review article efficacy and safety of iguratimod for the ...rheumatoid arthritis (ra) of all...

Hindawi Publishing CorporationClinical and Developmental ImmunologyVolume 2013, Article ID 310628, 16 pageshttp://dx.doi.org/10.1155/2013/310628

Review ArticleEfficacy and Safety of Iguratimod for the Treatment ofRheumatoid Arthritis

Jiangtao Li,1,2 Hejuan Mao,3 Yan Liang,1 Yanrong Lu,1 Shuo Chen,4

Nanping Yang,1 and Guixiu Shi5

1 West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China2Department of Rheumatology and Immunology, The First People’s Hospital of Yibin, Yibin, Sichuan 644000, China3Department of Otolaryngology, The First People’s Hospital of Yibin, Yibin, Sichuan 644000, China4The Chinese Cochrane Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China5 Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China

Correspondence should be addressed to Guixiu Shi; [email protected]

Received 1 May 2013; Revised 15 September 2013; Accepted 18 September 2013

Academic Editor: Xuan Zhang

Copyright © 2013 Jiangtao Li et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

All randomized controlled trials (RCTs) of iguratimod for rheumatoid arthritis (RA) to assess its efficacy and safety are included inthis paper.The ReviewManager software was used for meta-analysis to assess risk bias of the studies included, and GRADE profilersoftware was used for the evidence quality of the studies included. Four RCTs involving 1407 patients with RA were included.Meta-analyses showed that, after 24-week therapy, ACR20, tender joint count, swollen joint count, rest pain, physician and patientglobal assessment of disease activity, HAQ score, ESR, and CRP in iguratimod group were better than those in placebo group andthat the difference between those of iguratimod group and those of other DMARDs (MTX and SASP) group was not significant.GRADE evidence classification of the studies included was moderate. Iguratimod for RA had few adverse events, and its efficacyand safety were the same as those of MTX and SASP for RA. The results of this systematic review suggest that more high-qualityand large-scaled RCTs were needed to determine the efficacy of iguratimod for RA and whether iguratimod is as effective as otherDMARDs besides MTX and SASP.

1. Introduction

Rheumatoid arthritis (RA) is chronic systemic inflammatoryand autoimmune disease of unknown etiology that primarilytargets synovial tissue and is characterized by an activationof T lymphocyte, an increase in interleukin and tumornecrosis factor, and severe chronic inflammation of the joints,resulting in erosion and destruction of cartilage, bone, andtendon [1, 2]. It is relatively common, with a prevalence ofslightly less than 1% in adults all over theworld [1]. Prevalenceof moderate and severe disability in adults aging over 60(in millions) due to rheumatoid arthritis by leading healthcondition associated with disability is 1.7 in high-incomecountries and 3.7 in low- and middle-income countries in2012 [3]. Years lost due to disability (YLD) per 100 000 adultsaging over 60 due to rheumatoid arthritis is the 11th in theworld in 2012 [3]. Current treatments for RA emphasize

the early use of traditional disease-modifying antirheumaticdrugs (DMARDs), such as methotrexate (MTX), salazosul-fapyridine (SASP), leflunomide, and cyclophosphamide tominimize or prevent joint damage. In addition, biologicagents such as necrosis factor-𝛼 blocker, anti-interleukinantibody, and CD20 monoclonal antibody are also used toteat RA. In the recent ten years, iguratimod (T-614) hasbeen used to treat RA as a novel immunomodulator. It func-tions by suppressing the production of some inflammatorycytokines, including interleukin-1 (IL-1), IL-4, IL-6, IL-17,tumor necrosis factor, nuclear factor-kappaB, and interferonin vitro (synovial cells and some cell lines) and in vivo (mousemodels) [4, 5]. Iguratimod also reduced immunoglobulinproduction by acting directly on human B lymphocytes with-out affecting B lymphocyte proliferation [6]. Direct evidencehas also showed that iguratimod can dramatically suppressdisease progression and markedly protect affected joints

2 Clinical and Developmental Immunology

Table 1: Characteristics of the included studies with iguratimod (T-614) for rheumatoid arthritis.

Study Method Participants Intervention Duration Outcomes Allocationconcealment

Haraet al.(2007)[14]

Double-blind,randomized,placebo-controlledtrial

Country: JapanSite: multicenterNumber: 376Iguratimod group(𝑛 = 147)SASP group (𝑛 = 156)Placebo group(𝑛 = 73)Sex: female/male =306 : 70

T-614 group:iguratimod 25mgdaily for the first 4weeks and 50mgdaily for thesubsequent 24weeksSASP group:salazosulfapyridine(SASP) 1000mgdailyPlacebo group:placebo tablets

28 weeks of clinicalassessment at 0, 4, 6,12, 18, 24, and 28weeks.

ACR20, ACR50,tender joint count,swollen joint count,rest pain, physician’sand patient’s globalassessment of diseaseactivity (VAS, mm),physician’s globalassessment of diseaseactivity, HAQ score,ESR, CRP, andadverse events.

Described inarticle but notvalidated becausethe author couldnot be reached viaemail.

Lü et al.(2008)[2]

Double-blind,randomized,placebo-controlledtrial

Country: ChinaSite: multicenterNumber: 280T-614 group 1 (𝑛 = 93)T-614 group 2(𝑛 = 92)Placebo group(𝑛 = 95)Sex: female/male =231 : 49

Group 1: T-61425mg daily for thefirst 4 weeks and50mg daily for thesubsequent 20weeksGroup 2: T-61450mg dailyPlacebo group:placebo tablets

24 weeks of clinicalassessment at 0, 2, 4,6, 12, 18, and 24 weeks.

ACR20, ACR50,ACR70, tender jointcount, swollen jointcount, tender jointscore (TJS), swollenjoint score (SJS), restpain, duration ofmorning stiffness,grip strength,physician and patientglobal assessment ofdisease activity, ESR,CRP, rheumatoidfactor, HAQ score,radiological damage,and adverse events.

Detailed in articleand validityascertainedthrough telephone.

Lü et al.(2009)[15]

Double-blind,randomized,controlledtrial

Country: ChinaSite: multicenterNumber: 489T-614 group 1(𝑛 = 163)T-614 group 2(𝑛 = 163)MTX group (𝑛 = 163)Sex: female/male =418 : 81

T-614 group 1:T-614 25mg dailyfor the first 4 weeksand 50mg daily forthe subsequent 20weeksT-614 group 2:T-614 50mg perdayMTX group: MTX10mg weekly forthe first 4 weeksand 15mg weeklyfor the subsequent20 weeks

24 weeks ofclinical assessmentat 0, 4, 10, 17, and 24weeks.

ACR20, ACR50,ACR70, tender jointcount, swollen jointcount, tender jointscore (TJS), swollenjoint score (SJS), restpain, duration ofmorning stiffness,grip strength,physician and patientglobal assessment ofdisease activity, ESR,CRP, and adverseevents.

Detailed in articleand validityascertainedthrough telephone.

Ishiguro(2013)[16]

Double-blind,randomized,controlledtrial

Country: JapanSite: multicenterNumber: 252T-614 + MTX group(𝑛 = 164)MTX + placebo group(𝑛 = 88)Sex: female/male =204 : 48

T-614 + MTXgroup: T-614 25mgdaily for the first 4weeks and 50mgdaily for thesubsequent 20weeksPlacebo + MTXgroup: MTX at lowdosages of 6 or8mg weekly andfolic acid at dosageof 5mg weekly

28 weeks ofclinical assessmentat 0, 4, 6, 8, 20, 12, 16,20, and 24 weeks.

ACR20, ACR50,ACR70, tender jointcount, swollen jointcount, patient’s andphysician’s globalassessment of diseaseactivity, HAQ score,DAS28-CRP, ESR,CRP, and adverseevents.

Described inarticle but notvalidated becausethe author couldnot be reached viaemail.

Clinical and Developmental Immunology 3

Table 2: Summary of the findings for the main comparison: iguratimod compared to placebo for rheumatoid arthritis.

OutcomesIllustrative comparative risks∗ (95% CI)

Relative effect(95% CI)

No. ofparticipants(studies)

Quality of theevidence(GRADE)

CommentsAssumed risk Corresponding riskPlacebo Iguratimod

ACR20/24 weeks 219 per 1000 514 per 1000 (398 to 660) RR 2.35 (1.82 to3.02) 636 (3 studies) ⊕⊕⊕⊝moderate1 Important

Tender joint countThe mean tender joint count in theintervention groups was −0.44lower (−0.61 to −0.27 lower)

593 (3 studies) ⊕⊕⊕⊝moderate1 Important

Swollen joint countThe mean swollen joint count in theintervention groups was −0.49 lower(−0.66 to −0.32 lower)


Assessment of restpain

The mean assessment of rest pain inthe intervention groups was −0.71lower (−0.89 to −0.54 lower)


Physician globalassessment ofdisease activity

The mean physician globalassessment of disease activity in theintervention groups was −0.74 lower(−0.93 to −0.55 lower)


Patient globalassessment ofdisease activity

The mean patient global assessmentof disease activity in theintervention groups was −0.58 lower(−0.80 to −0.36 lower)


HAQ scoreThe mean HAQ score in theintervention groups was −0.67 lower(−0.84 to −0.50 lower)


CRPThe mean CRP in the interventiongroups was −0.31 lower (−0.53 to−0.09 lower)


ESRThe mean ESR in the interventiongroups was −0.64 lower (−0.82 to−0.45 lower)


∗The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidenceinterval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: riskratio; MTX: methotrexate; SASP: salazosulfapyridine.GRADE working group grades of evidence.High quality: further research is very unlikely to change our confidence in the estimate of effect.Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.Very low quality: we are very uncertain about the estimate.1Two studies had unclear selective biases and no intent-to-treat analyses.

against cartilage destruction and bone erosion in collagen-induced arthritis rats [5]. In addition, iguratimod decreasedproduction of matrix metalloproteinases (MMP-1 andMMP-3) and inhibits the migratory expansion of rheumatoidsynovial fibroblasts in vitro [7]. Although iguratimod hasbeen used to treat RA for 10 years since 2003, no systematicreview has been done on its efficacy and safety. Therefore, weconducted this systematic review to assess the efficacy andsafety of iguratimod (T-614) for RA.

2. Materials and Methods

2.1. Types of Studies and Inclusion and Exclusion Criteria

2.1.1. Types of Studies. All randomized clinical trials (RCTs)were published in all journals, with a minimum duration ofstudy of at least six months (or 24 weeks).

2.1.2. Types of Participants(1) Inclusion Criteria. Patients with clinical diagnosis ofrheumatoid arthritis (RA) of all eligible RCTs according tothe American Rheumatism Association (ARA) criteria areenrolled within the inclusion criteria. Age of patients withonly RCTs was at least 18 years old, and sex, race, and regionof patients were not limited. These patients must have activedisease as shown in the following outcomes: (a) ACR20;(b) tender joint count (TJC); (c) swollen joint count (SJC);(d) assessment of rest pain; (e) physician global assessmentof disease activity; (f) patient global assessment of diseaseactivity; (g) health assessment questionnaire (HAQ) score;(h) erythrocyte sedimentation rate (ESR); (i) C-reactiveprotein (CRP); and (j) adverse events reports.

(2) Exclusion Criteria. The studies on patients with both RAand cancer, abnormal hepatic dysfunction or renal dysfunc-tion, or pregnant women and patients with diabetes mellitus,


Table 3: Summary of the findings for the main comparison: iguratimod compared to the other DMARDs (MTX and SASP) for rheumatoidarthritis.

OutcomesIllustrative comparative risks∗ (95% CI)

Relative effect(95% CI)

No. ofparticipants(studies)

Quality of theevidence(GRADE)

CommentsAssumed risk Corresponding riskOther

DMARDs(MTX andSASP)

Iguratimod

ACR20/24 weeks 581 per 1000 505 per 1000 (435 to 592) RR 0.87 (0.75 to1.02) 533 (2 studies) ⊕⊕⊕⊝moderate1 Important

Tender joint countThe mean tender joint count in theintervention groups was −0.01 lower(−0.18 lower to 0.16 higher)


Swollen joint countThe mean swollen joint count in theintervention groups was −0.15 lower(−0.32 lower to 0.02 higher)


Assessment of restpain

The mean assessment of rest pain inthe intervention groups was −0.10lower (−0.27 lower to 0.07 higher)


Physician globalassessment ofdisease activity

The mean physician globalassessment of disease activity in theintervention groups was −0.03higher (−0.14 lower to 0.20 higher)


Patient globalassessment ofdisease activity

The mean patient global assessmentof disease activity in theintervention groups was −0.05 lower(−0.22 lower to 0.12 higher)


HAQ scoreThe mean HAQ score in theintervention groups was −0.09higher (−0.08 lower to 0.26 higher)


CRPThe mean CRP in the interventiongroups was −0.13 lower (−0.3 to 0.04lower)


ESRThe mean ESR in the interventiongroups was −0.05 lower (−0.22lower to 0.12 higher)


∗The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidenceinterval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: riskratio; MTX: methotrexate; SASP: salazosulfapyridine.GRADE working group grades of evidence.High quality: further research is very unlikely to change our confidence in the estimate of effect.Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.Very low quality: we are very uncertain about the estimate.1Random sequence of one study cannot mention how to be generated in detail, and no intent-to-treat analysis was included.

hypertension, or abnormal function of gastrointestinal tractwere excluded. The studies of duplicate records, non-RCTs,nonclinical trials, the same study, ongoing without outcomesreported, or no full text were excluded.

2.1.3. Types of Intervention. Studies comparing iguratimodtreatment (as monotherapy or in combination with otherDMARDs) at a dose of 25 or 50mg/day with placebo or otherDMARDs were included. The duration of treatment in thetrials must have been at least six months (or 24 weeks).

2.1.4. Types of Outcome Measures

(1) PrimaryOutcomes.Primary outcomemeasures were thosedefined as the ACR core set of disease activity measures

for RA for clinical trials, which were endorsed by EULARand the Outcome Measures in Rheumatology Clinical Trials(OMERACT) [8, 9]. They included (1) tender joint count;(2) swollen joint count; (3) assessment of rest pain; (4)patient global assessment of disease activity; (5) physicianglobal assessment of disease activity; (6) health assessmentquestionnaire (HAQ) score; (7) acute phase reactants (ESRand CRP); and (8) radiographic change of bone and jointdamage for trials lasting at least one year. In addition,the numbers of patients who met the ACR20, ACR50,and ACR70 response criteria were included. The EULARresponse criteria are measured as the Disease ActivityScore (DAS) according to the EULAR response criteria[10].


15 of records after duplicates removal

15 of records screened

9 of records excluded. 4 among 9of records excluded with reason ofnonclinical trials and 5 of records

with reason of ongoing trial withoutoutcomes reported.

6 of full-text articles for eligibility

1 of full-text articles excluded withreason of non-RCT; 1 of full-textarticles excluded with reason of

the same study.

4 of studies included in qualitative synthesis (meta-analysis)

Figure 1: Search study flow diagram.

Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting bias)

Other biases

0 25 50(%)

75 100

Low risk of biasUnclear risk of biasHigh risk of bias

Figure 2: Risk of bias in the 4 studies included.

(2) Secondary Outcomes. Secondary outcome measuresincluded health-related quality of life (HRQoL) of thepatients, reported side effects, total number of patients with-drawn from the studies, and withdrawals due to adverseevents.

We defined serious adverse events according to the ICHGuidelines [11] as any event that led to death, that waslife-threatening, and required in-patient hospitalization orprolongation of existing hospitalization, and that resultedin persistent or significant disability and as any importantmedical events, which might have jeopardized the patient orrequired intervention to prevent them. We did not considerother adverse events to be serious.

2.2. Search Methods for Identification of Studies2.2.1. Electronic Search. We searched the Cochrane CentralRegister of Controlled Trials (the Cochrane Library, 11 July2012), PubMed (1950 to 29 March 2013), Embase (1980 to 29March 2013), the Chinese Biomedical Database (CBM) (1975

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Figure 3: Summary of risk bias in the 4 studies included.

to 18 March 2013), China National Knowledge Infrastructure(CNKI) (1917 to 18 March 2013), VIP Database (1989 to 18March 2013), and the WHO ICTRP (18 March 2013).

2.2.2. Search Strategy. Search strategy for the CochraneLibrary, PubMed, Embase, and so forth, in English is givenas follows:

#1 iguratimod#2 T-614#3 CAS 123663-49-0


Study or subgroup

2.2.1 Iguratimod versus placeboHara (2007)

Total events

Ishiguro (2013)

Total eventsHeterogeneity: not applicable

Total events

Events

7128

99

114

114

213

Total

13293

164

Events

1116

27

27

27

54

Total

6495

88

Weight

22.5%24.1%

53.4%

3.13 [1.79, 5.48]1.79 [1.04, 3.08]

2.27 [1.63, 3.15]

Iguratimod Placebo Risk ratio Risk ratio

0.2 0.5 1 2 5Favors [placebo] Favors [iguratimod]

Test for overall effect: Z = 4.47 (P < 0.00001)


Lü (2008)ˇ


Subtotal (95% CI)

Subtotal (95% CI)

Total (95%CI)

225

164

389

159

88

247

46.6%

53.4%

100.0%

2.44 [1.65, 3.60]

2.27 [1.63, 3.15]

2.35 [1.82, 3.02]

2.2.2 Iguratimod + MTX versus placebo + MTX

Heterogeneity: 𝜒2 = 2.02; df = 2 (P = 0.36); I2 = 1%


Test for subgroup differences: 𝜒2 = 0.08; df = 1(P = 0.78); I2 = 0%

(a)

Study or subgroup

Hara (2007)

Total events

Events5283

135

Total103163

Events54

101

155

Total104163

Weight34.7%65.3%

0.97 [0.75, 1.27]0.82 [0.68, 1.00]

Iguratimod Other DMARDs Risk ratio Risk ratio

0.5 0.7 1 1.5 2Favors [iguratimod] Favors [other DMARDs]

Lü (2009)ˇ

Total (95% CI) 266 267 100.0% 0.87 [0.75, 1.02]

Heterogeneity: 𝜒2 = 1.01; df = 1 (P = 0.32); I2 = 1%Test for overall effect: Z = 1.69 (P = 0.09)

(b)

Study or subgroup

3.10.1 Iguratimod versus MTX

Total eventsHeterogeneity: not applicableTest for overall effect: Z = 1.94 (P = 0.05)

3.10.2 Iguratimod versus SASPHara (2007)

Total eventsHeterogeneity: not applicable

Total events

Test for overall effect: Z = 1.04 (P = 0.30)

Events

53

53

35

35

88

Total

163

104

267

Events

70

70

34

34

104

Total

163

103

266

Weight

57.5%

42.5%

Lü (2009)ˇ


M-H, random, 95% CI

0.64 [0.41, 1.01]

1.03 [0.58, 1.83]

Iguratimod MTX Odds ratio Odds ratioM-H, random, 95% CI

0.5 0.7 1 1.5 2Favors [iguratimod] Favors [other DMARDs]

Subtotal (95%CI)

Subtotal (95% CI)

Total (95%CI)

163

104

267

163

103

266

57.5%

42.5%

100.0%

0.64 [0.41, 1.01]

1.03 [0.58, 1.83]

0.78 [0.49, 1.24]

Heterogeneity: 𝜏2 = 0.04; 𝜒2 = 1.61; df = 1 (P = 0.20); I2 = 38%

Test for subgroup differences: 𝜒2 = 1.61; df = 1 (P = 0.20); I2 = 38.0%

(c)

Figure 4: (a) Comparison of ACR20 at 24 weeks between iguratimod and placebo groups. (b) Comparison of ACR20 at 24 weeks betweeniguratimod and other DMARDs (MTX and SASP) groups. (c) Comparison of ACR50 at 24 weeks between iguratimod and other DMARDs(MTX and SASP) groups.


Study or subgroup



Ishiguro (2013)

Heterogeneity: not applicableTest for overall effect: Z = 3.13 (P = 0.002)


Mean

−7.1

−6

−7.4

SD

7.98

6

Total

13279

164

Mean

−3.6

−2

−4.6

SD

8.39

7.8

Total

6367

88

Weight

31.4%26.5%

42.2%

−0.43 [−0.74, −0.13]−0.47 [−0.80, −0.14]−0.45 [−0.67, −0.23]

−0.42 [−0.68, −0.16]−0.42 [−0.68, −0.16]

−0.44 [−0.61, −0.27]

Iguratimod Placebo Std. mean difference Std. mean difference

−0.5 −0.25 0 0.25 0.5Favors [iguratimod] Favors [placebo]

Lü (2008)ˇSubtotal (95% CI)

Subtotal (95% CI)

Total (95% CI)

211

164

375

130

88

218

57.8%

42.2%

100.0%



Test for subgroup differences: 𝜒2 = 0.03; df = 1 (P = 0.85); I2 = 0%


(a)

Study or subgroup

Hara (2007)


Mean−7.810.5

SD7.5

10.6

Total103163

Mean−7.1

10

SD6.98.1

Total104163

Weight38.8%61.2%

−0.10 [−0.37, 0.18]0.05 [−0.16, 0.27]

−0.01 [−0.18, 0.16]

Iguratimod 50 mg Other DMARDs Std. mean difference Std. mean difference

−0.5 −0.25 0 0.25 0.5 Favors [iguratimod 50 mg]

Favors [other DMARDs]

Lü (2009)ˇ

Total (95% CI) 266 267 100.0%Heterogeneity: 𝜒2 = 0.71; df = 1 (P = 0.40); I2 = 0%

(b)

Figure 5: (a) Comparison of tender joint count between iguratimod and placebo groups. (b) Comparison of tender joint count betweeniguratimod and other DMARDs (MTX and SASP) groups.

#4 C17H14N2O6S

#5 Ailamode

#6 N-3-formylamino-4-oxo-6-phenoxy-4H-chrom-en-7-yl-methanesulfonamide

#7 3-formylamino-7-methylsulfonylamino-6-phe-noxy-4H-1-benzopyran-4-one

#8 or/#1–7

#9 randomized controlled trials

#10 random

#11 control

#12 trials

#13 or/#9–12

#14 rheumatoid arthritis

#15 (#8, #13, and #14).

We searched the Chinese Biomedical Database (CBM),China National Knowledge Infrastructure (CNKI), and VIPDatabase by using the strategy adjusted in Chinese.

2.3. Data Collection and Analysis

2.3.1. Selection of Studies. Three review authors (Jiangtao Li,Hejuan Mao, and Shuo Chen) independently assessed forinclusion all of the potential studies identified as a resultof the search strategy. We resolved disagreements throughdiscussion. We included only those studies that used a strictrandomization procedure. We telephoned or wrote letter byemail to contact the authors of those articles in which “ran-domly allocated participants” was mentioned to determinewhether the randomization procedure was adequate or not.

2.3.2. Data Extraction andManagement. Wedesigned a formto extract data for retrieval of records to meet the needsof the project design. For eligible studies, the three reviewauthors extracted the data using the agreed form.We resolveddiscrepancies through discussion.Where disagreement couldnot be resolved even through discussion, experts in the areawere contacted to make a decision. We input the data intoReview Manager software (RevMan Manager version 5.2.4,2013) and checked them for accuracy.

2.3.3. Assessments Risk of Bias in Included Studies and Qualityof Evidence. According to assessing risk of bias in included


Study or subgroup


Subtotal (95% CI)


Lü (2008)ˇ

Ishiguro (2013)Subtotal (95% CI)Heterogeneity: not applicableTest for overall effect: Z = 4.31 (P < 0.0001)

Total (95% CI)


Mean

−5

−6

−6.5

SD

6.26

5.9

Total

13179

210

164164

374

Mean

−3.1

−2

−2.9

SD

5.78

6.7

Total

6367

130

8888

218

Weight

31.9%26.4%58.2%

41.8%41.8%

100.0%

−0.31 [−0.62, −0.01]−0.57 [−0.90, −0.24]−0.43 [−0.65, −0.21]

−0.58 [−0.84, −0.32]−0.58 [−0.84, −0.32]

−0.49 [−0.66, −0.32]







(a)

Study or subgroup

Hara (2007)

Total (95% CI)


Mean−5.5

4.9

SD6

5.5

Total103163

266

Mean−4.5

5.6

SD4.65.3

Total104163

267

Weight38.8%

Lü (2009)ˇ 61.2%

100.0%

−0.19 [−0.46, 0.09]−0.13 [−0.35, 0.09]

−0.15 [−0.32, 0.02]





(b)

Figure 6: (a) Comparison of swollen joint count between iguratimod and placebo groups. (b) Comparison of swollen joint count betweeniguratimod and other DMARDs (MTX and SASP) groups.

studies in the Cochrane Handbook for Systematic Reviewsof Interventions (version 5.1.0, updated in March 2011) [12],we assessed each study included in random sequence gen-eration and allocation concealment (selection bias), blinding(performance bias and detection bias), incomplete outcomedata (attrition bias), selective reporting (reporting bias), andother biases. According to GRADE Handbook for gradingquality of evidence and strength of recommendation, version3.2 (updated in March 2009) [13] and GRADE profiler 3.6software, we assessed quality of evidence of each studyincluded.

2.3.4. Methods of Statistical Analysis. Statistical analysis wasmade by using the ReviewManager software (Cochrane Col-laboration’s RevMan 5.2.4, 2013). For continuous variables,mean differences (MD) or standardized mean differences(SMD) were used to describe effect size with confidenceinterval (CI) set at 95%. For dichotomous variables, oddsratio (OR), relative risk (RR), and risk difference (RD) wereused to describe effect with confidence interval (CI) set at95%. 𝜒2 test was used to analyze the heterogeneity amongresults. Where there is no heterogeneity (𝑃 > 0.1; 𝐼2 < 50%),the fixed effects model analysis was made. If there is het-erogeneity between studies, random effects model was used,

and the source, cause, and sensitivity of heterogeneity wereanalyzed in subgroups. Where there is clinical heterogeneitybetween studies, descriptive analysis was made.

3. Results and Discussion

3.1. Results

3.1.1. Results of the Search. We identified 21 records byelectronic searches and hand searches, including 1 of recordsindentified from the Chinese database, four from PubMed,nine from Embase, two from Ovid, and five from ICRTP.We excluded 17 records because of duplicate records, non-RCTs, nonclinical trials, the same study, ongoing withoutoutcomes reported, or no full text. At the end, we finalizedfour studies [2, 14–16] to make quantitative synthesis (meta-analysis) (Figure 1).

3.1.2. Characteristics of Included Studies (Table 1)

(1) Types of Studies.All of the four included studies were mul-ticenter, double-blind, randomized controlled trials. Threeof them had a placebo control group. The duration of thesestudies was about six months (from 24 weeks to 28 weeks).


Study or subgroup


Subtotal (95% CI)



Total (95% CI)


Mean

−17.3

−30

−22

SD

3033

23.8

Total

12979

208

164164

372

Mean

−1.7

−5

−2.5

SD

27.426

27

Total

6367

130

8888

218

Weight

32.1%26.1%58.1%

41.9%41.9%

100.0%

−0.53 [−0.84, −0.23]−0.83 [−1.17, −0.49]−0.67 [−0.89, −0.44]

−0.78 [−1.05, −0.51]−0.78 [−1.05, −0.51]

−0.71 [−0.89, −0.54]


−1 −0.5 0 0.5 1Favors [iguratimod] Favors [placebo]

Lü (2008)ˇ





(a)

Study or subgroup

Hara (2007)

Total (95% CI)


Mean

−22

24.9

SD

27.728.4

Total

102163

265

Mean

−21

28.7

SD

28.326.1

Total

102

163

265

Weight

38.5%

61.5%

100.0%

−0.04 [−0.31, 0.24]−0.14 [−0.36, 0.08]

−0.10 [−0.27, 0.07]




Lü (2009)ˇ


(b)

Figure 7: (a) Comparison of assessment of rest pain between iguratimod and placebo groups. (b) Comparison of assessment of rest painbetween iguratimod and other DMARDs (MTX and SASP) groups.

The studies were conducted in China (𝑛 = 2) and Japan(𝑛 = 2).

(2) Participants of Included Studies. In the four RCT studiesincluded [2, 14–16], in total, 1407 patients with RA wereenrolled (1159 females and 248 males; mean age was from45.9 to 58.2 years old). Diagnosis of RA was based on theAmerican Rheumatism Association (ARA) criteria in 1987[17] in the two Japanese studies [15, 16] and on the AmericanRheumatism Association (ARA) criteria in 1991 [18] in thetwo Chinese studies [2, 15].

(3) Interventions of Studies Included. Among the four studiesincluded [2, 14–16], four different types of intervention wereused: (a) iguratimod versus placebo and iguratimod versusSASP [14], (b) iguratimod versus placebo [2], (c) iguratimodversus MTX, and (d) iguratimod + MTX versus placebo +MTX [16]. The low dose of MTX (6–8mg per week) was inthe study of iguratimod + MTX versus placebo + MTX, andthe low dose of MTX (15mg per week) was in the study ofiguratimod versusMTX. Duration of treatment was 24 weeks[2, 15, 16] and 28 weeks in one study [14].

(4) Measures of Outcomes. Primary outcomes (ACR20) andsecondary outcomes (tender joint count; swollen joint count;

assessment of rest pain; physician global assessment ofdisease activity; patient global assessment of disease activity;HAQ score; ESR; CRP; adverse events, etc.) were all reportedin the four studies included.

3.1.3. Assessment of Methodological Quality ofStudies Included [13] (Figures 2 and 3)

(1) Randomized Method and Allocation Concealment. In allof the four studies included [2, 14–16], randomization wasdescribed. In two studies [2, 15], random sequence generationand allocation concealment were detailed, and the validityof method was ascertained by telephone. In the other twostudies [14, 16], random sequence generation and allocationconcealment were described but not ascertained because theauthor could not be reached via email. For this reason, somedegree risk of selection bias of two studies included [15, 16]existed.

(2) Blinding of Participants and Personnel. In all of the fourstudies [2, 14–16] blinding of participants and personnel wasdescribed. Double blinding was detailed in three studies [2,14, 15] and not mentioned in one study [16].The author could


Study or subgroup


Subtotal (95% CI)



Total (95% CI)


Mean

−18.9−31

−27.1

SD

21.434

19.3

Total

13179

210

164164

374

Mean

−6.9−3

−10.4

SD

20.524

26.6

Total

6367

130

8888

218

Weight

32.2%25.6%57.8%

42.2%42.2%

100.0%

−0.57 [−0.87, −0.26]−0.93 [−1.28, −0.59]−0.73 [−0.96, −0.50]

−0.75 [−1.02, −0.49]−0.75 [−1.02, −0.49]

−0.74 [−0.91, −0.57]


−1 −0.5 0 0.5 1 Favors [iguratimod] Favors [placebo]

Lü (2008)ˇ





(a)

Study or subgroup

Hara (2007)

Total (95% CI)


Mean−23.426.3

SD20.925.3

Total103163

266

Mean−2929.3

SD20.824.2

Total104163

267

Weight47.6%52.4%

100.0%

IV, random, 95% CI0.27 [−0.01, 0.54]−0.12 [−0.34, 0.10]

0.06 [−0.32, 0.44]

Iguratimod 50 mg Other DMARDs Std. mean difference Std. mean differenceIV, random, 95% CI


Favors[other DMARDs]

Lü (2009)ˇ


(b)

Figure 8: (a) Comparison of physician global assessment of disease activity between iguratimod and placebo groups. (b) Comparison ofphysician global assessment of disease activity between iguratimod and other DMARDs (MTX and SASP) groups.

not be reached via email. Thus, low risk of performance biasand detection bias of outcome assessment existed.

(3) Incomplete Outcome Data.Withdrawals, dropouts, loss offollowup, and intent-to-treat analysis were reported in detailin two studies included [2, 15] and were not described in theother two studies included [14, 16]. Therefore, high risk ofattrition bias in general existed.

(4) Selective Reporting Bias. The four studies [2, 14–16] in-cluded reported all outcomes, including adverse events.Therewas no selective reporting bias.

(5) Other Biases. Baseline information including sex, ageand secondary outcomes of the four studies [2, 14–16] wasdescribed in detail, and outcomes of different groups hadrobust comparability. Sample sizes of three studies [2, 15, 16]were estimated. All of the studies included were conductedin general hospitals or good clinical practice bases of medicaluniversities, with all of which having high scientific researchlevel and thus reducing other risk biases of these studies to alarge extent.

3.1.4. Meta-Analysis

(1) Primary Outcomes

(a) ACR20, ACR50, and ACR70 at 24 Weeks. Superioritypooled analysis of three studies [2, 14, 16] included shows thatACR20 at 24weeks amongpatientswithRA in the iguratimodgroup was significantly superior to that of the placebo group(RR = 2.35, 95% CI: 1.82, 3.02 in Figure 4(a)). Noninferioritypooled analysis of two studies [14, 15] included showed thatACR20 at 24 weeks among patients with RA in iguratimodgroup did not differ significantly from that of other DMARDs(MTX and SASP) group (RR = 0.87, 95% CI: 0.75, 1.02 inFigure 4(b)). Only in one study [2], ACR50 at 24 weeks didnot differ significantly between the iguratimod group and theplacebo group (RR = 0.62, 95% CI: 0.21, 1.82), and ACR70 at24 weeks differed significantly (RR = 0.06, 95% CI: 0.01, 0.51).ACR50 at 24 weeks did not differ significantly between theiguratimod group and the other DMARDs (MTX and SASP)group [14, 15] (RR = 0.78, 95% CI: 0.49, 1.24 in Figure 4(c)).Only in one study [15], ACR70 at 24 weeks did not differ


Study or subgroup


Subtotal (95% CI)



Total (95% CI)

Mean

−17.1−30

−21.2

SD

31.435

26.4

Total

13079

209

164164

373

Mean

−5.7−5

−5

SD

28.628

27.1

Total

6367

130

8888

218

Weight

32.0%25.8%57.9%

42.1%42.1%

100.0%

−0.37 [−0.68, −0.07]−0.78 [−1.12, −0.44]−0.55 [−0.78, −0.33]

−0.61 [−0.87, −0.34]−0.61 [−0.87, −0.34]

−0.58 [−0.75, −0.40]



Lü (2008)ˇ

Heterogeneity: 𝜒2 = 3.07; df = 1 (P = 0.08); I2=67%



Test for subgroup differences: 𝜒2 = 0.09; df = 1 (P = 0.76); I2 = 0%Test for overall effect: Z = 6.57 (P < 0.00001)

(a)

Study or subgroup

Hara (2007)

Total (95% CI)


Mean−21.3

25.9

SD30.227.1

Total103163

266

Mean−21.8

28.3

SD26.726

Total102163

265

Weight38.6%61.4%

100.0%

0.02 [−0.26, 0.29]−0.09 [−0.31, 0.13]

−0.05 [−0.22, 0.12]




Lü (2009ˇ


(b)

Figure 9: (a) Comparison of patient global assessment of disease activity between iguratimod and placebo groups. (b) Comparison of patientglobal assessment of disease activity between iguratimod and other DMARDs (MTX and SASP) groups.

significantly between the iguratimod group and the otherDMARDs (MTX) group (RR = 0.75, 95% CI: 0.43, 1.32).

(b) Tender Joint Count. Superiority analysis of three studies[14] included showed that tender joint count among patientswith RA in the iguratimod group reduced more than thatof the placebo group with a significant difference (MD =−0.44, 95% CI: −0.61, −0.27 in Figure 5(a)). Noninferiorityanalysis of two studies [14, 15] included showed that tenderjoint count among patients with RA in the iguratimod groupand in the other DMARDs (MTX and SASP) group didnot differ significantly (MD = −0.01, 95% CI: −0.18, 0.16 inFigure 5(b)).

(c) Swollen Joint Count. Superiority analysis of three studies[2, 15, 16] included showed that swollen joint count amongpatients with RA in the iguratimod group reducedmore thanthat of the placebo group with a significant difference (MD =−0.49, 95% CI: −0.66, −0.32 in Figure 6(a)). Noninferiorityanalysis of two studies [14, 15] included showed that swollenjoint count among patients with RA in the iguratimod groupand in the other DMARDs (MTX and SASP) group didnot differ significantly (MD = −0.15, 95% CI: −0.32, 0.02 inFigure 6(b)).

(d) Assessment of Rest Pain. Superiority analysis of threestudies included [2, 14, 16] showed that assessment of restpain among patients with RA in the iguratimod group wasworse than that of the placebo group with a significantdifference (MD = −0.71, 95% CI: −0.89, −0.54 in Figure 7(a)).Noninferiority analysis of two studies included [14, 15] showsthat assessment of rest pain among patients with RA in theiguratimod group and in the other DMARDs (MTX andSASP) group did not differ significantly (MD = −0.10, 95%CI: −0.27, 0.07 in Figure 7(b)).

(e) Physician Global Assessment of Disease Activity. Superi-ority analysis of three studies included [2, 15, 16] showedthat physician global assessment of disease activity amongpatients with RA in the iguratimod group reducedmore thanthat of the placebo group with a significant difference (MD =−0.74, 95% CI: −0.93, −0.57 in Figure 8(a)). Noninferiorityanalysis of two studies included [14, 15] showed that physicianglobal assessment of disease activity among patients with RAin the iguratimod group and in the other DMARDs (MTXand SASP) did not differ significantly (MD = 0.06, 95% CI:−0.32, 0.44 in Figure 8(b)).

(f) Patient Global Assessment of Disease Activity. Superiorityanalysis of three studies included [14–16] showed that patient


Study or subgroup


Subtotal (95% CI)


Ishiguro (2013)Subtotal (95% CI)Heterogeneity: not applicable

Total (95% CI)

Mean

−0.2−0.4

−0.35

SD

0.40.65

0.45

Total

13079

209

164164

373

Mean

0.1−0.1

0.03

SD

0.50.55

0.55

Total

6367

130

8888

218

Weight

31.2%27.3%58.5%

41.5%41.5%

100.0%

−0.69 [−1.00, −0.38]−0.49 [−0.82, −0.16]−0.60 [−0.82, −0.37]

−0.78 [−1.05, −0.51]−0.78 [−1.05, −0.51]

−0.67 [−0.84, −0.50]



Lü (2008)ˇ

Heterogeneity: 𝜒2 = 0.71; df = 1 (P = 0.40); I2=0%



Heterogeneity: 𝜒2 = 1.74; df = 2 (P = 0.42); I2 = 0%Test for overall effect: Z = 7.63 (P < 0.00001)Test for subgroup differences: 𝜒2 = 1.03; df = 1 (P = 0.31); I2 = 3.0%

(a)

Study or subgroup

Hara (2007)

Total (95% CI)


Mean

−0.30.6

SD

0.40.7

Total

103163

266

Mean

−0.3

0.5

SD

0.50.6

Total

104163

267

Weight

38.9%61.1%

100.0%

0.00 [−0.27, 0.27]0.15 [−0.06, 0.37]0.09 [−0.08, 0.26]




Lü (2009)ˇ


(b)

Figure 10: (a) Comparison of HAQ score between iguratimod and placebo groups. (b) Comparison of HAQ score between iguratimod andother DMARDs (MTX and SASP) groups.

global assessment of disease activity among patients withRA in the iguratimod group reduced more than that ofplacebo group with a significant difference (MD = −0.58,95% CI: −0.80, −0.36 in Figure 9(a)). Noninferiority analysisof two studies included [14, 15] showed that patient globalassessment of disease activity among patients with RA inthe iguratimod group and in the other DMARDs (MTX andSASP) group did not differ significantly (MD = −0.05, 95%CI: −0.22, 0.12 in Figure 9(b)).

(g) HAQ Score. Superiority analysis of three studies included[14–16] shows that HAQ score among patients with RA in theiguratimod group improved more than that of the placebogroup with a significant difference (MD = −0.67, 95% CI:−0.84, −0.50 in Figure 10(a)). Noninferiority analysis of twostudies included [14, 15] showed that HAQ score amongpatients with RA in the iguratimod group and in the otherDMARDs (MTX and SASP) group did not differ significantly(MD = 0.09, 95% CI: −0.08, 0.26 in Figure 10(b)).

(h) C-Reactive Protein (CRP). Superiority analysis of threestudies included [14–16] showed that CRP among patientswith RA in the iguratimod group decreased more than

that of the placebo group with a significant difference(MD = −0.32, 95% CI: −0.49, −0.15 in Figure 11(a)). Non-inferiority analysis of two studies included [14, 15] showedthat CRP among patients with RA in the iguratimod groupand in the other DMARDs (MTX and SASP) group didnot differ significantly (MD = −0.13, 95% CI: −0.30, 0.04 inFigure 11(b)).

(i) Erythrocyte Sedimentation Rate (ESR). Superiority analysisof three studies included [14–16] showed that ESR amongpatients with RA in the iguratimod group decreased morethan that of the placebo group with a significant difference(MD = −0.64, 95% CI: −0.81, −0.46 in Figure 12(a)). Non-inferiority analysis of two studies included [14, 15] showedthat ESR among patients with RA in the iguratimod groupand in the other DMARDs (MTX and SASP) group didnot differ significantly (MD = −0.05, 95% CI: −0.22, 0.12 inFigure 12(b)).

(j) Radiographic Change of Bone and Joint Damage. Radio-graphic change of bone and joint damage was not analyzedfor trials of under one year of duration.


Study or subgroup


Subtotal (95% CI)


Ishiguro (2013)Subtotal (95% CI)Heterogeneity: not applicableTest for overall effect: Z = 3.62 (P = 0.0003)

Total (95% CI)


Mean

−0.7−1.81

−0.53

SD

3.819.55

2.07

Total

12779

206

164164

370

Mean

0.30

0.47

SD

2.215.26

2.03

Total

6267

129

8888

217

Weight

31.0%27.2%58.1%

41.9%41.9%

100.0%

−0.30 [−0.60, 0.01]−0.10 [−0.43, 0.22]−0.21 [−0.43, 0.02]

−0.48 [−0.75, −0.22]−0.48 [−0.75, −0.22]

−0.32 [−0.49, −0.15]



Lü (2008)ˇ




Test for subgroup differences: 𝜒2 = 2.53; df = 1 (P = 0.11); I2 = 60.6%

(a)

Study or subgroup

Hara (2007)

Total (95% CI)


Mean

−1.24.9

SD

3.224.3

Total

103163

266

Mean

−0.98.8

SD

2.131.9

Total

103163

266

Weight

38.7%61.3%

100.0%

−0.11 [−0.38, 0.16]−0.14 [−0.35, 0.08]

−0.13 [−0.30, 0.04]


−0.5 −0.25 0 0.25 0.5 Favors [other DMARDs]

Favors [iguratimod 50 mg]

Lü (2009)ˇ


(b)

Figure 11: (a) Comparison of CRP score between iguratimod and placebo groups. (b) Comparison of CRP score between iguratimod andother DMARDs (MTX and SASP) groups.

(2) Secondary Outcomes. Adverse events of the four stud-ies included [2, 14–16] were described in detail. Pooledanalysis of these studies showed no significant differ-ence between the iguratimod group and the placebogroup (RR = 1.17, 95% CI: 0.41, 3.31 in Figure 13(b)) orbetween the iguratimod group and the other DMARDsgroup (MTX and SASP) (RR = 1.14, 95% CI: 0.80, 1.62in Figure 13(b)). Adverse events mainly included leucope-nia, abnormal level function, upper digestive tract disor-der, skin rash, or pruritus. No fatal adverse events werereported.

(3) Quality of GRADE Evidence. Assessment for quality ofevidence was made using GRADE profiler software rec-ommended by the Cochrane Collaboration. The result ofassessment for the four studies included [2, 14–16] wasmoderate quality (Tables 2 and 3).

3.2. Discussion. This systematic review included four eligiblestudies [2, 14–16]. In three studies, superiority pooled analysisof outcomes showed a significant difference between theiguratimod group and the placebo group with RA. Results

showed that iguratimod obviously improved ACR20 andACR70 at 24 weeks, and patients’ health assessment ques-tionnaire (HAQ) score showed reduced rest pain, tenderjoint count, and swollen joint count; lowered CRP level andESR; and lowered physician and patient global assessmentlevel of disease activity, but ACR50 at 24 weeks has nosignificant difference. In two studies [14, 15], noninferioritypooled analysis showed no significant difference between theiguratimod group and the other DMARDs (MTX and SASP)group. Iguratimod was not superior to the other DMARDs(MTX and SASP) in treating RA. All of the four studies[2, 14–16] reported adverse events of iguratimod in treatingRA. No significant difference was found in adverse eventsbetween the iguratimod group and the placebo group (RR= 1.38, 95% CI: 0.74, 2.55) or the iguratimod group andthe other DMARDs (MTX and SASP) group (RR = 1.14,95% CI: 0.80, 1.62). Major adverse events included hepaticdysfunction, leucopenia, upper digestive tract disorder, skinrash, and pruritus. No fatal adverse events were reported.A long-term clinical study by Hara on iguratimod intakein RA patients for 1 and 2 years showed that iguratimodhad the same efficacy and adverse events as those ofSASP [19]. Such finding was confirmed by this systematicreview.


Study or subgroup


Subtotal (95% CI)



Total (95% CI)


Mean

−13.1−12

−9.3

SD

23.633

20.8

Total

12379

202

164164

366

Mean

6.24

2.6

SD

21.629

19.7

Total

5967

126

8888

214

Weight

29.1%27.6%56.7%

43.3%43.3%

100.0%

−0.84 [−1.16, −0.51]−0.51 [−0.84, −0.18]−0.68 [−0.91, −0.45]

−0.58 [−0.84, −0.32]−0.58 [−0.84, −0.32]

−0.64 [−0.81, −0.46]



Lü (2008)ˇ





(a)

Study or subgroup

Hara (2007)

Total (95% CI)


Mean−16.2

8.6

SD23.425

Total97

163

260

Mean−17.111.4

SD24.426.6

Total100163

263

Weight37.7%62.3%

100.0%

0.04 [−0.24, 0.32]−0.11 [−0.33, 0.11]

−0.05 [−0.22, 0.12]

Iguratimod Other DMARDs Std. mean difference Std. mean difference

−0.5 −0.25 0 0.25 0.5 Favors [other DMARDs]

Lü (2009)ˇ

Favors [iguratimod 50 mg]


(b)

Figure 12: (a) Comparison of ESR score between iguratimod and placebo groups. (b) Comparison of ESR score between iguratimod andother DMARDs (MTX and SASP) groups.

The units carrying out studies included are all gen-eral hospitals or good clinical practice bases of medicaluniversities that have high scientific research diathesis andabilities. Duration and dosage of iguratimod had homo-geneity. The evidence of the studies included is moderatequality by carrying out GRADE profiler 3.6 software inspite of some degree-selective biases and no intent-to-treatanalyses.

This systematic review has two limitations. First, both thenumber and the sample size of the studies included are toosmall. Second, these studies were conducted either in Chinaor in Japan. Similar trials in other countries and regions werenot indentified in this review, thus making our review resultsnot representative enough.

In the four studies included [2, 14–16], two described indetail the randomization procedure, allocation concealment,and blinding. We ascertained the validity of the two studies[14, 15] by telephone. For the other two studies [14, 16], wecould not reach the authors by email to validate the ran-domization procedure, allocation concealment, and blinding.Two studies [14, 16] did not have intent-to-treat analysis,and we speculated that participants enrolled were includedbecause of incomplete data. This shortage of two studies[15, 16] made it difficult for us to assess the rationality ofstudy design, and reliability and validity of study results,

to some degree, have affected the application of evidence.We hope that future researchers can try to avoid suchweaknesses.

4. Conclusions

In summary, this systemic review shows that iguratimod isrelatively safe and effective in treating RA and its efficacyis the same as that of MTX and SASP. Nevertheless, dueto methodological defects, small number, and small samplesize of the studies included, we still do not know whetheriguratimod is as effective as other DMARDs besides MTXand SASP. We suggest that more high-quality and large-scaled RCTs should be done to determine the efficacyand safety of iguratimod for RA and whether igurati-mod is as effective as other DMARDs besides MTX andSASP.

Conflict of Interests

The authors of the paper have no conflict of interests withthe manufacturers of iguratimod, RevMan, and GRADEprofiler.


Study or subgroup


Subtotal (95% CI)Total events


Ishiguro (2013)Subtotal (95% CI)Total eventsHeterogeneity: not applicableTest for overall effect: Z = 1.01 (P = 0.31)

Total (95% CI)Total events


Events

12310

133

132

132

265

Total

13095

225

164164

389

Events

5742

99

66

66

165

Total

67195262

8888

350

Weight

29.7%34.2%63.9%

36.1%36.1%

100.0%

M-H, random, 95% CI

3.08 [1.12, 8.51]0.43 [0.20, 0.90]1.11 [0.16, 7.71]

1.38 [0.74, 2.55]1.38 [0.74, 2.55]

1.17 [0.41, 3.31]

Iguratimod Placebo Odds ratio Odds ratioM-H, random, 95% CI

0.1 0.2 0.5 1 2 5 10Favors [iguratimod] Favors [placebo]

Lü (2008)ˇ

Heterogeneity: 𝜏2 = 1.75; 𝜒2 = 9.51; df= 1 (P = 0.002); I2 = 89%




(a)

Study or subgroup

Hara (2007)

Total (95% CI)Total events


Events12375

198

Total130163

293

Events132145

277

Total145326

471

Weight11.4%88.6%

100.0%

1.73 [0.67, 4.48]1.06 [0.73, 1.55]

1.14 [0.80, 1.62]

Iguratimod DMARDs (MTX and SASP) Odds ratio Odds ratio

0.2 0.5 1 2 5Favors [iguratimod] Favors [DMARDs

(MTX and SASP)]

Lü (2009)ˇ


(b)

Figure 13: (a) Comparison of adverse events between iguratimod and placebo groups. (b) Comparison of adverse events between iguratimodand other DMARDs (MTX and SASP) groups.

Acknowledgment

The authors thank Professor Dongtao Lin of Sichuan Univer-sity for copyediting the paper.

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[3] World Health Organization, “Good health adds life to yearsglobal brief for World Health Day 2012,” WHO DocumentProduction Services, WHO, Geneva, Switzerland, 2012.

[4] F. Du, L. J. Lü, Q. Fu et al., “T-614, a novel immunomodulator,attenuates joint inflammation and articular damage in collagen-induced arthritis,” Arthritis Research andTherapy, vol. 10, no. 6,article R136, 2008.

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