Systematic review/meta-analysis Efficacy and safety of various anti-rheumatic treatments for patients with rheumatoid arthritis: a network meta-analys

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1 Systematic review/meta-analysis Efficacy and safety of various anti-rheumatic treatments for patients with rheumatoid arthritis: a network meta-analysis Kexun Ma 1, Ling Li 2, Chunhui Liu 1, Lingling Zhou 3, Xueping Zhou 1 1 The First Clinical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China 2 Department of Rheumatology, Taizhou Hospital of TCM, Taizhou, Jiangsu, China 3 College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China Submitted: 23 December 2016 Accepted: 22 March 2017 Arch Med Sci 2019; 15, 1: DOI: Copyright 2018 Termedia & Banach Corresponding author: Xueping Zhou The First Clinical College Nanjing University of Chinese Medicine No. 138 Xianlin Avenue Qixia District, Nanjing Jiangsu, China Phone: yuhuali05@163.com Abstract Introduction: Biologics and traditional disease-modifying anti-rheumatic drugs (DMARDs) are generally used in treating patients with rheumatoid arthritis (RA). Previous studies have presented abundant data and information about the efficacy of such treatments, but the results were incomplete and inconclusive. This network meta-analysis was conducted to compare and assess the efficacy and safety of 15 therapies employing biologics and DMARDs for RA patients. Material and methods: Six outcomes (American College of Rheumatology 20% response rate (ACR20), ACR50, ACR70, remission, adverse events (AEs) and serious adverse events (SAEs)) were used to evaluate the efficacy and safety of different treatments. The node-splitting method was used to assess the inconsistency, and the rank probabilities of the therapies were estimated by surface under the cumulative ranking curve. Besides, Jadad scale was used to evaluate the methodological quality of eligible studies. Results: A total of 67 randomized controlled trials with 20,898 patients met the inclusion criteria. Most of the therapies presented better performance than conventional DMARDs (cdmards) and placebo in ACR20, ACR50 and ACR70. Conversely, the safety of cdmards and placebo seemed to be superior in AEs and SAEs. Also, tocilizumab (TCZ) and TCZ + methotrexate () showed better remission in pain compared to other treatments. Overall, certolizumab pegol (CZP) + and TCZ + had higher probability than the other treatments in efficacy outcomes. Conclusions: We recommend CZP + as the optimal drug therapy because it has the highest ranking in efficacy outcomes and relatively low risk of adverse events. TCZ + is recommended as an alternative. Abatacept (ABT) and cdmards are not recommended due to their low efficacy. Key words: rheumatoid arthritis, biologics, disease-modifying antirheumatic drugs, network meta-analysis. Introduction Rheumatoid arthritis (RA), a chronic systemic autoimmune disease distributed in all racial and ethnic groups, leads to joint stiffness, deformity and damage [1]. It is characterized by irreversible, alternating episodes, swelling, pain and tenderness, which results in worsening

2 Kexun Ma, Ling Li, Chunhui Liu, Lingling Zhou, Xueping Zhou of physical condition, a reduction of life quality, a decline in employment and increasing direct or indirect expenses [2]. Based on recent statistics, the morbidity of patients with RA in developed countries was approximately 1% in the adult population [3]. Generally, the prevalence of RA in Asian countries was less than that in North America ( %) or in Northern Europe ( %) [4]. A number of drugs which were used in treating the patients with RA separately or together responded well. Among them, infliximab, etanercept, adalimumab, golimumab, tocilizumab, abatacept, certolizumab pegol, methotrexate, and conventional disease-modifying anti-rheumatic drugs (cdmards) were the most common choices [5]. A report showed that the difference between certolizumab pegol and placebo in the American College of Rheumatology 20% response rate (ACR20) was statistically significant from 1 week to 24 weeks. For example, the ACR20 was 45.5% for certolizumab pegol (400 mg every 4 weeks) compared to 9.3% for placebo at week 24 [6]. However, in order to minimize the risk of neutralizing antibodies and to enhance efficacy, biologic agents are combined with cdmards most of the time, though several biologic agents were applied as single therapy [7]. According to the studies, patients with RA treated with placebo plus methotrexate, golimumab (100 mg) plus placebo, golimumab (50 mg) plus methotrexate and golimumab (100 mg) plus methotrexate had ACR20 response rates of 33.1%, 44.4%, 55.1% and 56.2% respectively. Apparently, the therapy combining golimumab with methotrexate can significantly relieve the disease and improve the physical condition [8]. Up to now, there have been dozens of pair-wise meta-analyses (MA) and network meta-analyses (NMA) which evaluate the efficacy and safety of different drug therapies for patients with RA. Nevertheless, most of the trials only focused on two interventions or just a few kinds of drugs, and some of the initial MAs were contradicted by subsequent studies. For instance, a 55% increase in risk of serious infection for patients who were treated with biologics was reported by a Cochrane review [9], while another trial evaluating malignancy risk in RA patients concluded that there was no significant evidence of an increased risk of malignancy using biologics [10]. In contrast, Bongartz et al. reported that RA patients who were treated by anti-tnf therapies had an increased risk of serious infections and malignancies [11]. Therefore, although previous studies have shown abundant data and information, they just verified the efficacy or safety of various therapies for patients with RA. However, the lack of head-to-head comparisons and the absence of systematical comparison made the results incomplete and inconclusive. An NMA seeks to infer the relative efficacy of two treatments by direct and indirect comparisons. Simultaneously, it extracts and analyzes data from all randomized control trials (RCTs) to select the best therapy [12]. Four efficacy outcomes and two safety outcomes were chosen to systematically assess 15 therapies from 56 RCTs with a sample size of 20,898 patients. The objective of the current study is to better characterize the efficacy and safety of each treatment for patients with RA and then make the best choice in clinical practice. Material and methods Search strategy We performed a systematic literature search in electronic databases, including PubMed, Embase and Cochrane Library, to retrieve eligible RCTs from 1997 to Key words and subject terms included rheumatoid arthritis, biological factors, anti-tnf agents, infliximab, etanercept, adalimumab, golimumab, certolizumab pegol, and rituximab. Two reviewers performed the initial search, and all references were reviewed to identify additional studies that were not included in the retrieval. After that, they screened the titles and abstracts to make sure that the studies met predefined selection criteria individually. Inclusion and exclusion criteria Studies included should meet the following criteria: (1) the study design should be RCT; (2) the trials included at least one pairwise comparison between two interventions, which should be used to treat patients with RA; (3) detailed data of at least one relevant outcome were provided. In addition, we excluded duplicate data, reviews, meeting or conference abstracts and case reports from the current analysis. Outcome measurement and data extraction The information as follows was extracted from each eligible study: study code, first author, year of publication, country in which the study was conducted, length of follow-up, interventions, sample size of each therapy and respective outcomes for efficacy and safety. There were 6 outcome indicators to assess the efficacy and safety. American College of Rheumatology 20%, 50%, and 70% response rate (ACR20, ACR50 and ACR70, defined as a 20%, 50% and 70% improvement in patients) at weeks and remission were the efficacy outcomes. Among them, the primary efficacy endpoints were ACR20 and ACR50, and the 34 Arch Med Sci 1, January / 2019

3 Efficacy and safety of various anti-rheumatic treatments for patients with rheumatoid arthritis: a network meta-analysis secondary endpoints were ACR70 and remission. Meanwhile, adverse events (AEs) and serious adverse events (SAEs) were safety outcomes. Statistical analysis The indirect and direct evidence from a wide range of data was analyzed through a Bayesian NMA. After each pair-wise comparison was conducted, the network diagrams of ACR20, ACR50, ACR70, remission, AEs and SAEs were plotted with different interventions. The size of circles indicated the quantity of specific interventions and the boldness of arms showed the number of included studies. The results of these binary variables were presented as odds ratios (ORs) with corresponding 95% credible intervals (CrIs). In addition, net heat plots and node-splitting test were used to analyze the inconsistency level between indirect and direct evidence. The rank probabilities of efficacy and safety of 15 therapies were assessed using surface under the cumulative ranking curve (SUCRA), and the Jadad scale was used to evaluate the methodological quality of eligible studies. All statistical analyses were implemented by STATA version Results Studies included in the network meta-analysis According to a systematic literature search in electronic databases, a total of 8,104 records were identified. Among them, 1,465 duplicate publications and 6,394 articles were excluded due to their irrelevant titles and abstracts. The remaining 245 articles were selected for full-text review and 178 articles assessed as ineligible were excluded. Eventually, 67 RCTs dating from 1997 to 2016 met the inclusion criteria with 20,898 patients [13 79]. The searching and selection steps are shown in Figure 1. Characteristics of included studies The characteristics of included trials are shown in Table I. In detail, 33 of 56 different trials covered patients around the world and 15 trials included patients predominantly from Asia. The rest of the trials were reported to include patients from Europe (5 studies) and America (3 studies). The length of follow-up ranged from 12 to 54 weeks. Most of the trials included a comparison between two interventions. Only 5 trials mentioned comparisons among three interventions. All trials involved 10 drugs as follows: infliximab (INF), etanercept (ETN), adalimumab (ADA), golimumab (GOL), tocilizumab (TCZ), abatacept (ABT), certolizumab pegol (CZP), methotrexate (), conventional disease-modifying anti-rheumatic drugs (cdmards) and placebo (PBO). The full network of comparisons categorized in different outcomes was shown in Figure 2. American College of Rheumatology 20% response rate (ACR20) ACR20 was normally defined as a 20% improvement for patients with rheumatoid arthritis. The estimated ORs with 95% CrIs of ACR20 for each comparison are shown in the lower panel of Table II. Among these 15 therapies, ABT + (OR = 5.42, 95% CrI: ), ADA (OR = 4.31, 95% CrI: ), ADA + (OR = 5.81, 95% CrI: ), CZP (OR = 11.3, 95% CrI: ), CZP + (OR = 9.68, 95% CrI: ), ETN (OR = 4.22, 95% CrI: ), ETN + (OR = 6.31, 95% CrI: ), GOL + (OR = 6.23, 95% CrI: ), INF + (OR = 5.75, 95% CrI: ), TCZ (OR = 5.64, 95% CrI: ) and TCZ + (OR = 7.10, 95% CrI: ) revealed superior efficacy under the endpoint of ACR20 compared with PBO. In addition, CZP + was more efficacious than ETN when comparing ACR20 (OR = 2.29, 95% CrI: ). Records identified through database searching (n = 8104) Records screened (n = 6639) Records excluded at title and abstract level (n = 6394) Full-text records screened (n = 245) Records excluded at the full-text stage (n = 178) 67 records included (67 RCTs) Figure 1. Flow diagram of study inclusion Arch Med Sci 1, January /

4 Kexun Ma, Ling Li, Chunhui Liu, Lingling Zhou, Xueping Zhou Table I. Patient characteristics in the studies included in the mixed-treatment comparison (MTC) analysis No. Study Author (year) Country Follow-up [weeks] Sizes Intervention 1 Intervention 2 Outcomes Drugs Cases Drugs Cases 1 Abe06 Abe (2006) Japan cdmards 47 IFX APPEAL Bae (2013) and Kim (2012) Asia ETN cdmards Combe06&09 Combe (2009) and Combe (2006) Finland cdmards 50 ETN ETN ACT-RAY Dougados (2013) UK TCZ TCZ JESMR Kameda (2010) Japan ETN 69 ETN RED-SEA Jobanputra (2012) UK ADA 60 ETN Kay08 Kay (2008) Global cdmards 35 GOL Kim07 Kim (2007) Korean cdmards 63 ADA LITHE Kremer (2011) Global cdmards 393 TCZ AIM Kremer (2006) Global ABT cdmards Lan04 Lan (2004) Taiwan ETN + 29 cdmards Mathias00& Moreland99 Mathias (2000) and Moreland (1999) North-America PBO 80 ETN CHANGE Miyasaka (2008) Japan PBO 87 ADA SAMURAI Nishimoto (2007) Japan cdmards 145 TCZ O Dell2013 O Dell (2013) and O Dell (2012) Global cdmards 178 ETN SATORI Nishimoto (2009) Japan TCZ + 61 cdmards GO-FORTH Tanaka (2012) Japan cdmards 88 GOL ATTEST Schiff (2008) Global ABT IFX ADORE VanRiel (2006) and VanRiel (2008) Europe ETN 159 ETN AUGUSTII Van Vollenhoven (2011) Global PBO 76 ADA ABT Arch Med Sci 1, January / 2019

5 Efficacy and safety of various anti-rheumatic treatments for patients with rheumatoid arthritis: a network meta-analysis Table I. Cont. No. Study Author (year) Country Follow-up [weeks] Sizes Intervention 1 Intervention 2 Outcomes Drugs Cases Drugs Cases 21 ARMADA Weinblatt (2003) and Weinblatt (2006) North-America cdmards 62 ADA START Westhovens (2006) Global cdmards 363 IFX Zhang2006 Zhang (2006) China IFX + 87 cdmards CREATEIIB Keystone (2012) Global cdmards 65 ETN CERTAIN Smolen (2011) Global cdmards 98 CZP ADACTA Gabay (2013) Global TCZ 163 ADA TOWARD Genovese (2008) Global TCZ cdmards HIKARI Yamamoto (2014) Japan PBO 114 CZP AMPLE Schiff (2014) and Weinblatt (2014) Global ABT ADA GO-FURTHER Weinblatt (2013) Global cdmards 197 GOL Fleischmann 2012 Fleischmann (2012) Global PBO 59 ADA Choy 2012 Choy (2012) Global CZP cdmards RAPID-II Smolen (2009) and Strand (2011) Global cdmards 127 CZP GO-FORWARD Keystone (2009) Global cdmards 133 GOL GOL Chen 2009 Chen (2009) Taiwan ADA + 35 cdmards FAST4WARD Fleischmann (2009) Global PBO 109 CZP Moreland 1997 Moreland (1997) Global PBO 44 ETN OPTION Smolen (2008) Global TCZ cdmards RAPIDI Keystone (2008) Global cdmards 199 CZP CHARISMA Maini (2006) Europe TCZ 159 TCZ cdmards VandePutte 2004 VandePutte (2004) Global ADA 434 PBO Arch Med Sci 1, January /

6 Kexun Ma, Ling Li, Chunhui Liu, Lingling Zhou, Xueping Zhou Table I. Cont. No. Study Author (year) Country Follow-up [weeks] Sizes Intervention 1 Intervention 2 Outcomes Drugs Cases Drugs Cases 42 TEMPO Klareskog (2004) Global cdmards 228 ETN ETN VandePutte 2003 VandePutte (2003) Global PBO 70 ADA ATTRACT Lipsky (2000) and Maini (1999) Global cdmards 88 IFX Kremer 2003 Kremer (2003) Global cdmards 119 ABT Chen 2016 Chen (2016) China ETN cdmards J-RAPID Yamamoto (2014) Japan cdmards 77 CZP LatinRA Machado (2014) and Fleischmann (2014) 49 BREVACTA Kivitz (2014) and Kivitz (2013) Latin America ETN cdmards Global TCZ 437 PBO Hobbs 2015 Hobbs (2015) Global PBO 104 ETN Li 2015 Li (2015) China cdmards 132 GOL ASSET Conaghan (2013) Global ABT + 27 cdmards Keystone 2004 Keystone (2004) Global ADA cdmards defilippis 2006 DeFilippis (2006) Global ETN + 15 IFX Weinblatt 1999 Weinbaltt (1999) Global cdmards 30 ETN STAR Furst (2003) Global ADA cdmards PBO placebo, methotrexate, IFX infliximab, ETN etanercept, ADA adalimumab, GOL golimumab, TCZ tocilizumab, ABT abatacept, CZP clonazepam, cdmards traditional synthetic disease modifying antirheumatic drugs, ACR American College of Rheumatology, AEs adverse events, SAEs serious adverse events. Outcomes: 1 ACR20 20% response rate, 2 ACR50 50% response rate, 3 ACR70 70% response rate, 4 Remission, 5 AEs, 6 SAEs. 38 Arch Med Sci 1, January / 2019

7 Efficacy and safety of various anti-rheumatic treatments for patients with rheumatoid arthritis: a network meta-analysis American College of Rheumatology 50% response rate (ACR50) Base on the upper panel of Table II, PBO showed the worst performance for ACR50 compared with all therapies except cdmards (OR = 1.86, 95% CrI: ). As for cdmards, it revealed worse efficacy than the other treatments except ABT, GOL and PBO. In addition, ETN +, CZP + and TCZ + were superior to ETN for the efficacy of ACR50 (ETN + : OR = 1.59, 95% CrI: ; CZP + : OR = 2.27, 95% CrI: ; TCZ + : OR = 2.10, 95% CrI: American College of Rheumatology 70% response rate (ACR70) As shown in the lower panel of Table III, only cdmards (OR = 2.41, 95% CrI: ) demonstrated no statistically significant difference from PBO. Similarly, all the therapies appeared superior to cdmards when comparing ACR70, except for ABT (OR = 1.60, 95% CrI: ), ADA (OR = 2.77, 95% CrI: ) and GOL (OR = 2.69, 95% CrI: ) Additionally, CZP enjoyed obvious superiority to ABT (OR = 0.05, 95% CrI: ) and ADA (OR = 0.09, 95% CrI: ). ACR20 ACR50 GOL ETN + GOL + IFX + PBO GOL + GOL ETN + IFX + PBO ETN TCZ ETN TCZ CZP + TCZ + CZP + TCZ + CZP cdmards ADA + ADA ABT ABT + CZP cdmards ADA + ADA ABT ABT + ACR70 Remission ETN + GOL GOL + IFX + PBO ETN TCZ TCZ + cdmards ETN TCZ GOL + CZP + CZP cdmards ADA + ADA ABT ABT + TCZ + ABT + IFX + ADA ADA + GOL ETN + AEs SAEs TCZ GOL + ADA + TCZ + ETN ETN + IFX + GOL + ADA TCZ TCZ + ETN ETN + IFX + ABT + cdmards GOL ADA + cdmards GOL PBO ABT + CZP CZP ADA PBO ABT CZP + ABT CZP + Figure 2. Full network of comparisons categorized in different outcomes. The width of the lines is proportional to the number of trials comparing each pair of treatments; the area of circles represents the cumulative number of patients for each intervention Arch Med Sci 1, January /

8 Kexun Ma, Ling Li, Chunhui Liu, Lingling Zhou, Xueping Zhou Table II. Odds ratio estimates with 95% credible intervals of ACR20 and ACR50 for each comparison Endpoint ACR50 ACR20 ABT ABT 0.47 (0.13, 1.72) ABT (0.07, 1.13) ADA 0.35 (0.12, 1.03) ADA (0.06, 1.02) cdmards 0.89 (0.24, 3.22) CZP 0.13 (0.03, 0.55) CZP (0.04, 0.63) ETN 0.35 (0.10, 1.23) ETN (0.06, 0.84) GOL 0.46 (0.09, 2.41) GOL (0.06, 0.98) IFX (0.07, 1.02) PBO 1.49 (0.51, 4.44) TCZ 0.26 (0.08, 0.93) TCZ (0.06, 0.79) 0.66 (0.24, 1.73) ABT (0.54, 3.53) 1.27 (0.45, 3.53) 0.93 (0.47, 1.86) 3.22 (1.80, 5.75) 0.49 (0.13, 1.82) 0.56 (0.25, 1.25) 1.28 (0.57, 2.92) 0.84 (0.41, 1.68) 1.67 (0.48, 5.58) 0.88 (0.39, 1.95) 0.94 (0.46, 1.93) 5.42 (2.12, 14.0) 0.97 (0.41, 2.27) 0.76 (0.35, 1.65) 0.38 (0.11, 1.36) 0.82 (0.44, 1.52) ADA 0.58 (0.23, 1.48) 0.73 (0.27, 1.97) 2.53 (1.09, 5.87) 0.38 (0.13, 1.12) 0.44 (0.16, 1.21) 1.02 (0.45, 2.25) 0.66 (0.28, 1.55) 1.31 (0.33, 5.16) 0.69 (0.25, 1.90) 0.75 (0.28, 1.97) 4.31 (2.53, 7.39) 0.76 (0.35, 1.63) 0.61 (0.24, 1.48) 1.79 (0.55, 5.81) 3.82 (2.29, 6.42) 2.72 (1.26, 6.11) ADA (2.89, 7.69) 3.46 (2.05, 5.87) 0.52 (0.14, 1.88) 0.60 (0.28, 1.30) 1.38 (0.63, 3.03) 0.90 (0.46, 1.73) 1.79 (0.54, 5.87) 0.94 (0.44, 2.03) 1.01 (0.49, 2.10) 5.81 (2.39, 14.7) 1.04 (0.46, 2.36) 0.82 (0.40, 1.72) 0.30 (0.07, 1.21) 0.64 (0.18, 2.32) 0.46 (0.15, 1.36) 0.79 (0.22, 2.83) cdmards 0.17 (0.05, 0.54) 0.15 (0.05, 0.49) 0.17 (0.10, 0.30) 0.40 (0.22, 0.71) 0.26 (0.17, 0.39) 0.51 (0.18, 1.51) 0.27 (0.16, 0.47) 0.29 (0.18, 0.49) 1.68 (0.81, 3.56) 0.30 (0.16, 0.56) 0.24 (0.14, 0.39) 0.31 (0.09, 1.14) 0.66 (0.32, 1.40) 0.48 (0.18, 1.25) 0.82 (0.39, 1.70) 0.17 (0.10, 0.30) CZP 1.04 (0.28, 3.82) 1.16 (0.32, 4.26) 2.66 (0.86, 8.25) 1.73 (0.52, 5.70) 3.42 (0.69, 17.1) 1.82 (0.50, 6.69) 1.95 (0.55, 7.03) 11.3 (4.48, 28.8) 1.99 (0.63, 6.42) 1.58 (0.46, 5.42) 0.70 (0.22, 2.27) 1.52 (0.72, 3.13) 1.08 (0.50, 2.32) 1.86 (0.90, 3.78) 0.39 (0.23, 0.66) 2.36 (0.74, 7.39) CZP (1.07, 4.76) 2.29 (1.03, 5.10) 1.49 (0.75, 2.94) 2.94 (0.89, 9.87) 1.57 (0.72, 3.42) 1.68 (0.79, 3.56) 9.68 (3.86, 24.5) 1.73 (0.76, 3.97) 1.36 (0.64, 2.89) 0.44 (0.13, 1.45) 0.94 (0.49, 1.77) 0.68 (0.30, 1.49) 1.16 (0.62, 2.14) 0.25 (0.17, 0.35) 1.48 (0.45, 4.85) 1.42 (0.73, 2.72) ETN 0.63 (0.39, 0.99) 0.65 (0.37, 1.13) 1.28 (0.38, 4.39) 0.68 (0.31, 1.54) 0.73 (0.34, 1.58) 4.22 (2.23, 8.17) 0.75 (0.36, 1.57) 0.76 (0.16, 3.63) 1.63 (0.52, 5.05) 1.16 (0.32, 4.22) 1.99 (0.65, 6.17) 0.43 (0.15, 1.16) 2.53 (0.53, 12.2) 2.46 (0.76, 7.77) 1.07 (0.34, 3.39) ETN (0.59, 5.16) 1.97 (0.63, 6.36) 1.05 (0.53, 2.10) 1.13 (0.60, 2.14) 6.49 (3.10, 14.0) 1.15 (0.58, 2.34) 0.41 (0.11, 1.52) 0.89 (0.41, 1.88) 0.63 (0.24, 1.67) 1.08 (0.52, 2.25) 0.23 (0.13, 0.39) 1.38 (0.38, 5.05) 1.34 (0.61, 2.86) 0.58 (0.28, 1.25) 0.93 (0.49, 1.82) GOL 0.54 (0.20, 1.45) 0.53 (0.18, 1.55) 0.57 (0.17, 1.90) 3.29 (0.89, 12.3) 0.58 (0.17, 2.01) 0.48 (0.13, 1.72) 1.03 (0.53, 1.93) 0.73 (0.30, 1.86) 1.26 (0.64, 2.46) 0.27 (0.16, 0.43) 1.60 (0.45, 5.70) 1.54 (0.75, 3.16) 0.68 (0.34, 1.38) 1.08 (0.61, 1.97) 0.63 (0.20, 1.93) GOL (0.57, 2.39) 1.07 (0.51, 2.29) 6.23 (2.46, 15.6) 1.11 (0.48, 2.51) 3.35 (1.22, 9.21) 7.17 (3.06, 17.0) 5.10 (3.03, 8.85) 8.85 (3.78, 20.7) 1.86 (0.94, 3.71) 11.1 (4.35, 29.7) 10.8 (4.53, 26.1) 4.71 (2.56, 9.12) 7.54 (3.82, 15.6) 4.39 (1.31, 15.2) 8.08 (3.39, 19.7) IFX (3.06, 16.1) 5.75 (2.39, 14.1) 1.03 (0.46, 2.29) 0.44 (0.14, 1.39) 0.95 (0.44, 2.03) 0.68 (0.34, 1.39) 1.16 (0.55, 2.46) 0.25 (0.14, 0.44) 1.48 (0.47, 4.76) 1.42 (0.66, 3.13) 0.63 (0.32, 1.25) 1.00 (0.54, 1.95) 0.58 (0.19, 1.86) 1.07 (0.50, 2.36) 0.92 (0.44, 1.95) PBO 0.13 (0.07, 0.25) 0.18 (0.09, 0.36) 0.34 (0.10, 1.14) 0.73 (0.36, 1.45) 0.52 (0.23, 1.20) 0.89 (0.45, 1.75) 0.19 (0.12, 0.30) 1.13 (0.34, 3.86) 1.08 (0.54, 2.23) 0.48 (0.25, 0.94) 0.76 (0.44, 1.39) 0.44 (0.15, 1.36) 0.82 (0.41, 1.70) 0.70 (0.37, 1.38) 0.10 (0.05, 0.21) TCZ 0.76 (0.43, 1.35) PBO placebo, methotrexate, IFX infliximab, ETN etanercept, ADA adalimumab, GOL golimumab, TCZ tocilizumab, ABT abatacept, CZP clonazepam, cdmards traditional synthetic disease modifying antirheumatic drugs, ACR American College of Rheumatology, AEs adverse events, SAEs serious adverse events (0.29, 1.25) 0.91 (0.49, 1.73) 0.46 (0.14, 1.51) 0.88 (0.41, 1.84) 0.81 (0.39, 1.67) 0.14 (0.06, 0.32) 0.79 (0.41, 1.52) TCZ + 40 Arch Med Sci 1, January / 2019

9 Efficacy and safety of various anti-rheumatic treatments for patients with rheumatoid arthritis: a network meta-analysis Table III. Odds ratio estimates with 95% credible intervals of ACR70 and remission for each comparison Endpoint Remission ACR70 ABT (0.05, 1.60) ADA 0.58 (0.17, 1.93) ADA (0.05, 1.55) cdmards 1.60 (0.32, 7.54) CZP ) CZP (0.04, 1.23) ETN 0.49 (0.09, 2.34) ETN (0.06, 1.49) GOL 0.59 (0.07, 4.71) GOL (0.05, 1.82) IFX (0.06, 1.86) PBO 3.86 (1.07, 14.6) TCZ 0.39 (0.09, 1.70) TCZ (0.05, 1.26) ABT (0.55, 6.96) 0.97 (0.45, 2.12) 5.26 (2.77, 10.4) ) 0.70 (0.25, 2.05) 1.62 (0.61, 4.06) 1.03 (0.44, 2.32) 1.97 (0.44, 8.94) 1.08 (0.40, 2.97) 1.19 (0.52, 2.66) 12.8 (4.01, 46.5) 1.30 (0.50, 3.67) 0.86 (0.36, 2.12) 0.34 (0.02, 6.11) 0.90 (0.12, 6.75) ADA 2.69 (0.08, 107) 0.51 (0.14, 1.73) 2.77 (0.93, 8.08) ) 0.37 (0.10, 1.43) 0.85 (0.25, 2.53) 0.54 (0.16, 1.63) 1.04 (0.18, 5.81) 0.57 (0.15, 2.10) 0.62 (0.17, 2.12) 6.69 (3.35, 14.7) 0.68 (0.28, 1.75) 0.45 (0.15, 1.36) ADA (2.92, 10.5) ) 0.73 (0.26, 2.08) 1.65 (0.63, 4.06) 1.06 (0.46, 2.32) 2.01 (0.47, 9.03) 1.12 (0.41, 2.97) 1.21 (0.51, 2.86) 13.1 (4.14, 47.0) 1.32 (0.52, 3.71) 0.88 (0.38, 2.14) 4.06 (1.03, 16.3) 12.1 (0.92, 185) 4.53 (0.39, 52.5) 2.10 (0.20, 23.8) 6.17 (0.26, 183) 2.34 (0.10, 54.1) cdmards 0.52 (0.08, 3.63) ) 0.13 (0.06, 0.30) 0.31 (0.15, 0.58) 0.20 (0.11, 0.31) 0.37 (0.10, 1.42) 0.21 (0.09, 0.43) 0.22 (0.12, 0.41) 2.41 (0.91, 7.10) 0.24 (0.12, 0.53) 0.16 (0.09, 0.29) 1.19 (0.18, 7.61) 3.53 (0.21, 70.1) 1.32 (0.08, 20.5) 0.29 (0.08, 0.98) 1.17 (0.09, 13.2) 3.49 (0.12, 104) 1.32 (0.05, 30.0) 0.29 (0.03, 2.10) 0.71 (0.12, 4.06) 2.14 (0.13, 38.1) 0.80 (0.05, 11.3) 0.18 (0.06, 0.50) 1.06 (0.20, 5.58) 3.16 (0.17, 68.7) 1.20 (0.09, 16.4) 0.26 (0.06, 1.09) ) 0.17 (0.02, 1.39) ) ) CZP 3.97 (0.34, 133) 9.03 (0.86, 276) 5.75 (0.55, 179) 11.4 (0.75, 424) 6.17 (0.52, 198) 6.69 (0.59, 211) 70.8 (9.49, 1900) 7.32 (0.77, 217) 4.85 (0.48, 148) CZP (0.75, 6.36) 1.46 (0.53, 3.71) 2.80 (0.57, 13.3) 1.54 (0.50, 4.57) 1.67 (0.58, 4.66) 18.0 (5.10, 69.4) 1.82 (0.64, 5.64) 1.22 (0.45, 3.32) ETN 0.57 (0.12, 2.53) 0.64 (0.36, 1.15) 1.22 (0.28, 5.75) 0.68 (0.25, 1.92) 0.73 (0.30, 1.86) 7.92 (2.94, 26.1) 0.80 (0.34, 2.27) 0.53 (0.23, 1.35) ETN (0.47, 8.41) 1.05 (0.43, 2.66) 1.14 (0.53, 2.59) 12.3 (4.53, 40.4) 1.25 (0.56, 3.25) 0.84 (0.41, 1.90) 0.57 (0.03, 9.03) 1.00 (0.09, 10.2) 0.34 (0.04, 3.00) 0.61 (0.11, 3.06) GOL 0.61 (0.09, 4.48) 0.55 (0.15, 1.93) 0.60 (0.13, 2.56) 6.49 (1.23, 37.3) 0.65 (0.15, 3.16) 0.44 (0.10, 1.92) GOL (0.41, 2.86) 11.7 (3.46, 45.6) 1.19 (0.43, 3.63) 0.79 (0.31, 2.12) 0.51 (0.04, 5.53) 0.90 (0.13, 5.87) 0.90 (0.08, 11.7) 1.48 (0.25, 9.30) IFX (3.46, 38.8) 1.09 (0.44, 3.03) 0.73 (0.32, 1.79) ) ) ) ) ) PBO 0.10 (0.04, 0.24) 0.07 (0.02, 0.19) 0.15 (0.03, 0.87) 0.46 (0.03, 6.42) ) ) ) 0.13 (0.02, 0.65) ) 0.22 (0.05, 0.98) 0.15 (0.02, 0.86) TCZ 2.66 (0.57, 13.5) 0.67 (0.32, 1.32) TCZ + PBO placebo, methotrexate, IFX infliximab, ETN etanercept, ADA adalimumab, GOL golimumab, TCZ tocilizumab, ABT abatacept, CZP clonazepam, cdmards traditional synthetic disease modifying antirheumatic drugs, ACR American College of Rheumatology, AEs adverse events, SAEs serious adverse events. Arch Med Sci 1, January /

10 Kexun Ma, Ling Li, Chunhui Liu, Lingling Zhou, Xueping Zhou Table IV. Odds ratio estimates with 95% credible intervals of AEs and SAEs for each comparison Endpoint SAEs AEs ABT ABT 3.71 (0.88, 16.9) ABT (0.76, 4.26) ADA 0.89 (0.48, 1.63) ADA (0.82, 4.48) cdmards 2.29 (1.08, 5.10) CZP 0.92 (0.42, 1.99) CZP (0.81, 4.35) ETN 1.42 (0.65, 3.16) ETN (0.86, 4.18) GOL 2.23 (0.86, 5.81) GOL (0.79, 4.18) ABT (0.23, 1.05) 1.05 (0.68, 1.65) 1.28 (0.90, 1.90) 0.52 (0.24, 1.13) 1.04 (0.64, 1.68) 0.80 (0.47, 1.30) 1.05 (0.68, 1.63) 1.26 (0.64, 2.46) 1.00 (0.63, 1.62) 2.39 (0.73, 8.67) 0.64 (0.24, 1.70) 2.94 (0.66, 13.5) 0.80 (0.45, 1.28) ADA 1.23 (0.44, 3.42) 2.10 (1.02, 4.48) 2.59 (1.35, 5.00) 1.05 (0.53, 1.97) 2.08 (1.01, 4.31) 1.60 (0.82, 3.10) 2.10 (1.08, 4.14) 2.51 (1.04, 5.99) 2.01 (0.99, 4.18) ADA (0.85, 1.75) 0.50 (0.22, 1.05) 1.00 (0.61, 1.58) 0.76 (0.45, 1.23) 1.00 (0.64, 1.54) 1.20 (0.61, 2.27) 0.96 (0.59, 1.51) 2.94 (0.73, 12.3) 0.80 (0.51, 1.17) 1.25 (0.51, 2.94) 1 (0.6, 1.68) 0.60 (0.12, 3.03) 0.16 (0.04, 0.66) 0.26 (0.08, 0.74) 0.21 (0.05, 0.86) cdmards 0.21 (0.05, 0.78) 0.40 (0.20, 0.79) 0.81 (0.58, 1.11) 0.62 (0.43, 0.87) 0.81 (0.64, 1.04) 0.97 (0.55, 1.68) 0.78 (0.58, 1.05) 1.82 (0.41, 8.76) 0.51 (0.24, 0.99) 0.78 (0.27, 2.25) 0.63 (0.29, 1.38) 0.63 (0.35, 1.12) CZP 3.03 (0.72, 13.9) 1.99 (0.93, 4.39) 1.54 (0.76, 3.06) 2.01 (1.01, 4.10) 2.44 (1.00, 5.81) 1.93 (0.92, 4.10) CZP (0.47, 1.21) 1.00 (0.68, 1.52) 1.21 (0.63, 2.27) 0.96 (0.63, 1.51) 1.88 (0.45, 7.92) 0.51 (0.25, 0.92) 0.79 (0.32, 1.79) 0.64 (0.31, 1.27) 0.64 (0.38, 1.02) 3.13 (0.81, 12.4) 1.01 (0.46, 2.14) 2.29 (0.54, 9.49) 0.62 (0.32, 1.07) 0.96 (0.38, 2.27) 0.78 (0.39, 1.46) 0.78 (0.50, 1.14) 3.78 (0.97, 14.2) 1.22 (0.59, 2.46) ETN 1.21 (0.76, 1.92) 1.31 (0.96, 1.86) 1.57 (0.82, 3.03) 1.26 (0.80, 2.03) ETN (0.65, 2.18) 0.96 (0.66, 1.40) 2.61 (0.38, 17.6) 0.68 (0.17, 2.64) 1.07 (0.23, 5.00) 0.87 (0.21, 3.49) 0.86 (0.22, 3.13) 4.31 (0.66, 25.5) 1.38 (0.34, 5.53) 1.36 (0.33, 5.31) 1.13 (0.27, 4.35) 1.31 (0.25, 6.55) 0.35 (0.14, 0.78) 0.55 (0.18, 1.67) 0.44 (0.17, 1.06) 0.44 (0.20, 0.89) 2.14 (0.45, 9.58) 0.70 (0.27, 1.75) 0.69 (0.28, 1.63) 0.57 (0.23, 1.32) GOL 0.51 (0.15, 1.55) 0.80 (0.47, 1.40) GOL (0.63, 12.2) 0.73 (0.41, 1.25) 1.13 (0.41, 2.97) 0.91 (0.48, 1.77) 0.91 (0.59, 1.39) 4.44 (1.09, 18.2) 1.45 (0.71, 3.00) 1.43 (0.75, 2.83) 1.19 (0.66, 2.20) 1.06 (0.27, 3.90) 2.08 (0.93, 4.95) 2.36 (0.73, 8.41) 0.64 (0.25, 1.62) 0.99 (0.63, 1.60) 0.81 (0.31, 2.14) 0.80 (0.35, 1.88) 3.86 (1.48, 11.5) 1.28 (0.45, 3.49) 1.26 (0.57, 2.92) 1.03 (0.45, 2.51) 0.91 (0.21, 4.48) 1.80 (0.63, 5.58) 1.84 (0.46, 7.92) 0.50 (0.24, 0.96) 0.76 (0.32, 1.80) 0.62 (0.30, 1.32) 0.63 (0.36, 1.06) 3.03 (0.82, 10.9) 0.98 (0.45, 2.20) 0.98 (0.49, 1.97) 0.80 (0.42, 1.57) 0.72 (0.18, 2.83) 1.42 (0.58, 3.53) 2.12 (0.50, 9.49) 0.57 (0.30, 1.02) 0.88 (0.34, 2.25) 0.71 (0.36, 1.42) 0.71 (0.45, 1.12) 3.49 (0.89, 13.6) 1.13 (0.54, 2.39) 1.13 (0.58, 2.23) 0.92 (0.52, 1.73) 0.83 (0.21, 3.22) 1.63 (0.70, 3.86) 42 Arch Med Sci 1, January / 2019

11 Efficacy and safety of various anti-rheumatic treatments for patients with rheumatoid arthritis: a network meta-analysis Table IV. Cont. Endpoint SAEs 0.78 (0.43, 1.45) 0.68 (0.34, 1.34) 0.88 (0.35, 2.25) IFX (0.59, 1.40) 0.75 (0.39, 1.40) 0.90 (0.59, 1.31) 1.17 (0.74, 1.88) 0.90 (0.57, 1.40) 1.79 (0.84, 3.82) 0.73 (0.52, 0.98) 0.90 (0.54, 1.39) 1.86 (0.90, 3.90) 0.94 (0.59, 1.45) IFX (0.73, 3.94) 0.89 (0.36, 2.12) PBO 0.77 (0.34, 1.70) 1.12 (0.63, 1.99) 1.04 (0.58, 1.82) 0.83 (0.40, 1.75) 1.00 (0.60, 1.63) 1.31 (0.80, 2.16) 1.00 (0.56, 1.80) 2.01 (1.25, 3.29) 0.81 (0.50, 1.31) 1.01 (0.54, 1.79) 2.10 (1.32, 3.25) 1.04 (0.57, 1.90) PBO 1.86 (1.03, 3.42) TCZ 1.15 (0.66, 2.03) 0.81 (0.53, 1.27) 0.90 (0.58, 1.46) 0.84 (0.54, 1.32) 0.68 (0.36, 1.31) 0.80 (0.57, 1.17) 1.05 (0.70, 1.68) 0.81 (0.52, 1.31) 1.62 (0.86, 3.16) 0.65 (0.47, 0.92) 0.81 (0.50, 1.31) 1.70 (0.91, 3.19) 0.84 (0.52, 1.40) TCZ 1.51 (0.73, 3.32) TCZ (0.76, 1.48) 0.85 (0.53, 1.43) 0.95 (0.64, 1.46) 0.90 (0.60, 1.32) 0.71 (0.39, 1.34) 0.85 (0.61, 1.19) 1.12 (0.76, 1.73) 0.85 (0.58, 1.31) 1.72 (0.87, 3.49) 0.69 (0.53, 0.90) 0.85 (0.54, 1.32) 1.80 (0.91, 3.53) 0.89 (0.58, 1.42) TCZ (0.74, 3.60) PBO placebo, methotrexate, IFX infliximab, ETN etanercept, ADA adalimumab, GOL golimumab, TCZ tocilizumab, ABT abatacept, CZP clonazepam, cdmards traditional synthetic disease modifying antirheumatic drugs, ACR American College of Rheumatology, AEs adverse events, SAEs serious adverse events. Remission The efficacy endpoint of remission was evaluated among 11 treatments as displayed in the upper panel of Table III. It could be observed that TCZ and TCZ + were significantly better than ABT + (OR = 0.06, 95% CrI: ; OR = 0.15, 95% CrI: ), cdmards (OR = 0.01, 95% CrI: ; OR = 0.04, 95% CrI: ), ETN (OR = 0.03, 95% CrI: ; OR = 0.07, 95% CrI: ), ETN + (OR = 0.05, 95% CrI: ; OR = 0.13, 95% CrI: ), GOL + (OR = 0.08, 95% CrI: ; OR = 0.22, 95% CrI: ) and IFX + (OR = 0.05, 95% CrI: ; OR = 0.15, 95% CrI: ) in disease remission. However, there was no particular evidence to confirm which one of TCZ and TCZ + was better. ABT + (OR = 0.25, 95% CrI: ), ETN + (OR = 0.29, 95% CrI: ) and GOL + (OR = 0.18, 95% CrI: ) also presented greater remission of pain compared to cdmards. Additionally, GOL (OR = 0.05, 95% CrI: ) was less efficacious than TCZ. Adverse events (AEs) The safety outcomes are shown in Table IV. Statistically, ABT (OR = 1.86, 95% CrI: ), ADA (OR = 2.10, 95% CrI: ) and CZP (OR = 2.01, 95% CrI: ) presented a higher risk of AEs than PBO. ADA was more likely to cause adverse events than ADA + (OR = 2.10, 95% CrI: ), cdmards (OR = 2.59, 95% CrI: ), CZP + (OR = 2.08, 95% CrI: ), ETN + (OR = 2.10, 95% CrI: ), GOL (OR = 2.51, 95% CrI: ) and PBO (OR = 2.10, 95% CrI: ). In comparison with ETN + (OR = 2.01, 95% CrI: ) and GOL (OR = 2.44, 95% CrI: ) more patients taking CZP dropped out due to AEs. Moreover, the safety of cdmards for adverse events was superior to CZP (OR = 0.40, 95% CrI: ), ETN (OR = 0.62, 95% CrI: ), IFX + (OR = 0.73, 95% CrI: ), TCZ (OR = 0.65, 95% CrI: ) and TCZ + (OR = 0.69, 95% CrI: ). Serious adverse events (SAEs) The comparison of SAEs for all the treatments is displayed in the upper panel of Table IV. CZP (OR = 3.86, 95% CrI: ) presented a worse performance than PBO (OR = 0.26, 95% CrI: ), INF + (OR = 0.23, 95% CrI: ), cdmards (OR = 0.21, 95% CrI: ), ADA + (OR = 0.21, 95% CrI: ), ADA (OR = 0.26, 95% CrI: ) and ABT + (OR = 0.16, 95% CrI: ). In contrast, ABT + was more efficacious in reducing the SAEs in comparison with CZP + (OR = 0.51, 95% CrI: 0.24 Arch Med Sci 1, January /

12 Kexun Ma, Ling Li, Chunhui Liu, Lingling Zhou, Xueping Zhou 0.99), ETN (OR = 0.51, 95% CrI: ), GOL + (OR = 0.35, 95% CrI: ) and TCZ (OR = 0.50, 95% CrI: ). Furthermore, cdmards (OR = 0.44, 95% CrI: ) worked better than GOL + in withdrawal due to SAEs. Relative ranking analysis Relative ranking of the treatments is assessed by SUCRA in Table V. Since CZP + not only had high efficacy in ACR20 (83.3%), ACR50 (84.2%) and ACR70 (75.1%) but also performed well in AEs and SAEs, we recommend CZP + as the optimal drug therapy. Another alternative was TCZ + for the same reason. By contrast, ABT was regarded as the worst choice in treating RA because of its low probability in efficacy outcomes (ACR20: 10.8%, ACR50 = 2.4%, ACR70 = 20.0%) and safety outcomes (AEs = 14.8%, SAEs = 17.2%). Also, cdmards are not recommended due to their low efficacy, though their safety seemed to be superior. Consistency test The node-splitting method was used to evaluate the consistency level between direct and indirect evidence. P-values < 0.05 implied the existence of a significant inconsistency. As listed in Table VI, a significant inconsistency did exist in the analysis of remission and AEs. As for remission, obvious inconsistency was found in the comparisons between TCZ and cdmards (p = 0.013), TCZ + and cdmards (p = 0.015), as well as TCZ + and TCZ (p = 0.019). On the other hand, no consistency between ETN + and cdmards (p < 0.001), TCZ and ETN + (p = 0.034), TCZ + and ETN + (p = 0.025) was demonstrated when comparing them with AEs. The results of the consistency test are also visually presented in Figure 3 with net heat plots, which indicated the same results as in Table VI. Publication bias The estimate of publication bias was performed by the symmetry characteristics of the dots representing included trials with different colors in the funnel plots. According to Figure 4, all of the funnel plots were focused in the triangle funnel areas in left and right directions, which suggested that the distribution of dots verified no significant publication bias or small study effect among the trials in ACR20, ACR50, ACR70, AEs, SAEs and remission. Evaluation of the methodological quality of eligible studies The Jadad scale was used to appraise the methodological quality of included studies, and the scores of the Jadad scale of each individual study Table V. Relative ranking of the treatments assessed by surface under cumulative ranking curve area Treatments ACR20 ACR50 ACR70 Remission AEs SAEs ABT ABT ADA ADA cdmards CZP CZP ETN ETN GOL GOL IFX PBO TCZ TCZ PBO placebo, methotrexate, IFX infliximab, ETN etanercept, ADA adalimumab, GOL golimumab, TCZ tocilizumab, ABT abatacept, CZP clonazepam, cdmards traditional synthetic disease modifying antirheumatic drugs, ACR American College of Rheumatology, AEs adverse events, SAEs serious adverse events. 44 Arch Med Sci 1, January / 2019

13 Efficacy and safety of various anti-rheumatic treatments for patients with rheumatoid arthritis: a network meta-analysis ACR20 ACR50 D : N C : H C : O M : O E : F A : B D : G K : L L : N G : H K : G K : H B : C B : M C : M D : N C : H C : O M : O E : F A : B D : G K : L L : N G : H K : G K : H B : C B : M C : M B : M C : M B : C G : H K : G C : H A : B D : G K : L L : N D : N E : F K : H C : O M : O B : M C : M B : C G : H K : G C : H A : B D : G K : L L : N D : N E : F K : H C : O M : O ACR70 Remission D : N K : L L : N G : H K : G C : O M : O A : B E : F D : G C : H K : H B : C B : M C : M D : N K : L L : N G : H K : G C : O M : O A : B E : F D : G C : H K : H B : C B : M C : M N : D F : E B : A N : D F : E B : A AEs SAEs A : G K : G B : G A : B G : H K : H B : C C : H K : L L : N E : F C : M C : O M : O D : N A : G K : G B : G A : B G : H K : H B : C C : H K : L L : N E : F C : M C : O M : O D : N D : N E : F K : L L : N C : H B : C K : H A : B G : H K : G H : M C : M C : O M : O D : N E : F K : L L : N C : H B : C K : H A : B G : H K : G H : M C : M C : O M : O Figure 3. Results of consistency analysis by heat plot. Inconsistency between direct and indirect evidence was assessed using the net heat plots, which visually displayed the inconsistency level with different colors. The more vibrant the color was, the more serious was the indicated inconsistency A TCZ +, B TCZ, C PBO, D IFX +, E GOL +, F GOL, G ETN +, H ETN, I CZP +, J CZP, K cdmards, L ADA +, M ADA, N ABT +, O ABT. Arch Med Sci 1, January /

14 Kexun Ma, Ling Li, Chunhui Liu, Lingling Zhou, Xueping Zhou Table VI. Results of consistency analysis by node-splitting plot Endpoint Comparison Direct OR (95% CI) Indirect OR (95% CrI) Network OR (95% CrI) P-value ACR20 ADA + vs. ABT (0.35, 3.50) 1.10 (0.48, 2.70) 1.10 (0.53, 2.10) cdmards vs. ABT (0.17, 0.68) 0.29 (0.07, 1.10) 0.31 (0.17, 0.56) cdmards vs. ADA (0.16, 0.52) 0.31 (0.08, 1.10) 0.29 (0.17, 0.49) ETN vs. cdmards 2.50 (1.00, 6.10) 2.40 (1.00, 5.90) 2.50 (1.40, 4.60) ETN + vs. cdmards 3.80 (2.50, 5.70) 4.70 (1.30, 15.0) 3.80 (2.60, 5.70) ETN + vs. ETN 1.50 (0.86, 2.90) 1.20 (0.27, 4.90) 1.50 (0.89, 2.70) IFX + vs. ABT (0.22, 2.40) 1.30 (0.53, 3.20) 1.10 (0.51, 2.30) IFX + vs. cdmards 3.50 (2.00, 5.80) 3.90 (0.52, 26.0) 3.50 (2.00, 5.60) IFX + vs. ETN (0.15, 7.30) 0.88 (0.46, 1.70) 0.90 (0.47, 1.70) PBO vs. ADA 0.22 (0.12, 0.38) 0.41 (0.10, 1.70) 0.23 (0.13, 0.40) PBO vs. ETN 0.22 (0.10, 0.48) 0.29 (0.08, 1.10) 0.23 (0.13, 0.45) TCZ vs. ADA 1.90 (0.53, 6.20) 1.00 (0.34, 2.70) 1.30 (0.62, 2.90) TCZ vs. cdmards 3.40 (1.40, 8.50) 3.30 (1.30, 8.40) 3.30 (1.80, 6.40) TCZ vs. PBO 3.50 (1.10, 11.0) 7.70 (3.10, 18.0) 5.60 (2.80, 12.0) TCZ + vs. cdmards 4.00 (2.40, 7.00) 4.80 (1.10, 21.0) 4.20 (2.50, 6.90) TCZ + vs. TCZ 1.40 (0.60, 3.20) 0.94 (0.35, 2.90) 1.30 (0.65, 2.50) ACR50 ADA + vs. ABT (0.42, 2.80) 1.40 (0.59, 3.00) 1.20 (0.63, 2.30) cdmards vs. ABT (0.16, 0.56) 0.22 (0.07, 0.74) 0.26 (0.15, 0.45) cdmards vs. ADA (0.12, 0.35) 0.24 (0.08, 0.82) 0.21 (0.13, 0.36) ETN vs. cdmards 2.20 (0.96, 4.80) 3.00 (1.40, 6.80) 2.50 (1.50, 4.50) ETN + vs. cdmards 4.30 (2.90, 6.50) 2.90 (0.92, 9.20) 4.10 (2.80, 6.20) ETN + vs. ETN 1.50 (0.89, 2.60) 1.80 (0.45, 7.00) 1.60 (0.97, 2.60) IFX + vs. ABT (0.30, 2.50) 1.10 (0.45, 2.40) 0.98 (0.51, 1.90) IFX + vs. cdmards 3.60 (2.10, 6.00) 5.80 (0.84, 41.0) 3.80 (2.40, 6.00) IFX + vs. ETN (0.24, 9.40) 0.87 (0.47, 1.60) 0.93 (0.52, 1.60) PBO vs. ADA 0.17 (0.09, 0.30) 0.41 (0.10, 1.40) 0.19 (0.11, 0.32) PBO vs. ETN 0.21 (0.10, 0.47) 0.20 (0.06, 0.64) 0.21 (0.10, 0.40) TCZ vs. ADA 2.40 (0.83, 6.90) 0.98 (0.37, 2.60) 1.50 (0.71, 3.00) TCZ vs. cdmards 3.50 (1.50, 8.30) 4.40 (1.90, 9.80) 4.10 (2.30, 7.40) TCZ vs. PBO 5.00 (1.90, 14.0) 9.80 (4.40, 22.0) 7.70 (4.00, 15.0) TCZ + vs. cdmards 4.60 ( 3.00, 7.20) 9.10 (2.70, 33.0) 5.30 (3.40, 8.30) TCZ + vs. TCZ 1.60 (0.84, 2.90) 0.73 (0.29, 1.90) 1.30 (0.71, 2.30) ACR70 ADA + vs. ABT (0.27, 2.90) 1.10 (0.39, 3.20) 1.00 (0.46, 2.20) cdmards vs. ABT (0.08, 0.42) 0.16 (0.04, 0.69) 0.19 (0.09, 0.37) cdmards vs. ADA (0.08, 0.36) 0.22 (0.05, 0.92) 0.18 (0.09, 0.35) ETN vs. cdmards 2.60 (1.00, 8.00) 4.40 (1.70, 13.0) 3.30 (1.70, 6.60) ETN + vs. cdmards 5.20 (3.20, 9.50) 6.80 (1.10, 46.0) 5.00 (3.20, 8.90) ETN + vs. ETN 1.60 (0.83, 2.80) 0.79 (0.07, 6.90) 1.60 (0.88, 2.70) IFX + vs. ABT (0.32, 4.30) 0.58 (0.21, 1.60) 0.85 (0.38, 1.90) IFX + vs. cdmards 3.90 (2.10, 7.70) 5.30 (0.13, 230) 4.50 (2.40, 8.70) IFX + vs. ETN (0.02, 33.0) 0.86 (0.38, 2.00) 0.89 (0.40, 1.80) PBO vs. ADA 0.12 (0.05, 0.27) 0.31 (0.07, 1.40) 0.15 (0.08, 0.29) Arch Med Sci 1, January / 2019

15 Efficacy and safety of various anti-rheumatic treatments for patients with rheumatoid arthritis: a network meta-analysis Table VI. Cont. Endpoint Comparison Direct OR (95% CI) Indirect OR (95% CrI) Network OR (95% CrI) P-value PBO vs. ETN ) 0.17 (0.04, 0.64) 0.13 (0.04, 0.34) TCZ vs. ADA 2.20 (0.70, 7.10) 0.85 (0.22, 3.60) 1.50 (0.58, 3.60) TCZ vs. cdmards 3.20 (1.10, 8.80) 5.40 (1.50, 18.0) 4.10 (1.90, 8.40) TCZ vs. PBO 4.80 (1.50, 15.0) 18.0 (6.30, 59.0) 10.0 (4.10, 25.0) TCZ + vs. cdmards 5.60 (3.30, 9.60) 7.70 (1.70, 30.0) 6.10 (3.50, 11.0) TCZ + vs. TCZ 1.60 (0.83, 3.50) 0.90 (0.30, 3.00) 1.50 (0.73, 3.20) Remission IFX + vs. ABT (0.10, 11.0) 0.66 (0.04, 13.0) 0.94 (0.16, 5.00) TCZ vs. cdmards 360 (73.0,1800) 12.0 (2.60, 71.0) 70.0 (13.0,380) TCZ + vs. cdmards 15.0 (7.10, 37.0) 430 (47.0, 3500) 26.0 (9.10, 78.0) TCZ + vs. TCZ 1.30 (0.34, 4.60) ) 0.38 (0.07, 1.70) AEs ADA + vs. ABT (0.41, 1.60) 1.00 (0.57, 1.80) 0.95 (0.60, 1.50) cdmards vs. ABT (0.53, 1.30) 0.65 (0.30, 1.50) 0.77 (0.53, 1.10) cdmards vs. ADA (0.50, 1.20) 0.96 (0.42, 2.20) 0.81 (0.57, 1.20) ETN vs. cdmards 2.00 (1.20, 3.50) 1.30 (0.85, 2.20) 1.60 (1.20, 2.40) ETN + vs. cdmards 1.00 (0.79, 1.30) 2.70 (1.70, 4.30) 1.20 (0.97, 1.60) < ETN + vs. ETN 0.86 (0.55, 1.20) 0.47 (0.24, 0.93) 0.77 (0.53, 1.10) IFX + vs. ABT (0.58, 2.30) 0.99 (0.56, 1.80) 1.10 (0.67, 1.70) PBO vs. ETN 0.76 (0.37, 1.50) 0.76 (0.35, 1.50) 0.77 (0.45, 1.20) TCZ vs. cdmards 1.60 (0.92, 2.70) 1.40 (0.83, 2.20) 1.50 (1.10, 2.10) TCZ vs. ETN (0.36, 1.30) 1.50 (0.97, 2.40) 1.20 (0.85, 1.80) TCZ vs. PBO 1.20 (0.75, 2.20) 1.20 (0.51, 2.80) 1.20 (0.79, 2.00) TCZ + vs. cdmards 1.60 (1.20, 2.10) 0.94 (0.54, 1.60) 1.40 (1.10, 1.80) TCZ + vs. ETN (0.30, 1.10) 1.40 (0.99, 2.00) 1.20 (0.84, 1.60) TCZ + vs. TCZ 0.86 (0.58, 1.30) 1.00 (0.53, 1.90) 0.95 (0.68, 1.30) SAEs ADA + vs. ABT (0.58, 2.40) 1.30 (0.61, 3.70) 1.20 (0.77, 2.20) cdmards vs. ABT (0.80, 2.30) 1.20 (0.42, 3.00) 1.20 (0.83, 1.90) cdmards vs. ADA (0.45, 1.90) 1.00 (0.45, 2.60) 0.99 (0.59, 1.70) ETN vs. ADA 1.30 (0.32, 4.30) 1.40 (0.43, 4.70) 1.30 (0.53, 3.40) ETN vs. cdmards 1.70 (0.92, 3.60) 1.40 (0.55, 4.00) 1.60 (0.97, 2.7) ETN + vs. cdmards 1.30 (0.88, 2.20) 1.70 (0.26,11.0) 1.30 (0.88,2.10) ETN + vs. ETN 0.81 (0.52, 1.30) 0.82 (0.18, 4.60) 0.82 (0.50, 1.30) IFX + vs. ABT (0.96, 6.60) 1.00 (0.56, 2.00) 1.30 (0.82, 2.40) IFX + vs. ETN (0.50, 3.80) 1.30 (0.34, 4.90) 1.30 (0.61, 3.30) PBO vs. ADA 1.00 (0.62, 1.70) 0.90 (0.16, 5.00) 1.00 (0.61, 1.50) PBO vs. ETN 0.61 (0.07, 4.30) 0.82 (0.31, 2.10) 0.76 (0.28, 1.70) TCZ vs. cdmards 1.70 (0.81,3.50) 1.40 (0.55,4.40) 1.60 (0.93,2.80) TCZ vs. PBO 0.85 (0.39, 1.80) 0.91 (0.37, 2.30) 0.88 (0.48, 1.50) TCZ + vs. cdmards 1.40 (0.87, 2.40) 1.50 (0.35, 6.30) 1.40 (0.90, 2.20) PBO placebo, methotrexate, IFX infliximab, ETN etanercept, ADA adalimumab, GOL golimumab, TCZ tocilizumab, ABT abatacept, CZP clonazepam, cdmards traditional synthetic disease modifying antirheumatic drugs, ACR American College of Rheumatology, AEs: adverse events, SAEs serious adverse events. Arch Med Sci 1, January /

16 Kexun Ma, Ling Li, Chunhui Liu, Lingling Zhou, Xueping Zhou are shown in Table VII. As shown in Table VII, most scores are greater than 4, which indicates that those included studies are of high quality. Discussion Based on the data and information of included RCTs, our study aims to evaluate the efficacy and safety of 15 drug therapies for RA patients. All available direct and indirect evidence of various treatment options was analyzed and compared simultaneously by NMA, which has a great advantage over traditional MA and makes up for the lack of head-to-head comparisons [80]. Therefore, our studies are much more reliable than the other MAs or NMAs. Moreover, it is more reasonable to select 4 efficacy and 2 safety endpoints as the evaluation indexes. Although there are also some NMA studies on this topic, they mostly include two or three outcomes to be compared. For example, some researchers only select ACR20 as the efficacy outcome and AEs as the safety outcome [1], which is not comprehensive enough. After a systematic analysis of 15 therapies for patients with RA from 56 RCTs, we prefer to rec- ACR20 ACR50 Standard error of effect size Standard error of effect size Standard error of effect size Standard error of effect size Effect size centred at comparison specific pooled effect (y ixy μ xy ) J vs. K J vs. O L vs. O M vs. O A vs. C A vs. D A vs. I B vs. J B vs. L B vs. O C vs. D D vs. J D vs. K D vs. N D vs. E D vs. F Effect size centred at comparison specific pooled effect (y ixy μ xy ) ACR70 J vs. K J vs. O L vs. O M vs. O A vs. C A vs. D A vs. I B vs. J B vs. L B vs. O C vs. D D vs. J D vs. K D vs. N D vs. E D vs. F SAE Effect size centred at comparison specific pooled effect (y ixy μ xy ) J vs. K J vs. O L vs. O M vs. O A vs. C A vs. D A vs. I B vs. L B vs. O B vs. E C vs. D D vs. J D vs. K D vs. N D vs. E D vs. F Standard error of effect size Standard error of effect size Effect size centred at comparison specific pooled effect (y ixy μ xy ) J vs. K J vs. O L vs. O M vs. O A vs. C A vs. D A vs. I B vs. J B vs. L B vs. O C vs. D D vs. J D vs. K D vs. N D vs. E D vs. F Effect size centred at comparison specific pooled effect (y ixy μ xy ) AE J vs. K J vs. O L vs. O M vs. O A vs. C A vs. D A vs. I B vs. L B vs. O C vs. D D vs. J D vs. K D vs. N D vs. E D vs. F D vs. G Remission Effect size centred at comparison specific pooled effect (y ixy μ xy ) J vs. K A vs. C A vs. D A vs. I B vs. J D vs. J D vs. K D vs. F D vs. G D vs. H D vs. I E vs. F G vs. H A ABT, B ADA, C ADA, D cdmards, E ETN, F ETN, G GOL, H GOL +, I IFX, J TCZ, K TCZ, L ABT, M CZP, N CZP, O PBO Figure 4. Publication bias of different outcomes 48 Arch Med Sci 1, January / 2019

17 Efficacy and safety of various anti-rheumatic treatments for patients with rheumatoid arthritis: a network meta-analysis Table VII. Jadad scale of 67 included studies Author, year Randomized Blinded Withdrawal Abe et al., Bae et al., Kim et al., Combe et al., Combe et al., Dougados et al., Kameda et al., Jobanputra et al., Kay et al., Kim et al., Kremer et al., Kremer et al., Lan et al., Mathias et al., Moreland et al., Miyasaka et al., Nishimoto et al., O Dell et al., O Dell et al., Nishimoto et al., Tanake et al., Schiff et al., Van Riel et al., Van Riel et al., Van Vollenhoven et al., Weinblatt et al., Weinblatt et al., Westhovens et al., Zhang et al., Keystone et al., Smolen et al., Smolen et al., Gabay et al., Genovese et al., Yamamoto et al., Schiff et al., Weinblatt et al., Weinblatt et al., Fleischmann et al., Feischmann et al., Choy et al., Arch Med Sci 1, January /