Impact of multimorbidity on disease modifying antirheumatic drug therapy in early rheumatoid arthritis: Data from the ESPOIR cohort.

OBJECTIVE: Multimorbidity is frequent in rheumatoid arthritis (RA) and could interfere with the therapeutic response. The aim of this study was to evaluate multimorbidity in the French cohort of early arthritis, the ESPOIR cohort, and its possible impact on the therapeutic response. METHODS: We included patients fulfilling 2010 ACR/EULAR criteria for RA. An adapted MultiMorbidity Index (aMMI) was developed. Each patient was assigned scores of binary aMMI (0=no comorbidity, 1=at least 1 comorbidity) and counted and weighted aMMI. The primary endpoint was achievement of Clinical Disease Activity Index (CDAI) low disease activity after initiation of a first disease-modifying antirheumatic drug (DMARD) according to the aMMI. We collected data from the visit preceding the first DMARD initiation and the visit after at least 3 months of treatment. The impact of aMMI on therapeutic maintenance at 1, 3, 5 and 10 years was evaluated. RESULTS: Analyses involved 472 patients: 302 (64%) had at least 1 comorbidity. Overall, 45.3% and 44.7% with binary aMMI=0 or 1, respectively (non-significant), achieved CDAI low disease activity. Similar results were found with counted and weighted aMMI. Therapeutic maintenance was significantly better with binary aMMI=1 than binary aMMI=0 (OR at 10 years=14.0 [CI 95% 3.3-59.4]). Increased counted aMMI was associated with increased probability of still being on the first initiated DMARD at each time point. CONCLUSION: In the ESPOIR cohort, therapeutic response to a first DMARD was not affected by multimorbidity but therapeutic maintenance was better in multimorbid patients.

Glucocorticoids in rheumatoid arthritis: current status and future studies.

Since their first use for treating rheumatoid arthritis (RA) in the late 1940s, glucocorticoids (GCs) have been representing a substantial part of the therapeutic arsenal for RA. However, even if GCs are still widely prescribed drugs, their toxicity is discussed controversially, so obtaining consensus on their use in RA is difficult. Hence, the most recent European League Against Rheumatism and American College of Rheumatology recommendations on early arthritis and RA management advocate the use of GCs as adjunct treatment to conventional synthetic disease-modifying antirheumatic drugs, at the lowest dose possible and for the shortest time possible. However, the recommendations remain relatively vague on dose regimens and routes of administration. Here, we describe literature data on which the current recommendations are based as well as data from recent trials published since the drafting of the guidelines. Moreover, we make proposals for daily practice and provide suggestions for studies that could help clarifying the place of GCs in RA management. Indeed, numerous items, including the benefit/risk ratio of low-dose and very low-dose GCs and optimal duration of GCs as bridging therapy, remain on the research agenda, and future studies are needed to guide the next recommendations for RA.

Clinical and Structural Efficacy of Hydroxychloroquine in Rheumatoid Arthritis: A Systematic Review.

OBJECTIVE: Hydroxychloroquine (HCQ) improves metabolic and cardiovascular outcomes in patients with rheumatoid arthritis (RA), but its efficacy appears to be moderate as compared to placebo. The aim of our study was to assess the current literature on the clinical and structural efficacy of HCQ in the joints of patients with RA. METHODS: We systematically searched MEDLINE (via PubMed), Embase, Cochrane Library, and the American College of Rheumatology and European League Against Rheumatism annual scientific meeting abstracts for studies available up to November 2017 comparing the efficacy of HCQ in patients with RA, in monotherapy or combined with other conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Data were extracted by 1 investigator and independently checked by a different investigator. RESULTS: The literature search revealed 197 articles and abstracts of potential interest, and 11 studies fulfilled inclusion criteria. The clinical and structural efficacy of HCQ was similar to or lower than that for methotrexate or sulfasalazine in monotherapy. HCQ combined with other DMARDs could increase the clinical efficacy. CONCLUSION: In addition to its metabolic benefit, combining HCQ with other DMARDs could provide some clinical improvement in patients with RA and inadequate response to previous csDMARDs.

Update of French society for rheumatology recommendations for managing rheumatoid arthritis.

The 2014 French Society for Rheumatology (Société Française de Rheumatologie, SFR) recommendations about the management of rheumatoid arthritis (RA) have been updated by a task force composed of 12 expert rheumatologists, 2 patient self-help group representatives, and an occupational therapist. The material used by the task force included recent EULAR recommendations, a systematic literature review, and expert opinion. Four general principles and 15 recommendations were developed. The general principles emphasize the need for shared decision-making between the rheumatologist and the patient and for a global management program including both pharmacological and non-pharmacological treatments. The recommendations deal with the diagnostic strategy for RA, treatment targets, management organization, drug selection based on the treatment line and prognostic factors, management of remissions, and global patient management. Disease-modifying anti-rheumatic drug (DMARD) therapy should be started as early as possible. Validated composite scores should be determined at regular intervals to assess disease activity - according to the tight disease control concept - to achieve the treatment target, i.e., a remission. Methotrexate is the recommended first-line DMARD. The treatment should be optimized when methotrexate is poorly tolerated or inadequately effective. While waiting for conventional synthetic DMARDs to take effect, glucocorticoid therapy can be used, for a brief period to keep the cumulative dose low. When a sustained remission without structural progression is achieved in a patient who is not taking glucocorticoid therapy, targeted therapy de-escalation according to tight disease control principles should be considered. Patients should be periodically screened for comorbidities and their risk factors, which should be evaluated and treated.

Metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid arthritis: a systematic review and meta-analysis.

OBJECTIVE: Cardiovascular disease (CVD) is the leading cause of mortality in patients with rheumatoid arthritis (RA). Hydroxychloroquine (HCQ) has been shown to improve survival rates in other inflammatory diseases. We aimed to assess the available literature on the cardiovascular impact of HCQ in patients with RA. METHODS: We systematically searched for studies evaluating the effects of HCQ on cardiovascular outcomes of known risk factors for CVD in patients with RA. Databases searched were MEDLINE (via PubMed), EMBase, Cochrane Library and the American College of Rheumatology and European League Against Rheumatism annual meetings. A meta-analysis was performed with a random-effects model, estimating mean differences (MDs), HRs and 95% CIs. Data were extracted by one investigator and independently checked by another. RESULTS: The literature search revealed 185 articles and abstracts of interest; further examination resulted in 16 studies fulfilling the criteria. The MDs between HCQ users and non-users in levels of total, low-density and high-density cholesterol and triglycerides were -9.8 (95% CI -14.0 to -5.6), -10.6 (95% CI -14.2 to -7.0), +4.1 (95% CI 2.2 to 6.0) and -19.2 (95% CI -27.2 to -11.1), respectively. Diabetes incidence was lower for HCQ ever users than never users (HR 0.59 (95% CI 0.49 to 0.70)). HCQ seemed to decrease insulin resistance and incidence of CVD, but data were too few for meta-analysis. CONCLUSION: Besides its limited efficacy for disease activity and progression, HCQ may benefit the metabolic profile and to a lesser extent cardiovascular events in patients with RA, which suggests its usefulness combined with other conventional synthetic disease-modifying antirheumatic drugs.

Non-pharmacological and pharmacological interventions in patients with early arthritis: a systematic literature review informing the 2016 update of EULAR recommendations for the management of early arthritis.

OBJECTIVE: To perform a systematic literature review (SLR) on pharmacological and non-pharmacological treatments, in order to inform the European League Against Rheumatism (EULAR) recommendations for the management of early arthritis (EA). METHODS: The expert committee defined research questions concerning non-pharmacological interventions, patient information and education, non-steroidal anti-inflammatory drug, glucocorticoid (GC) and disease-modifying antirheumatic drugs (DMARDs) use, as well as on disease monitoring. The SLR included articles published after the last EULAR SLR until November 2015 found in the MEDLINE, EMBASE and Cochrane databases and abstracts from the 2014 and 2015 American College of Rheumatology and EULAR conferences. RESULTS: Exercise programmes may improve pain and physical function in patients with EA. Patients with EA treated within the first 3 months of symptoms have better clinical and radiological outcomes than those treated beyond 3 months. The clinical and radiological efficacy of GCs is confirmed, with similar efficacy of oral and parenteral administrations. Long-term data raise concerns regarding cardiovascular safety when using GCs. Step-up DMARD therapy is as effective as intensive DMARD therapy 'ab initio' for the long-term outcome of EA. Short-term superiority of intensive therapy with bDMARDs is not maintained on withdrawal of bDMARD. Patients with early psoriatic arthritis have better skin and joint outcomes when tight control is used compared to standard care. CONCLUSIONS: The findings confirm the beneficial effect of exercise programmes and the importance of early drug therapy and tight control. They support the use of methotrexate and GCs as first-line drugs, although the long-term use of GCs raises safety concerns.

Diagnosis, prognosis and classification of early arthritis: results of a systematic review informing the 2016 update of the EULAR recommendations for the management of early arthritis.

OBJECTIVE: To update the evidence pertaining to the diagnosis, prognosis and classification of patients with early arthritis (EA), and to inform the 2016 European League Against Rheumatism (EULAR) recommendations for the management of patients with EA. METHODS: MEDLINE, EMBASE and Cochrane databases were searched up to October 2015. The first part of the systematic literature review (SLR) involved a search for studies investigating the recognition and referral of EA. The second part involved a search for studies to identify the place of laboratory and imaging tests in establishing a diagnosis and a prognosis in patients with EA. RESULTS: Regarding the issue of referral of patients with EA (1643 hits), 4 studies were included. These studies were in support of early referral for patients with EA. Regarding the issue of diagnosis and prognosis of patients with EA (11 435 hits), 88 studies were included, evaluating mainly the value of rheumatoid factor (RF) and anticitrullinated-peptide antibodies (ACPAs). Sensitivity of these antibodies for a RA diagnosis in patients with EA was moderate (40-80%). Specificity was higher, notably for ACPAs (frequently >80%). ACPAs also showed better prognostic performance than RF (negative predictive values around 80%). We confirmed that structural damage on baseline X-rays is predictive of further radiographic progression in patients with EA. Regarding other imaging modalities, data are sparse. CONCLUSIONS: This SLR highlights the importance of early referral for patients with EA and confirms that RF and mainly ACPAs as well as a search for structural X-rays changes may help in the diagnosis and prognosis of patients with EA.

Phosphatidylserine Outer Layer Translocation Is Implicated in IL-10 Secretion by Human Regulatory B Cells.

B cells can have a regulatory role, mainly mediated by interleukin 10 (IL-10). IL-10 producing B cells (B10 cells) cells remain to be better characterized. Annexin V binds phosphatidylserine (PS), which is externalized during apoptosis. Previous works suggested that B10 cells are apoptotic cells since they bind Annexin V. Others showed that Annexin V binding could also be expressed on viable B cells. We aimed to explore if PS exposure can be a marker of B10 cells and if PS exposure has a functional role on B cell IL-10 production in healthy subjects. We found that B10 cells were significantly more often Annexin V+ than IL-10 non-producing B cells. After CpG activation, Annexin V+ B cells differentiated more often into B10 cells than Annexin Vneg B cells. Cell death and early apoptosis were similar between Annexin V+ and Annexin Vneg B cells. PS blockage, using biotinylated AnV and glyburide, decreased B10 cell differentiation. This study showed that B10 cells have an increased PS exposure independently of any apoptotic state. B cells exposing PS differentiate more into B10 cells whereas PS blockage inhibits B10 cells generation. These results strongly suggest a link between PS exposure and B10 cells.

2016 update of the EULAR recommendations for the management of early arthritis.

OBJECTIVES: Since the 2007 recommendations for the management of early arthritis have been presented, considerable research has been published in the field of early arthritis, mandating an update of the 2007 European League Against Rheumatism (EULAR) recommendations for management of early arthritis. METHODS: In accordance with the 2014 EULAR Standardised Operating Procedures, the expert committee pursued an approach that was based on evidence in the literature and on expert opinion. The committee involved 20 rheumatologists, 2 patients and 1 healthcare professional representing 12 European countries. The group defined the focus of the expert committee and target population, formulated a definition of 'management' and selected the research questions. A systematic literature research (SLR) was performed by two fellows with the help of a skilled librarian. A set of draft recommendations was proposed on the basis of the research questions and the results of the SLR. For each recommendation, the categories of evidence were identified, the strength of recommendations was derived and the level of agreement was determined through a voting process. RESULTS: The updated recommendations comprise 3 overarching principles and 12 recommendations for managing early arthritis. The selected statements involve the recognition of arthritis, referral, diagnosis, prognostication, treatment (information, education, pharmacological and non-pharmacological interventions), monitoring and strategy. Eighteen items were identified as relevant for future research. CONCLUSIONS: These recommendations provide rheumatologists, general practitioners, healthcare professionals, patients and other stakeholders with an updated EULAR consensus on the entire management of early arthritis.

A proliferation inducing ligand (APRIL) promotes IL-10 production and regulatory functions of human B cells.

B cells may have a negative regulatory role, mainly mediated by interleukin 10 (IL-10). We recently showed that regulatory B-cell functions are impaired in patients with rheumatoid arthritis (RA) and that mice transgenic for a proliferation-inducing ligand (APRIL) are protected against collagen-induced arthritis. We aimed to explore the effect of APRIL on human B-cell IL-10 production, in healthy subjects and in patients with RA. The IL-10 production of B-cell was greater with APRIL than with BLyS or control medium, in a dose dependent manner. TACI expression was greater in IL-10 producing B cells (B10) than non-IL-10-producing B cells whereas BAFF-R expression was lower. TNF-α and IFN-γ secretion of T-cells were decreased by APRIL-stimulated B cells. APRIL stimulated STAT3 and STAT3 inhibition decreased B10 cells. APRIL also promoted B10 cells in RA patients. In conclusion, APRIL but not BLyS promotes IL-10 production by CpG-activated B cells and enhances the regulatory role of B cells on T cells. B10 cells in RA patients are responsive to APRIL, which suggests a possible therapeutic application of APRIL to expand B10 cells. This could also explain the difference of clinical efficacy observed between belimumab and atacicept in RA.

Effect of methotrexate, anti-tumor necrosis factor α, and rituximab on the immune response to influenza and pneumococcal vaccines in patients with rheumatoid arthritis: a systematic review and meta-analysis.

OBJECTIVE: To assess the current literature on the impact of rheumatoid arthritis (RA) treatments on the humoral response to pneumococcal and influenza vaccines. METHODS: We systematically searched the literature for studies evaluating the immune response to vaccines in RA patients receiving methotrexate (MTX) and/or biologic agents. The efficacy of vaccination, assessed by the response rate based on increased antibody titers before and 3-6 weeks after vaccination, was extracted by one investigator and verified by another. RESULTS: In total, 12 studies were included. RA patients mainly received MTX, anti-tumor necrosis factor α (anti-TNFα), or rituximab (RTX). Influenza vaccination response was reduced for RTX (43 patients; pooled odds ratio [OR] 0.44 [95% confidence interval (95% CI) 0.17-1.12] for H1N1, OR 0.11 [95% CI 0.04-0.31] for H3N2, and OR 0.29 [95% CI 0.10-0.81] for B) but not for anti-TNFα (308 patients; OR 0.93 [95% CI 0.36-2.37] for H1N1, OR 0.79 [95% CI 0.34-1.83] for H3N2, and OR 0.79 [95% CI 0.37-1.70] for B). For MTX, results differed depending on the method of analysis (222 patients; OR 0.35 [95% CI 0.18-0.66] for at least 2 strains, ORs were close to 1.0 in the single strain analysis). Pneumococcal vaccination response was reduced for 139 patients receiving MTX compared with controls (OR 0.33 [95% CI 0.20-0.54] for serotype 6B and OR 0.58 [95% CI 0.36-0.94] for 23F) but not for anti-TNFα (258 patients; OR 0.96 [95% CI 0.57-1.59] for 6B and OR 1.20 [95% CI 0.57-2.54] for 23F). For RTX, the response was reduced (88 patients; OR 0.25 [95% CI 0.11-0.58] for 6B and OR 0.21 [95% CI 0.04-1.05] for 23F). CONCLUSION: MTX decreases humoral response to pneumococcal vaccination and may impair response to influenza vaccination. The immune response to both vaccines is reduced with RTX but not with anti-TNFα therapy in RA patients.