Effect of janus kinase inhibitors and methotrexate combination on malignancy in patients with rheumatoid arthritis: a systematic review and meta-analysis of randomized controlled trials

Methotrexate (MTX) combination therapy with biological agents has gained increasing interest. Here, we assessed the efficacy and tolerability of the MTX combination therapy in patients with Crohn's disease (CD). We performed a multicenter observational study with 185 patients with CD with MTX and biologics combination therapy; the patients were recruited from three IBD Clinics in Korea. We evaluated the outcomes of the MTX combination therapy and examined the predictive factors of clinical and endoscopic remission. MTX was administered orally to 62.7% of patients; the mean dose was 15.5mg per week, and the mean treatment duration was 36months. Of the 169 patients treated with MTX combination therapy for over 6months, the steroid-free clinical remission rates were 34.3%, 26.0%, 29.8%, and 32.7% at 4, 12, 18, and 24months, respectively. Previous thiopurine use was a significant negatively associated independent factor (p < 0.001), and a higher dose of MTX (≥ 15mg/week) was a positively associated independent factor of steroid-free clinical remission (p = 0.035). Ninety-six patients underwent follow-up endoscopy after 28months, and 36 (37.5%) achieved endoscopic remission. Longer disease duration (p = 0.006), ileocolonic type of Montreal location (p = 0.036), and baseline C-reactive protein (CRP) level of more than 5mg/L (p = 0.035) were significant negatively associated independent factors and a higher dose of MTX (≥ 15mg/week) was a positively associated independent factor of endoscopic remission (p = 0.037). MTX combination therapy with biologics was effective and tolerable in patients with CD.

FRI0029 The Impact of Very Early Treatment on Patient Reported Outcomes in Rheumatoid Arthritis

Background: Methotrexate (MTX) and cyclosporine have been used as effective systemic mono-therapy for psoriasis. Several factors are considered to switch monotherapy to combination therapy because monotherapy is no longer effective and has higher side effects. Hence,clinicians have avoided systemic therapy combinations due to its toxicity. However, some studies showed that this combination therapy could be usedeffectively for psoriasis patients. Purpose: This study aimed to analyze the efficacy and adverse effects of systemic MTX and cyclosporine combination therapy in Indonesian psoriasis vulgaris patients. Methods: The retrospective study assessed the effectiveness of 3 monthsmono-therapyand combination therapy of systemic MTX and cyclosporine in psoriasisvulgaris patients from 2016–2017 in Dermatology Clinic, Dr. Hasan Sadikin Hospital, Bandung, West Java, Indonesia. Result: Psoriasis area and severity index (PASI) score 90 were achieved in the group MTX (50%) and cyclosporine group (50%), while none in the combination group.However, eight patients (50%) in group MTX and cyclosporine reached the primary endpoint of PASI 50. One patient in cyclosporine group had adverse effects on kidney profiles. Nonetheless, other patients had no biochemical changes. But, there was no significant difference in the change of PASI between each group (p=0.102). Conclusion: We propose that combination therapy of MTX and cyclosporine is relatively safe and efficacious in treating Indonesian psoriasis vulgaris patients. This combination treatment isas effective as MTX or cyclosporinemono-therapy.

Objective:To evaluate the efficacy and toxicity of methotrexate (MTX) monotherapy compared with MTX combination with non-biological disease-modifying antirheumatic drugs (DMARDs) in adults with rheumatoid arthritis.Method:A systematic review of randomised trials...

This present study was designed to examine (1) whether a combination therapy of TNF (tumor necrosis factor) blockers and methotrexate (MTX) is better than MTX monotherapy, and (2) if the TNF inhibitors such as etanercept, infliximab and adalimumab are all same for treating patients with active rheumatoid arthritis (RA). We performed meta-analysis of a combination therapy of TNF-blockers and MTX compared to MTX monotherapy and we performed adjusted indirect comparison of the TNF-blocking agents for their efficacy and toxicity. Three studies met the inclusion criteria for the analysis. Meta-analysis showed that the combination of MTX with anti-TNF inhibitors was more effective than MTX monotherapy and this indicated that combination therapy of anti-TNF inhibitors and MTX was comparable with MTX monotherapy in terms of withdrawal due to the side effects (RR: 1.05, 95% CI: 0.52-2.09, P = 0.86). The adjusted indirect comparison did not show any differences between infliximab and adalimumab. However, there was a significant difference for clinical efficacy and side effects between etanercept, adalimumab and infliximab. The RRs for achieving ACR20, ACR50 and ACR70 responses and withdrawal due to the side effect in the etanercept group were lower when compared with the adalimumab group. The RR for achieving an ACR20 response in the etanercept group was lower when compared with the infliximab group. The adjusted indirect comparison analysis suggests that the TNF-blocking agents all are not the same with respect to effectiveness and toxicity for the treatment of active RA.

Objective. We retrospectively investigated the inhibitory effect on radiographic joint damage (RJD) for non-biological disease-modifying antirheumatic drug (non-bioDMARD) monotherapy or methotrexate (MTX) combination therapy for rheumatoid arthritis (RA) in the disease activity score with 28 joint counts with erythrocyte sedimentation rate (DAS28) remission.Methods. Eighty-four patients (55 cases of monotherapy, 29 cases of MTX-combination therapy) in DAS28 remission (DAS28 ≤ 2.6) were investigated from 538 RA patients newly registered between February 2007 and August 2010. The patients were analyzed for radiological assessments using the modified total Sharp score/year (mTSS/y).Results. The remission rates and ΔmTSS/y for each agent using monotherapy were 7.1% and 0.17 for sulfasalazine; 11.9% and 0.49 for bucillamine (BUC); and 23.9% and 2.06 for MTX. Those using combination therapy were 6.8% and 1.39 for MTX + BUC; 23.5% and −1.64 for MTX + leflunomide; and 8.0% and 0.31 for MTX + tacrolimus. The cumulative distribution in the single and combination therapy groups showed improvement of percentages in structural remission from baseline to 1-year treatment, 34.1% to 60.9% (P < 0.05) and from 0% to 56.7%(P < 0.0001), respectively. Baseline mTSS (r = 0.67, P < 0.0001), disease duration (r = 0.40, P < 0.01), swollen joint counts (r = 0.33, P < 0.05), and anti-cyclic citrullinated peptide antibody (r = 0.31, P < 0.05) were useful predictors of RJD for non-bioDMARD monotherapy, but not for combination therapy.Conclusion. Satisfactory inhibition of RJD was observed in the DAS28 remission cases of monotherapy or MTX combination therapy with a non-bioDMARD.

SAT0100 Bone marrow OEDEMA is more associated with rapid radiographic progression than synovitis or bone erosion by using low field MRI in bio-naïve rheumatoid arthritis patients treated with adalimumab and...

Cyclosporin A monotherapy versus cyclosporin A and methotrexate combination therapy in patients with early rheumatoid arthritis: a double blind randomised placebo controlled trial

Objective. The aim of this study was to compare the efficacy and safety of golimumab (GLM) 50 mg + methotrexate (MTX) combination therapy and GLM 100 mg monotherapy in patients with rheumatoid arthritis (RA).Methods. The subjects were 115 RA patients (92 females and 23 males; median (range) age, 64 (17–87) years; median (range) disease duration, 8 (0.6–48) years) started on GLM. Eighty-three patients received GLM 50 mg/4 weeks + MTX (C group; median (range) MTX dosage 8 (2–16) mg/week), and 32 patients received GLM 100 mg/4 weeks (M group).Serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), matrix metalloproteinase-3, disease activity score (DAS) 28-ESR, DAS28-CRP, simplified disease activity index, and clinical disease activity index were evaluated 4, 12, and 24 weeks after starting GLM.Results. There were no significant differences in disease activity, adverse events, and drug continuation rates at 24 weeks between the groups. The DAS28-ESR remission rate was 34% in the C group and 26% in the M group.Conclusions. GLM 100 mg monotherapy improved disease activity as well as GLM 50 mg + MTX combination therapy. GLM 100 mg monotherapy appears to have a sufficient therapeutic effect in RA patients who cannot take MTX.

To investigate the efficacy of etanercept and MTX (methotrexate) combination therapy in Chinese patients with ankylosing spondylitis hip joint lesion, the possible courses and maintenance protocol, altogether 97 ankylosing spondylitis patients fulfilling the modified New York criteria with hip joint lesion were enrolled in a 12-month trial treated with combined etanercept and MTX. All these patients were required to be poor responders to SSZ (Sulfasalazine) or MTX therapy for 6 consecutive months or the longer. Etanercept was administered subcutaneously twice a week at a fixed dosage of 25 mg for the first six months, followed by 25 mg once a week in patients with good control of both symptoms and radiological progression, or twice a week for another six months in patients with BASDAI > or = 4. Combined MTX was administered intravenously once a week at the dosage of 15 mg. Demographics, clinical and laboratory features, physical function and quality of life using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI), Harris hip score, and radiological assessment using the BASRI-hip index were recorded. Most patients achieved pain release at the end point of assessment. Significant improvement in Bath AS Disease Activity Index (BASDAI) (P < 0.05), Bath AS Functional Activity Index (BASFI) (P < 0.05), and Harris hip score (P < 0.05) was demonstrated. Radiographic progression was recorded as no exacerbation or alleviated. Larger interval between two etanercept administrations would provide similar advantages to standard method and possibly less adverse events if MTX was combined. Etanercept and MTX combination therapy was beneficial to ankylosing spondylitis patients with hip joint lesion, and staged dosage deduction in the long term proved to be effective as well as adverse event preventing.

Background:The administration of Janus kinase inhibitors as well as biological disease-modifying anti-rheumatic drugs has dramatically improved the clinical outcomes of patients with rheumatoid arthritis (RA). Previous trials have shown that upadacitinib, a Janus kinase inhibitor, can effectively improve disease activity and prevent progression of joint destruction in RA patients with inadequate responses to methotrexate (MTX). It remains unclear whether reduced disease activity can be maintained after discontinuation of MTX in patients treated with upadacitinib plus MTX. Thus, the aim of this study is to evaluate changes in disease activity after administration of upadacitinib plus MTX in RA patients who failed to achieve an adequate response to MTX and to determine whether clinical relapse can be avoided after discontinuation of MTX in those who achieved clinical remission.Methods/design:The proposed study is an interventional, multicenter, open-label, single-arm clinical trial with a 48-week follow-up. The cohort will include 155 RA patients with at least moderate disease activity during treatment with MTX. Patients will receive upadacitinib and MTX will be discontinued for those who achieve clinical remission. Disease activity will be evaluated longitudinally by measuring clinical disease activity indices and with musculoskeletal ultrasound (MSUS). The primary endpoint is the proportion of patients who sustain a disease activity score-28- C reactive protein score of ≤3.2 from week 24 to 48 after a disease activity score-28- C reactive protein score of <2.6 at week 24. Important secondary endpoints are changes from baseline MSUS scores. Serum levels of multiple biomarkers, including cytokines and chemokines, will be comprehensively analyzed.Discussion:The study results are expected to show the clinical benefit of the discontinuation of MTX after achieving clinical remission by treatment with upadacitinib plus MTX combination therapy. The strength of this study is the prospective evaluation of therapeutic efficacy using clinical disease activity indices and standardized MSUS, which can accurately and objectively evaluate disease activity at the joint level among patients drawn from multiple centers. Furthermore, parameters to predict clinical remission after administration of upadacitinib plus MTX combination therapy and nonclinical relapse after discontinuation of MTX will be screened by integrated multilateral assessments (i.e., clinical disease activity indices, MSUS findings, and serum biomarkers).

ObjectivesTo compare the risk of serious adverse events, serious infections and death caused by methotrexate and biological disease-modifying antirheumatic drug (bDMARD) combination therapy versus a bDMARD prescribed as monotherapy in...

Combination therapy with an immunomodulator and anti-tumour necrosis factor (TNF) is one of the crucial therapeutic strategies for inflammatory bowel disease (IBD) management. Methotrexate (MTX) is a second-line immunomodulator and has received much attention in recent years due to several advantages over thiopurine. We aimed to investigate clinical outcomes and prognostic factors of MTX therapy when combined with anti-TNF in IBD patients. We retrospectively reviewed 70 IBD patients (Crohn’s disease [n = 57], Ulcerative colitis [n = 13]) (age, 18–63 years) treated with MTX in combination with anti-TNF agents for induction or maintenance therapy at Severance and Gangnam Severance Hospital, Seoul, Korea. 22 (31.4%) were initially commenced on oral and 48 (68.6%) started subcutaneous route. Initial MTX dosage was 7.5–25.0 mg/week. Drug data for MTX therapy and outcomes data for clinical efficacy were analysed. Moreover, sustained clinical benefit of MTX therapy which was defined as ongoing use of MTX or intentional discontinuation of successful therapy before last follow-up was also evaluated. Recruitment algorithm. A total of 49 patients were selected for the analysis of induction therapy, and steroid free clinical remission was achieved in 22 (44.9%) of the 49 patients at 3 months, 13 (50.0%) of the 26 patients at 12 months, and 4 (44.4%) of the 9 patients at 24 months. Co-therapy with second line anti-TNF agent was associated with a failure of clinical remission at 3 months (odds ratio [OR]: 0.084, 95% confidence interval [CI]: 0.009–0.838). Meanwhile, 60 patients were selected for the analysis of maintenance therapy, and 17 (28.3%) patients experienced relapse during follow-up period of 3–26 months. Anaemia (Haemoglobin < 11 mg/l) at maintenance initiation was independent predictor of relapse (hazard ratio [HR]: 3.847, 95% CI: 1.153–12.829). Factors related with failure of sustained clinical benefit of MTX in combination therapy were obesity (≥23 kg/m2) (HR: 4.117, 95% CI: 1.380–12.296), concomitant adalimumab (vs. infliximab) therapy (HR: 3.872, 95% CI: 1.419–10.571), and female sex (HR: 3.271, 95% CI: 1.119–9.561). Adverse event related with MTX occurred in 24 (34.3%) patients, and 3 (4.3%) patients discontinued MTX due to adverse event. MTX therapy in combination with anti-TNF was relatively well tolerated. The type of combined anti-TNF agents and baseline patient characteristics rather than the MTX dosage and administration route were crucial factors in determining clinical outcome.

Tumor necrosis factor-α (TNF-α) inhibitors are increasingly being used as treatment for rheumatoid arthritis (RA). However, the administration of these drugs carries the risk of inducing injection site reaction (ISR). ISR gives rise to patient stress, nervousness, and a decrease in quality of life (QoL). In order to alleviate pain and other symptoms, early countermeasures must be taken against this adverse event. In order to improve understanding of the risk factors contributing to the induction of ISR, we evaluated the association between TNF-α inhibitors and ISR by applying a logistic regression model to age-stratified data obtained from the Food and Drug Administration Adverse Event Reporting System (FAERS) database.The FAERS database contains 7,561,254 reports from January 2004 to December 2015. Adjusted reporting odds ratios (RORs) (95% Confidence Intervals) were obtained for interaction terms for age-stratified groups treated with etanercept (ETN) and adalimumab (ADA). The adjusted RORs for ETN* ≥ 70 and ADA* ≥ 70 groups were the lowest among the age-stratified groups undergoing the respective monotherapies. Furthermore, we found that crude RORs for ETN + methotrexate (MTX) combination therapy and ADA + MTX combination therapy were lower than those for the respective monotherapies.This study was the first to evaluate the relationship between aging and ISR using the FAERS database.

OP0227 Remission induction with methotrexate step-up therapy versus combination of hydroxychloroquine, methotrexate and triamcinolone: 3 year results