Methotrexate Combination Therapy Research Articles

Methotrexate inhibits glucocorticoids-induced osteoclastogenesis via activating IFN-γR/STAT1 pathway in the treatment of rheumatoid arthritis

ObjectivesRheumatoid arthritis (RA) is a chronic autoimmune disease characterised by the synovitis and bone erosion. The combination therapy of glucocorticoids (GCs) and methotrexate (MTX) is recommended in early RA management,...

Efficacy and safety of methotrexate plus hydroxychloroquine combination therapy vs. methotrexate monotherapy in the treatment of rheumatoid arthritis: A randomized controlled clinical trial.

To explore the efficacy and safety of combination therapy with methotrexate (MTX) plus hydroxychloroquine (HCQ) vs. MTX monotherapy in patients with rheumatoid arthritis (RA). Sixty patients without prior RA treatments were randomly allocated in a 1:1 ratio to two groups: one receiving MTX plus HCQ, and the other receiving MTX monotherapy. We conducted a comparative analysis before and after the 12-week trial, evaluating the visual analogue scale (VAS), the disease activity score in 28 joints (DAS), serum inflammatory factor (including serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), as well as the outcome of the World Health Organization Quality of Life Brief Version questionnaire (WHOQOL-BREF) and the treatment-emergent adverse events (TEAEs) for all the participants in the study. At the 12th week of the trial, a more remarkable decrease in pain score (VAS), disease activity score (DAS), and serum inflammatory factor levels could be noticed in individuals on the combination therapy. The quality of life score was as well found to be higher in the MTX + HCQ group than the MTX monotherapy group. The incidence of adverse reactions in the MTX + HCQ and the MTX monotherapy groups were 10.00% and 6.67%, respectively. However, no statistical significance could be observed (p > .05). In our study, both the MTX + HCQ combination therapy and MTX monotherapy demonstrated improvements in symptoms, conditions and quality of life for patients with RA. Notably, the combination therapy could achieve better outcomes across all indices compared to MTX monotherapy, highlighting its potential as the optimal first-line treatment for RA. © 2024 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

Increasing the etanercept dose in a treat-to-target approach in juvenile idiopathic arthritis: does it help to reach the target? A post-hoc analysis of the BeSt for Kids randomised clinical trial

BackgroundEtanercept has been studied in doses up to 0.8 mg/kg/week (max 50 mg/week) in juvenile idiopathic arthritis (JIA) patients. In clinical practice higher doses are used off-label, but evidence regarding the relation with outcomes is lacking. We describe the clinical course of JIA-patients receiving high-dose etanercept (1.6 mg/kg/week; max 50 mg/week) in the BeSt for Kids trial.Methods92 patients with oligoarticular JIA, RF-negative polyarticular JIA or juvenile psoriatic arthritis were randomised across three treat-to-target arms: (1) sequential DMARD-monotherapy (sulfasalazine or methotrexate (MTX)), (2) combination-therapy MTX + 6 weeks prednisolone and (3) combination therapy MTX + etanercept. In any treatment-arm, patients could eventually escalate to high-dose etanercept alongside MTX 10mg/m2/week.Results32 patients received high-dose etanercept (69% female, median age 6 years (IQR 4–10), median 10 months (7–16) from baseline). Median follow-up was 24.6 months. Most clinical parameters improved within 3 months after dose-increase: median JADAS10 from 7.2 to 2.8 (p = 0.008), VAS-physician from 12 to 4 (p = 0.022), VAS-patient/parent from 38.5 to 13 (p = 0.003), number of active joints from 2 to 0.5 (p = 0.12) and VAS-pain from 35.5 to 15 (p = 0.030). Functional impairments (CHAQ-score) improved more gradually and ESR remained stable. A comparable pattern was observed in 11 patients (73% girls, median age 8 (IQR 6–9)) who did not receive high-dose etanercept despite eligibility (comparison group). In both groups, 56% reached inactive disease at 6 months. No severe adverse events (SAEs) occurred after etanercept dose-increase. In the comparison group, 2 SAEs consisting of hospital admission occurred. Rates of non-severe AEs per subsequent patient year follow-up were 2.27 in the high-dose and 1.43 in the comparison group.ConclusionsEscalation to high-dose etanercept in JIA-patients who were treated to target was generally followed by meaningful clinical improvement. However, similar improvements were observed in a smaller comparison group who did not escalate to high-dose etanercept. No SAEs were seen after escalation to high-dose etanercept. The division into the high-dose and comparison groups was not randomised, which is a potential source of bias. We advocate larger, randomised studies of high versus regular dose etanercept to provide high level evidence on efficacy and safety.Trial registrationDutch Trial Register; NTR1574; 3 December 2008; https://onderzoekmetmensen.nl/en/trial/26585.

Risks of malignant lymphoma in rheumatoid arthritis patients receiving methotrexate-alone and in combination therapy compared with the general population: A study based on a Japanese medical claims database.

The risk of malignancy in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) and biological disease-modifying antirheumatic drug (bDMARD) combination therapy is unknown. This study aimed to clarify the incidence of malignancy and the recommended monitoring period in patients receiving this combination therapy. A retrospective, observational study based on a large Japanese medical claims database was conducted between April 2013 and February 2020. Patients with RA were classified into MTX-alone and combination therapy groups, and the standardized incidence rates (SIR) of malignancy were calculated. The time of onset of malignancy in both groups was calculated. In total, 2,052 patients received MTX-alone and 782 received combination therapy. The incidence of malignant lymphoma was significantly higher with MTX-alone therapy (SIR: 6.09, 95% confidence interval (CI): 1.58-10.61) and combination therapy (SIR: 20.86, 95% CI: 8.53-33.19) than in the general Japanese population. Furthermore, the combination therapy had a significantly higher risk of malignant lymphoma than the MTX-alone therapy (adjusted odds ratio: 4.27, 95% CI: 1.64-11.12). The median time from MTX prescription to the onset of malignant lymphoma was 3.58 years (interquartile range (IQR): 2.00-5.34 years) for MTX-alone and 3.42 years (IQR: 1.25-4.92 years) for combination therapy. The incidence of malignant lymphoma in the combination therapy group was extensively higher than that in the general Japanese population. Special attention is required for early symptoms of malignant lymphoma, particularly in the 3rd - 4th year after initiating MTX therapy.

The use of methotrexate in rheumatoid arthritis. Recommendations of the All-Russian public organization “Association of Rheumatologists of Russia”

Rheumatoid arthritis (RA) is the most frequent immunoinflammatory (autoimmune) rheumatic disease characterized by chronic erosive arthritis and systemic damage to internal organs. The data obtained in the course of basic research on deciphering the mechanisms of action of methotrexate (MT) and the materials of numerous randomized placebocontrolled trials, observational studies and national registries have strengthened the position of MT as the “gold standard” of RA pharmacotherapy and a key component of the “Treatment to Target” strategy. This was the basis for the development of new recommendations of the Association of Rheumatologists of Russia (ARR) concerning the use of MT in RA, according to which MT is considered as the drug of “choice” for induction and maintenance of remission in patients with early and advanced RA, including those who need combination therapy of MT with glucocorticoids, standard Disease-Modifying Antirheumatic Drugs (DMARDs), biologics and targeted synthetic DMARDs. Special attention is paid to the safety of MT therapy and the impact of MT on comorbid pathology associated with cardiovascular complications and interstitial lung disease. Implementation of the ARR recommendations into clinical practice will reduce the risk of disability and improve life prognosis in patients with RA.

A Combination Therapy of Methotrexate and Xianling Gubao Capsule for Female Patients with Moderate to Severe Active Rheumatoid Arthritis and its Impact on Ovarian Function

Rheumatoid arthritis is a common immune disease with early symptoms of joint swelling, morning stiffness, pain, and swelling. It could develop into a joint deformity as the disease progresses, resulting in the loss of normal joint function and seriously affecting the patient’s quality of life. Methotrexate is the “anchor drug” for rheumatoid arthritis treatment, which has an immunosuppressive effect and could effectively prevent the abnormal activation of B cells in vivo, inhibit the abnormal generation of cytokines, and relieve related symptoms. However, in some cases, methotrexate alone is not ideal and often needs to be combined with other drugs like xianlinggubao capsules. This study has provided an experimental basis for the combined efficacy of methotrexate and xianlinggubao capsules for female patients with moderate to severe rheumatoid arthritis and their impact on ovarian function.

Tripterygium wilfordii Hook F combination therapy with methotrexate for rheumatoid arthritis: An updated meta-analysis.

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory arthropathy. Tripterygium wilfordii Hook F (TwHF) is common herbal medicine for the treatment of RA in China. However, many important issues, such as efficacy, safety and optimal doses of the combination therapy of TwHF and Methotrexate (MTX) for RA remain to be evaluated. This study aims to evaluate the efficacy and safety of combination therapy of TwHF and MTX for RA by meta-analysis of randomized clinical trials (RCTs). Relevant literature was searched from English (PubMed, Web of Science, EMBASE, and Cochrane library) and Chinese databases (WanFang, VIP, CNKI) until December 2021. Response rates and rates of adverse events (AEs) were independently extracted and analyzed. Fourteen randomized controlled trials (RCTs) were included with a total of 1446 patients, which included eight new RCTs with a total of 803 new patients when compared with the previous meta-analysis (Wang et al., 2017). Compared to MTX monotherapy, TwHF+MTX was revealed a higher effective rate (RR=1.15, 95% CI: 1.10, 1.21), partial remission rate (RR=1.27, 95% CI: 1.15, 1.40) and remission rate (RR=1.31, 95% CI: 1.11, 1.55). The addition of TwHF benefited the clinical symptoms (such as tender joint count) and most laboratory indexes (such as the tumor necrosis factor-α). According to the subgroup analyses, the efficacy of the TwHF+MTX seems to be positively associated with the dose of TwHF (10mg/d vs 30-60mg/d), negatively related to the dose of MTX (∼10 mg/w vs ∼15 mg/w) and methodological risk of bias of included RCTs, and unrelated to the duration of therapy (12-week vs 24-week). For safety, the addition of TwHF did not increase the risk of most AEs and even reduced the risk of infection and liver AEs. Combining TwHF with MTX may be a superior strategy in the treatment of RA compared with MTX monotherapy. The optimal combination of TwHF+MTX therapy might be TwHF at 30-60mg/d with MTX (∼10 mg/w). Further high-quality double-blind RCTs may be able to change the conclusions of our study, which are still warranted.

Febrile Ulceronecrotic Mucha-Habermann Disease: A Case Report and Review of Literature in the Paediatric Population

Febrile ulceronecrotic Mucha-Habermann disease (FUMHD) is a rare fulminant variant of pityriasis lichenoides et varioliformis acuta (PLEVA) that is characterized by a large ulceronecrotic appearance with high fever and a variety of systemic symptoms. We report here a case of FUMHD in a 17-year-old male Chinese patient who was treated successfully with a combination therapy of methotrexate, methylprednisolone, and intravenous immunoglobulin. In addition, a literature review was conducted to summarize the key characteristics of paediatric FUMHD cases.

Risk factors associated with relapse after methotrexate dose reduction in patients with rheumatoid arthritis receiving golimumab and methotrexate combination therapy.

To identify risk factors for relapse after methotrexate (MTX) dose reduction in rheumatoid arthritis (RA) patients receiving golimumab (GLM)/MTX combination therapy. Data on RA patients ≥20 years old receiving GLM (50 mg) + MTX for ≥6 months were retrospectively collected. MTX dose reduction was defined as a reduction of ≥12 mg from the total dose within 12 weeks of the maximum dose (≥1 mg/wk average). Relapse was defined as Disease Activity Score in 28 joints using C-reactive protein level (DAS28-CRP) score ≥3.2 or sustained (≥ twice) increase of ≥0.6 from baseline. A total of 304 eligible patients were included. Among the MTX-reduction group (n = 125), 16.8% of patients relapsed. Age, duration from diagnosis to the initiation of GLM, baseline MTX dose, and DAS28-CRP were comparable between relapse and no-relapse groups. The adjusted odds ratio (aOR) of relapse after MTX reduction was 4.37 (95% CI 1.16-16.38, P = 0.03) for prior use of non-steroidal anti-inflammatory drugs (NSAIDs), and the aORs for cardiovascular disease (CVD), gastrointestinal disease and liver disease were 2.36, 2.28, and 3.03, respectively. Compared to the non-reduction group, the MTX-reduction group had a higher proportion of patients with CVD (17.6% vs 7.3%, P = 0.02) and a lower proportion of prior use of biologic disease-modifying antirheumatic drugs (11.2% vs. 24.0%, P = 0.0076). Attention should be given to RA patients with history of CVD, gastrointestinal disease, liver disease, or prior NSAIDs-use when considering MTX dose reduction to ensure benefits outweigh the risks of relapse.

Comparative Effectiveness of Anti-TNF in Combination With Low-Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn’s Disease: A Pragmatic Randomized Trial

Tumor necrosis factor inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn's disease therapy; however, nonresponse and loss of response are common. As combination therapy with methotrexate may improve response, we performed a multicenter, randomized, double-blind, placebo-controlled pragmatic trial to compare tumor necrosis factor inhibitors with oral methotrexate to tumor necrosis factor inhibitor monotherapy. Patients with pediatric Crohn's disease initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12-36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included anti-drug antibodies and patient-reported outcomes of pain interference and fatigue. Adverse events (AEs) and serious AEs (SAEs) were collected. Of 297 participants (mean age, 13.9 years, 35% were female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). In the overall population, time to treatment failure did not differ by study arm (hazard ratio, 0.69; 95% CI, 0.45-1.05). Among infliximab initiators, there were no differences between combination and monotherapy (hazard ratio, 0.93; 95% CI, 0.55-1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (hazard ratio, 0.40; 95% CI, 0.19-0.81). A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio, 0.72; 95% CI, 0.49-1.07; adalimumab: odds ratio, 0.71; 95% CI, 0.24-2.07). No differences in patient-reported outcomes were observed. Combination therapy resulted in more AEs but fewer SAEs. Among adalimumab but not infliximab initiators, patients with pediatric Crohn's disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile. gov, Number: NCT02772965.

Combination Therapy for Psoriasis with Methotrexate and Other Oral Disease-Modifying Antirheumatic Drugs: A Systematic Review

Although the introduction of biologics and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) has reshaped the treatment paradigm for immune-mediated inflammatory diseases (IMIDs) such as psoriasis, oral conventional synthetic DMARDs (csDMARDs) remain the cornerstone in their treatment. Combinational use of DMARDs is common in rheumatological practice, but for the treatment of many skin diseases, dermatologists typically use a single oral DMARD, with methotrexate (MTX) being the most commonly prescribed csDMARD for psoriasis. To better understand the potential benefits of MTX combination therapy in psoriasis, a literature review was conducted using Medline (PubMed), Embase, Web of Science, and the Cochrane Library, covering articles published from inception untilOctober 2022. Randomized controlled trials, cohort, open-label, and observational studies, and case reports with efficacy and safety results for combination therapy with MTX, csDMARDs, and tsDMARDs or comparisons between MTX monotherapy and combination therapy with other oral DMARDs in psoriasis were included. Studies involving MTX monotherapy alone or sequential treatment with MTX and other oral DMARDs were excluded, as were non-English articles. The results are presented as a systematic review, and the risk of bias was assessed by the corresponding author using the Cochrane Handbook for Systematic Reviews of Interventions, version 6.3, and confirmed by an independent assessor. Eleven studies comprising 494 participants were included in the review. Overall, combination treatment with MTX and other oral DMARDs exhibited good efficacy and tolerability in psoriasis. However, the included studies were primarily small scale or retrospective, and larger prospective randomized trials are needed to provide stronger evidence. This literature review suggests that combination therapy with MTX and csDMARDs may serve as an efficacious treatment for psoriasis patients with an inadequate response to oral DMARD monotherapy.

Comparison of the efficacy and safety of methotrexate alone or in combination with leflunomide in the treatment of juvenile idiopathic arthritis: a double-blind, placebo-controlled, randomized trial.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disorder in children. Although methotrexate (MTX) is the first line disease-modifying antirheumatic drug for JIA, many patients do not respond well or cannot tolerate MTX. The aim of this study was to compare the effect of combination therapy of MTX and leflunomide (LFN) with MTX in patients who do not respond to MTX. Eighteen patients (2-20 years old) with polyarticular, oligoarticular or extended oligoarticular subtypes of JIA who did not respond to conventional JIA therapy participated in this double-blind, placebo-controlled, randomized trial. The intervention group received LFN and MTX for 3 months while the control group received oral placebo and MTX at a similar dose to the intervention group. Response to treatment was assessed every 4 weeks using the American College of Rheumatology Pediatric criteria (ACRPed) scale. Clinical criteria, including number of active joints and restricted joints, physician and patient global assessment, Childhood Health Assessment Questionnaire (CHAQ38) score, and serum erythrocyte sedimentation ratelevel, did not differ significantly between groups at baseline and at the end of the 4th and 8th weeks of treatment. Only the CHAQ38 score was significantly higher in the intervention group at the end of the 12th week of treatment. Analysis of the effect of treatment on study parameters revealed that only the global patient assessment score differed significantly between groups (p = 0.003). The results of this study showed that combining LFN with MTX does not improve clinical outcomes of JIA and may increase side effects in patients who do not respond to MTX.

Evaluation of cost-effectiveness of various drugs used in the treatment of rheumatoid arthritis: An observational and prospective study

Background: Rheumatoid arthritis (RA) is a joint disorder which affects the quality of life. Early diagnosis and symptomatic treatment can reduce the progression of disease. The treatment is associated with multiple drug therapy for long time. The use of multiple drugs can affect the patient’s economic status. The present study aimed to evaluate the cost-effectiveness of drugs used in the treatment of RA. Aims and Objectives: The aim of the study was to evaluate the cost of mono and multiple drug therapy in the treatment of RA. Materials and Methods: The study was conducted in the Department of Pharmacology and Orthopedic of Adichunchanagiri Institute of Medical Sciences, Karnataka for 6 months. A total of 50 patients were screened and 16 patients were included in the study. All the patients were explained study protocol and informed consent was obtained. Data related to age, gender, past history, and type of drug usage were recorded and analyzed. Microsoft Excel and SPSS (20.0) version were used for analysis. Results: A total of 16 patients were analyzed in the study. The average cost-effective ratio was high for methotrexate and low is hydroxychloroquine. Comparison of cost-effectiveness between different drug combination therapies not showed any significant difference. Combination of non-steroidal anti-inflammatory drugs drug therapy has low cost compared to monoclonal antibody combination therapy. Conclusion: Methotrexate and hydroxychloroquine combination therapy showed a high cost compared to monotherapy. Combination of low-price drugs can reduce the economic burden on patients.

Efficacy of synthetic and biological DMARDs: a systematic literature review informing the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis

ObjectivesTo update the evidence on efficacy of DMARDs (disease-modifying antirheumatic drugs) and inform the taskforce of the 2022 update of the European Alliance of Associations for Rheumatology (EULAR) recommendations for...

A Comparative Study of Oral Methotrexate and Combination of Oral Methotrexate and Narrow Band Ultraviolet-B in Chronic Plaque Psoriasis

Background: Psoriasis is a chronic common skin condition which alters the skin appearance, causes an inflammation in the outerepidermis, and proliferates the skin epidermal layers. It is influenced by both genomic and other external factors like environmental factors.1The most common lesions are red, scaly, sharply demarcated plaques that appear primarily on extensor surfaces. Psoriasis exhibits a chronic relapsing nature and variable clinical features. The cutaneous lesions are typically thus distinct for clinical diagnosis. Material & Methods: Prospective hospital based observational study. The study was conducted in Department of Department of Dermatology, Narayana Medical College, Nellore, A.P. Patients of chronic plaque psoriasis not responding to any other therapeutic modality. Initially a detailed history regarding the age of onset, the duration of illness, past modalities of treatment, family history of the disease, seasonal variation, other triggering factors, occupation were taken. The patients were explained regarding the duration of treatment, the need for regular follow up of therapy, clinic and probable side effects that could be encountered during treatment. Results: Among all (n=50 including group A and B, 25 of each) participants, relapse of treatment in weeks observed between the range of 6-12, mean was 9 with the standard deviation of 1.6 in group A. For group B relapse of medical regimen in weeks observed between the range 8-12, Mean was 10.5 with the standard deviation of 1.9 which is nearly similar in group A. This results were statistically significant as p= 0.01 where p<0.05. Conclusion: From our study it,we concluded that Combination therapy of oral methotrexate and NBUVB is found to be most effective, feasible from the economic point of view as well as the side effects profile and patient compliance.

Combination of Methotrexate and Leflunomide Is Efficient and Safe for 60 Patients with Rheumatoid Arthritis.

The present work is aimed at exploring the clinical efficacy and safety of methotrexate (MTX) and leflunomide (LEF) combination therapy for rheumatoid arthritis. From June 2019 to June 2021, a total of 120 individuals with rheumatoid arthritis received a diagnosis. Sixty patients each were randomly assigned to the control and observation groups. The observation group received MTX and LEF combo medication while the control group only received MTX treatment. Clinical efficacy, complication incidence, and the alleviation of inflammatory markers, joint pain, and clinical symptoms were compared between the 2 groups. Posttreatment, the observation group had overall response rate of 96.66%, while the control group had 86.67%, with significant differences. Compared with pretreatment, both control and observation group patients showed decreasing trends of IL-1 levels and increasing trends of IL-10 levels posttreatment, with significant differences (P < 0.05). Compared with the control group, patients in the observation group had lower IL-1 and TNF-α levels with significant differences (P < 0.05) and higher levels of IL-10 with significant difference (P < 0.05). In both groups, the pain score and the number of painful joints were much lower than they were prior to treatment. Following treatment, the observation group displayed significantly lower levels of erythrocyte sedimentation rate, rheumatoid factor, and C-reactive protein than the control group (P < 0.05). Clinical measures in the observation group were all lower than those in the control group with statistically significant differences (P < 0.05). Moreover, the incidence rate of adverse reactions showed no significant difference between these 2 groups (P > 0.05). In conclusion, the combination therapy of MTX and LEF is efficacious for rheumatic arthritis.

Retrospective analysis of methylprednisolone treatment alone and in combination with methotrexate in patients with extensive alopecia areata.

Alopecia areata (AA) is a chronic autoimmune disorder that primarily affects the hair follicle. Systemic corticosteroids and methotrexate (MTX) are among the therapeutic options in severe cases. This study aimed to show whether the combination therapy of methylprednisolone (MP) and MTX was superior to MP alone in the management of extensive AA. A total of 26 patients with extensive AA, 14 treated with MP alone and 12 treated with the combination of MP and MTX, were retrospectively evaluated in terms of gender, age, severity of disease, clinical characteristics, disease duration, dose and duration of medications, therapy response, and side effects. Of the 26 patients with extensive AA, 14 were male and 12 were female, and the average age was 17.02 ± 10.70 years. All patients had more than 50% hair loss, 23 had extensive multifocal AA, and three had alopecia totalis. A total of 14 patients were treated with MP alone (starting dose: 0.3-0.5mg/kg, maximum 32 mg/day), and 12 were treated with MP + MTX (starting dose: 5-15 mg/week, maximum 20 mg/week). A total of 12 of the 14 patients (85.7%) who were treated with MP alone showed a complete response, with the response rate of the patients who showed more than 50% response being 92.85%. Seven of the 12 patients (58.3%) who were treated with MP + MTX achieved complete healing, and all patients on this regimen had more than 50% treatment response. Our results showed that the combination therapy of MP and MTX was not superior to MP alone in the management of extensive alopecia areata.

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

Conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs) are the preferred first-line treatment in patients with psoriatic arthritis, although there is a paucity of evidence for the efficacy of conventional synthetic DMARDs and especially their combination. We aimed to investigate whether a combination of methotrexate plus leflunomide is superior to methotrexate monotherapy at improving disease activity in patients with psoriatic arthritis. This single centre, investigator-initiated, double-blind, randomised, placebo-controlled trial was conducted at Sint Maartenskliniek in the Netherlands (locations included Boxmeer, Geldrop, Woerden, and Nijmegen). Patients aged 16 years or older with a clinical diagnosis of psoriatic arthritis and active disease (defined as two or more swollen joints; dactylitis counting as one swollen joint) were included. Patients were randomly allocated (1:1) and stratified by high disease activity (psoriatic arthritis disease activity score [PASDAS] ≥5·4) to either methotrexate plus leflunomide (combination therapy) or methotrexate plus placebo (monotherapy), using computer-generated stratified variable block randomisation. In both groups, patients received oral methotrexate 15 mg per week for the first 4 weeks and 25 mg per week thereafter combined with two leflunomide 10 mg tablets once per day or two placebo tablets. During the study period, the patients, nurses, researchers, and treating physicians were all masked to treatment allocation. The primary outcome was the difference in mean PASDAS at week 16, adjusted for baseline PASDAS, between the combination and monotherapy groups, assessed in the intention-to-treat population. This trial was registered with the Netherlands Trial Register (NL7404) on Dec 3, 2018. Between Feb 19, 2019, and March 11, 2021, 82 patients were screened for eligibility. Four patients were ineligible and 78 were enrolled and randomly assigned to either methotrexate plus leflunomide (n=39) or methotrexate plus placebo (n=39). 50 (64%) of 78 patients were male, 28 (36%) were female, and the median age of patients was 55·0 years (IQR 42·0-64·0). Methotrexate plus leflunomide combination therapy was superior to methotrexate monotherapy at week 16 (PASDAS 3·1 [SD 1·4] vs 3·7 [SD 1·3]; treatment difference -0·6, 90% CI -1·0 to -0·1; p=0·025). There were no study deaths. The most frequently occurring adverse events were nausea or vomiting (17 [44%] of 39 patients in the methotrexate plus leflunomide group vs 11 [28%] of 39 in the methotrexate plus placebo group), tiredness (9 [23%] vs 13 [33%]) and elevated alanine aminotransferase (12 [31%] vs 7 [18%]. Generally, the incidence of mostly mild adverse events was higher in the methotrexate plus leflunomide group than in the methotrexate plus placebo group. Methotrexate plus leflunomide combination therapy results in greater improvement in disease activity according to PASDAS in patients with psoriatic arthritis. However, methotrexate plus leflunomide combination therapy is less well tolerated than methotrexate monotherapy. Regional Junior Researcher Grant from the Sint Maartenskliniek.

Efficacy of Tocilizumab Monotherapy Versus Tocilizumab and Methotrexate Combination Therapy in the Prevention of Radiographic Progression in Rheumatoid Arthritis: An Analysis Using Individual Patient Data From Multiple Clinical Trials

ObjectiveTo compare the effects of preventing radiographic progression (in its 3 components) of tocilizumab (TCZ) monotherapy with those of TCZ and methotrexate (MTX) in combination therapy (TCZ + MTX), and to evaluate possible effect modifiers in this model.MethodsRandomized trials that compared TCZ monotherapy to TCZ + MTX combination therapy for differences in radiographic progression were analyzed on an individual patient data level using mixed‐effects models, and data were collected from 820 subjects with either early rheumatoid arthritis (RA) or established RA. Outcomes were classified as the absence of radiographic progression after 2 years (i.e., preventing radiographic progression) as measured by total Sharp/van der Heijde score (SHS), erosion score, and joint space narrowing (JSN) score. Effect modification by baseline joint damage, disease duration, and Disease Activity Score in 28 joints (DAS28) was studied.ResultsOverall, TCZ + MTX combination therapy was more effective in preventing radiographic progression compared to TCZ monotherapy, which was measured by total SHS score. However, in patients with early RA who had more joint damage compared to those with less joint damage at baseline (relative risk [RR] 1.02 versus RR 0.91, respectively) or in patients with a lower DAS28 score compared to those with a higher DAS28 score (RR 1.04 versus RR 0.92, respectively) at baseline, this advantage disappeared. In patients with established RA, the advantage of TCZ + MTX versus TCZ alone in the prevention of radiographic progression disappeared with a longer disease duration at baseline (RR 1.04 versus 0.83). Results of erosion scores as an outcome were in line with these findings, though findings for JSN scores were less clear.ConclusionCombination therapy with TCZ + MTX is more effective in preventing radiographic progression compared to TCZ monotherapy, but the effectiveness of TCZ monotherapy may approximate the effectiveness of TCZ + MTX in patients with early RA who have more joint damage and/or a lower DAS28 at baseline and in patients with established RA who have longer disease duration.

Adalimumab with Methotrexate vs. Adalimumab Monotherapy in Psoriasis: First-Year Results of a Single-Blind Randomized Controlled Trial

Adalimumab is normally prescribed with methotrexate (MTX) in rheumatoid arthritis given the enhanced treatment effect and reduced antidrug antibody formation compared with adalimumab monotherapy (ADL). In psoriasis, the long-term treatment effects and pharmacokinetic profile have not been investigated extensively. We conducted a randomized controlled trial to assess the efficacy, safety, pharmacokinetics, and immunogenicity of adalimumab combined with MTX 10 mg per week (ADL-MTX group) compared with that of ADL (ADL group) in chronic plaque psoriasis. A total of 31 patients in the ADL-MTX group and 30 in the ADL group were analyzed. After 1 year, a (nonsignificant) better drug survival was found in the ADL-MTX group (74.2 vs. 58.6%, P= 0.15). The PASI 75 response in week 49 was 58.1 versus 36.7% (P= 0.13), and the median (interquartile range) serum-trough concentrations were 6.8 (5.5‒9.2) versus 5.9 (3.5‒8.8) mg/l (P= 0.26) in the ADL-MTX group and ADL group, respectively. Fewer patients showed antidrug antibodies in the ADL-MTX group (22.6 vs. 60.0%, P < 0.01). No serious adverse events occurred. Combination therapy of adalimumab and MTX results in fewer patients showing antidrug antibodies, with a trend toward a better PASI 75 response, drug survival, and higher serum-trough concentrations than ADL. Patient-reported outcomes and adverse events were comparable between the groups.