Methotrexate Combination Therapy Research Articles

THU0088 PREDICTORS OF DISEASE FLARE AFTER DISCONTINUATION OF CONCOMITANT METHOTREXATE IN JAPANESE PATIENTS WITH RHEUMATOID ARTHRITIS TREATED WITH TOCILIZUMAB

Background:All biologics should primarily be combined with a conventional synthetic DMARD, such as methotrexate (MTX), in rheumatoid arthritis (RA) patients. However, the use of MTX may lead to the development of adverse events (AEs), and de-escalation of MTX while maintaining a favorable disease activity state may be beneficial from the perspective of reducing AEs during long-term RA treatment. Several studies have evaluated the impact of MTX discontinuation in RA patients who achieved good clinical response with tocilizumab (TCZ) plus MTX combination therapy, finding that discontinuing MTX is noninferior to continuing MTX in terms of maintaining clinical response (1-3). However, information on risk factors for disease flare after MTX discontinuation is lacking.Objectives:To investigate predictors of disease flare after MTX discontinuation in Japanese RA patients with sustained low disease activity undergoing TCZ plus MTX combination therapy.Methods:Participants of this multicenter, open-label, uncontrolled, prospective study were RA patients maintaining low disease activity (Clinical Disease Activity Index [CDAI] ≤10) for ≥12 weeks with TCZ plus MTX. Patients had to be receiving MTX orally at a stable dose of ≥6 mg/week, and TCZ at a stable dosage regimen irrespective of the route of administration, for ≥12 weeks prior to obtaining informed consent. MTX was discontinued after 12 weeks of biweekly administration while continuing TCZ therapy (Fig. 1). Disease flare was defined as a CDAI score >10 or intervention with rescue treatments for any reason. The impact of baseline characteristics on disease flare at week 64 (52 weeks after MTX discontinuation) was assessed with logistic regression models.Results:Efficacy analyses were performed in 49 patients, of whom 15 had a disease flare by week 64. The proportion [95% confidence interval (CI)] of patients who maintained low disease activity without a flare at week 64 was 69.4% (54.6 – 81.8%) (Fig. 2A). According to Kaplan-Meier estimates, the cumulative flare-free rate was 70.0% at week 64 (Fig. 2B). The dosing interval of TCZ was longer than that described on the drug label (i.e., intravenously every 4 weeks, or subcutaneously every 2 weeks) in 27% and 6% of patients with and without a flare, respectively (Table 1). Multivariate analysis revealed that male sex [odds ratio (OR): 18.00, 95% CI: 2.80-115.56] and extended dosing interval of TCZ (OR: 12.00, 95% CI: 1.72-83.80) were independent predictors of disease flare.Table 1.Impact of baseline variables on disease flareNon-flareFlareOdds ratio (95% confidence interval)(n=34)(n=15)UnivariateMultivariateAge, years62 ± 1163 ± 91.01 (0.95-1.08)aMale, %64010.67 (1.83-62.18)*18.00 (2.80-115.56)*Weight, kg54 ± 858 ± 151.03 (0.98-1.09)aDisease duration, years11 ± 813 ± 91.03 (0.95-1.11)aRF positive, %76861.85 (0.34-10.04)ACPA positive, %85100-bRoute of TCZ, intravenous, %59802.80 (0.66-11.79)Extended TCZ dosing interval, %6275.82 (0.93-36.28)†12.00 (1.72-83.80)*MTX dose, mg/week8.2±2.28.0±2.60.95 (0.73-1.25)aUse of glucocorticoids, %26331.39 (0.37-5.18)Use of csDMARDs other than MTX, %9335.17 (1.04-25.57)*-Previous biologic use, %56803.16 (0.75-13.26)CDAI remission, %65731.50 (0.39-5.75)CRP, mg/dl0.04 ± 0.060.04 ± 0.060.42 (0.00-15115.38)aMMP-3, ng/ml58.5 ± 22.476.6 ± 37.61.02 (1.00-1.05)a†-Data are shown as mean ± SD or percentage.aOdds ratio for 1-unit increase in each item.bOdds ratio was not evaluated. *P<0.05. †P<0.10.Conclusion:Male patients and those receiving TCZ at an extended dosing interval are at high risk of disease flare after discontinuation of concomitant MTX.This work was supported by Chugai Pharmaceutical Co., Ltd.

Comparison of combination therapy of methotrexate with etanercept and etanercept alone in psoriasis in Tertiary care center in South India

Psoriasis is a disorder of chronic nature. But the present day systemic therapies for psoriasis of moderate to severe nature are associated with toxicity and also have a greater level of displeasure in the patients. Hence the current focus for treatment is with intermittent or combination therapy that helps to overcome the loss of effectiveness in treatment over time and decrease the side effects as a result of cumulative toxicities during monotherapy. To assess the effectiveness of oral Methotrexate and Etanercept combination therapy in comparison to Etanercept monotherapy for treatment of moderate to severe plaque type of psoriasis among patients. This was a prospective analytical study conducted in dermatology OPD of Madras Medical College, a tertiary care centre in south India between August 2015 and July 2016. About Forty subjects clinically diagnosed with plaque type of psoriasis based upon the clinical history and morphology of the dermatological lesions were included in this hospital based study depending on inclusion and exclusion criteria and were randomly allocated into two groups. Group C: Combination therapy with oral methotrexate and Etanercept and Group M:Monotherapy with Etanercept alone. All the patients were reviewed every 4 weeks at intervals of 0,4,8 and 12 weeks for complaints and for assessment of clinical response using PASI scoring and DLQI scoring and other investigations. Data was compiled and analyzed with the help of Statistical Package for Social Science (SPSS) Version 20.0. Mean age of the study population was 37.43 ± 10.1 years. Twenty two subjects were males (55%) and eighteen subjects were females (45%). The subjects who received Group C (Methotrexate and Etanercept combination therapy) therapy achieved 75% reduction of PASI in comparison to subjects who received Group M (Etanercept monotherapy) after 8 weeks (30% vs 5%) and after 12 weeks (100% vs 50%). Also Group C showed good response to treatment after 12 weeks in comparison to Group M (85% vs 50%) and this difference in proportion of treatment response between the two groups was statistically significant. Subjects who received Group C showed greater decline (77.4% vs 68.7) in DLQI score after 12 weeks in comparison to subjects who received Group M.

Temporary interruption of baricitinib: characterization of interruptions and effect on clinical outcomes in patients with rheumatoid arthritis

BackgroundIn clinical practice, temporary interruption of rheumatoid arthritis (RA) therapy is common for various reasons including side effects, non-compliance, or necessity for surgery. To characterize temporary interruptions of baricitinib and placebo-matched tablets in phase 3 studies of patients with moderate-to-severe rheumatoid arthritis (RA) and describe their impact on efficacy and safety.MethodsDuring 4 baricitinib phase 3 studies, investigators documented timing, reason, and duration of investigator-initiated temporary interruptions of study drug. In 2 studies, patients recorded RA symptoms in daily diaries for 12 weeks. Post hoc analyses investigated changes in symptom scores during interruptions and resumption of treatment. Interruptions were evaluated for reoccurrence of adverse events or laboratory abnormalities after retreatment.ResultsAcross the placebo-controlled studies, interruptions occurred in larger proportions of baricitinib- (2 mg, 18%; 4 mg, 18%) vs placebo-treated (9%) patients in only one study (bDMARD-inadequate responder patients, RA-BEACON). In the active comparator-controlled studies, the lowest rates of interruption were in the baricitinib monotherapy arm (9%) of RA-BEGIN (vs methotrexate monotherapy or combination therapy), and proportions were similar for baricitinib (10%) and adalimumab (9%) in RA-BEAM. Adverse events were the most common reason for interruption, but their reoccurrence after drug restart was infrequent. Most interruptions lasted ≤ 2 weeks. Daily diaries indicated modest symptom increases during interruption with return to pre-interruption levels or better after resumption. Interruptions had no impact on long-term efficacy outcomes.ConclusionsConsistent with its pharmacologic properties, brief interruptions of baricitinib during phase 3 studies were associated with minor increases in RA symptoms that resolved following retreatment. This analysis provides useful information for clinicians, as temporary interruption of antirheumatic therapy is common in the care of patients with RA.Trial registrationClinicalTrials.gov; NCT01710358, NCT01711359, NCT01721057, NCT01721044

EP14 Association between initial csDMARD strategy and disease activity at 6 months in patients with new onset rheumatoid arthritis

Abstract Background Until 2018, NICE guidance recommended the use of a combination of disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate (MTX), in the initial management of people with rheumatoid arthritis (RA). In 2018 the guideline was updated to recommend monotherapy with MTX due to uncertainties in the evidence for combination therapy. However, it remains a requirement for progression onto any biologic that the patient should have persistent high disease activity and/or have intolerance to, a minimum of two DMARDs. The aim of this study was to understand the association between initial treatment strategy and EULAR response at 6 months. Methods This analysis included patients recruited to the longitudinal observational Rheumatoid Arthritis Medication Study (RAMS) in the UK who were DMARD naïve and had symptoms for less than 1 year. Patients were defined as either starting MTX monotherapy or MTX in combination with another DMARD (6 weeks either side of MTX start date) and categorised into EULAR non responders or moderate/ good responders after 6 months. A logistic regression model was applied to test the association between initial treatment strategy and EULAR response at 6 months, adjusting for confounders. Results A total of 948 participants were included in the analysis. MTX monotherapy was prescribed in 72% (n = 678) of patients and combination therapy was prescribed in 28% (n = 270) of patients, the majority of whom received MTX plus hydroxychloroquine (HCQ) (n = 236, 87%). There was no significant difference between the MTX monotherapy and combination therapy groups in EULAR response at 6-months (adjusted odds ratio [aOR] 0.77, 95% CI 0.53 to 1.14). Conclusion In this large UK observational study investigating the effect of treatment strategy within the first 6 weeks of presentation and treatment response at 6 months, there was no significant difference between combination DMARD therapy and MTX monotherapy on EULAR response. Most patients received MTX in combination with HCQ, for which little evidence exists. Disclosures S. Wood None. K. Hyrich Consultancies; ABBVIE. Grants/research support; BMS, PFIZER, UCB. S. Verstappen None. D. Steinke None.

Interpretation of Safety and Efficacy of Hydroxychloroquine Alone and Along with Methotrexate Combination in Rheumatoid Arthritis

BACKGROUND: Several drugs for rheumatoid arthritis are available. Comparative studies of treatment with Hydroxychloroquine (against Methotrexate) reported a better quality of life. AIM: The study was designed to evaluate safety and efficacy of patient with rheumatoid arthritis when treated as combination therapy of Methotrexate and Hydroxychloroquine and Hydroxychloroquine alone, a Disease Modifying Anti Rheumatoid Drug (DMARD). MATERIAL AND METHODS: This was a prospective observational study which was conducted in rheumatology department in a tertiary care Hospital, Warangal, India. Patients who were diagnosed with rheumatoid arthritis as per Guidelines of American College of Rheumatology aged between 18 and 60 years were recruited. First group patient were treated with Hydroxychloroquine 400 mg and second group patient were treated with combination of Methotrexate 7.5 mg and Hydroxychloroquine 400 mg. Simple Disease Activity Index criteria of improvement according to disease activity score 28 was considered as the primary efficacy variable. The Baseline and end of study values were evaluated. RESULT: After 3 months, improvement was noted in patient treated with Methotrexate and Hydroxychloroquine combination when compared to Hydroxychloroquine mono therapy alone. There was statistical significance in improvement of disease activity between the two groups (P = 0.02). CONCLUSION: The study concluded Methotrexate and Hydroxychloroquine combination therapy is more effective to Hydroxychloroquine therapyalone in efficacy of reducing disease activity in the treatment of severe rheumatoid arthritis.

Successful Treatment of Pityriasis Rubra Pilaris with Brodalumab

Pityriasis Rubra Pilaris (PRP) is a rare inflammatory skin disease with highly variable clinical appearance. Treatment of PRP remains a challenge and has been mostly guided by case reports and case series. We report the first case of pityrisis rubra pilaris that is successfully treated with combination therapy of brodalumab and methotrexate.

Comparing methotrexate monotherapy with methotrexate plus leflunomide combination therapy in psoriatic arthritis: protocol of a randomized, placebo-controlled, double-blind clinical trial (COMPLETE-PsA)

BackgroundBoth methotrexate (MTX) and leflunomide (LEF) are registered and regularly prescribed as first-line treatments for the use in patients with psoriatic arthritis (PsA) and they are occasionally used in combination. However, evidence about their individual, and especially combined efficacy, in PsA is lacking. The aim of this study is to compare the effectiveness and safety of MTX and LEF combination therapy to MTX monotherapy in patients with PsA.MethodsCOMPLETE-PsA is a randomized, placebo-controlled, double-blind clinical trial. Disease-modifying antirheumatic drug (DMARD)-untreated patients (n = 78) with clinical diagnosis of active (i.e. ≥2 swollen joints) PsA will be randomized 1:1 (stratified for high disease activity, Psoriatic Arthritis Disease Activity Score [PASDAS] ≥ 5.4) to the combination or monotherapy. The intervention group receives MTX 25 mg (oral or subcutaneous) once weekly plus LEF 20 mg daily, and the control group receives the same but with placebo instead of LEF daily. Primary endpoint is between-group difference in PASDAS at 16 weeks, adjusted for baseline PASDAS. Key secondary parameters include between-group comparisons in change in Disease Activity in Psoriatic Arthritis (DAPSA) score, skin score, enthesitis score, dactylitis score, and swollen/tender joint count, as well as the proportion of patients fulfilling minimal disease activity (MDA), American College of Rheumatology (ACR) 20/50/70 response criteria at week 16. Furthermore, safety, function and quality of life (Health Assessment Questionnaire [HAQ], Psoriatic Arthritic Impact of Disease [PSAID], Short Form 12 [SF-12]) will be assessed.DiscussionThis is, to our knowledge, the first randomized, placebo-controlled, double-blind clinical trial assessing the effectiveness of MTX and LEF combination therapy in patients with PsA. The study will provide important information for treatment strategies and treatment recommendations.Trial registrationDutch Trial Register NTR7632 (3 December 2018). CMO NL66544.091.18 (19 November 2018).

Thrombotic microangiopathy and liver toxicity due to a combination therapy of leflunomide and methotrexate: a case report

BackgroundTreatment of active rheumatoid arthritis may necessitate a methotrexate mono- or combination therapy. As in the present case, novel side effects may occur, when escalating therapy.Case presentationA 63-year-old Caucasian female patient with rheumatoid arthritis on methotrexate for 8 years and on leflunomide for 6 years was admitted for weakness, edema, ascites, and petechiae of the lower legs. Comorbidities included a urinary tract infection, metabolic syndrome with obesity, type-2 diabetes without necessity for insulin or oral antidiabetics, and non-alcoholic fatty liver disease. Laboratory results showed acute liver failure, oliguric acute kidney injury, thrombocytopenia, and schistocyte-positive, Coombs-negative hemolytic anemia. On admission, her ADAMTS13 activity was decreased, and her leflunomide plasma level was elevated (120 μg/l). Due to severe hypoalbuminemia, an intravascular hypovolemia, and severe metabolic alcalosis with hypokalemia were found.For the newly diagnosed thrombotic microangiopathy, leflunomide and methotrexate were discontinued, and 4 units of fresh-frozen plasma were given. Steroid therapy was administered for 5 days, until thrombotic thrombocytopenic purpura was excluded. Intravenous human albumin, oral vitamin K, and cholestyramine were administered for liver failure and leflunomide overdosage, respectively. Liver biopsy revealed a non-alcoholic fatty liver disease transforming into liver cirrhosis. After 2 weeks, our patient was discharged. However, within 3 weeks after discharge, our patient was rehospitalized for a relapse of acute liver failure, urinary tract infection, and influenza. Leflunomide and methotrexate were not reintroduced before or thereafter. Over a period of 11 months after discharge, her thrombotic microangiopathy subsided, and her renal and liver function fully recovered.ConclusionsUnder a combination of leflunomide and methotrexate, liver toxicity and, for the first time, thrombotic microangiopathy occurred as side effects. Non-alcoholic fatty liver disease may have predisposed for the drug-induced liver toxicity.

Characteristics of coexisting localized scleroderma and inflammatory arthritis.

Localized scleroderma (LS), including morphea and linear scleroderma, is an autoimmune disease where excessive subcutaneous collagen deposits lead to thickening, scarring, and fibrosis of the tissues. LS coexisting with inflammatory arthritis is less well-described but has been reported in as many as 20% of 53 LS patients in a recent cohort. Herein, we describe a cohort of 8 children with both LS and inflammatory arthritis. The objective of this study is to determine the characteristics of inflammatory arthritis in children with LS and their response to treatment regimens. A retrospective chart review was completed on patients less than 19 years of age who were diagnosed with either morphea or linear scleroderma at the Children of Alabama center from 2004-2018. Patients were identified using ICD-9 and ICD-10 diagnostic codes. Records were reviewed for additional diagnostic codes, exams, and laboratory findings confirming coexisting inflammatory arthritis and LS. A total of 87 patients with a diagnosis of either morphea or linear scleroderma were identified. Eight (9%) had coexisting inflammatory arthritis according to the diagnostic codes with documented active arthritis. Median age of initial rheumatic disease diagnosis was 7.5 years. A majority of patients with both LS and inflammatory arthritis were female (62.5%). Half of the patients (n=4, 50%) had LS lesions over arthritic joints. All of the identified patients were diagnosed with a form of juvenile idiopathic arthritis (JIA). The JIA diagnoses varied widely in 3 (37.5%) patients with rheumatoid factor (RF) negative polyarticular JIA, 2 (25%) with oligoarticular JIA, 2 (25%) with psoriatic JIA, and 1 (12.5%) with enthesitis-related JIA. The timing of onset of LS and inflammatory arthritis varied widely. Three (37.5%) patients had LS lesions preceding clinical arthritis, and three (37.5%) had arthritis before the appearance of LS. Two (25%) patients had both LS and arthritis at the time of diagnosis. All patients received methotrexate (MTX) during their disease course with only 3 (37.5%) receiving systemic steroids during treatment. All 8 patients showed resolution of LS lesions. However, 6 of the 8 patients demonstrated active arthritis on combination MTX and TNFi therapy. In this cohort of pediatric LS, 9% of patients had coexisting inflammatory arthritis. The characteristics of this cohort varied widely. All patients received MTX initially and showed a resolution of LS lesions. However, in the majority of patients, the arthritis failed to respond to MTX and TNFi combination therapy. These results suggest that inflammatory arthritis coexisting with LS may be less likely to respond to traditional inflammatory arthritis or JIA therapies.

Combination therapy of ginsenoside compound K and methotrexate was efficient in elimination of anaemia and reduction of disease activity in adjuvant-induced arthritis rats

Context Ginsenoside compound K (CK) has anti-inflammatory, immunoregulatory, and myelosuppressive protective effects. Methotrexate (MTX) is widely used in combination therapy for rheumatoid arthritis (RA). Objective To evaluate the effects of combination therapy of CK and MTX on anaemia and anti-arthritis in adjuvant-induced arthritis (AA) rats. Materials and methods AA was induced in rats by Complete Freund’s adjuvant, and divided into five groups (n = 10): normal, AA, CK 80 mg/kg, combination therapy (80 mg/kg CK combined with 0.5 mg/kg MTX), and MTX 0.5 mg/kg. From day 12, CK (once a day for 15 days) or MTX (once every 3 days, five times) were intragastrically administered. Results Combination therapy showed increased haemoglobin to 148.5 ± 10.1 g/L compared with AA (129.8 ± 11.7 g/L) and MTX (128.8 ± 18.4 g/L), and decreased reticulocytes in peripheral blood to 4.9 ± 1.1% compared with MTX (9.3 ± 3.3%). In combination therapy group, paw swelling decreased to 5.6 ± 4.3 mL compared with CK (9.4 ± 3.9 mL) and MTX (13.5 ± 7.4 mL), and swollen joint count decreased to 1.4 ± 0.8 compared with CK (2.1 ± 1.0) and MTX (2.4 ± 1.2) at day 24. Combination therapy showed decreased IL-6 to 25.1 ± 17.2 pg/mL compared with MTX (44.9 ± 4.8 pg/mL), and decreased IL-17 to 5.8 ± 3.9 pg/mL compared with MTX (10.7 ± 4.2 pg/mL). Conclusion The anti-anaemia effect of CK deserves further study, and CK can be a candidate effective drug for combined treatment in RA with anaemia.

Etanercept biosimilar (recombinant human tumor necrosis factor-α receptor II: IgG Fc fusion protein) and methotrexate combination therapy in Chinese patients with moderate-to-severe plaque psoriasis: a multicentre, randomized, double-blind, placebo-controlled trial.

Etanercept biosimilar recombinant human tumour necrosis factor-α receptor II: IgG Fc fusion protein (rhTNFR-Fc, trade name Yisaipu) has shown good efficacy in the treatment of moderate-to-severe plaque psoriasis. To compare the efficacy and safety of rhTNFR-Fc plus methotrexate (MTX) and rhTNFR-Fc plus placebo in Chinese patients with moderate-to-severe plaque psoriasis. In this multicentre, randomized, placebo-controlled trial, patients with moderate-to-severe plaque psoriasis were enrolled and randomly assigned in a 1:1 ratio to receive rhTNFR-Fc plus MTX or rhTNFR-Fc plus placebo. The primary endpoint was the proportion of patients achieving Psoriasis Area and Severity Index improvement of at least 75% (PASI 75) from baseline at week 24. Adverse events (AEs) were recorded to evaluate safety. Efficacy analysis was performed using the intent-to-treat principle. A total of 466 patients were enrolled and randomly received rhTNFR-Fc plus MTX (combination group, n = 233) or rhTNFR-Fc plus placebo (monotherapy group, n = 233). PASI 75 at week 24 was significantly higher in the combination group than in the monotherapy group (81.86% vs. 65.50%, p < 0.001). Similar results were observed in other PASI improvement scores at week 12 [PASI 75, 62.39% vs. 44.54% (p < 0.001); PASI 50, 87.17% vs. 75.55% (p = 0.001); and PASI 90, 34.07% vs. 18.78% (p < 0.001)] and week 24 [PASI 50, 92.48% vs. 85.59% (p = 0.019); and PASI 90, 64.16% vs. 42.36% (p < 0.001)]. Significantly more patients had a static Physicians' Global Assessment of clear or almost clear in the combination group than in the monotherapy group at week 12 (26.46% vs. 12.50%, p < 0.001) and week 24 (62.38% vs. 40.83%, p < 0.001). The most common AEs in the two groups were upper respiratory tract infection and abnormal liver function. The combination therapy of rhTNFR-Fc plus MTX was an effective therapy for moderate-to-severe plaque psoriasis with an acceptable safety and tolerability profile, indicating that it was feasible and well tolerated for patients.

Joint Surgery in Tunisian Rheumatoid Arthritis Patients: Prevalence and Risk Factors.

Objectives This study aims to assess the prevalence of joint surgery in Tunisian patients with rheumatoid arthritis (RA) and to determine the risk factors of surgical treatment.Patients and methods This retrospective cross-sectional study was performed over a period of 15 years between January 2000 and December 2014 and included 500 Tunisian patients with RA (78 males, 422 females; mean age 53.4 years; range, 21 to 83 years). The prevalence of joint surgery indication was evaluated. Clinical, paraclinical and therapeutic characteristics of RA were compared according to the need of surgery.Results Female to male ratio was 5. The indication of joint surgery was noted in 59 patients (12%). Knee joint surgery was the most performed surgical procedure (56% of surgical treatment). A decrease in surgery prevalence from 30% in 2004 to 4% in 2013 was noted. Statistical study showed that factors associated with joint surgery were: delayed diagnosis (p=0.037), long RA duration (p=0.017), young onset of RA (p<0.001), presence of joint deformities (p=0.034), presence of osteoporosis (p=0.029), presence of antinuclear antibodies (p<0.001), combination therapy of methotrexate with other conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) (p=0.001), short period of first medical treatment (p=0.012) and high erythrocyte sedimentation rate (ESR) (p=0.027). In multivariate analysis, three factors were independently related to the use of joint surgery: age at disease onset [odds ratio (OR): 2.799 95% confidence interval (CI): 1.49-5.22; p=0.01], high ESR level (OR: 2.807 95% CI: 1.5-5.24; p=0.01) and association of methotrexate with other csDMARDs (OR: 3.500 95% CI: 1.61-7.56; p=0.01).Conclusion Twelve percent of RA patients needed joint surgical treatment. Predictive factors of surgery were age at disease onset, high ESR level and association of methotrexate with other csDMARDs.

Comparative Effectiveness of Combining MTX with Biologic Drug Therapy Versus Either MTX or Biologics Alone for Early Rheumatoid Arthritis in Adults: a Systematic Review and Network Meta-analysis

BackgroundComparative effectiveness of early rheumatoid arthritis (RA) treatments remains uncertain.PurposeCompare benefits and harms of biologic drug therapies for adults with early RA within 1 year of diagnosis.Data SourcesEnglish language articles from the 2012 review to October 2017 identified through MEDLINE, Cochrane Library and International Pharmaceutical s, gray literature, expert recommendations, reference lists of published literature, and supplemental evidence data requests.Study SelectionTwo persons independently selected studies based on predefined inclusion criteria.Data ExtractionOne reviewer extracted data; a second reviewer checked accuracy. Two independent reviewers assigned risk of bias ratings.Data SynthesisWe identified 22 eligible studies with 9934 participants. Combination therapy with tumor necrosis factor (TNF) or non-TNF biologics plus methotrexate (MTX) improved disease control, remission, and functional capacity compared with monotherapy of either MTX or a biologic. Network meta-analyses found higher ACR50 response (50% improvement) for combination therapy of biologic plus MTX than for MTX monotherapy (relative risk range 1.20 [95% confidence interval (CI), 1.04 to 1.38] to 1.57 [95% CI, 1.30 to 1.88]). No significant differences emerged between treatment discontinuation rates because of adverse events or serious adverse events. Subgroup data (disease activity, prior therapy, demographics, serious conditions) were limited.LimitationsTrials enrolled almost exclusively selected populations with high disease activity. Network meta-analyses were derived from indirect comparisons relative to MTX due to the dearth of head-to-head studies comparing interventions. No eligible data on biosimilars were found.ConclusionsQualitative and network meta-analyses suggest that the combination of MTX with TNF or non-TNF biologics reduces disease activity and improves remission when compared with MTX monotherapy. Overall adverse event and discontinuation rates were similar between treatment groups.RegistrationPROSPERO (available at http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42017079260).

Does Triple Conventional Synthetic Disease-Modifying Antirheumatic Drug Therapy Improve upon Methotrexate as the Initial Treatment of Choice for a Rheumatoid Arthritis Patient?

Although many treatment options exist for the initial management of rheumatoid arthritis, there has long been discussion about whether initial treatment should be with methotrexate (MTX) as monotherapy or in combination with other conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Although studies initially showed additional benefit from combining MTX with other csDMARDs, this benefit disappears when glucocorticoids are added to MTX, a strategy recommended in current guidelines as a short-term bridging approach until MTX therapy exhibits its full efficacy. Also concomitant use of glucocorticoids, with MTX may not be inferior to combination therapy of MTX with TNF-inhibitors.

Should Methotrexate Have Any Place in the Treatment of Psoriatic Arthritis?

Methotrexate (MTX) is widely used in the treatment of psoriatic arthritis (PsA), despite the evidence base for this being limited. This narrative review summarizes the evidence to date of using MTX within different domains of psoriatic disease, including peripheral arthritis, axial disease, dactylitis, enthesitis, psoriasis, and nail disease. We also explore the role of MTX in combination therapy with tumor necrosis factor inhibitors, in addition to its safety and tolerability, to answer the question: should methotrexate have any place in the treatment of psoriatic arthritis?

Dynamics of concomitant therapy in children with juvenile idiopathic arthritis treated with etanercept and methotrexate

Both the steroid- and NSAID-sparing effects of biologics in juvenile idiopathic arthritis (JIA) treatment are key aspects of the dynamics of patient's condition. The proper selection of biologics enables maximum treatment effectiveness and reduction of the dosage of concomitant therapy. Our aim was to study the dynamics of concomitant therapy during etanercept (ETA) and methotrexate (MTX) treatment in patients with JIA. This analysis included 215 JIA patients (63.3% females) showing sufficient response to main therapy. One hundred patients received MTX as main therapy, 24 received ETA monotherapy, and 91 received ETA þ MTX combination therapy. The dynamics of concomitant therapy were analyzed after 1 month, every 3 months during the first year, and every 6 months during the long-term follow-up (up to 5 years). At the baseline, 24 (11.2%) patients received concomitant oral glucocorticoids (orGCs) and NSAIDs; the remaining 191 (88.8%) patients were treated with concomitant NSAIDs only. Within 1-year treatment, NSAIDs were discontinued in 162 (75.3%) patients. There were no significant differences in the dynamics of withdrawal of NSAIDs in patients who received and did not receive concomitant MTX. However, the percentage of treatment discontinuation in the MTX group was significantly lower compared to the other two groups (p< 0.001). Oral GCs were discontinued completely in 4 children (16.7%), and the dose of oral GCs was reduced in another 4 patients (16.7%). By the end of the follow-up period, 44 of 115 patients (38.3%) treated with ETA in combination with any concomitant therapy could switch to ETA monotherapy. Therapy with ETA makes it possible to reduce the dosage or completely discontinue most concomitant medications (orGCs, NSAIDs, MTX) in a significant percentage of patients. This reduces the risk of development of NSAID- and GC-induced pathological conditions, while the effectiveness of therapy of the underlying condition remains high.

P058 LOW DOSE METHOTREXATE HAS SIMILAR OUTCOMES AS HIGH-DOSE METHOTREXATE IN COMBINATION WITH ANTI-TNF THERAPY IN INFLAMMATORY BOWEL DISEASES

Methotrexate (MTX) is a well-known immunomodulator in the treatment of inflammatory bowel disease (IBD) and often combined with biological agents. The ideal MTX dose for combination therapy has not been determined. Our aim is to investigate the effect of varying doses of MTX when used with anti-TNF agents in IBD on efficacy and safety outcomes. This study included patients with Crohn’s disease (CD) or ulcerative colitis (UC) receiving care between January 2005 and June 2018. Low-dose MTX was defined as ≤15mg/week and high-dose as >15mg/week. The primary efficacy outcome was a composite of need for IBD-related hospitalization or surgery, steroid initiation, or change of biologic agent within 1 year. Safety outcomes included side effects related to MTX, serious infections, malignancy and need to discontinue MTX therapy within 1 year. Multivariable logistic regression models adjusting for relevant covariates examined the independent association between MTX dose and outcomes. Our study included 222 patients with IBD (163 CD, 59 UC). Just over half were receiving low dose MTX (51%). We found no difference in gender, IBD type, disease location and behavior, disease duration, prior IBD treatments, serum albumin and CRP between the two groups. The primary efficacy composite outcome was noted in 51 patients (47%) in the high dose MTX group compared to 47 patients (42%) in the low-dose MTX group (p=0.436). After adjusting for relevant confounders, there remained no difference in primary outcome between the two dose groups of MTX (OR 0.62, 95% CI 0.31 – 1.24, p=0.179). Separately, we also observed no difference in hospitalization, surgery or steroid initiation within 1 year between the low-dose and high-dose MTX groups (Figure 1). MTX dosage was not associated with likelihood of side effects (high dose 22.9% vs low dose 27.4%, p=0.44). A total of 20 serious infections (9%) were reported during the first year of combination therapy but there was no significant difference between high versus low dose MTX (9.2% vs. 8.9%, p=0.93). We found no significant associations with MTX dose and any side effect (OR 1.34, 95% CI 0.67 – 2.70, p=0.410) or development of serious infections (OR 0.97, 95% CI 0.35 – 2.67, p=0.946). Two cases developed a malignancy (thyroid carcinoma and hepatocellular carcinoma) during the first year of combination therapy, both in the high dose MTX group. Discontinuation of MTX therapy occurred in one fourth of the low dose MTX patients (24.8%) and 29.5% in patients with high dose MTX (p=0.442). Low dose and high dose MTX combination therapy were equally effective and no difference in infection and malignancy rates was observed. There is an important need for prospective trials comparing low and high dose MTX when used in combination with biologic therapy to determine optimal dosing. Figure 1. Comparison of safety (a) and efficacy (b) outcomes between low dose MTX and high dose MTX combination therapy

Cotreatment with methotrexate in routine care patients with rheumatoid arthritis receiving biological treatment yields better outcomes over time

ObjectivesWe aimed to evaluate the effects of methotrexate (MTX) comedication added to biological disease-modifying antirheumatic drugs (bDMARD) on disease activity measures in patients with rheumatoid arthritis (RA) in routine care.MethodsPatients...

Perioperative Use of Methotrexate and Tumor Necrosis Factor α Inhibitors Combination Therapy Is Not Likely to Increase Post-Operative Infection Rate in the National Veterans Health Administration Administrative Databases

Objective: The aim of the study is to assess the risk of post-operative outcome in rheumatoid arthritis (RA) patients continuing versus stopping combination therapy of methotrexate (MTX) and hydroxychloroquine (HCQ) or tumor necrosis factor α inhibitors (TNF) prior to surgery. Methods: Using the United States Veterans Affairs (VA) databases, we identified surgical procedures in a 17-year cohort of RA patients. Among those patients, those on MTX + HCQ or MTX + TNF were identified. Post-operative outcome variables include infection, length of post-operative hospital stay and death. Results: We identified a total of 29,708 surgeries in RA patients. Among them, we identified the most recent elective surgeries without pre-operative infection in 16,174 patients. There were 783 and 550 patients on MTX + HCQ and MTX + TNF, respectively. The rates of post-op infection were 5% and 4% for the MTX + HCQ and MTX + TNF continuing medication groups, respectively, similar to the general RA population (5%). Sensitivity analyses at various time points of discontinuation combination therapies prior to surgery did not show significant change in terms of infection. Conclusions: The prevalence of adverse outcome is low. The proportion of post-operative infection in continuing and discontinuing medicine groups is similar for both MTX + HCQ and MTX + TNF. While we were unable to formally compare proportions of post-operative infection among the two groups, these preliminary findings do not support the hypothesis that continuing either MTX + TNF or MTX + HCQ combination during perioperative period increases post-operative infection compared with discontinuation prior to therapy.

Comparison of combination therapy with methotrexate and sinomenine or leflunomide for active rheumatoid arthritis: A randomized controlled clinical trial

BackgroundA combination of conventional disease-modifying anti-rheumatic drugs improves the treatment of rheumatoid arthritis but with high side-effects. Methotrexate (MTX) combination therapy that with high therapeutic efficacy and low toxicity is in demand in many countries to replace the use of expensive biological agents. Study designThis study was an open-label, 24-week, parallel randomized controlled trial conducted between November 2015 and December 2017. MethodsPatients were randomly assigned at a 3:2 ratio to receive MTX combined with sinomenine (SIN) at a dose of 120 mg twice daily, or leflunomide (LEF) at a dose of 20 mg once daily. Efficacy and safety were assessed at weeks 4, 12 and 24. The primary efficacy endpoint was the proportion of patients achieving an American College of Rheumatology (ACR)50 response and a European League Against Rheumatism (EULAR) good response at week 24. ResultsA total of 101/120 (84.2%) patients completed 24 weeks of observation. In the intention-to-treat (ITT) analysis, 65.3% of patients treated with MTX + SIN showed improved disease activity as determined by the ACR50 response at week 24 compared to 69.6% of patients treated with MTX + LEF. A similar insignificant pattern was found for the ACR20 and ACR70 responses, as well as the clinical disease activity index, EULAR response, and remission and low disease activity rates between these two treatment groups. The per-protocol analysis showed results consistent with those of the ITT analysis. Notably, significant reductions in gastrointestinal adverse reactions and liver toxicity were found in patients treated with MTX + SIN compared to patients treated with MTX + LEF (p < 0.05). ConclusionConsidering the balance of efficacy and toxicity, the current study provides evidence that MTX + SIN combination therapy is probably one of the choices for treating patients with active rheumatoid arthritis in addition to MTX + LEF combination therapy.