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Metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid arthritis: a systematic review and meta-analysis.
Rempenault, C, Combe, B, Barnetche, T, Gaujoux-Viala, C, Lukas, C, Morel, J, Hua, C
Annals of the rheumatic diseases. 2018;(1):98-103
Abstract
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.
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Targeting Acquired Hemophilia A with Rheumatoid Arthritis by a Rituximab Shot: A Case Report and Review of the Literature.
Ghozlani, I, Mounach, A, Ghazi, M, Kherrab, A, Niamane, R
The American journal of case reports. 2018;:582-588
Abstract
BACKGROUND Acquired hemophilia A (AH) is a rare hemorrhagic diathesis, characterized by the presence of autoantibodies directed against the pro-coagulant activity of factor VIII. It is associated with rheumatoid arthritis (RA) in 4% to 8% of cases and its prognosis remains severe. CASE REPORT A 66-year-old patient has been followed up for 20 years for deforming and severe RA, which was in low-disease activity. However, the patient presented a polyarticular flare involving the metacarpophalangeal and the proximal interphalangeal joints, the left elbow, and the right knee, which was warm and swollen. Articular puncture of this knee yielded a hematic fluid that did not coagulate. Its cytological analysis showed significant presence of red blood cells, which were also abundantly present in the other cell lines. Activated partial thromboplastin time was lengthened and not corrected by the addition of control plasma. Prothrombin time (Quick's test), fibrinogen level, and vitamin K-dependent factors were without abnormalities. In contrast, factor VIII was collapsed at 7% and the anti-factor VIII antibody was positive. The diagnosis of AH with anti-factor VIII inhibitor was thus retained. With regard to RA, the Disease Activity Score was 6.32 and exhibited a very active RA. Rituximab with methotrexate was begun and the evolution was favorable. After 6 months, the reappearance of the anti-factor VIII inhibitor was found, thus justifying a second cycle of rituximab. CONCLUSIONS AH is not exceptional in RA. Rituximab remains a relevant alternative for managing simultaneous AH with inhibitor and RA.
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Systematic review, and meta-analysis of steroid-sparing effect, of biologic agents in randomized, placebo-controlled phase 3 trials for systemic lupus erythematosus.
Oon, S, Huq, M, Godfrey, T, Nikpour, M
Seminars in arthritis and rheumatism. 2018;(2):221-239
Abstract
OBJECTIVES To systematically review, and conduct a meta-analysis of steroid-sparing effect in, phase 3 randomized, placebo-controlled trials of biologic therapies for systemic lupus erythematosus (SLE). METHODS Studies were identified by searching Medline (via Pubmed), EMBASE, CINAHL and SCOPUS databases, the Cochrane library, and clinicaltrials.gov. Adult human studies published in English in the last ten years (until 18/04/2017) were included. A random-effects meta-analysis comparing a common corticosteroid-reduction endpoint in the trials of rituximab, belimumab, tabalumab and epratuzumab in SLE, was conducted. RESULTS Twenty-eight studies were identified; nine were conducted in SLE, five in lupus nephritis and the remaining 14 were post hoc analyses of phase 3 trials in SLE. All therapies trialed targeted B-cells (rituximab (anti-CD20 monoclonal antibody (mAb)), belimumab (anti-BAFF mAb), tabalumab (anti-BAFF mAb), epratuzumab (anti-CD22 mAb), atacicept (TACI-Ig), ocrelizumab (anti-CD20 mAb)), except for abetimus sodium and abatacept (CTLA4-Ig). Only the three trials of belimumab met their primary endpoints, although benefit in secondary endpoints and reduction in serological activity was often seen in the other studies. Meta-analysis showed that most therapies (belimumab, tabalumab, and epratuzumab) had a steroid-sparing effect, compared to placebo (pooled RR 1.36 (1.19, 1.56), I2 = 0, p < 0.67). Therapies were generally well tolerated; however, three studies were terminated prematurely due to serious side effects. CONCLUSIONS With the exception of belimumab, none of the phase 3 trials of biologic therapy in SLE have met their primary endpoint. However, the significant steroid-sparing effect of these agents suggests that future trials may need to include steroid dose in a composite primary endpoint.
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Methotrexate in juvenile idiopathic arthritis: advice and recommendations from the MARAJIA expert consensus meeting.
Ferrara, G, Mastrangelo, G, Barone, P, La Torre, F, Martino, S, Pappagallo, G, Ravelli, A, Taddio, A, Zulian, F, Cimaz, R, et al
Pediatric rheumatology online journal. 2018;(1):46
Abstract
BACKGROUND Conventional pharmacological therapies for the treatment of juvenile idiopathic arthritis (JIA) consist of non-biological, disease-modifying antirheumatic drugs, among which methotrexate (MTX) is the most commonly prescribed. However, there is a lack of consensus-based clinical and therapeutic recommendations for the use of MTX in the management of patients with JIA. Therefore, the Methotrexate Advice and RecommendAtions on Juvenile Idiopathic Arthritis (MARAJIA) Expert Meeting was convened to develop evidence-based recommendations for the use of MTX in the treatment of JIA. METHODS The preliminary executive committee identified a total of 9 key clinical issues according to the population, intervention, comparator, outcome (PICO) approach, and performed an evidence-based, systematic, literature review. During the subsequent Expert Meeting, the relevant evidence was assessed and graded, and 10 recommendations were made. RESULTS Recommendations relating to the efficacy, optimal dosing and route of administration and duration of treatment with MTX in JIA, and to the issue of folic acid supplementation to prevent MTX side effects, use of MTX in the treatment of chronic JIA-associated uveitis, combination treatment with biologic agents, and the use of vaccinations in patients with JIA were developed. The selected topics were considered to represent clinically important issues facing clinicians caring for patients with JIA. Evidence was insufficient to formulate recommendations for the use of biomarkers predictive of treatment response. CONCLUSIONS These consensus recommendations provide balanced and evidence-based recommendations designed to have broad value for physicians and healthcare clinicians involved in the clinical management of patients with JIA.
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Baseline metabolic profiles of early rheumatoid arthritis patients achieving sustained drug-free remission after initiating treat-to-target tocilizumab, methotrexate, or the combination: insights from systems biology.
Teitsma, XM, Yang, W, Jacobs, JWG, Pethö-Schramm, A, Borm, MEA, Harms, AC, Hankemeier, T, van Laar, JM, Bijlsma, JWJ, Lafeber, FPJG
Arthritis research & therapy. 2018;(1):230
Abstract
BACKGROUND We previously identified, in newly diagnosed rheumatoid arthritis (RA) patients, networks of co-expressed genes and proteomic biomarkers associated with achieving sustained drug-free remission (sDFR) after treatment with tocilizumab- or methotrexate-based strategies. The aim of this study was to identify, within the same patients, metabolic pathways important for achieving sDFR and to subsequently study the complex interactions between different components of the biological system and how these interactions might affect the therapeutic response in early RA. METHODS Serum samples were analyzed of 60 patients who participated in the U-Act-Early trial (ClinicalTrials.gov number NCT01034137) and initiated treatment with methotrexate, tocilizumab, or the combination and who were thereafter able to achieve sDFR (n = 37); as controls, patients were selected who never achieved a drug-free status (n = 23). Metabolomic measurements were performed using mass spectrometry on oxidative stress, amine, and oxylipin platforms covering various compounds. Partial least square discriminant analyses (PLSDA) were performed to identify, per strategy arm, relevant metabolites of which the biological pathways were studied. In addition, integrative analyses were performed correlating the previously identified transcripts and proteins with the relevant metabolites. RESULTS In the tocilizumab plus methotrexate, tocilizumab, and methotrexate strategy, respectively, 19, 13, and 12 relevant metabolites were found, which were subsequently used for pathway analyses. The most significant pathway in the tocilizumab plus methotrexate strategy was "histidine metabolism" (p < 0.001); in the tocilizumab strategy it was "arachidonic acid metabolism" (p = 0.018); and in the methotrexate strategy it was "arginine and proline metabolism" (p = 0.022). These pathways have treatment-specific drug interactions with metabolites affecting either the signaling of interleukin-6, which is inhibited by tocilizumab, or affecting protein synthesis from amino acids, which is inhibited by methotrexate. CONCLUSION In early RA patients treated-to-target with a tocilizumab- or methotrexate-based strategy, several metabolites were found to be associated with achieving sDFR. In line with our previous observations, by analyzing relevant transcripts and proteins within the same patients, the metabolic profiles were found to be different between the strategy arms. Our metabolic analysis further supports the hypothesis that achieving sDFR is not only dependent on predisposing biomarkers, but also on the specific treatment that has been initiated. TRIAL REGISTRATION ClinicalTrials.gov, NCT01034137 . Registered on January 2010.
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A systemic review and meta-analysis of the clinical efficacy and safety of total glucosides of peony combined with methotrexate in rheumatoid arthritis.
Feng, ZT, Xu, J, He, GC, Cai, SJ, Li, J, Mei, ZG
Clinical rheumatology. 2018;(1):35-42
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Abstract
To assess the efficacy and safety of the combination of total glucoside of peony (TGP) and methotrexate (MTX) for the treatment of rheumatoid arthritis (RA). Randomized controlled trial (RCT) data on the traditional Chinese active component TGP combined with MTX vs. MTX alone for the treatment of RA was collected by searching the Pubmed, Embase, Cochrane Library, CNKI, VIP Journals database, and Wanfang database up to February 2017. Study selection, data extraction, data synthesis, and data analyses were performed according to the Cochrane standards. A total of eight RCTs involving 522 participants were included in this meta-analysis. Compared with MTX alone, the use of TGP combined with MTX exhibited better therapeutic effects for the treatment of RA (P = 0.004). In addition, TGP combined with MTX caused a more significant decrease in erythrocyte sedimentation rate (ESR) (P < 0.0001) and swollen joint count (SJC) (P < 0.00001). However, no significant differences were found in C-reactive protein (CRP) (P = 0.19), duration of morning stiffness (DMS) (P = 0.32), or tender joint count (TJC) (P = 0.23) between the two groups. In addition, adverse events were more frequently reported in the MTX monotherapy group than in the TGP and MTX combination group (P = 0.0007). Our study demonstrates that TGP combined with MTX is more effective than MTX alone for the treatment of RA. Nevertheless, the adverse effects of the combination of TGP and MTX need to be further assessed. Due to the poor methodological quality of included trials, well-designed, multi-center, and large-scale RCTs are necessary to draw a more definitive conclusion.
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Remodeling of the HDL proteome with treatment response to abatacept or adalimumab in the AMPLE trial of patients with rheumatoid arthritis.
Charles-Schoeman, C, Gugiu, GB, Ge, H, Shahbazian, A, Lee, YY, Wang, X, Furst, DE, Ranganath, VK, Maldonado, M, Lee, T, et al
Atherosclerosis. 2018;:107-114
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Abstract
BACKGROUND AND AIMS To evaluate changes in the high-density lipoprotein (HDL) proteome and HDL function in active rheumatoid arthritis (RA) patients initiating therapy with abatacept or adalimumab in the Abatacept Versus Adalimumab Comparison in Biologic-Naïve RA Subjects with Background Methotrexate (AMPLE) study. METHODS Ultra high-pressure liquid chromatography (UHPLC) coupled with ion mobility mass spectrometry (LC-IM-MS) was used to analyze proteins associated with immunoaffinity-captured HDL from plasma of 30 patients with RA randomized to either abatacept (n = 15) or adalimumab (n = 15) therapy. Paraoxonase 1 (PON1) activity, HDL anti-oxidant capacity, cholesterol profiles, and homocysteine levels were also measured at baseline and following treatment. Repeated-measures analyses were performed using mixed-effect linear models to model the within-subject covariance over time. RESULTS In models controlling for age, sex and treatment group, improvement in inflammation measured by decreases in CRP was associated with improvement in HDL function and changes in several HDL-associated proteins including significant decreases in lipopolysaccharide-binding protein, serum amyloid A-I (SAA-I) and inter-alpha-trypsin inhibitor heavy chain H4 (p values < 0.05). Improvement in disease activity was also associated with changes in multiple HDL-associated proteins. Adalimumab was associated with higher PON1 activity, HDL-associated serotransferrin, and HDL-associated immunoglobulin J chain, and lower HDL-associated SAA-I over time compared with abatacept. CONCLUSIONS Improvement in inflammation associated with treatment of RA, using either abatacept or adalimumab in the AMPLE study, was associated with improvement in HDL function and significant alterations in the HDL proteome, including proteins involved in the immune response, proteinase inhibition, and lipid metabolism.
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Gender Is a Risk Factor for Annual Decline in Estimated Glomerular Filtration Rate in Patients Treated with Biological DMARDs in Rheumatoid Arthritis and Ankylosing Spondylitis: a Retrospective Observational Study.
Kim, SK, Choe, JY
Journal of Korean medical science. 2018;(30):e188
Abstract
BACKGROUND This study identified the risk factors of changes in renal function in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) treated with biological disease-modifying anti-rheumatic drugs (bDMARDs). METHODS We retrospectively enrolled patients with RA (n = 293) and AS (n = 125) treated with bDMARDs. The estimated glomerular filter rate (eGFR) using the Modification of Diet in Renal Disease equation was applied for assessment of annual changes in renal function between initiation and last visit after bDMARD therapy. The annual change in eGFR was used as an indicator for change in renal function. Statistical significance was assessed by Mann-Whitney test, Spearman's correlation coefficient, and multivariate linear regression analysis. RESULTS The positive annual change in eGFR in women was significantly noted, compared to that in men (P = 0.004). The annual change in eGFR was different between men and women (P = 0.038) in RA, but not in AS patients (P = 0.126). In multivariate linear regression analysis, women patients and increased serum creatinine at baseline were closely associated with positive annual change in eGFR in both RA and AS patients. In RA patients, younger age and lower ESR level were considered risk factors of positive annual change in eGFR (P = 0.013 and P = 0.022, respectively). However, disease duration and duration of bDMARD use were not associated with annual change in eGFR. CONCLUSION This study found that gender, especially men, might be responsible for annual decline in eGFR in RA and AS patients treated with bDMARDs.
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[Diagnosis and treatment of rheumatoid arthritis:toward the best practice. Management of elderly rheumatoid arthritis.].
Sugihara, T
Clinical calcium. 2018;(5):649-654
Abstract
Elderly rheumatoid arthritis(RA)is classified into 2 clinical subsets, elderly-onset RA(EORA)and younger-onset elderly RA. Anti-CCP antibody positive, high disease activity, presence of bone erosion are associated with progression of joint destruction of EORA, and intensive treatment using a treat-to-target strategy is needed in the patients with the poor prognostic factors. Working ability is one of most important goals for RA and also non-frail status should be goal of elderly RA, since it is associated with health expectancy. Biological DMARDs are slightly less or equally effective in reducing disease activity in elderly patients, and disease duration may have a greater impact on disease outcomes than age. Elderly patients had multi-morbidities and risk factors for serious infections, which make it difficult to establish a treatment strategy for elderly RA. We will discuss the treatment strategy of elderly RA in this review.
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Impact of biological therapy on work outcomes in patients with axial spondyloarthritis: results from the British Society for Rheumatology Biologics Register (BSRBR-AS) and meta-analysis.
Shim, J, Jones, GT, Pathan, EMI, Macfarlane, GJ
Annals of the rheumatic diseases. 2018;(11):1578-1584
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OBJECTIVES To quantify, among patients with axial spondyloarthritis (axSpA), the benefit on work outcomes associated with commencing biologic therapy. METHODS The British Society for Rheumatology Biologics Register in Axial Spondyloarthritis (BSRBRAS) recruited patients meeting Assessment of SpondyloArthritis International Society criteria for axSpA naïve to biological therapy across 83 centres in Great Britain. Work outcomes (measured using the Work Productivity and Activity Impairment Index) were compared between those starting biological therapy at the time of recruitment and those not. Differences between treatment groups were adjusted using propensity score matching. Results from BSRBR-AS were combined with other studies in a meta-analysis to calculate pooled estimates. RESULTS Of the 577 participants in this analysis who were in employment, 27.9% were starting biological therapy at the time of recruitment. After propensity score adjustment, patients undergoing biological therapy, at 12-month follow-up, experienced significantly greater improvements (relative to non-biological therapy) in presenteeism (-9.4%, 95% CI -15.3% to -3.5%), overall work impairment (-13.9%, 95% CI -21.1% to -6.7%) and overall activity impairment (-19.2%, 95% CI -26.3% to -12.2%). There was no difference in absenteeism (-1.5%, 95% CI -8.0 to 4.9). Despite these improvements, impact on work was still greater in the biological treated cohort at follow-up. In the meta-analysis including 1109 subjects across observational studies and trials, treatment with biological therapy was associated with significantly greater improvements in presenteeism, work impairment and activity impairment, but there was no difference in absenteeism. CONCLUSIONS There is consistent evidence that treatment with biological therapy significantly improves work productivity and activity impairment in people with axSpA. However, there remain substantial unmet needs in relation to work.