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  1. 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.
  2. 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.
  3. 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
  4. 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
  5. 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.
  6. 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)
  7. 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.
  8. 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
  9. 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.
  10. 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
  11. Pneumococcal Vaccine PPSV23 Does Not Protect RA patients News | February 13, 2017 | Rheumatoid Arthritis By Aisha T. Langford, PhD, MPH The 23-valent pneumococcal polysaccharide vaccine (PPSV23) does not prevent pneumonia in rheumatoid arthritis patients, a new study finds. This study appears in the January 25 online issue of Arthritis Research & Therapy. “While PPSV23 vaccination is recommended for adults who are at least 65 years of age, our results suggest uncertainty regarding its effectiveness for pneumonia in rheumatoid arthritis patients at high risk for infections. Clinicians should keep in mind the patient’s age and the presence of interstitial pneumonia because such patients are at an increased risk of developing pneumonia,” researchers wrote. This was a prospective, double-blind, randomized, placebo-controlled trial conducted with 900 rheumatoid arthritis patients treated with biological or immunosuppressive agents. The goal of the study was to evaluate the effectiveness of PPSV23 in preventing overall pneumonia in high risk patients. Patients were recruited between December 2012 and March 2014 from 32 hospitals across Japan and randomized in a 1:1 ratio to the vaccine group receiving 0.5 ml of PPSV23 or the placebo group. The two primary endpoints were pneumonia and pneumococcal pneumonia. Additionally, demographic and clinical characteristics were evaluated for potential associations with risk for developing pneumonia. Patients were monitored for 12 months after enrollment. In total, 17 of 464 patients in the vaccine group, or 3.7 percent, and 15 patients of 436 in the placebo group, or 3.4 percent, developed pneumonia. There was no significant difference between the two groups. Independent of group assignment, researchers found that the presence of interstitial pneumonia and older age were significantly associated with increased risk of developing pneumonia. It should be noted that neither glucocorticoid dosage or biologic disease-modifying anti-rheumatic drugs usage predicted risk of developing pneumonia in this study. Patients with rheumatoid arthritis are at higher risk for developing pneumonia compared to the general population. Pneumonia is a vaccine-preventable condition in most patients and PPSV23 has been demonstrated to be effective at preventing invasive pneumococcal disease in older adults. However, the efficacy of PPSV23 in patients undergoing immunotherapy is not well researched or understood. To date, few of the clinical trials that have evaluated the effectiveness of PPSV23 have included patients with autoimmune diseases. Given that pneumonia is a leading cause of death among patients with rheumatoid arthritis, a better understanding of how and when to use PPSV23 with this population is needed. This is one of the first-known studies to evaluate a pneumonia vaccine in patients with autoimmune disease. “Our study confirmed that polysaccharide vaccine alone is not effective for prevention of pneumonia. Therefore, sequential administration of PCV13 and PPSV23 could also be an appropriate approach for the prevention for pneumonia in RA patients receiving immunosuppressive treatments,” wrote Kiyoshi Migita, of the Japanese National Hospital Organization, and colleagues. DISCLOSURES This research was supported by a grant from the Japanese National Hospital Organization Evidence-based Medicine study group. REFERENCES Yasumori Izumi, Manabu Akazawa, Yukihiro Akeda, et al. “The 23-valent pneumococcal polysaccharide vaccine in patients with rheumatoid arthritis: a double-blinded, randomized, placebo-controlled trial,” Arthritis Research & Therapy. Published online January 25, 2017. DOI: 10.1186/s13075-016-1207-7. http://www.rheumatologynetwork.com/news/pneumococcal-vaccine-ppsv23-does-not-protect-ra-patients?GUID=&XGUID=&rememberme=1&ts=14022017 Full Report URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5264490/
  12. Evidence for Cognitive Aging in Midlife Women: Study of Women’s Health Across the Nation Arun S. Karlamangla , Margie E. Lachman, WeiJuan Han, MeiHua Huang, Gail A. Greendale Published: January 3, 2017 http://dx.doi.org/10.1371/journal.pone.0169008 Abstract Although cross-sectional studies suggest that cognitive aging starts in midlife, few longitudinal studies have documented within-individual declines in cognitive performance before the seventh decade. Learning from repeat testing, or practice effects, can mask the decline in younger cohorts. In women, the menopause transition also affects test performance and can confound estimates of underlying decline. We designed this study to determine if, after controlling for practice effects, the menopause transition, and the symptoms associated with it, there is evidence of cognitive aging in midlife women. We used data from a longitudinal observational study in 2,124 participants from the Study of Women’s Health Across the Nation. Outcomes examined were scores on annual tests of processing speed, verbal episodic memory (immediate and delayed), and working memory. To reduce the impact of practice effects and of the menopause transition, we used the third cognition testing visit as the baseline. Average age at this baseline was 54 years, and the majority of the women were postmenopausal; half the cohort was 2 or more years beyond the final menstrual period. There were 7,185 cognition assessments with median follow-up time of 6.5 years. In mixed effects regression, adjusted for practice effects, retention, menopause symtoms (depressive, anxiety, vasomotor, and sleep disturbance), and covariates, scores on 2 of 4 cognition tests declined. Mean decline in cognitive speed was 0.28 per year (95% confidence interval [CI] 0.20 to 0.36) or 4.9% in 10 years, and mean decline in verbal episodic memory (delayed testing) was 0.02 per year (95% CI: 0.00 to 0.03) or 2% in 10 years. Our results provide strong, longitudinal evidence of cognitive aging in midlife women, with substantial within-woman declines in processing speed and memory. Further research is needed to identify factors that influence decline rates and to develop interventions that slow cognitive aging. Figures Citation: Karlamangla AS, Lachman ME, Han W, Huang M, Greendale GA (2017) Evidence for Cognitive Aging in Midlife Women: Study of Women’s Health Across the Nation. PLoS ONE 12(1): e0169008. doi:10.1371/journal.pone.0169008 Editor: Hemachandra Reddy, Texas Technical University Health Sciences Center, UNITED STATES Received: April 24, 2016; Accepted: December 10, 2016; Published: January 3, 2017 Copyright: © 2017 Karlamangla et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: SWAN data up to the 10th follow up visit are currently available in a publicly accessible repository managed by ICPSR, at http://www.icpsr.umich.edu/icpsrweb/ICPSR/series/00253. Not all of the data used in the manuscript (e.g., data from the 11th and 12th follow up visits) are contained in the public use data sets. Members of the scientific community who are interested in working with the SWAN data that are not contained in the public use datasets may submit an application to become a SWAN Investigator. Any interested researcher can apply to become a SWAN Investigator, and get access to the data not yet on the public use ICPSR site. Links to each of the public use data sets, as well as instructions for how to apply for SWAN Investigator status, are located on the SWAN web site: http://www.swanstudy.org/swan-research/data-access/. Contact for access to data is Susan Janiszewski at the SWAN Coordinating Center (email: swanaccess@edc.pitt.edu). Funding: The Study of Women's Health Across the Nation has grant support from the National Institutes of Health (NIH), DHHS, through the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR) and the NIH Office of Research on Women’s Health (ORWH) (Grants U01NR004061; U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495). The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIA, NINR, ORWH or the NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Introduction Although decline in cognitive functioning is common in older ages [1,2], there is controversy about whether there is significant decline in cognitive abilities in midlife. Inverse associations between age and cognitive functioning have been seen in cross-sectional analyses of data from middle-aged adults [3,4]; yet within-person longitudinal declines in cognitive performance have not been consistently documented in those under 60 years of age [5,6]. One large study that assessed cognitive performance 3 times over 10 years, did demonstrate longitudinal declines in cognitive performance in midlife, albeit at a slower rate than that of older adults [7]. Yet, in midlife women going through the menopause transition (MT), at least 2 cohorts found no evidence of cognitive aging; instead they documented significant improvements in performance over multiple years [8,9]. Similar improvements in cognitive performance in midlife have been documented in the Baltimore Longitudinal Study of Aging, and attributed to learning or practice effects from repeat testing [10]. The phenomenon of learning from repeat testing has long been recognized as hampering the estimation of underlying longitudinal change in cognitive performance, and is thought to lead to underestimation—even masking—of true decline [4,6,10,11,12]. Practice effects are largest at first re-testing and diminish significantly with further re-testing [13,14]. We therefore, undertook an analysis of longitudinal cognitive performance data in midlife women from the Study of Women’s Health Across the Nation (SWAN), after excluding data from SWAN’s first 2 cognition testing visits to reduce the impact of practice effects. It has also been suggested that the MT and associated symptoms may impair performance [8,14,15]; both may have confounded previous studies that failed to find evidence of cognitive aging in midlife women. The majority of the SWAN cohort was post menopausal at 3rdcognition testing; thus commencing analysis at 3rd testing reduces effects of the MT on estimates of cognitive performance trajectories. We hypothesized that, after largely eliminating practice effects by initiating our analysis at the 3rd third testing occasion, and explicitly controlling for the MT and associated symptoms, midlife women would indeed show gradual declines in cognitive performance. Methods SWAN is a community-based, longitudinal study of midlife women. Entry requirements were: 42 to 52 years of age; intact uterus; at least one ovary; no estrogen use; and at least one menstrual period in the 3 months prior. Seven study sites together recruited 3302 women [16]; the baseline visit occured in 1996/97, and participants were followed annually thereafter. SWAN participants provided written informed consent, and approval was obtained from Institutional Review Boards at each of the seven SWAN clinical sites and the SWAN coordinating center—Massachusetts General Hospital, Boston, MA; Rush University Medical Center, Chicago, IL; University of Michigan, Ann Arbor, MI; University of California, Los Angeles, CA; Albert Einstein Medical College, New York, NY; Kaiser Permanente Northern California, Oakland, CA; University of California, Davis, CA; and University of Pittsburgh, Pittsburgh, PA. Cognition testing was first administered at the 4th follow-up to 2709 women, and repeated in 6th and subsequent visits up to the 12th follow-up, except that only half the cohort was tested in the 8th follow-up and the remainder in the 9th, and there was no cognition testing in the 11th follow-up. Study Sample Of the 2709 women in the SWAN cognition cohort, 2168 (80%) had testing at 3 or more visits—an inclusion criterion for this analysis, which used the 3rd cognition testing as baseline. Because only 21 (<1%) were from the Hudson County (New Jersey) site, they were excluded; an additional 23 were excluded because of a stroke before their 3rd test, leaving a sample of 2124. Because cognitive aging may accelerate after the menopause [17], we created a subsample of 1224 women whose date of final menstrual period (FMP) was known; FMP date may be unknowable due to interim hysterectomy and/or use of exogenous sex hormones. Measurements Outcomes. Cognitive processing speed was assessed with the the symbol digit modalities test (SDMT), in which participants match numbers to symbols in a specified time period [18]; score range, 0–110. Verbal episodic memory was evaluated using the East Boston Memory test (EBMT) [19]: Respondents recall story elements from a paragraph read to them, immediately and after ~10 minutes delay; score range, 0–12. Working memory, the ability to manipulate information held in memory, was assessed by digit span backwards (DSB) [20]: Participants repeat strings of single-digit numbers backwards, with 2 trials at each string length, increasing from 2 to 7, stopped after errors in both trials at a string length, and scored as the number of correct trials (range, 0–12). Covariates. At SWAN baseline, questionnaires collected age, race/ethnicity, and education. Annually administered questionnaires assessed financial hardship (difficulty paying for basics), diabetes mellitus, sex hormone use, interim hysterectomy and/or bilateral oophorectomy, MT stage (premenopausal: no change in menses regularity, early perimenopausal: menses within the prior 3 months but less predictable, late perimenopausal: > 3 months but < 12 months of amenorrhea, postmenopausal: ≥12 months without menses, and indeterminate because of premenopausal hysterectomy or use of sex steroid hormones before the MT is completed), and FMP date. The Center for Epidemiologic Studies Depression (CES-D) Scale quantified depressive symptoms [21], and coded present if in the top quartile (≥13). Anxiety symptoms were assessed using the SWAN anxiety score [22], and coded present if in the top quartile (≥7). Sleep disturbance was assessed using an abbreviated Pittsburgh Sleep Quality Index, and coded present if either difficulty falling asleep, waking up several times, or waking up earlier than planned with inability to fall asleep again were reported for ≥3 nights per week [23]. Vasomotor symptoms were coded present if any of hot flashes, cold sweats, or night sweats occurred ≥6 days per week [22]. Statistical Analysis After excluding scores from the first 2 cognition testing occasions, we examined LOESS-smoothed plots of cognition scores as a function of ‘time from FMP’ (negative for dates before the FMP and positive for dates after; a proxy for ovarian aging) and ‘time elapsed since the 3rd cognition testing’ (a measure of chronological aging). Time from FMP more closely captures biological aging in a midlife woman, because of the large changes around the FMP not only in sex hormone levels but also in multiple other physiological markers [24,25,26]. At least one prior study found that cognitive aging accelerates after the menopause [17]. The LOESS plots showed steady declines in the mean values of each of the 4 cognition scores as time from FMP increased (SDMT: Fig 1, EBMT-Delayed: Fig 2, EBMT-Immediate and DSB: not shown). In contrast, the LOESS plots against ‘time since 3rd testing occasion’ showed gradual decline only in SDMT (Fig 3), and not in the other scores (data not shown), and revealed a persistent learning/practice effect from the 3rd to 4th testing in all scores. Download: PPT PowerPoint slide PNG larger image TIFF original image Fig 1. Symbol Digit Modalities Test Scores as Function of Time Prior to and After the Final Menstrual Period. LOESS Smoothed Plot of Scores on Symbol Digit Modalities Test (SDMT), relative to time prior to and after the Final Menstrual Period (FMP), an assessment of the relation between ovarian aging and cogntive processing speed. http://dx.doi.org/10.1371/journal.pone.0169008.g001 Download: PPT PowerPoint slide PNG larger image TIFF original image Fig 2. East Boston Memory Test Delayed Recall Scores as a Function of Time Prior to and After the Final Menstrual Period. LOESS Smoothed Plot of Scores on East Boston Memory Test Delayed Recall (EBMT-D) relative to time prior to and after the Final Menstrual Period (FMP), an assessment of the relation between ovarian aging and verbal episodic memory. http://dx.doi.org/10.1371/journal.pone.0169008.g002 Download: PPT PowerPoint slide PNG larger image TIFF original image Fig 3. Symbol Digit Modalities Test Scores as Function of Chronological Aging. LOESS Smoothed Plot of Scores on Symbol Digit Modalities Test (SDMT), relative to time elapsed since study baseline (for this analysis, the 3rd cognitive testing occasion), an assessment of the relation between chronological aging and cogntive processing speed. http://dx.doi.org/10.1371/journal.pone.0169008.g003 We fit linear growth curves to the repeated measurements of each cognition score as function of time from FMP, allowing for a residual practice/learning effect from the 3rd to 4th testing, and censoring observations after an incident stroke. We used linear mixed effects regression with a random intercept at the participant level to account for clustering of repeated observations from the same woman. Covariates, chosen for known or hypothesized relation to cognitive performance, were modeled as fixed effects on the level (intercept), and included the following time-fixed variables: age at FMP, education (≤high school, some college, baccaleurate, post-graduate), race/ethnicity (Black, Chinese,Japanese White), testing language (English, Cantonese Chinese, Japanese), difficulty paying for basics (no hardship, somewhat hard, very hard, refused), use of sex steroids prior to the 3rd cognition testing (yes/no), and the total number of cognition assessments per participant (proxy for characteristics that affect retention in the study, strongly associated with cognitive performance in older cohorts [1,27,28]). The ‘age at FMP’ covariate controls for differences in cognition performance due to any chronological aging effects prior to the FMP, and isolates biological aging effects related to the MT. Models also included these time-varying covariates: learning/practice effect (0 for the 3rd testing and 1 for ≥4th), use of sex steroid hormone therapy (yes/no), bilateral oophorectomy before natural menopause (yes/no), diabetes (yes/no), and MT-associated symtoms (depressive, anxiety, sleep disturbance, and vasomotor). Analyses were conducted using complete cases (no covariates missing). To examine the relation between cognitive performance and chronlogical aging, we ran parallel models that fit linear growth curves to the cognition scores as a function of time since 3rdcognition testing, with all the same covariates except that age at FMP was replaced by age at the 3rd cognition testing (to capture cross-sectional age differences in cognition). We included one additional time-varying covariate, MT stage at the time of testing, to remove effects of the MT, and isolate chronological aging effects. Because this analysis did not require an FMP date, it was done in the larger sample of 2124 participants who met study entry criteria (except not requiring known date of FMP). Results The study sample was similar to the SWAN cognition cohort (Table 1). At the 3rd cognition testing (baseline for this analysis), median age was 54 years (interquartile range 52 to 56), and the majority of the women were post-menopausal. Nearly half were Caucasian, and the majority were tested in English. About a quarter had post-graduate education. The FMP subsample was very similar to the study sample (Table 1); at the baseline for this analysis, half of these women were at least 2 years past the FMP. Download: PPT PowerPoint slide PNG larger image TIFF original image Table 1. Descriptive Statistics1 for the Study Sample and the FMP Subsample compared to the SWAN Cognition Cohort. http://dx.doi.org/10.1371/journal.pone.0169008.t001 In the study sample and FMP subsample, the mean number of cognition testing occasions available for analysis was 3.4, but the majority of women participated in all 4 cognitive visits (at the 7th, either 8th or 9th, 10th, and 12th follow-ups). There was a total of 7,185 repeated assessments in the study sample, and 4,163 in the FMP subsample. Some women did not complete all 4 cognition tests at every testing occasion: in the study sample, there were 31 missing SDMT scores, 2 missing EBMT immediate recall, 6 missing EBMT delayed recall, and 171 missing DSB scores; corresponding missing numbers in the FMP subsample were 18, 0, 2, and 94. The median length of follow-up was 6.5 years (interquartile range 5.2 to 6.8) in the study sample, and 6.5 years (interquartile range 5.6 to 6.8) in the FMP subsample. In linear, mixed effects regression in the FMP subsample, adjusted for age at the FMP, practice (learning) from the 3rd to the 4th testing, and retention, SDMT scores decreased on average by 0.27 per year (p < .0001), and EBMT delayed recall scores decreased on average by 0.02 per year (p = 0.01). These declines persisted after additional adjustment for education, race/ethnicity, testing language, clinical site, financial hardship, oophorectomy, sex hormone use, diabetes, and symptoms of depression, anxiety, sleep disturbance, and vasomotor instabily, although the decline in EBMT-delayed recall scores became marginally significant (Table 2, ovarian aging model). Between-women difference in SDMT score by age at FMP (0.31 decline per year) was nearly identical in magnitude to the longitudinal aging effect (0.28 decline per year). There were no cross-sectional or longitudinal aging effects seen for the other 2 cognition test scores: EBMT immediate recall and DSB (Table 2). Download: PPT PowerPoint slide PNG larger image TIFF original image Table 2. Adjusted, Annualized Rates of Change1 in Cognition Test Scores: Results of Linear Mixed Effects Regressions. http://dx.doi.org/10.1371/journal.pone.0169008.t002 There were also strong practice effects in SDMT, but not in the other 3 test scores: mean SDMT learning from 3rd to 4th testing was 0.62 (p = 0.01). In addition, there were retention effects seen in 3 of the 4 tests; scores were higher in those who were tested more often: SDMT (p = 0.0001), EBMT delayed recall (p = 0.04) and DSB (p = 0.06). The second set of models examined test scores as a function of chronological aging—calendar time since the 3rd cognition testing—and yielded similar findings. Adjusted only for age at the 3rd testing, practice from the 3rd to 4th fourth testing, and retention, SDMT scores decreased on average by 0.24 per year (p < .0001). This decline persisted in the fully adjusted model (Table 2, chronological aging model). Between-women difference in SDMT score by age at 3rd testing was more than double the longitudinal aging effect: 0.54 vs. 0.25 decline per year (Table 2). There were no longitudinal aging effects seen for the other 3 cognition tests, but there was a cross-sectional age effect on DSB scores (Table 2). As before, there were strong practice (0.60; p = 0.001) and retention effects (p<0.0001) on SDMT scores. There was also a positive retention effect on EBMT immediate recall (p = 0.02) and EBMT delayed recall (p = 0.0005). To remove residual confounding by persisting practice effects, we conducted a sensitivity analysis in which we ran the mixed effects models after dropping data from the 3rd cognition testing and allowing for a practice effect from 4th to 5th testing. Longitudinal aging estimates from the fully adjusted models were somewhat larger: SDMT declined 0.35 per year (95% confidence interval [CI]: 0.24, 0.46) in the ovarian aging model (2,926 observations from 1,130 women) and 0.25 per year (95% CI: 0.15, 0.36) in the chronological aging model (5,041 observations from 1,963 women). Discussion As hypothesized, after controlling for practice effects, the MT and MT symptoms, midlife women did show longitudinal declines in cognitive performance, mainly in processing speed. The average, within-woman rate of decline (longitudinal aging effect) in processing speed was essentially identical to the average, between-women difference by age at time of FMP (0.28 per year vs. 0.31 per year). However, as in previous studies [7], cross-sectional differences by chronological age at time of testing were substantially larger than longitudinal aging effects (0.54 per year vs. 0.25 per year), likely because between-women differences in ovarian age were not completely eliminated by controls for MT stage. Previous studies have found that cognitive procesing speed is especially sensitive to early changes [29,30,31]. We found longitudinal declines in both processing speed and verbal memory (delayed recall) in this study. The estimated decline rates translate to a 10-year reduction of approximately 0.25 standard deviations (SD) of the baseline score or 4.9% of the mean baseline score in processing speed, and 0.11 SD of the baseline score or 2.0% of the mean baseline score in delayed recall. These rates are similar to the 10-year longitudinal decline of 3.6% in reasoning score seen in 45–49 year old women in the Whitehall cohort [7]. Consistent with previous work, we also did not see longitudinal declines in immediate recall and working memory; however, more sensitive measures of episodic and working memory might indeed show declines in midlife. Although there is some evidence that circulating estrogen might protect premenopausal women from cognitive aging [32,33], we did not see a sharp acceleration of cognitive decline during or after the menopause transition (Figs 1 and 2). Instead, the rates of longitudinal decline in SDMT scores were nearly identical regardless of whether time was indexed to the date of the FMP (ovarian aging model) or measured from study baseline (chronological aging model). However, MT-related declines in circulating estradiol level start 2 years before the FMP, and declines in other estrogen-dependent biological systems, such as bone, commence well before the FMP [26,34]. Because 75% of participants in the current analysis were 52 years of age or older at study baseline and the mean age at FMP was 52, the vast majority were “past” the time when an estradiol-related inflection in the cognitive performance trajectory might occur. The likelihood of such an inflection in cognitive performance trajectory prior to the FMP is supported by our finding that between-women differences by age at FMP were smaller than between-women differences by age at time of testing. As in older cohorts, we also saw a retention effect in this midlife cohort: Cognitive performance was better in women who stayed in the study longer, although attrition was not primarily due to death in this cohort. At least one other study found similar differences by retention in cognitive performance in the 6th decade, but concluded that selective retention did not bias estimates of longitudinal cognitive decline [35]. Limitations of our study include the inability described above to detect initiation or acceleration of cognitive decline at the time that estrogen starts declining, absence of men from the study, and limited generalizability to women not represented in this study, including those who use sex hormones during the MT, who had a hysterectomy without bilateral oophorectomy prior to natural menopause, who were too ill to participate, from less developed economies, and women from race/ethnicity groups not represented in SWAN. In conclusion, this study provides good new evidence of cognitive aging in women in midlife, with significant longitudinal declines in both processing speed and verbal memory. Unlike previous longitudinal studies in midlife that were based on 3 or fewer cognition assessments, and could not adequately account for practice effects, we analyzed up to 6 annual or biennial assessements, allowing us to minimize the impact of practice effects and unmask declines. Practice effects are larger in younger, cognitively intact individuals than in older adults [36] and can dominate over the smaller declines in cognitive performance in midlife; more complete elimination of practice effects may show that midlife declines are even steeper. A decline in processing speed in midlife is not a harbinger of declines in other domains of functioning [37], there are individual differences in cognitive aging, and resilience and compensatory mechanisms can ameliorate the impact of cognitive aging on functioning and well-being [38]. Cognitive aging may also be malleable [39,40]. Further research is needed to determine factors that influence differential rates of decline in cognitive performance with an eye towards developing interventions aimed at slowing cognitive aging. Acknowledgments We thank SWAN participants, the investigators and study staff at SWAN clinical sites, central laboratory, and coordinating center, the steering committee chair, and the NIH program officers and staff. Author Contributions Conceptualization: ASK MEL GAG. Data curation: MHH. Formal analysis: ASK WJH. Funding acquisition: GAG. Methodology: ASK. Project administration: ASK. Software: WJH. Supervision: ASK. Writing – original draft: ASK. Writing – review & editing: ASK MEL WJH MHH GAG. References 1.Karlamangla AS, Miller-Martinez D, Aneshensel CS, Wight RG, Seeman TE, and Chodosh J. Trajectories of cognitive function in late life in the United States: Demographic and socioeconomic predictors. Amer J Epidemiol 2009; 170(3):331–342. View Article PubMed/NCBI Google Scholar 2.Deary IJ, Corley J, Gow AJ, Harris SE, Houlihan LM, Marioni RE, et al. Age-associated cognitive decline. 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  13. Habitual Weight-Bearing Exercise Best for Bone Strength in Elderly Bone strength and size in lower limbs were positively affected by exercise with higher vertical impacts in a study of day-to-day weight-bearing physical activity in older women. The study investigated vertical acceleration peaks as measured by 7-day accelerometer recordings, according to an article published Dec. 13 in Osteoporosis International. Observations in younger individuals have shown exposure to higher exercise impacts to confer greater lower limb bone strength. The Hannam et al. study asked whether the observed benefit of habitual weight-bearing physical activity on bone strength in lower limbs in older women is also attributable to higher impacts. To address that question, 408 women (mean age 76.8 years) from the Cohort for Skeletal Health in Bristol and Avon (U.K.) consented to 7-day physical activity monitoring with the GCDC X15-1c triaxial accelerometer. Mid and distal peripheral quantitative computed tomography scans of the tibia and radius were performed, as were hip and lumbar spine Dual Xray Absorptiometry (DXA) scans. The monitoring device, which measured vertical acceleration peaks according to g level, had shown in earlier research that impacts exceeding 3.9 g confer bone size and strength benefits in premenopausal women, and impacts of 4.2 g confer benefit in adolescents. Allowing that osteogenic thresholds in younger populations may not be applicable to older individuals with weaker skeletons, investigators measured exposure to vertical impacts >1.5 g in their cohort of older women. Specifically, Hannam et al. asked if habitual exposure to such higher impacts (despite the relatively low 1.5 g threshold and the relative rarity of such impacts), as opposed to medium or low level impacts, explain the benefits of weight-bearing physical activity. High impacts of 1.5 g or greater exceed that those associated with walking (typically 0.5–1.0 g), but are achieved in the majority of aerobics class exercises undertaken by older individuals, particularly those with a jumping component, Hannam et al. state. In the measurement week, analysis revealed 8809 low impacts, 345 medium impacts and 42 higher impacts. Bone strength of lower limbs, fully adjusted for numerous potentially confounding factors, was positively associated with higher vertical impacts as reflected by cross-sectional moment of inertia (CSMI) of the tibia [0.042 (0.012, 0.072) p = 0.01] and hip [0.067 (0.001, 0.133) p = 0.045] (beta coefficients show standard deviations change per doubling in impacts, with 95% confidence interval). Higher impacts were positively associated with tibial periosteal circumference (PC) [0.015 (0.003, 0.027) p = 0.02], but unrelated to hip bone mineral density. Low or medium impacts were not associated with equivalent positive changes. “We found that higher, but not medium or low, vertical impacts,” Hannam et al. concluded, “were positively related to estimated bone strength as reflected by hip and tibial cross-sectional moment of inertia (CSMI), and tibial strength strain index.” The authors underscored that the bone strength in lower limbs appeared to reflect changes in overall bone size, with little relationship to bone mineral density. Because hip bone mineral density increases are more strongly associated with reduced hip fracture risk than are CSMI increases, fracture reductions are likely to be limited. Higher impacts on the order of 4-g, Hannam et al. suggested, may be necessary (and are achievable), to reduce fracture risk. References K. Hannam, K. C. Deere, A. Hartley, et al. “Habitual levels of higher, but not medium or low, impact physical activity are positively related to lower limb bone strength in older women: findings from a population-based study using accelerometers to classify impact magnitude,” Osteoporosis International. Dec. 13, 2016. DOI: 10.1007/s00198-016-3863-5. http://www.rheumatologynetwork.com/osteoporosis/habitual-weight-bearing-exercise-best-bone-strength-elderly?GUID=&XGUID=&rememberme=1&ts=17012017
  14. CDC Grand Rounds Chronic Fatigue Syndrome — Advancing Research and Clinical Education Elizabeth R. Unger, PhD, MD; Jin-Mann Sally Lin, PhD; Dana J. Brimmer, PhD; Charles W. Lapp, MD; Anthony L. Komaroff, MD; Avindra Nath, MD; Susan Laird, MSN; John Iskander, MD Morbidity and Mortality Weekly Report. 2016;65(5051):1434-1438. Abstract and Introduction Introduction Chronic fatigue syndrome (CFS) is a complex and serious illness that is often misunderstood. Experts have noted that the terminology "chronic fatigue syndrome" can trivialize this illness and stigmatize persons who experience its symptoms.[1] The name was coined by a group of clinicians convened by CDC in the late 1980s to develop a research case definition for the illness, which, at the time, was called chronic Epstein-Barr virus syndrome. The name CFS was suggested because of the characteristic persistent fatigue experienced by all those affected and the evidence that acute or reactivated Epstein-Barr virus infection was not associated with many cases.[2] However, the fatigue in this illness is striking and quite distinct from the common fatigue everyone experiences. A variety of other names have been used, including myalgic encephalomyelitis (ME), ME/CFS, chronic fatigue immune dysfunction, and most recently, systemic exertion intolerance disease.[3] The lack of agreement about nomenclature need not be an impediment for advancing critically needed research and education. The term ME/CFS will be used in this article. ME/CFS Is a Significant Public Health Problem Extrapolating from the three U.S. population-based studies, it is estimated that at least one million persons in the United States suffer from ME/CFS.[4–6] These studies indicate that ME/CFS is three to four times more common in women than in men. Persons of all racial and ethnic backgrounds are affected; however, the illness is more prevalent in minority and socioeconomically disadvantaged groups. The highest prevalence of illness is in persons aged 40–50 years, but the age range is broad and includes children and adolescents. ME/CFS patients, their families, and society all bear significant costs associated with this illness. These include direct medical costs for provider visits and medications and indirect costs of lost productivity. In the United States, the estimated annual cost of lost productivity ranges from 9–37 billion dollars, and for direct medical costs, ranges from 9–14 billion dollars, with nearly one quarter of direct medical expenses paid directly by patients and their families.[7–9] When ME/CFS occurs in patients aged <25 years, these patients might not achieve their full educational potential, resulting in a life-long impact on their earnings.[7] ME/CFS patients have significant functional impairment as illustrated by findings from CDC's ongoing study of patients in seven clinics of ME/CFS specialists (Figure). Functioning of ME/CFS patients, as measured by subscale scores on the 36-Item Short Form Survey (SF-36), were well below those of healthy persons except for the two subscales reflecting mental and emotional functioning. Despite the severity of their illness, ME/CFS patients face significant barriers to receiving appropriate health care. A population-based study in Georgia found that 55% of persons with ME/CFS reported at least one barrier to health care; for example, 10% had financial barriers to seeking needed health care.[10] Most persons with ME/CFS identified in population surveys have been ill >5 years and only approximately half continue to seek medical care.[4–6] Further, only approximately 20% received a diagnosis, emphasizing the need for more physician education about this illness. Figure. Functional status* of 471 patients enrolled in CDC's Multisite Clinical Assessment† of ME/CFS§ — United States, September 2015 Abbreviations: CFS = chronic fatigue syndrome; ME = myalgic encephalomyelitis; SF-36 = short form 36. *Measured by box plots of scores in the eight subscales of SF-36 scores (25th and 75th percentile at bottom and top of box). SF-36 scores range from 0–100, with higher scores indicating better functioning. †https://www.cdc.gov/cfs/programs/clinical-assessment/index.html. §ME/CFS patients show significant impairment, particularly in vitality and physical functioning subscale scores, but with preservation of mental health and emotional role functioning. Clinical Approach to ME/CFS There is no "typical" case, but a patient history can be useful in educating physicians about ME/CFS (). This composite case history illustrates the key features of ME/CFS: significant reduction in ability to perform usual activities accompanied by profound fatigue; significant worsening of symptoms after minimal physical or mental exertion (termed postexertional malaise); unrefreshing sleep; cognitive difficulties; and orthostatic intolerance (such as dizziness and lightheadedness upon standing up). In addition, this patient experienced widespread muscle pain, joint pain, and unpredictable waxing and waning of symptoms. Persons with ME/CFS might be misunderstood because they appear healthy and often have no abnormalities on routine laboratory testing. Clinicians need to be alert to this difficulty and take the time to elicit a good history of the illness, which is critical in the differential diagnosis and can provide evidence of ME/CFS. Box 1. Myalgic encephalomyelitis/chronic fatigue syndrome case history The patient, aged 37 years, was an internet technologist for a community bank. She had been physically active in sports and working out, and had been maintaining her own household when she experienced a flu-like illness in 2011. She was bedbound at first and slow to recover. Within days she noted an unusual fatigue after minimal activity, then insomnia, achiness in the joints, and generalized muscle pain and weakness. She soon found it difficult to recall recent conversations and events. Reading concentration was limited, and she had trouble comprehending what she had read or even television shows. She would search for words, lose her train of thought, and friends would sometimes have to finish sentences for her. Previously her sleep had always been good, but now she was restless at night and would awaken unrefreshed even after many hours of bed rest. She felt stiff, sore, and foggy for 1–2 hours after awakening. She noted dizziness or lightheadedness on getting up quickly, and on a couple of occasions "saw stars," but did not experience tunnel vision or fainting. The patient was unable to keep up the house, and she had to rely on friends and family to help her with cleaning, laundry, and shopping. She would attempt to keep up at home and at work, but exertion would inevitably make symptoms worse, and if she exerted too much she would end up sick and chairbound for 1–2 days afterward. Evaluation by her primary care physician revealed low blood pressure, but there was no immediate orthostatic blood pressure drop and otherwise the examination was unremarkable. Blood work was unremarkable. Having no explanation for her symptoms despite the profound reduction in her physical abilities, the patient became anxious about her future and both frustrated and discouraged. Clinical evaluation includes a thorough medical history, psychosocial history, complete physical examination, mental health assessment, and basic laboratory tests to screen for conditions that could cause symptoms similar to ME/CFS and that should be treated before attributing the illness to ME/CFS. The screening laboratory tests can include complete blood count with differential white blood cell count, sodium, potassium, glucose, blood urea nitrogen, creatinine, lactate dehydrogenase, aspartate transaminase, alanine transaminase, alkaline phosphatase, total protein, albumin, calcium, phosphorus, magnesium, thyroid stimulating hormone, free thyroxine, sedimentation rate, C-reactive protein, antinuclear antibodies, rheumatoid factor, and urinalysis.[11] Patients might also have comorbid conditions such as fibromyalgia, irritable bowel and bladder, Sjögren's syndrome, chemical sensitivities, and allergies.[11] Additional tests might be clinically indicated. Cause or Causes of ME/CFS The cause or causes of ME/CFS remain unknown. Patients often report an acute onset after a flu-like illness that does not go away, and some patients have a history of frequent infections before their illness. This suggests that an infection can trigger the illness, though it is less clear that the ongoing chronic illness is perpetuated by an infection. Investigators have looked for, and failed to find, a single etiologic agent. However, chronic fatiguing illnesses have long been described in the medical literature following infection with several different agents. For example, a syndrome with similarities to ME/CFS occurs in approximately 10% of patients with a variety of viral and nonviral pathogens, such as Epstein-Barr Virus, Ross River Virus, Coxiella burnetti (Q fever), or Giardia.[12] The severity of the acute infection was most predictive of subsequent illness, and there is no evidence of unusual persistence of infections in those who remain ill; baseline psychological profile and socioeconomic status did not predict who would become chronically ill.[12] Other studies have found that, compared with healthy controls, persons with ME/CFS have had exposure to significantly more stressors (trauma and other adverse life events) and are more likely to have metabolic syndrome, as well as higher physiologic measures of neuroendocrine response to stress (allostatic load).[13] These associations are not specific to ME/CFS, because stress is a factor in many chronic illnesses. Twin and family studies support the contribution of both genetic and environmental factors in CFS.[14] No single mutation or polymorphism has been found that explains most cases of the illness, and a polygenetic explanation for increased susceptibility is most likely. Treatment of ME/CFS At this time, there are no treatments (pharmacologic or nonpharmacologic) that have been proven effective in large randomized trials and replicated by other investigators in other groups of patients with ME/CFS. Recommendations are based on expert clinical opinion and the standard clinical approach to symptom management.[15] Sleep disruption and pain are the symptoms usually addressed first, and consultation with sleep or pain management specialists might be helpful. Nonpharmacologic approaches might include Epsom salt soaks, massage, acupuncture, and, most importantly, activity management. Patients should be encouraged to stay active but not too active. They need to start with very low levels of activity and escalate the levels slowly. Brief intervals of activity should be followed by adequate rest to avoid triggering relapse or flare of symptoms, a manifestation of postexertional malaise. Finally, living with a chronic illness is extremely challenging, so attention should be given to addressing depression, anxiety, and improving coping skills. Addressing ME/CFS Recently, three important reports about ME/CFS have been published by authoritative agencies.[1] The Institute of Medicine (IOM) issued a 300-page report in which a panel of physicians and scientists reviewed nearly 9,000 published articles.[3] They concluded that ME/CFS is a biologically based illness and proposed a new case definition and name (systemic exertion intolerance). The National Institutes of Health (NIH) held a Pathways to Prevention workshop, drawing similar conclusions about the biology of ME/CFS, and the Agency for Healthcare Research and Quality prepared a review of published literature on diagnosis and treatment.[16,17] The IOM panel concluded that "ME/CFS is a serious, chronic, complex systemic disease that often can profoundly affect the lives of patients." Both the IOM and NIH reports conclude that ME/CFS is not primarily a psychological illness, although it might lead to a reactive depression in some patients. Although none of the biologic abnormalities identified in ME/CFS patients are sufficiently sensitive or specific to be used as a diagnostic test, the neurologic and immunologic abnormalities documented emphasize that patients' symptoms are real. In the absence of a diagnostic test, the IOM report proposes use of a new clinical case definition (). The new case definition is shorter, easier to apply consistently, and emphasizes that ME/CFS is a diagnosis to be actively made, not simply a diagnosis of exclusion. The IOM report also recommended a new name be considered for the condition: systemic exertion intolerance disease. Box 2. Institute of Medicine criteria for diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome Patient has each of the following three symptoms at least half of the time, to at least a moderately severe degree: A substantial reduction or impairment in the ability to engage in preillness levels of occupational, educational, social, or personal activities that persists for >6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest. Postexertional malaise* Unrefreshing sleep* Plus at least one of the two following manifestations (chronic, severe): Cognitive impairment* Orthostatic intolerance Source: Institute of Medicine. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: redefining an illness. Washington, D.C.: The National Academies Press; 2015. http://www.nationalacademies.org/hmd/reports/2015/me-cfs.aspx *Frequency and severity of symptoms should be assessed. The diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome should be questioned if patients do not have these symptoms at least half of the time with moderate, substantial, or severe intensity. It is clear that more basic science research is needed. In September 2015, the NIH intramural program began developing a research protocol to study ME/CFS. The overall hypothesis is that ME/CFS is attributable to an infection that results from immune-mediated brain dysfunction in some patients with acute onset illness. Aim 1 will define the clinical phenotype based on history and physical examination, neurologic assessment, neurocognitive testing, psychiatric evaluation, infectious disease, rheumatologic and neuroendocrine evaluations, and exercise testing. Aim 2 will define the physiologic basis of postexercise fatigue and malaise using functional magnetic resonance imaging, detailed metabolic studies, transcranial magnetic stimulation, and detailed autonomic testing before and after exercise challenge. Aim 3 will determine if there are abnormal immune parameters in the blood and spinal fluid and changes in microbiome profiles. Aim 4 will determine if features of the illness can be reproduced in ex vivo studies using cells or serum from patients and a variety of novel approaches such as induced pluripotent stem cell-derived neurons. Patients will be recruited primarily from well-studied cohorts under the care of clinicians with expertise in diagnosis and management of ME/CFS. CDC is continuing its efforts to provide evidence-based information about ME/CFS to health care professionals. In 2012 and 2013, CDC partnered with Medscape to present two roundtable discussions that were targeted to primary care physicians. These reached more than 22,000 physicians and more than 6,000 CME credits were issued. CDC provided free online courses about ME/CFS accredited for both physicians, nurses, and other health care professionals. Because the topic of ME/CFS is rarely covered in medical school courses, CDC initiated a project to develop content for the MedEd Portal, a free online service of peer-reviewed content provided by the Association of American Medical Colleges to medical school faculty. To continue communication with the general public and advocacy community, CDC introduced patient-centered outreach and communication calls. These are 1-hour teleconferences held twice a year that are available toll-free in the United States. CDC uses the first 10 minutes to give an update on current activities of the ME/CFS program, and then an outside expert or group of experts presents information on a topic of interest to the community. These are followed by answers to questions submitted to the patient-centered outreach and communication email. Topics have included exercise, infection, and immunity in ME/CFS, ME/CFS and cognitive function, sleep research and ME/CFS, Stanford's research program, and self-management strategies in ME/CFS. Most recently, CDC has begun a new initiative to include broad stakeholder collaboration into developing educational materials. Including the viewpoints of patients, medical professional organizations, medical educators, expert clinicians, and government agencies will help assure the quality and usefulness of these products and facilitate broader dissemination in the medical community. With its demonstrated burden on individual patients and public health, ME/CFS should continue to be an area of active basic science and epidemiologic research, enhanced clinical diagnostic attention and training, and continued outreach, communication, and education. References Komaroff AL. Myalgic encephalomyelitis/chronic fatigue syndrome: a real illness. Ann Intern Med 2015;162:871–2. http://dx.doi.org/10.7326/M15-0647 Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome: a working case definition. Ann Intern Med 1988;108:387–9. http://dx.doi.org/10.7326/0003-4819-108-3-387 Institute of Medicine. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: redefining an illness. Washington, DC: The National Academies Press; 2015. http://www.nationalacademies.org/hmd/reports/2015/me-cfs.aspx Jason LA, Richman JA, Rademaker AW, et al. A community-based study of chronic fatigue syndrome. Arch Intern Med 1999;159:2129–37. http://dx.doi.org/10.1001/archinte.159.18.2129 Reyes M, Nisenbaum R, Hoaglin DC, et al. Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Intern Med 2003;163:1530–6. http://dx.doi.org/10.1001/archinte.163.13.1530 Reeves WC, Jones JF, Maloney E, et al. Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Popul Health Metr 2007;5:5. http://dx.doi.org/10.1186/1478-7954-5-5 Lin JM, Resch SC, Brimmer DJ, et al. The economic impact of chronic fatigue syndrome in Georgia: direct and indirect costs. Cost Eff Resour Alloc 2011;9:1. http://dx.doi.org/10.1186/1478-7547-9-1 Reynolds KJ, Vernon SD, Bouchery E, Reeves WC. The economic impact of chronic fatigue syndrome. Cost Eff Resour Alloc 2004;2:4. http://dx.doi.org/10.1186/1478-7547-2-4 Jason LA, Benton MC, Valentine L, Johnson A, Torres-Harding S. The economic impact of ME/CFS: individual and societal costs. Dyn Med 2008;7:6. http://dx.doi.org/10.1186/1476-5918-7-6 Lin JM, Brimmer DJ, Boneva RS, Jones JF, Reeves WC. Barriers to healthcare utilization in fatiguing illness: a population-based study in Georgia. BMC Health Serv Res 2009;9:13. http://dx.doi.org/10.1186/1472-6963-9-13 Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A; International Chronic Fatigue Syndrome Study Group. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Ann Intern Med 1994;121:953–9. http://dx.doi.org/10.7326/0003-4819-121-12-199412150-00009 Hickie I, Davenport T, Wakefield D, et al.; Dubbo Infection Outcomes Study Group. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ 2006;333:575. http://dx.doi.org/10.1136/bmj.38933.585764.AE Maloney EM, Boneva RS, Lin JMS, Reeves WC. Chronic fatigue syndrome is associated with metabolic syndrome: results from a case-control study in Georgia. Metabolism 2010;59:1351–7. http://dx.doi.org/10.1016/j.metabol.2009.12.019 Buchwald D, Herrell R, Ashton S, et al. A twin study of chronic fatigue. Psychosom Med 2001;63:936–43. International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. Chronic fatigue syndrome/myalgic encephalomyelitis primer for clinical practitioners. Bethesda, MD: International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis; 2014. http://iacfsme.org/portals/0/pdf/Primer_Post_2014_conference.pdf Green CR, Cowan P, Elk R, O'Neil KM, Rasmussen AL. National Institutes of Health Pathways to Prevention Workshop: advancing the research on myalgic encephalomyelitis/chronic fatigue syndrome. Ann Intern Med 2015;162:860–5. http://dx.doi.org/10.7326/M15-0338 Haney E, Smith MEB, McDonagh M, et al. Diagnostic methods for myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med 2015;162:834–40. http://dx.doi.org/10.7326/M15-0443 Morbidity and Mortality Weekly Report. 2016;65(5051):1434-1438. © 2016 Centers for Disease Control and Prevention (CDC) http://www.medscape.com/viewarticle/873894_print
  15. Randomized, Double-blind, Placebo-controlled Phase III Trial of Duloxetine Monotherapy in Japanese Patients With Chronic Low Back Pain Shinichi Konno, MD, PhD; Natsuko Oda, MS; Toshimitsu Ochiai, MS; Levent Alev, MD Spine. 2016;41(22):1709-1717. Abstract and Introduction Abstract Study Design. A 14-week, randomized, double-blind, multicenter, placebo-controlled study of Japanese patients with chronic low back pain (CLBP) who were randomized to either duloxetine 60 mg once daily or placebo. Objective. This study aimed to assess the efficacy and safety of duloxetine monotherapy in Japanese patients with CLBP. Summary of Background Data. In Japan, duloxetine is approved for the treatment of depression, diabetic neuropathic pain, and pain associated with fibromyalgia; however, no clinical study of duloxetine has been conducted for CLBP. Methods. The primary efficacy measure was the change in the Brief Pain Inventory (BPI) average pain score from baseline to Week 14. Secondary efficacy measures included BPI pain (worst pain, least pain, pain right now), Patient's Global Impression of Improvement, Clinical Global Impressions of Severity, and Roland-Morris Disability Questionnaire, among other measures, and safety and tolerability. Results. In total, 458 patients were randomized to receive either duloxetine (n = 232) or placebo (n = 226). The BPI average pain score improved significantly in the duloxetine group compared with that in the placebo group at Week 14 [-2.43 ± 0.11 vs.−1.96 ± 0.11, respectively; between-group difference (95% confidence interval), − 0.46 [-0.77 to-0.16]; P = 0.0026]. The duloxetine group showed significant improvement in many secondary measures compared with the placebo group, including BPI pain (least pain, pain right now) (between-group difference: −1.69 ± 0.10, P = 0.0009; −2.42 ± 0.12, P P = 0.0230, respectively), Patient's Global Impression of Improvement (2.46 ± 0.07, P = 0.0026), Clinical Global Impressions of Severity (-1.46 ± 0.06, P = 0.0019), and Roland-Morris Disability Questionnaire (-3.86 ± 0.22, P = 0.0439). Adverse events occurring at a significantly higher incidence in the duloxetine group were somnolence, constipation, nausea, dizziness, and dry mouth, most of which were mild or moderate in severity and were resolved or improved. Conclusion. Duloxetine 60 mg was effective and well tolerated in Japanese CLBP patients. Level of Evidence: 2 Introduction Low back pain (LBP) has an estimated lifetime prevalence of 83%, and approximately 25% to 35% of Japanese patients complain of LBP.[1,2] Chronic LBP (CLBP) is usually defined as pain persisting for at least 3 months. Patients with acute LBP show rapid improvement within 1 month after onset, followed by gradual improvement until 3 months after onset; however, a high incidence of protracted treatment has been reported along with low patient satisfaction with treatment.[3,4] Treatment strategies for LBP include drug therapy, physical and orthotic therapy, exercise, nerve block injection, and surgery. Nonsteroidal antiinflammatory drugs (NSAIDs), acetaminophen, anxiolytics, muscle relaxants, antidepressants, and opioids are recommended by international[5,6] and Japanese LBP treatment guidelines.[7] In Japan, NSAIDs, acetaminophen, and some opioids have been approved for the treatment of LBP. First-line treatment with NSAIDs has been demonstrated to be effective for acute LBP, but its efficacy for CLBP has not been confirmed,[8] and possible gastrointestinal, cardiac, and renal[9] adverse drug reactions (ADRs) should be considered with long-term use. The evidence of the effectiveness of other drugs is insufficient, and concerns about ADRs remain. Duloxetine, a serotonin–norepinephrine reuptake inhibitor (SNRI), inhibits the reuptake of serotonin and norepinephrine, which are neurotransmitters of the descending pain inhibitory pathways. Although the exact mechanisms of central pain inhibition by duloxetine in humans are unknown, it is believed that duloxetine increases synaptic cleft levels of these neurotransmitters in the spinal and supraspinal pathways, activating the descending pain inhibitory systems and producing an analgesic effect.[10] Three clinical studies in patients with CLBP have been conducted overseas.[11–13] Two of these provided clinical evidence that duloxetine significantly reduces pain compared with placebo and is well-tolerated. Based on these results and those of clinical studies of osteoarthritis patients, duloxetine has been approved for "chronic musculoskeletal pain" or "chronic low back pain and chronic pain associated with osteoarthritis" in the United States and 28 other countries. Furthermore, in the field of pain management, it has been approved for diabetic neuropathic pain and fibromyalgia. In Japan, duloxetine is approved for the treatment of major depressive disorder, diabetic neuropathic pain, and pain associated with fibromyalgia;[14–16] however, no clinical study of duloxetine has been conducted in Japanese patients with CLBP. Therefore, the current study aimed to assess the efficacy and safety of duloxetine monotherapy in Japanese patients with CLBP. Materials and Methods Study Design and Treatment This randomized, placebo-controlled, double-blind phase III study was conducted in 58 medical institutions in Japan from May 2013 to July 2014. This study consisted of four study periods: a 1-week to 2-week pretreatment period, 14-week treatment period, 1-week taper period, and 1-week follow-up period. In the pretreatment period, patients were withdrawn from analgesics (including NSAIDs) and other therapeutic drugs (including muscle relaxants, antidepressants, sedatives, and benzodiazepines) for CLBP, and concomitant use of these drugs was prohibited during the study. Additional details of allowed or prohibited treatments are provided (see text, Supplemental Digital Content 1, http://links.lww.com/BRS/B165). Patients who met the inclusion criteria were randomized to treatment with duloxetine 60 mg once daily or placebo, orally, after completion of the pretreatment period, using a stochastic minimization procedure. The Brief Pain Inventory (BPI) average pain score at baseline (<6, ≥6) was used as the allocation factor. Patients and investigators were blinded to the treatment; the appearance and labeling of the doses were indistinguishable between placebo and the study drug. The investigator in charge of allocation randomly assigned patients to treatment or placebo based on an assignment table developed using the SAS Version 9.1 (SAS Institute Inc., Cary, NC) PLAN procedure. After allocation, the assignment table was sealed by the investigator in charge of allocation, and remained inaccessible by all involved parties until after finalization of the clinical report. After randomization, patients received treatment after breakfast under double-blind conditions. In the treatment period, the duloxetine group received duloxetine at 20 mg/day for 1 week and then at 40 mg/day for 1 week, followed by 60 mg/day for 12 weeks. The placebo group received placebo during the 14-week treatment period. Patients underwent tapering after completion of the treatment period or after discontinuation after 2 weeks of treatment. Informed consent was obtained from all patients before the study start. The study was approved by the Institutional Review Board of each medical institution. This study was conducted in compliance with Good Clinical Practice (GCP) guidelines and was registered in clinicaltrials.gov (NCT01855919). Patients The inclusion criteria were as follows: (i) male and female outpatients of age 20 to <80 years who had LBP persisting for at least 6 months; (ii) had used NSAIDs for at least 14 days per month for an average of 3 months before the start of the study and for at least 14 days during the 1-month period before the start of the study, regardless of dose of NSAIDs and route of administration; (iii) did not have radiculopathy symptoms or other specific low back diseases; and (iv) had a BPI pain (average pain)[17] of ≥4 at Visit 1 (Week −1 to −2) and Visit 2 (Week 0). The exclusion criteria were as follows: (i) patients with a history of low back surgery; (ii) those receiving invasive treatment for the relief of LBP within 1 month before Visit 1; (iii) those requiring crutches or a walker; and (iv) those diagnosed as having major depressive disorders according to the Mini International Neuropsychiatric Interview[18] or suicidal tendencies according to the Columbia-Suicide Severity Rating Scale (C-SSRS).[19] Efficacy The primary efficacy measure was the BPI average pain score, which measures average pain during the past 24 hours on a scale from 0 (no pain) to 10 (pain as bad as you can imagine).[17] The secondary efficacy measures were (i) the worst, least, and pain right now item scores of BPI and pain interference with seven daily activities (general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life); (ii) the 24-hour average pain and 24-hour worst pain score (weekly mean); (iii) Patient's Global Impression of Improvement (PGI-I)[20] and Clinical Global Impressions of Severity (CGI-S) scores; (iv) LBP-specific quality of life (QOL) using the Roland-Morris Disability Questionnaire (RDQ-24);[21–23] (v) the 36-Item Short-Form Health Survey (SF-36; Japanese version 2) score;[24,25] (vi) the European QOL Questionnaire-5 Dimension (EQ-5D) score;[26] and (vii) the Work Productivity and Activity Impairment Instrument (WPAI) score.[27] Additional details on the assessment of the secondary efficacy measures are provided (see text, Supplemental Digital Content 2, http://links.lww.com/BRS/B165). Safety For safety, the incidences of adverse events (AEs), serious adverse events (SAEs), discontinuation because of AEs, and ADRs during the study period were calculated. AEs and SAEs were monitored from the beginning of administration till the end of the follow-up period. In addition, laboratory tests (hematology, clinical chemistry, and urinalysis), electrocardiogram, and measurements of body weight, blood pressure, and pulse were performed. The occurrence of falls was investigated, and the presence of suicidal tendencies was assessed using the C-SSRS. Statistical Analyses The between-group difference in the change in BPI average pain at 14 weeks was estimated to be −0.60 with a standard deviation (SD) of 1.94, in reference to the study by Skljarevski et al,[11] in which the conditions of use for NSAIDs during the study period were similar to those of the current study. Under this assumption, 450 patients (225 per group) would provide at least 90% power at a two-sided significance level of 0.05. All efficacy and safety analyses were performed on the full analysis set (FAS) and safety analysis set, respectively. Unless otherwise noted, the treatment effects were tested with a two-sided significance level of 0.05. A mixed-effects model repeated measures approach (MMRM analysis) was used to compare the change in BPI average pain score from baseline to Week 14 between duloxetine and placebo groups. The model included the fixed effects of treatment, time point, and treatment-by-time point interaction as well as a covariate of baseline BPI average pain. The unstructured covariance was applied in this primary analysis. The response rate was examined as another analysis of the primary efficacy measure. In the responder analysis, the number of responders and the response rate were calculated in each group in terms of 30% pain reduction, 50% pain reduction, and sustained pain reduction, which was defined as BPI average pain reduction of at least 30% from baseline at any point before the last visit, and remaining at least >20% below baseline for the remainder of the study period. These response rates were compared between the groups using a Mantel-Haenszel test with baseline BPI average pain score as the stratification factor. The categorical distribution of the PGI-I results at the final evaluation were also investigated using the Wilcoxon rank sum test. Path analysis was performed to estimate the ratio between the direct analgesic effect of duloxetine and its indirect analgesic effect through antidepressant action. In the analyses of the change in secondary efficacy measures, MMRM analysis was performed using longitudinal data on BPI pain (worst pain, least pain, pain right now), BPI interference, 24-hour average and worst pain score (weekly mean), and CGI-S to compare the change at Week 14 between the two treatment groups. The PGI-I was analyzed using an MMRM model as a covariate of baseline PGI-S score. For the RDQ-24, SF-36, EQ-5D, and WPAI, ANCOVA was performed to compare the change from baseline to Week 14 between both treatment groups. In the safety analysis set, the incidence of AEs and ADRs was compared between the groups using Fisher's exact test. All statistical analyses were performed using SAS Version 9.2. Additional details of the statistical analysis are provided (see text, Supplemental Digital Content 3, http://links.lww.com/BRS/B165). Results Patient Disposition and Baseline Characteristics A total of 458 patients were enrolled in the study and randomized to the duloxetine (n = 232) and placebo groups (n = 226) (Figure 1). Discontinuation during the treatment period occurred in 23 (9.9%) and 26 (11.5%) patients in the duloxetine and placebo groups, respectively. The most common reason for discontinuation during the treatment period was the development of AEs in the duloxetine group (16 patients: 6.9%) and consent withdrawal in the placebo group (10 patients: 4.4%). In total, 428 patients entered the taper period. Only one patient in the duloxetine group requested discontinuation of treatment and was withdrawn from the study during the taper period. Figure 1. Patient disposition. The baseline characteristics of the 456 patients included in the FAS are shown in . The distribution of patient baseline characteristics showed no imbalance (significance level: 0.15) between the duloxetine and placebo groups, except for age. However, this difference was not considered to have affected the study results. Table 1. Baseline Demographic and Clinical Characteristics (Full Analysis Set) Placebo (n=226) Duloxetine (n=230) P* Age, years 57.8±13.7 60.0±13.2 0.0745 Male 104 (46.0) 115 (50.0) 0.4007 Female 122 (54.0) 115 (50.0) Weight, kg 63.15±13.42 63.56±12.75 0.7377 Height, cm 159.81±9.23 161.05±9.43 0.1558 Duration of CLBP, years 10.3±10.6 9.8±10.1 0.6442 BPI average pain (0–10) 5.1±1.0 5.1±1.1 0.6165 Pretreatment (physical therapy) 120 (53.1) 119 (51.7) 0.7793 Data are presented as mean±SD or n (%). BPI indicates Brief Pain Inventory; CLBP, chronic low back pain. *The data were analyzed using Welch's t test for continuous variables and Fisher exact test for categorical variables at the significance level of 0.15. Efficacy Figure 2 shows the changes over time in least squares (LS) mean ( ± SE) BPI average pain score up to Week 14 (primary endpoint) in both groups. The change in BPI average pain from baseline to Week 14 was −2.43 ± 0.11 in the duloxetine group and −1.96 ± 0.11 in the placebo group, with a between-group difference (95% confidence interval) of −0.46 (−0.77 to −0.16) (P = 0.0026). Furthermore, at all other evaluation time points, a significantly greater improvement in BPI average pain was observed in the duloxetine group than in the placebo group. The proportions of patients with 30% reduction, 50% reduction, and sustained reduction of the BPI average pain score in each group are shown in Figure 3; in each of the three response rate categories, the proportion of patients was significantly higher in the duloxetine group than in the placebo group (P = 0.0003, 0.0003, and 0.0012, respectively) (Figure 3). Moreover, in the post hoc analyses, the proportion of patients with a reduction in the BPI average pain score of ≥2 points at Week 14 was 69.6% and 54.4% in the duloxetine and placebo groups, respectively (P = 0.0010 by the Mantel-Haenszel test). Figure 2. Change in the Brief Pain Inventory average pain score in the full analysis set (MMRM analysis). Data are presented as adjusted mean±standard error. LS indicates least squares; MMRM, mixed-effects model repeated measures. Figure 3. Response rates according to the BPI average pain score in the full analysis set. BPI indicates Brief Pain Inventory. Changes in the secondary efficacy measures at Week 14 are shown in . Significantly, higher improvement in PGI-I and CGI-S was observed at Week 14 in the duloxetine group compared with the placebo group. In addition, in most of the secondary efficacy measures related to pain, significant pain reduction was observed in the duloxetine group compared with the placebo group, with significant improvement in the RDQ-24. shows the categorical distribution of the PGI-I results at the final evaluation. The ratio between the direct and indirect effect of duloxetine is shown in Figure 4. Table 2. Least-squares Mean Changes in Secondary Efficacy Measures From Baseline to Week 14 of Treatment Placebo N=226 Duloxetine N=230 P Baseline Mean±SD (n) Week 14 LS Mean Change±SE (n) Baseline Mean±SD (n) Week 14 LS Mean Change±SE (n) BPI-average pain MMRM 5.09±1.04 (226) −1.96±0.11 (200) 5.14±1.11 (230) −2.43±0.11 (209) 0.0026‡ LOCF 5.09±1.04 (226) −1.83±0.11 (226) 5.14±1.11 (230) −2.29±0.11 (230) 0.0024‡ BOCF 5.09±1.04 (226) −1.74±0.11 (226) 5.14±1.11 (230) −2.19±0.11 (230) 0.0034‡ m-BOCF 5.09±1.04 (226) −1.78±0.11 (226) 5.14±1.11 (230) −2.23±0.11 (230) 0.0034‡ BPI-other pain Worst pain, MMRM 6.60±1.26 (226) −2.33±0.13 (200) 6.63±1.30 (230) −2.63±0.13 (209) 0.1010 Least pain, MMRM 3.41±1.58 (226) −1.19±0.11 (200) 3.53±1.63 (230) −1.69±0.10 (209) 0.0009‡ Right now pain, MMRM 4.87±1.45 (226) −2.03±0.12 (200) 4.76±1.61 (230) −2.42±0.12 (209) 0.0230‡ Diary (24-h average pain), MMRM 4.88±1.07 (226) −1.73±0.11 (202) 4.94±1.15 (230) −2.15±0.10 (210) 0.0049‡ Diary (worst pain), MMRM 6.30±1.20 (226) −1.91±0.12 (202) 6.32±1.22 (230) −2.25±0.12 (210) 0.0442‡ BPI interference, MMRM Activity 4.05±2.11 (226) −2.16±0.13 (200) 4.36±2.17 (230) −2.46±0.13 (209) 0.0874 Mood 3.31±2.27 (226) −1.83±0.11 (200) 3.43±2.39 (230) −2.15±0.11 (209) 0.0436‡ Walk 3.53±2.36 (226) −1.92±0.11 (200) 3.40±2.37 (230) −2.05±0.11 (209) 0.3902 Work 3.91±2.30 (226) −2.17±0.12 (200) 3.93±2.37 (230) −2.17±0.12 (209) 0.9910 Relate 2.10±2.22 (226) −0.98±0.10 (200) 1.91±2.12 (230) −1.02±0.10 (209) 0.7848 Sleep 2.65±2.42 (226) −1.40±0.11 (200) 2.63±2.33 (230) −1.41±0.11 (209) 0.9424 Enjoy 2.86±2.41 (226) −1.48±0.11 (200) 2.77±2.30 (230) −1.52±0.11 (209) 0.7932 Average of 7 questions 3.20±1.92 (226) −1.70±0.10 (200) 3.20±1.90 (230) −1.83±0.10 (209) 0.3761 CGI severity, MMRM 4.22±0.71 (226) −1.17±0.06 (200) 4.23±0.66 (230) −1.46±0.06 (209) 0.0019‡ PGI improvement, MMRM − 2.76±0.07 (200)± − 2.46±0.07 (209)± 0.0026‡ RDQ-24, LOCF 7.77±4.77 (226) −3.23±0.22 (226) 7.59±4.38 (230) −3.86±0.22 (230) 0.0439‡ EQ-5D, LOCF 0.69±0.10 (226) 0.08±0.01 (226) 0.69±0.11 (230) 0.09±0.01 (230) 0.5237 SF-36, LOCF Physical functioning 72.52±19.53 (226) 7.20±0.80 (226) 71.87±18.30 (230) 8.47±0.79 (230) 0.2581 Role-Physical 71.79±22.07 (226) 10.00±1.16 (226) 70.41±22.28 (230) 10.58±1.15 (230) 0.7208 Bodily pain 48.96±11.76 (226) 11.01±0.95 (226) 49.11±12.24 (230) 12.56±0.94 (230) 0.2487 General health 58.35±16.78 (226) 3.78±0.86 (226) 58.54±16.53 (230) 6.72±0.85 (230) 0.0151‡ Vitality 57.44±17.35 (226) 4.41±0.97 (226) 59.78±17.61 (230) 5.56±0.97 (230) 0.4000 Social functioning 82.25±20.83 (226) 4.77±1.01 (226) 81.79±20.78 (230) 6.40±1.00 (230) 0.2529 Role-emotional 80.57±22.57 (226) 6.18±1.14 (226) 82.14±23.22 (230) 5.78±1.13 (230) 0.8042 Mental health 72.99±16.69 (226) 2.42±0.82 (226) 73.67±16.37 (230) 5.63±0.81 (230) 0.0058‡ WPAI, LOCF† Work time missed 0.01±0.05 (140) 0.02±0.01 (143) 0.02±0.08 (135) −0.01±0.01 (140) 0.0460‡ Impairment at work 0.31±0.24 (140) −0.09±0.02 (143) 0.29±0.24 (136) −0.13±0.02 (140) 0.0753 Work productivity loss 0.31±0.25 (140) −0.09±0.02 (143) 0.30±0.24 (135) −0.13±0.02 (140) 0.0795 Work activity impairment 0.35±0.22 (226) −0.12±0.01 (226) 0.34±0.23 (230) −0.14±0.01 (230) 0.1466 BOCF indicates Baseline Observed Carried Forward; BPI, Brief Pain Inventory; CGI, Clinical Global Impressions; EQ-5D, European QOL Questionnaire–5 Dimension; LOCF, Last Observation Carried Forward; m-BOCF, modified BOCF; MMRM, mixed-effects model repeated measures; PGI, Patient's Global Impression; RDQ-24, Roland-Morris Disability Questionnaire; SF-36, 36-Item Short-Form Health Survey; WPAI, Work Productivity and Activity Impairment Instrument. *LS mean_SE at week 14. †Work time missed, impairment at work, and work productivity loss were assessed only in patients who were actively employed throughout the examination period. ‡Indicates statistical significance. Table 3. Categorical Distribution of Patient's Global Impression of Improvement Results at the Final Evaluation Category Placebo n=226 Duloxetine n=230 P Improved* 163 (72.1) 191 (83.0) 0.0067 Unchanged 59 (26.1) 34 (14.8) Worsened† 4 (1.8) 5 (2.2) Data are presented as n (%). *The ''Improved'' category included patients who responded ''Very much improved'', ''Much improved'', or ''Minimally improved''. †The ''Worsened'' category included patients who responded ''Very much worse'', ''Much worse'', or ''Worse''. Figure 4. Ratio between direct and indirect effects. Safety No deaths were reported during the study. SAEs occurred in four patients (cerebral hemorrhage, gastric polyps, urethral calculus, and intervertebral disc protrusion) in the duloxetine group and four patients (osteoarthritis, pneumococcal pneumonia, bacterial pneumonia, and hemothorax) in the placebo group. A causal relationship with the study drug was denied for all events. AEs occurring at a significantly higher incidence in the duloxetine group compared with the placebo group were somnolence, constipation, nausea, dizziness, and dry mouth ( ). The most common ADRs (at an incidence of ≥3%) observed within the first 2 weeks after treatment initiation occurred in the early phase of treatment in most patients, and their incidence tended not to increase with dose escalation. (Figure 5). No obvious changes attributable to duloxetine were observed in laboratory tests; blood pressure, pulse, and body weight measurements; or electrocardiogram findings. In the post hoc analyses, falls occurred in 10.3% (24/232) and 8.0% (18/224) of patients in the duloxetine and placebo groups, respectively (P = 0.4217). No apparent suicide risk was observed according to the C-SSRS. Table 4. Adverse Events That Occurred at an Incidence of ≥5% Placebo n=224 Duloxetine n=234 P Constipation 5 (2.2) 25 (10.7) 0.0002* Nausea 6 (2.7) 21 (9.0) 0.0049* Dry mouth 0 (0.0) 14 (6.0) 0.0001* Nasopharyngitis 39 (17.4) 26 (11.1) 0.0610 Contusion 7 (3.1) 16 (6.8) 0.0867 Somnolence 16 (7.1) 45 (19.2) 0.0002* Dizziness 2 (0.9) 15 (6.4) 0.0020* Data are presented as n (%). *Indicates statistical significance. Figure 5. Incidence of the most common adverse drug reactions (ADRs) (those that occurred at an incidence of 3% or higher within 2 weeks of starting administration). Discussion The current study found that duloxetine was superior to placebo in the primary and many secondary efficacy measures, which is consistent with the findings of previous studies conducted overseas.[11–13] The difference (95% confidence interval) in the change in BPI average pain at 14 weeks of treatment between the treatment groups was −0.46 (−0.77 to −0.16) (P = 0.0026), confirming the superiority of duloxetine over placebo. In addition, regarding pain reduction, a reduction of 2 points or at least 30% in the Numeric Rating Scale is generally considered as a clinically significant change.[28] In this study, the proportion of patients with a reduction of 2 points or more in BPI average pain at Week 14 and that of patients with a 30% or 50% pain reduction were significantly higher in the duloxetine group than in the placebo group (P = 0.0010, 0.0003, and 0.0003, respectively). Regarding the category analysis of PGI, improvement was reported by a significantly higher proportion of patients in the duloxetine group than in the placebo group (P = 0.0067). In the current study, the ratio of the direct analgesic effect of duloxetine was as high as 97.3%, suggesting that duloxetine has analgesic activity independent of its antidepressant effect. The goal of chronic pain treatment is QOL improvement. In this study, RDQ-24 scores, a low back pain-specific QOL measurement, improved significantly in the duloxetine group compared with the placebo group, which suggests that duloxetine is an effective medication for CLBP patients. Significant improvements in the primary and many secondary efficacy measures were shown with duloxetine administered once daily compared with placebo. In general, patient adherence increases as dosing frequency decreases.[29] The dosage regimens of many drugs approved for LBP in Japan require multiple daily doses. Therefore, a once-daily dosing regimen of duloxetine may be useful from the standpoint of patient adherence. This is the first study to report the efficacy of an SNRI in Japanese CLBP patients. A similar pattern and magnitude of pain reduction with duloxetine treatment was also observed in studies of other chronic pain conditions, including diabetic peripheral neuropathic pain,[15,30–32] pain associated with fibromyalgia,[16,33,34] and pain caused by osteoarthritis.[35,36] This consistent finding suggests that the analgesic efficacy of duloxetine across distinctively different chronic pain states may be caused by a single, common central mechanism of action-potentiation of descending inhibitory pain pathways.[37] The current study reported the effectiveness of duloxetine as monotherapy in patients responding poorly to NSAIDs. Because duloxetine has a different mechanism of action from NSAIDs and acetaminophen, used as the first-line treatment for LBP, duloxetine is expected to provide a new treatment option for patients with CLBP. Moreover, previous studies conducted overseas have reported its effectiveness in NSAID-naïve patients. Taken together, these findings suggest that duloxetine may play a significant role in the future treatment of CLBP in Japan. In the current study, the safety profile of duloxetine was similar to that from previous studies in patients with approved indications.[14–16] Although the discontinuations because of AEs did not differ significantly between duloxetine and placebo, the discontinuations because of ADRs were significantly more frequent in the duloxetine group. The current study has some limitations. First, the treatment period was relatively short, and the treatment for CLBP requires a longer period. Second, the current study only included patients responding poorly to NSAIDs, and no confirmation was made regarding the efficacy of duloxetine in Japanese NSAID-naïve patients. A long-term extension study that included NSAID-naïve patients was conducted separately and will be submitted for publication in the near future. Finally, this study lacks an active comparator arm, which would perhaps have allowed for comparison of duloxetine efficacy with at least one of the commonly used therapeutic options. In conclusion, the current study findings suggest that duloxetine 60 mg once daily is effective and well tolerated in the treatment of Japanese patients with CLBP. Sidebar Key Points This is the first study to report the efficacy and safety of duloxetine 60 mg once daily for the treatment of Japanese patients with CLBP. In this 14-week, randomized, double-blind, multicenter, placebo-controlled study, 458 Japanese patients with CLBP were randomized to treatment with either duloxetine 60 mg once daily or placebo. The duloxetine group showed a significantly greater improvement in the BPI average pain score at Week 14 (primary efficacy measure) than the placebo group, and in many secondary measures such as BPI pain (least pain, pain right now), PGI-I, CGI-S, and RDQ. The safety profile of duloxetine was similar to that from previous studies in patients with approved indications. The current study findings suggest that duloxetine 60 mg once daily is effective and well tolerated in the treatment of Japanese patients with CLBP. References Fujii T, Matsudaira K. Prevalence of low back pain and factors associated with chronic disabling back pain in Japan. Eur Spine J 2013;22:432–8. Yoshimura N, Muraki S, Oka T, et al. Epidemiology of low back pain: from a large scale epidemiologic survey ''ROAD''. 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Acknowledgments The authors would like to thank all of the investigators from the following 58 study sites who cooperated in this research (in no particular order): Hakodate Ohmura Orthopedics, Asano Orthopedic Clinic, Takahashi Orthopedic Clinic, Maehara Orthopedics, Higashimaebashi Orthopedics, Segawa Hospital, Saitamakinen Hospital, Wakasa Clinic, Kobayashi Orthopedics, Ozawa Orthopedics, Saino Clinic, Hanazono Orthopedics and Internal Medicine Clinic, Yamazaki Orthopedics Clinic, Jin Orthopedic Clinic, Shiraishi Orthopedic Clinic, Masaki Orthopedics, Sekimachi Hospital, Sato Orthopedics, Tsukahara Orthopedics, Koenji Orthopedics, Kyobashi Orthopedics, Musashino Clinic, Otakibashi Orthopedics, Wada Orthopedic Clinic, Oimachi Orthopedic Clinic, Nishiwaseda Orthopedics, Meguro Yuai Clinic, Miya Orthopedics, Ando Orthopedics, Morinosato Hospital, Kubodera Orthopedics, Shibata Orthopedics, Akiyama Orthopedics, Aoki Orthopedics, Keyaki-dori Orthopedics, Nakatsu Hospital, Amagasaki Central Hospital, Yamamoto Rheumatology Clinic, Omuro Orthopedic Clinic, Mitta Orthopedics, Ohta Orthopedic Clinic, Takagi Hospital, Nagata Orthopedic Hospital, Morooka Orthopedic Clinic, Nakayama Orthopedics, Shinkomonji Hospital, Sata Orthopedic Hospital, Matsunaga Orthopedics, Kuroda Orthopedics, Fukahori Orthopedic Clinic, Fukushima Orthopedic Clinic, Hyakutake Orthopedic Hospital, Metabaru Orthopedics, Suga Orthopedic Hospital, Fukuda Orthopedics, Fujigaki Clinic, Nagamine Orthopedics, and Hashiguchi Orthopedics. The authors would also like to acknowledge the editorial assistance provided by Dr. Michelle Belanger of Edanz Group Ltd. in the preparation of this article. Spine. 2016;41(22):1709-1717. © 2016 Lippincott Williams & Wilkins http://www.medscape.com/viewarticle/872140?src=wnl_edit_tpal&uac=60604BR