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. 2022 Feb 16;13:814429. doi: 10.3389/fimmu.2022.814429

The Risk of Adverse Effects of TNF-α Inhibitors in Patients With Rheumatoid Arthritis: A Network Meta-Analysis

Bei He 1,†, Yun Li 1,†, Wen-wen Luo 1, Xuan Cheng 1, Huai-rong Xiang 1, Qi-zhi Zhang 1, Jie He 1, Wen-xing Peng 1,2,*
PMCID: PMC8888889  PMID: 35250992

Abstract

Objectives

To evaluate the safety of each anti-TNF therapy for patients with rheumatoid arthritis (RA) and then make the best choice in clinical practice.

Methods

We searched PUBMED, EMBASE, and the Cochrane Library. The deadline for retrieval is August 2021. The ORs, Confidence Intervals (CIs), and p values were calculated by STATA.16.0 software for assessment.

Result

72 RCTs involving 28332 subjects were included. AEs were more common with adalimumab combined disease-modifying anti-rheumatic drugs (DMARDs) compared with placebo (OR = 1.60, 95% CI: 1.06, 2.42), DMARDs (1.28, 95% CI: 1.08, 1.52), etanercept combined DMARDs (1.32, 95% CI: 1.03, 1.67); certolizumab combined DMARDs compared with placebo (1.63, 95% CI: 1.07, 2.46), DMARDs (1.30, 95% CI: 1.10, 1.54), etanercept combined DMARDs (1.34, 95% CI: 1.05, 1.70). In SAEs, comparisons between treatments showed adalimumab (0.20, 95% CI: 0.07, 0.59), etanercept combined DMARDs (0.39, 95% CI: 0.15, 0.96), golimumab (0.19, 95% CI: 0.05, 0.77), infliximab (0.15, 95% CI: 0.03,0.71) decreased the risk of SAEs compared with golimumab combined DMARDs. In infections, comparisons between treatments showed adalimumab combined DMARDs (0.59, 95% CI: 0.37, 0.95), etanercept (0.49, 95% CI: 0.28, 0.88), etanercept combined DMARDs (0.56, 95% CI: 0.35, 0.91), golimumab combined DMARDs (0.51, 95% CI: 0.31, 0.83) decreased the risk of infections compared with infliximab combined DMARDs. No evidence indicated that the use of TNF-α inhibitors influenced the risk of serious infections, malignant tumors.

Conclusion

In conclusion, we regard etanercept monotherapy as the optimal choice for RA patients in clinical practice when the efficacy is similar. Conversely, certolizumab + DMARDs therapy is not recommended.

Systematic Review Registration

identifier PROSPERO CRD42021276176.

Keywords: adverse effects, TNF-α inhibitors, rheumatoid arthritis, network meta-analysis, serious adverse events

Introduction

Rheumatoid arthritis (RA) is one of the most prevalent chronic inflammatory diseases, which can cause cartilage and bone damage as well as a disability that carries a substantial burden for both the individual and society (1). Currently, antitumors necrosis factor (anti-TNF) therapy has been established as an efficacious therapeutic strategy in RA (2). TNF-α is a pro-inflammatory cytokine known to have a key role in the pathogenesis of chronic immune-mediated diseases (3). Five TNF-α inhibitors have received regulatory approval for clinical use in rheumatology: adalimumab, golimumab, infliximab, certolizumab, and etanercept (4). They are commonly used in the treatment of rheumatoid arthritis.

Besides therapeutic effects, some studies reported that TNF-α inhibitors may also cause some adverse effects in patients with RA (5–8). Although there have been some pair-wise meta-analyses and network meta-analyses that evaluate the safety of different TNF-α inhibitors therapies for patients with RA. Nevertheless, most of the trials only focused on total AEs and SAEs or just one kind of detailed AEs, and some of the initial meta-analyses were contradicted by subsequent studies. For instance, Bongartz et al. reported that RA patients who were treated by anti-TNF therapies had an increased risk of serious infections and malignancies (9), while another trial evaluating malignancy risk in RA patients concluded that there was no significant evidence of an increased risk of malignancy using TNF-α inhibitors (10).

To evaluate the safety of TNF-α inhibitors in patients with RA, we choose six safety outcomes to systematically assess 10 anti-TNF therapies from 72 RCTs with a sample size of 28332 patients. Our network meta-analysis seeks to infer the risk of adverse effects of two therapies in patients with rheumatoid arthritis by direct and indirect comparisons. Simultaneously, it extracts and analyzes data from all randomized control trials (RCTs) to select the best therapy. The objective of the current study is to better characterize the safety of each anti-TNF therapy for patients with RA and then make the best choice in clinical practice.

Method

Study Selection

We searched PUBMED, EMBASE, and the Cochrane Library with the terms of drugs (adalimumab, certolizumab, etanercept, infliximab, and golimumab) and diseases (rheumatoid arthritis). After matching each “drug” and “disease”, restricting search results with the condition “randomized controlled trial”, we finally form the retrieval expressions that adapt to different databases. The deadline for retrieval is August 2021. Two investigators performed the literature screening according to the inclusion and exclusion criteria independently. The repeated studies were excluded firstly. Afterward, excluded unrelated studies by reading the titles and abstracts. The literature that met the inclusion and exclusion criteria was further screened by reading the full text. Disagreements were resolved by consensus Equations.

Inclusive Criteria

RCTs associated with adalimumab, certolizumab, etanercept, infliximab, and golimumab in the treatment of rheumatic diseases are included. Subjects should be greater than or equal to 18 years old and should be diagnosed with rheumatoid arthritis according to American College of Rheumatology criteria or other authoritative criteria. Disease progression, race, nationality, and complications are not limited. For the types of interventions, the experimental groups use TNF-α inhibitors, with or without disease-modifying antirheumatic drugs (DMARDs). The control groups use placebo (with or without DMARDs) or DMARDs alone.

Exclusive Criteria

RCTs that accord with any of the following criteria will be excluded: (1) studies with no accessible records of AE, SAE, malignant tumors, infections, severe infections, or malignant tumors (requiring intravenous antibiotic treatment or hospitalization or threatening patient’s life); (2) repetitive studies with shorter follow-up time; (3) studies with improper control (other therapy in experimental group or control group); (4) studies with Jadad score lower than or equal to 3 points; (5) studies with full texts not available.

Data Extraction

Data extraction was performed independently by He Bei and Li Yun, and the EndNote software was used to filter duplications and irrelevant literature by reading titles and abstracts. The remaining articles were then browsed in full text to determine whether they met the inclusion criteria. After removing ineligible publications, the two reviewers independently extracted data from each study, and disagreements were resolved by reaching a consensus. From each eligible study, we extracted and summarized the following details: the first author, year of publication, country, the total number of participants, type of TNF-α inhibitors, age range, follow-up time, duration of trials.

Assessment of Risk of Bias

Two investigators independently assessed each study’s risk of bias as low, unclear, and high. Disagreements were resolved by consensus. The items included: Random sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessment; incomplete outcome data; selective reporting; other bias.

Quality Assessment

Two reviewers independently used the modified Jadad scale to assess the quality of RCTs (randomized control trials). NOS includes three aspects (selection, comparability, and exposure for case-control studies or outcomes for cohort studies), as well as scores of 4, 2, and 3, respectively. The modified Jadad scale comprises four parts: generation of the allocation sequence, concealment of allocation, blinding, and incomplete outcome data, and scores of 2, 2, 2, and 1 for four parts, respectively. Studies with scores of 1-3 were considered to be of low quality; 4-7 high quality.

Data Synthesis and Analysis

Network meta-analysis was performed to compare each of the 10 anti-TNF therapies. Based on the multivariate framework, the network meta-analysis was conducted using frequency theory, and two program packages, network, and mvmeta, developed by STATA 16 software based on multiple regression theory, were used for statistical analysis. Firstly, an evidence network diagram was drawn to show the comparison between interventions, and the consistency test was conducted according to the existence of closed rings. Second, for counting data, OR was used for calculation, the network meta of adverse drug reactions was analyzed, 95% confidence interval was used for all effect sizes, and 95%CI of OR did not cross effect line 1, indicating that P<0.05 was statistically significant. SUCRA analysis was used to seek therapies that had the highest probability of adverse events, with the higher the SUCRA value, the higher the risk. Stata 16.0 draws a comparative-correction funnel plot to determine whether there is a small sample effect in the analysis and recognition network, to evaluate the publication bias of the final screening. All tests were two-sided with a significance level of 0.05.

Result

By searching databases, we retrieved 3200 original records. After excluding duplicates and irrelevant articles, 211 full-text articles were assessed for eligibility. By reading full-text, 72 articles met the inclusive criteria and exclusive criteria (11–82). The following diagram of the study selection process for this meta-analysis is shown in Figure 1 . The 72 articles included 28332 patients, followed up for about 16-104 weeks. 72 articles involved RCT experiments, including 21 adalimumab trials, 13 certolizumab trials, 21 etanercept trials, 9 golimumab trials, and 8 infliximab trials. Table 1 summarizes the relevant characteristics.

Figure 1.

Figure 1

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Flow diagram of search results.

Table 1.

Characteristics of included studies.

Author, Year Duration of trials (years) Quality score Follow-up time(Week) Average age(years old) Duration of rheumatoid arthritis (years) Number of women(n) Number of patients (n) Total number of cases (n) Intervention measures
Den et al. (11) NA 4 4 55 11.9 22 31 120 Placebo
54 11 10 17 adalimumab 0.5mg/Kg
58 11.2 10 18 adalimumab 1mg/Kg
54 10.8 8 18 adalimumab 3mg/Kg
59 14.5 15 18 adalimumab 5mg/Kg
53 8.9 12 18 adalimumab 10mg/Kg
Frust et al. (15) NA 4 24 55 9.3 253 318 636 adalimumab 40mg eow+DMARD
55.8 11.5 252 318 placebo+DMARD
Van der Putte et al. (13) NA 4 12 53.7 10.4 61 72 284 adalimumab 20mg qw
52.6 10 57 70 adalimumab 40mg qw
53.2 10.1 50 72 adalimumab 80mg qw
50.2 9.4 57 70 placebo
Weinblatt et al. (14) NA 5 24 53.5 13.1 52 69 271 adalimumab 20mg eow+MTX
57.2 12.2 50 67 adalimumab 40mg eow+MTX
55.5 12.8 55 73 adalimumab 80mg eow+MTX
56 11.1 51 62 placebo+MTX
Keystone et al. (16) NA 5 52 56.1 11 158 207 619 adalimumab 40mg eow+MTX
57.3 11 160 212 adalimumab 20mg qw+MTX
56.3 10.9 146 200 placebo+MTX
van der Putte et al. (19) 2000.1-2001.6 7 26 53.1 9.3 84 106 544 adalimumab 20mg eow
54.4 11.3 81 112 adalimumab 20mg qw
52.7 10.6 90 113 adalimumab 40mg eow
51.8 11.9 81 103 adalimumab 40mg qw
53.5 11.6 85 110 placebo
Breedveld et al. (20) PREMIER(NCT00195663) NA 6 104 51.9 0.7 193 268 799 adalimumab 40mg eow+MTX
52.1 0.7 212 274 adalimumab 40mg eow
52 0.8 190 257 placebo+MTX
Kim et al. (25) NA 5 18 48.5 6.8 62 65 128 40 mg adalimumab eow+MTX
49.8 6.9 53 63 placebo +MTX
Miyasaka et al. (31) CHANGE 2004.2-2005.6 5 24 54.8 10 69 87 352 adalimumab 20mg eow
56.9 9.9 72 91 adalimumab 40mg eow
54.3 9.5 72 87 adalimumab 80mg eow
53.4 8.4 67 87 placebo
Bejarano et al. (28) 2003.3.5-2004.12.2 7 56 47 9.5 44 75 148 adalimumab 40mg eow+MTX
47 7.9 39 73 placebo+MTX
Chen et al. (33) NA 5 12 53 6.2 26 35 47 adalimumab 40mg eow+MTX
53 8.3 11 12 MTX
van Vollenhoven et al. (46) NCT00853385 2009.1.30-2011.2.10 3 12 52.5 8.1 162 204 312 adalimumab 40 mg eow
53.7 7.9 82 108 placebo
Detert et al. (48) HIT HARD 2007.6-2010.9 5 24 47.2 0.15 61 87 172 adalimumab 40mg eow+MTX
52.5 0.14 57 85 MTX
Kavanaugh et al. (49) OPTIMA(NCT00420927) 2006.12-2010.7 5 26 50.7 0.33 380 515 1032 adalimumab 40mg eow+MTX
50.4 0.38 382 517 placebo+MTX
Hørslev-Petersen et al. (57) OPERA 2007.8-2009.12 5 104 56.2 0.24 56 89 180 adalimumab 40mg eow+MTX
54.2 0.23 63 91 placebo+MTX
Kennedy et al. (58) ALTARA 2010.11-2012.7 5 12 50.2 NR 78 85 214 patecilizumab
50.6 NR 68 85 adalimumab 40mg eow
48.8 NR 37 44 placebo
Takeuchi et al. (62) HOPEFUL 1 2009.3-2010.11 5 26 54 0.3 144 171 334 adalimumab 40mg eow+MTX
54 0.3 128 163 placebo+MTX
Taylor et al. (74) RA-BEAM 2012.11-2015.9 5 24 53 10 251 330 818 adalimumab 40mg eow
53 10 382 488 placebo
Fleischmann et al. (77) SELECT - COMPARE 2015.12-2017.6 6 26 54 8 512 651 1629 placebo +MTX
54 8 159 327 adalimumab 40 mg+MTX
Ducourau et al. (78) (NCT01895764) 2013.3-2014.10 4 26 43 3 22 52 107 adalimumab 40mg qw+MTX
41 2 28 55 adalimumab 40 mg qw
Combe et al. (81) NCT02889796 2016.8.30-2019.6.20 7 24 53 8 266 325 800 adalimumab 40 mg biw+MTX
53 7.3 391 475 placebo +MTX
Fleischman et al. (77) FAST4WARD 2003.6-2004.7 6 24 52.7 8.7 87 111 220 certolizumab 400mg
54.9 10.4 97 109 placebo
Smolen et al., 2009 RAPID 2 20005.6-2006.9 4 24 51.9 6.5 192 246 619 certolizumab 400mg + MTX
52.2 6.1 206 248 certolizumab 200mg + MTX
51.5 5.6 107 125 placebo + MTX
Choy et al. (42) NCT00544154 2002.10-2004.1 7 24 53 9.4 91 126 247 certolizumab 400mg + MTX
55.6 9.9 80 121 placebo + MTX
Weinblatt et al. (47) REALISTIC(NCT00717236) 2008.7-2010.3 7 12 55.4 8.6 660 q 1063 certolizumab (certolizumab 400 mg qw 0, 2 and 4,followed by certolizumab 200 mg eow)+DMARDs
53.9 8.9 169 212 placebo +DMARDs
schiff et al. (61) NCT01147341 4 52 56.1 12 NR 27 37 certolizumab(400 mg qw 0, 2 and 4, followed by 200mg eow)+DMARDs
59 14 NR 10 placebo +DMARDs
Yamamoto et al. (63) J-RAPID 2008.11.19-2010.8.18 7 24 54.3 6.0 58 72 316 certolizumab 100mg eow + MTX
50.6 5.6 69 82 certolizumab 200mg eow + MTX
55.4 6.0 69 85 certolizumab 400mg eow + MTX
51.9 5.8 66 77 placebo + MTX
Furst et al. (64) DOSEFLEX 5 16 51.5 6.5 56 69 208 Placebo +MTX
55.6 5.9 49 70 certolizumab 200 mg eow +MTX
53.1 6.4 57 69 certolizumab 400 mg q4w +MTX
Smolen et al. (65) CERTAIN 2008.6-2010.12 5 24 53.6 4.5 81 96 194 certolizumab(400 mg certolizumab qw 0, 2 and 4, followed by 200 mg certolizumab eow)+DMARDs
54 4.7 75 98 placebo +DMARDs
Atsumi et al. (66) C-OPERA (NCT01451203) 2011.10-2013.8 7 52 49.4 4.0 129 159 316 certolizumab 400mg/200mg eow +MTX
49 4.3 127 157 placebo + MTX
Emery et al. (72) C-EARLY (NCT01519791) 2012.1-2015.9 6 52 50.4 0.24 497 660 879 certolizumab 400mg/200mg eow +MTX
51.2 0.24 170 219 placebo + MTX
Kang et al. (75) (NCT00993317) 2009.12-2011.8 4 24 51.6 6.5 72 85 127 certolizumab 400mg/200mg eow +MTX
50.8 5.5 35 42 placebo + MTX
Bi et al. (76) RAPID-C (NCT02151851) 2014.7.23-2016.6.17 6 24 48.2 7.0 268 316 429 certolizumab 200 mg eow (loading dose: 400 mg certolizumab qw 0, 2 and 4) + MTX
47.1 6.6 95 113 (PBO) + MTX
Hetland et al. (79) NCT01491815 2012.12.3-2018.12.11 6 24 54.6 0.53 139 197 399 active conventional treatment
55.3 0.56 139 202 certolizumab 200 mg qw (400 mg qw 0, 2, and 4)+MTX
Genovese et al. (39) 1997.5-1999.3 5 104 49 1 75 217 632 three 2.5-mg MTX qw and placebo biw
50 0.9 75 208 10 mg of etanercept biw and three placebo tablets qw,
51 1 74 207 25 mg of etanercept biw and three placebo tablets qw
Smolen et al. (1) 2011.12.14-2013.11.11 4 12 53 5.9 96 457 914 certolizumab pegol (400 mg weeks 0, 2,
457 adalimumab (40 mg once q2w) plus
Keystone et al. (16) NA 5 8 54 10.8 38 53 420 placebo
53 9.0 169 214 50 mg etanercept qw
52 8.2 121 153 25 mg etanercept biw
van der Heijde et al. (26) TEMPO 2000.10-2001.7 6 104 52.5 6·8 171 231 682 etanercept 25mg biw + MTX
53.2 6·8 171 223 etanercept 25mg biw + placebo
53 6·3 180 228 placebo + MTX
Lan et al. (21) NR 4 12 47.55 NR 50 29 58 etanercept 25mg biw + MTX
50.79 29 placebo +MTX
van Riel et al. (22) ADORE 2003.3-2004.5 4 16 53 10 126 159 314 etanercept 25 mg biw
54 9.8 119 155 etanercept 25 mg biw + MTX
Weisman et al. (27) RA NA 6 16 60.6 10.1 192 266 535 etanercept 25mg biw
59.3 9.4 210 269 placebo
Emery et al. (29) COMET 2004.10-2006.2 7 52 50.5 8·8 196 274 542 etanercept 50mg qw + MTX
52.3 9·3 191 268 MTX
Kameda et al. (41) JESMR(NCT00688103) 2005.6-2007.1 4 24 58.1 10.6 62 71 146 etanercept 25 mg eow
56.5 8.1 60 75 MTX+etanercept
Jobanputra et al. (43) EU Clinical 2007.5-2010.4 4 52 55 7.0 15 60 120 adalimumab 40 mg qw
Trials Register 2006-006275-21/GB 53.2 5.5 18 60 etanercept 50 mg qw
Kim et al. (44) APPEAL 2007.6-2009.3 6 16 48.4 6.5 17 197 300 etanercept 25 mg biw+MTX
48.5 6.9 12 103 DMARD+MTX
Takeuchi et al. (80) NCT00445770 NA 6 52 51.8 3.0 145 182 550 etanercept 25 mg biw
51.5 2.9 154 192 etanercept 10 mg biw
50.4 3.0 140 176 MTX
Emery et al. (56) NCT00913458 2009.10.20-2012.12.17 5 39 49.6 0.54 47 63 193 etanercept (25 mg)+MTX
47.7 0.58 36 65 placebo +MTX
50.9 0.59 42 65 placebo
Machado et al. (59) NCT00848354 2009.6-2011.3 5 24 48.4 7.9 248 281 423 etanercept(50 mg qw)+MTX
48.6 9.0 128 142 (DMARD) + MTX
Nam et al. (60) EMPIRE 2006.10-2009.5 7 78 47.9 0.5 44 55 110 etanercept 50mg qw + MTX
48.4 0.67 40 55 placebo + MTX
Smolen et al. (52) PRESERVE(NCT00565409) 2008.3.6-2009.9.9 3 52 46.4 6·4 157 202 34 etanercept 25mg qw+MTX
48.1 6·8 164 202 etanercept 50mg qw+MTX
48.3 7·3 167 200 placebo+MTX
Keystone et al. (67) CAMEO (NCT00654368) 2008.6-2012.12 6 104 54.3 9.0 72 98 205 etanercept 50 mg qw
54.4 9.3 84 107 etanercept 50 mg qw + MTX
van Vollenhovn et al. (70) NCT00858780 NR 4 20 53.8 11.5 17 23 73 etanercept50mg qw + MTX
59.6 16.6 18 27 etanercept25mg qw + MTX
56.1 12.3 16 23 placebo +MTX
Yamanaka et al. (71) ENCOURAGE (UMIN000002687) 2009.8-2014.4 5 52 52.8 2.0 138 161 191 etanercept 25 mg biw + MTX
54.6 1.9 25 30 MTX
Pavelka et al. (73) NCT01578850 2012.7-2015.3 6 28 46.1 8.0 136 167 343 etanercept 50mg qw +DMARDs
47.2 8.3 143 176 placebo +DMARDs
Curtis et al. (82) SEAM- RA 2015.2.20-2018.6.26 6 48 56.2 9.7 76 101 153 MTX
54.8 11.0 77 101 etanercept
55.9 10.3 40 51 MTX + etanercept
Kay et al. (30) 2003.12.1-2006.2.21 5 20 52 5.6 26 35 172 placebo + MTX
57 8.2 30 35 50mg golimumab q4w + MTX
48 8.2 23 34 50mg golimumab eow + MTX
57.5 6.3 26 34 100mg golimumab eow + MTX
53.5 9.0 27 34 50mg golimumab eow + MTX
Emery et al. (34) GO-BEFORE 2005.12.12-2007.10.1 6 24 50.9 3.5 135 159 634 Golimumab 50 mg q4w + MTX
50.2 3.6 125 159 Golimumab 100 mg q4w + MTX
48.2 4.1 159 159 Golimumab 100 mg q4w + Placebo
48.6 2.9 134 160 Placebo+MTX
Keystone et al. (36) GO-FORWARD 20005.12.19-2007.9.17 5 16 52 4.5 72 89 444 Golimumab 50 mg q4w + MTX
50 6.7 72 89 Golimumab 100 mg q4w + MTX
51 5.9 105 133 Golimumab 100 mg q4w + Placebo
52 6.5 109 133 Placebo+MTX
Smolen et al. (38) GO-AFTER (NCT00299546) 2006.2.21-2007.9.26 7 16 55 9.6 113 153 461 Golimumab 50 mg q4w
55 8.7 122 153 Golimumab 100 mg q4w
54 9.8 132 155 Placebo
Kremer et al. (40) NCT00361335 2006.8.24-2008.8.25 6 16 49.9 7.4 21 128 643 Golimumab 2mg/kg q12w
48.4 8.4 10 129 Golimumab 4mg/kg q12w
49.7 8.1 30 129 Golimumab 2mg/kg q12w + MTX
49.6 9.4 25 128 Golimumab 4mg/kg q12w + MTX
50.2 7.4 24 129 Placebo + MTX
Tanaka et al. (45) GO-FORTH 2008.5-2009.11 5 16 50.4 8.8 15 86 261 Golimumab 50 mg q4w + MTX
50 8.1 78 87 Golimumab 100 mg q4w + MTX
51.1 8.7 73 88 Placebo + MTX
Takeuchi et al. (53) GO-MONO NA 4 16 52.9 8.1 81 101 308 Golimumab 50 mg q4w
51.6 9.4 85 102 Golimumab 100 mg q4w
52.4 9.2 86 105 Placebo
Weinblatt et al. (55) GO-FURTHER(NCT00973479) 2009.9.14-2011.5.18 7 16 51.4 7.0 157 197 592 Placebo +MTX
51.9 6.9 326 395 Golimumab2 mg/kg+MTX
Li et al. (68) NCT01248780 2010.8-2012.7 4 24 47.7 7.6 110 132 264 Golimumab 50 mg q4w + MTX
46.7 8.0 104 132 Placebo + MTX
Maini et al. (17) 1997.3.31-2000.3.9 7 102 54 10 70 86 428 infliximab 3mg/kg, q8w+MTX
52 9 66 86 infliximab 3mg/kg, q4w+MTX
54 11 67 87 infliximab 10mg/kg, q8w+MTX
52 12 59 81 infliximab 10mg/kg, q4w+MTX
51 11 70 88 placebo +MTX
St. Clair et al. (18) 2000.7.21-2002.2.28 7 54 51 0.8 255 359 1004 infliximab 3mg/kg, q8w+MTX
50 0.9 247 363 infliximab 6mg/kg, q8w+MTX
50 0.9 212 282 placebo +MTX
Abe et al. (12) 2000.4.19-2000.10.27 4 6 55.2 9.1 40 49 147 infliximab 3mg/kg, q8w+MTX
56.8 7.1 40 51 infliximab 10mg/kg, q8w+MTX
55.1 7.5 35 47 placebo +MTX
Westhoven et al. (23) START 2001.9-2003.11 6 22 53 7.8 288 360 1082 infliximab 3mg/kg +MTX
52 6.3 281 361 infliximab 10mg/kg +MTX
52.0 8.4 302 361 placebo+MTX
Zhang et al. (24) 2003.7-2004.7 4 18 47.9 NR 13 87 173 infliximab (Remicade, Centocor) at a dose of 3 mg/kg body weight qw 0, 2, 6 and 14.
48.9 NR 13 86 placebo
Schiff et al. (32) ATTEST 2005.2-2007.2 6 28 49.1 7.3 136 165 275 infliximab 3mg/kg, q8w+MTX
49.4 8.4 96 110 placebo +MTX
Kim et al. (50) NCT00202852, NCT00732875 2005.6-2006.5 5 30 49.3 7.4 64 69 138 Infliximab
51.4 9.8 64 69 placebo
Leirisalo-Repo et al. (51) NCT00908089 2003.3-2005.4 6 102 47 0.33 35 50 3403 infliximab
46 0.33 31 49 placebo
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biw, twice a week; qw, weekly; eow, every two weeks; q4w, every four weeks; q8w, every 8 weeks; q12w, every 12 weeks; MTX, methotrexate; DMARD, disease-modifying anti-rheumatic drugs; NA, not re.

Adverse Events

58 articles (12, 15, 16, 19, 21–26, 28–38, 40–42, 44–47, 49–56, 58–69, 71–75, 77, 79–82) reported the occurrence of AEs and 23778 RA patients was included. The network of eligible comparisons is shown in Figure 2 . Network meta-analysis showed that adalimumab combined DMARDs compared with placebo therapy statistically significantly increased the risk of AEs by 60% (1.60, 95% CI: 1.06, 2.42); compared with DMARDs, the risk of AEs increased by 28% (1.28, 95% CI: 1.08, 1.52) ( Table 2 and Figure 3 ). Certolizumab also found that compared with placebo therapy, the risk of AE increased by 127% (2.27, 95% CI: 1.22, 4.24). In addition, certolizumab combined DMARDs compared with placebo therapy statistically significantly increased the risk of AEs by 63% (1.63, 95% CI: 1.07, 2.46); compared with DMARDs, the risk of AEs increased by 30% (1.30, 95% CI: 1.10, 1.54). Comparisons between treatments showed certolizumab combined DMARDs increased the risk of AEs compared with etanercept combined DMARDs (1.34, 95% CI: 1.05, 1.70); adalimumab combined DMARDs increased the risk of AEs compared with etanercept combined DMARDs (1.32, 95% CI: 1.03, 1.67) ( Table 2 ). There was no statistically significant difference between other comparisons.

Figure 2.

Figure 2

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Network of treatment comparisons for adverse events. The size of the circles corresponds to the total number of people. Direct comparable treatments are connected with a line. ADA, adalimumab; + D, plus DMARD; CZP, certolizumab; ETA, etanercept; GOL, golimumab; INF, infliximab; PBO, placebo; DMARD, disease-modifying anti-rheumatic drugs.

Table 2.

OR of adverse events for 12 therapies.

ADA 1.31 (0.83,2.07) 1.86 (0.93,3.71) 1.33 (0.84,2.12) 1.04 (0.68,1.60) 1.00 (0.64,1.55) 1.16 (0.72,1.85) 1.20 (0.74,1.92) 1.15 (0.65,2.03) 1.21 (0.71,2.06) 0.82 (0.61,1.10) 1.02 (0.66,1.58)
0.76 (0.48,1.20) ADA+DMARD 1.42 (0.67,3.00) 1.02 (0.80,1.29) 0.79 (0.57,1.10) 0.76 (0.60,0.97) 0.88 (0.50,1.55) 0.91 (0.70,1.18) 0.88 (0.46,1.67) 0.92 (0.65,1.30) 0.62 (0.41,0.94) 0.78 (0.66,0.92)
0.54 (0.27,1.07) 0.70 (0.33,1.49) CZP 0.72 (0.34,1.51) 0.56 (0.27,1.15) 0.54 (0.26,1.11) 0.62 (0.30,1.31) 0.64 (0.30,1.37) 0.62 (0.28,1.37) 0.65 (0.30,1.42) 0.44 (0.24,0.82) 0.55 (0.26,1.14)
0.75 (0.47,1.20) 0.98 (0.78,1.25) 1.40 (0.66,2.96) CZP+DMARD 0.78 (0.56,1.09) 0.75 (0.59,0.95) 0.87 (0.49,1.54) 0.90 (0.69,1.17) 0.86 (0.45,1.64) 0.91 (0.65,1.27) 0.62 (0.41,0.93) 0.77 (0.65,0.91)
0.96 (0.63,1.48) 1.26 (0.91,1.75) 1.79 (0.87,3.69) 1.28 (0.92,1.78) ETA 0.96 (0.73,1.25) 1.11 (0.65,1.90) 1.15 (0.81,1.63) 1.11 (0.60,2.04) 1.16 (0.77,1.75) 0.79 (0.55,1.14) 0.98 (0.74,1.30)
1.00 (0.65,1.56) 1.32 (1.03,1.67) 1.87 (0.90,3.88) 1.34 (1.05,1.70) 1.04 (0.80,1.36) ETA+DMARD 1.16 (0.67,2.01) 1.20 (0.92,1.56) 1.15 (0.62,2.14) 1.21 (0.86,1.70) 0.82 (0.56,1.20) 1.02 (0.86,1.21)
0.86 (0.54,1.38) 1.13 (0.64,1.99) 1.61 (0.77,3.38) 1.15 (0.65,2.04) 0.90 (0.53,1.53) 0.86 (0.50,1.49) GOL 1.03 (0.58,1.84) 0.99 (0.53,1.87) 1.04 (0.56,1.95) 0.71 (0.47,1.06) 0.88 (0.51,1.52)
0.84 (0.52,1.34) 1.10 (0.85,1.42) 1.56 (0.73,3.32) 1.11 (0.86,1.44) 0.87 (0.61,1.23) 0.83 (0.64,1.09) 0.97 (0.54,1.73) GOL+DMARD 0.96 (0.50,1.85) 1.01 (0.70,1.45) 0.69 (0.45,1.05) 0.85 (0.70,1.04)
0.87 (0.49,1.54) 1.14 (0.60,2.17) 1.62 (0.73,3.58) 1.16 (0.61,2.20) 0.90 (0.49,1.67) 0.87 (0.47,1.61) 1.01 (0.53,1.90) 1.04 (0.54,2.00) INF 1.05 (0.53,2.09) 0.71 (0.44,1.16) 0.89 (0.48,1.65)
0.83 (0.49,1.41) 1.09 (0.77,1.53) 1.54 (0.70,3.39) 1.10 (0.79,1.55) 0.86 (0.57,1.30) 0.83 (0.59,1.16) 0.96 (0.51,1.79) 0.99 (0.69,1.42) 0.95 (0.48,1.89) INF+DMARD 0.68 (0.42,1.10) 0.85 (0.63,1.14)
1.22 (0.91,1.63) 1.60 (1.06,2.42) 2.27 (1.22,4.24) 1.63 (1.07,2.46) 1.27 (0.88,1.83) 1.22 (0.83,1.78) 1.41 (0.95,2.11) 1.46 (0.95,2.25) 1.40 (0.86,2.29) 1.47 (0.91,2.38) PBO 1.25 (0.85,1.82)
0.98 (0.63,1.51) 1.28 (1.08,1.52) 1.82 (0.88,3.79) 1.30 (1.10,1.54) 1.02 (0.77,1.35) 0.98 (0.82,1.16) 1.13 (0.66,1.96) 1.17 (0.96,1.43) 1.13 (0.60,2.10) 1.18 (0.88,1.59) 0.80 (0.55,1.17) DMARD
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Results below the diagonal are the rate ratios with 95% confidence intervals from the network meta-analysis of direct and indirect comparisons between the row-defining treatment and the column-defining treatment. Numbers in red highlight statistically significant results. ADA, adalimumab; + D, plus DMARD; CZP, certolizumab; ETA, etanercept; GOL, golimumab; INF, infliximab; PBO, placebo; DMARD, disease-modifying anti-rheumatic drugs.

Figure 3.

Figure 3

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The analysis SUCRA of adverse events for 12 therapies. ADA, adalimumab; + D, plus DMARD; CZP, certolizumab; ETA, etanercept; GOL, golimumab; INF, infliximab; PBO, placebo; DMARD, disease-modifying anti-rheumatic drugs.

We have made global consistency. The test result p-value was 0.9095, so the consistency model could be used. We also established local consistency and the p-value of the test result exceeded 0.05, which was considered local. We analyzed SUCRA to research the probability of adverse events for each therapy. The results indicated that certolizumab had the highest probability to cause AEs (SUCRA = 0.906), while PBO had the lowest probability to cause AEs (SUCRA = 0.066) compared with the other therapies ( Figure 3 ). There was a funnel plot with no obvious asymmetry, indicating no publication bias ( Figure 4 ).

Figure 4.

Figure 4

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Network of funnel plot for adverse events. A, adalimumab; B, adalimumab + DMARD; C, certolizumab; D, certolizumab + DMARD; F, etanercept; G, etanercept + DMARD; H, golimumab; I, golimumab + DMARD; J, infliximab; K, infliximab + DMARD; L, DMARD; DMARD, disease-modifying anti-rheumatic drugs.

Serious Adverse Events

58 articles (12, 13, 15, 17–19, 22, 24–27, 29–32, 34–36, 38, 40–52, 54, 56–60, 62–70, 72–82) reported the occurrence of SAEs and 23805 RA patients was included. The network of eligible comparisons was shown in Figure 5 . Network meta-analysis showed that golimumab combined DMARDs compared with placebo therapy statistically significantly increased the risk of SAEs by 227% (3.27, 95% CI: 1.08, 9.92); Compared with DMARDs, the risk of SAEs increased by 170% (2.70, 95% CI: 1.15, 6.32). Comparisons between treatments showed adalimumab (0.20, 95% CI: 0.07, 0.59), etanercept(0.35, 95% CI: 0.12, 1.00), etanercept combined DMARDs (0.39, 95% CI: 0.15, 0.96), golimumab (0.19, 95% CI: 0.05, 0.77) decreased the risk of SAEs compared with golimumab combined DMARDs; adalimumab (0.39, 95% CI: 0.18, 0.84) decreased the risk of SAEs compared with certolizumab combined DMARDs; golimumab combined DMARDs increased the risk of SAEs compared with infliximab (6.50, 95% CI: 1.41, 29.90) ( Table 3 ). There was no statistically significant difference between other comparisons.

Figure 5.

Figure 5

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Network of treatment comparisons for serious adverse events. The size of the circles corresponds to the total number of people. Direct comparable treatments are connected with a line. ADA, adalimumab; + D, plus DMARD; CZP, certolizumab; ETA, etanercept; GOL, golimumab; INF, infliximab; PBO, placebo; DMARD, disease-modifying anti-rheumatic drugs.

Table 3.

OR of serious adverse events of 12 therapies.

ADA 2.05 (0.94,4.49) 4.27 (0.94,19.46) 2.57 (1.19,5.56) 1.80 (0.94,3.42) 1.96 (0.97,3.97) 0.96 (0.36,2.60) 5.08 (1.68,15.30) 0.78 (0.24,2.49) 2.20 (1.00,4.81) 1.55 (0.94,2.56) 1.88 (0.93,3.80)
0.49 (0.22,1.07) ADA+DMARD 2.08 (0.40,10.71) 1.25 (0.78,2.02) 0.88 (0.44,1.75) 0.95 (0.59,1.54) 0.47 (0.15,1.52) 2.48 (0.99,6.22) 0.38 (0.10,1.42) 1.07 (0.65,1.75) 0.76 (0.34,1.68) 0.92 (0.65,1.30)
0.23 (0.05,1.07) 0.48 (0.09,2.47) CZP 0.60 (0.12,3.08) 0.42 (0.09,1.99) 0.46 (0.09,2.27) 0.23 (0.04,1.20) 1.19 (0.19,7.30) 0.18 (0.03,1.08) 0.51 (0.10,2.65) 0.36 (0.09,1.53) 0.44 (0.09,2.19)
0.39 (0.18,0.84) 0.80 (0.49,1.29) 1.66 (0.32,8.50) CZP+DMARD 0.70 (0.35,1.38) 0.76 (0.48,1.21) 0.38 (0.12,1.20) 1.98 (0.79,4.92) 0.30 (0.08,1.12) 0.85 (0.53,1.38) 0.61 (0.28,1.32) 0.73 (0.53,1.02)
0.56 (0.29,1.06) 1.14 (0.57,2.29) 2.38 (0.50,11.25) 1.43 (0.72,2.83) ETA 1.09 (0.62,1.91) 0.54 (0.19,1.53) 2.83 (1.00,8.02) 0.43 (0.13,1.45) 1.22 (0.61,2.45) 0.87 (0.47,1.58) 1.05 (0.57,1.91)
0.51 (0.25,1.04) 1.05 (0.65,1.69) 2.18 (0.44,10.77) 1.31 (0.83,2.08) 0.92 (0.52,1.61) ETA+DMARD 0.49 (0.16,1.50) 2.59 (1.04,6.47) 0.40 (0.11,1.41) 1.12 (0.69,1.82) 0.79 (0.39,1.61) 0.96 (0.69,1.34)
1.04 (0.38,2.80) 2.13 (0.66,6.85) 4.42 (0.83,23.50) 2.66 (0.83,8.50) 1.86 (0.65,5.32) 2.03 (0.67,6.15) GOF 5.26 (1.29,21.45) 0.81 (0.21,3.13) 2.28 (0.70,7.36) 1.61 (0.68,3.80) 1.95 (0.64,5.97)
0.20 (0.07,0.59) 0.40 (0.16,1.01) 0.84 (0.14,5.15) 0.51 (0.20,1.26) 0.35 (0.12,1.00) 0.39 (0.15,0.96) 0.19 (0.05,0.77) GOF+DMARD 0.15 (0.03,0.71) 0.43 (0.17,1.08) 0.31 (0.10,0.93) 0.37 (0.16,0.87)
1.28 (0.40,4.08) 2.63 (0.71,9.76) 5.46 (0.93,32.24) 3.29 (0.89,12.15) 2.30 (0.69,7.70) 2.51 (0.71,8.85) 1.24 (0.32,4.79) 6.50 (1.41,29.90) INF 2.81 (0.76,10.45) 1.99 (0.70,5.67) 2.41 (0.68,8.55)
0.46 (0.21,1.00) 0.93 (0.57,1.53) 1.94 (0.38,10.02) 1.17 (0.72,1.89) 0.82 (0.41,1.64) 0.89 (0.55,1.45) 0.44 (0.14,1.42) 2.31 (0.92,5.79) 0.36 (0.10,1.32) INF+DMARD 0.71 (0.32,1.57) 0.86 (0.61,1.21)
0.64 (0.39,1.06) 1.32 (0.60,2.92) 2.74 (0.65,11.51) 1.65 (0.76,3.61) 1.16 (0.63,2.11) 1.26 (0.62,2.55) 0.62 (0.26,1.46) 3.27 (1.08,9.92) 0.50 (0.18,1.43) 1.41 (0.64,3.13) PBO 1.21 (0.59,2.47)
0.53 (0.26,1.07) 1.09 (0.77,1.55) 2.27 (0.46,11.25) 1.37 (0.98,1.90) 0.95 (0.52,1.74) 1.04 (0.75,1.45) 0.51 (0.17,1.57) 2.70 (1.15,6.32) 0.41 (0.12,1.47) 1.17 (0.83,1.65) 0.83 (0.40,1.69) DMARD
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Results below the diagonal are the rate ratios with 95% confidence intervals from the network meta-analysis of direct and indirect comparisons between the row-defining treatment and the column-defining treatment. Numbers in red highlight statistically significant results. ADA, adalimumab; + D, plus DMARD; CZP, certolizumab; ETA, etanercept; GOL, golimumab; INF, infliximab; PBO, placebo; DMARD, disease-modifying anti-rheumatic drug.

We did the global consistency test. The test result p-value was 0.8840. We also made local consistency and the test result p-value was greater than 0.05, which was considered to be locally consistent. According to the SUCRA analysis, golimumab combined DMARDs had the highest risk to cause SAEs (SUCRA = 0.940), while adalimumab had the lowest risk to cause SAEs (SUCRA = 0.130) compared with the other 11 therapies ( Figure 6 ). There was a funnel plot asymmetry, with the right corner of the pyramidal part of the funnel missing, which suggested a possible bias ( Figure 7 ).

Figure 6.

Figure 6

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The analysis SUCRA of serious adverse events for 12 therapies. ADA, adalimumab; + D, plus DMARD; CZP, certolizumab; ETA, etanercept; GOL, golimumab; INF, infliximab; PBO, placebo; DMARD, disease-modifying anti-rheumatic drugs.

Figure 7.

Figure 7

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Network of funnel plot for serious adverse events. A, adalimumab; B, adalimumab + DMARD; C, certolizumab; D, certolizumab + DMARD; F, etanercept; G, etanercept + DMARD; H, golimumab; I, golimumab + DMARD; J, infliximab; K, infliximab + DMARD; L, DMARD; DMARD, disease-modifying anti-rheumatic drugs.

Infections

40 articles (12, 15, 17, 22, 25–28, 30, 31, 33, 34, 36, 38, 40–42, 45, 49, 54–56, 58–60, 62–66, 72–77, 79–82) reported the occurrence of AEs and 15285 RA patients was included. The network of eligible comparisons was shown in the Supplementary Figure 1 . Network meta-analysis showed that golimumab combined DMARDs compared with DMARDs increased the risk of infections by 35% (1.35, 95% CI: 1.10, 1.66); infliximab combined DMARDs compared with DMARDs increased the risk of infections by 102% (2.02, 95% CI: 1.31, 3.11). Comparisons between treatments showed adalimumab combined DMARDs (0.59, 95% CI: 0.37, 0.95), etanercept(0.49, 95% CI: 0.28, 0.88), etanercept combined DMARDs (0.56, 95% CI: 0.35, 0.91), golimumab combined DMARDs (0.51, 95% CI: 0.31, 0.83) decreased the risk of infections compared with infliximab combined DMARDs ( supplementary Table 1 ). There was no statistically significant difference between other comparisons.

We did the global consistency test. The test result p-value was 0.6713. We also established local consistency and the p-value of the test result exceeded 0.05, which was considered local. According to the SUCRA analysis, infliximab combined DMARDs had the highest risk to cause infections (SUCRA = 0.910), while DMARDs had the lowest risk to cause infections SUCRA = 0.210) compared with the other 11 therapies ( Supplementary Figure 2 ). There was a funnel plot ( Supplementary Figure 3 ) with no obvious asymmetry, indicating no publication bias.

Serious Infections

55 articles (11–20, 22, 23, 26–38, 40, 42, 45, 47–49, 51, 52, 54, 56–60, 62–66, 68, 69, 72–77, 80–82) reported the occurrence of serious infections, involving a total of 24740 RA patients. The network of eligible comparisons was shown in the Supplementary Figure 4 . Network meta-analysis showed that there was no statistically significant difference between 12 therapies ( Supplementary Table 2 ).

We did the global consistency test. The resulting p-value was 0.4900. We also made local consistency and the test result p-value was greater than 0.05, which was considered to be locally consistent. According to the SUCRA analysis, certolizumab had the highest risk to cause serious infections (SUCRA =0.817), while etanercept combined DMARDs had the lowest risk to cause serious infections (SUCRA = 0.285) compared with the other 11 therapies ( Supplementary Figure 5 ). There was a funnel plot asymmetry, with the right corner of the pyramidal part of the funnel missing, which suggested a possible bias ( Supplementary Figure 6 ).

Malignant Tumors

32 articles (14–20, 23, 26, 27, 29–32, 34–39, 43, 47–49, 52, 57, 60, 65, 74, 75, 77, 79) reported the occurrence of malignant tumors, involving 16947 RA patients. The network of eligible comparisons was shown in the Supplementary Figure 7 . Mesh meta-analysis showed that there was no statistically significant difference between 12 therapies ( Supplementary Table 3 ).

We did the global consistency test. The test result p-value was 0.6219. We also made local consistency and the test result p-value was greater than 0.05, which was considered to be locally consistent. According to the SUCRA analysis ( Supplementary Figure 8 ), golimumab had the highest risk to cause malignant tumors (SUCRA =0.778), while golimumab combined DMARDs had the lowest risk to cause malignant tumors (SUCRA = 0.285) compared with the other 11 therapies.

Discussion

Based on the data and information of included RCTs, our study aims to evaluate the risk of adverse effects of 10 anti-TNF therapies in patients with rheumatoid arthritis. All available direct and indirect evidence of various treatment options was analyzed and compared simultaneously by network meta-analysis, which has a great advantage over traditional meta-analysis and makes up for the lack of head-to-head comparisons (83). To comprehensively assess the safety of anti-TNF therapies in RA patients, we also pay attention to detailed AEs like infections, serious infections, malignant tumors. What’s more, our meta-analysis included all RCTs with medium or high quality more recent studies to August 2021, which avoided the deficiency of observational studies and low-quality studies. Therefore, our studies are much more reliable than the other meta-analyses or network meta-analyses.

After analysis of 10 therapies for patients with RA from 72 RCTs, we found golimumab monotherapy, infliximab monotherapy, etanercept monotherapy, adalimumab monotherapy, and etanercept+DMARDs therapy are the safer treatments when the efficacies are similar, they did not increase the risk of all analyzed safety indexes. A comprehensive analysis of the results of network meta-analysis and SUCRA sequencing diagram of adverse reactions showed that etanercept monotherapy is the safest therapy of the 10 therapies was etanercept monotherapy. Etanercept monotherapy was recommended as an alternative treatment due to its good safety outcomes. Certolizumab+DMARDs was considered the worst therapy, so it was necessary to avoid using this therapy. Besides, etanercept may be able to reduce the expression and production of vascular endothelial growth factor, NO, and inducible NO synthase and contribute to having a beneficial effect upon the progression of atherosclerosis, reducing the risk of acute cardiovascular and/or cerebrovascular events (84). This is further demonstrated that etanercept therapy is safer. In 2014, Murdaca et al. investigated the role of single-nucleotide polymorphisms (SNPs) at positions -238, - 308, and + 489 of the TNF-a gene in the response to TNF-a inhibitors (adalimumab, etanercept, or infliximab) and found that the SNP + 489 G allele may promote the response to etanercept. Thus, genetic polymorphisms could be performed before treatment to determine suitability for the etanercept monotherapy (85).

After head-to-head comparisons for the effects of these 10 anti-TNF therapies on the risk of serious infections, malignant tumors, we found no difference of 10 therapies. And compared with PBO therapy or DMARDs therapy, these 10 anti-TNF therapies did not affect the risk of serious infections, malignant tumors, and tuberculosis infection. This may be indicated that these 10 anti-TNF therapies are safe for serious infections, malignant tumors, and tuberculosis infection.

Interestingly, among these 10 anti-TNF therapies, five are TNF-a inhibitor monotherapies and another five are TNF-α inhibitors combinations of DMARDs. It was easy to find that in most cases the safety of TNF-α inhibitor monotherapy was superior to the corresponding TNF-α inhibitors combinations of DMARDs. For example, the SUCRAs of safety outcomes for golimumab+ DMARDs are as follows: 59.1% (AEs), 94.0% (SAEs), and 57.5% (serious infections). By contrast, golimumab monotherapy was safer with corresponding SUCRAs of 53.5%, 16.7%, and 31.8%. Previous researchers have also conducted comparisons between TNF-α inhibitor monotherapy and TNF-α inhibitor combined with MTX. For instance, Breedveld et al. demonstrated that the proportions of RA patients inducing AEs and serious infections were higher under the treatment of adalimumab + DMARDs than the adalimumab monotherapy, which was in line with our results. However, some studies published before also presented no difference between the two kinds of treatment groups (86). Patients with RA treated with etanercept and those treated with etanercept + DMARDs were similar. Thus, further research should be conducted to estimate whether TNF-α inhibitor combined with DMARDs therapy benefits TNF-α inhibitor monotherapy or not.

Although we have made the study as comprehensive as possible, there are still some limitations. Firstly, even though the included trials were all RCTs, the results of safety comparisons among 10 drug therapies still showed some statistical inconsistency. Perhaps the RCTs with contradictions between direct and indirect evidence should be reconsidered. Secondly, 22 trials only had a follow-up time of fewer than 20 weeks. A short duration was not enough to judge the safety of treatment. Thirdly, medication dose, treatment cost, patient compliance, and other influential factors also affected trial homogeneity. Last but not least, different RCTs included in our research had different definitions of safety outcomes. There was still a shortage of clear definitions of AEs and SAEs.

In conclusion, we regard etanercept monotherapy as the optimal choice for RA patients in clinical practice when the efficacy was similar. Conversely, certolizumab+DMARDs therapy was not recommended. It was necessary to conduct long-term studies on patients with RA to provide a more complete assessment of diverse treatments and make a more judicious choice in clinical practice. All efforts should be made to improve the life quality and health standards for patients with RA.

Data Availability Statement

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

Author Contributions

W-xP, YL, and BH conceived this meta-analysis. YL and XC extracted data. H-rX provided statistical advice and Q-zZ did all statistical analyses. YL, BH, H-rX, and XC checked for statistical inconsistency and interpreted data. YL, BH, and W-wL contributed to data interpretation. YL, BH, and JH drafted the report. H-rX, XC, and JH critically reviewed the article. All authors read and approved the final manuscript.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2022.814429/full#supplementary-material

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Data Availability Statement

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