Effectiveness of iguratimod as monotherapy or combined therapy in patients with rheumatoid arthritis: a systematic review and meta-analysis of RCTs

Background This study aims to evaluate the efficacy and safety of the iguratimod (IGU) as monotherapy or combined therapy in patients with rheumatoid arthritis (RA) by using meta-analysis. Methods We searched Medline, EMBASE, Cochrane library, CNKI, Wanfang medical network from initial to 30 June, 2020, for randomized clinical trials (RCTs). Two authors independently screened the studies via reading the title, abstract, and full text. The risk of bias in individual studies was assessed using the Cochrane Risk of Bias tool. STATA 12.0 was used for pooled analysis of all included studies. Results A total of 23 RCTs were included in this analysis. Meta-analysis showed that patients in the IGU monotherapy or combined therapy group had significantly higher ACR20 (OR = 1.97, 95% CI 1.29 to 3.00, P = 0.002), lower DAS28-CRP (SMD = −3.49, 95% CI −5.40 to −1.58, P < 0.001) and DAS28-ESR (SMD = −2.61, 95% CI −3.64 to −1.57, P < 0.001), as well as shorter duration of morning stiffness (SMD = −2.06, 95% CI −2.86 to −1.25, P < 0.001) and lower HAQ score (SMD = −0.91, 95% CI −1.61 to −0.21, P = 0.011), than those received other disease-modifying antirheumatic drugs (DMARDs) monotherapy (primarily comprising methotrexate). For the safety profile, IGU monotherapy had similar risks for gastrointestinal reactions (P = 0.070), leucopenia (P = 0.309), increment in transaminase (P = 0.321), increase of ALT (P = 0.051), and liver damage (P = 0.182) to methotrexate monotherapy, and IGU combined with other DMARDs therapy did not increase the risks of these AEs (P > 0.05). Conclusions Our evidence suggests that IGU is effective and tolerant as monotherapy or combined therapy especially with methotrexate in patients with active RA. IGU may be regarded as a potential alternative to methotrexate, and a preferable choice when combined with other DMARDs for the treatment of RA. Supplementary Information The online version contains supplementary material available at 10.1186/s13018-021-02603-2.

Conclusions: Our evidence suggests that IGU is effective and tolerant as monotherapy or combined therapy especially with methotrexate in patients with active RA. IGU may be regarded as a potential alternative to methotrexate, and a preferable choice when combined with other DMARDs for the treatment of RA.
Keywords: Iguratimod, Monotherapy, Combined therapy, Rheumatoid arthritis, Meta-analysis Background Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease, which is characterized by inflammation of synovial joints and cartilage erosion, leading to functional disability and increased risk of premature death [1]. Despite there being abundant drugs for treating RA, including conventional synthetic diseasemodifying antirheumatic drug (csDMARD), biologic DMARD (bDMARD), and targeted synthetic DMARD (tsDMARD), a considerable number of patients (about 20-30%) still do not achieve remission or at least low disease activity [2]. The use of bDMARD and tsDMARD often result in rapid and sustained clinical remission for the majority of patients, while are also associated with the risk of adverse events (AEs), such as prolonged immunosuppression, infection, and economic implications [3,4]. Hence, csDMARD, ideally methotrexate, remains the basis of RA treatment in clinic, especially in lowincome countries. According to the 2019 EULAR recommendations, csDMARD are primarily used as induction and maintenance therapy for patients who receive initial treatment or have inadequate response to initial csDMARD monotherapy to reach the target of sustained remission [5]. For patients with persistent remission after bDMARD or tsDMARD therapy, tapering bDMARD or tsDMARD should be considered, and may be maintained with csDMARD [6]. Therefore, csDMARD plays a pivotal role in RA treatment.
There are amounts of studies on IGU monotherapy or combined therapy. Previous studies demonstrated that IGU monotherapy was non-inferior to methotrexate (MTX) in efficacy, but more tolerant than MTX [18]. In addition, several randomized controlled trials (RCTs) indicated that IGU plus MTX has also achieved better effectiveness than MTX monotherapy in patients with RA [19,20]. Consequently, in the 2015 Asia Pacific League of Associations of Rheumatology (APLAR) guideline, iguratimod was suggested as first-line treatment in the condition that patients who cannot tolerate MTX in some Asia-Pacific countries [21]. Moreover, the latest version of 2018 APLAR guideline also recommends the application of iguratimod as the 2015 version [22]. Iguratimod may be added to methotrexate to enhance efficacy when response to MTX monotherapy is inadequate [23].
A recently published meta-analysis evaluated the efficacy and safety of iguratimod monotherapy over other DMARDs [24]. Although amounts of evidences of IGU combined therapy have been accumulated, the efficacy and safety of IGU combined therapy have been poorly estimated. Therefore, this systematic review aims to comprehensively assess the efficacy and safety of IGU therapy (IGU monotherapy and combined therapy) for RA to provide more guidance of IGU use in the future.

Literature search
Two researchers searched the Medline, EMBASE, Cochrane library, CNKI, Wanfang medical network from initial to 30 June, 2020, and they reviewed the title, abstract, and even the full text at the same time to determine whether the study met the inclusion criteria independently. Search strategy for the PubMed database is given as follows: ((Iguratimod OR T-614 OR IGU) AND (rheumatoid arthritis OR RA)) AND (English[Language]).

Inclusion and exclusion criteria
The following criteria were adopted: (1) randomized control trials (RCTs) that evaluate the efficacy and safety of IGU monotherapy and IGU combined MTX therapy with MTX as a comparator drug, and the efficacy of IGU plus other DMARDs compared with other DMAR Ds monotherapy in treating patients with RA; (2) patients receiving a diagnosis of RA according to the 1987 American College of Rheumatology (ACR) or 2010 ACR/European League against Rheumatism (EULAR) RA classification criteria [25,26]; and (3) there are no mixed intervention in the test group and control group.
(4) One or more of the following outcomes were reported to allow data on to be extracted: American College of Rheumatology (ACR) 20, Disease Activity Score in 28 joints-C-reactive protein (DAS28-CRP), DAS28erythrocyte sedimentation rate (ESR), Health Assessment Questionnaire (HAQ) score, and duration of morning stiffness.
We excluded the following articles: (1) incomplete or duplicative data; (2) Chinese medicine in the combination group and/or the control group; (3) the control group was intervention with placebo; (4) patients with both RA and cancer, renal dysfunction, or other complications; (5) case reports, reviews, etc.

Data extraction and quality assessment
Two researchers read the full text of selected eligible studies at the same time, and extracted the following data from each study, including the author, title, year, design, outcome, and other specific values in the study. Methodological quality of the included studies was assessed using Cochrane Risk of Bias tool (version 5.1.0, updated in March 2011) which is developed for assessing the quality of RCTs. The Cochrane Risk of Bias tool included 6 domains: selection, performance, detection, attrition, reporting, and other bias [27].

Statistical analysis
The statistical analysis was performed by authors using STATA 12.0 (StataCorp LP, College Station, Texas).
Heterogeneity among the included studies was tested, and the size of heterogeneity was determined according to Cochran's Q statistic and the I 2 statistic. Low heterogeneity was defined as 25% < I 2 < 50%; moderate heterogeneity was defined as I 2 ≥ 50% and high heterogeneity was defined as I 2 ≥ 75%. According to the heterogeneity, fixed or random effect models were used between different studies. When there was no heterogeneity in the included studies, the fixed effects model was used for meta-analysis; otherwise, the random effects model was used, and P < 0.05 was considered statistically significant. In addition, sensitivity analysis was performed to ensure the robustness of results, and the summarized odd ratio (OR) or standard mean difference (SMD) was analyzed with the omission of one study at a time to detect whether the overall results were strongly affected by a specific study. Publication bias was evaluated through Egger's linear regression and visual inspection of funnel plots.

Quality assessment
As displayed in Fig. 2, random allocation was reported in all included studies, but only a few studies adopted random number table. Allocation concealment, blinding of participants and personnel, and blinding of outcome assessment for most studies were assessed as unclear risk due to the related data was not described. All studies had low risk of incomplete outcome, while the risk of other bias was assessed as high.

Efficacy
The overall pooled analysis of ACR20 response was displayed in Fig. 3. We found that IGU therapy was associated with a significant increase of ACR20 response

Adverse events
We combined data for adverse events including gastrointestinal reactions, leucopenia, increment in transaminase, increase of ALT, liver damage, and other adverse reactions. The meta-analysis of these adverse events was summarized in Table 2

Analysis of sensitivity and publication bias
The sensitivity analysis of ACR20 showed that the removing individual studies at one time alter the overall effect slightly (upper limit of 95% CI interval lower than 3.53 in all cases, Supplementary Figure 1). The publication bias was estimated utilizing a funnel plot, which showed there was no evidence of asymmetry (Supplementary Figure 2). Furthermore, we performed an Egger test to quantify the publication bias, and the P value was 0.898, suggesting bias of the studies were non-existent.

Discussion
This systematic review of 23 RCTs demonstrated that IGU, as monotherapy or combination therapy, remarkable effectiveness, and good safety in the treatment of Regarding safety, IGU monotherapy or combined with other DMARDs therapy did not increase the risk of gastrointestinal reactions, leucopenia, increment in transaminase, increase of ALT, and liver damage compared to MTX monotherapy. Thus, taken together, these results indicated that IGU monotherapy or combined therapy may be a promising therapeutic strategy for RA.

Efficacy
IGU has been shown to display a comparable efficacy to MTX on RA amelioration when used as monotherapy. A phase III study comparing 2 initial doses of IGU to MTX in 489 RA patients revealed that IGU 50 mg/day was equivalent to methotrexate in terms of ACR20 response (63.8% vs. 62.0%) [18]. A recently published meta-analysis of 12 trials by Sajan Shrestha [24] demonstrated that IGU monotherapy has similar ACR 20 and HAQ, and better disease state, lower CRP level and ESR compared with other DMARDs therapy, which is basically consistent with our findings, indicating that IGU may be considered a potential alternative to MTX to treat RA. In clinical practice, combination of multiple antirheumatic drugs is usually required for RA treatment, since that the combination of IGU and other DMARDs, such as MTX, etanercept, and leflunomide have synergic efficacy for RA treatment. Our results showed that IGU plus MTX was more effective than the MTX monotherapy. A study by Hara et al. implied that improvement of IGU plus MTX therapy in ACR20 response could sustain through 52 weeks, and HAQ at week 52 significantly improved compared with the values at week 24 in the patients with active RA [48]. IGU combined etanercept (a biologic agent) [46] or leflunomide (an immunosuppressive agent) [45] was demonstrated to improve functional ability, and disease status of patients with RA at 12 weeks in terms of DAS 28-ESR.

Pharmacological mechanism
From a mechanistic view, therapeutic effects of IGU could be traced back to its anti-inflammatory, immunological action, and anabolic effects on bone metabolism. A preclinical study by Luo et al. found that the intervention of IGU plus MTX could remarkably inhibit infiltration of inflammatory cells into the synovium, and suppressed production of cytokines (IL-17, IFN-γ, IL-6, and TNF-α) and antibodies (IgG and IgG2b) in serum in the mice with collagen-induced arthritis which is widely used in preclinical studies of RA [49]. Ishiguro  declined the rheumatoid factor (33%, P < 0.001), and immunoglobulins, such as IgA, IgM, and IgG levels (P < 0.001) at 24 weeks in patients with RA, but these measures have no significantly change in the MTX group [20]. Dai et al. [45] found that IGU combined with leflunomide could significantly decreased serum inflammatory cytokines (TNF-α, sTREM-1), and increase the level of bone metabolic markers (25(OH)D and TPINP) in patients of RA compared with etanercept monotherapy (P < 0.05). Therefore, IGU may exert its clinical effect through an anti-inflammatory action, immunomodulatory action, and osteoprotective action in RA treatment.

Adverse events
The data of post-marketing surveillance involving 2666 patients showed that long-term treatment (52-week) with IGU resulted in a tolerable safety profile in patients with RA [50]. The incidences of serious AEs, and serious adverse drug reactions were 7.35% and 4.58%, respectively. The adverse drug reactions appeared at approximately 4 weeks of treatment. Elevation of liver enzymes has been reported as a common adverse drug reaction of IGU. Treatment with IGU monotherapy (50 mg/day for 24 weeks or 25 mg/day for the first 4 weeks and 50 mg/ day for the subsequent 20 weeks) result in fewer patients with increases of ALT in IGU group than in the MTX group (13.5% or 6.1% vs 23.9%, P < 0.05) [18]. Increases of ALT and AST were indicated to be similar at 24 weeks between combination therapy of IGU and MTX and MTX monotherapy (5.5% vs 8.0% and 9.8% vs 5.7%) [20]. This increase of liver enzymes was temporary, and patients would to recover during IGU treatment. Baseline liver dysfunction and low body weight were reported to be risk factors of liver dysfunction during IGU treatment [50]. In summary, IGU had a superior safety profile to MTX, and IGU combination did not increase incidence of AEs, which may be explained by multitarget mechanism of IGU. IGU targets upstream and downstream effectors of RA-related pathways, and did not effectively target a particular molecule. Thus, when IGU is used alone or in combination with MTX or other drugs to treat RA, its adverse events are tolerable, but patients still need to be closely monitored.

Limitations
The limitations of this study are as follows: (1) most RCTs included do not describe the details such as allocation concealment and blind method, and there may be bias in implementation and measurement; (2) at present, the clinical data are mainly from China and Japan, and there is a lack of population from other countries; (3) the included studies reported ACR20, DAS28, etc. which may be are approximations of disease progress. Some measures which can more exactly indicate the status of disease progress need to be developed. Therefore, it is recommended that multi-center, large-scale, strictly designed, randomized, double-blind clinical studies should be performed, and the data of international clinical studies should be collected in order to better evaluate the therapeutic effect of IGU.

Conclusion
Our analysis showed that the efficacy and safety of IGU in RA treatment was similar to that of MTX, and when combined with MTX or other DMARDs, the addition of IGU would have more benefits in terms of ACR20, DAS28-CRP, DAS28-ESR, and the duration of morning stiffness. Therefore, IGU has good efficacy and tolerance, and is a promising drug in clinical practice. IGU may be regarded as a potential alternative to MTX, and also a preferable choice when combined with other DMARDs for the treatment of RA. Large-scale and high-quality RCTs are necessary to further confirm our findings.