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ID PMID Title PublicationDate abstract
29303707 The influence of disease-modifying anti-rheumatic drugs and corticosteroids on the associa 2018 May OBJECTIVES: To investigate the influence of corticosteroids and disease-modifying anti-rheumatic drugs (DMARDs, including conventional synthetic and biologic DMARDs) treatment on the association between rheumatoid arthritis (RA) and non-melanoma skin cancer (NMSC). METHODS: This nationwide retrospective case-control study retrieved data from Taiwan National Health Insurance Research Database during 1995-2013. Cases with newly-diagnosed NMSC (n=19,603) were matched with control without NMSC in a 1:1 ratio according to age, sex, and reference date. The aforementioned association was analysed using conditional logistic regression and adjustments for age, sex, residential regions, occupations, and co-morbidities. Causality cannot be inferred by case-control study. RESULTS: Compared to patients without RA, the patients with RA had a significantly higher association with NMSC (adjusted odds ratio (AOR)=2.23, 95% confidence interval (CI) 1.6-3.1, p<0.001), especially those using cyclosporine (AOR=5.7, 95%CI 2.2-14.86; ≥65 years: AOR=7.28, 95%CI 2.16-24.56), etanercept (AOR=5.27, 95%CI 1.15-24.27; ≥65 years: AOR=8.95, 95%CI 1.12-71.85), and d-penicillamine (AOR=4.79, 95%CI 1.63-14.12; ≥65 years: AOR=3.81, 95%CI 1.26-11.52); those using higher cumulative doses of corticosteroids and methotrexate (corticosteroids: >10g: AOR=2.96, 95%CI 1.67-5.22; >10g and ≥65years: AOR=3.5, 95%CI 1.77-6.92; methotrexate: 1-3g: AOR=2.57, 95%CI 1.13-5.82; >3g: AOR=4.64, 95%CI 1.74-12.4; >3g and ≥65 years: AOR=10.17, 95%CI 2.34-44.26); and those using more kinds of DMARDs (any 3: AOR=3.72, 95%CI 1.67-8.26; any 5: AOR=2.81, 95%CI 1.13-7.04; any 6: AOR=5.23, 95%CI 1.14-24.14; 7-8: AOR=4.06, 95%CI 1.14-14.49). CONCLUSIONS: The patients with RA had significantly increased associations with NMSC, especially those receiving cyclosporine, etanercept, and d-penicillamine; higher cumulative doses of corticosteroids and methotrexate; or more kinds of DMARDs in combination or in sequence. The aforementioned associations were much stronger in the elderly.
27217051 Clinical-pharmacogenetic predictive models for MTX discontinuation due to adverse events i 2017 Oct We describe a novel approach to investigate and evaluate combined effect of a large number of clinical and pharmacogenetic factors on treatment outcome. We have used this approach to investigate predictors of methotrexate (MTX)-induced adverse events (AEs) leading to treatment discontinuation in rheumatoid arthritis (RA) patients. In total, 333 RA patients were genotyped for 34 polymorphisms in MTX transporters, folate and adenosine pathways. The effect of clinical and pharmacogenetic factors was assessed with penalized regression in the cause-specific Cox proportional hazards model. The predictive capacity was evaluated with the area under time-dependent receiver operating characteristic curve where cross-validation was applied. SLC19A1, ABCG2, ADORA3 and TYMS were associated with discontinuation because of AEs in clinical-pharmacogenetic model. Cross-validation showed that both clinical-pharmacogenetic model and nongenetic model had worthless predictive ability for MTX discontinuation because of AEs. These models could be further improved, either with additional polymorphisms or with epigenetic predictors.
27921185 Hand bone loss in early rheumatoid arthritis during a methotrexate-based treat-to-target s 2017 Apr This study aims to investigate 1-year hand bone loss (HBL(1-year)) in early rheumatoid arthritis (RA) patients treated with a methotrexate (MTX) and intra-articular triamcinolone treat-to-target strategy +/- adalimumab and to determine if HBL(6months) is associated with radiographic progression after 2 years. In a clinical trial (OPERA) of 180 treatment-naive early RA patients, bone mineral density (BMD) was estimated from hand radiographs with digital X-ray radiogrammetry (DXR) at baseline, after 6 (n = 90) and 12 months (n = 70) of follow-up. Baseline and 2-year radiographs were scored according to the Sharp/van der Heijde method. Baseline characteristics and HBL(6months) (0-6 months changes in DXR-BMD) were investigated as predictors of structural damage by univariate linear (∆ total Sharp/van der Heijde score (TSS) as dependent variable) and logistic (+/-radiographic progression (∆TSS >0) as dependent variable) regression analyses. Variables with p < 0.10 were included in multivariable models. In 70 patients with available HBL(1-year) data, HBL(1-year) was median (interquartile range (IQR)) -1.9 (-3.3; -0.26 mg/cm(2)) in the MTX + placebo group and -1.8 (-3.6; 0.06) mg/cm(2) in the MTX + adalimumab group, p = 0.98, Wilcoxon signed-rank. Increased HBL (compared to general population reference values) was found in 26/37 and 23/33 patients in the MTX + placebo and MTX + adalimumab groups, chi-squared = 0.99. In 90 patients with HBL(6months) data and 2-year radiographic data, HBL(6months) was independently associated with ∆TSS after 2 years (β = -0.086 (95% confidence interval = -0.15; -0.025) TSS unit/mg/cm(2) increase, p = 0.006) but not with presence of radiographic progression (∆TSS >0) (OR 0.96 (0.92-1.0), p = 0.10). In early RA patients treated with a methotrexate-based treat-to-target strategy, the majority of patients had increased HBL(1-year), irrespective of adalimumab; HBL(6months) was independently associated with ∆TSS after 2 years.
28068848 The safety of emerging biosimilar drugs for the treatment of rheumatoid arthritis. 2017 Mar Biological disease-modifying anti-rheumatic drugs (bDMARDs), often administered in combination with methotrexate, target specific inflammatory mediators and have transformed the treatment of rheumatic diseases, especially rheumatoid arthritis (RA) but also the spondyloarthritides. However, the high cost of these drugs in many countries restricts patient access. As many bDMARDs have reached or are near to patent expiration, numerous biosimilar drugs are in development and some have already been approved. Biosimilars are generally priced lower than their reference products (RPs), or bio-originators, and as prices come down it is hoped that patient access to these drugs will increase, making the safety of these drugs an area of major interest. Areas covered: This article reviews publicly available safety data on biosimilars in RA. Expert opinion: Most available data for biosimilars in RA relate to tumor necrosis factor inhibitors (TNFi) and rituximab (an anti-CD20 monoclonal antibody). As biosimilar use around the world increases, evidence supporting the clinical safety of the biosimilars compared with their RPs also grows. To date, no new safety concerns have been raised in studies with TNFi or rituximab biosimilars for the treatment of RA; safety profiles have been consistent with those of their RPs. However, careful post-marketing pharmacovigilance remains necessary.
28598776 Expression of the genes facilitating methotrexate action within subcutaneous rheumatoid no 2017 Nov OBJECTIVES: We sought further understanding of the association between methotrexate (MTX) therapy and accelerated development of subcutaneous rheumatoid nodules. The objective was to establish expression of genes involved in the transport, metabolism, and mechanism of action of MTX within nodule tissue. We also examined for differences in gene expression between nodules from patients actively receiving MTX compared to those not receiving MTX. METHODS: Subcutaneous nodule tissues (n=23) were obtained from 21 patients with RA, undergoing elective surgery. Expression of genes important to the transport (SLC19A1, ABCB1, ABCC1, ABCG2), metabolism (FPGS, GGH), and mechanism of action (TYMS, MTR, MTRR) of MTX, including for the adenosine receptors ADORA1, ADORA2A, ADORA2B, ADORA3 and ADORA3variant were quantitated by real-time PCR in each nodule sample. RESULTS: Transcripts for all genes were found in all nodules. Expression of MTR was significantly reduced in nodules from patients receiving MTX therapy. Patterns of gene expression differed, with those metabolising MTX more prominent in nodules from patients receiving MTX when compared to nodules from those not receiving MTX, where genes involved in MTX transport were more prominent. CONCLUSIONS: Genes involved in MTX handling are expressed in rheumatoid nodules, providing further evidence that metabolism of MTX within nodules could exert a local effect. Furthermore the profile of gene expression in nodules differed from that previously observed in rheumatoid synovial membrane. The significant reduction of MTR expression in nodules has implications for MTR- and MTRR-mediated re-methylation reactions. Our data suggest that in contrast to synovium, downstream methylation reactions involving methionine and the biosynthesis of S-adenosylmethionine (SAM) could be reduced in nodule tissue. This could help explain differing responses to MTX in rheumatoid nodules and synovium and warrants further investigation.
28859470 Medication nonadherence in Korean patients with rheumatoid arthritis: the importance of be 2018 Jan BACKGROUND/AIMS: To investigate medication nonadherence in Korean patients with rheumatoid arthritis (RA) and analyze related factors. METHODS: A total of 292 patients with RA participated in this study. Medication nonadherence, intentional or unintentional, was gauged via self-reported questionnaire. Patient perceptions of illness, treatment beliefs, and moods were measured via Brief Illness Perception Questionnaire, Beliefs about Medicines Questionnaire, and Patient Health Questionnaire-2, respectively. Demographic and clinical data were also collected. Multinomial regression analysis was used to assess the impact of demographic, clinical, and psychological factors on medication nonadherence. RESULTS: The medication nonadherence rate was 54.1% (intentional, 21.6%; unintentional, 32.5%). Intentional nonadherence was reported most often in patients treated daily drugs (nonsteroidal anti-inflammatory drugs and/or disease-modifying antirheumatic drugs) (24.2%), and unintentional nonadherence was highest in patients receiving methotrexate (33.3%) (p = 0.872). In univariate analysis, beliefs in necessity and concerns of medication differed significantly in adherent and nonadherent patients (intentional or unintentional). When controlling for other factors that may impact medication nonadherence, less belief in necessity of medication (odds ratio [OR], 0.81; 95% confidence interval [CI], 0.68 to 0.95) and greater emotional response to disease (OR, 1.19; 95% CI, 1.01 to 1.40) were important predictors of intentional nonadherence. CONCLUSIONS: Medication nonadherence is common in Korean patients with RA. Less belief in necessity of medication and greater emotional response to disease were identified as key factors prompting intentional nonadherence. These factors may be strategically targeted to improve medication adherence rates and subsequent clinical outcomes.
29119481 Prevalence of rheumatoid cachexia assessed by bioelectrical impedance vector analysis and 2018 Mar Rheumatoid arthritis (RA) patients frequently have changes in their body composition, with a decrease in muscle mass and an increase in fat mass, a syndrome that is termed rheumatoid cachexia (RC). The prevalence of this nutritional alteration is not well known; there is as yet no consensus, seeing as it depends on the methods, techniques, and cutoff points that are used for its diagnosis. The main aim of this study was to identify RC through assessment by bioelectrical impedance vector analysis (BIVA) and its association with metabolic causes, physical function, and the main disease status, among others. The prevalence of RC was identified in those subjects who fell outside the right lower quadrant of the reference curve of RXc graph of BIVA. Clinical, anthropometric, biochemical and physical activity, emotional status, and diet markers were also evaluated. Ninety-four patients were included (92.55% women). The prevalence of RC assessed by BIVA was 21.28%. BIVA-cachexia patients had a lesser value of handgrip strength vs. patients without BIVA-cachexia 10.2 kg (7.2-13.4) vs. 14.7 kg (9.6-19), p = 0.0062. Disability and folic acid with methotrexate consumption are related to BIVA-cachexia ((OR 4.69, 95% CI 1.33, 16.54, p = 0.016) and (OR 0.19, 95%CI 0.058, 0.651, p = 0.008), respectively). BIVA could represent a valuable tool to assess presence of RC. It is important that RA patients have physical therapy to improve their nutritional status.
27775461 Effect of a treat-to-target strategy based on methotrexate and intra-articular betamethaso 2017 Sep OBJECTIVES: To investigate whether a treat-to-target strategy based on methotrexate (MTX) and intra-articular (IA) betamethasone suppresses magnetic resonance imaging (MRI)-determined measures of disease activity and reduces joint destruction in early rheumatoid arthritis (eRA) patients, and to investigate whether concomitant cyclosporin A (CyA) provides an additional effect. METHOD: In the 2-year randomized, double-blind, treat-to-target trial CIMESTRA, 160 patients with eRA (< 6 months) were randomized to MTX, intra-articular betamethasone and CyA, or placebo CyA. A total of 129 patients participated in the MRI substudy, and had contrast-enhanced MR images of the non-dominant hand at months 0, 6, 12, and 24. MR images were evaluated for osteitis, synovitis, tenosynovitis, bone erosion, and joint space narrowing (JSN), using validated scoring methods. RESULTS: Significant reductions were seen at 6 months in all inflammatory parameters [synovitis, mean change -1.6 (p < 0.001, Wilcoxon), tenosynovitis, -3.5 (p < 0.001), and osteitis, -1.3 (p < 0.05)] and at 12/24 months in synovitis and tenosynovitis [-1.6/-2.2 and -3.6/-3.8, respectively; all p < 0.001]. MRI signs of inflammation were not fully eliminated, and increases in erosion and JSN scores were observed at 6 months [0.4 (p < 0.01)/0.1 (p < 0.05)], 12 months [0.8 (p < 0.001)/0.3 (p < 0.01)], and 24 months [1.0 (p < 0.001)/0.4 (p < 0.001)]. Clinical measures decreased significantly (p < 0.001) at all time points. There were no consistent statistically significant differences between treatment groups. CONCLUSIONS: In this eRA treat-to-target trial, MTX and intra-articular glucocorticoids markedly reduced, but did not eliminate, MRI osteitis, synovitis, and tenosynovitis. Accordingly, minimal but statistically significant increases in bone erosion and JSN were observed. No additional effect of CyA was demonstrated.
28756532 Etanercept is effective as monotherapy or in combination with methotrexate in rheumatoid a 2017 Sep Approximately 30% of patients with rheumatoid arthritis receiving biological disease-modifying antirheumatic drugs (bDMARDs) take them as monotherapy. Although etanercept (ETN) monotherapy has been evaluated in clinical trials, data in the real-world setting are sparse. We compared the efficacy and safety of ETN, given alone or in combination with methotrexate (MTX), in routine clinical practice. This was a subanalysis of patients who received either ETN alone or ETN + MTX during a 52-week prospective, observational study conducted at 329 German centers. The primary endpoint was "Funktionsfragebogen Hannover" (Hannover Functional Ability Questionnaire [FFbH]; low FFbH = worse function) functional remission at week 26 and week 52. Secondary endpoints included the 28-joint count Disease Activity Score (DAS28), DAS28 remission (DAS28 < 2.6), and adverse events (AEs). Participating centers applied ETN monotherapy in 43.1% of patients and ETN + MTX in 56.9%. A smaller proportion of patients achieved FFbH functional remission with ETN vs ETN + MTX (31.9%, 95% confidence interval [CI] 29.1-34.9% vs 39.8%, 37.2-42.5%, respectively; p < 0.001) at 26 weeks and at 52 weeks (38.4%, 35.1-41.7% vs 44.3%, 41.5-47.2%, respectively; p = 0.007). After 52 weeks, the mean DAS28 (±SD) decreased from 5.5 ± 1.3 to 3.4 ± 1.4 (ETN) vs 5.3 ± 1.3 to 3.2 ± 1.3 (ETN + MTX) and DAS28 remission was achieved by 32.5% (95% CI 29.0-36.1%) of patients with ETN vs 38.8% (35.8-41.9%; p = 0.007) with ETN + MTX. Overall, 20.6 (ETN) and 19.7% (ETN + MTX) of patients reported treatment-related AEs. Patients received ETN monotherapy almost as often as ETN + MTX. ETN + MTX appeared marginally more effective than ETN monotherapy in some, but not all, outcomes measured.
28972441 Efficacy and safety of infliximab: A comparison with other biological disease-modifying an 2018 Jul OBJECTIVES: The intensification of infliximab (IFX) treatment, involving escalation of the dose and shortening of interval, was approved in Japan in July 2009. We consider IFX intensification therapy to be preferable for patients with treatment-resistant active rheumatoid arthritis (RA). We retrospectively compared the efficacy of IFX with that of other bDMARDs in methotrexate (MTX)-resistant patients. METHODS: Patients who satisfied the following criteria were enrolled: (i) those who started bDMARDs between February 2011 and December 2016, and (ii) those who required bDMARDs after 180 d of MTX treatment. We compared 33 patients who had been treated with IFX (IFX group) and 146 who had received other bDMARDs treatment (non-IFX group). RESULTS: IFX was administered at a dose of 6.98 mg/kg/8-week equivalent at 52 weeks. Clinical disease activity index clinical remission (CDAI-CR) was achieved in 49 of the 179 patients at 52 weeks and 13 of these 49 patients received IFX. Logistic regression analysis showed that treatment with IFX was an important variable for the achievement of CDAI-CR at 52 weeks (odds ratio 2.69, 95% confidence interval 1.13-6.42). The severity and frequency of adverse events did not differ. CONCLUSION: Intensification of IFX was effective and well tolerated for MTX resistant patients.
28214596 Early non-response to certolizumab pegol in rheumatoid arthritis predicts treatment failur 2018 Jan OBJECTIVES: To compare different early clinical criteria of non-response determined at three months as predictors of clinical failure at one year in patients with rheumatoid arthritis starting therapy with certolizumab pegol. METHODS: Data were derived from a randomised Phase III clinical trial in patients with rheumatoid arthritis who failed to respond to methotrexate monotherapy. Patients included in this post-hoc analysis were treated with certolizumab pegol (400mg qd reduced to 200mg qd after one month) and with methotrexate. The study duration was twelve months. Response at three months was determined with the American College of Rheumatology-50, Disease Assessment Score-28 ESR, Health Assessment Questionnaire and the Clinical Disease Activity Index. The performance of these measures at predicting treatment failure at twelve months defined by the American College of Rheumatology-50 criteria was determined, using the positive predictive values as the principal evaluation criterion. RESULTS: Three hundred and eighty two patients were available for analysis and 225 completed the twelve-month follow-up. At Week 52, 149 (38.1%) patients met the American College of Rheumatology-50 response criterion. Positive predictive values ranged from 81% for a decrease in Health Assessment Questionnaire- Disability index score since baseline >0.22 to 95% for a decrease in Disease Assessment Score-28 score since baseline≥1.2. Sensitivity was≤70% in all cases. Performance of these measures was similar irrespective of the definition of treatment failure at 12months. CONCLUSIONS: Simple clinical measures of disease activity can predict future treatment failure reliably and are appropriate for implementing treat-to-target treatment strategies in everyday practice.
29142030 Plasma MicroRNA Profiles in Patients with Early Rheumatoid Arthritis Responding to Adalimu 2018 Jan OBJECTIVE: The aim was to identify plasma (i.e., cell-free) microRNA (miRNA) predicting antitumor necrosis and/or methotrexate (MTX) treatment response in patients enrolled in an investigator-initiated, prospective, double-blinded, placebo-controlled trial (The OPERA study, NCT00660647). METHODS: We included 180 disease-modifying antirheumatic drug-naive patients with early rheumatoid arthritis (RA) randomized to adalimumab (ADA; n = 89) or placebo (n = 91) in combination with MTX. Plasma samples before and 3 months after treatment initiation were analyzed for 91 specific miRNA by quantitative reverse transcriptase-polymerase chain reaction on microfluidic dynamic arrays. A linear mixed-effects model was used to test for associations between pretreatment miRNA and changes in miRNA expression and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean (28 joints) remission at 3 and 12 months, applying false discovery rate correction for multiple testing. Using leave-one-out cross validation, we built predictive multivariate miRNA models and estimated classification performances using receiver-operating characteristics (ROC) curves. RESULTS: In the ADA group, a higher pretreatment level of miR-27a-3p was significantly associated with remission at 12 months. The level decreased in remitting patients between pretreatment and 3 months, and increased in nonremitting patients. No associations were found in the placebo group receiving only MTX. Two multivariate miRNA models were able to predict response to ADA treatment after 3 and 12 months, with 63% and 82% area under the ROC curves, respectively. CONCLUSION: We identified miR-27a-3p as a potential predictive biomarker of ACR/EULAR remission in patients with early RA treated with ADA in combination with MTX. We conclude that pretreatment plasma-miRNA profiles may be of predictive value, but the results need confirmation in independent cohorts.
27165179 Certolizumab pegol in combination with dose-optimised methotrexate in DMARD-naïve patient 2017 Jan OBJECTIVES: To assess the efficacy and safety of certolizumab pegol (CZP)+dose-optimised methotrexate (MTX) versus placebo (PBO)+dose-optimised MTX in inducing and sustaining clinical remission in DMARD-naïve patients with moderate-to-severe, active, progressive rheumatoid arthritis (RA), with poor prognostic factors over 52 weeks. METHODS: DMARD-naïve patients with ≤1 year of active RA were randomised (3:1) in a double-blind manner to CZP (400 mg Weeks 0, 2, 4, then 200 mg Q2W to Week 52)+MTX or PBO+MTX (the mean optimised-MTX dose=21 and 22 mg/week, respectively). Sustained remission (sREM) and sustained low disease activity (sLDA; DAS28(ESR)<2.6 and DAS28(ESR)≤3.2, respectively, at both Weeks 40 and 52) were the primary and secondary endpoints. RESULTS: Patients were randomised to CZP+MTX (n=660) and PBO+MTX (n=219). At Week 52, significantly more patients assigned to CZP+MTX compared with PBO+MTX achieved sREM (28.9% vs 15.0%, p<0.001) and sLDA (43.8% vs 28.6%, p<0.001). Inhibition of radiographic progression and improvements in physical functioning were significantly greater for CZP+MTX versus PBO+MTX (van der Heijde modified total Sharp score (mTSS) mean absolute change from baseline (CFB): 0.2 vs 1.8, p<0.001, rate of mTSS non-progressors: 70.3% vs 49.7%, p<0.001; least squares (LS) mean CFB in Health Assessment Questionnaire-Disability Index (HAQ-DI): -1.00 vs -0.82, p<0.001). Incidence of adverse events (AEs) and serious AEs was similar between treatment groups. Infection was the most frequent AE, with higher incidence for CZP+MTX (71.8/100 patient-years (PY)) versus PBO+MTX (52.7/100 PY); the rate of serious infection was similar between CZP+MTX (3.3/100 PY) and PBO+MTX (3.7/100 PY). CONCLUSIONS: CZP+dose-optimised MTX treatment of DMARD-naïve early RA resulted in significantly more patients achieving sREM and sLDA, improved physical function and inhibited structural damage compared with PBO+dose-optimised MTX. TRIAL REGISTRATION NUMBER: NCT01519791.
29134891 Efficacy and safety of baricitinib in Japanese patients with rheumatoid arthritis: Subgrou 2018 Jul OBJECTIVES: To evaluate efficacy/safety of baricitinib for rheumatoid arthritis (RA) in Japanese subpopulations from four phase 3 studies, and assess whether results in these subpopulations are consistent with the overall study populations. METHODS: Subgroup analyses (394 patients) of four phase 3 randomized controlled trials: RA-BEGIN [no or limited treatment with disease-modifying antirheumatic drugs (DMARDs)], RA-BEAM [inadequate response (IR) to methotrexate], RA-BUILD [IR to conventional synthetic DMARDs (csDMARDs)], and RA-BEACON (IR to tumor necrosis factor inhibitors receiving csDMARDs). RESULTS: For American College of Rheumatology 20% improvement (ACR20) response rate, Japanese patients receiving baricitinib 4-mg showed similar improvement compared to methotrexate at Week 24 (72 versus 69%; RA-BEGIN), and greater improvement compared with placebo at Week 12 (67 versus 34%; RA-BEAM). Japanese patients receiving baricitinib 4-mg also showed greater improvement compared with placebo at Week 12 in RA-BUILD and RA-BEACON. Across all studies, baricitinib was well-tolerated, with no deaths and one malignancy. In RA-BEGIN and RA-BEAM, herpes zoster rates were higher for Japanese patients than for overall populations; all events were mild/moderate. CONCLUSION: Data for baricitinib, with/without methotrexate, in Japanese subpopulations across all stages of the RA treatment continuum accord with the efficacy/safety profile in overall study populations. Baricitinib appears to be similarly effective in Japanese patients.
28461107 Tofacitinib attenuates arthritis manifestations and reduces the pathogenic CD4 T cells in 2017 Nov Rheumatoid arthritis (RA) is an autoimmune disease characterized by pronounced inflammation and leukocyte infiltration in affected joints. Tofacitinib is new agent, a selective inhibitor of Janus kinase (JAK) signaling pathways mediated by JAK1 and JAK3 and inhibits the key transcription factors STAT1 and STAT3. We investigated the action mechanisms of tofacitinib in rats with adjuvant-induced-arthritis (AIA). AIA-rats were treated orally with tofacitinib or with methotrexate. Arthritis severity and serum C-reactive protein (CRP) levels were evaluated, splenic cells were examined by flow cytometry and cytokines were analyzed by real-time PCR. Tofacitinib markedly reduced the clinical status of treated rats in comparison to control group. Reduced joints inflammation and down-regulated serum CRP levels reflected the clinical manifestations of the treated rats. Tofacitinib down-regulated significantly the frequency of CD4(+)IFN-γ(+) T cells and reduced IL-1β mRNA expression levels in the spleen of the treated rats. These results show that tofacitinib attenuated arthritis severity, modified splenic populations and cytokine imbalance.
28440680 Efficacy and safety of baricitinib in Japanese patients with active rheumatoid arthritis: 2018 Jan OBJECTIVES: The objective of this study is to evaluate the efficacy and safety of long-term (64 weeks; 52-week extension of a 12-week study) baricitinib treatment in Japanese patients with active rheumatoid arthritis (RA) despite methotrexate therapy. METHODS: Patients (N = 145) with active RA were randomized to placebo, 1mg, 2mg, 4mg, or 8mg baricitinib for the first 12 weeks. During the 52-week extension period, patients on 4mg or 8mg baricitinib remained on the same dose and all other patients were re-randomized to 4mg or 8mg baricitinib. Most patients on 8mg baricitinib were switched to 4mg by week 64 (protocol amendment); data analysis was based on the treatment group at the beginning of the extension period. RESULTS: Increases in the American College of Rheumatology (ACR) response rates (ACR20, ACR50, and ACR70) observed during the first 12 weeks were maintained during the extension period, accompanied by improvements in ACR core components. At week 64, a large proportion of patients (>40%) had low disease activity. Most treatment-related adverse events were mild or moderate; herpes zoster was the most common reason (11/27 patients) for discontinuation. CONCLUSIONS: The efficacy and safety profile of baricitinib was maintained during long-term treatment of Japanese patients with RA and background methotrexate therapy. Clinicaltrials.gov NCT01469013; Funding: Eli Lilly and Incyte.
28213566 A randomised phase IIb study of mavrilimumab, a novel GM-CSF receptor alpha monoclonal ant 2017 Jun OBJECTIVES: Despite the therapeutic value of current rheumatoid arthritis (RA) treatments, agents with alternative modes of action are required. Mavrilimumab, a fully human monoclonal antibody targeting the granulocyte-macrophage colony-stimulating factor receptor-α, was evaluated in patients with moderate-to-severe RA. METHODS: In a phase IIb study (NCT01706926), patients with inadequate response to ≥1 synthetic disease-modifying antirheumatic drug(s), Disease Activity Score 28 (DAS28)-C reactive protein (CRP)/erythrocyte sedimentation rate ≥3.2, ≥4 swollen joints despite methotrexate (MTX) were randomised 1:1:1:1 to subcutaneous mavrilimumab (150, 100, 30 mg), or placebo every other week (eow), plus MTX for 24 weeks. Coprimary outcomes were DAS28-CRP change from baseline to week 12 and American College of Rheumatology (ACR) 20 response rate (week 24). RESULTS: 326 patients were randomised (150 mg, n=79; 100 mg, n=85; 30 mg, n=81; placebo, n=81); 305 completed the study (September 2012-June 2013). Mavrilimumab treatment significantly reduced DAS28-CRP scores from baseline compared with placebo (change from baseline (SE); 150 mg: -1.90 (0.14), 100 mg: -1.64 (0.13), 30 mg: -1.37 (0.14), placebo: -0.68 (0.14); p<0.001; all dosages compared with placebo).Significantly more mavrilimumab-treated patients achieved ACR20 compared with placebo (week 24: 73.4%, 61.2%, 50.6% vs 24.7%, respectively (p<0.001)). Adverse events were reported in 43 (54.4%), 36 (42.4%), 41 (50.6%) and 38 (46.9%) patients in the mavrilimumab 150, 100, 30 mg eow and placebo groups, respectively. No treatment-related safety signals were identified. CONCLUSIONS: Mavrilimumab significantly decreased RA disease activity, with clinically meaningful responses observed 1 week after treatment initiation, representing a novel mechanism of action with persuasive therapeutic potential. TRIAL REGISTRATION NUMBER: NCT01706926; results.
28728599 A phase III, randomized, two-armed, double-blind, parallel, active controlled, and non-inf 2017 Jul 20 BACKGROUND: This study aimed to compare efficacy and safety of test-adalimumab (CinnoRA®, CinnaGen, Iran) to the innovator product (Humira®, AbbVie, USA) in adult patients with active rheumatoid arthritis (RA). METHODS: In this randomized, double-blind, active-controlled, non-inferiority trial, a total of 136 patients with active RA were randomized to receive 40 mg subcutaneous injections of either CinnoRA® or Humira® every other week, while receiving methotrexate (15 mg/week), folic acid (1 mg/day), and prednisolone (7.5 mg/day) over a period of 24 weeks. Physical examinations, vital sign evaluations, and laboratory tests were conducted in patients at baseline and at 12-week and 24-week visits. The primary endpoint in this study was the proportion of patients achieving moderate and good disease activity score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR)-based European League Against Rheumatism (EULAR) response. The secondary endpoints were the proportion of patients achieving American College of Rheumatology (ACR) criteria for 20% (ACR20), 50% (ACR50), and 70% (ACR70) responses along with the disability index of health assessment questionnaire (HAQ), and safety. RESULTS: Patients who were randomized to CinnoRA® or Humira® arms had comparable demographic information, laboratory results, and disease characteristics at baseline. The proportion of patients achieving good and moderate EULAR responses in the CinnoRA® group was non-inferior to the Humira® group at 12 and 24 weeks based on both intention-to-treat (ITT) and per-protocol (PP) populations (all p values >0.05). No significant difference was noted in the proportion of patients attaining ACR20, ACR50, and ACR70 responses in the CinnoRA® and Humira® groups (all p values >0.05). Further, the difference in HAQ scores and safety outcome measures between treatment arms was not statistically significant. CONCLUSION: CinnoRA® was shown to be non-inferior to Humira® in terms of efficacy at week 24 with a comparable safety profile to the reference product. TRIAL REGISTRATION: IRCT.ir, IRCT2015030321315N1 . Registered on 5 April 2015.
28601838 Are dietary vitamin D, omega-3 fatty acids and folate associated with treatment results in 2017 Jun 10 BACKGROUND: Dietary intake of vitamin D and omega-3 fatty acids (FA) may be associated with superior response to antirheumatic treatments. In addition, dietary folate intake may be associated with worse response to methotrexate (MTX). The aim of this study was to investigate the association between dietary vitamin D, omega-3 FA, folate and treatment results of disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA). METHODS: This prospective study was based on data from the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study, and included 727 patients with early RA from 10 hospitals in Sweden. Data on dietary vitamin D, omega-3 FA and folate intake based on food frequency questionnaires were linked with data on European League Against Rheumatism (EULAR) response after 3 months of DMARD treatment. Associations between vitamin D, omega-3 FA, folate and EULAR response were analysed with logistic regression adjusted for potential confounders. RESULTS: The majority of patients (89.9%) were initially treated with MTX monotherapy and more than half (56.9%) with glucocorticoids. Vitamin D and omega-3 FA were associated with good EULAR response (OR 1.80 (95% CI 1.14 to 2.83) and OR 1.60 (95% CI 1.02 to 2.53), respectively). Folate was not significantly associated with EULAR response (OR 1.20 (95% CI 0.75 to 1.91)). Similar results were seen in a subgroup of patients who were initially treated with MTX monotherapy at baseline. CONCLUSIONS: Higher intake of dietary vitamin D and omega-3 FA during the year preceding DMARD initiation may be associated with better treatment results in patients with early RA. Dietary folate intake was not associated with worse or better response to treatment, especially to MTX. Our results suggest that some nutrients may be associated with enhanced treatment results of DMARDs.
28225768 Anti-rheumatic treatment is not associated with reduction of pentraxin 3 in rheumatoid art 2017 BACKGROUND: Pentraxin 3 is proposed to be a marker of inflammation and cardiovascular risk, but its role in inflammatory rheumatic diseases (IRDs) is still uncertain. Therefore, we wanted to examine if anti-rheumatic treatment reduced serum PTX3 (s-PTX3) levels in IRDs, and if s-PTX3 levels were related to other markers of inflammation and to endothelial function (EF). METHODS: We examined s-PTX3, EF and established inflammatory biomarkers in 114 IRD patients from the PSARA study before and after 6 weeks and 6 months of treatment with methotrexate (MTX) or anti-tumor necrosis factor alpha (anti-TNF) therapy with or without MTX co-medication. RESULTS: s-PTX3 levels in all IRD diagnoses were above the upper limit of the reference range. In contrast to established inflammatory markers, in particular CRP and ESR, s-PTX3 levels did not change significantly after 6 weeks and 6 months of anti-rheumatic therapy. There was no difference in change in s-PTX3 levels from baseline to 6 weeks and 6 months between MTX monotherapy and anti-TNF regimens. CRP, ESR and EF were not related to changes in s-PTX3 neither in crude nor adjusted analyses. CONCLUSION: IRD patients have increased s-PTX3 levels, which, in contrast to other inflammatory markers, do not seem to improve within 6 months of therapy with MTX and/or anti-TNF. Thus, s-PTX3 might reflect a persisting immune process, even a causal factor of inflammation, not inhibited by the standard anti-rheumatic treatment. Furthermore, even though s-PTX3 is thought to be a strong predictor of cardiovascular prognosis, it was not related to EF.