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ID PMID Title PublicationDate abstract
29404725 Comparison of the efficacy and tolerability of tocilizumab, sarilumab, and sirukumab in pa 2018 Jun The relative efficacy and tolerability of tocilizumab, sarilumab, and sirukumab were assessed in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) or tumor necrosis factor (TNF) inhibitors. We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of tocilizumab, sarilumab, and sirukumab in RA patients and an inadequate MTX or TNF inhibitor response. Fourteen RCTs, comprising 9753 patients, met the inclusion criteria. Tocilizumab 8 mg combined with MTX or as monotherapy was the most effective treatment for active RA with an inadequate MTX or TNF antagonist response, followed by sarilumab and sirukumab, regardless of MTX combination. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that tocilizumab 8 mg + MTX had the highest probability of being the best treatment to achieve the ACR50 response rate, followed by tocilizumab 8 mg, sarilumab 200 mg, sarilumab 200 mg + MTX, sirukumab 100 mg, tocilizumab 4 mg + MTX, sirukumab 100 mg + MTX, sirukumab 50 mg + MTX, sarilumab 150 mg + MTX, adalimumab 40 mg, and sirukumab 50 mg, and placebo + MTX. No significant differences were observed in withdrawals owing to adverse events after treatment with tocilizumab 8 mg + MTX, sirukumab 100 mg + MTX, or sarilumab 200 mg + MTX. In RA patients with an inadequate MTX or anti-TNF therapy response, tocilizumab 8 mg as monotherapy and combined with MTX showed acceptable tolerability and the highest performance based on the ACR50 response rate, followed by sarilumab and sirukumab.
30210123 An Analysis of the Biological Disease-modifying Antirheumatic Drug-free Condition of Adali 2019 Feb 15 Objectives The present study was performed with the aim of analyzing the biological disease-modifying antirheumatic drug (bDMARD)-free (Bio-free) condition of adalimumab (ADA)-treated rheumatoid arthritis (RA) patients in a real-world setting. Methods ADA was used in the treatment of 130 (male, n=21; female, n=109 females) RA patients. Among them, 26 patients (20.0%) discontinued ADA due to a good response. We analyzed 20 patients who were followed up for more than 6 months after the discontinuation of ADA. The Disease Activity Score 28 based on C-reactive protein (DAS28-CRP) and modified health assessment questionnaires (mHAQs) were evaluated. Results The mean age of the patients was 53.4±11.1 years. The mean disease duration was 4.5±4.3 years. Sixteen patients were bDMARD-naïve, while 4 switched from bDMARDs to ADA. At 6 months after the discontinuation ADA, 19 patients had achieved a clinical remission, and 1 had achieved a low disease activity. The Bio-free period was 26.4±15.5 months. The dose of prednisolone was significantly reduced from baseline (3.45±3.17 mg/day) at 6 months after the discontinuation of ADA (2.63±2.78 mg/day). The dose of methotrexate was unchanged. The number of conventional synthetic DMARDs (csDMARDs) was significantly increased (0.8±0.6 to 1.4±1.06). The mHAQ values were significantly ameliorated by ADA and remained good in patients with a Bio-free condition. A multivariate analysis showed that the dose of methotrexate (MTX) was an important factor for achieving a Bio-free condition. Conclusion A sustainable Bio-free condition in a real clinical setting can be achieved and may be a suitable way of reducing medical costs. The dose of MTX and the additional administration of csDMARDs is therefore thought to be important for ensuring a good outcome in these patients.
30005689 Prediction of primary non-response to methotrexate therapy using demographic, clinical and 2018 Jul 13 BACKGROUND: Methotrexate (MTX) remains the disease-modifying anti-rheumatic drug of first choice in rheumatoid arthritis (RA) but response varies. Predicting non-response to MTX could enable earlier access to alternative or additional medications and control of disease progression. We aimed to identify baseline predictors of non-response to MTX and combine these into a prediction algorithm. METHODS: This study included patients recruited to the Rheumatoid Arthritis Medication Study (RAMS), a UK multi-centre prospective observational study of patients with RA or undifferentiated polyarthritis, commencing MTX for the first time. Non-response to MTX at 6 months was defined as "no response" using the European League Against Rheumatism (EULAR) response criteria, discontinuation of MTX due to inefficacy or starting biologic therapy. The association of baseline demographic, clinical and psychosocial predictors with non-response was assessed using logistic regression. Predictive performance was assessed using the area under the receiver operating characteristic curve (AUC) and calibration plots. RESULTS: Of 1050 patients, 449 (43%) were classified as non-responders. Independent multivariable predictors of MTX non-response (OR (95% CI)) were rheumatoid factor (RF) negativity (0.62 (0.45, 0.86) for RF positivity versus negativity), higher Health Assessment Questionnaire score (1.64 (1.25, 2.15)), higher tender joint count (1.06 (1.02, 1.10)), lower Disease Activity score in 28 joints (0.29 (0.23, 0.39)) and higher Hospital Anxiety and Depression Scale anxiety score (1.07 (1.03, 1.12)). The optimism-corrected AUC was 0.74. CONCLUSIONS: This is the first model for MTX non-response to be developed in a large contemporary study of patients commencing MTX in which demographic, clinical and psychosocial predictors were considered. Patient anxiety was a predictor of non-response and could be addressed at treatment commencement.
29148403 Treatment patterns in rheumatoid arthritis after discontinuation of methotrexate: data fro 2018 Mar OBJECTIVES: In active rheumatoid arthritis (RA) patients with inadequate response to methotrexate (MTX), guidelines support adding or switching to another conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) and/or a biologic DMARD (bDMARD). The purpose of this analysis was to describe treatment practices in routine care and to evaluate determinants of regimen selection after MTX discontinuation. METHODS: Biologic-naïve patients in the Ontario Best Practice Research Initiatives registry discontinuing MTX due to primary/secondary failure, adverse events, or patient/physician decision were included. RESULTS: Of 313 patients discontinuing MTX, 102 (32.6%) were on MTX monotherapy, 156 (49.8%) on double, and 55 (17.6%) on multiple csDMARDs. Patients on MTX monotherapy were older than patients on double or multiple csDMARDs (p=0.013), less likely to have joint erosions (p=0.009) and had lower patient global assessment (p=0.046) at MTX discontinuation. Post-MTX discontinuation, 169 (54.0%) transitioned to, or added new DMARD(s) (new csDMARD(s): 139 [44.4%]; bDMARD: 30 [9.6%]), and 144 (46.0%) opted for no new DMARD treatment. Patients on MTX monotherapy transitioning monotherapy, whereas patients on combination csDMARDs switched more to new csDMARDs and bDMARD combination therapy. Early RA (adjOR [95%CI]: 3.07 [1.40-6.72]) and treatment with multiple csDMARDs vs. MTX monotherapy (4.15 [1.35-12.8]) at MTX discontinuation were significant predictors of transitioning to or adding new csDMARD(s)/bDMARD treatment versus opting for no new DMARD treatment. CONCLUSIONS: Differences in subsequent treatment patterns exist between patients discontinuing MTX when used as monotherapy versus in combination with other csDMARDs where the former are more likely to use a subsequent monotherapy treatment.
29566740 Effect of filgotinib, a selective JAK 1 inhibitor, with and without methotrexate in patien 2018 Mar 23 BACKGROUND: The aim was to assess patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA) treated with filgotinib during two phase 2b, 24-week, randomized, placebo-controlled studies. METHODS: Patients with moderate-to-severe active RA and an inadequate response to methotrexate (MTX) were randomized to daily placebo or filgotinib 50 mg, 100 mg, or 200 mg as add-on therapy to MTX (NCT01888874) or as monotherapy (NCT01894516). At week 12, nonresponders receiving filgotinib 50 mg in both studies or placebo in the add-on study, and all patients receiving placebo as monotherapy, were re-assigned to filgotinib 100 mg. PROs were measured using the Health Assessment Questionnaire - Disability Index (HAQ-DI) including Patient Pain assessed by visual analog scale, and the Patient Global Assessment of Disease Activity (Patient Global), the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale (Version 4), and the 36-Item Short Form Health Survey (SF-36). RESULTS: At week 12, improvements in all PROs, apart from the SF-36 mental component in the add-on study, were statistically better with filgotinib than placebo; some improvements were noted as early as the first assessment time point (week 1 or week 4). Filgotinib improved HAQ-DI by 0.58-0.84 points, FACIT-Fatigue by 6.9-11.4 points, Patient Global by 25.2-35.6 mm, and Pain by 24.2-37.9 mm; scores were maintained or improved to week 24. Across all PROs, more patients achieved minimal clinically important differences and normative values with filgotinib 200 mg than placebo. Patients re-assigned to filgotinib 100 mg at week 12 experienced improvements in PROs between weeks 12 to 24. CONCLUSIONS: Filgotinib as MTX add-on therapy or as monotherapy demonstrated rapid and sustained (to 24 weeks) improvements in health-related quality of life and functional status in patients with active RA. TRIAL REGISTRATION: MTX add-on study: ClinicalTrials.gov , NCT01888874 . Registered on 28 June 2013. Monotherapy study: ClinicalTrials.gov , NCT01894516 . Registered on 10 July 2013.
29900829 Alternative tumour necrosis factor inhibitors (TNFi) or abatacept or rituximab following f 2018 Jun BACKGROUND: Rheumatoid arthritis (RA), the most common autoimmune disease in the UK, is a chronic systemic inflammatory arthritis that affects 0.8% of the UK population. OBJECTIVES: To determine whether or not an alternative class of biologic disease-modifying antirheumatic drugs (bDMARDs) are comparable to rituximab in terms of efficacy and safety outcomes in patients with RA in whom initial tumour necrosis factor inhibitor (TNFi) bDMARD and methotrexate (MTX) therapy failed because of inefficacy. DESIGN: Multicentre, Phase III, open-label, parallel-group, three-arm, non-inferiority randomised controlled trial comparing the clinical and cost-effectiveness of alternative TNFi and abatacept with that of rituximab (and background MTX therapy). Eligible consenting patients were randomised in a 1 : 1 : 1 ratio using minimisation incorporating a random element. Minimisation factors were centre, disease duration, non-response category and seropositive/seronegative status. SETTING: UK outpatient rheumatology departments. PARTICIPANTS: Patients aged ≥ 18 years who were diagnosed with RA and were receiving MTX, but had not responded to two or more conventional synthetic disease-modifying antirheumatic drug therapies and had shown an inadequate treatment response to a first TNFi. INTERVENTIONS: Alternative TNFi, abatacept or rituximab (and continued background MTX). MAIN OUTCOME MEASURES: The primary outcome was absolute reduction in the Disease Activity Score of 28 joints (DAS28) at 24 weeks post randomisation. Secondary outcome measures over 48 weeks were additional measures of disease activity, quality of life, cost-effectiveness, radiographic measures, safety and toxicity. LIMITATIONS: Owing to third-party contractual issues, commissioning challenges delaying centre set-up and thus slower than expected recruitment, the funders terminated the trial early. RESULTS: Between July 2012 and December 2014, 149 patients in 35 centres were registered, of whom 122 were randomised to treatment (alternative TNFi, n = 41; abatacept, n = 41; rituximab, n = 40). The numbers, as specified, were analysed in each group [in line with the intention-to-treat (ITT) principle]. Comparing alternative TNFi with rituximab, the difference in mean reduction in DAS28 at 24 weeks post randomisation was 0.3 [95% confidence interval (CI) -0.45 to 1.05] in the ITT patient population and -0.58 (95% CI -1.72 to 0.55) in the per protocol (PP) population. Corresponding results for the abatacept and rituximab comparison were 0.04 (95% CI -0.72 to 0.79) in the ITT population and -0.15 (95% CI -1.27 to 0.98) in the PP population. General improvement in the Health Assessment Questionnaire Disability Index, Rheumatoid Arthritis Quality of Life and the patients' general health was apparent over time, with no notable differences between treatment groups. There was a marked initial improvement in the patients' global assessment of pain and arthritis at 12 weeks across all three treatment groups. Switching to alternative TNFi may be cost-effective compared with rituximab [incremental cost-effectiveness ratio (ICER) £5332.02 per quality-adjusted life-year gained]; however, switching to abatacept compared with switching to alternative TNFi is unlikely to be cost-effective (ICER £253,967.96), but there was substantial uncertainty in the decisions. The value of information analysis indicated that further research would be highly valuable to the NHS. Ten serious adverse events in nine patients were reported; none were suspected unexpected serious adverse reactions. Two patients died and 10 experienced toxicity. FUTURE WORK: The results will add to the randomised evidence base and could be included in future meta-analyses. CONCLUSIONS: How to manage first-line TNFi treatment failures remains unresolved. Had the trial recruited to target, more credible evidence on whether or not either of the interventions were non-inferior to rituximab may have been provided, although this remains speculative. TRIAL REGISTRATION: Current Controlled Trials ISRCTN89222125 and ClinicalTrials.gov NCT01295151. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 34. See the NIHR Journals Library website for further project information.
30504508 Associations Between Methotrexate Use and the Risk of Cardiovascular Events in Patients wi 2019 May OBJECTIVE: We evaluated the associations between time-varying methotrexate (MTX) use and risk of cardiovascular events (CVE) in patients with rheumatoid arthritis (RA). METHODS: We studied an inception cohort of 23,994 patients with RA diagnosed after their 65th birthday. Multivariable Cox regression models were fit to evaluate the associations between time-varying MTX use, controlling for other risk factors, and time to CVE. Alternative models assessed the cumulative duration of MTX use over the (1) first year, (2) previous year (recent use), and (3) entire duration of followup. We also assessed whether the strength of the association varied over time. RESULTS: Over 115,453 patient-years (PY), 3294 (13.7%) patients experienced a CVE (28.5 events per 1000 PY; 95% CI 27.6-29.5). In the multivariable analyses, the model assessing time-varying continuous use in the most recent year yielded the best fit. Increasing recent MTX use was associated with lower CVE risks (HR 0.79 for continuous use vs no use in past 12 months, 95% CI 0.70-0.88; p < 0.0001). Greater MTX use in the first year after cohort entry was also protective (HR 0.84, 95% CI 0.72-0.96; p = 0.0048), but this effect decreased with increasing followup. In contrast, longer MTX use during the entire followup was not clearly associated with CVE risk (HR 0.98, 95% CI 0.95-1.01; p = 0.1441). CONCLUSION: We observed about a 20% decrease in CVE associated with recent continuous MTX use. Greater MTX use in the first year of cohort entry also appeared to be important in the association between MTX and CVE risk.
28448195 Design characteristics of the Corrona Japan rheumatoid arthritis registry. 2018 Jan OBJECTIVES: The primary objective is to prospectively study the comparative safety and effectiveness of older and newer classes of nonbiologic DMARDs (Disease-modifying antirheumatic drugs), biologic DMARDs and targeted synthetic therapies approved for rheumatoid arthritis (RA) in a real-world patient population in Japan. METHODS: Prospective, multicenter, noninterventional, observational study across geographic distribution of both private and public institutions for patients with RA who are newly prescribed one of the following medications: (1) methotrexate; (2) anti-TNF biologic DMARDs; (3) non-TNF biologic DMARDs; and (4) approved JAK inhibitors at the time of enrollment into the registry. Target enrollment is currently 2000 subjects. Baseline and follow-up data on patient demographics, medical history, disease activity, laboratory results, comorbidities, hospitalizations, and targeted safety events are obtained via Physician and Patient Questionnaires. RESULTS: Fifty sites are anticipated to participate with 40 sites ethics committee (EC) approved at the time of submission consisting of 23% clinics, 21% private academic hospitals, 29% private mid-sized to large hospitals, 15% national academic hospitals, and 12% national hospitals. CONCLUSION: The Corrona Japan RA Registry will provide real-world evidence from both private and public institutions on the comparative effectiveness and safety of recently approved RA therapies in Japan.
30426454 Losartan suppresses the inflammatory response in collagen-induced arthritis by inhibiting 2019 Jun The angiotensin II type 1 receptor (AT1R) antagonist losartan has been confirmed to have a moderate anti-inflammatory effect in vitro and in vivo. However, how it affects immune cells in Rheumatoid Arthritis (RA) is still unknown. We found that in human synovial tissues, AT1R is significantly expressed on T cells and B cells. Treatment with losartan (15 mg/kg) alone and in combination with a low dose of methotrexate (MTX 0.25 mg/kg/3 days) significantly suppressed the progression of CIA. Secondary paw swelling, joint destruction and the presence of pro-inflammatory cytokines (TNF-α and IFN-γ) in the serum were alleviated after treatment. The therapeutic effects of losartan were based on reduced T-cell and B-cell activation, specifically by decreased cell vitality and pro-inflammatory cytokine production. In addition, losartan combined with a low dose of MTX achieved a similar therapeutic effect, while protecting liver and kidney from MTX damage. Mechanistically, losartan inhibits the production of pro-inflammatory mediators, reduces the phosphorylation of p38, ERK, and p65, p50 nuclear transposition in T cells and B cells. Phosphorylation of JNK is not affected by losartan in the CIA rat model. losartan can be used as an effective RA treatment, which exhibits anti-arthritic effects potentially through down-regulating the phosphorylation of p38, ERK and signaling through NF-κB. While achieving similar anti-rheumatic effects, a combination therapy of losartan with a low dose of MTX, can protect from liver and renal damage caused by giving a high dose of MTX.
30641538 Determinants of non-nociceptive pain in Rheumatoid Arthritis. 2018 Oct INTRODUCTION: Features suggestive of neuropathic pain (NP) have been described in RA in addition to nociceptive pain. We aimed to determine the clinical predictors of NP in RA patients and study its association with radiographic structural damage. METHODS: Cross-sectional study was performed with RA patients followed at our Rheumatology department. Patients with diagnosed neuropathy of other origin, non-RA related risk factors for NP (e.g. diabetes mellitus) or fibromyalgia according to expert opinion were excluded. Demographic and clinical data were collected and disease activity/functional measures were evaluated. Two questionnaires were applied to assess NP: the Leeds Assessment of Neuropathic Symptoms (LANSS) and the painDETECT questionnaire (PDQ). Radiographs performed in up to 12 months before/after the evaluation were classified according to the modified van der Heijde Sharp´s method. Univariate and multivariate logistic regression were performed to identify the predictors of NP. RESULTS: 112 patients were included. 86 (77%) were women, with a mean (SD) age of 55.1 (10.8) years and median disease duration of 13 [2-41] years. 45 (40%) patients had NP by the LANSS (≥12) and 28% had a possible/likely NP in the PDQ (≥13). Female sex was predictive of NP by both tests and disease duration was inversely associated with LANSS NP. After adjusting for those two variables, pain VAS and TJC were positive predictors of NP by both tests. The same was not true for SJC, ESR or CRP levels. DAS28-CRP was significantly associated with PDQ NP, losing its statistical significance after adjustment for TJC and pain VAS. The HAQ score increased the odds of NP for both tests, independently of DAS 28-CRP. Positivity for ACPA and previous/current hydroxychloroquine treatment had lower odds of NP. 90 patients performed radiographic evaluation. Joint narrowing score was a significant negative predictor of LANSS NP. After adjusting for global radiographic score, current methotrexate treatment had lower odds of LANSS NP and previous/current leflunomide was a positive predictor of NP by both tests. CONCLUSION: NP was associated with disease activity/functional scores but not with objective inflammatory measures. Greater structural damage, increased disease duration and ACPA positivity did not seem to increase the odds of NP. Possible association of NP and underlying csDMARD treatment was uncovered.
29294598 Rapid onset of efficacy predicts response to therapy with certolizumab plus methotrexate i 2018 Nov BACKGROUND/AIMS: The objective of this study was to determine the efficacy and safety of add-on therapy with certolizumab pegol (CZP) in active rheumatoid arthritis (RA) patients of a single ethnicity. METHODS: In this 24-week, phase 3, randomized, double-blind, placebo-controlled trial, eligible patients (n = 127) were randomized 2:1 to subcutaneous CZP + methotrexate (MTX; 400 mg at week 0, 2, and 4 followed by 200 mg every 2 weeks) or placebo + MTX. RESULTS: At week 24, the American College of Rheumatology criteria for 20% (ACR20) response rate was significantly greater with CZP + MTX than with placebo (66.7% vs. 27.5%, p < 0.001). Differences in ACR20 response rates for CZP vs. placebo were significant from week 1 (p < 0.05) and remained significant through week 24. The CZP group reported significant improvement in physical function and disability compared to the placebo group (p < 0.001) at week 24, as assessed by Korean Health Assessment Questionnaire-Disability Index (KHAQ-DI). Post hoc analysis indicated that the proportion of patients who had ACR70 responses, Disease Activity Score 28 (DAS28) low disease activity, and DAS28 remission at week 24 was greater in CZP + MTX-treated patients who achieved a decrease in DAS28 ≥ 1.2 (43.8%) at week 4 than in nonresponders. Among 18 (22.2%) and 14 patients (35.0%) in CZP and placebo groups who had latent tuberculosis (TB), none developed active TB. Most adverse events were mild or moderate. CONCLUSION: CZP treatment combined with MTX in active RA patients with moderate to severe disease activity and an inadequate response to MTX resulted in rapid onset of efficacy, which is associated with better clinical outcome at week 24 and has an acceptable safety profile, especially in an intermediate TB-burden population.
29264637 Outcomes after rheumatoid arthritis patients complete their participation in a long-term o 2018 Apr To describe disease activity and disability during the first year of follow-up, from rheumatoid arthritis (RA) patients who discontinue tofacitinib after they end participation in a clinical trial. From 2008 to 2016, 36 patients were enrolled in the "Long term follow-up study with tofacitinib (and methotrexate) for RA treatment". At the end of the study, tofacitinib was discontinued and patients were proposed to enter an observational study; 35 agree and had scheduled evaluations at baseline, at 15 and 30 days of follow-up, at month 2 and 3, and thereafter every 3 months. Disease activity was evaluated as per DAS28-ESR and disability as per HAQ. During follow-up, treatment was treat-to-target oriented, only conventional DMARDs were indicated. Descriptive statistics and nonparametric test were used. The study was approved by IRB. Patients were primarily females (N = 34), had median (Q25-75) age of 52 years (45-58), and had received tofacitinib for a median of 7.9 years (6.3-8.3). The proportion of patients with remission and low disease activity decreased from day 30 of follow-up and recovered after 270 days, meanwhile patients with high disease activity increased from 0% at baseline to 6.3% at 1 year. At study entry, 20 patients had remission/low disease activity; during follow-up, 85% deteriorated after (median) 30 days; among them, 23.5% recovered their baseline status after a median of 172.5 days. The HAQ showed a similar behavior, but 66.7% recovered. A substantial proportion of RA patients deteriorated outcomes early after tofacitinib cessation; some patients recovered baseline status with traditional DMARDS.
29043871 A review of sarilumab for the treatment of rheumatoid arthritis. 2018 Jan Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease predominantly affecting the peripheral diarthrodial joints. Sarilumab is a human monoclonal antibody against the IL-6 receptor-α. In Phase II and III clinical trials, sarilumab in the background of methotrexate showed superior clinical efficacy over placebo in RA patients with inadequate response to methotrexate or inadequate response or intolerance to TNF inhibitors. Sarilumab monotherapy also showed superior efficacy compared with adalimumab monotherapy in RA patients with inadequate response or intolerance to methotrexate. For safety, injection site reaction, neutropenia and elevation of liver enzymes and serum cholesterol were more commonly observed with sarilumab than with placebo. Overall, sarilumab is expected to serve as another useful antirheumatic drug against active RA.
29764965 Effect of Treat-to-target Strategies Aiming at Remission of Arterial Stiffness in Early Rh 2018 Aug OBJECTIVE: To determine the efficacy of 2 tight control treatment strategies aiming at Simplified Disease Activity Score (SDAI) remission (SDAI ≤ 3.3) compared to 28-joint count Disease Activity Score (DAS28) remission (DAS28 < 2.6) in the prevention of arterial stiffness in patients with early rheumatoid arthritis (RA). METHODS: This was an open-label study in which 120 patients with early RA were randomized to receive 1 year of tight control treatment. Group 1 (n = 60) aimed to achieve SDAI ≤ 3.3 and Group 2 (n = 60), DAS28 < 2.6. Pulse wave velocity (PWV) and augmentation index (AIx) were measured at baseline and 12 months. A posthoc analysis was also performed to ascertain whether achieving sustained remission could prevent progression in arterial stiffness. RESULTS: The proportions of patients receiving methotrexate monotherapy were significantly lower in Group 1 throughout the study period. At 12 months, the proportions of patients achieving DAS28 and SDAI remission, and the change in PWV and AIx, were comparable between the 2 groups. In view of the lack of differences between the 2 groups, a posthoc analysis was performed at Month 12, including all 110 patients with PWV, to elucidate the independent predictors associated with the change in PWV. Multivariate analysis revealed that achieving sustained DAS28 remission at months 6, 9, and 12 and a shorter disease duration were independent explanatory variables associated with less progression of PWV. CONCLUSION: With limited access to biologic disease-modifying antirheumatic drugs, treatment efforts toward DAS28 and SDAI remission had similar effects in preventing the progression of arterial stiffness at 1 year. However, achieving sustained DAS28 remission was associated with a significantly greater improvement in PWV. [Clinical Trial registration: Clinicaltrial.gov NCT01768923.].
30565876 Association between cumulative methotrexate dose, non-invasive scoring system and hepatic 2019 Feb BACKGROUND: Methotrexate (MTX) is recommended by recent American College of Rheumatology and European League against Rheumatism guidelines as a first-line drug for rheumatoid arthritis (RA). Liver fibrosis, which occurs as a long-term side effect is of major concern. Monitoring aminotransferase and albumin is suggested in the guidelines, unfortunately this method is unreliable for detecting liver fibrosis. We try to find the association between clinical parameters, cumulative MTX dosage, liver fibrosis scoring systems and the presence of liver fibrosis assessed by transient elastography (TE; Fibroscan®). METHOD: Rheumatoid arthritis patients prescribed MTX were evaluated for liver fibrosis with TE. Two subgroups of patients were compared: non-fibrosis and fibrosis (TE > 7 kPa). Univariate and multivariate logistic regression analysis was performed to identify factors associated with liver fibrosis. RESULTS: One hundred and eight patients were recruited. Twenty-nine patients (26.8%) were classified by transient elastography as liver fibrosis cases. The multivariate analysis demonstrated statistical significance only in the association of body mass index (odds ratio [OR] = 1.22; 95% CI 1.05-1.41; P = 0.01); fatty liver (OR = 2.32; 95% CI 1.58-9.19; P = 0.02); alanine transaminase (OR = 1.04; 95% CI 1.02-1.09; P = 0.04) and cumulative MTX dosage (OR = 1.03; 95% CI 1.01-1.04; P = 0.001). CONCLUSIONS: Liver fibrosis measured with Fibroscan was associated with cumulative MTX. RA patients with metabolic syndrome including high body mass index and fatty liver, had a higher risk of MTX-induced hepatic fibrosis. RA patients with high cumulative MTX dose, especially patients with concurrent metabolic syndrome, should be cautiously monitored for liver fibrosis.
28324148 Comparative efficacy and tolerability of sarilumab 150 and 200 mg in patients with activ 2018 Jun OBJECTIVE: This study aimed to assess the relative efficacy and tolerability of every other week (q2w) dosing of sarilumab 150 and 200 mg in patients with active rheumatoid arthritis (RA). METHODS: In this network meta-analysis, randomized controlled trials (RCTs) examining the efficacy and tolerability of sarilumab in patients with active RA were included. A Bayesian network meta-analysis was conducted to combine the direct and indirect evidence from the RCTs. RESULTS: Four RCTs, involving 2667 patients, met the inclusion criteria. The American College of Rheumatology (ACR)50 response rate was significantly higher in the sarilumab 200 mg and sarilumab 200 mg + methotrexate (MTX) groups than in the placebo + MTX group (odds ratio, OR, of 4.05, 95% credible interval, CrI, of 2.04-8.33 and OR of 3.75, 95% CrI of 2.37-5.72, respectively). Compared to the placebo + MTX group, the sarilumab 150 mg + MTX and adalimumab 40 mg groups showed a significantly higher ACR50 response rate. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that sarilumab 200 mg was likely to achieve the best ACR50 response rate (SUCRA = 0.8518), followed by sarilumab 200 mg + MTX (SUCRA = 0.8225), sarilumab 150 mg + MTX (SUCRA = 0.5112), adalimumab 40 mg (SUCRA = 0.3072), and placebo + MTX (SUCRA = 0.0072). The ACR50 and ACR70 response rate distributions were comparable, except that sarilumab 200 mg + MTX was likely to achieve the best ACR70 response rate. The tolerability based on the number of patient withdrawals due to adverse events (AEs) did not differ significantly between the treatments, except that placebo + MTX was likely to be the best tolerated. CONCLUSION: Sarilumab 150 and 200 mg are efficacious treatments for active RA and are well tolerated.
29514803 Similar efficacy, safety and immunogenicity of adalimumab biosimilar BI 695501 and Humira 2018 Jun OBJECTIVE: To demonstrate clinical equivalence of adalimumab biosimilar candidate BI 695501 with Humira. METHODS: Patients with active rheumatoid arthritis on stable methotrexate were randomised to BI 695501 or Humira in a double-blind, parallel-group, equivalence study. At week 24, patients were rerandomised to continue BI 695501 or Humira, or switch from Humira to BI 695501. The coprimary endpoints were the percentage of patients achieving the American College of Rheumatology 20% response criteria (ACR20) at weeks 12 and 24. Further efficacy and safety endpoints and immunogenicity were assessed up to week 58. RESULTS: 645 patients were randomised. At week 12, 67.0% and 61.1% (90% CI -0.9 to 12.7) of patients receiving BI 695501 (n=324) and Humira (n=321), respectively, achieved ACR20; at week 24 the corresponding values were 69.0% and 64.5% (95% CI -3.4 to 12.5). These differences were within prespecified margins (week 12: 90% CI (-12% to 15%); week 24: 95% CI (-15% to 15%)), demonstrating therapeutic bioequivalence. 593 patients were rerandomised at week 24. Up to week 48, mean change from baseline in Disease Activity Score 28-erythrocyte sedimentation rate and ACR20/ACR50/ACR70 response rates were similar across the switched (n=147), continuous BI 695501 (n=298) and continuous Humira (n=148) groups. Similar immunogenicity (antidrug antibodies (ADAs), ADA titres and neutralising antibodies) was seen between BI 695501 and Humira (to week 24) and across rerandomised groups (to week 48). Safety and tolerability profiles were similar between groups. CONCLUSIONS: BI 695501 demonstrated similar efficacy, safety and immunogenicity to Humira; switch from Humira to BI 695501 had no impact on efficacy, safety and immunogenicity. TRIAL REGISTRATION NUMBER: NCT02137226, Results.
29618584 Leflunomide Increases Hepatic Exposure to Methotrexate and Its Metabolite by Differentiall 2018 Jun Methotrexate (MTX) is the gold standard drug for the treatment of rheumatoid arthritis (RA), and it is frequently combined with leflunomide (LEF) to enhance its clinical efficacy. However, this combination can exacerbate liver toxicity, and the underlying mechanism has not yet been clarified. We investigated whether LEF affects the pharmacokinetics of MTX and its primary toxic metabolite, 7-hydroxyl methotrexate (7OH MTX), in mice. LEF significantly increased the plasma concentration (area under the plasma concentration-time curve) of MTX and 7OH MTX (2.4 and 4.5 times, respectively), decreased their bile excretion, and increased their accumulation in the liver and kidneys. When we investigated the effect of LEF on the MTX absorption, distribution, metabolism, and excretion process, we found that LEF had little effect on liver aldehyde oxidase and 7OH MTX formation. However, LEF significantly decreased the expression of the apical efflux transporter multidrug resistance-associated protein 2 (Mrp2) and increased that of the basolateral efflux transporters Mrp3/4, except there was no significant change in Mrp4 protein expression. Mrp2/3/4 alteration changed the distribution of MTX and 7OH MTX in plasma and tissues. Further studies suggested that LEF indirectly activated peroxisome proliferator-activated receptor α (PPARα), which was likely responsible for the Mrp2/3/4 alteration in the liver. The MTX plasma concentration change induced by LEF was reversed by the PPARα-specific antagonist GW6471. These results may partially explain the exacerbated liver toxicity caused by combination treatment with MTX and LEF and may raise concerns regarding the risk of potential drug-drug interactions between PPARα agonists and Mrp substrates in the clinic.
30532219 Development and validation of a prognostic multivariable model to predict insufficient cli 2018 OBJECTIVE: The objective was to predict insufficient response to 3 months methotrexate (MTX) in DMARD naïve rheumatoid arthritis patients. METHODS: A Multivariable logistic regression model of rheumatoid arthritis patients starting MTX was developed in a derivation cohort with 285 patients starting MTX in a clinical multicentre, stratified single-blinded trial, performed in seven secondary care clinics and a tertiary care clinic. The model was validated in a validation cohort with 102 patients starting MTX at a tertiary care clinic. Outcome was insufficient response (disease activity score (DAS)28 >3.2) after 3 months of MTX treatment. Clinical characteristics, lifestyle variables, genetic and metabolic biomarkers were determined at baseline in both cohorts. These variables were dichotomized and used to construct a multivariable prediction model with backward logistic regression analysis. RESULTS: The prediction model for insufficient response in the derivation cohort, included: DAS28>5.1, Health Assessment Questionnaire>0.6, current smoking, BMI>25 kg/m2, ABCB1 rs1045642 genotype, ABCC3 rs4793665 genotype, and erythrocyte-folate<750 nmol/L. In the derivation cohort, AUC of ROC curve was 0.80 (95%CI: 0.73-0.86), and 0.80 (95%CI: 0.69-0.91) in the validation cohort. Betas of the prediction model were transformed into total risk score (range 0-8). At cutoff of ≥4, probability for insufficient response was 44%. Sensitivity was 71%, specificity 72%, with positive and negative predictive value of 72% and 71%. CONCLUSIONS: A prognostics prediction model for insufficient response to MTX in 2 prospective RA cohorts by combining genetic, metabolic, clinical and lifestyle variables was developed and validated. This model satisfactorily identified RA patients with high risk of insufficient response to MTX.
29352842 Amylin in the insulin resistance of patients with rheumatoid arthritis. 2018 May OBJECTIVES: Amylin, which is co-secreted with insulin, plays a role in glycemic regulation and is impaired in type 2 diabetes. In the present study we assess, for the first time, the implication of amylin in the development of insulin resistance (IR) in rheumatoid arthritis (RA). METHODS: This was a cross-sectional study involving 361 non-diabetic individuals, 151 patients with RA and 210 sex-matched controls. Insulin, C-peptide, amylin, lipoprotein serum concentrations, and IR indexes by homeostatic model assessment (HOMA2) were evaluated in patients and controls. A multivariable analysis, adjusted for IR-related factors, was performed to determine the differences between patients and controls vis-à-vis amylin and how it is related to IR in RA. RESULTS: Insulin, C-peptide and HOMA2-IR indexes were higher in RA patients than in controls. Amylin serum levels were found to be upregulated in RA patients compared to controls (1.36 ± 0.81 vs. 1.79 ± 1.51 ng/ml, p=0.011), although this difference was lost after adjusting for covariates (p=0.46). While amylin positively correlated with the presence of rheumatoid factor (beta coef. 0.90 [95%CI -0.23-1.56], p=0.009) and SDAI (beta coef 0.01 [95%CI 0.00-0.03], p=0.034), no significant association with other disease activity scores, glucocorticoid intake, methotrexate use or TNF-alpha inhibitors was found. CONCLUSIONS: IR in RA does not appear to be mediated by amylin. This would imply that the mechanisms associated with IR in RA patients differ from those at work in type 2 diabetes.