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Concept: Disease-modifying antirheumatic drug


Accompanying the increased use of biologic and non-biologic antirheumatic agents, patients with RA have been exposed to an increased risk of Pneumocystis jirovecii infection, which causes acute fulminant P. jirovecii pneumonia (PCP). Mortality in this population is higher than in HIV-infected individuals. Several guidelines and recommendations for HIV-infected individuals are available; however, such guidelines for RA patients remain less clear. Between 2006 and 2008 we encountered a clustering event of P. jirovecii infection among RA outpatients. Through our experience with this outbreak and a review of the recent medical literature regarding asymptomatic colonization and its clinical significance, transmission modes of infection and prophylaxis of PCP, we have learned the following lessons: PCP outbreaks among RA patients can occur through person-to-person transmission in outpatient facilities; asymptomatic carriers serve as reservoirs and sources of infection; and short-term prophylaxis for eradication of P. jirovecii is effective in controlling PCP outbreaks among RA outpatients.

Concepts: Epidemiology, Rheumatoid arthritis, Rheumatology, Methotrexate, Cyclophosphamide, Disease-modifying antirheumatic drug, Hydroxychloroquine, Sulfasalazine


Background Few blinded trials have compared conventional therapy consisting of a combination of disease-modifying antirheumatic drugs with biologic agents in patients with rheumatoid arthritis who have active disease despite treatment with methotrexate - a common scenario in the management of rheumatoid arthritis. Methods We conducted a 48-week, double-blind, noninferiority trial in which we randomly assigned 353 participants with rheumatoid arthritis who had active disease despite methotrexate therapy to a triple regimen of disease-modifying antirheumatic drugs (methotrexate, sulfasalazine, and hydroxychloroquine) or etanercept plus methotrexate. Patients who did not have an improvement at 24 weeks according to a prespecified threshold were switched in a blinded fashion to the other therapy. The primary outcome was improvement in the Disease Activity Score for 28-joint counts (DAS28, with scores ranging from 2 to 10 and higher scores indicating more disease activity) at week 48. Results Both groups had significant improvement over the course of the first 24 weeks (P=0.001 for the comparison with baseline). A total of 27% of participants in each group required a switch in treatment at 24 weeks. Participants in both groups who switched therapies had improvement after switching (P<0.001), and the response after switching did not differ significantly between the two groups (P=0.08). The change between baseline and 48 weeks in the DAS28 was similar in the two groups (-2.1 with triple therapy and -2.3 with etanercept and methotrexate, P=0.26); triple therapy was noninferior to etanercept and methotrexate, since the 95% upper confidence limit of 0.41 for the difference in change in DAS28 was below the margin for noninferiority of 0.6 (P=0.002). There were no significant between-group differences in secondary outcomes, including radiographic progression, pain, and health-related quality of life, or in major adverse events associated with the medications. Conclusions With respect to clinical benefit, triple therapy, with sulfasalazine and hydroxychloroquine added to methotrexate, was noninferior to etanercept plus methotrexate in patients with rheumatoid arthritis who had active disease despite methotrexate therapy. (Funded by the Cooperative Studies Program, Department of Veterans Affairs Office of Research and Development, and others; CSP 551 RACAT number, NCT00405275 .).

Concepts: Medicine, Rheumatoid arthritis, Rheumatology, Methotrexate, Ankylosing spondylitis, Psoriatic arthritis, Disease-modifying antirheumatic drug, Hydroxychloroquine


Background In phase 2 studies, baricitinib, an oral Janus kinase 1 and 2 inhibitor, reduced disease activity in patients with rheumatoid arthritis who had not previously received treatment with biologic disease-modifying antirheumatic drugs (DMARDs). Methods In this phase 3 study involving 527 patients with an inadequate response to or unacceptable side effects associated with one or more tumor necrosis factor inhibitors, other biologic DMARDs, or both, we randomly assigned the patients in a 1:1:1 ratio to baricitinib at a dose of 2 or 4 mg daily or placebo for 24 weeks. End points, tested hierarchically at week 12 to control type 1 error, were the American College of Rheumatology 20% (ACR20) response (primary end point), the Health Assessment Questionnaire-Disability Index (HAQ-DI) score, the 28-joint Disease Activity Score based on C-reactive protein level (DAS28-CRP), and a Simplified Disease Activity Index (SDAI) score of 3.3 or less (on a scale of 0.1 to 86.0, with a score of 3.3 or less indicating remission). Comparisons with placebo were made first with the 4-mg dose of baricitinib and then with the 2-mg dose. Results Significantly more patients receiving baricitinib at the 4-mg dose than those receiving placebo had an ACR20 response at week 12 (55% vs. 27%, P<0.001). Differences between the higher-dose baricitinib group and the placebo group were also significant for the HAQ-DI score and the DAS28-CRP but not for an SDAI score of 3.3 or less. Adverse-event rates through 24 weeks were higher for patients receiving the 2-mg dose of baricitinib and those receiving the 4-mg dose than for patients receiving placebo (71% and 77%, respectively, vs. 64%), including infections (44% and 40%, vs. 31%). The rates of serious adverse events were 4%, 10%, and 7% in the three groups, respectively. Two nonmelanoma skin cancers and two major adverse cardiovascular events, including a fatal stroke, occurred in the higher-dose group. Baricitinib was associated with a small reduction in neutrophil levels and increases in serum creatinine and low-density lipoprotein cholesterol levels. Conclusions In patients with rheumatoid arthritis and an inadequate response to biologic DMARDs, baricitinib at a daily dose of 4 mg was associated with clinical improvement at 12 weeks. (Funded by Eli Lilly and Incyte; number, NCT01721044 .).

Concepts: Inflammation, Clinical trial, Atherosclerosis, Cardiovascular disease, Rheumatoid arthritis, Rheumatology, Tumor necrosis factor-alpha, Disease-modifying antirheumatic drug


In this article, the 2010 European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA) with synthetic and biological disease-modifying antirheumatic drugs (sDMARDs and bDMARDs, respectively) have been updated. The 2013 update has been developed by an international task force, which based its decisions mostly on evidence from three systematic literature reviews (one each on sDMARDs, including glucocorticoids, bDMARDs and safety aspects of DMARD therapy); treatment strategies were also covered by the searches. The evidence presented was discussed and summarised by the experts in the course of a consensus finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) were determined. Fourteen recommendations were developed (instead of 15 in 2010). Some of the 2010 recommendations were deleted, and others were amended or split. The recommendations cover general aspects, such as attainment of remission or low disease activity using a treat-to-target approach, and the need for shared decision-making between rheumatologists and patients. The more specific items relate to starting DMARD therapy using a conventional sDMARD (csDMARD) strategy in combination with glucocorticoids, followed by the addition of a bDMARD or another csDMARD strategy (after stratification by presence or absence of adverse risk factors) if the treatment target is not reached within 6 months (or improvement not seen at 3 months). Tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, biosimilars), abatacept, tocilizumab and, under certain circumstances, rituximab are essentially considered to have similar efficacy and safety. If the first bDMARD strategy fails, any other bDMARD may be used. The recommendations also address tofacitinib as a targeted sDMARD (tsDMARD), which is recommended, where licensed, after use of at least one bDMARD. Biosimilars are also addressed. These recommendations are intended to inform rheumatologists, patients, national rheumatology societies and other stakeholders about EULAR’s most recent consensus on the management of RA with sDMARDs, glucocorticoids and bDMARDs. They are based on evidence and expert opinion and intended to improve outcome in patients with RA.

Concepts: Rheumatoid arthritis, Rheumatology, Infliximab, Psoriatic arthritis, Etanercept, Disease-modifying antirheumatic drug, Adalimumab, TNF inhibitor


To compare persistence and adherence to triple therapy with nonbiologic disease-modifying antirheumatic drugs (DMARDs) methotrexate (MTX), hydroxychloroquine, and sulfasalazine, versus a tumor necrosis factor inhibitor plus MTX (TNFi+MTX) in patients with rheumatoid arthritis (RA).

Concepts: Rheumatoid arthritis, Methotrexate, Arthritis, Tumor necrosis factor-alpha, Ankylosing spondylitis, Disease-modifying antirheumatic drug, Hydroxychloroquine, Sulfasalazine


This study aims to measure the serum level of 25-hydroxyvitamin D(3) (25-OH-D(3)) in 302 patients with rheumatoid arthritis (RA), studying the association to disease activity. Three hundred two RA patients underwent clinical examination and serological analysis. 25-Hydroxyvitamin D(3) was determined by high-performance liquid chromatography-tandem mass spectrometry. Vitamin D(3) deficiency defined as serum levels of 25-hydroxyvitamin D(3) below 50 nmol/l was detected in 101 RA patients (33.4 %). There was no significant correlation between the serum level of 25-hydroxyvitamin D(3) and Disease Activity Score 28 (DAS28) (3w) score. In a subpopulation of RA patients with very low serum level of 25-OH-D(3) (≤15 nmol/l) (n = 15), there were significant differences compared to patients with normal 25-OH-D(3) (n = 200): higher percentage of patients with positive rheumatoid factor (100.0 versus 77.5 %; p = 0.05), higher CRP (28.7 versus 14.8 mg/l; p = 0.001), higher number of patients treated with at least three disease-modifying antirheumatic drugs (DMARDs) (40.0 versus 14.5 %; p = 0.02), higher number of patients with high disease activity DAS28 score of ≥5.1 (20.0 versus 4.5 %; p = 0.01), lower age (54.5 versus 64.0 years; p = 0.003) and shorter disease duration (5.1 versus 10.3 years; p = 0.06). Deficiency of 25-hydroxyvitamin D(3) was detected in 33.4 % of the RA patients. A subpopulation of patients with severe deficiency of vitamin D(3) serum level of ≤15 nmol/l was characterised by all being positive for rheumatoid factor, high percentage of patients with very high disease activity and high percentage of patients treated with at least three DMARDs.

Concepts: Immunology, Rheumatoid arthritis, Rheumatology, Arthritis, Liquid chromatography-mass spectrometry, Disease-modifying antirheumatic drug, Hydroxychloroquine, Rheumatoid factor


ABSTRACT Rheumatoid arthritis (RA) is a painful, debilitating disease characterized by inflammation of the joints, with the proliferation of the synovium and the progressive erosion of cartilage and bone. The treatment of RA is still unsatisfactory, but a number of powerful disease-modifying antirheumatic drugs have become available, such as methotrexate (MTX). Even in the current era of biological targeted therapies, MTX remains the initial preferred antirheumatic drug and is considered to be the gold standard for treatment of RA. The combination of its perceived efficacy, acceptable safety profile, and low cost, as well as decades of clinical experience, makes MTX the cornerstone of treatment for RA and the anchor drug in combination with various biological agents. In this review, the authors aim to summarize the research done in the field of drug delivery systems of MTX according to its routes of administration for treatment of RA. The last part of the review addresses combination therapy with MTX and future direction in the drug delivery of MTX. This review also provides the reader with a general overview of RA and its therapeutic strategies with respect of MTX, which may bring uniformity in medical practice for effective management of RA.

Concepts: Pharmacology, Medicine, Rheumatoid arthritis, Therapy, Osteoarthritis, Drugs, Methotrexate, Disease-modifying antirheumatic drug


A European League Against Rheumatism (EULAR) task force was established to define points to consider on use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Based on a systematic literature review and pregnancy exposure data from several registries, statements on the compatibility of antirheumatic drugs during pregnancy and lactation were developed. The level of agreement among experts in regard to statements and propositions of use in clinical practice was established by Delphi voting. The task force defined 4 overarching principles and 11 points to consider for use of antirheumatic drugs during pregnancy and lactation. Compatibility with pregnancy and lactation was found for antimalarials, sulfasalazine, azathioprine, ciclosporin, tacrolimus, colchicine, intravenous immunoglobulin and glucocorticoids. Methotrexate, mycophenolate mofetil and cyclophosphamide require discontinuation before conception due to proven teratogenicity. Insufficient documentation in regard to fetal safety implies the discontinuation of leflunomide, tofacitinib as well as abatacept, rituximab, belimumab, tocilizumab, ustekinumab and anakinra before a planned pregnancy. Among biologics tumour necrosis factor inhibitors are best studied and appear reasonably safe with first and second trimester use. Restrictions in use apply for the few proven teratogenic drugs and the large proportion of medications for which insufficient safety data for the fetus/child are available. Effective drug treatment of active inflammatory rheumatic disease is possible with reasonable safety for the fetus/child during pregnancy and lactation. The dissemination of the data to health professionals and patients as well as their implementation into clinical practice may help to improve the management of pregnant and lactating patients with rheumatic disease.

Concepts: Pregnancy, Rheumatoid arthritis, Rheumatology, Rheumatism, Immunosuppressants, Mycophenolic acid, Disease-modifying antirheumatic drug, Teratology


The aim of this report was to propose a definition for erosive disease in the context of inflammatory arthritis in light of the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) criteria for use in clinical practice and studies. A EULAR task force was formed including 16 rheumatologists and one rheumatology fellow. The process was both evidence based and consensus based, and included, between March 2010 and April 2012, analyses of data from two cohorts, two face-to-face meetings, one online voting and one teleconference. The Leiden Early Arthritis Cohort and the French ESPOIR cohort were used for the evidence-based part. The outcome measures, which were initiation of methotrexate therapy, or any disease-modifying antirheumatic drug therapy within the first year of disease and arthritis persistency over 5 years, were studied with the aim to give the best definition of erosive disease. A decision was made to select a definition with a high specificity and focus on patients who did not otherwise fulfil the 2010 ACR/EULAR RA criteria (<6 points). By a unanimous vote the following definition was selected: erosive disease for use in the 2010 ACR/EULAR RA classification criteria is defined when an erosion (defined as a cortical break) is seen in at least three separate joints at any of the following sites: the proximal interphalangeal, the metacarpophalangeal, the wrist (counted as one joint) and the metatarsophalangeal joints on radiographs of both hands and feet. A highly specific definition for erosive disease has thus been formulated.

Concepts: Rheumatoid arthritis, Rheumatology, Osteoarthritis, Methotrexate, Arthritis, Disease-modifying antirheumatic drug, Septic arthritis, Hydroxychloroquine


To monitor whether biologic DMARD (bDMARD) home storage temperatures comply with the manufacturers' Summary of Product Characteristics (SmPC) recommendations.

Concepts: Chemical reaction, Temperature, Thermodynamics, Manufacturing, Disease-modifying antirheumatic drug