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Objective: To assess the efficacy and safety of ABBV‐3373, a novel antibody–drug conjugate (ADC) composed of the anti–tumor necrosis factor (anti‐TNF) monoclonal antibody adalimumab linked to a glucocorticoid receptor modulator (GRM), compared to adalimumab, in patients with rheumatoid arthritis (RA). Methods: In this randomized, double‐blind, active‐controlled, proof‐of‐concept trial (ClinicalTrials.gov identifier: NCT03823391), adults with moderate‐to‐severe RA receiving background methotrexate were administered intravenously (IV) ABBV‐3373 100 mg every other week for 12 weeks, followed by placebo for 12 weeks, or subcutaneous adalimumab 80 mg every other week for 24 weeks. The primary end point was change from baseline in the Disease Activity Score in 28 joints using C‐reactive protein (DAS28‐CRP) at week 12, with 2 prespecified primary comparisons of ABBV‐3373 versus historical adalimumab (80 mg every other week or equivalent dose) and versus combined in‐trial/historical adalimumab. Secondary end points included change from baseline in the Clinical Disease Activity Index, Simplified Disease Activity Index, and DAS28 using erythrocyte sedimentation rate, as well as the proportion of patients achieving a DAS28‐CRP of ≤3.2 and the American College of Rheumatology 50% improvement criteria. Results: Forty‐eight patients were randomized to receive either ABBV‐3373 (n = 31) or adalimumab (n = 17). At week 12, ABBV‐3373 demonstrated a reduction in DAS28‐CRP compared to historical adalimumab (−2.65 versus −2.13; P = 0.022) and compared to combined in‐trial/historical adalimumab (−2.65 versus −2.29; probability 89.9%), with numerically greater improvement than in‐trial adalimumab (−2.51). For secondary end points, greater efficacy was observed with ABBV‐3373 compared to historical adalimumab; ABBV‐3373 was predicted with 79.3–99.5% probability to be more effective than adalimumab based on combined in‐trial/historical adalimumab data. Of the ABBV‐3373–treated patients who achieved DAS28‐CRP ≤3.2 at week 12, 70.6% maintained this response at week 24 despite switching to placebo. Four serious adverse events (SAEs) were reported with ABBV‐3373 (noncardiac chest pain, pneumonia, upper respiratory tract infection, and anaphylactic shock) and 2 SAEs with adalimumab (breast abscess and bronchitis). After increasing the duration of IV ABBV‐3373 administration from 3 minutes to 15–30 minutes, no similar events of anaphylactic shock were reported. Conclusion: Data from this proof‐of‐concept trial support the continued development of a TNF–GRM ADC for the treatment of RA, with the potential to achieve superior outcomes compared to currently available therapies. [ABSTRACT FROM AUTHOR]

Background: Mood disorders, such as anxiety and depression, are extremely prevalent among patients with rheumatoid arthritis (RA). In this study, we assessed the impact of treatment with tocilizumab (TCZ), an IL‐6 antagonist, upon anxiety and depressive symptoms in a cohort of RA patients. Materials and Methods: Study participants were adults diagnosed with RA who received a weekly subcutaneous injection of tocilizumab for 24 weeks. We used the Hamilton Depression (HDRS) and Anxiety (HAMA) scores in order to assess the severity of depression and anxiety, respectively. RA disease activity indices and depression and anxiety levels were assessed at baseline, 4 weeks and study completion. Results: Ultimately, 91 patients were included in the study. The mean age was 54 years, and the majority were female (79%). The mean score in all disease activity indices as well as depression and anxiety levels decreased dramatically from baseline to study completion. Sixty patients (66%) demonstrated a significant decrease in anxiety and/or depression levels. When logistic regression was performed, an HDRS score indicative of depression at study baseline demonstrated an independent association with a significant psychiatric response whilst older age and increased baseline weight were negatively associated. HAMA and HDRA scores correlated with the following RA disease activity parameters, respectively; HAQ‐DI (r =.4,.42), DAS28 (r =.29,.32) and CDAI (0.28 and 0.33), all of them were statistically significant (P <.01). Conclusions: This study has demonstrated a favourable impact of TCZ therapy on parameters reflecting depression and anxiety severity in patients with RA. [ABSTRACT FROM AUTHOR]

Background: Patients with rheumatoid arthritis (RA) are at a high risk for life-threatening conditions requiring admission to the intensive care unit (ICU), but the data regarding the outcomes of these patients is limited. The present study investigated the clinical characteristics and outcomes of RA patients admitted to an ICU. Methods: This retrospective cohort study included RA patients admitted to the general ICU of the Sheba Medical Center during 2002–2018. The main outcome was 30-day mortality. Using Student's t test, χ2, and multivariable analyses, we compared the demographic, clinical, and laboratory parameters of the survivors and the non-survivors. Figures with p value < 0.05 were considered statistically significant. Results: Forty-three RA patients were admitted to the ICU during the study period (mean age, 64.0 ± 13.1 years; 74.4% female). The leading causes of ICU admission were infection (72.1%), respiratory failure (72.1%), renal failure (60.5%), and septic shock (55.8%). The 30-day mortality rate was 34.9%, with infection (9/15, 60%) as the most frequent cause. The mean Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores were 19.7 ± 12.5 and 7.0 ± 4.5, respectively. Multivariable analysis showed that heart failure (p = 0.023), liver failure (p = 0.012), SOFA score (p = 0.007), and vasopressor treatment in ICU (p = 0.039) were significantly associated with overall mortality. SOFA score was linked with overall mortality (area under the curve (AUC) = 0.781 ± 0.085, p = 0.003) and mortality from respiratory failure (AUC = 0.861 ± 0.075, p = 0.002), while APACHE II score was only correlated with mortality from infection (AUC = 0.735 ± 0.082, p = 0.032). Conclusions: Our study demonstrated a relatively high mortality rate among RA patients who were admitted to the general ICU. RA patients with risk factors such as heart failure, liver failure, elevated SOFA score, and vasopressor treatment in ICU should be promptly identified and treated accordingly. Key Points • The 30-day mortality rate of patients with RA that were admitted to the general ICU of a tertiary hospital was 34.9%. • The most common causes of ICU admission among patients with RA were infections and respiratory failure. Infections were the most common cause of death among these patients. • Patients with RA that present to the ICU with heart failure, liver failure, elevated SOFA score, and/or require vasopressor treatment in ICU should be promptly identified and treated accordingly. [ABSTRACT FROM AUTHOR]

Background and objectives: Rheumatoid arthritis (RA) is the most common inflammatory joint disorder presenting also with extra-articular manifestations. As many other autoimmune diseases, it has been suggested that infectious diseases might contribute to its emergence. Hepatitis viruses were suggested by several reports as a trigger of RA onset. We aimed to assess the association between RA and chronic hepatitis B viral infection (HBV). Methods: Patients with RA were compared with age- and sex-matched controls regarding the proportion of chronic HBV infection in a case-control study. The chi-square and t tests were used for univariate analysis, whereas a logistic regression model was used for multivariate analysis. The study was performed utilizing the medical database of Clalit Health Services. Results: There was a significantly higher proportion of chronic HBV infection in RA patients compared with controls (1.19% vs 0.63%, respectively; p < 0.001). In a multivariate logistic regression analysis, RA was significantly associated with chronic HBV infection (OR = 1.89, 95%CI 1.55–2.29, p < 0.001). Conclusions: Patients with RA have a greater proportion of chronic HBV infection than matched controls. Screening for HBV infection among RA patients may be warranted. [ABSTRACT FROM AUTHOR]

Aims: Published data on long‐term adherence and persistence with adalimumab (Humira®) in clinical practice are scarce and often limited to selected patient populations. This study assessed adherence with adalimumab across different indications and identified correlates and outcomes of poor adherence. Methods: We analysed data originating from the electronic database of Maccabi Healthcare Services (MHS) that includes 2.1 million enrolees. We randomly selected patients with at least one dispense of adalimumab since it was included in the local health basket in Israel in 2008 until the end of 2013. Patients with the following indications (n = 1339) were included: Crohn's disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), psoriatic arthritis (PSA), ankylosing spondylitis (AS) and psoriasis. Adherence with therapy was assessed by the medication possession ratio (MPR) during the follow‐up period. Results: Good adherence (MPR ≥ 80%) was observed among 80% of study patients and was associated with lower risk for ≥1 hospitalization per year of follow‐up (adjusted‐OR = 1.94, 95% CI:1.15–3.28). Patients with AS and CD persisted on adalimumab therapy the most, reaching median use of 27.0 and 26.7 months, respectively. Half (52.4%) of the patients discontinued treatment during a mean (SD) follow‐up of 3.07 (1.71) years. High socioeconomic status was associated with lower risk for discontinuation (adjusted‐HR = 0.74; 0.60–0.91). UC and concomitant prednisolone use were associated with increased risk for treatment discontinuation (HR = 1.31; 1.00–1.72, and HR = 1.40; 1.17–1.68, respectively). Conclusion: Our results indicate encouraging persistence and adherence with adalimumab of patients with inflammatory conditions. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to evaluate if association exist between rheumatoid arthritis and malignant diseases.Methods: A cross-sectional study was conducted comparing rheumatoid arthritis patients with age and gender matched controls regarding the proportion of patients with comorbid malignant conditions. Chi-square tests and t-tests were used for univariate analysis. A logistic regression model was used for multivariate analysis. The study was performed utilising the medical database of Clalit Health Services.Results: The study group included 11 782 rheumatoid arthritis patients and 57 973 controls. The total proportion of malignancies was significantly higher in the study group than in the control group (21.4% vs 11.2%; P<.001). The disease for which there was the strongest association among patients with rheumatoid arthritis was non-Hodgkin's lymphoma (1.1% vs 0.6%; P<.01). After multivariate analysis, lung cancer was not found to be significantly associated with rheumatoid arthritis.Conclusion: Rheumatoid arthritis is associated with several malignant disorders, in particular non-Hodgkin's lymphoma. Appropriate measures for non-Hodgkin's lymphoma screening in this patient population should be considered. [ABSTRACT FROM AUTHOR]

Anti-citrullinated protein autoantibodies (ACPAs) are the major autoantibodies in rheumatoid arthritis (RA). Anti-citrullinated protein autoantibodies are directed against different citrullinated antigens, including filaggrin, fibrinogen, vimentin, and collagen. Presence of ACPA is associated with joint damage and extra-articular manifestations, suggesting that ACPAs are most likely pathogenic autoantibodies in RA. In vitro, ACPAs induce macrophage tumor necrosis factor alpha (TNF-α) production, osteoclastogenesis, and complement activation. These autoantibodies also induce the formation of neutrophil extracellular traps (NETs). Additionally, ACPAs induce pathogenic cytokines expression and oxidative stress in immune cells derived from RA patients. The aim of this review is to show the pathogenic roles of these autoantibodies in RA. [ABSTRACT FROM AUTHOR]

Objective. To create a tool to predict probability of remission and low disease activity (LDA) in patients with RA being considered for anti-TNF treatment in clinical practice. Methods. We analysed data from GO-MORE, an open-label, multinational, prospective study in biologic naïve patients with active RA (DAS28-ESR ≥3.2) despite DMARD therapy. Patients received 50 mg s.c. golimumab (GLM) once monthly for 6 months. In secondary analyses, regression models were used to determine the best set of baseline factors to predict remission (DAS28-ESR<2.6) at month 6 and LDA (DAS28-ESR ≤3.2) at month 1. Results. In 3280 efficacy-evaluable patients, of 12 factors included in initial regression models predicting remission or LDA, six were retained in final multivariable models. Greater likelihood of LDA and remission was associated with being male; younger age; lower HAQ, ESR (or CRP) and tender joint count (or swollen joint count) scores; and absence of comorbidities. In models predicting 1-, 3- and 6-month LDA or remission, area under the receiver operating curve was 0.648-0.809 (R²=0.0397-0.1078). The models also predicted 6-month HAQ and EuroQoL-5-dimension scores. A series of matrices were developed to easily show predicted rates of remission and LDA. Conclusion. A matrix tool was developed to show predicted GLM treatment outcomes in patients with RA, based on a combination of six baseline characteristics. The tool could help provide practical guidance in selection of candidates for anti-TNF therapy. [ABSTRACT FROM AUTHOR]

Objective: To assess the efficacy and safety of tocilizumab (TCZ) plus methotrexate/placebo (MTX/PBO) over 2 years and the course of disease activity in patients who discontinued TCZ due to sustained remission.Methods: ACT-RAY was a double-blind 3-year trial. Patients with active rheumatoid arthritis despite MTX were randomised to add TCZ to ongoing MTX (add-on strategy) or switch to TCZ plus PBO (switch strategy). Using a treat-to-target approach, open-label conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), other than MTX, were added from week 24 if Disease Activity Score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) >3.2. Between weeks 52 and 104, patients in sustained clinical remission (DAS28-ESR <2.6 at two consecutive visits 12 weeks apart) discontinued TCZ and were assessed every 4 weeks for 1 year. If sustained remission was maintained, added csDMARDs, then MTX/PBO, were discontinued.Results: Of the 556 randomised patients, 76% completed year 2. Of patients entering year 2, 50.4% discontinued TCZ after achieving sustained remission and 5.9% achieved drug-free remission. Most patients who discontinued TCZ (84.0%) had a subsequent flare, but responded well to TCZ reintroduction. Despite many patients temporarily stopping TCZ, radiographic progression was minimal, with differences favouring add-on treatment. Rates of serious adverse events and serious infections per 100 patient-years were 12.2 and 4.4 in add-on and 15.0 and 3.7 in switch patients. In patients with normal baseline values, alanine aminotransferase elevations >3×upper limit of normal were more frequent in add-on (14.3%) versus switch patients (5.4%).Conclusions: Treat-to-target strategies could be successfully implemented with TCZ to achieve sustained remission, after which TCZ was stopped. Biologic-free remission was maintained for about 3 months, but most patients eventually flared. TCZ restart led to rapid improvement.Trial Registration Number: NCT00810199. [ABSTRACT FROM AUTHOR]

Evidence points to an association of prolactin to autoimmune diseases. We examined the correlation between hyperprolactinemia and disease manifestations and activity in a large patient cohort. Age- and sex-adjusted prolactin concentration was assessed in 256 serum samples from lupus patients utilizing the LIASON prolactin automated immunoassay method (DiaSorin S.p.A, Saluggia, Italy). Disease activity was defined as present if European Consensus Lupus Activity Measurement (ECLAM) > 2 or Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) > 4. Lupus manifestations were grouped by organ involvement, laboratory data, and prescribed medications. Hyperprolactinemia was presented in 46/256 (18%) of the cohort. Hyperprolactinemic patients had significantly more serositis (40% vs. 32.4%, p = 0.03) specifically, pleuritis (33% vs. 17%, p = 0.02), pericarditis (30% vs. 12%, p = 0.002), and peritonitis (15% vs. 0.8%, p = 0.003). Hyperprolactinemic subjects exhibited significantly more anemia (42% vs. 26%, p = 0.02) and marginally more proteinuria (65.5% vs. 46%, p = 0.06). Elevated levels of prolactin were not significantly associated with other clinical manifestations, serology, or therapy. Disease activity scores were not associated with hyperprolactinemia. Hyperprolactinemia in lupus patients is associated with all types of serositis and anemia but not with other clinical, serological therapeutic measures or with disease activity. These results suggest that dopamine agonists may be an optional therapy for lupus patients with hyperprolactinemia. [ABSTRACT FROM AUTHOR]

Abstract: Rheumatoid arthritis (RA) therapy has been revolutionized in recent years following the introduction of three main anti-tumor necrosis factor-alpha inhibitors (anti-TNF) agents, infliximab, adalimumab and etanercept. Evidence in the literature indicates that patients treated with anti-TNF agents are at increased risk for bacterial infections, but it is not clear if this is a result of the treatment or of disease severity. The treatment has been recognized as a clear risk factor for reactivation of latent TB infections. So far, observational studies have not indicated any increased overall risk of cancer in RA patients treated with anti-TNF. The overall risk of lymphoma in these patients does not appear to differ greatly from that recorded among untreated patients, but rather is associated with the degree of disease activity rather than the type of therapy. There is a consensus in the literature that the likelihood of drug survival with infliximab is inferior to both adalimumab and etanercept, mostly due to increased risk of infection or allergic reactions. Due to the lack of head to head studies, there is no agreement as to which agent has the highest rates of treatment response and disease remission. [Copyright &y& Elsevier]

Background: The beneficial effects of statins in rheumatoid arthritis (RA) have been suggested previously, but it is unclear whether statins may prevent its development. The aim of this retrospective cohort study was to explore whether persistent use of statins is associated with onset of RA. Methods and Findings: The computerized medical databases of a large health organization in Israel were used to identify diagnosed RA cases among adults who began statin therapy between 1998 and 2007. Persistence with statins was assessed by calculating the mean proportion of follow-up days covered (PDC) with statins for every study participant. To assess the possible effects of healthy user bias, we also examined the risk of osteoarthritis (OA), a common degenerative joint disease that is unlikely to be affected by use of statins. A total of 211,627 and 193,770 individuals were eligible for the RA and OA cohort analyses, respectively. During the study follow-up period, there were 2,578 incident RA cases (3.07 per 1,000 personyears) and 17,878 incident OA cases (24.34 per 1,000 person-years). The crude incidence density rate of RA among nonpersistent patients (PDC level of ,20%) was 51% higher (3.89 per 1,000 person-years) compared to highly persistent patients who were covered with statins for at least 80% of the follow-up period. After adjustment for potential confounders, highly persistent patients had a hazard ratio of 0.58 (95% confidence interval 0.52-0.65) for RA compared with nonpersistent patients. Larger differences were observed in younger patients and in patients initiating treatment with high efficacy statins. In the OA cohort analysis, high persistence with statins was associated only with a modest decrement in risk ratio (hazard ratio = 0.85; 0.81-0.88) compared to nonadherent patients. Conclusions: The present study demonstrates an association between persistence with statin therapy and reduced risk of developing RA. The relationship between continuation of statin use and OA onset was weak and limited to patients with short-term follow-up. [ABSTRACT FROM AUTHOR]

Objectives: To review the clinical aspects of cardiac arrhythmias and conduction disturbances in several common and less encountered adult rheumatic diseases and to underline the importance of prompt diagnosis and management in these patients. Methods: The PubMed database was searched for articles published between the years 1960 and 2008 for keywords referring to autoimmune diseases. All relevant English-written articles were reviewed. Most were uncontrolled series and case reports, due to the lack of prospective studies and randomized trials. Results: Rheumatologic conditions may affect the cardiovascular system and increase morbidity and mortality. Rhythm and conduction defects are usually mild but may be life-threatening; in certain diseases, such as in systemic lupus erythematosus they may resolve following therapy with corticosteroids. Conduction defects occur frequently in patients with spondyloarthropathies and in those with various forms of vasculitis. Enhanced variation of the QT interval may be a sensitive marker of a higher arrythmogenic tendency in patients with autoimmune conditions. Conclusions: It is important to identify patients at high risk for cardiac arrhythmias. Treating such patients with arrhythmias should not differ fundamentally from other patients. Nevertheless, appropriate clinical attention and judgment should be applied to exclude the possibility that arrhythmias reflect uncontrolled myocardial inflammation. [Copyright &y& Elsevier]

Objective. MTX hepatotoxicity is considered to occur more frequently in patients with psoriasis than in patients with RA. However, toxicity guidelines are based on reports from studies with small sample sizes and limited follow-up periods. The current study's objective was to examine the long-term risk of MTX hepatotoxicity based on a database review of patients with RA or psoriasis, and to examine whether the two populations differed.Methods. We conducted a retrospective cohort review among members of a large health maintenance organization (HMO) in Israel who were diagnosed with either RA (n = 119) or psoriasis (n = 690) and who had purchased at least one dose of MTX. Liver function analyses were performed serially in these patients during the follow-up. All abnormal assays were recorded in the computerized database of the HMO.Results. Both groups had hepatic enzyme elevation; the pre-disposing factors predictive of liver damage were female gender and a higher cumulative dose of MTX (hazard ratios, 1.46 and 1.07, respectively, P < 0.001). Age, concurrent diseases and type of disease had no influence on susceptibility to liver damage. No statistically significant difference was detected in any abnormal liver function test among patients with either RA or psoriasis.Conclusion. Our study did not corroborate previous findings of significant differences between psoriasis patients and RA patients concerning susceptibility to hepatotoxicity from MTX therapy. The only significant factor predicting a higher risk of hepatic damage was female gender. [ABSTRACT FROM PUBLISHER]

This article analyzes the serum cytokine profile of a nonrandomized group of patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) who are destined to be treated with infliximab following failure after failure of different disease-modifiying antirheumatic drugs (DMARDs). Serial serum samples were collected from 11 patients with refractory RA, three with PsA and one with undifferentiated spondyloarthropathy. All were treated with the antitumor necrosis factor (TNF)α agent, infliximab, after failing to sustain a clinical remission with conventional DMARDs. Blood samples were obtained at different phases of their therapy. Serum levels of tumor necrosis factor (TNF)α, interferon (IFN)γ, interleukin (IL)-1β, IL-6, sIL-2R, IL-10, and IL-1 receptor antagonist (IL-1RA) were determined by commercial ELISA kits. Interestingly, only eight of the 11 patients with RA had elevated TNFα serum levels (at least once in their serial measurements). Only one was unresponsive to therapy and despite anti-TNFα therapy her serum TNFα levels remained extremely high. Two RA patients who responded to infliximab had normal TNFα serum levels prior to and following infliximab administration. One RA patient improved after infliximab therapy despite unrelenting high serum levels of TNFα, IL-6, and sIL-2R. Patients with active PsA who responded to infliximab therapy had sustained high serum TNFα levels. In an unselected population of RA and PsA patients, we noticed diverse patterns of serum cytokine profiles. These results imply that the cytokine profiles of RA and PsA are diverse and their pathogenesis is heterogeneous. [ABSTRACT FROM AUTHOR]

The development of autoimmune diseases may be influenced by hormonal, immunomodulatory, and metabolic pathways. Prolactin (PRL), ferritin, vitamin D, and the tumor marker tissue polypeptide antigen (TPA) were measured in autoimmune diseases: systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), polymyositis (PM), dermatomyositis (DM), multiple sclerosis (MS), autoimmune thyroid diseases, and antiphospholipid syndrome. Hyperprolactinemia (HPRL) was detected in 24% of PM patients, in 21% of SLE patients, in 6.7% of MS patients, 6% of RA patients, and in 3% of SSc patients. Hyperferritinemia was detected in 23% of SLE patients, 15% of DM patients, 8% of MS patients, and 4% of RA patients. The patients had relatively low levels of 25 OH Vitamin D: the average results (mean ± SD) were between 9.3 ± 4.4 to 13.7 ± 7.1 ng/mL in the different diseases, while the 25 OH Vitamin D concentrations less than 20 ng/mL are regarded as deficient. TPA levels were in the same range of the controls, elevated only in SLE. HPRL, hyperferritinemia, hypovitaminosis D, and TPA levels did not correlate with SLE activity elevated levels of rheumatoid factor or anti-CCP antibodies in RA. HPRL, hyperferritinemia, and hypovitaminosis D have different immunological implications in the pathogenesis of the autoimmune diseases. Preventive treatment with vitamin D or therapy for HPRL with dopamine agonists, may be considered in certain cases. Hyperferritinemia may be used as an acute-phase reactant marker in autoimmune diseases mainly SLE. TPA may be used to indicate the tendency for malignancies. [ABSTRACT FROM AUTHOR]

A response from the author of the article "Hepatotoxicity rates do not differ in patients with rheumatoid arthritis and psoriasis treated with methotrexate" in the 2009 issue is presented.

This report presents the case of a young woman with seropositive rheumatoid arthritis in whom bilateral septic arthritis of the hip developed after four months of therapy with etanercept alone. Staphylococcus aureus infection was found unexpectedly during exposure of the hips at the beginning of an elective total hip arthroplasty. This report highlights a possible association between tumor necrosis factor TNF-α blockade therapy and multifocal septic arthritis. Several studies have demonstrated that both etanercept and infliximab are highly effective in the treatment of patients who have inadequate responses to conventional diseasemodifying antirheumatic drugs such as methotrexate.

Abstract Background Anti-citrullinated peptide antibodies (ACPA) play an important role in rheumatoid arthritis (RA) diagnosis. In our study, we sought to assess the potential diagnostic value of synthetically manufactured peptides that contain epitopes believed to have a pathogenic role in RA. Methods Serum samples from RA patients and healthy controls were obtained. Two synthetic peptides were manufactured containing the common epitopes considered to play a pivotal role in the RA pathogenesis including the antigenic epitopes of filaggrin, beta-fibrinogen, collagen, vimentin and enolase. Three different ELISA kits for citrullinated peptides (namely: CCP3, Cit-ME-Vim and Cit-ME-Eno) were tested and compared. To assess the diagnostic value of the three ELISA tests, for each test the optical densities (OD) were recorded. The statistical power of each test was calculated measuring the area under the curve (AUC) corresponding with each peptide. Results Serum levels of ACPA recognized by the commercial CCP3 in RA and healthy controls were 1.31 ± 0.88 optic density units (ODU) and 0.21 ± 0.11 ODU, respectively. Cit-ME-Vim levels were 0.55 ± 0.46 ODU in RA subjects and 0.17 ± 0.182 ODU in healthy controls whereas Cit-ME-Eno was 0.61 ± 0.65 ODU in RA subjects and 0.22 ± 0.20 ODU in healthy controls. AUC results were as follows: CCP3, 0.89 [95%CI 0.75–0.87]; Cit-ME-Vim, 0.76 [95%CI 0.69–0.82]; Cit-ME-Eno, 0.73 [95%CI 0.65–0.79]. Statistical significance for all results was achieved (p <.0001). Sensitivity values for each kit are as follow: CCP3 70.42%; Cit-ME-Vim 63.38%; Cit-ME-Eno 40.85%, and specificity 91% for all tests. Conclusion Our study supports the presence of an added value for the Cit-ME-Vim peptides in the diagnosis of RA. Further studies are needed to replicate such findings. [ABSTRACT FROM AUTHOR]

Background The use of immune checkpoint inhibitors (ICI) has grown incessantly since they were first approved in 2014. These monoclonal antibodies inhibit T cell activation, yielding a dramatic tumor response with improved survival. However, immunotherapy is frequently hampered by immune adverse events (iAE) such as hypophysitis, colitis, hepatitis, pneumonitis and rash. Until recently, rheumatic side effects were only infrequently reported. Aim To describe the rheumatic manifestations encountered among patients treated with ICIs in a large tertiary cancer center in Israel Methods The cancer center's patient registry was screened for patients who had ever been treated with ipilimumab, pembrolizumab and/or nivolumab with relevant data gathered from clinical charts. Results Rheumatic manifestations were encountered in 14 of 400 patients (3.5%) who had received immunotherapy between January 1st 2013 and April 30th, 2017. The most common rheumatic manifestation was inflammatory arthritis (85%) for which a third (4/11) had a clear cut predisposing factor such as a personal or family history of psoriasis, a prior episode of uveitis or ACPA positivity. Pulmonary sarcoidosis and biopsy-proven eosinophilic fasciitis were diagnosed in two additional patients. Treatment with NSAIDS was mostly unsuccessful while steroid therapy was beneficial in doses ≥20 mg/d. Methotrexate enabled steroid tapering without an excess of side effects or tumor progression in the short follow-up available. Overall, rheumatic manifestations tended to occur later in the course of immunotherapy as compared to other iAE. Conclusions Our findings underscore that rheumatic iAE are part of the side effect profile of ICIs and require heightened awareness as these therapies are becoming the standard of care for various malignancies. We show that these appear later in the course of iAEs and respond preferentially to high dose steroids. MTX appears effective as a steroid sparing agent. [ABSTRACT FROM AUTHOR]

Physical activity, by definition, is any skeletal muscle body movement that results in energy expenditure. In the last few decades, a plethora of scientific evidences have accumulated and confirmed the beneficial role of physical activity as a modifiable risk factor for a wide variety of chronic diseases including cardiovascular diseases (CVDs), diabetes mellitus and cancer, among others. Autoimmune diseases are a heterogeneous group of chronic diseases, which occur secondary to loss of self-antigen tolerance. With the advent of biological therapies, better outcomes have recently been noted in the management of autoimmune diseases. Nonetheless, recent research highlights the salient role of modifiable behaviors such as physical inactivity on various aspects of the immune system and autoimmune diseases. Physical activity leads to a significant elevation in T-regulatory cells, decreased immunoglobulin secretion and produces a shift in the Th1/Th2 balance to a decreased Th1 cell production. Moreover, physical activity has been proven to promote the release of IL-6 from muscles. IL-6 released from muscles functions as a myokine and has been shown to induce an anti-inflammatory response through IL-10 secretion and IL-1β inhibition. Physical activity has been shown to be safe in most of autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), inflammatory bowel diseases (IBD), as well as others. Additionally, the incidence of RA, MS, IBD and psoriasis has been found to be higher in patients less engaged in physical activity. As a general trend, patients with autoimmune diseases tend to be less physically active as compared to the general population. Physically active RA patients were found to have a milder disease course, better cardiovascular disease (CVD) profile, and improved joint mobility. Physical activity decreases fatigue, enhances mood, cognitive abilities and mobility in patients with MS. In SLE patients, enhanced quality of life and better CVD profile were documented in more physically active patients. Physically active patients with type 1 diabetes mellitus have a decreased risk of autonomic neuropathy and CVD. Both fibromyalgia and systemic sclerosis patients report decreased disease severity, pain, as well as better quality of life with more physical activity. Further, SSc patients improve their grip strength, finger stretching and mouth opening with increased level of exercise. The purpose of this paper is to review the clinical evidence regarding the safety, barriers to engagement, and impact of physical activity on autoimmune diseases. [ABSTRACT FROM AUTHOR]

Coffee is one of the world's most consumed beverage. In the last decades, coffee consumption has attracted a huge body of research due to its impact on health. Recent scientific evidences showed that coffee intake could be associated with decreased mortality from cardiovascular and neurological diseases, diabetes type II, as well as from endometrial and liver cancer, among others. In this review, on the basis of available data in the literature, we aimed to investigate the association between coffee intake and its influence on the immune system and the insurgence of the most relevant autoimmune diseases. While some studies reported conflicting results, general trends have been identified. Coffee consumption seems to increase the risk of developing rheumatoid arthritis (RA) and type 1 diabetes mellitus (T1DM). By contrast, coffee consumption may exert a protective role against multiple sclerosis, primary sclerosing cholangitis, and ulcerative colitis. Concerning other autoimmune diseases such as systemic lupus erythematosus, psoriasis, primary biliary cholangitis and Crohn's disease, no significant association was found. In other studies, coffee consumption was shown to influence disease course and management options. Coffee intake led to a decrease in insulin sensitivity in T1DM, in methotrexate efficacy in RA, and in levothyroxine absorption in Hashimoto's disease. Further, coffee consumption was associated with cross reactivity with gliadin antibodies in celiac patients. Data on certain autoimmune diseases like systemic sclerosis, Sjögren's syndrome, and Behçet's disease, among others, are lacking in the existent literature. As such, further research is warranted. [ABSTRACT FROM AUTHOR]

Background: Psychiatric disorders occur in a considerable proportion of patients with rheumatoid arthritis (RA), often reflecting the difficulties of these patients in coping with a chronic debilitating disorder.Aim Of the Study: To evaluate the proportion of anxiety disorder in RA patients using a large database analysis.Methods: The study was designed as a case-control population-based study using data from the Clalit Health Services (CHS) database. Patients were defined as having RA or anxiety disorder when there was at least one documented diagnosis identified by the International Classification of Diseases-9 (ICD-9) from the medical records. The proportion of anxiety disorder was compared between RA patients and controls. A logistic regression model was used to estimate the association between RA and anxiety disorder in a multivariate analysis adjusted for age, gender and socioeconomic status (SES).Results: The study included 11,782 patients with RA and 57,973 age- and sex-frequency matched controls. The proportion of anxiety in RA patients was higher than in controls (7.1% vs 6.3%, p=0.001). In multivariate analysis, RA was found to be independently associated with anxiety (OR 1.11 [95%CI 1.03-1.20], p=0.01). Our study has some shortcomings, as its cross-sectional nature does not allow to make inferences about a causal relationship between RA and anxiety.Conclusion: Our study confirms the higher proportion of anxiety in RA patients, especially young women with low SES. Physicians should be aware of such findings and, therefore, apply proper screening strategies. [ABSTRACT FROM AUTHOR]

Background Over the last few decades, several studies have demonstrated the connection between Rheumatoid Arthritis (RA) and Ischemic Heart Disease (IHD). The additional risk for RA patients to also suffer from IHD varies based on the definition of the diseases in question, the populations evaluated, and the variables included in the studies. Objectives To quantify the association between RA and IHD according to certain demographics as well as traditional cardiovascular risk factors in order to determine their roles in the development of coronary artery disease among patients with RA. Methods Using data from the largest HMO in Israel, the Clalit Health Services, we selected for patients with RA. These patients were compared with age and sex matched controls with regards to the prevalence of IHD in a case–control study. Chi-square and t-tests were used for univariate analysis and a logistic regression model was used for multivariate analysis. Results The study included 11,782 patients with RA and 57,973 age and sex matched controls. The prevalence of IHD in patients with RA was increased compared with the prevalence in controls (16.6% and 12.8% respectively, P < 0.001). In a multivariate analysis, RA was associated with higher proportions of IHD (OR 1.346, 95% confidence interval 1.255–1.431). [ABSTRACT FROM AUTHOR]

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with systemic comorbidities. Recent data suggests that patients with RA have increased prevalence of the bipolar disorder. The current study investigates the association between RA and bipolar disorder.Methods: A case-control study was conducted as Patients with RA were compared with age- and gender-matched controls regarding the prevalence of bipolar disorder. Pearson χ(2) test was used for univariate analysis and a logistic regression model was used for multivariate analysis. The study was performed utilizing the medical database of Clalit Health Services.Results: The study included 11,782 patients with RA and 57,973 age- and gender-matched controls. The prevalence of Bipolar disorder in patients with RA was increased compared with the prevalence in controls (0.6% and 0.4% respectively, p=0.036). However, in a multivariate analysis the association between RA and Bipolar disorder was not significant, whereas smoking is positively correlated with Bipolar disorder (p<0.001).Conclusions: By univariate analysis our data implied that patients with RA have a greater prevalence of bipolar disorder than matched controls. However, our analysis suggests that this association may have been confounded by smoking status. Further research is warranted before making inferences about this association in the level of clinical practice. [ABSTRACT FROM AUTHOR]

Abstract: Selective targeting of cells engaged in pathological activities is a major challenge for medical research. We generated monoclonal antibodies (mAbs) that exclusively bind, at concentrations ranging from 2 to 100μg/ml, to a modified CD44 variant (designated CD44vRA) expressed on synovial fluid cells from joints of rheumatoid arthritis (RA) patients. These mAbs cross-reacted with keratinocytes expressing wild type CD44vRA (CD44v3–v10) only at a relatively high concentration (200μg/ml). Sequence analysis of CD44vRA cDNA revealed, in 33 out of 43 RA and psoriatic arthritis patients, an extra intron-derived trinucleotide, CAG, which allows translation of an extra alanine. This insertion imposes a configurational change on the cell surface CD44 of RA synovial fluid cells, creating an immunogenic epitope and potentiating the ability to produce disease-specific antibodies. Indeed, the anti-CD44vRA mAbs (designated F8:33) were able to induce apoptosis in synovial fluid cells from RA patients, but not in peripheral blood leukocytes from the same patients, in keratinocytes from normal donors or in synovial fluid cells from osteoarthritis patients. Furthermore, injection of anti-CD44vRA mAbs reduced joint inflammation in DBA/1 mice with collagen-induced arthritis. These findings show that anti-CD44vRA mAbs are both bioactive and RA-specific. [Copyright &y& Elsevier]