A systematic review and meta-analysis to determine relative efficacy and safety of iguratimod monotherapy for the treatment of patients with rheumatoid arthritis

Evidences suggest that iguratimod can be considered as a potential alternative to methotrexate for treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammation of synovial joints leading to progressive erosion of cartilage and bone. Although RA is an incurable disease but clinical remission can be achieved by optimized pharmacotherapy. Inflammatory cytokines plays a major role in disease progression by dysregulating the systemic and local immune systems. Therefore, therapeutic modalities are intended towards regulating these cytokines. Methotrexate and various other disease-modifying anti rheumatic drugs (DMARDs) is mainstay for management for RA, when used in combination as well as monotherapy. Studies revealed that approximately two third of RA patients treated with methotrexate needs substitution of methotrexate due to lack of efficacy and safety concerns.

Iguratimod is a novel synthetic DMARD recognized as first-line drug in RA in specific conditions by the Asia Pacific League of Association for Rheumatology (APLAR). It was initially used as an anti-inflammatory agent, later its promising potential as an antirheumatic agent was identified in several animal and human studies. Its antirheumatic effect is attributed to inhibition of antigen-specific T cell proliferation, TNF-α–stimulated production, signaling of interleukins, NF-kB and matrix metalloproteinase-3 expression and production of IgG and IgM. Several randomized and observational studies have been conducted to determine the efficacy and benefits of iguratimod, after its introduction in China and Japan since 2011-2012 respectively. A systematic review was also conducted to evaluate the efficacy and safety of iguratimod in comparison with other DMARDs, but the limited evidences suggested the need for further studies.

Rationale behind research

Previous literature lacks in establishing the efficacy and safety of iguratimod in the treatment of RA patients. Also the risks and benefits of iguratimod remain unknown. Therefore, the present systematic review was conduct to update the evidences of existing systematic review.

Objective

The present study was conducted to compare the efficacy and safety of the iguratimod with placebo and other disease-modifying anti rheumatic drugs (DMARDs) in adults with RA.

Literature search

A systematic search of studies was performed by two reviewers using Pub Med and MEDLINE (from 1946 onwards), Cochrane Central Register of Controlled Trials (CENTRAL), Embase Ovid (from 1974 onwards), China National Knowledge Infrastructure, Chinese Biomedical Literature database, WANFANG database, VIP information/ Chinese Scientific Journals database, and some Japanese databases. Trial registries were also searched from various other platforms including the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), Chinese clinical trial registry, ClinicalTrials.gov, UMIN Clinical Trial Registry, JMA clinical trial registry and JAPIC clinical trials information. Additional trials were also included from bibliographies of included/excluded studies.

Inclusion criteria

Studies were included if:

• they were parallel randomized controlled trials conducted for 24 to 28 weeks irrespective of time, language, and quality
• they constitute patients with at least 20 years old and were diagnosed with RA as per American College of Rheumatology (ACR) criteria
• they constitute patients with no other co morbidities, were not pregnant or breast feeding, and were not contraindicated to and previously treated with iguratimod
• they considered iguratimod monotherapy (50 mg/ day) as the intervention drug and placebo and all the other DMARD monotherapy as a comparator drug

Study selection

Two reviewers collected and extracted data from selected trials in a preformed data collection form independently. Search results and extracted data were compared and any discrepancies were resolved by discussion. Corresponding authors were mailed to collect missing information and to reassure any reported information.

Quality assessment

The certainty and quality of evidences was rated by two reviewers independently using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach applying the GRADEpro GDT software.

Data extraction

The data related to study design, patient demographics, improvement in ACR status, functional ability, disease status, pain intensity and safety outcomes after administering iguratimod, placebo and other DMARDs was extracted. The odds were compared for both efficacy and safety outcomes between the intervention and comparator group using a post hoc analysis.

Data Analysis and Risk of Bias

A superiority meta-analysis (with placebo) and non-inferiority meta-analysis (with other DMARDs) was performed using the Review Manager (RevMan 5) software and random effects model. Dichotomous and continuous outcomes were estimated using the Mantel Haenszel (MH) method and the inverse variance (IV) method respectively. Effect estimates were generated using mean difference at 95% CI for disease status, pain intensity, patient assessment of disease activity; odds ratio at 95% CI for ACR 20, ACR 50, ACR 70, and safety outcomes; and standardized mean difference (SMD) at 95% CI for tender joint count (TJC), swollen joint count (SJC), and HAQ. Statistical data was presented on forest plots.

Risk of bias was calculated using revised Cochrane risk-of-bias tool for randomized trials whereas the heterogeneity among studies was estimated by I² statistics and chi square test. If the total number of participants/ events failed to satisfy optimal information size, the outcomes were downgraded for imprecision. 

Study outcomes

• Primary outcome included a 20% improvement in American College of Rheumatology Criteria (ACR 20), functional ability measured using the health assessment questionnaire (HAQ), disease status of patients measured using disease activity score in 28 joints (DAS28) 
• Secondary outcomes included a 50% and 70% improvement in American College of Rheumatology Criteria (ACR 50, ACR 70), tender joint count (TJC), swollen joint count (SJC), pain intensity measured using VAS 100- mm scale, and patient’s & physician’s global assessment of disease activity measured using VAS 100-mm scale
• Other outcomes included incidence of adverse events calculated by comparing odds for withdrawal of participants due to adverse events, the incidence of abnormal hematological values, the elevated liver enzymes, and dermatological disorders between the groups

Outcomes

Study characteristics: A total of 12 trials involving 1938 participants were included. Among 12 trials, 4 trials were double-blinded, 3 were multicentre, 1 was single-blinded and others trials did not report any information

Study quality: Ten trials reported to have high risk of bias, only one trial reported low risk of bias and remaining one trial was judged to have some concerns of bias

Effect of intervention on outcome:

• There was a significant improvement in all primary and secondary efficacy outcomes except for CRP in iguratimod group when compared to placebo
• Similar treatment response, 50% and 70% improvement in ACR criteria and functional ability at 24 weeks was observed in iguratimod group when compared to other DMARDs
• A significantly lower CSR and ESR values were obtained in the patients treated with iguratimod when compared to other DMARDs
• Swollen joint count, tender joint count, pain intensity, and patient's and physician's global assessment of disease state were comparable between both iguratimod and other DMARDs group
• Similar odds of adverse events were reported in both the iguratimod and other DMARDs group

The present review provides an evidence based recommendation for practice, by bringing together evidences collected from the randomized controlled trials. The findings suggested the superiority of iguratimod over placebo in terms of all the efficacy outcomes, except CRP due to heterogeneity among trials in CRP. The patients treated with iguratimod reported higher adverse effects when compared with placebo; however, these safety results may be imprecise. Other safety analysis did not report any greater harm with iguratimod.

When compared to DMARDs, iguratimod was comparable to other DMARDs in both efficacy and safety analyses. Moreover, iguratimod had lower CRP values and better disease state at 24 weeks than other DMARDs. The certainty of the evidence was low to moderate and the heterogeneity in the ACR 20, ACR 50, ACR 70, and HAQ was low and insignificant. These results imply that the benefit of iguratimod 50 mg was comparable (better for HAQ) with other DMARDs for these outcomes irrespective of the disease duration, baseline disease state, and sensitivity to other DMARDs.

The current analysis is based on the random effects model; however, some significant changes in the results of some efficacy outcomes may occur in sensitivity analysis using the fixed effect model. Patients treated with iguratimod shows superior CRP value when compared to placebo, when applying the fixed-effect model. Similarly, iguratimod showed better swollen joint count, pain intensity, and patient’s and physicians global assessment of disease activity score in comparison with other DMARDs. These differences resulted when the same trials were assigned different weightage in different models.

The findings of the present systematic review were consistent with the results of previous systematic reviews suggesting similar efficacy and safety of iguratimod when compared to methotrexate and salazosulfapyridine. However, the current review did not present any information about the benefits and harms of iguratimod in doses other than 50 mg and treatment duration shorter or longer than 24 to 28 weeks. There is a need to conduct larger and high-quality trials in a diverse population group to provide strong confidence and support these findings.