were carried out in lupus clinics, and could well have included “lupus features.” Perhaps surprisingly, time has shown little difference between primary APS and the APS associated with lupus. There are, undoubtedly, some classical features of lupus (e.g., Libman Sachs endocarditis, stroke, seizures) that are more likely to be aPL related. It also appears likely that aPL positivity in lupus confers a higher chronicity index. The passage of time has also revealed one positive finding: It’s very unusual for patients with primary APS to develop lupus in later years. The Big 3 The association between Hughes syndrome, Sjögren’s and hypothyroidism is so common that I have taken to calling them the big 3. Clinically, it’s an important association because the clinical symptoms of the three conditions—fatigue, cold circulation, aches and pains, and balance and memory problems—are common to all three. Similarly, many of these patients are burdened with the label fibromyalgia. Each of the three interconnecting syndromes can respond well to treatment—for example, the clinical Sjögren’s to hydroxychloroquine and so on. Many of these patients are on my two trees treatment—willow (aspirin) and cinchona (quinine). Seronegative APS I believe that one of the benefits of a trainee clinician’s time spent in the lab is the recognition that many laboratory tests are open to variation. Many, many studies have attempted to assess the importance of titer, immunoglobulin class, triple or double positivity, relevance of “other” aPL such as anti-phosphatidyl-serine etc.43,44 Broadly, all of these have relevance, but in the clinic, some don’t fit, such as those patients with all of the clinical features of APS whose aPL tests remain doggedly negative. Some years ago, we wrote a paper introducing the term seronegative APS, calling attention to patients with strong clinical features of APS but with negative tests.45 The concept goes back to the early days of seronegative RA and seronegative lupus—both of which labels, although based on clinical observation alone, had important therapeutic and prognostic consequences. Three possible explanations for seronegative APS are: 1) The diagnosis is incorrect (unlikely in all cases); 2) the previously positive tests have become negative over time (uncommon in my experience); or 3) new tests are needed.46 Perhaps the most potent reason for open-mindedness about seronegative APS comes from family studies. Some weeks ago, I saw a pair of identical twins—the first with classical seropositive APS, who later brought along her (absolutely) identical twin sister. The second twin had identical sets of symptoms, but unlike the first twin, she had negative aPL tests. Both patients responded to treatment. Once a year, we hold a patients meeting at our hospital. At the last meeting, we arranged a simple anonymous questionnaire with two questions: Are you a patient with APS or a friend/spouse? Have you any close female relative (sister, mother, aunt) with autoimmune disease (i.e., lupus, RA, thyroid, multiple sclerosis, APS)? The result: Sixty percent of patients had a positive history of autoimmune illnesses in close relatives. Less than 20% of friends/spouses answered positive. It may be that my own experience is skewed by referral bias from families of APS patients—but seropositive or not, most patients with seronegative APS respond just as well to treatment. If some of these individuals in the family study did, in fact, have seronegative APS yet were potentially responsive to treatment, then the possibilities are intriguing. Perhaps a higher percentage of our migraine, young stroke, young angina patients might benefit from a closer look for more of the clues to APS—the dry Schirmer’s, the livedo, the family history of autoimmune disease—for example. Treatment Aspects In many ways, it’s disappointing to confess that 30 years on, there are few new treatments. Introduction of the new oral anticoagulants in the treatment of APS has been predictably cautious, and it is too early to generalize.47 Statins, IVIG and hydroxychlorquine have been thrown into the mix and, of course, anti-B cell therapy has received favorable anecdotes. A recent study from Paris suggested that sirolimus, used in renal transplantation, might have a protective effect on aPL-induced vasculopathy.48 So in 2016, the current treatment of APS is still largely confined to aspirin, clopidogrel, heparin and warfarin. Low-dose aspirin, despite its detractors, is, of course, first choice in many APS patients. However, clopidogrel remains a useful alternative in patients with gastritis or in asthmatics. But there is a third role for clopidogrel—important in the real world of practical medicine—that is, in those patients who, for whatever reason, have tried aspirin, without clear benefit. Heparin—Low molecular weight heparin has, in most countries, largely replaced old heparin, and with it, fears of thrombocytopenia and osteoporosis have largely disappeared. This is an important point to make, because many practitioners are reluctant to prolong heparin usage. Two observations: First, a number of patients improve dramatically on heparin, only to feel less well on warfarin. Where to go next? When dosage issues, warfarin resistance and compliance are (hopefully) ruled out, one immediate option is a temporary return to heparin. In some cases, temporary has turned into semi-long term. In our APS clinic we have a couple dozen such patients who, by choice, have remained on subcutaneous heparin for two years or more. Yes, they have experienced bruising, but so far, we have not seen worsening DEXA scans. The second (and very clinical) observation concerns a heparin trial. It is a regular observation that aPL/APS patients on heparin during pregnancy are often headache free for the full eight or nine months. This led us to develop a clinical tool—a therapeutic trial that has stood us in good stead. The trial is a three- or four-week course of LMW heparin.49 Let me give an example of its use: In the aPL/APS patient with increasingly severe headaches despite aspirin/clopidogrel (and with a normal brain MRI), a trial of 10,000 units of dalteparin (or enoxaparin) for three or four weeks can achieve substantial results. First, it can give a surprisingly clear indication of whether anticoagulation is the correct path. Second, in the traumatized patient who has been down the familiar pathway of multiple specialist consultations, with borderline clinical success, it can be a major turning point—the first palpable sign of improvement. Warfarin—There is little new to say about warfarin. It has been vilified by the media, but it remains one of the most useful drugs in our armamentarium. Warfarin, to put it in simple terms, protects against stroke and heart attack in APS. Mention has been made of the frequent need for a higher INR in many APS patients—especially those with neurological features. I am a strong believer in the use of self-testing INR machines whenever possible in our patients. Sadly, some anticoagulant clinics oppose the use of self-testing machines. To me, this is wrong. Look at the freedom self-testing for insulin-dependent diabetics has achieved. As physicians, I believe we have a duty (until better, newer anticoagulants become established) to support warfarin as a largely safe, effective medicine that has saved many thousands of lives. Miscellany Spontaneous bone fracture is becoming well recognized following the report of 27 spontaneous metatarsal fractures by Dr. Shirish Sangle in APS patients. Image Credit: Puwadol Jaturawutthichai/shutterstock.com The Family—It comes as no surprise that a family history is an important clue in Hughes syndrome. Autoimmune disease (particularly thyroid) crops up regularly as a diagnosis in relatives of our patients. But how often are these family cases diagnosed? Examples could include the 17-year-old daughter of an APS patient suffering from headache and glandular fever, the sibling with multiple sclerosis or the mother and aunt of a newly diagnosed APS patient who suffered a stroke in their early 40s. It is not inconceivable that APS has changed the course of history, as in the case reported by my friend, Dr. Gerald Weissmann, of Queen Anne of England who had 17 failed pregnancies and died childless, thereby bringing an end to the Stuart reign and the start of the Hanoverians—with George III, American Colony taxes, the revolution and the birth of the U.S.50 The Offspring—To date, most studies have suggested that the offspring of aPL-positive mothers have no major adverse effects (other than, perhaps, the later-developing inherited APS features in some). However, some worrying case reports of fetal and neonatal problems indicate a need for further study. The ongoing studies of Drs. Anne Parke, Angela Tincani, Maria Claire Boffa and others will, in time, provide some of these missing data.51,52 Classification vs. diagnosis— Dear Doctor, I would be grateful if you could advise on this patient. She developed thrombosis on the oral contraceptive pill. She has had one positive test for aPL, but did not have a repeat test 12 weeks later. As in the case of lupus, classification criteria do sometimes become mixed up with diagnosis. Many patients don’t come armed with tests “12 weeks apart” (this criterion was introduced to cover the risk that an inter-current infection might have led to a transient positive aPL test—not a major factor in our assessment of this patient). There are also financial considerations, such as in the following study from Beirut, Lebanon. “Only 50.5% had both aCL and LA tested. … The cost of each test was around US$50 for the patient. … It remains to be seen whether the test costs might partly explain the very small percentage of patients who did undergo a follow-up confirmatory test.” The recognition of the many non-thrombotic manifestations of APS has added to the importance of separating diagnosis from classification. Perhaps, laboratory advances in the measurement of potential risk markers will, in time, come to our aid.44 Fear of Flying—This clinical anecdote appears regularly in my clinic. So much so that I believe it needs further study. A number of my APS patients, notably before treatment has been started, suffer badly from prolonged jet lag after a long-haul flight, with fatigue, headache and confusion, sometimes lasting for days. Interestingly, once heparin or warfarin treatment is successfully commenced, this phenomenon disappears. Whether these symptoms relate to mild cerebral hypoxia second to slightly reduced cabin pressure is not known. Nevertheless, some of my patients with APS will supplement their aspirin treatment prior to a long-haul flight with an injection of LMW heparin. Although the placebo effect may be considerable, I am sufficiently impressed by the clinical experience of these (observant) patients to believe that the phenomenon of prolonged jet lag in many of our patients is very real. The Future—At the 14th International Congress on Antiphospholipid Antibodies held in Rio de Janeiro in 2013, I was asked for my predictions on the future of APS.23 In summary, I believe: aPL testing will become worldwide and routine; Over-the-counter aPL testing kits will become available; A substantial subset of migraine sufferers will have new hope; APS will become recognized as the major link between migraine and stroke; Heart attacks in young women (especially those under 45) will be reduced; Strokes in those under 45 will be reduced; Some cases of accelerated arterial disease will be recognized as being associated with (untreated) aPL; Some cases of memory loss are treatable; APS will continue to have a profound effect on our clinical assessment and treatment of lupus; and Finally, to return to the opening theme, the incidence of stillbirth will be reduced, thanks, in part, to a more proactive approach to aPL testing in pregnancy. To repeat a sentence taken from the 1983 paper:1 For those of us hardened into nihilism by years of study of various autoantibodies in SLE, there is a rare sense of excitement at the implications of the associations now being reported. Thirty years on, that clinical excitement remains undimmed. Graham R.V. Hughes, MD, FRCP, is a consultant rheumatologist and head of the London Lupus Centre. He trained at The London Hospital, and spent two years in New York working on the introduction of the DNA-binding test, under the leadership of Dr. Charles Christian. In 1971, he opened a specialist clinic in London, dealing uniquely with lupus and related diseases. He is founder and editor of the international journal, Lupus. In 1983, he described the antiphospholipid syndrome and in 1991, was awarded the ILAR (world research) prize for this work. Other honors include Doctor Honoris Causa in the Universities of Marseille and Barcelona, and Master of the ACR. References Hughes GR. Thrombosis, abortion, cerebral disease, and the lupus anticoagulant. Br Med J (Clin Res Ed). 1983 Oct 15;287(6399):1088–1089. Harris EN, Gharavi AE, Boey ML, et al. Anticardiolipin in antibodies: Detection by radioimmunoassay and association with thrombosis in SLE. Lancet. 1983 Nov 26;2(8361):1211–1214. Boey ML, Colaco CB, Gharavi AE, et al. Thrombosis in SLE: Striking association with the presence of circulating lupus anticoagulant. Br Med J (Clin Res Ed). 1983 Oct 8;287:1021–1023. Hughes GR. The Prosser White oration 1983: Connective tissue disease and the skin. Clin Exp Dermatol. 1984 Nov;9(6):535–544. Asherson RA, Mackworth-Young CG, Boey ML, Hughes GRV. Pulmonary hypertension in systemic lupus erythematosus. Br Med J (Clin Res Ed). 1983 Oct 8;287(6398):1024–1025. Derue GJ, Englert HJ, Harris EN, et al. Fetal loss in systemic lupus: Association with anticardiolipin antibodies. J Obstet Gynaecol. 1985;5(4):207–209. Hughes GR, Harris NN, Gharavi AE. The anticardiolipin syndrome. J Rheumatol. 1986 Jun;13(3):486–489. Hughes GR. Hughes’ syndrome: The anticardiolipin syndrome. A historical view.Lupus. 1998;7 Suppl 2:S1–S4. Carecchio M, Cantello R, Comi C. Revisiting the molecular mechanism in antiphospholipid syndrome: Beyond vascular damage. J Immunol Res. 2014;2014:239398. Bluestein HG, Zvaifler NJ. Brain-reactive lymphocytotoxic antibodies in the serum of patients with SLE. J Clin Invest. 1976 Feb;57(2):509–516. Bresnihan B, Oliver N, Grigor R, Hughes GR. Brain-reactivity of lymphocytotoxic anitibodies in systemic lupus erythematosus with and without cerebral involvement. Clin Exp Immunol. 1977 Dec;30(3):333–337. Bresnihan B, Hohmeister R, Cutting J, et al. The neuropsychiatric disorder in SLE: Evidence for both vascular and immune mechanisms. Ann Rheum Dis. 1979 Aug;38(4):301–306. Denburg SD, Behmann SA, Carbotte RM, et al. Lymphocyte antigens in neuropsychiatric systemic lupus erythematosus. Relationship of lymphocyte antibody specificities to clinical disease. Arthritis Rheum. 1994 Mar;37(3):369–375. Harris EN, Gharavi AE, Asherson RA, et al. Cerebral infarction in SLE. Association with anticardiolipin antibodies. Clin Exp Rheumatol. 1984 Jan-Mar;2(1):47–51. Navarrete MG, Brey RL, Levine SR. “Cerebral disease in the antiphospholipid syndrome” in Hughes Syndrome—Antiphospholipid Syndrome. Khamashta MA, ed. Springer, London: 2000. Sanna G, Bertolaccini ML, Cuadrado MJ, et al. Central nervous system involvement in the antiphospholipid (Hughes) syndrome. Rheumatology (Oxford). 2003 Feb;42(2):200–213. Etminan M, Takkouche B, Isorna FC, Samii A. Risk of ischaemic stroke in people with migraine: Systemic review and meta-analysis of observational studies. BMJ. 2005 Jan 8;330(7482):63. Nencini P, Baruffi MC, Abbate R, et al. Lupus anticoagulant and anticardiolipin antibodies in young adults with cerebral ischaemia. Stroke. 1992 Feb;23(2):189–193. Hughes GR. Antiphospholipid syndrome, migraine and stroke. Lupus. 2010 Apr;19(5):555–556. Mackworth-Young CG, Hughes GR. Epilepsy: An early symptom of systemic lupus erythematosus. J Neurol Neurosurg Psychiatry. 1985 Feb;48(2):185. Cimaz R, Meroni PL, Shoenfeld Y. Epilepsy as part of systemic lupus erythematosus and systemic antiphospholipid syndrome (Hughes syndrome). Lupus. 2006;15(4):191–194. Hughes GR. “Diplomatic epilepsy” in Understanding Hughes Syndrome. Springer-Verlag, London: 2009. Hughes GR. Hughes syndrome/APS. 30 years on, what have we learnt? Opening talk at the 14th International Congress on antiphospholipid antibodies. Rio de Janeiro, October 2013. Lupus. 2014;23:400–406. Cuadrado MJ, Khamashta MA, Ballesteros A, et al. Can neurologic manifestations of Hughes (antiphospholipid) syndrome be distinguished from multiple sclerosis? Analysis of 27 patients and review of the literature. Medicine (Baltimore). 2000 Jan;79(1):57–68. Hughes GR. Migraine, memory loss, and “multiple sclerosis.” Neurological features of the antiphospholipid (Hughes’) syndrome. Postgrad Med J. 2003 Feb;79(928):81–83. Uthman I, Noureldine MH, Berjawi A, et al. Hughes syndrome and multiple sclerosis. Lupus. 2015 Feb;24(2):115–121. Cervera R, Asherson RA, Font J, et al. Chorea in the antiphospholipid syndrome. Clinical, radiologic, and immunologic characteristics of 50 patients from our clinics and the recent literature. Medicine (Baltimore). 1997 May;76(3):203–212. Baizabal-Carvallo JF, Bonnet C, Jankovic J. Movement disorders in systemic lupus erythematosus and the antiphospholipid syndrome. J Neural Transm (Vienna). 2013 Nov;120(11):1579–1589. Schofield JR, Blitshteyn S, Shoenfeld Y, et al. Postural tachycardia syndrome (POTS) and other autonomic disorders in antiphospholipid (Hughes) syndrome (APS). Lupus. 2014 Jun;23(7):697–702. Sangle S, D’Cruz DP, Khamashta MA, et al. Antiphospholipid antibodies, systemic lupus erythematosus, and non-traumatic metatarsal fractures. Ann Rheum Dis. 2004 Oct;63(10):1241–1243. Greco TP1, Conti-Kelly AM, Greco T Jr., et al. Newer antiphospholipid antibodies predict adverse outcomes in patients with acute coronary syndrome. Am J Clin Pathol. 2009 Oct;132(4):613–620. Urbanus RT, Siegerink B, Roest M, et al. Antiphospholipid antibodies and risk of myocardial infarction and ischaemic stroke in young women in the RATIO study: A case-control study. Lancet Neurol. 2009 Nov;8(11):998–1005. Nair S, Khamashta MA, Hughes GR. Syndrome X and Hughes syndrome. Lupus. 2002;11(5):332. Sangle SR, Jan W, Lau IS, et al. Coeliac artery stenosis and antiphospholipid (Hughes) syndrome/antiphospholipid antibodies. Clin Exp Rheumatol. 2006 May–Jun;24(3):349. Mackworth-Young CG, Melia WM, Harris EN, et al. The Budd-Chiari syndrome. Possible pathogenetic role of anti-phospholipid antibodies. J Hepatol. 1986;3(1):83-86. Hanouna G, Morel N, Le Thi Huong D, et al. Catastrophic antiphospholipid syndrome and pregnancy: An experience of 13 cases. Rheumatology (Oxford). 2013 Sep;52(9):1635–1641. Sangle SR, D’Cruz DP, Jan W, et al. Renal artery stenosis in antiphospholipid syndrome (Hughes) and hypertension. Ann Rheum Dis. 2003 Oct;62(10):999–1002. Englert HJ, Loizou S, Derue GG, et al. Clinical and Immunological features of livedo reticularis in lupus. Am J Med. 1989 Oct;87(4):408–410. Sangle SR, D’Cruz DP. Livedo reticularis: An enigma. Isr Med Assoc J. 2015 Feb;17(2):104–107. Ateka-Barrutia O, Khamashta MA. The challenge of pregnancy for patients with SLE. Lupus. 2013 Oct;22(12):1295–1308. Hughes GR. The stillbirth scandal. Lupus. 2013 Jul;22(8):759–760. Silver RM, Parker CB, Reddy UM, et al. Antiphospholipid antibodies in stillbirth. Obstet Gynecol. 2013 Sep;122(3):641–657. Rodriguez-Garcia JL, Bertolaccini ML, Cuadrado MJ, et al. Clinical manifestations of antiphospholipid syndrome (APS) with and without antiphospholipid antibodies (the so-called ‘seronegative APS’). Ann Rheum Dis. 2012 Feb;71(2):242–244. Meroni PL, Chighizab CB, Rovelli F, et al. Antiphospholipid syndrome in 2014: More clinical manifestations, novel pathogenic players and emerging biomarkers. Arthritis Res Ther. 2014;16(2):209. Hughes GR, Khamashta MA. Seronegative antiphospholipid syndrome. Ann Rheum Dis. 2003 Dec;62(12):1127. Rodguez-Garcia JL, Bertolaccini ML, Cuadrado MJ, et al. Clinical manifestations of antiphospholipid syndrome (APS) with and without antiphospholipid antibodies. Ann Rheum Dis. 2012 Feb;71(2):242–244. Giles I, Khamashta M, D’Cruz D, et al. A new dawn of anticoagulation for patients with antiphospholipid syndrome. Lupus. 2012 Oct;21(12):1263–1265. Canuad G, Bienaimé C, Taborin F, et al. Inhibition of the mTORC pathway in the antiphospholipid syndrome. New Eng J Med. 2014 Jul 24;371(4):303–312. Hughes GR. Heparin, antiphospholipid antibodies and the brain. Lupus. 2012 Sep;21(10):1039–1040. Weissmann G. Queen Anne’s lupus: Phospholipids and the course of the empire. FASEB J. 2014 Apr;28(4):1527–1530. Mekinian A, Lachassinne E, Nicaise-Roland P, et al. European registry of babies born to mothers with antiphospholipid syndrome. Ann Rheum Dis. 2013 Feb;72(2):217–222. Nalli C, Iodice A, Andreoti L, et al. Children born to SLE and APS mothers. Lupus. 2014 Oct;23(12):1246–1248. Major S, Pashayan N, Atweh S, et al. Practice patterns of antiphospholipid syndrome at a tertiary teaching hospital in Lebanon. Lupus. 2002;11(11):759–764. https://www.the-rheumatologist.org/article/aps-what-rheumatologists-know-about-hughes-syndrome/?singlepage=1
  26. APRIL 2019 11 April 2019 by Professor Graham R V Hughes MD FRCP Easter comes late this year. Frenetic Brexit politics – the Westminster establishment fighting to overturn the ‘popular vote’. So sad. Last week I gave a lecture at an ‘immuno-therapy’ meeting in Madrid. Three hundred attendees, including representatives of the Spanish patients’ APS Society. The atmosphere was fantastic. So many doctors (and patients’) wanting to learn more about our syndrome. Talking about ‘learning more’, we now have a date for our own Patients’ Meeting – Friday, 13th September 2019. (For details of the programme and admission, please visit our website: www.ghic.world). This year we are opening up the meeting to include topics on Sjogren’s and lupus, as well as antiphospholipid syndrome. I will also send this blog, as well as details or our annual Patients’ Meeting, to our colleagues in Spain. Patient of the Month “I still feel tired all the time”. Mrs J.S. aged 55, was referred by her G.P. complaining of a variety of symptoms, including aches and pains, headaches, constipation, pins and needles and mental sluggishness. Above all else, she felt constantly fatigued. Despite this very full set of symptoms, the diagnosis remained uncertain. The pins and needles in both hands were put down to carpal tunnel syndrome. But there was little else to find. In view of the frequent headaches, Mrs J.S. was referred to a neurologist who arranged for further tests, including a brain MRI (which showed two small ‘dot’ lesions – reported as probably not significant. To her credit, the neurologist considered lupus and arranged lupus blood tests among the more routine ones. The tests came back showing a normal blood count. However, the ESR (the guide to inflammation) came back ‘borderline positive’ at 35 (normal under 20). The tests for lupus were essentially negative (anti-DNA negative, ANA ‘weak’ (1 in 80). What is the diagnosis (1)? The penny dropped. Could this be thyroid? Bilateral carpal tunnel syndrome is certainly seen in ‘low thyroid’, and significantly Mrs J.S. had a sister with ‘Hashimotos thyroiditis’ – and underactive thyroid with auto-immune features. As with all her other tests the thyroid blood tests were ‘borderline’. Nevertheless, the fatigue, the constipation, the aches and pains, could all be down to ‘low thyroid’. Following a *‘kerbside consult’, with her endocrinology colleague, she instituted thyroxine treatment. Within 2 months the pins and needles were gone and the mental sluggishness, as well as the constipation, were improving. BUT – the aches and pains and the fatigue remained – as bad as ever. What is the diagnosis (2)? It turned out that Mrs J.S. had suffered a series of miscarriages in her early 20’s and she and her husband remained childless. Could the problems – especially the frequent headaches – be due to Hughes Syndrome? Sure enough the antiphospholipid antibody (aPL) tests were strongly positive – not even ‘borderline’. She was started on clopidogrel (‘Plavix’) – an anti-clotting drug similar to aspirin (Mrs J.S. had previously tried aspirin but found it caused indigestion. Result? An almost immediate lessening of the headaches. And, if anything, a further improvement in her memory problems. BUT: no improvement in the fatigue or the aches and pains. What is the diagnosis (3)? Mrs J.S. was referred to a lupus clinic. Again, the results were similar (‘borderline’ ANA and negative anti-DNA). The lupus clinic doctor had seen this before – possible ‘Sjogren’s syndrome’. And, sure enough, the Shirmer’s test – a simple ‘blotting paper’ eye test was completely dry – a useful and very inexpensive screening test for the dry eyes of Sjogren’s Syndrome. Low dose hydroxychloroquine (Plaquenil) (one a day) was started. Three months later at follow-up clinic, ‘fatigue gone. Aches gone. Back to normal life”. What is this patient teaching us? I often talk of ‘The Big Three’ diseases – Lupus, Sjogren’s and Hughes Syndrome, which can overlap clinically However, the world of auto-immune diseases in which I practice includes another ‘big three’, which frequently go together : Hughes Syndrome, Sjogren’s Syndrome and low thyroid (often, specifically, Hashimoto’s thyroiditis) – three ‘named’ syndromes. Clearly, to miss one or even two of the triad would be an ‘under-treatment’. The three conditions can have similar features. And fortunately, potentially very successful treatment – thyroid, aspirin (or Plavix) and hydroxychloroquine. I call the combination of aspirin and hydroxychloroquine (derived from quinine) my ‘two trees’ – treatment –willow and cinchona. Perhaps the biggest lesson from this patient is that there may be more than one diagnosis causing the problems. PROFESSOR GRAHAM R V HUGHES MD FRCP Head of The London Lupus Centre London Bridge Hospital http://www.ghic.world/blog/april-2019
  1. Load more activity
×
×
  • Create New...