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  2. Benlysta Formulation for Lupus Gets FDA Nod August 01, 2017 | Lupus By Rheumatology Network Staff A new subcutaneous formulation of Benlysta (belimumab) has received FDA approval for the treatment of adult patients with active, autoantibody-positive systemic lupus erythematosus (SLE) who are receiving standard therapy, GSK announced. This is the first subcutaneous self-injection treatment option for patients with SLE, according to GSK. Patients will be able to administer the medicine as a once-weekly injection of 200 mg, from a single-dose prefilled syringe or a single-dose autoinjector, after receiving training from their health care provider. This is the second formulation of Benlysta to be granted FDA approval for SLE, GSK noted. The intravenous formulation, approved in 2011, is administered to patients as a weight-based dose of 10 mg/kg, via a 1-hour infusion in a hospital or clinic setting every 4 weeks (after an initial loading phase given on days 0, 14, and 28). “Lupus can impact the lives of patients in many different ways with varied and often unpredictable symptoms,” said Vlad Hogenhuis, GSK’s Senior Vice President, Head of Specialty Care. “Since it launched in its IV form, thousands of patients worldwide have received treatment with Benlysta. The approval of the new injectable formulation will now provide an additional choice for patients, allowing them to self-administer their medicine at home rather than going to hospitals or clinics for their infusions.” The approval is based on data from the BLISS-SC phase III pivotal study of more than 800 patients with active SLE. The study measured reduction in disease activity at Week 52 in patients receiving belimumab plus standard of care versus those receiving placebo plus standard of care (assessed by the SLE Responder Index). The Benlysta subcutaneous formulation will be available in specialty pharmacies in the United States in late August. Further regulatory submissions for the subcutaneous formulation of Benlysta are under review or planned in other countries during the course of 2017.
  3. GSK receives FDA approval for a new self-injectable formulation of Benlysta (belimumab) for systemic lupus erythematosus Issued: London, UK GSK receives FDA approval for a new self-injectable formulation of Benlysta (belimumab) for systemic lupus erythematosus GSK announced today that the US Food and Drug Administration (FDA) has approved a new subcutaneous formulation of Benlysta (belimumab) for the treatment of adult patients with active, autoantibody‑positive SLE who are receiving standard therapy. Systemic Lupus Erythematosus (SLE) is the most common form of lupus, a chronic, incurable autoimmune disease producing autoantibodies that can attack almost any system in the body. The approval marks the first subcutaneous self-injection treatment option for patients with SLE. After training from their health care provider, patients will be able to administer the medicine as a once weekly injection of 200mg, from either a single-dose prefilled syringe or from a single-dose autoinjector. This is the second formulation of Benlysta to be granted approval for SLE, adding to the existing intravenous (IV) formulation, approved in 2011, which is administered by healthcare professionals to patients as a weight-based dose of 10mg/kg, via a one-hour infusion in a hospital or clinic setting every four weeks (following an initial loading phase given on days 0, 14 and 28). Vlad Hogenhuis, Senior Vice President, Head of Specialty Care, GSK said, “We are delighted with today’s decision. Lupus can impact the lives of patients in many different ways with varied and often unpredictable symptoms. Since it launched in its IV form, thousands of patients worldwide have received treatment with Benlysta. The approval of the new injectable formulation will now provide an additional choice for patients, allowing them to self-administer their medicine at home rather than going to hospitals or clinics for their infusions.” The approval is based on data from the BLISS-SC phase III pivotal study of more than 800 patients with active SLE, which measured reduction in disease activity at Week 52 in patients receiving belimumab plus standard of care, versus those receiving placebo plus standard of care (assessed by SRI, a composite measure of efficacy in lupus). Benlysta subcutaneous formulation will be available in specialty pharmacies in the US in late August. Further regulatory submissions for the subcutaneous formulation of Benlysta are under review or planned in other countries during the course of 2017. About Benlysta (belimumab) Benlysta is currently the only medicine specifically developed and approved for SLE. Benlysta, a BLyS-specific inhibitor, is a human monoclonal antibody that binds to soluble BLyS. Benlysta does not bind B cells directly. By binding BLyS, Benlysta inhibits the survival of B cells, including autoreactive B cells, and reduces the differentiation of B cells into immunoglobulin-producing plasma cells. Benlysta is indicated in the US for the treatment of adult patients with active, autoantibody‑positive, systemic lupus erythematosus (SLE) who are receiving standard therapy: Limitations of Use: The efficacy of Benlysta has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus. Benlysta has not been studied in combination with other biologics or intravenous cyclophosphamide. Use of Benlysta is not recommended in these situations. Full US prescribing information including Medication Guide will be available in the near future at: gsksource.com. In the meantime, you may request a copy through GSK Communications. Benlysta is licensed in the European Union as an add-on therapy in adult patients with active autoantibody-positive SLE, with a high degree of disease activity (e.g. positive anti-dsDNA and low complement), despite standard therapy. Benlysta subcutaneous formulation is currently not approved in the European Union. For the EU Summary of Product Characteristics for Benlysta, please visit www.ema.europa.eu About systemic lupus erythematosus (SLE) Systemic lupus erythematosus (SLE) is the most common form of lupus, affecting approximately 70 percent of an estimated 5 million people with lupus worldwide. Approximately 170,000-200,000 Americans live with SLE. It is a chronic, incurable autoimmune disease producing autoantibodies that can attack almost any system in the body. Important Safety Information for belimumab Please consult the full Prescribing Information for all the labelled safety information for Benlysta (belimumab). BENLYSTA (belimumab): CONTRAINDICATION BENLYSTA is contraindicated in patients who have had anaphylaxis with belimumab. WARNINGS AND PRECAUTIONS MORTALITY There were more deaths reported with BENLYSTA than with placebo during the controlled period of the intravenous clinical trials. Out of 2,133 patients in 3 clinical trials, a total of 14 deaths occurred during the placebo-controlled, double-blind treatment periods: 3/675 (0.4%), 5/673 (0.7%), 0/111 (0%), and 6/674 (0.9%) deaths in the groups receiving placebo, BENLYSTA 1 mg/kg, BENLYSTA 4 mg/kg, and BENLYSTA 10 mg/kg, respectively. Etiologies included infection, cardiovascular disease, and suicide. In the controlled clinical trial of BENLYSTA administered subcutaneously (N = 836), a total of 5 deaths occurred during the placebo-controlled, double-blind treatment period (0.7% [2/280] of patients receiving placebo and 0.5% [3/556] of patients receiving BENLYSTA). Infection was the most common cause of death. SERIOUS INFECTIONS Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including BENLYSTA. Caution should be exercised when considering use in patients with severe or chronic infections. Consider interrupting therapy with BENLYSTA in patients who develop a new infection while receiving BENLYSTA and monitor these patients closely. In controlled clinical trials of BENLYSTA administered intravenously, serious infections occurred in 6.0% and 5.2% of patients receiving BENLYSTA and placebo, respectively. The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis. Infections leading to discontinuation of treatment occurred in 0.7% and 1.0% of patients receiving BENLYSTA and placebo, respectively. Infections resulting in death occurred in 0.3% (4/1,458) and 0.1% (1/675) of patients receiving BENLYSTA and placebo, respectively. In the controlled trials of BENLYSTA administered subcutaneously (N = 836), serious infections occurred in 4.1% and 5.4% of patients receiving BENLYSTA and placebo, respectively. Progressive Multifocal Leukoencephalopathy (PML): Cases of JC virus-associated PML resulting in neurological deficits, including fatal cases, have been reported in patients with SLE receiving immunosuppressants, including BENLYSTA. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. Consider the diagnosis of PML in any patient presenting with new-onset or deteriorating neurological signs and symptoms and consult with a neurologist or other appropriate specialist as clinically indicated. In patients with confirmed PML, consider stopping immunosuppressant therapy, including BENLYSTA. HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS) Acute hypersensitivity reactions, including anaphylaxis and death, have been reported in association with BENLYSTA. These events generally occurred within hours of the infusion; however, they may occur later. Non-acute hypersensitivity reactions including rash, nausea, fatigue, myalgia, headache, and facial edema have been reported and typically occurred up to a week following the most recent infusion. Hypersensitivity, including serious reactions, has occurred in patients who have previously tolerated infusions of BENLYSTA. Limited data suggest that patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. In the controlled clinical trials of BENLYSTA administered intravenously, hypersensitivity reactions occurring on the day of the infusion were reported in 13% (191/1,458) and 11% (76/675) of patients receiving BENLYSTA and placebo, respectively. Anaphylaxis was observed in 0.6% (9/1,458) and 0.4% (3/675) of patients receiving BENLYSTA and placebo, respectively. Manifestations included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea. Some patients (13%) received premedication, which may have mitigated or masked a hypersensitivity response. There is insufficient evidence to determine whether premedication diminishes the frequency or severity of these reactions. Healthcare providers should be aware of the risk of hypersensitivity reactions and be prepared to manage anaphylaxis. In the event of a serious hypersensitivity reaction, discontinue BENLYSTA immediately and administer appropriate medical therapy. Patients should be monitored during and for an appropriate period of time after the intravenous administration of BENLYSTA. Patients receiving BENLYSTA should be informed of the signs and symptoms of an acute hypersensitivity reaction, and be instructed to seek immediate medical care should a reaction occur. In the controlled trial of BENLYSTA administered subcutaneously (N = 836), the incidence and severity of systemic hypersensitivity reactions were similar to those observed in the intravenous clinical trials. INFUSION REACTIONS In the controlled clinical trials, infusion reactions occurring on the day of the infusion were reported in 17% (251/1,458) and 15% (99/675) of patients receiving BENLYSTA and placebo, respectively. Serious infusion reactions (excluding hypersensitivity reactions) were reported in 0.5% and 0.4% of patients receiving BENLYSTA and placebo, respectively. Serious infusion reactions included bradycardia, myalgia, headache, rash, urticaria, and hypotension. The most common infusion reactions occurring in ≥3% of patients receiving BENLYSTA were headache, nausea, and skin reactions. Some patients (13%) received premedication, which may have mitigated or masked an infusion reaction; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of these reactions. BENLYSTA should be administered by healthcare providers prepared to manage infusion reactions. The infusion rate may be slowed or interrupted if the patient develops an infusion reaction. Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and monitor patients closely. DEPRESSION In controlled clinical trials of BENLYSTA administered intravenously, serious psychiatric events were reported in 0.8% and 0.4% of patients receiving BENLYSTA and placebo, respectively. Serious depression was reported in 0.4% and 0.1% of patients receiving BENLYSTA and placebo, respectively. Two suicides were reported in patients receiving BENLYSTA. In the controlled trial of BENLYSTA administered subcutaneously, serious psychiatric events were reported in 0.2% of patients receiving BENLYSTA and in no patients receiving placebo. It is unknown if treatment with BENLYSTA is associated with increased risk for these events. Instruct patients to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other mood changes. MALIGNANCY The impact of treatment with BENLYSTA on the development of malignancies is not known. The mechanism of action of BENLYSTA could increase the risk for the development of malignancies. IMMUNIZATION Live vaccines should not be given for 30 days before or concurrently with BENLYSTA. BENLYSTA may interfere with the response to immunizations. USE WITH BIOLOGIC THERAPIES OR IV CYCLOPHOSPHAMIDE BENLYSTA has not been studied in combination with other biologic therapies, including B-cell targeted therapies, or IV cyclophosphamide. Therefore, use of BENLYSTA is not recommended in combination with these therapies. ADVERSE REACTIONS Intravenous administration Adverse reactions, regardless of causality, occurring in at least 3% of patients with SLE who received BENLYSTA 10 mg/kg and placebo respectively and, at an incidence at least 1% greater than that observed with placebo in the 3 controlled studies, were: nausea 15% and 12%; diarrhea 12% and 9%; pyrexia 10% and 8%; nasopharyngitis 9% and 7%; bronchitis 9% and 5%; insomnia 7% and 5%; pain in extremity 6% and 4%; depression 5% and 4%; migraine 5% and 4%; pharyngitis 5% and 3%; cystitis 4% and 3%; leukopenia 4% and 2%; viral gastroenteritis 3% and 1%. Subcutaneous administration The safety profile observed for BENLYSTA administered subcutaneously was consistent with the known safety profile of BENLYSTA administered intravenously, with the exception of local injection site reactions, which occurred in 6.1% and 2.5% of patients receiving BENLYSTA and placebo, respectively. OTHER IMPORTANT INFORMATION FOR BENLYSTA USE IN SPECIFIC POPULATIONS Pregnancy: There are insufficient data on use of BENLYSTA in pregnant women to establish whether there is drug-associated risk for major birth defects or miscarriage. Following an assessment of benefit versus risk, if prevention is warranted, women of childbearing potential should use effective contraception during treatment and for at least 4 months after the final treatment. Lactation: There is no information available on the presence of belimumab in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BENLYSTA and any potential adverse effects on the breastfed child from BENLYSTA or from the underlying maternal condition. Black/African American Patients: In controlled clinical trials of BENLYSTA administered intravenously, SLE Responder Index-4 (SRI-4) response rates were lower for black/African American patients receiving BENLYSTA relative to black/African American patients receiving placebo. In the controlled trial of BENLYSTA administered subcutaneously, SRI-4 response was slightly higher for black/African American patients receiving BENLYSTA relative to black/African American patients receiving placebo, but the treatment difference was not as great as that observed in the overall population. Use with caution in black/African American patients. Populations not studied Benlysta has not been studied in the following patient groups, and is not recommended in patients with: ∙ severe active central nervous system lupus ∙ severe active lupus nephritis ∙ HIV ∙ a history of, or current, hepatitis B or C ∙ hypogammaglobulinaemia (IgG <400 mg/dl) or IgA deficiency (IgA <10 mg/dl) ∙ a history of major organ transplant or hematopoietic stem /cell /marrow transplant or renal transplant.
  4. Researchers identify new genetic markers in patients with lupus Langefeld CD, et al. Nat Commun. 2017;doi:10.1038/ncomms16021. July 21, 2017 Among patients with lupus, researchers have identified new genetic markers that predispose patients to the disease, according to a recently published study. “This study is the largest multi-ethnic lupus genetics study to date and allowed us to identify many new genetic markers, some of which are specific to individual ethnic groups and others that are shared across ethnicities,” Carl Langefeld, PhD, lead author of the study and professor of biostatistical sciences at Wake Forest School of Medicine, said in a press release. “With this information, we can begin to better understand the differences in the rates and severity of disease across ethnic groups.” Researchers assessed 27,574 participants. They identified 58 distinct non-human leukocyte antigen regions in the Europeans, nine in the Africans and 16 in the Hispanic Americans. All of these included 24 new lupus regions. “In addition, we observed that many of the genetic markers associated with lupus are shared across numerous autoimmune diseases, and those that are not shared may allow us to understand why a person develops lupus instead of another autoimmune disease,” Langefeld said. “These results will help us identify the biological pathways that pharmaceutical companies may target, and ultimately, develop personalized medicine for the treatment of lupus.” Reference: www.wakehealth.edu/News-Releases/2017/Large_Multiethnic_Study_Identifies_Many_New_Genetic_Markers_for_Lupus.htm Large Multi-ethnic Study Identifies Many New Genetic Markers for Lupus WINSTON-SALEM, N.C. – July 17, 2017 – Scientists from an international consortium have identified a large number of new genetic markers that predispose individuals to lupus. The study is published in the July 17 issue of the journal Nature Communications and was led by researchers at Wake Forest Baptist Medical Center, Oklahoma Medical Research Foundation, King’s College of London and Genentech Inc. Autoimmune diseases strike one in 15 Americans, are among the top 10 causes of death in women and cost an estimated $100 billion a year in medical care. In autoimmune diseases, the body attacks itself. Systemic lupus erythematosus, the form of lupus studied here, is the most common type of lupus and is a prototypical autoimmune disease. Lupus strikes women nine times more often than men and its onset is most common during childbearing age. Also, African-American and Hispanic women are two to three times more likely to develop lupus and tend to have more severe cases than Caucasian women. At present, there is no cure for lupus, which can affect many parts of the body, including joints, skin, kidney, heart, lungs, blood vessels and brain, according to the Lupus Research Alliance. “This study is the largest multi-ethnic lupus genetics study to date and allowed us to identify many new genetic markers, some of which are specific to individual ethnic groups and others that are shared across ethnicities,” said Carl Langefeld, Ph.D., lead author of the study and professor of biostatistical sciences at Wake Forest School of Medicine, a part of Wake Forest Baptist. “With this information, we can begin to better understand the differences in the rates and severity of disease across ethnic groups. “In addition, we observed that many of the genetic markers associated with lupus are shared across numerous autoimmune diseases, and those that are not shared may allow us to understand why a person develops lupus instead of another autoimmune disease. These results will help us identify the biological pathways that pharmaceutical companies may target, and ultimately, develop personalized medicine for the treatment of lupus.” This study analyzed genetic data from 27,574 individuals of European, African American and Hispanic ancestry using the Immunochip, a genotyping technology designed specifically for autoimmune diseases. The researchers identified 58 regions of the genome in Caucasians, nine in African Americans and 16 in Hispanics. These regions appear independent of the well-known Human Leukocyte Antigen (HLA) associations, also studied in depth here. An important observation was that nearly 50 percent of these regions had multiple genetic variants that predispose someone to lupus, Langefeld said. Another key finding was that as the number of genetic risk variants (alleles) a person has increases, the risk for lupus increases more than expected if the variants were working independently. These observations led the authors to propose a “cumulative hits hypothesis for autoimmune disease”. In future research, the team hopes to better understand how these genetic variants influence the risk of lupus, identify any possible drug targets and determine if any environmental factors, such as infections, can trigger the development of the disease in someone who has a genetic susceptibility. They emphasize that it is important to increase the number of understudied populations, such as African-American and Hispanic, to better understand the genetic causes of health disparities in lupus and the unique risks in all ethnic groups. “We are delighted to see the work we funded on the ImmunoChip come to fruition and congratulate Dr. Langefeld along with his colleagues on this tremendous success," said Kenneth M. Farber, CEO and President, Lupus Research Alliance. "This study is among the few to concentrate heavily on non-Caucasian populations for a significantly broader evaluation, while utilizing the most current and comprehensive information about human DNA.” Key support for the study was provided by the Lupus Research Alliance and the National Institutes of Health. Additional corresponding authors are: Patrick M. Gaffney, M.D., Oklahoma Medical Research Foundation; Robert R. Graham, Ph.D., Genentech, Inc.; and Timothy J. Vyse, M.D., Ph.D., King’s College London. Media Relations Contacts: Marguerite Beck: marbeck@wakehealth.edu,336-716-2415
  5. Large Multi-ethnic Study Identifies Many New Genetic Markers for Lupus http://www.wakehealth.edu/News-Releases/2017/Large_Multiethnic_Study_Identifies_Many_New_Genetic_Markers_for_Lupus.htm WINSTON-SALEM, N.C. – July 17, 2017 – Scientists from an international consortium have identified a large number of new genetic markers that predispose individuals to lupus. The study is published in the July 17 issue of the journal Nature Communications and was led by researchers at Wake Forest Baptist Medical Center, Oklahoma Medical Research Foundation, King’s College of London and Genentech Inc. Autoimmune diseases strike one in 15 Americans, are among the top 10 causes of death in women and cost an estimated $100 billion a year in medical care. In autoimmune diseases, the body attacks itself. Systemic lupus erythematosus, the form of lupus studied here, is the most common type of lupus and is a prototypical autoimmune disease. Lupus strikes women nine times more often than men and its onset is most common during childbearing age. Also, African-American and Hispanic women are two to three times more likely to develop lupus and tend to have more severe cases than Caucasian women. At present, there is no cure for lupus, which can affect many parts of the body, including joints, skin, kidney, heart, lungs, blood vessels and brain, according to the Lupus Research Alliance. “This study is the largest multi-ethnic lupus genetics study to date and allowed us to identify many new genetic markers, some of which are specific to individual ethnic groups and others that are shared across ethnicities,” said Carl Langefeld, Ph.D., lead author of the study and professor of biostatistical sciences at Wake Forest School of Medicine, a part of Wake Forest Baptist. “With this information, we can begin to better understand the differences in the rates and severity of disease across ethnic groups. “In addition, we observed that many of the genetic markers associated with lupus are shared across numerous autoimmune diseases, and those that are not shared may allow us to understand why a person develops lupus instead of another autoimmune disease. These results will help us identify the biological pathways that pharmaceutical companies may target, and ultimately, develop personalized medicine for the treatment of lupus.” This study analyzed genetic data from 27,574 individuals of European, African American and Hispanic ancestry using the Immunochip, a genotyping technology designed specifically for autoimmune diseases. The researchers identified 58 regions of the genome in Caucasians, nine in African Americans and 16 in Hispanics. These regions appear independent of the well-known Human Leukocyte Antigen (HLA) associations, also studied in depth here. An important observation was that nearly 50 percent of these regions had multiple genetic variants that predispose someone to lupus, Langefeld said. Another key finding was that as the number of genetic risk variants (alleles) a person has increases, the risk for lupus increases more than expected if the variants were working independently. These observations led the authors to propose a “cumulative hits hypothesis for autoimmune disease”. In future research, the team hopes to better understand how these genetic variants influence the risk of lupus, identify any possible drug targets and determine if any environmental factors, such as infections, can trigger the development of the disease in someone who has a genetic susceptibility. They emphasize that it is important to increase the number of understudied populations, such as African-American and Hispanic, to better understand the genetic causes of health disparities in lupus and the unique risks in all ethnic groups. “We are delighted to see the work we funded on the ImmunoChip come to fruition and congratulate Dr. Langefeld along with his colleagues on this tremendous success," said Kenneth M. Farber, CEO and President, Lupus Research Alliance. "This study is among the few to concentrate heavily on non-Caucasian populations for a significantly broader evaluation, while utilizing the most current and comprehensive information about human DNA.” Key support for the study was provided by the Lupus Research Alliance and the National Institutes of Health. Additional corresponding authors are: Patrick M. Gaffney, M.D., Oklahoma Medical Research Foundation; Robert R. Graham, Ph.D., Genentech, Inc.; and Timothy J. Vyse, M.D., Ph.D., King’s College London. Media Relations Contacts: Marguerite Beck: marbeck@wakehealth.edu,336-716-2415
  6. Cumulative hydroxychloroquine and aspirin may prevent cardiovascular events in patients with SLE https://www.healio.com/rheumatology/lupus/news/online/{f8a80a3a-3122-457d-ae5e-b2f34606cc5d}/cumulative-hydroxychloroquine-and-aspirin-may-prevent-cardiovascular-events-in-patients-with-sle?utm_source=selligent&utm_medium=email&utm_campaign=rheumatology news&m_bt=1879111151405 Fasano S. Et al. J Rheumatol. 2017;doi:https://doi.org/10.3899/jrheum.161351. July 14, 2017 In patients with lupus, ongoing use of hydroxychloroquine plus low-dose aspirin may be associated with increased effectiveness in the primary prevention of cardiovascular events, according to recently published findings. Researchers identified 189 patients from a database of the Rheumatology Unit of the Second University of Naples. The study group included 175 women and the overall mean age at baseline was 31 years. Patients had a diagnosis of systemic lupus erythematosus (SLE) upon admission, and had never experienced a cardiovascular event (CVE). Patients were seen for follow-up every 3 months to 6 months, depending upon their clinical condition. Investigators documented any CVE that occurred during the intervening time and information about the use of aspirin (ASA) and cumulative dosages of hydroxychloroquine (c-HCQ). Researchers used Kaplan-Meier analysis to determine the cumulative dosage that yielded a lower rate of CVE. Cox regression analysis was used to determine factors linked to an initial CVE. They found 10 patients experienced the following non-lethal thrombotic events: stroke, one patient; transient ischemic attack, five patients; and acute myocardial infarction, four patients. The mean time to the first CVE was 5 years. Four (2.1%) patients died during the course of the study; none of these deaths were related to CV complications. Kaplan-Meier analysis demonstrated a significant disparity in CVE-free rates among the four patient subgroups. There was no difference in CVE-free rate between the 135 patients treated with ASA plus HCA and the 28 patients treated with aspirin monotherapy. A lower rate of CVEs was reported in the c-HCQ patients. A higher CVE-free rate was documented in the 85 patients on an ASA-HCA regimen who had arrived at a cHCQ dosage greater than 600 g than in the 28 patients who were treated with ASA monotherapy or the 51 patients treated with ASA/cHCQ at a dosage less than 600g. There were no differences in traditional CV risk factors and those specific to SLE among the patient groups, nor were there differences between medications (statins, high-dose steroids). Multivariate analysis revealed that cumulative treatment with hydroxychloroquine, when added to ASA, was thromboprotective. High blood pressure and antiphospholipid antibody positivity were identified as predictive of an initial CVE. Serena Fasano “Systemic lupus erythematosus is associated with an increased risk of cardiovascular disease. This study was performed to investigate the role of aspirin and distinct hydroxychloroquine cumulative dosages and treatment durations,” researcher Serena Fasano told Healio/Rheumatology. “We found that aspirin and antimalarials, when administered for more than 5 years at a cumulative dosage greater than 600 g, may reduce the CVE risk in SLE patients.” – by Jennifer Byrne Disclosure: The researchers report no relevant disclosures.
  7. Speakers: Lupus remains challenging disease July 6, 2017 Healio Rheumatology recently interviewed Richard Furie, MD, from Hofstra Northwell School of Medicine, Lars Rönnblom, MD, from Uppsala University in Sweden, and Peggy K. Crow, MD, from Hospital for Special Surgery, about the future of lupus during the Interferon Summit. “We need better drugs,” Furie said. “There is a major need for safer and more efficacious therapies. The typical patient who gets this disease is a young woman and it can be devastating.” SEE ALSO Furie discusses advances in SLE treatment Through the Cracks: Niche Patient Population Battles... Elusive Target: A Rundown of the Drug Pipeline for Systemic... Richard Furie To illustrate the need for better therapies, Furie discussed the progression of treatments for the disease. “We have come a long way with treatments,” he said. “If you go back before steroids were developed, the mortality was high. It was probably 50% at 7 years, but steroids were introduced and they have been a major advance. Then, after that, it was the immunosuppressives; but, until we get rid of all mortality and morbidity, we need new drugs.” To derive better therapies for a disease, there needs to be better disease classification. Rönnblom talked about the current classification of lupus patients and how to treat the underlying cause vs. a cluster of symptoms. “We classify patients with an auto[body] or antibody profile,” Rönnblom said. “In lupus, we classify them according to organ manifestation, but also when they have this interferon signature. My guess is that we will see more pathways coming up. Much of this data will be generated by the clinical trials, of course, who responds and who does not respond.” Lars Rönnblom Crow said better understanding about the molecular pathway and underlying mechanisms of the disease can lead to better therapy. “My own speculation is that we will probably end up with combination therapies and maybe combinations will allow us to use lower doses, each of one or two or three therapies to avoid toxicity. For example, we might want to target this type 1 interferon pathway that I believe is active in a sustained way throughout the disease, but may be more important in some stages than others,” she said. Peggy K. Crow “To have a more effective therapeutic activity, we might also want to target activated T cells or B cell differentiation. My guess is that we, as a community, will end up trying different combinations and some of the selection of those might be informed by the molecular pathways that an individual shows to be activated or abnormal.” – by Will A. Offit Disclosures: The researchers report no relevant financial disclosures. https://www.healio.com/rheumatology/lupus/news/online/{0b28f725-2f50-4168-b619-abd1de8a4266}/speakers-lupus-remains-challenging-disease?utm_source=selligent&utm_medium=email&utm_campaign=rheumatology news&m_bt=1879111151405
  8. Glucocorticoids Use and Organ Damage in Lupus http://www.rheumatologynetwork.com/lupus/glucocorticoids-use-and-organ-damage-lupus Glucocorticoids exposure is strongly associated with the accrual of irreversible organ damage in systemic lupus erythematosus patients, independent of disease activity, researchers report. “Our findings suggest that only extremely low doses of glucocorticoid can be considered free of association with damage accrual in patients with SLE,” write researchers in the Nov. 22 issue of Lupus Science and Medicine Glucocorticoids are a mainstay treatment in both acute and chronic systemic lupus erythematosus. Previous studies have demonstrated that damage accrual is associated with cumulative disease activity. However, more recent studies suggest that damage accrual may also be associated with systemic lupus erythematosus treatment. Approximately 60 percent of systemic lupus erythematosus patients experience permanent organ damage within seven years of being diagnosed with the disease. Given that glucocorticoids are often used in the context of high disease activity, it has been challenging for researchers to tease out the independent effect of systemic lupus erythematosus treatment on damage accrual. This was an observational study of 162 systemic lupus erythematosus patients — 75 percent of whom received glucocorticoids. The patients were observed for two to 4.7 years by Diane Apostolopoulos, M.D., of Monash University in Australia, and colleagues. They measured damage accrual finding that glucocorticoid patients were 42 percent more likely to have significantly more damage as compared to patients who were not prescribed glucocorticoids (42% vs 15%, p<0.01). The observational nature of the study was one of the limitations of the study, yet, it is noteworthy, the researchers wrote. “Given the limitations of observational studies in the face of confounding by indication, our findings suggest the urgent need for a randomized study comparing the effect on damage accrual of usual care with that of a strategy that stringently limits glucocorticoid dosing,” Dr. Apostolopoulos and colleagues wrote. In an editorial that was published online April 7 in Lupus Science and Medicine, Maarten Boers, M.D., of VU University Medical Center in the Netherlands, conveys concerns of the medical community misinterpreting observational studies by limiting applications of a potentially life-saving treatment. “The truth of the matter is that trials on glucocorticoid beneficial and adverse effects are not being done, and that observational studies (invariably only focusing on glucocorticoid adverse effects, both related and unrelated to the disease) are hopelessly and irretrievably confounded by indication,” wrote Boers. “In brief, patients with the most severe disease are preferentially treated with glucocorticoids, and this leads to the associations found in observational studies, regardless of the beneficial effects of glucocorticoids.” The study Glucocorticoid use is associated with harm in both domains of the (Systemic Lupus International Collaborating Clinics Damage Index (SDI) traditionally associated with glucocorticoid-induced harm (cataracts, osteoporotic fracture, avascular necrosis, diabetes mellitus) and the residual SDI domains not previously associated with glucocorticoid-induced harm. Even lower doses of glucocorticoid are associated with damage accrual in SLE. The threshold identified was a time-adjusted mean prednisolone of 4.4 mg per day. Cumulative prednisolone exposure was associated with overall damage accrual after controlling for ethnicity and disease activity and was significant at time-adjusted mean doses above 4.42 mg prednisolone per day. A dose-response relationship between cumulative prednisolone use and irreversible organ damage accrual was observed, with increasing odds ratios with each ascending quartile. Compared to patients in the lowest quartile, patients in the highest quartile of cumulative prednisolone had adjusted odds ratio of 13.46, 95 percent CI (3.59 to 50.4), p<0.01 for damage accrual. Of the demographic factors evaluated, only ethnicity was associated with damage accrual. Asian patients had reduced odds of damage accrual compared with Caucasians (adjusted OR=0.22, 95% CI (0.09 to 0.53), p<0.01). “Our findings further emphasize the need for new, more effective treatments for SLE that minimize or eliminate the need for glucocorticoids,” wrote Apostolopoulos and team. DISCLOSURES This research was supported by a grant from Eli Lilly. REFERENCES Apostolopoulos D, Kandane-Rathnayake R, Raghunath S, et al. “Independent association of glucocorticoids with damage accrual in SLE,” Lupus Science and Medicine. Published online November 22, 2016. DOI: 10.1136/lupus-2016-000157. Boers M. “Observational studies on glucocorticoids are harmful!” Lupus Science and Medicine. Published online April 7, 2017. DOI: 10.1136/lupus-2017-000219
  9. Neonatal Lupus May Not Require Steroid Treatment News | June 30, 2017 | Lupus By Whitney L. Jackson One in 50 pregnant women with systemic lupus erythematosus (SLE) are at risk for having a child with neonatal lupus erythematosus (NLE), according to Dr. Jill Buyon, a rheumatologist with New York University School of Medicine. Although neonatal lupus is rare and is most often benign, when it is not, it can be life-threatening for at-risk newborns. Awareness is important, she said. “Though we think of it as being rare, the recurrence rate is about 18 percent. This is a significant portion of people,” Dr. Buyon said. The first signs of disease often occur during the first few weeks of birth as nonscarring and non-atrophic skin lesions that resemble subacute cutaneous lupus erythematosus. More serious abnormalities effect the cardiovascular system, but can also effect the hematological, hepatobiliary, central nervous and pulmonary systems (1). One of the most controversial issues associated with neonatal lupus is whether the use of fluorinated steroids during pregnancy can protect the fetus from worsening heart block, which is associated with NLE. Dr. Buyon’s research shows that it does not. Neonatal lupus Neonatal lupus occurs when a mother with active or asymptomatic lupus or other autoimmune disease passes autoantibodies against Ro/SSA, La/SSB and U1-ribonucleoprotein (U1-RNP), through the placenta to the fetus. It is rare and one estimate shows only a 1-2 percent risk of having a child with NLE, regardless of whether the mother is symptomatic (1). Dexamethasone or fluorinated steroids have been standard treatments to prevent heart block in NLE. “The idea behind this is that maybe heart block is caused by inflammation and maybe we could stop the inflammation in the beginning, during or even after the initial insult. The question is whether this would change the ultimate prognosis for the fetus,” she said. A 2015 retrospective chart review by Dr. Buyon and colleagues published in the Annals of Rheumatic Diseases addressed whether daily doses of fluorinated steroids effectively treated isolated heart block in utero to prevent the progression of disease beyond the atrioventricular (AV) node. They found that fluorinated steroids did not significantly prevent the development of disease beyond the AV node, reduce mortality or delay or prevent the need for a pacemaker (2). It is believed inflammation plays a significant role in the development and worsening of heart block, making steroids an attractive treatment option. However, evidence doesn't support the use of these steroids to prevent worsening disease or death from this condition. The results, she said, should alleviate worries from providers and expectant mothers who have concerns about using steroids, such as dexamethasone, during pregnancy. There has been a concern about the effect of steroids crossing the placenta into the fetal circulation system. Additionally, steroid use can cause complications in the mother, such as increased risk of infection, as well as other problems in the fetus, including low-birth weight and the loss of amniotic fluids. The 20-year retrospective study analyzed treatment and outcomes for enrollees in the Research Registry for Neonatal Lupus. Only women with diagnosed cases of anti-SSA/Ro-associated cardiac neonatal lupus, meaning their fetus had second- or third-degree heart block, were included. Heart block scars the atrioventricular node, the structure responsible for heart rate. Children born with permanent heart block require pacemaker implantation, and approximately 20 percent die. Although there is some disagreement with Canadian research that supports the use of fluorinated steroids when second- or third-degree heart block is present, recently published French investigations verify her team's findings, she said. Previous studies over the last 20 years have shown that the most challenging aspect in heart block is that once it’s reached a third-degree level, it is generally immutable and by then, steroids cannot reverse the course of disease. “There is a vulnerable period to the development of heart block which is usually about 16 – 26 weeks, with the most heightened time around 19-20 weeks. Once the heart block has happened it’s not common to develop worsening injury because the vulnerable period begins to pass. Admittedly, our colleagues in Canada don’t agree and they almost always subject the mother to steroids for the rest of the pregnancy. And because that carries risk, we felt this study was important,” she said. Now, with this study, Dr. Buyon hopes that physicians will reconsider steroid therapy in these cases. “I appreciate that a mother wants to do all she can to save her baby, but there are also health considerations for her part and on part of the fetus. The idea of taking a steroid that will cross into the fetal circulation can be very anxiety provoking both for the patient and physician. This is the study that was needed to help in pregnancy counseling,” she said. Dr. Buyon discusses the structure, findings and importance of this work with Rheumatology Network in this video. http://www.rheumatologynetwork.com/lupus/neonatal-lupus-may-not-require-steroid-treatment REFERENCES 1. Kam Lun Hon and Alexander K. C. Leung. "Neonatal Lupus Erythematosus." Autoimmune Dis. 2012; 2012: 301274. Published online 2012 Sep 2. DOI: 10.1155/2012/301274 2. Izmirly PM, Saxena A, Sahl SK, et al. “Assessment of fluorinated steroids to avert progression and mortality in anti-SSA/Ro-associated cardiac injury limited to the fetal conduction system.” the Annals of Rheumatic Diseases. Published Online First: 01 December 2015. DOI: 10.1136/annrheumdis-2015-208311
  10. Women with Lupus Overwhelmingly Have Healthy Pregnancies News | June 30, 2017 | Lupus By Whitney L. Jackson In contradiction to long-standing beliefs, a healthy pregnancy is possible for women who have lupus, says Jill Buyon, M.D., a rheumatologist and lupus specialist from New York University School of Medicine. “Patients with lupus have been under the impression that pregnancy would be a very dangerous thing for them. From the mother’s perspective, the concerns are: Will the mother sustain a lupus flare? For mothers who have once had kidney involvement: How safe is it to get pregnant? Will there be adverse pregnancy outcomes? Will the baby be very small? Will the baby be born so early that it needs to be in the hospital for a long time. And, of course, the scary question is: Will my baby die? These are the outcomes we look at from the perspective of counseling and what we wanted to learn from this study,” she said. Dr. Buyon recently published research in the Annals of Internal Medicine showing that women with relatively inactive lupus without serious flares experienced a normal pregnancy with a positive outcome. Study participants were women, ages 18-to-45, enrolled in the Predictors of Pregnancy Outcome: Biomarker in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus (PROMISSE) Trial. The investigation was multi-center, multi-racial and multi-ethnic. Out of the 385 women followed during the study, 81 percent experienced no adverse events. Overall, 9 percent of pregnancies resulted in premature birth, 4 percent experienced pregnancy loss during the second or third trimester, 1 percent encountered infant death due to pregnancy complications, and 10 percent had very low birth weight. Throughout the study, investigators identified four factors that appeared to increase a woman's likelihood for a negative outcome — high blood pressure during pregnancy, more active lupus during gestation, low platelet count, and a positive lupus anticoagulant test during the first trimester. “The patients who tended to be more sick at the outset, tended to be those who might have an adverse pregnancy outcome. The highest risk factor is the presence of something called a lupus anticoagulant. The presence of this abnormal blood test is very important and one that absolutely all doctors should test for,” Dr. Buyon said. In addition, race and ethnicity — black, Hispanic and Asian — contributed to poor outcomes and was in and of itself, a risk factor. Dr. Buyon said she doubts it is due to socioeconomic factors because the patients were treated by similar doctors in tertiary care centers. She suspects it may be due to genetics, which needs to be explored. Although the findings point to the possibility of healthy pregnancies for this population, Dr. Buyon cautioned women who have high protein levels in urine due to uncontrolled kidney disease could still face significant problems with pregnancy. These women are typically advised to postpone pregnancy until their kidney disease improves. Ten to 15 percent of patients had a moderate flare requiring minimal medication changes, but less than 5 percent of patients had a flare that required high dose steroids or hospitalization. About one in five patients had a renal flare. “The other optimistic perspective was that 225 patients never had kidney disease, but many of them had anti DNA antibodies which is an antibody we worry about in developing renal disease. Only four people developed de novo renal disease. For people who had previous kidney disease ... but were in complete remission, they too had very few renal flares. I think this is very encouraging news for women with past renal disease who really are so worried that maybe they’ll never have a healthy pregnancy, that simply is not true (14:01),” Dr. Buyon said. The hope, she said, is that these findings can be used to inform discussions between doctors and their patients with lupus who are also interested in pursuing pregnancy. Dr. Buyon discusses the study, its findings and implications in the following video with Rheumatology Network. http://www.rheumatologynetwork.com/lupus/women-lupus-overwhelmingly-have-healthy-pregnancies REFERENCES Jill P. Buyon, MD; Mimi Y. Kim, ScD; Marta M. Guerra, MS, et al. "Predictors of Pregnancy Outcomes in Patients With Lupus: A Cohort Study," Annals of Internal Medicine, Aug. 4, 2015. DOI: 10.7326/M14-2235
  11. Systemic lupus erythematosus increases risk for cervical neoplasia June 15, 2016 LONDON — Women with systemic lupus erythematosus, or SLE, are at a greater risk for cervical neoplasia, especially those treated with immunosuppressive drugs, according to a speaker here at the EULAR Annual Congress. “Women with SLE appear to be at increased risk for cervical neoplasia. It is more pronounced for premalignant and invasive cancers,” Johan Askling, MD, PhD,from the department of medicine at Karolinska Institutet in Stockholm, Sweden, said during a press conference. “Treatment with SLE is a marker of further increasing the risk. In fact, it contains the overall increase for invasive cancers, but whether this is due to drugs or the indication, we do not really know.” Askling and colleagues identified 4,450 women with SLE from Swedish registries and 28,113 matched controls from the general population. The Swedish National Cervical Screening Registry was used to collect data on cervical screenings. Patients were further divided by whether they used antimalarial drugs (n = 1,783) or other immunosuppressive treatments (n = 1,981), as defined by the Swedish Prescribed Drug Register. At follow-up, the Swedish National Cervical Screening Registry and Swedish Cancer Registry were used to determine outcomes of cervical dysplasia and invasive cervical cancer. Other outcomes assessed separately included cervical intraepithelial neoplasia grades 1 and 2/3, and invasive malignancy. Askling and colleagues used Cox models to estimate hazard ratios. Investigators found women with SLE had a doubled rate for cervical dysplasia or invasive cancer compared with the general population. Women treated with systemic immunosuppressive drugs vs. those treated with antimalarial drugs had a higher rate for cancer. Immunosuppressives were correlated with a higher chance of cervical dysplasia or neoplasms compared with women treated with antimalarials. “Women with SLE should be screened for cervical cancer, and if there is a population-based screening program … [it] is particularly good to adhere to that program,” Askling said. “We do not think, at this stage, additional measures should be taken.” – by Monica Jaramillo Reference: Wadström H, et al. Abstract #OP0189. Presented at: EULAR Annual Congress; June 8-11, 2016; London. Disclosure: Askling reports no relevant financial disclosures.
  12. UK rheumatologists use factors other than NICE guidelines to treat patients with RA June 27, 2016 LONDON — Rheumatologists from the United Kingdom consider other factors apart from the National Institute for Health and Care Excellence, or NICE, clinical guidelines on cost to make decisions on anti-tumor necrosis factor therapy prescription doses, according to a speaker here at the EULAR Annual Congress. “Rheumatologists’ … experiences come into some of this as well, so if they are used to using one particular treatment they would be more likely to use it subsequently,” Sean Gavan, PhD, of the Manchester Centre for Health Economics, United Kingdom,said during a press conference. “There was a sense from all of my participants that, to some extent, NICE guidance was restrictive of what they could do, and so to combat this, they were selective to what treatments they gave patients earlier on to free up more treatments down the line. Occasionally, they would manipulate the DAS28 score to give [anti-tumor necrosis factor] therapy to patients who, according to NICE guidance, would not be allowed to have that treatment.” Gavan and colleagues conducted telephone interviews with 11 consultant rheumatologists from hospitals in England. Rheumatologists were asked to speak of factors that influence their decisions for treatment of patients with rheumatoid arthritis (RA), which included the decision to initiate anti-tumor necrosis factor (anti-TNF) therapy, choice of first-line anti-TNF therapy and treatment options in remission. Investigators used thematic framework analysis to analyze interview transcripts. Results showed that the participants’ choice for first-line anti-TNF treatment was rarely influenced by costs, except when local service commissioners offered a less expensive anti-TNF. Gavan and colleagues found when it came to first-line biosimilar anti-TNF agents, participants’ expressed cautious optimism due to potential cost savings. Participants’ tried to maintain clinical autonomy and involved patients in decision-making when use of cheapest anti-TNF was considered. “A lot of the participants suggested the clinical evidence base was, perhaps, slightly ahead of what NICE was saying currently in its guidance, but then when they decided to implement certain treatments decisions they were selective over which pieces of evidence they used to guide certain decisions,” Gavan said. – by Monica Jaramillo Reference: Gavan S, et al. Abstract #OP0198-HPR. Presented at: EULAR Annual Congress; June 8-11, 2016; London. Disclosure: Gavan reports no relevant financial disclosures.
  13. Staying Ahead of Multiple Autoimmune Disorders Healio Rheumatology, August 2016 There is a well-established body of evidence cataloguing the co-occurrence of autoimmune disorders. Patients with rheumatoid arthritis, multiple sclerosis, autoimmune thyroiditis, Sjögren’s syndrome or a host of other such conditions carry a substantially increased risk for another autoimmune disease. Although some pairings are reported more frequently than others, the likelihood that a patient with any autoimmune disorder will ultimately acquire another autoimmune disorder is high. The question, then, is why. Regina Berkovich, PhD, MD assistant professor of clinical neurology at Keck Medicine at the University of Southern California, laid out some of the principal arguments. “It is a case of mistaken and activated immune system,” she said. “If the immune system already follows the autoimmune pattern, it is just a higher possibility that there will be another target.” This seems to be the main reason autoimmune disorders tend to coincide, according to Berkovich, who has studied multiple sclerosis (MS) extensively. “A second scenario is that when we use immunomodulatory drugs to treat MS, the initial landscape of the immune system changes,” she said. “When we create changes to the immune system, it may predispose them to further complications.” Other researchers, including Emily C. Somers, PhD, ScM an associate professor of internal medicine, environmental health sciences and obstetrics and gynecology at the University of Michigan, have suggested genetic factors are in play. However, untangling the myriad genetic associations in patients who have multiple disorders has remained elusive to the clinical and research communities. “A current line of thinking is there are certain genetic and environmental factors that may disrupt the immune system in a manner that may set the stage for future development of autoimmune diseases,” she said. However, she noted there are no concrete answers on the genetic front. Regina Berkovich Healio Rheumatology lays out the issues and associations, beginning with a look at trends in comorbid autoimmune diseases. Overview of Associations Cojocaru and colleagues outlined factors involved in multiple autoimmune syndrome, which they defined as the existence of three or more of these conditions. “Disorders of autoimmune pathogenesis occur with increased frequency in patients with a history of another autoimmune disease,” they wrote, suggesting the rate of a second disorder may be about 25%. “At least one of them is usually a skin disease, such as psoriasis or scleroderma.” Although some patients may experience as many as five of these conditions, it is unlikely, according to Cojocaru and colleagues. Multiple autoimmune disorder may be the result of familial or genetic factors, along with immunological or psychological factors. However, environmental triggers may set in motion the occurrence of a second disorder. “The pathogenesis of multiple autoimmune disorders is not known,” they wrote. Multiple autoimmune syndrome can be classified into three types, according to the authors. “Type 1 [multiple autoimmune syndrome] includes myasthenia gravis, thymoma, polymyositis and giant cell myocarditis,” they wrote. “Type 2 [multiple autoimmune syndrome] includes Sjögren’s syndrome, [rheumatoid arthritis] RA, primary biliary cirrhosis, scleroderma and autoimmune thyroid disease. Type 3 [multiple autoimmune syndrome] groups together autoimmune thyroid disease, myasthenia gravis and/or thymoma, Sjögren’s syndrome, pernicious anemia, idiopathic thrombopenic purpura, Addison’s disease, type 1 diabetes mellitus, vitiligo, autoimmune hemolytic anemia, [systemic lupus erythematosus] SLE and dermatitis herpetiformis.” Antoine G. Sreih, MD, assistant professor of clinical medicine in rheumatology at the University of Pennsylvania, echoed this point. “Clusters of autoimmune disorders can occur together, such as Schmidt syndrome or other autoimmune polyendocrine syndromes, which are often due to genetic predisposition,” he said. “Once the immune system loses its tolerance to self, it becomes more prone to causing other autoimmune diseases.” Eric Matteson Speaking more specifically, researchers have suggested inflammatory bowel disease is commonly associated with autoimmune comorbidities. For example, hypothyroidism, primary sclerosing cholangitis, vitiligo and alopecia areata frequently occur in ulcerative colitis. Multiple sclerosis is common in the third type of multiple autoimmune disorder, according to Cojocaru and colleagues. An association of Reynolds syndrome and the lupus erythematosus/lichen planus-overlap syndrome is a hallmark of the second type of this disorder. Overall, vitiligo is often the first autoimmune disease diagnosed, while bullous pemphigoid is the most common blistering skin disease. “The significance of the association of bullous pemphigoid with other autoimmune diseases is still unknown,” they wrote. “The most frequent associations are those with [primary biliary cirrhosis] PBC, psoriasis.” Sjögren’s syndrome frequently occurs with SLE and RA, according to Cojocaru and colleagues. “The presence of Sjögren’s syndrome influences the expression of the other autoimmune disease to some degree, for instance by increasing fatigue and lymphoma risk,” they wrote. “The underlying mechanisms for this syndrome are not yet understood, but it may be more prevalent than currently recorded.” “Overlapping syndromes between two or more autoimmune diseases in rheumatology are not uncommon,” Sreih said. “We see this with SLE, RA, scleroderma, Sjögren’s syndrome, vasculitis and polymyositis.” Other common combinations include pemphigus and autoimmune thyroid disease in type 1 [multiple autoimmune syndrome]; chronic active hepatitis, SLE, pemphigus, bullous pemphigoid, [autoimmune hemolytic anemia], [idiopathic thrombopenic purpura], alopecia areata and Addison’s disease in type 2 [multiple autoimmune syndrome]; and acquired primary hypogonadism, hypophysitis, RA, PBC, relapsing polychondritis, multiple sclerosis, [congenital adrenal hyperplasia] CAH, ulcerative colitis and scleroderma in type 3 [multiple autoimmune syndrome],” they wrote. Cojocaru and colleagues suggested clinicians may find the pathogenesis of ulcerative colitis in clusters of autoimmune diseases, and the presence of one of these disorders may likely lead to discovery of another. They urged ongoing surveillance. “The underlying mechanisms for this syndrome are not yet understood, but it may be more prevalent than currently recoded,” they wrote. “I would point out that only some, but certainly not all, of the clustering they suggest is based on pathophysiological understanding of the diseases and so is in the end opinion of the authors,” Eric Matteson, MD, a rheumatologist at the Mayo Clinic in Rochester, Minn., told Healio Rheumatology. “The practical clinical implications of the clustering could include making clinicians aware of certain associations, such as Sjögren’s syndrome and rheumatoid arthritis as they follow patients, and may be helpful in unraveling some of the common pathophysiological basis for them. Some other associations may not have a practical value in terms of understanding the disease causation of management.” A number of data sets validate the findings described by Cojocaru and colleagues. Sardu and colleagues described the prevalence of 12 autoimmune diseases in a general population sample from Sardinia, Italy that included data for more than 25,000 individuals. Results were calculated in terms of prevalence per 100,000. Investigators found RA occurred in 552 individuals per 100,000, while the rate was 124 for ulcerative colitis, 15 for Crohn’s disease, 464 for type 1 diabetes, 81 for SLE, 124 celiac disease, 35 for myasthenia gravis, 939 for psoriasis/psoriatic arthritis, 35 for systemic sclerosis, 224 for MS, 31 Sjögren’s syndrome and 2,619 for autoimmune thyroiditis. “An overall association between autoimmune disorders was highlighted,” the researchers wrote. “People already affected by a first autoimmune disease have a higher probability of being affected by a second autoimmune disorder.” Antoine G. Sreih “This paper recapitulates findings from other populations which also show this interrelatedness of autoimmune diseases, and is not surprising,” Matteson said. “It is necessary to keep in mind that some of the autoimmune diseases have low frequencies, so that lack of an association can be real or spurious.” Sreih built on this point. “The findings in this paper support the notion that having one autoimmune disease increases the risk of having another autoimmune disease and that the majority of the autoimmune diseases examined in this paper are more common in women than men,” he said. “It is important, however, to indicate that findings in one specific population — in this case South Sardinia — may not apply to another population because of differences in genetic composition.” Another caveat is that despite the broad nature of the study, there are still a finite number of autoimmune disorders that underwent analysis, according to Sreih. “Therefore, the findings apply only to those studied autoimmune diseases,” he said. “Also, observation bias may exist since patients with an autoimmune disease are frequently seen and tested by their physicians and therefore more diseases can be detected.” Autoimmune Therapies Berkovich and colleagues investigated the frequency of comorbid diseases in MS. They suggested certain MS drugs may be preferable to others when comorbid autoimmune conditions are present. Moreover, comorbid autoimmune conditions could predict response to MS therapies. “Treatment with interferon beta has been reported to precipitate immune-mediated abnormalities or to exacerbate existing autoimmune diseases,” they wrote. “In comparison, there are fewer reported cases of treatment-associated comorbidities linked with autoimmune disease in patients taking glatiramer acetate. Knowledge of the factors influencing autoimmune comorbidities may provide insights into the complex pathogenesis of MS and help inform treatment choices.” “According to what we know, some immunomodulatory therapies may contribute to a second autoimmune disorder,” Berkovich told Healio Rheumatology. “The association has been noticed with interferon-based therapies. Another more recent medication that may predispose patients to autoimmune complications is alemtuzumab (Lemtrada, Genzyme). We found that if patients already had MS and one other autoimmune condition, such as psoriasis or lupus, interferon was not the best choice of drug.” This information can have practical implications for the clinic, according to Berkovich. “The evidence tells us that interferon may exacerbate the conditions,” she said. “Evidence of those complications should be used as a surrogate biomarker to be careful when using interferon in these patients.” That said, Berkovich is hopeful novel therapies, such as teriflunomide (Aubagio, Genzyme) or, dimethyl fumarate (Tecfidera, Biogen) or glatiramer acetate injection (Copaxone, Teva), may improve this situation. “Some of these new immunomodulatory therapies have known risks,” she said. “The symptomatology of MS can overlap with other conditions.” Clinicians weight the benefit-risk ratioassociated with treating a primary autoimmune disorder, according to Berkovich. “Treatment is justified, first, by the efficacy of the drugs for the primary potentially progressive condition — MS,” she said. “If we give medicine to treat MS, we are well aware that it has associated risks, and always discuss this with patients. It is worth it because if we do not treat the MS, patients are highly likely to progress and develop advanced disability. We have no choice but to address the primary condition. The risk for a second condition is relatively minor and manageable when compared to what happens when MS takes its natural course, which may be a grave prognosis.” Genetic Factors Many experts, including Sreih, have suggested genetic factors may be worth investigating. “Patients with one autoimmune disease may be predisposed to acquiring another autoimmune disease,” he said. “Genetic predispositions to having an autoimmune disorder can be common among several autoimmune diseases.” Somers acknowledged the understanding of these associations is increasing, albeit slowly. “Over the last decade, several genetic factors have been found in common between multiple autoimmune diseases,” she said. “However, the particular combinations of genetic and environmental factors will influence the way that autoimmunity is expressed, or what we refer to as the disease phenotype.” Matteson agreed. “This is likely because in some cases common genetic predisposition exposures, such as possibly infections, and common inflammatory pathways of many of these diseases also have overlapping features, like rheumatoid arthritis, Sjögren’s syndrome, and lupus erythematous, to name three,” he said. Conflicting Data Although the overwhelming consensus is that autoimmune diseases co-occur, there are data sets that show the opposite or at least muddy the picture. Farez and colleagues suggested results investigating comorbid autoimmune disorders have been “controversial.” They added this phenomenon has not been studied in patients in Latin America. Results from their case-control study indicated no significant differences in autoimmune disease prevalence in patients with MS compared to controls. Patients with one or more autoimmune disorders did not experience an increased likelihood of acquiring MS (odds ratio = 0.85), according to their findings. “Our results indicate absence of increased comorbid autoimmune disease prevalence in MS patients, as well as of increased risk of MS in patients suffering from other autoimmune disorders,” they concluded. Somers and colleagues conducted a series of population-based cohort studies with data from the United Kingdom General Practice Research Database between 1990 and 1999. The aim was to evaluate risks for co-occurrence of RA, autoimmune thyroiditis, MS and insulin-dependent diabetes mellitus. The analysis included outcomes for 22,888 patients with RA, 26,198 patients with autoimmune thyroiditis, 4,332 patients with MS and 6,170 patients with diabetes whose outcomes were compared with those reported in the general population. Among patients in the diabetes group, adjusted rates of autoimmune thyroiditis were increased among men (standardized incidence ratio[SIR] = 646) and women (SIR = 409.6). Rates of RA also were higher among women with diabetes (SIR = 181.6). Autoimmune thyroiditis and RA showed a trend for coexistence regardless of the disease sequence (sex-specific SIRs = 130.4 to 162). However, the researchers noted an inverse relationship between RA and MS. “The strongest association we found was between type 1 diabetes and autoimmune thyroiditis, with rates of coexistence up to six-times higher than expected,” Somers said. “Since these are both endocrine disorders, this indicates that they may share risk factors relevant to disruption of the endocrine system.” Somers noted that RA and autoimmune thyroiditis are among the most common autoimmune disorders in the general population. “Therefore, detection of comorbidity between this pair of diseases is easiest to detect statistically,” she said. “We found that for someone with RA or autoimmune thyroiditis, their risk of developing the other one is approximately 1.5-times higher than expected by chance.” The inverse relationship in this data set should not be ignored, according to Somers. “The inverse association between RA and MS is puzzling and we do not have a firm explanation for this, although genetic variants have been reported that are negatively correlated between these two diseases,” she said. “That is, variants associated with increased susceptibility for one but decreased susceptibility for the other.” The other noteworthy data from the study involve gender differences in comorbid autoimmune disorders, according to Somers. Emily C. Somers “Females have a much greater risk of autoimmune disease overall compared to males, and the female excess holds true for most individual autoimmune disorders,” she said. “For example, 90% of lupus patients are female. Thus, the risk of developing a second disorder should be examined separately for each sex, given the higher underlying risk among females. We believe that our data support similar patterns of coexistence for both sexes, but given the rarity of autoimmune diseases in males, the associations among males are more challenging to detect.” Regarding other conflicting evidence, there are also data demonstrating that autoimmune therapies may not always lead to increased risk for further disorders. Chouhfeh and colleagues investigated how disease modifying therapies impact comorbid autoimmune diseases in MS using data from a cohort of 1,792 patients in the New York State MS Consortium registry. There were 1,478 patients with no other autoimmune diseases and 314 with a comorbid condition that occurred after enrollment. The researchers grouped the patients into those with a disorder after initiation of disease modifying therapies (n = 281) and patients with a disorder who were naïve to disease modifying therapies (n = 33). Disease-modifying therapies failed to alter the frequency of self-reported autoimmune disorders (17.2 vs. 20.4%), according to the results. However, the duration between initial symptoms of MS and the initial report of a comorbid autoimmune condition was 192 ± 115 months among patients treated with disease-modifying therapies and 262 ± 107 months among those who were not. “The findings of this paper are interesting,” Sreih said. “One would expect that the use of disease-modifying therapies in general would decrease the incidence of autoimmune diseases given that many of these medications are therapies given to autoimmune diseases.” Sreih highlighted this paper also shows that women are at higher risk of developing autoimmune diseases than men. He also had some comments about the limitations of the paper. “The number of patients with autoimmune disorders who are naïve to disease-modifying therapies is relatively small compared to patients with autoimmune disorders who are on those drugs,” he said. “Also, the authors lumped different medications with different mechanisms of action under one category of disease-modifying therapies. However, some medications may cause autoimmune diseases more than others and therefore one cannot generalize to all medications. It would have been interesting to know which medications were more associated with autoimmune disorders or with shorter duration to developing an autoimmune disorder than others.” The final point Sreih made is there may have been a bias by indication of therapy. “Patients who are sicker or have a specific disease receive therapy or certain medications as opposed to patients who are not as sick or have another subtype of multiple sclerosis,” he said. Commonly Reported Associations A number of comorbid autoimmune conditions have been described extensively. Boelaert and colleagues conducted a multicenter, cross-section study that included 2,791 patients with Graves’ disease and 495 patients with Hashimoto’s thyroiditis at a center in the United Kingdom. The aim was to assess prevalence rates of coexisting autoimmune disorders. A second autoimmune disorder occurred in 9.67% of Graves’ disease index cases and 14.3% of Hashimoto’s thyroiditis index cases. RA was the most frequently reported comorbid condition, occurring in 3.15% of Graves’ disease and 4.24% of Hashimoto’s thyroiditis cases. Increases in relative risk for a number of other autoimmune disorders were reported for both Graves’ disease and Hashimoto’s thyroiditis, according to the findings (greater than 10 for pernicious anemia, SLE, Addison’s disease, celiac disease and vitiligo). The parents of index cases also experienced increased relative risks for a number of other coexisting autoimmune disorders. “There was relative ‘clustering’ of Graves’ disease in the index case with parental hyperthyroidism and of Hashimoto’s thyroiditis in the index case with parental hypothyroidism,” the researchers wrote. “These risks highlight the importance of screening for other autoimmune diagnoses if subjects with autoimmune thyroid disease present with new or nonspecific symptoms.” For Berkovich, this makes clinical decision-making of utmost importance. “We should cooperate and collaborate with other clinicians treating these patients,” she said. “Early screening and diagnosis along with early intervention can mitigate further risk.” Gill and colleagues investigated prevalence of comorbid autoimmune diseases in a cohort of 1,098 patients with vitiligo at Henry Ford Health System in Detroit during January 2002 and October 2012. Around 20% of the group had at least one comorbid autoimmune disease. The researchers reported increased rates of a number of conditions in vitiligo patients compared with the general population, including thyroid disease (12.9%), alopecia areata (3.8%), inflammatory bowel disease (0.9%), pernicious anemia (0.5%), SLE (0.3%), Guillain-Barre syndrome (0.3%), discoid lupus (0.2%), linear morphea (0.2%), myasthenia gravis (0.2%) and Sjögren’s syndrome (0.2%). “We observed a high prevalence of comorbid autoimmune diseases in patients with vitiligo and report several new associations,” the researchers concluded. “These associations can tell us about the immune landscape we are dealing with in these patients,” Berkovich said. “The presence of multiple conditions gives us valuable information to help define therapies and understand these diseases.” Sreih said vitiligo can accompany many autoimmune diseases and may be associated with many autoimmune polyendocrinopathies. “The study was relatively large, but unfortunately lacked a control group, and used the general population autoimmune diseases’ estimates for comparison,” he said. “One can potentially compare to the general population if the assumption is the population being studied is representative of the general population, which is probably not the case for this study. The studied population in this paper belongs to one hospital and one specific geographic area of Detroit.” Another key point was thyroid disease was the most common comorbid disease in this population, according to Sreih. “However, hypo- and hyperthyroidism, which are not necessarily caused by autoimmune processes, were included in the definition of thyroid disease and therefore lead to possible overestimation of the true number,” he said. Lauret and Rodrigo addressed approaches to dealing with celiac disease, which remains poorly understood. “Remarkable breakthroughs have been achieved in the last decades, due to a greater interest in the diagnosis of atypical and asymptomatic patients, which are more frequent in adults,” they wrote. “The known presence of several associated diseases provides guidance in the search of oligosymptomatic cases, as well as studies performed in relatives of patients with [celiac disease].” However, they cautioned there is diversity in the etiology of associated diseases. “Some share a similar genetic base, like type 1 diabetes mellitus; others share pathogenic mechanisms, and yet, others are of unknown nature,” they wrote, and warned the disease may present with extra-intestinal manifestations. A gluten-free diet has demonstrated the capacity to improve clinical symptoms of celiac disease, including associated conditions, according to Lauret and Rodrigo. This diet may eliminate anemia or offer improved control of type 1 diabetes. Moving Forward “According to data sets in a number of publications, there is strong evidence that patients with one autoimmune disease have a higher probability of developing another,” Berkovich said. “In my professional experience — 95% of my patients have MS — it is common to see coexisting autoimmune conditions, such as psoriasis. The presence of other autoimmune conditions gives us a lot of information about these patients. We should be paying attention to this.” The good news is drug developers are investigating drugs that minimize the risk of a second condition in patients with MS and other primary disorders, according to Berkovich. “This is the high possible priority in the pipeline right now,” she said. “While I believe it is impossible to create a medication without the potential side effect or risks of complications, I believe we learn to mitigate and stratify the risks. Patients’ safety is always our priority – and this means safety from complications of treatment and also safety from the potentially debilitating complications of MS progression.” -by Rob Volansky References: Berkovich R, et al. US Neurology. 2011doi:10.17925/USN.2011.07.02.132. Boelaert K, et al. Am J Med. 2010;doi:10.1016/j.amjmed.2009.06.030. Chouhfeh L, et al. Multiple Sclerosis and Related Disorders.2015;doi:10.1016/j.msard.2015.02.004. Cojocaru M, et al. Maedica (Buchar). 2010;5:132-134. Farez MF, et al. Multiple Sclerosis International. 2014;doi:10.1155/2014/828162. Gill L, et al. J Am Acad Dermatol. 2016;doi:10.1016/j.jaad.2015.08.063. Lauret E, et al. BioMed Research International. 2013;doi:10.1155/2013/127589. Ni C, et al. Clin Cosmet Investig Dermatol. 2014;doi:10.2147/CCID.S44843 Sardu C, et al. Plos. 2012;doi:10.1371/journal.pone.0032487. Somers EC, et al. Am J Epidemiol. 2009:doi:10.1093/aje/kwn408. For more information: Regina Berkovich, PhD, MD, can be reached at 1520 San Pablo St, #3000, Los Angeles, CA 90033; email: regina.berkovich@med.usc.edu. Eric Matteson, MD, can be reached at 701 Fairview Blvd., Red Wing, MN 55066; email: theimer.sharon@mayo.edu. Emily C. Somers, PhD, ScM, can be reached at the Division of Rheumatology, University of Michigan, 3918 Taubman Center, 1500 East Medical Center Dr., Ann Arbor, MI, 48109; email: emsomers@umich.edu. Antoine G. Sreih, MD, can be reached at Perelman Center for Advanced Medicine, South Pavilion, 1st Floor, 3400 Civic Center Blvd., Philadelphia, PA 19104; email: greg.richter@uphs.upenn.edu. Disclosures: Berkovich reports she is a consultant on advisory boards for Acorda, Bayer, Biogen Idec, Questcor and Teva; and receives research support from Biogen Idec, Questcor, Teva and the National Multiple Sclerosis Society. Matteson and Somers report no relevant financial disclosures. Sreih reports research funding from Glaxo SmithKline, Roche/Genentech, Celgene, Chemocentryx and Bristol-Myers Squibb; and has consulted for Genentech, Krogg and Partners, Rupert Case Management and Naxion.
  14. Multiple sclerosis study reveals possible trigger Israeli scientists discover an abnormality in neurons’ protective membrane may enable the immune system to launch a mistaken attack. By ISRAEL21c Staff June 20, 2017, 9:00 am Multiple sclerosis, one of the most devastating neurodegenerative diseases, affects some 2.5 million people worldwide and has no known cure. Researchers have long speculated that MS is triggered by the body’s own immune system unleashing an uncontrolled attack on myelin sheaths that protect nerve cells (neurons). A study published by Israeli scientists in the Journal of the American Chemical Society (JACS) pinpoints a structural instability in the myelin membranes, the “insulating tape” surrounding neurons. This vulnerability seems to be what gives the immune system access to otherwise protected regions. “We found that small modifications in the myelin sheaths create structural instabilities that may help the immune system to enter and attack neurons,” said principal investigator Prof. Roy Beck of Tel Aviv University’s School of Physics and Astronomy and Sagol School of Neurosciences. “Current therapeutic approaches have focused on the autoimmune response without identifying a clear mechanism. Our research suggests a new avenue for multiple sclerosis therapies and diagnostics,” Beck said. Breaking down the insulation Axons, which carry electrical impulses in neurons, are surrounded by protective myelin sheaths. In MS, an autoimmune “error” mistakenly identifies these sheaths as hostile foreign entities and breaks them down. The research, conducted by Rona Shaharabani, a doctoral student in Prof. Beck’s lab, pinpoints the precise alterations to the myelin sheaths that result in structural instabilities, creating “easy access” for autoimmune attacks. “After years of research, we were amazed to discover that a possible trigger for the outbreak of the disease could be found in the membrane’s physical structure,” said Beck. Cylindrical instead of flat He explained that the lipid-and-protein building blocks of the myelin sheaths give the membrane a shape that is critical to their functioning. “If the basic building blocks are straight, the membrane will be flat, which is the preferred structure for a neuron’s ‘insulating tape,’” said Beck. “However, if they exhibit a more cone-like shape, the membrane will tend to form closed round cylinders. These produce spontaneous holes in the surface of the sheath, rendering it vulnerable to attack.” For the purpose of the research, the scientists harnessed X-ray light to examine hundreds of membrane model systems that mimicked those of healthy and diseased animal models. In collaboration with Prof. Ruth Arnon of the Weizmann Institute of Science in Rehovot, co-developer of the leading MS drug Copaxone, and Prof. Yeshayahu Talmon of the Technion-Israel Institute of Technology in Haifa, the team also used electron microscopy to determine the different nanoscopic structures of both natural myelin sheaths and model system membranes. “The next step is to find a way to reverse the disease progression and find new techniques for early detection,” said Beck. MS is "lupus of the myelin sheath." In SLE, the autommune system causes the body to attack itself via inflammation. In SLE, every body system, not just the myelin sheath, can be attacked, including body organs.
  15. EULAR publishes recommendations for women with lupus Andreoli L, et al. Ann Rheum Dis. 2017;doi:10.1136/annrheumdis-2016-209770. March 9, 2017 A team of EULAR researchers published recommendations for health issues and family planning for women with lupus or antiphospholipid syndrome. Laura Andreoli, PhD, in the Department of Clinical and Experimental Sciences at the University of Brescia in Italy, and colleagues performed a systematic review of evidence and compiled questions and expert opinions to reach a consensus. According to a published extended report, they made the following recommendations for women with lupus or antiphospholipid syndrome: family planning should be discussed after disease diagnosis; most women can have successful pregnancies, and steps can be taken to reduce adverse maternal or fetal outcomes; risk stratification includes disease activity, autoantibody profile, previous vascular morbidity, previous pregnancy morbidity, hypertension and drug use — with an emphasis on the use of hydroxychloroquine and anti-platelets or anti-coagulants; for patients with stable and inactive disease and a low risk for thrombosis, hormonal contraception and menopause replacement therapy can be used; fertility preservation with gonadotropin-releasing hormone analogues should be considered before use of alkylating agents; assisted reproduction techniques are safe for patients with stable and inactive disease; anticoagulants or low-dose aspirin should be given to patients with positive antiphospholipid antibodies; assessment of disease activity, renal function and serological markers is important to diagnose disease flares and monitor adverse obstetrical results; fetal monitoring includes Doppler ultrasonography and fetal biometry — especially in the third trimester — to screen for placental insufficiency and fetuses that are small given gestational age; gynecological malignancy screens are similar to that of the general population, but with increased vigilance for cervical premalignant lesions if patients exposed to immunosuppressive drugs; and the human papillomavirus vaccine can be given in women with stable and inactive disease. – by Will Offit Disclosure : The researchers report no relevant financial disclosures. Perspective This helpful review from EULAR represents a paradigm shift in the management of reproductive health in patients with systemic lupus erythematosus (SLE). We as physicians can ensure patients with SLE achieve healthy pregnancies starting with knowledge of contraception to prevent unwanted pregnancies, and appropriate prenatal risk stratification. With wider availability of varied contraception methods, we can offer IUDs, particularly non-hormonal copper, to all SLE patients of reproductive age. While hormonal contraception methods, such as oral contraceptive pills and patches, have been shown to be safe and effective in patients with stable disease and no APL antibodies, these methods should be used with caution in patients with increased thrombotic risk. In women who wish to become pregnant, fertility counseling should be offered with special attention to treatments which may limit fertility, including alkylating agents, and need to delay pregnancy due to disease activity. If alkylating agents cannot be avoided, preservation of fertility techniques, such as administration of gonadotropin-releasing hormone analogues can be considered. Importantly, SLE patients without risk factors such as active disease (including nephritis), antiphospholipid antibody syndrome, and Ro antibodies most often have healthy pregnancies. Strategies to prevent pregnancy complications include ensuring 6 disease-inactive prenatal months, continuing hydroxychloroquine during pregnancy, and low dose aspirin particularly in antiphospholipid antibody (APL) positive patients. Perinatal SLE may be managed using low-dose oral glucocorticoids, azathioprine or calcineurin inhibitors. APL-positive patients should get ultrasounds and biometric parameters, particularly during the third trimester to screen for placental insufficiency and small for gestational age fetuses. Ro-positive patients should be screened for fetal congenital heart block in the second trimester. Emerging evidence suggests hydroxychloroquine may significantly reduce CHB risk particularly in Ro-positive mothers with prior affected pregnancies. Finally, apart from cervical dysplasia due to human papillomavirus (HPV), gynecological malignancies do not have increased prevalence in SLE, therefore screening should follow age appropriate protocols. All young women with SLE should be offered HPV vaccination. Ashira D. Blazer, MD Instructor of Medicine Division of Rheumatology NYU Langone Medical Center New York Disclosures: Blazer reports no relevant financial disclosures.
  16. Longterm hydroxychloroquine therapy may reduce cardiovascular events in SLE June 16, 2017 MADRID — Long-term use of hydroxychloroquine was associated with reduced cardiovascular risks in a cohort of patients with systemic lupus erythematosus,according to findings presented at the EULAR Annual Congress. “[Systemic lupus erythematosus] SLE may be considered a coronary heart disease condition,” Serena Fasano, MD, of the Rheumatology Unit at the University of Campania Luigi Vanvitelli in Naples, said. “Patients should be investigated for traditional and SLE-related risk factors. SLE patients are candidates for aspirin prophylaxis and long-term hydroxychloroquine. Statins are recommended for patients with persistently high LDL cholesterol levels.” The aim of the study was to assess the role of aspirin, hydroxychloroquine and statins as primary prophylaxis of cardiovascular events in SLE. The study included clinical chart reviews of 291 patients with 8 years of follow-up. “The primary outcome was the first cardiovascular event,” Fasano said. Results showed 16 events in that time. There were seven myocardial infarctions and two strokes in the group. The event-free rate was higher in the 120 patients treated with low-dose aspirin (hazard ratio = 0.27) and hydroxychloroquine for more than 5 years (HR = 0.26) than in 98 patients who were treated with aspirin alone or hydroxychloroquine for fewer than 5 years. “Low-dose aspirin and hydroxychloroquine were negative predictors of events,” Fasano said. No such association was reported for statins. Smoking, obesity, hypertriglyceridemia, diabetes mellitus, disease activity, severe SLE, or use of immunosuppressive agents or steroids failed to demonstrate any kind of association with cardiovascular events, according to Fasano. Multivariable analysis results showed the associations between low-dose aspirin (HR = 0.24) or hydroxychloroquine use for longer than 5 years (HR = 0.27) and reduced incidence of cardiovascular events persisted. — by Rob Volansky Reference: Fasano S, et al. Abstract #OP0233. Presented at: EULAR Annual Congress; June 14-17, 2017; Madrid. Disclosure: The researchers report no relevant financial disclosures. Measure Measure
  17. Medication Use Among Pregnant Women With Systemic Lupus Erythematosus and General Population Comparators Kristin Palmsten; Julia F. Simard; Christina D. Chambers; Elizabeth V. Arkema Rheumatology. 2017;56(4):561-569. Abstract and Introduction Abstract Objective. The aim was to characterize SLE medication trends before, during and after pregnancy and to compare other commonly used medications during SLE pregnancies with non-SLE pregnancies. Methods. Women with pregnancies ending in live birth or stillbirth were identified from the Swedish Medical Birth Register (2006–12). National registers were used to identify women with prevalent SLE during pregnancy and a sample without SLE and to identify prescription medications dispensed from 3 months pre-pregnancy until 6 months postpartum. We reported the prevalence of DMARDs, systemic CSs and NSAIDs (aspirin reported separately) in SLE pregnancies. We calculated prevalence estimates of other medications that were dispensed during pregnancy to ≥ 5% of SLE pregnancies and for the same medications among non-SLE pregnancies. Results. There were 483 pregnancies among women with SLE and 5723 pregnancies among women without SLE. In SLE pregnancies, 49.3% had one or more dispensing for DMARDs during pregnancy; the prevalence was 48.0% for CSs, 40.8% for aspirin and 6.0% for other NSAIDs and varied by pregnancy period. The prevalence of common medications among SLE pregnancies was 1.2- to 20-fold higher than among non-SLE pregnancies; for example, dalteparin (20.9 vs 1.0%), paracetamol (18.2 vs 2.9%) and levothyroxine (15.9 vs 4.9%). Conclusion. In nearly half of SLE pregnancies, women were dispensed DMARDs and CSs. Commonly used medications in SLE pregnancies had far higher prevalence estimates compared with non-SLE pregnancies. Research regarding benefits and risks of commonly used medications on SLE pregnancies, breast milk and long-term outcomes for offspring is needed. Introduction The incidence of SLE is greatest among women of reproductive ages.[1] Decisions regarding medication use during pregnancy are crucial for women with this multisystem autoimmune disease. Treatment with immunosuppressants, CSs and NSAIDs during pregnancy may be indicated to treat flares or to keep disease activity under control.[2] Other medications may also be used during pregnancy to treat co-morbidities that are more common among individuals with SLE (e.g. APS, hypertension and depression).[3,4] The most prevalent prescription medications among pregnant women in general include antibacterials and antihistamines,[5] and these may also be used commonly in SLE pregnancies. There is limited information regarding medication use among pregnant women with SLE. Most reports from the past 15 years are based on a few hundred women or less and are often from women who attended one health-care centre, which limits generalizability.[6–14] Previous reports tended to focus on medications used to treat SLE, including HCQ, AZA and CSs, and few addressed heparin or other medications.[6,8,11,13,15] There is limited information regarding the timing and trajectory of medication use before, during and, especially, after SLE pregnancies.[7,10,11,14,16] To our knowledge, no studies have compared medication use among pregnant women with SLE vs women without SLE. Besides rheumatologists, other physicians, including obstetricians and general practitioners, prescribe medications for pregnant women with SLE. The spectrum of commonly used medications among pregnant women with SLE may not be apparent to their health-care providers. A more holistic approach to studying medication use among pregnant women with SLE is needed to gain a better understanding of the medication counselling needs of women with SLE who are pregnant or are planning pregnancy. We used population-based health register data from Sweden to address the limited information on medication use among pregnant women with SLE. We identified the most prevalent medications among SLE pregnancies, characterized pre-pregnancy, pregnancy and postpartum medication prevalence, and compared medication prevalence among SLE pregnancies with non-SLE pregnancies. Methods Study Population Women With Pregnancies. Nearly all deliveries in Sweden (>98%) are captured by the Medical Birth Register (MBR), which contains standardized information on maternal health during pregnancy, delivery and neonatal outcomes.[5,17] Pregnancies with a delivery date between 5 August 2006 and 31 December 2012 were included in this study. For most of the study, the MBR captured births from 22 weeks gestation onward. However, between 2006 and 1 July 2008, stillbirths were included only if they occurred at 28 gestational weeks or later. Women could have multiple pregnancies captured during the study period. Women With SLE. To identify women with SLE, we used the MBR and the National Patient Register, which contains information from hospitalizations since 1964, with complete nationwide coverage beginning in 1987, and from hospital-based outpatient specialist visits since 2001. The first SLE diagnosis for women included in this study occurred in 1977. Women were classified as having prevalent SLE during each pregnancy if they had the following: (i) at least two discharges from either inpatient or outpatient records with diagnosis codes indicative of SLE [International Classification of Diseases (ICD), Eighth, Ninth or Tenth Revision, ICD-8 734.1, ICD-9 710.0 or ICD-10 M32], excluding drug-induced lupus, and including at least one SLE diagnosis from a department or specialist that typically diagnoses, treats or manages SLE (rheumatology, dermatology, nephrology, internal medicine and paediatrics) and at least one SLE diagnosis before the beginning of pregnancy; or (ii) at least one SLE discharge diagnosis from a department or specialist as described above and at least one self-reported diagnosis of SLE in the MBR for the current pregnancy. Using Swedish registers, it has been shown that two inpatient or outpatient SLE diagnoses, including one from a specialist, accurately identifies women with SLE.[18] Similar case definitions yielded prevalence estimates of ~100 SLE cases per 100 000 women of child-bearing age in the Swedish registers, which demonstrates face validity of the definition.[19] Women Without SLE. Women without prevalent SLE during pregnancy were identified from individuals who were sampled from the Total Population Register as previously described.[20] Women without pregnancies or women with pregnancies ending prior to 28 weeks (2006–07) or 22 weeks (2008–12) were excluded. Maternal and Pregnancy Characteristics Maternal characteristics, including age, pre-pregnancy BMI and parity, were obtained from the MBR as were multiple gestation and gestational weeks at delivery. Maternal diagnoses before or during pregnancy, including asthma, chronic hypertension, type I or type II diabetes, mood disorders and APS, were obtained from the National Patient Register any time before delivery. We used a strict definition of APS (ICD-10 code D68.6: other thrombophilia) and a broad definition of APS (ICD-10 code O99.1: Other diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism complicating pregnancy, childbirth and the puerperium). The date of the last menstrual period (LMP) was obtained from the MBR. The LMP date was most often estimated using prenatal ultrasound (89%); otherwise, maternal report of the first day of the LMP was used.[21] Medications Prescribed Drug Register. The prescribed drug register, which was established in July 2005, contains information on prescription medications dispensed outside of hospitals, including Anatomical Therapeutic Chemical (ATC) classification code and date of dispensing.[22] In Sweden, prescription drugs are provided free of charge above a specified high-cost threshold (SEK 2200 in 2014).[23] Women were linked to the prescribed drug register to identify prescription medications dispensed in the 3 months before pregnancy until 6 months after pregnancy. No information is available on i.v. infusions or medications obtained over the counter. Timing. Women could have multiple dispensings for the same medication within a pregnancy. The timing of dispensing of medication was classified relative to the estimated date of the LMP and the delivery date. We defined medication prevalence as the proportion of pregnancies with at least one dispensing date for medications of interest during each of the following periods of interest: pregnancy, LMP date until the day before the delivery date; pre-pregnancy, 94 days before LMP date until the day before the LMP date; first trimester, LMP date until 93 days after the LMP date; second trimester, 94 days after the LMP date until 187 days after the LMP date; third trimester, 188 days after the LMP date until the day before the delivery date; first postpartum, delivery date until 93 days after the delivery date; and second postpartum, 94 days after the delivery date until 187 days after the delivery date. SLE-related Medications. We reported the prevalence of medications used to treat SLE across pregnancy periods among SLE pregnancies according to medication name and class (i.e. DMARDs, systemic CSs and NSAIDs, with aspirin reported separately). In addition to more commonly prescribed DMARDs in SLE, such as AZA, MTX and HCQ, we searched for less commonly prescribed DMARDs, such as LEF and SSZ (see supplementary material Table S1 , available at Rheumatology Online, for the complete list). We stratified the four classes by term and preterm deliveries (<37 weeks gestation). The working group on anti-rheumatic drugs during pregnancy and lactation at the Fourth International Conference on Sex Hormones, Pregnancy and the Rheumatic Diseases published a recommendation in 2006 to continue HCQ during pregnancy.[24] Therefore, we conducted a secondary analysis to determine whether the prevalence of HCQ increased after the recommendation. Specifically, we stratified the prevalence of HCQ and prednisolone, separately, dispensed during pregnancy by early (2006–07) and late (2008–12) study years. Prednisolone served as a control medication, and we expected the prevalence of this medication to be similar in early and late study years. We compared prevalence estimates in early and late years using χ2 tests. Most commonly used medications among SLE pregnancies. We identified medications or vitamins/supplements that were dispensed during pregnancy to at least 5% of pregnancies with SLE using fifth level ATC classification codes; the fifth level identifies the chemical substance.[25] We calculated the prevalence of these treatments among SLE pregnancies and separately among pregnancies from the general population. Then we used generalized estimating equations to calculate prevalence ratios and 95% CIs accounting for dependence among women with more than one observed pregnancy.[26] In SLE pregnancies, we stratified prevalence estimates by pregnancy periods. Finally, we identified medication or vitamins/supplement groups that were dispensed during pregnancy to ≥5% of SLE pregnancies using the fourth level of ATC codes; the fourth level identifies the chemical/pharmacological/therapeutic subgroups.[25] We reported prevalence estimates for fourth level groups that did not have complete overlap with treatments identified from the fifth level codes. This project was approved by the Ethical Review Board of Karolinska Institute (PROTOKOLL 2011/1:7) on 20 July 2011 and declared exempt by Stanford University and the University of California, San Diego's Institutional Review Board. Results with five or fewer individuals were suppressed. Results Cohort Characteristics We identified 483 pregnancies from 391 women with prevalent SLE and 5723 pregnancies from 4322 women without SLE. There were nine women diagnosed with SLE before the age of 16 years. SLE pregnancies had shorter gestational duration on average than non-SLE pregnancies ( ). Co-morbidities, including asthma, hypertension, diabetes and mood disorders, were more common among women with SLE than without SLE. Between 5 and 15% of SLE pregnancies also had a diagnostic code related to APS. Table 1. Maternal and pregnancy characteristics in women with and without SLE Maternal and pregnancy characteristics With SLE, n = 483 Without SLE, n = 5723 Age, mean (s.d.), years 31.7 (4.7) 31.6 (4.9) BMI, mean (s.d.), kg/m2 24.2 (4.1) 24.7 (4.6) Gestational weeks at delivery, mean (s.d.) 37.8 (3.3) 39.3 (1.9) Parity, n (%) 1 226 (46.8) 2358 (41.2) 2 180 (37.3) 2178 (38.1) 3 54 (11.2) 834 (14.6) 4 or more 23 (4.8) 353 (6.2) Multiple gestation, n (%) 9 (1.9) 93 (1.6) Asthma, n (%) 25 (5.2) 193 (3.4) Hypertension, n (%) 29 (6.0) 15 (0.3) Type I or type II diabetes, n (%) 9 (1.9) 37 (0.6) Mood disorder, n (%) 38 (7.9) 325 (5.7) APS, strict definition, n (%) 25 (5.2) 0 (0) APS, broad definition, n (%) 71 (14.7) 36 (0.6) SLE-related Medications In SLE pregnancies, 49.3% had one or more dispensing for DMARDs during pregnancy, 48.0% for CSs, 40.8% for aspirin and 6.0% for other NSAIDs. The prevalence of these medications varied by pregnancy period ( ). The highest prevalence estimates were observed in the postpartum periods with the exception of aspirin, which was highest in the first and second trimesters. HCQ was the most prevalent DMARD during pregnancy (36.4%), followed by AZA (20.7%). The prevalence estimate for HCQ was highest in the first trimester and during the second postpartum period, whereas the prevalence estimate for AZA prevalence was highest in the first and second trimesters. There were no prescribed drug register-registered biologic DMARDs dispensed during pregnancy. MTX dispensings during pregnancy were rare and occurred in five or fewer individuals. There were no dispensings for mycophenolic acid during pregnancy in this cohort. Prednisolone was the most prevalent CS during pregnancy (46.2%). The prevalence of HCQ during pregnancy in 2008–12 was higher than in 2006–07 (39.1 vs 23.8%, P < 0.01), whereas the prevalence of prednisolone was similar in both time periods (46.4 vs 45.2%, P = 0.95). Table 2. SLE-related medication dispensing prevalence by pregnancy period in women with SLE Medication group Medication name During pregnancya Pre-pregnancy Trimester 1 Trimester 2 Trimester 3 Postpartum 1 Postpartum 2 (%) (%) (%) (%) (%) (%) (%) DMARDs 49.3 35.4 38.9 36.7 28.6 37.1 40.4 HCQ 36.4 23.4 28.0 25.5 20.1 25.9 30.0 AZA 20.7 14.3 16.6 16.6 11.6 14.3 11.2 Ciclosporin 1.9 1.9 1.5 1.7 1.2 1.5 1.2 Chloroquine 1.7 2.1 NA NA NA 1.5 1.2 Other DMARDb NA 1.7 NA NA NA 1.7 4.4 CSs 48.0 29.8 31.5 35.8 32.5 40.0 34.2 Prednisolone 46.2 28.2 30.4 34.4 30.6 38.1 33.1 Betamethasone 1.7 1.5 NA NA 1.2 2.1 NA Other CSc 1.5 NA NA NA NA 1.2 NA Aspirin 40.8 6.4 28.2 32.1 17.2 8.7 6.2 Other NSAIDs 6.0 8.5 5.0 NA NA 11.0 8.1 Diclofenac 1.9 2.7 NA NA NA 6.8 2.5 Naproxen 1.7 2.1 1.7 NA 0 1.2 2.7 NSAIDs excluding aspirin, diclofenac and naproxend 2.5 4.4 2.3 NA 0 3.1 3.3 aDuring pregnancy includes trimesters 1, 2 and 3. bIncludes the following medications with n ≤ 5 during pregnancy: SSZ, mycophenolic acid, etanercept and MTX. cIncludes the following medications with n ≤ 5 during pregnancy: methylprednisolone, prednisone and dexamethasone. dIncludes the following medications with n ≤ 5 during pregnancy: ibuprofen, ketoprofen, dexibuprofen, celecoxib, etoricoxib and nabumetone. NA: there are five or fewer individuals. In SLE pregnancies, 28% had no DMARD and no CS dispensings during pregnancy. When considering the three major SLE treatments, that is, HCQ, AZA and prednisolone, 14% had dispensings for HCQ only during pregnancy, 2% had dispensings for AZA only, 17% had dispensings for prednisolone only and 32% had dispensings for at least two of these treatments. Term pregnancies had a mean gestational length of 275.8 days (s.d. 9.1) or 39 completed weeks, and preterm pregnancies had a mean gestational length of 231.5 days (s.d. 28.4) or 33 completed weeks. DMARD and CS pregnancy period-specific prevalence estimates stratified by preterm birth status are presented for SLE pregnancies in Fig. 1. Aspirin prevalence is not presented in the figure because prevalence estimates did not vary greatly between term and preterm deliveries. Other NSAID prevalence is not presented because some results had fewer than five individuals. Compared with term deliveries, DMARD prevalence was higher in the first (47.3 vs 36.9%) and second (49.5 vs 33.6%) trimesters in preterm deliveries. In the third trimester, DMARD prevalence for preterm deliveries dipped below that of term deliveries (22.6 vs 30.0%). Postpartum DMARD prevalence rebounded to ~50% for preterm deliveries. The pattern observed for CSs was similar to that for DMARDs. Figure 1. Proportion of SLE pregnancies with one or more dispensing for DMARDs or CSs, by pregnancy period Most Common Medications The prevalence of common medications among SLE pregnancies was 1.2- to 21-fold higher than among non-SLE pregnancies ( ); for example, dalteparin (20.9 vs 1.0%), paracetamol (18.2 vs 2.9%), levothyroxine (15.9% vs 4.9%), phenoxymethylpenicillin (also known as penicillin V; 14.3 vs 11.6%), pivmecillinam (10.8 vs 4.7%) and omeprazole (10.4 vs 2.3%). Supplements dispensed at the pharmacy, including calcium, folic acid, ferrous sulphate and cyanocabalmin, were 4- to 33-fold higher than among non-SLE pregnancies. Table 3. Non SLE-related medicationsa dispensed to at least 5% of SLE pregnancies, by SLE status Medication group SLE, n = 483 Non-SLE, n = 5723 PRb (95% CIc) Medication name n (%) n (%) Supplements Calcium, combinations with vitamin D or other drugs 106 (22.0) 38 (0.66) 33.05 (22.22, 49.16) Folic acid 53 (11.0) 134 (2.3) 4.69 (3.39, 6.48) Ferrous sulphate 34 (7.0) 48 (0.84) 8.39 (5.39, 13.08) Cyanocabalamin 30 (6.2) 90 (1.6) 3.95 (2.61, 5.97) Low-molecular weight heparins Dalteparin 101 (20.9) 57 (1.0) 21.00 (14.91, 29.57) Tinzaparin 41 (8.5) 15 (0.26) 32.39 (16.73, 62.71) Antibiotics Phenoxymethylpenicillin (penicillin V) 69 (14.3) 664 (11.6) 1.23 (0.97, 1.57) Pivmecillinam 52 (10.8) 268 (4.7) 2.30 (1.70, 3.11) Nitrofurantoin 35 (7.3) 272 (4.8) 1.52 (1.08, 2.16) Nasal or cough and cold preparations Mucolytic combinations 31 (6.4) 218 (3.8) 1.68 (1.15, 2.47) Opium derivatives and expectorants 36 (7.5) 249 (4.4) 1.71 (1.21, 2.43) Phenylpropanolamine 26 (5.4) 235 (4.1) 1.31 (0.89, 1.94) Other medications Paracetamol 88 (18.2) 167 (2.9) 6.24 (4.81, 8.11) Levothyroxine sodium 77 (15.9) 282 (4.9) 3.24 (2.50, 4.19) Omeprazole 50 (10.4) 129 (2.3) 4.59 (3.27, 6.45) Codeine, combinations excluding psycholeptics 35 (7.3) 132 (2.3) 3.14 (2.18, 4.52) Promethazine 34 (7.0) 288 (5.0) 1.40 (0.97, 2.03) Clemastine 33 (6.8) 276 (4.8) 1.42 (0.98, 2.06) Carbamide 27 (5.6) 67 (1.2) 4.77 (2.97, 7.68) Prevalence ratio (PR) and 95% CI. aMost common medications are those with a prevalence ≥5% during pregnancy. bReference = SLE pregnancies. c95% CIs account for multiple pregnancies per woman. The prevalence estimates for medications dispensed to at least 15% of SLE pregnancies are plotted in Fig. 2 according to pregnancy period (see supplementary material Table S2 , available at Rheumatology Online, for all commonly used medications). Dalteparin had the greatest change; from a high of 18.0% in the second trimester to a low of 1.2% in the second postpartum period. Levothyroxine prevalence was highest in the second and third trimesters. Figure 2. Non-SLE-related medications dispensed to at least 15% of SLE patients, by pregnancy period *Calcium, combinations with vitamin D or other drugs. Groups with fourth level ATC codes that did not directly overlap with fifth level ATC codes included the following: heparin group (27.5% SLE vs 1.2% non-SLE); penicillins with extended spectrum (13.7 vs 7.1%); proton pump inhibitors (12.0 vs 2.6%); iron bivalent, oral preparations (10.4 vs 1.5%); phenothiazine derivatives (9.1 vs 7.7%), for example, promethazine; natural opium alkaloids (8.1 vs 2.4%), for example, codeine; aminoalkyl ethers (6.8 vs 4.9%), for example, clemastine; mucolytics (6.8 vs 4.1%), for example, acetylcysteine; and caries prophylactic agents (5.4 vs 1.6%), for example, sodium fluoride. Discussion This descriptive population-based study demonstrates that pregnant women with SLE are a highly medicated group. In nearly half of SLE pregnancies, women were dispensed DMARDs and CSs. Compared with term SLE pregnancies, SLE pregnancies with preterm delivery had higher prevalence estimates for CSs across each pregnancy period. Postpartum CS prevalence was particularly high for pregnancies with preterm delivery in the 90 days postpartum; three out of five were dispensed a CS. Women with preterm births may have had more severe disease, and the increase in CS prevalence during the postpartum period for women with preterm births may reflect the need to treat disease flares. In two out of five SLE pregnancies, women were dispensed aspirin, primarily during the first and second trimesters. There were major differences in prevalence estimates between commonly used medications and supplements in SLE pregnancies vs non-SLE pregnancies. HCQ prevalence during pregnancy was higher in this study than in several previous reports.[8,11,13,14,27] The previous studies included several years prior to the 2006 recommendation that endorsed continuation of HCQ treatment during pregnancy and, consequently, time trends could contribute to the discrepancies. In the present study, HCQ prevalence was higher in later study years. Compared with previous studies, CS prevalence during pregnancy in Sweden was lower than reports from single hospital cohorts in Asia, Saudi Arabia and Argentina (71–89%)[6,8,12,14,27] and was similar to reports from hospital cohorts in the USA and Denmark (36–48%).[11,13] Aspirin prevalence varied greatly across previous studies of SLE pregnancies (9–60%),[6–8,11,13,14] and the estimate in this study was similar to that from the hospital-based cohort in Denmark (39%).[11] In previous studies, anti-hypertensives, as a broad therapeutic class, have been reported to have a relatively high prevalence (13–29%).[6,11,13] In this cohort of pregnancies, anti-hypertensive medications, at the fourth or fifth ATC level, had prevalence estimates of < 5% during pregnancy. MTX and mycophenolic acid are teratogenic exposures and are contraindicated during pregnancy.[28]Only rarely was a MTX dispensing during pregnancy observed in this cohort. This study provides population-based snapshots of medications dispensed across the antenatal and postpartum periods in SLE pregnancies. Pregnancies with preterm delivery had an average gestational length that was 44 days shorter than term pregnancies. The shortened opportunity to obtain prescriptions contributed to the decreased prevalence of DMARDs and CSs that was observed among preterm deliveries only in the third trimester. If the majority of individuals were given a 30 day supply for all prescriptions, we may have not observed as large a decrease in the final trimester. Overall, DMARD prevalence estimates increased from pre-pregnancy to the first trimester, decreased in the third trimester and increased postpartum, and CS prevalence estimates increased from pre-pregnancy to the first postpartum period, with the exception of a dip during the third trimester. Fifteen of the commonly dispensed medications that were identified among SLE pregnancies had prevalence estimates that were at least 50% higher among SLE pregnancies vs non-SLE pregnancies and many reflect treatment for conditions or symptoms that co-occur with SLE. Dalteparin and tinzaparin were among the most commonly dispensed medications. These low-molecular weight heparins, among others, are indicated for women with aPL and a history of obstetric complications.[29]The prevalence of levothyroxine sodium during pregnancy was 3.2-fold higher among SLE pregnancies compared with general population pregnancies, which is consistent with the higher prevalence of hypothyroidism among women with SLE.[30]Omeprazole prevalence was 4.6-fold higher during pregnancy among SLE pregnancies compared with non-SLE pregnancies, which is consistent with heartburn being a common symptom among individuals with SLE.[31] Prevalence estimates for penicillin antibiotics, that is, phenoxymethylpenicillin and pivmecillinam, and nitrofurantoin were higher among SLE pregnancies compared with pregnancies from the general population, which reflects the increased susceptibility of SLE patients to infection owing to both abnormal immunological response and immunosuppressive treatments.[32] Paracetamol prevalence was 6.2-fold higher among SLE pregnancies and codeine prevalence 3.1-fold higher among SLE pregnancies compared with non-SLE pregnancies. The prevalence estimates for several supplements (calcium combinations, folic acid, ferrous sulphate and cyanocobalamin) were much higher in the SLE population than the in non-SLE population. Women with SLE are at increased risk for osteoporosis, and calcium with vitamin D is recommended for women treated with heparin during pregnancy.[33,34]Furthermore, a high prevalence of anaemia and decreased serum B12 levels have been observed among non-pregnant individuals with SLE.[35] It is possible that women with SLE are more likely to have reached the annual high-cost threshold[23]and receive all of their prescriptions free compared with women without SLE. Women who meet the high-cost threshold have an incentive to obtain over-the-counter medications as prescriptions. Consequently, the observed imbalance in medications that are also available over the counter, for example, paracetemol and supplements, between women with SLE and women without SLE could be attributed in part to women with SLE obtaining these medications by prescription. Pharmaceutical dispensing data are useful to understand not only what physicians prescribed during pregnancy but also what prescriptions patients filled. Compared with prescribing information, dispensing information is more similar to real use. The date of dispensing does not necessarily mean that the drug was taken on the day when it was dispensed, or at all, but it can be used as a proxy for exposure. For some drugs this may be more accurate than for others. For example, one study found that agreement between self-reported and dispensed immunosuppressant therapy was high, but for CSs the agreement was low.[5]Furthermore, the data in the present study do not include infusions, such as some biological DMARDs, nor the number of days of medication supplied for each dispensing. Besides the potential for exposure misclassification, this study has some additional limitations to consider. First, there could be misclassification of SLE because of our reliance on ICD codes to identify SLE, although this is likely to be minimal considering the findings from previous studies.[18,19] Second, there may be measurement error of the pregnancy time windows because the windows are based on the estimated date of the LMP. However, for the majority of pregnancies, the date of the LMP was estimated using ultrasound. Third, medications that cause fetal harm may be underestimated because pregnancies ending in spontaneous abortions and terminations are not included. To our knowledge, this is the first population-based study to describe the prevalence of medications used to treat SLE before, during and after pregnancy. Our study is also novel because it identifies the most common medications in SLE pregnancies, not only the medications that are used to treat SLE. As such, it provides practitioners with a robust picture of medication use during pregnancy among SLE patients, beyond the medications they typically prescribe. Moreover, our study provides perspective by contrasting prevalence estimates with non-SLE pregnancies. A major strength of our study is that data were collected prospectively throughout pregnancy and avoids recall problems. We anticipate that our results are generalizable to most other populations because some medications used to manage SLE in the absence of pregnancy are contraindicated, leaving few treatment options in pregnancy. In future research, the population-based approach to study medication use among pregnant women with SLE should be implemented in other counties. Pregnant women with SLE are commonly dispensed medications. This includes not only DMARDs and CSs to treat and/or prevent flares, but numerous other medications to treat co-morbidities associated with SLE. For clinicians, it is crucial to consider the risks and benefits of all medications used in SLE pregnancies. For researchers, medications that are commonly used among women with SLE should be accounted for when studying associations between SLE-related medications and pregnancy outcomes. Research regarding the benefits and risks of these commonly used medications and their combinations on SLE pregnancies, breast milk and long-term outcomes for offspring is needed. We plan to study the associations between medication exposures and pregnancy outcomes within this cohort. Sidebar Rheumatology Key Messages Pregnant women with SLE are commonly dispensed medications. Nearly half of lupus pregnancies in Sweden used DMARDs, CSs or aspirin. Many medications besides DMARDs are used more often in SLE pregnancies than in non-SLE pregnancies. References Siegel M, Lee SL. The epidemiology of systemic lupus erythematosus. Semin Arthritis Rheum 1973;3:1–54. Clowse ME. Lupus activity in pregnancy. Rheum Dis Clin North Am 2007;33:237–52, v. Clowse ME, Jamison M, Myers E, James AH. A national study of the complications of lupus in pregnancy. Am J Obstet Gynecol 2008;199:127.e1–6. van Exel E, Jacobs J, Korswagen LA et al. Depression in systemic lupus erythematosus, dependent on or independent of severity of disease. Lupus 2013;22:1462–9. Stephansson O, Granath F, Svensson T et al. Drug use during pregnancy in Sweden – assessed by the Prescribed Drug Register and the Medical Birth Register. Clin Epidemiol 2011;3:43–50. Aggarwal N, Raveendran A, Suri V et al. Pregnancy outcome in systemic lupus erythematosus: Asia's largest single centre study. Arch Gynecol Obstet 2011;284:281–5. Imbasciati E, Tincani A, Gregorini G et al. Pregnancy in women with pre-existing lupus nephritis: predictors of fetal and maternal outcome. Nephrol Dial Transplant 2009;24:519–25. Cavallasca JA, Laborde HA, Ruda-Vega H, Nasswetter GG. Maternal and fetal outcomes of 72 pregnancies in Argentine patients with systemic lupus erythematosus (SLE). Clin Rheumatol 2008;27:41–6. Clowse ME, Magder L, Witter F, Petri M. Hydroxychloroquine in lupus pregnancy. Arthritis Rheum 2006;54:3640–7. Georgiou PE, Politi EN, Katsimbri P, Sakka V, Drosos AA. Outcome of lupus pregnancy: a controlled study. Rheumatology 2000;39:1014–9. Jakobsen IM, Helmig RB, Stengaard-Pedersen K. Maternal and foetal outcomes in pregnant systemic lupus erythematosus patients: an incident cohort from a stable referral population followed during 1990–2010. Scand J Rheumatol 2015;44:377–84. Teh CL, Wong JS, Ngeh NK, Loh WL. Systemic lupus erythematosus pregnancies: the Sarawak experience and review of lupus pregnancies in Asia. Rheumatol Int 2011;31:1153–7. Chakravarty EF, Colón I, Langen ES et al. Factors that predict prematurity and preeclampsia in pregnancies that are complicated by systemic lupus erythematosus. Am J Obstet Gynecol 2005;192:1897–904. Koh JH, Ko HS, Kwok SK, Ju JH, Park SH. Hydroxychloroquine and pregnancy on lupus flares in Korean patients with systemic lupus erythematosus. Lupus 2015;24:210–7. Buyon JP, Kim MY, Guerra MM et al. Predictors of pregnancy outcomes in patients with lupus: a cohort study. Ann Intern Med 2015;163:153–63. Desai RJ, Huybrechts KF, Bateman BT et al. Brief report: Patterns and secular trends in use of immunomodulatory agents during pregnancy in women with rheumatologic conditions. Arthritis Rheumatol 2016;68:1183–9. Cnattingius S, Ericson A, Gunnarskog J, Källén B. A quality study of a medical birth registry. Scand J Soc Med 1990;18:143–8. Arkema EV, Jönsen A, Rönnblom L et al. Case definitions in Swedish register data to identify systemic lupus erythematosus. BMJ Open 2016;6:e007769. Simard JF, Sjöwall C, Rönnblom L, Jönsen A, Svenungsson E. Systemic lupus erythematosus prevalence in Sweden in 2010: what do national registers say? Arthritis Care Res 2014;66:1710–7. Arkema EV, Simard JF. Cohort profile: systemic lupus erythematosus in Sweden: the Swedish Lupus Linkage (SLINK) cohort. BMJ Open 2015;5:e008259. Høgberg U, Larsson N. Early dating by ultrasound and perinatal outcome. A cohort study. Acta Obstet Gynecol Scand 1997;76:907–12. Wettermark B, Hammar N, Fored CM et al. The new Swedish Prescribed Drug Register—opportunities for pharmacoepidemiological research and experience from the first six months. Pharmacoepidemiol Drug Saf 2007;16:726–35. TLV. What is the high cost threshold? How it works. http://www.tlv.se/In-English/medicines-new/the-swedish-highcost-threshold/how-it-works/ (2 October 2015, date last accessed). Østensen M, Khamashta M, Lockshin M et al. Anti-inflammatory and immunosuppressive drugs and reproduction. Arthritis Res Ther 2006;8:209. ATC Structure and principles. http://www.whocc.no/atc/structure-and-principles/. (15 September 2015, date last accessed). Zou GY, Donner A. Extension of the modified Poisson regression model to prospective studies with correlated binary data. Stat Methods Med Res 2013;22:661–70. Al Arfaj AS, Khalil N. Pregnancy outcome in 396 pregnancies in patients with SLE in Saudi Arabia. Lupus 2010;19:1665–73. Običan S, Scialli AR. Teratogenic exposures. Am J Med Genet C Semin Med Genet 2011;157C:150–69. Baer AN, Witter FR, Petri M. Lupus and pregnancy. Obstet Gynecol Surv 2011;66:639–53. Antonelli A, Fallahi P, Mosca M et al. Prevalence of thyroid dysfunctions in systemic lupus erythematosus. Metabolism 2010;59:896–900. Ebert EC, Hagspiel KD. Gastrointestinal and hepatic manifestations of systemic lupus erythematosus. J Clin Gastroenterol 2011;45:436–41. Sciascia S, Cuadrado MJ, Karim MY. Management of infection in systemic lupus erythematosus. Best Pract Res Clin Rheumatol 2013;27:377–89. Ruiz-Irastorza G, Khamashta MA, Hughes GR. Heparin and osteoporosis during pregnancy: 2002 update. Lupus 2002;11:680–2. Di Munno O, Mazzantini M, Delle Sedie A, Mosca M, Bombardieri S. Risk factors for osteoporosis in female patients with systemic lupus erythematosus. Lupus 2004;13:724–30. Segal R, Baumoehl Y, Elkayam O et al. Anemia, serum vitamin B12, and folic acid in patients with rheumatoid arthritis, psoriatic arthritis, and systemic lupus erythematosus. Rheumatol Int 2004;24:14–9. Funding This work was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health [K01-AR06687801]. Rheumatology. 2017;56(4):561-569. © 2017 Oxford University Press http://www.medscape.com/viewarticle/880421?src=wnl_edit_tpal&uac=60604BR
  18. Ben-Gurion U and Sheba Medical Center scientists announce creation of nano-polymer that may be better than statins BY SHOSHANNA SOLOMON May 22, 2017 Researchers at Ben-Gurion University of the Negev and the Sheba Medical Center said they have have developed a way to treat atherosclerosis and prevent heart failure with a new biomedical polymer that reduces arterial plaque and inflammation in the cardiovascular system. E SIGN UP! Atherosclerotic cardiovascular disease causes 56 million deaths annually worldwide, according to the 2015 Lancet Global Burden of Disease Report. Arteries are lined by a thin layer of cells called the endothelium which keep them toned and smooth and maintain blood flow. Atherosclerosis begins with damage to the endothelium and is caused by high blood pressure, smoking or high cholesterol. The resulting damage leads to plaque formation. When endothelial cells become inflamed, they produce a molecule called E-selectin that brings white blood cells (monocytes) to the area and causes plaque accumulation in the arteries. “Our E-selectin-targeting polymer reduces existing plaque and prevents further plaque progression and inflammation, preventing arterial thrombosis, ischemia, myocardial infarction, and stroke,” said Prof. Ayelet David of the BGU Department of Clinical Biochemistry and Pharmacology in a statement. BGU’s Prof. Ayelet David (Dani Machlis/BGU) This new nano-polymer has several advantages, the researchers said. First, it reverses arterial damage and improves the heart muscle. At present, there are several available treatment options for atherosclerosis, but no other therapy reverses arterial damage and improves the heart muscle. Also, the polymer targets only damaged tissue and does not harm healthy tissue so it has no side effect — unlike statins, which are currently the leading medication used for treating atherosclerosis. Patented and in preclinical stage, the new polymer has been tested on mice with positive results. In a study that has been submitted for publication, the researchers treated atherosclerotic mice with four injections of the new biomedical polymer and tested the change in their arteries after four weeks. “We were stunned by the results,” said Prof. Jonathan Leor, director of the Cardiovascular Research Institute of the Sheba Medical Center and professor of cardiology at Tel Aviv University, who collaborated with David on the research study. “The myocardial function of the treated mice was greatly improved; there was less inflammation and a significant decrease in the thickness of the arteries.” “We achieved an adherence level similar to that of an antibody, which may explain the strong beneficial effect we observed,” said David. David and Leor suggested that this polymer-based therapy can also be helpful to people with diabetes, hypertension and other age-related conditions, impacting the lives of millions of people. “We are now seeking a pharmaceutical company to bring our polymer therapy through the next stages of drug development and ultimately to market,” said Dr. Ora Horovitz, senior vice president of business development at BGN Technologies, BGU’s technology and commercialization company.
  19. Q&A with XTL Biopharmaceuticals CEO Josh Levine on a Promising New Treatment for Lupus Lupus, a chronic debilitating inflammatory autoimmune disease, impacts 1.5 million people, mostly women, in the U.S. and 5 million worldwide. With a 10 year survival rate of 90%, patients suffer with a disease for which there is no effective treatment. Current drugs like immunosuppressants only provide palliative care by making symptoms easier to live with. These immunosuppressants often come with harmful side effects. Lupus impacts the entire body including skin, musculoskeletal, digestive, nervous and reproductive systems, as well as blood, lungs and heart. Only one drug has been approved to treat lupus in the past 50 years. Benlysta received the FDA’s blessing in March 2011 and was subsequently acquired and is marketed by GlaxoSmithKline. Sales have been slower than expected due to limited efficacy, among other things. As other drugs for lupus gain FDA approval, the market for their sales is projected to reach $4 billion annually by 2022. Despite strong interest and efforts by big pharma to develop lupus drugs, an effective and safe therapy for this indication remains elusive. Israel-based XTL Biopharmaceuticals is set to commence a Phase II study of its drug hCDR1 in the treatment of systemic lupus erythematosus (SLE), which accounts for 70% of lupus cases worldwide. If data show efficacy, it would position XTL and its drug very favorably in a market that is in dire need of a safe and effective treatment. The Bio Connection recently spoke with XTL’s CEO Josh Levine about the company’s lupus drug hCDR1. Q: Why has lupus been such a difficult disease for the medical community to understand and treat? Levine: Lupus is more of a syndrome than a strictly defined disease with many different manifestations. It affects different people in vastly different ways. Furthermore, the course of lupus is characterized by flares and remissions, i.e. periods of intense disease manifestations are followed by periods of relatively few signs and symptoms. There are many categories of drugs physicians use to treat lupus, including corticosteroids, anti-malarials and B-cell inhibitors like Benlysta. Physicians do not like to prescribe steroids, especially long term, and other therapies have not proven to be sufficiently effective in treating the symptoms of this disease. Q: Would you tell us how hCDR1 is different from FDA approved Benlysta and other drug candidates that are also B-cell inhibitors? How would hCDR1’s safety and efficacy profile offer benefits over B-cell inhibitors? Levine: Due to the complexity of the disease (see question 1 above), many Key Opinion Leaders are excited about hCDR1’s unique Mechanism of Action, as it can be used as a stand-alone therapy or as part of a future combination therapy to combat the disease. Belimumab, or Benlysta, is a B Lymphocyte Stimulator (BLyS)-specific inhibitor that blocks the binding of soluble BLyS, a B-cell survival factor, to its receptor on B-cells. By binding BLyS, Belimumab inhibits the survival of B-cells, including autoreactive B-cells, which are the basis of autoimmune disease. hCDR1 is the acetate salt of a synthetic peptide composed of 19 amino acid residues. Unlike B-Cell inhibitors, hCDR1 has a unique Mechanism of Action that induces the generation of Regulatory T Cells, which, in turn, lead downstream to the lowering of the activated, autoreactive B-Cells. hCDR1 down-regulates the autoimmune responses elicited by the various autoreactive cell populations (e.g., T and B cells) and pathogenic autoantibodies, as well as up-regulates the expression of gene markers of immunosuppressive molecules, such as TGF-β and FoxP3. In three clinical trials conducted to date involving >400 patients, hCDR1 has demonstrated a favorable safety profile, is well tolerated by patients, and has demonstrated efficacy in one and possibly more clinically meaningful endpoints. Results were published in Lupus Science & Medicine in August 2015. Q: You have a Phase II trial coming up in the U.S. Can you tell us more about how the data compiled from the previous clinical studies and the use of BILAG as the primary measure of efficacy in the upcoming study significantly enhance the likelihood of a positive outcome? Levine: As noted above, hCDR1 was studied in three clinical studies involving more than 400 patients including a Phase II study (the PRELUDE© study) which included more than 300 patients. In PRELUDE©, hCDR1 failed to meet the primary endpoint (SLEDAI) but the 0.5 mg dose showed a statistically significant effect (p=0.03) in the ITT (Intend to Treat) cohort against a pre-defined secondary endpoint – the BILAG index. Further, in a post-hoc analysis of patients on less than 20 mg daily dose of steroids, the 0.5 mg dose showed a highly statistically significant effect (p=0.007) against the pre-defined secondary BILAG endpoint. XTL recently approached the US FDA, which provided guidance supporting our plan to use the BILAG endpoint as the primary efficacy endpoint in our upcoming study (confirming the current FDA guidelines for lupus studies) and agreed with our proposed patient population. Therefore, we believe our proposed design of the upcoming study has an increased likelihood to succeed as the FDA’s guidance encourages the study to be substantially similar to the prior Phase II (PRELUDE©) trial which demonstrated safety and efficacy in the 0.5 mg dose using the BILAG index. We believe the FDA’s guidance validates the value and relevance of the safety and efficacy data from the previous trials performed on our drug. To further increase our likelihood of success, we plan on testing the 0.5 mg dose, that showed the best effect in PRELUDE©, as well another dose. Q: hCDR1 has been tested in over 400 people, and in more than 200 animal experiments, with studies published in over 40 peer reviewed articles. What makes hCDR1 so compelling and such a well researched drug candidate? Levine: I believe the answer begins with the disease itself. As noted above, SLE is a very difficult disease that affects millions of patients worldwide (primarily women of child-bearing years) and one in which there is an extremely high unmet medical need. There is currently no effective and safe treatment for the disease. In addition, hCDR1 has a unique mechanism of action (an immunomodulator as opposed to an inhibitor), which generates significant interest among researchers and clinicians. Further, as noted above, it can be used both as a stand-alone treatment as well as part of a combination therapy. It also has a clean safety profile on hundreds of patients including at doses far higher than what we intend to test in the upcoming study. Finally, from the PRELUDE© study, we have very encouraging efficacy data on the BILAG endpoint, which will be the primary efficacy endpoint in the upcoming study. Q: If the Phase II study produces good efficacy and safety results, as expected, how do you see your development path moving forward? Would XTL seek a big-pharma partner or advance hCDR1 further along independently? Levine: I believe that if we can achieve good efficacy/safety data in our upcoming study, hCDR1 will interest many Big-Pharma partners who are already active in the autoimmune space and who are looking for solutions for this very difficult disease. An example of such interest in the lupus space is GlaxoSmithKline’s purchase of Benlysta for $3 billion upon regulatory approval and ongoing studies in this space by Big Pharma. Having said that, the FDA also provided guidance to XTL concerning the number of patients required for its safety database to support an NDA filing for marketing approval Based on such guidance, it is possible that XTL could independently advance hCDR1 following a successful study. Much will depend on the results of the upcoming study, in which, we believe we have an increased likelihood to succeed, as noted above. For more information on XTL visit www.xtlbio.com (NASDAQ:XTLB)
  20. My diet is very up and down, I have managed to keep the sugar contents down and to have smaller portions, doing this I have managed to lose a 1lb in weight.It's a start. I may have loss more if I hadn't hit a bad week where I have done nothing but sleep. I've also been out for a pub meal with a friend and I didn't have a pudding. I went to see Lord Of The Dance with my daughters and we had a great time but the diet was put on hold for that night. Cutting down the sugar in my diet has stopped the none stop thirst which has made me feel a bit better. This is a very good sign. I hope that this means I can control my diabetes with my diet rather than tablets.
  21. www.medscape.com Ketamine for Chronic Pain on the Rise Pauline Anderson April 04, 2017 ORLANDO — Pain medicine specialists are concerned about the growing use of the anesthetic ketamine in private pain clinics across the United States. There are reports of some centers providing "cash only" intravenous (IV) ketamine infusions to patients coming in with a variety of pain disorders, they say. "It's like a Wild West out there," said Steven P. Cohen, MD, professor of anesthesiology and critical care medicine and of physical medicine and rehabilitation at Johns Hopkins Hospital, Baltimore, and at the Uniformed Services University of the Health Sciences, Bethesda, Maryland. Dr Steven P. Cohen "It can be very lucrative" for doctors running these clinics, said Dr Cohen. At least some of those doctors are pain medicine specialists. Dr Cohen and other experts addressed a symposium during the American Academy of Pain Medicine (AAPM) 2017 Annual Meeting titled, "Ketamine for Chronic Pain: Panacea or Snake Oil?" Ketamine, an N-methyl-D-aspartic acid (NMDA) receptor antagonist, was first used as an anesthetic in 1966. In recent years, interest in the drug as a possible effective therapy for myriad chronic pain conditions has resurged, including neuropathic pain, complex regional pain syndrome (CRPS), fibromyalgia, postherpetic neuralgia, migraines, and spinal cord injury. "Pain is the biggest cause of disability in the world, and there is no really good treatment for it," Dr Cohen said in an interview with Medscape Medical News. Ketamine's significant psychomimetic and euphoric properties have led to abuse. Oral ketamine, sometimes called Special K, has become a popular nightclub drug. "It's one of the biggest causes of car accidents in many parts of Asia; people drive while high on ketamine," said Dr Cohen. As well as pain, ketamine is used to treat depression and post-traumatic stress disorder. The relationship between chronic pain and depression "is very complicated" and is something of "a two-way street," said Dr Cohen. "Chronic pain can cause people to become depressed, but people who are depressed who hurt their back or who have surgery are more likely to develop chronic pain." These patients "suffer physically and emotionally, and ketamine sometimes gives them euphoric feelings and they feel better," added Dr Cohen. But although ketamine is "a very, very potent analgesic," it has drawbacks, one of them being that its effects last for only a short period, said Dr Cohen. "As well, we don't know the long-term effects and unfortunately it's associated with significant side effects," he added. Adverse effects can include nausea, headaches, fatigue, and dysphoria. In Demand In providing ketamine, pain clinics are answering to a growing public demand. "Patients coming to a doctor know what they have and because of the Internet, they know what they want, and they request it," said Dr Cohen. "People may come in with complex regional pain syndrome and say they want a ketamine infusion because nothing else works." In addition to private clinics, some academic centers provide ketamine infusions. But as a teaching hospital, "we are required to accept whatever Medicare and Medicaid pays," and in some cases, this can be a money loser, said Dr Cohen. That's not the case with private clinics, he noted. "They can charge whatever they want." As a result, prices for ketamine infusions vary widely, and in his region they can range from $500 to sometimes more than $2000, depending on the duration, Dr Cohen noted. Clinicians are worried about the unregulated use of ketamine at these private clinics. Concern about off-label use of ketamine for depression without a firm evidence base has already been raised among psychiatrists. To answer some of these concerns, in March 2017, a group of psychiatrists issued a consensus statement for ketamine use for severe depression and other mood disorders. The panel recommended that before considering ketamine, clinicians should confirm that the patient meets the appropriate diagnostic criteria for depression, has undergone an adequate trial of approved antidepressant therapies, and has no history of substance abuse or psychotic disorders. Now, pain doctors too want some direction. Oscar Deleon-Casasola, MD, president of the American Society of Regional Anesthesia and Pain Medicine, confirmed to Medscape Medical News that his association is preparing guidelines for use of ketamine for pain management. It's too early to say what areas the guidelines will cover, "but we will look at the evidence as it pertains to pain medicine indications," said Dr Deleon-Casasola. He added that the society "would like to have the guidelines out within the next 6 months." Ajay Wasan, MD, professor of anesthesia and psychiatry, University of Pittsburgh, Pennsylvania, who also addressed the AAPM ketamine session, pointed out that a lot is still unknown about the use of ketamine in chronic pain. Dr Ajay Wasan "So guidelines are not going to be a recipe for what clinicians should and should not do," Dr Wasan told Medscape Medical News. "The data just isn't strong enough to say that." While pain experts work out guidelines surrounding ketamine use, they're gathering information on whether this drug actually works in chronic pain. At the ketamine session, delegates learned that ketamine elicits analgesia primarily through noncompetitive antagonism of the NMDA receptor at the level of the spinal cord and higher brain centers, which play a major role in nociceptive transmission, cognition, mood regulation, opioid tolerance, and central sensitization. But the drug also acts through various other receptors, including α-amino-3-hydoxyl-5-methyl-4-isoxazole propionate, kainite, and γ-amino-butyric acid. In reviewing the literature on ketamine for CRPS, Dr Cohen cited a randomized, double-blind, placebo-controlled trial (Pain.2009;147:107-115) that compared a 4-hour ketamine infusion to saline on 10 consecutive workdays in 19 patients with CRPS. The maximum ketamine infusion rate was 0.35 mg/kg per hour, not to exceed 25 mg/h over a 4-hour period. All patients were given midazolam and clonidine. That study showed pain scores decreased from a mean of 7.7 to 6.1 at 2 weeks in the treatment group, with the effect maintained throughout the 12-week study period, while the placebo group had a nonsignificant change in pain scores. In this study, the ketamine group had a decrease in nocturnal awakenings at 12 weeks but no increase in quality of life compared with placebo. About 44% of the ketamine and 20% of the placebo patients experienced adverse events, including dysphoria and fatigue. No patient reported psychomimetic effects. Blinding Issues But this and other studies, including those in patients with neuropathic pain after a spinal cord injury, were hampered by their small numbers, limited generalization, and lack of effective blinding, which often skews pain relief outcomes, said Dr Cohen. Research shows that lack of adequate blinding in randomized controlled trials can exaggerate the effect size by 33%, he added. Most research on ketamine for chronic pain has focused on IV infusions, which limits its use as long-term therapy and dramatically increases the cost, Dr Cohen said. Oral and intranasal ketamine have been shown to be effective in clinical practice and in research studies, he said. Dr Cohen concluded that ketamine is no miracle drug, but it's also likely not just a passing fad. "It falls somewhere in between," he said. Dr Wasan agreed that the data "are not conclusive" and that the use of ketamine in patients with chronic pain "needs to be evaluated more carefully." During the session, he cited a recent review (Anesthes Analges. 2017;124:661-674), which he called one of the best to date. Here, researchers reviewed 26 articles on IV ketamine infusions, most involving CRPS or mixed neuropathic pain. The review concluded that the current state of the literature leaves the use of ketamine infusions without meaningful guidance from high-quality comparative evidence. Many Unknowns While a variety of conditions, including CRPS, might benefit from ketamine infusions, "it's not clear at all at this point exactly how to administer it," Dr Wasan said. "We don't really know how beneficial it is or which patients would be the best ones to put on it," he said. "We also don't know exactly how much ketamine to infuse and for how long and how frequently to give the infusions." It's also possible that the responders in the pain trials also had major depressive disorder (MDD). Some 50% to 75% of patients in pain clinics have MDD. "It could be that the people who respond best — and this is speculation on my part — could be those with both pain and depression," Dr Wasan said. In future trials of IV ketamine, researchers may want to include patients with chronic pain and MDD and track the improvement in both over a period of at least a month, he said. A third speaker at the AAPM session, Aubrey Verdun, MD, Anesthesiology and Pain Management, Walter Reed National Military Medical Center, Bethesda, Maryland, presented research on low-dose ketamine for postoperative analgesia. Dr Aubrey Verdun The evidence here, said Dr Verdun, shows that ketamine reduces pain scores, decreases opioid consumption by up to 40%, has an excellent safety profile, and facilitates recovery and rehabilitation in the postoperative period. Uncontrolled acute pain, said Dr Verdun, can lead to chronic pain, which affects over 70 million people and is on the rise. The cost of chronic pain to the US economy is now over $100 million per year. Ketamine is not approved for chronic pain management and may never be, said Dr Cohen. "You have an incredibly cheap drug and there's no patent protection, so no company is going to do the 350-patient, double-blind study that costs $100 million." Dr Cohen is a consultant for Halyard, Scintilla, Boston Scientific, and Medtronic. Dr Wasan is a consultant for Analgesic Solutions, Egalet Pharmaceuticals, Cara Therapeutics, and North American Partners in Anesthesia. Dr Verdun has disclosed no relevant financial relationships. American Academy of Pain Medicine (AAPM) 2017 Annual Meeting. "Ketamine for Chronic Pain: Panacea or Snake Oil?" Session 407. Presented March 19, 2017. For more Medscape Neurology news, join us on Facebook and Twitter Medscape Medical News © 2017 Cite this article: Ketamine for Chronic Pain on the Rise. Medscape. Apr 04, 2017.
  22. I have been struggling to cut out my evening snack. I’ve tried to occupy my hands, this hasn’t been successful. Now I’m trying shear will power telling myself I don’t need to snack in the evening. This has only helped for 3 nights last week, this is a start. My main meal of the day is now served on a smaller plate and this has been mostly successful. Due to my endless feeling of being exhausted I sleep a lot during the day this means I really don’t need a large main meal. I think I have never really considered that I don’t need to eat large meals as I’m not very active. Eating low fat margarine, wholemeal bread and semi skimmed milk hasn’t been difficult at all. Tomorrow I’m going to ladies day at Aintree with my daughters, I think the diet will be broken. As far as I’m aware I haven’t loss any weight at all and I will not be weighing myself till the end of next, as my weight goes up and down rapidly and I don't want to be dissappointed if I have put weight on . Any advice will be very welcome.
  23. Day 1

    Well today I haven't been very successful, I hadn’t realised how much food I eat for one reason or another.in the day. A friend came round this morning and we had a biscuit with our cup of tea. Lunchtime I had a cheese sandwich, then Laura offered me a sweet and I should have said no, but I didn’t. It looks like when I do our next food shop there will have to be some changes. Butter, milk and bread will be the first to be changed. I have decided to try a different strategy to begin losing weight, that will be to stop the evening snack, this is the time of day when I am at my lowest point and comfort eat. I’m going to start tonight. I have also begun to reduce the size of my meals.
  24. U.K. Study Rejects Rituximab for Sjogren’s News | March 20, 2017 | Sjögren's Syndrome By Amy Reyes A British study finds that rituximab is "neither clinically or cost-effective" in a study of patients with primary Sjogren’s syndrome who were being treated for fatigue and oral dryness. These findings differ from the newly issued treatment guidelines for Sjogren's syndrome in the U.S. in which the Sjogren’s Syndrome Foundation recommends the use of rituximab for patients with oral dryness. However, for fatigue, the foundation strongly recommended exercise. The guidelines were based on a review of published studies, case reports and input from both physicians and patients. In the new study, which was accepted for publication on March 7 in the journal Arthritis & Rheumatology, researchers led by Simon J. Bowman, Ph.D., of University Hospitals Birmingham NHS Foundation Trust in the United Kingdom, conducted a randomized, double-blind, placebo-controlled trial (referred to as the TRACTISS trial ) of 133 patients from 25 clinics with primary Sjogren’s syndrome. This trial enrolled Sjogren’s patients who suffered from symptomatic fatigue and oral dryness. They received two doses of 1,000 mg rituximab, but at the 48-week assessment, patients did not report having a response to treatment that was considered significant (30% reduction from baseline of Oral Dryness or Fatigue VAS) as compared to those in the placebo group. “These and other patient-reported outcomes of Ocular and Overall Dryness, Joint Pain and Global Assessment of disease activity were not significantly improved by rituximab at any time-point,” the researchers wrote. “We also did not observe a significant benefit in terms of lachrymal flow, or in any of the composite patient-reported outcomes, or disease activity indices, except for a one-off significant difference between groups in the ESSDAI score at week 36.” Composite disease activity scores, and patient-reported outcome measures confirmed no benefit for rituximab. There was no improvement in any domain of the SF-36 for rituximab over placebo, or in the SF-36 component scores. There was also no improvement in the PROFAD-SSI domains at any time-point for rituximab compared to placebo. There were slightly more adverse events reported in total for rituximab, but no difference in serious adverse events (ten in each group). "Although there did not appear to be any excess risk due to rituximab, the results of the TRACTISS trial do not support the general use of rituximab in treating PSS, particularly in patients with recent disease onset and / or low disease activity," the authors wrote. "Rituximab may still have a role in treating PSS patients with high levels of systemic disease activity who have failed to improve following conventional immunosuppressive therapy." TRACTISS is the fourth, double-blind, placebo-controlled, randomized trial of rituximab. The first study, a pilot in 17 patients, reported a greater reduction in fatigue among patients randomized to rituximab, but it wasn’t sustained. The TEARS study analyzed 120 patients randomized to either rituximab or placebo. A significant response was detected at six weeks, particularly in fatigue, but it wasn’t sustained at 24 weeks. “Although there did not appear to be any excess risk due to rituximab, the results of the TRACTISS trial do not support the general use of rituximab in treating primary Sjogren’s syndrome, particularly in patients with recent disease onset and/or low disease activity,” the researchers wrote. “Rituximab may still have a role in treating these patients with high levels of systemic disease activity who have failed to improve following conventional immunosuppressive therapy.” DISCLOSURES The study was funded by Arthritis Research UK. Hoffman La Roche provided rituximab free of charge to the study. Hoffman La Roche was permitted to review results prior to submission, but final decision on content and publication remained with the authors. REFERENCES Simon J Bowman PhD, Colin C Everett, John L O’Dwyer, et al. "Randomized Controlled Trial of Rituximab and cost effectiveness analysis in treating fatigue and oral dryness in primary Sjogren’s Syndrome," Accepted Article for publication March 7, 2017. Arthritis & Rheumatology. DOI 10.1002/art.40093 http://www.rheumatologynetwork.com/sjogrens-syndrome/uk-study-rejects-rituximab-sjogren’s?GUID=&rememberme=1&ts=21032017
  25. Israeli autoimmune disease treatment with parasitic worms has ‘marvelous’ results Professor Yehuda Schoenfeld of Tel-Aviv University, co-founder of medical startup TPCera, uses parasitic worms to treat autoimmune diseases, and the results have been “marvellous.” An expert in SLE & autoimmune diseases, such as MS & Rheumatoid Arthritis.
  26. MEETING NEWS WASHINGTON AMERICAN COLLEGE OF RHEUMATOLOGY ANNUAL MEETING — Frailty — a syndrome of weight loss, weakness, slowness, exhaustion and inactivity — was associated with mortality, poor physical and cognitive function and overall functional decline in patients with systemic lupus erythematosus, according to findings presented at the American College of Rheumatology Annual Meeting. “It does appear that frailty is something that might be a relevant concept in lupus, and it does predict declines in physical and cognitive functioning and a high risk of mortality,” Patricia P. Katz, PhD, professor of medicine at the University of California, San Francisco School of Medicine, said during her presentation. “The effects were not simply due to disease itself, because we saw these effects even after adjusting for disease activity and damage. The combination of frailty components appeared to create a combined risk for poor outcomes that was greater than any of the elements alone.” Katz and colleagues performed an in­person research visit of 138 women with lupus between 2008 and 2009, and assessed the frailty components of weight loss, weakness, slowness, exhaustion and inactivity. The researchers determined slowness by a 4­meter walk using sex and height criteria. Weakness was determined by grip strength using sex and BMI criteria, and investigators determined both exhaustion and inactivity with a questionnaire. If the patient had a deficit in at least three of the five categories, researchers deemed the patient to be “frail.” Researchers considered a deficit in one or two categorizes to be “pre­frail” and a deficit in none of the categorized to be a “robust” patient. Of the patients, the mean age was 48 years; the mean lupus duration was 16 years; and 65% were white, non­Hispanic. Overall, 24% of patients were classified as frail and 48% were classified as pre­frail. Researchers measured physical function with the SF­36 Physical Functioning subscale and the Valued Life Activities disability scale. They determined cognitive function using a 12­test battery, with scores below ­1 standard deviation of age ­adjusted population norms considered as impaired, and they determined mortality as of December 2015. Researchers calculated differences in function and 2­year changes in function using multiple regression analyses adjusted for factors such as age, lupus duration, glucocorticoid use, obesity, self­ reported lupus activity and baseline function. Researchers found frail women had significantly worse physical function compared with robust and prefrail women. In addition, frail women were more likely to have cognitive impairment. The mortality rate was 16.7% in the frail group, 4.1% in the pre­frail group and 2.3% in the robust group. In the regression analysis, the frail group had an increased risk for death (risk ratio = 5.1). “In terms of future directions, it may be important to try and develop a lupus­ specific measure,” Katz said. “It may need to include different measures or additional factors.” – by Will Offit 25/02/2017 Frailty associated with mortality in patients with lupus http://www.healio.com/rheumatology/lupus/news/online/{8d084f81-b0d5-40bf-897d-0dfeb6c5dda2}/frailty-associated-with-mortality-in-patients-with-lupus?sc_trk=internalsearch Reference: Katz P, et al. Abstract #3051. Presented at: American College of Rheumatology Annual Meeting; Nov. 11­ 16, 2016; Washington. Disclosure: The researchers report no relevant financial disclosures
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