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 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 (1.1–1.6%) or in Northern Europe (0.4–0.8%) [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 2016. 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 12–54 weeks and remission were the efficacy outcomes. Among them, the primary efficacy endpoints were ACR20 and ACR50, and the 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 12.0.

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 [1379]. The searching and selection steps are shown in Figure 1.

Figure 1

Flow diagram of study inclusion

https://www.archivesofmedicalscience.com/f/fulltexts/69683/AMS-15-31923-g001_min.jpg

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 (MTX), conventional disease-modifying anti-rheumatic drugs (cDMARDs) and placebo (PBO). The full network of comparisons categorized in different outcomes was shown in Figure 2.

Table I

Patient characteristics in the studies included in the mixed-treatment comparison (MTC) analysis

No.StudyAuthor (year)CountryFollow-up [weeks]SizesIntervention 1Intervention 2Outcomes
DrugsCasesDrugsCases
1Abe06Abe (2006)Japan14137cDMARDs47IFX + MTX90①②③⑤⑥
2APPEALBae (2013) and Kim (2012)Asia16300ETN + MTX197cDMARDs103①②③④⑤⑥
3Combe06&09Combe (2009) and Combe (2006)Finland24254cDMARDs50ETN103①②③⑤⑥
ETN + MTX101
4ACT-RAYDougados (2013)UK24553TCZ + MTX277TCZ276①②③④⑤⑥
5JESMRKameda (2010)Japan24142ETN69ETN + MTX73①②③④⑤⑥
6RED-SEAJobanputra (2012)UK52120ADA60ETN60
7Kay08Kay (2008)Global16171cDMARDs35GOL + MTX136①②③④⑤⑥
8Kim07Kim (2007)Korean24128cDMARDs63ADA + MTX65①②③⑤⑥
9LITHEKremer (2011)Global521190cDMARDs393TCZ + MTX797①②③④
10AIMKremer (2006)Global26652ABT + MTX433cDMARDs219①②③④⑤⑥
11Lan04Lan (2004)Taiwan1258ETN + MTX29cDMARDs29①②③⑤
12Mathias00& Moreland99Mathias (2000) and Moreland (1999)North-America26234PBO80ETN154①②③
13CHANGEMiyasaka (2008)Japan24352PBO87ADA265①②③⑤⑥
14SAMURAINishimoto (2007)Japan52302cDMARDs145TCZ157①②③④⑤⑥
15O’Dell2013O’Dell (2013) and O’Dell (2012)Global48353cDMARDs178ETN + MTX175①②③④⑤⑥
16SATORINishimoto (2009)Japan24125TCZ + MTX61cDMARDs64①②③④⑤⑥
17GO-FORTHTanaka (2012)Japan24261cDMARDs88GOL + MTX173①②③④⑤⑥
18ATTESTSchiff (2008)Global27321ABT + MTX156IFX + MTX165①②③④⑤⑥
19ADOREVanRiel (2006) and VanRiel (2008)Europe16314ETN159ETN + MTX155①②③④⑤⑥
20AUGUSTIIVan Vollenhoven (2011)Global26311PBO76ADA79①②③⑤⑥
ABT156
21ARMADAWeinblatt (2003) and Weinblatt (2006)North-America24271cDMARDs62ADA + MTX209①②③
22STARTWesthovens (2006)Global221084cDMARDs363IFX + MTX721①②③④⑤⑥
23Zhang2006Zhang (2006)China18173IFX + MTX87cDMARDs86①②③⑤
24CREATEIIBKeystone (2012)Global26129cDMARDs65ETN + MTX64①②③⑤⑥
25CERTAINSmolen (2011)Global24194cDMARDs98CZP + MTX96①②③⑤⑥
26ADACTAGabay (2013)Global24325TCZ163ADA162①②③④
27TOWARDGenovese (2008)Global241216TCZ + MTX803cDMARDs413①②③④⑤⑥
28HIKARIYamamoto (2014)Japan24230PBO114CZP116①②③④⑤⑥
29AMPLESchiff (2014) and Weinblatt (2014)Global52646ABT + MTX318ADA + MTX328①②③④⑤⑥
30GO-FURTHERWeinblatt (2013)Global24592cDMARDs197GOL + MTX395①②③⑤⑥
31Fleischmann 2012Fleischmann (2012)Global24112PBO59ADA53①②③⑤⑥
32Choy 2012Choy (2012)Global24247CZP + MTX126cDMARDs121①②③⑤⑥
33RAPID-IISmolen (2009) and Strand (2011)Global24619cDMARDs127CZP + MTX492①②③⑤⑥
34GO-FORWARDKeystone (2009)Global14444cDMARDs133GOL133①②③④⑤⑥
GOL + MTX178
35Chen 2009Chen (2009)Taiwan1447ADA + MTX35cDMARDs12①②③⑤⑥
36FAST4WARDFleischmann (2009)Global24220PBO109CZP111①②③⑤⑥
37Moreland 1997Moreland (1997)Global12180PBO44ETN136①②
38OPTIONSmolen (2008)Global16622TCZ + MTX418cDMARDs204①②③④⑤⑥
39RAPIDIKeystone (2008)Global52982cDMARDs199CZP + MTX783①②③
40CHARISMAMaini (2006)Europe20359TCZ159TCZ + MTX151①②③⑤⑥
cDMARDs49
41VandePutte 2004VandePutte (2004)Global26544ADA434PBO110①②③⑤⑥
42TEMPOKlareskog (2004)Global52682cDMARDs228ETN223①②③⑤⑥
ETN + MTX231
43VandePutte 2003VandePutte (2003)Global12284PBO70ADA214①②③⑥
44ATTRACTLipsky (2000) and Maini (1999)Global54428cDMARDs88IFX + MTX340①②③⑥
45Kremer 2003Kremer (2003)Global26339cDMARDs119ABT + MTX220①②③⑥
46Chen 2016Chen (2016)China12358ETN + MTX239cDMARDs119①②③⑤⑥
47J-RAPIDYamamoto (2014)Japan24316cDMARDs77CZP + MTX239①②③⑤⑥
48LatinRAMachado (2014) and Fleischmann (2014)Latin America24423ETN + MTX281cDMARDs142①②③④⑤⑥
49BREVACTAKivitz (2014) and Kivitz (2013)Global24656TCZ437PBO219①②③⑤⑥
50Hobbs 2015Hobbs (2015)Global12210PBO104ETN106①②③⑤⑥
51Li 2015Li (2015)China14264cDMARDs132GOL + MTX132①②③④⑤⑥
52ASSETConaghan (2013)Global1650ABT + MTX27cDMARDs23④⑤⑥
53Keystone 2004Keystone (2004)Global24619ADA + MTX419cDMARDs200①②③⑤
54deFilippis 2006DeFilippis (2006)Global2230ETN + MTX15IFX + MTX15①②③
55Weinblatt 1999Weinbaltt (1999)Global2489cDMARDs30ETN + MTX59①②③
56STARFurst (2003)Global24636ADA + MTX318cDMARDs318③⑤⑥

[i] PBO – placebo, MTX – 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.

[ii] Outcomes: ① – ACR20 20% response rate, ② – ACR50 50% response rate, ③ – ACR70 70% response rate, ④ – Remission, ⑤ – AEs, ⑥ – SAEs.

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

https://www.archivesofmedicalscience.com/f/fulltexts/69683/AMS-15-31923-g002_min.jpg

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 + MTX (OR = 5.42, 95% CrI: 2.12–14.0), ADA (OR = 4.31, 95% CrI: 2.53–7.39), ADA + MTX (OR = 5.81, 95% CrI: 2.39–14.7), CZP (OR = 11.3, 95% CrI: 4.48–28.8), CZP + MTX (OR = 9.68, 95% CrI: 3.86–24.5), ETN (OR = 4.22, 95% CrI: 2.23–8.17), ETN + MTX (OR = 6.31, 95% CrI: 3.10–14.0), GOL + MTX (OR = 6.23, 95% CrI: 2.46–15.6), INF + MTX (OR = 5.75, 95% CrI: 2.39–14.1), TCZ (OR = 5.64, 95% CrI: 2.8–11.47) and TCZ + MTX (OR = 7.10, 95% CrI: 3.16–16.1) revealed superior efficacy under the endpoint of ACR20 compared with PBO. In addition, CZP + MTX was more efficacious than ETN when comparing ACR20 (OR = 2.29, 95% CrI: 1.03–5.10).

Table II

Odds ratio estimates with 95% credible intervals of ACR20 and ACR50 for each comparison

EndpointACR50
ACR20ABTABT0.47 (0.13, 1.72)0.66 (0.24, 1.73)0.38 (0.11, 1.36)1.79 (0.55, 5.81)0.30 (0.07, 1.21)0.31 (0.09, 1.14)0.70 (0.22, 2.27)0.44 (0.13, 1.45)0.76 (0.16, 3.63)0.41 (0.11, 1.52)0.48 (0.13, 1.72)3.35 (1.22, 9.21)0.44 (0.14, 1.39)0.34 (0.10, 1.14)
ABT + MTX0.28 (0.07, 1.13)ABT + MTX1.40 (0.54, 3.53)0.82 (0.44, 1.52)3.82 (2.29, 6.42)0.64 (0.18, 2.32)0.66 (0.32, 1.40)1.52 (0.72, 3.13)0.94 (0.49, 1.77)1.63 (0.52, 5.05)0.89 (0.41, 1.88)1.03 (0.53, 1.93)7.17 (3.06, 17.0)0.95 (0.44, 2.03)0.73 (0.36, 1.45)
ADA0.35 (0.12, 1.03)1.27 (0.45, 3.53)ADA0.58 (0.23, 1.48)2.72 (1.26, 6.11)0.46 (0.15, 1.36)0.48 (0.18, 1.25)1.08 (0.50, 2.32)0.68 (0.30, 1.49)1.16 (0.32, 4.22)0.63 (0.24, 1.67)0.73 (0.30, 1.86)5.10 (3.03, 8.85)0.68 (0.34, 1.39)0.52 (0.23, 1.20)
ADA + MTX0.26 (0.06, 1.02)0.93 (0.47, 1.86)0.73 (0.27, 1.97)ADA + MTX4.71 (2.89, 7.69)0.79 (0.22, 2.83)0.82 (0.39, 1.70)1.86 (0.90, 3.78)1.16 (0.62, 2.14)1.99 (0.65, 6.17)1.08 (0.52, 2.25)1.26 (0.64, 2.46)8.85 (3.78, 20.7)1.16 (0.55, 2.46)0.89 (0.45, 1.75)
cDMARDs0.89 (0.24, 3.22)3.22 (1.80, 5.75)2.53 (1.09, 5.87)3.46 (2.05, 5.87)cDMARDs0.17 (0.05, 0.54)0.17 (0.10, 0.30)0.39 (0.23, 0.66)0.25 (0.17, 0.35)0.43 (0.15, 1.16)0.23 (0.13, 0.39)0.27 (0.16, 0.43)1.86 (0.94, 3.71)0.25 (0.14, 0.44)0.19 (0.12, 0.30)
CZP0.13 (0.03, 0.55)0.49 (0.13, 1.82)0.38 (0.13, 1.12)0.52 (0.14, 1.88)0.15 (0.05, 0.49)CZP1.04 (0.28, 3.82)2.36 (0.74, 7.39)1.48 (0.45, 4.85)2.53 (0.53, 12.2)1.38 (0.38, 5.05)1.60 (0.45, 5.70)11.1 (4.35, 29.7)1.48 (0.47, 4.76)1.13 (0.34, 3.86)
CZP + MTX0.15 (0.04, 0.63)0.56 (0.25, 1.25)0.44 (0.16, 1.21)0.60 (0.28, 1.30)0.17 (0.10, 0.30)1.16 (0.32, 4.26)CZP + MTX2.27 (1.07, 4.76)1.42 (0.73, 2.72)2.46 (0.76, 7.77)1.34 (0.61, 2.86)1.54 (0.75, 3.16)10.8 (4.53, 26.1)1.42 (0.66, 3.13)1.08 (0.54, 2.23)
ETN0.35 (0.10, 1.23)1.28 (0.57, 2.92)1.02 (0.45, 2.25)1.38 (0.63, 3.03)0.40 (0.22, 0.71)2.66 (0.86, 8.25)2.29 (1.03, 5.10)ETN0.63 (0.39, 0.99)1.07 (0.34, 3.39)0.58 (0.28, 1.25)0.68 (0.34, 1.38)4.71 (2.56, 9.12)0.63 (0.32, 1.25)0.48 (0.25, 0.94)
ETN + MTX0.23 (0.06, 0.84)0.84 (0.41, 1.68)0.66 (0.28, 1.55)0.90 (0.46, 1.73)0.26 (0.17, 0.39)1.73 (0.52, 5.70)1.49 (0.75, 2.94)0.65 (0.37, 1.13)ETN + MTX1.73 (0.59, 5.16)0.93 (0.49, 1.82)1.08 (0.61, 1.97)7.54 (3.82, 15.6)1.00 (0.54, 1.95)0.76 (0.44, 1.39)
GOL0.46 (0.09, 2.41)1.67 (0.48, 5.58)1.31 (0.33, 5.16)1.79 (0.54, 5.87)0.51 (0.18, 1.51)3.42 (0.69, 17.1)2.94 (0.89, 9.87)1.28 (0.38, 4.39)1.97 (0.63, 6.36)GOL0.54 (0.20, 1.45)0.63 (0.20, 1.93)4.39 (1.31, 15.2)0.58 (0.19, 1.86)0.44 (0.15, 1.36)
GOL + MTX0.24 (0.06, 0.98)0.88 (0.39, 1.95)0.69 (0.25, 1.90)0.94 (0.44, 2.03)0.27 (0.16, 0.47)1.82 (0.50, 6.69)1.57 (0.72, 3.42)0.68 (0.31, 1.54)1.05 (0.53, 2.10)0.53 (0.18, 1.55)GOL + MTX1.16 (0.57, 2.39)8.08 (3.39, 19.7)1.07 (0.50, 2.36)0.82 (0.41, 1.70)
IFX + MTX0.26 (0.07, 1.02)0.94 (0.46, 1.93)0.75 (0.28, 1.97)1.01 (0.49, 2.10)0.29 (0.18, 0.49)1.95 (0.55, 7.03)1.68 (0.79, 3.56)0.73 (0.34, 1.58)1.13 (0.60, 2.14)0.57 (0.17, 1.90)1.07 (0.51, 2.29)IFX + MTX7.03 (3.06, 16.1)0.92 (0.44, 1.95)0.70 (0.37, 1.38)
PBO1.49 (0.51, 4.44)5.42 (2.12, 14.0)4.31 (2.53, 7.39)5.81 (2.39, 14.7)1.68 (0.81, 3.56)11.3 (4.48, 28.8)9.68 (3.86, 24.5)4.22 (2.23, 8.17)6.49 (3.10, 14.0)3.29 (0.89, 12.3)6.23 (2.46, 15.6)5.75 (2.39, 14.1)PBO0.13 (0.07, 0.25)0.10 (0.05, 0.21)
TCZ0.26 (0.08, 0.93)0.97 (0.41, 2.27)0.76 (0.35, 1.63)1.04 (0.46, 2.36)0.30 (0.16, 0.56)1.99 (0.63, 6.42)1.73 (0.76, 3.97)0.75 (0.36, 1.57)1.15 (0.58, 2.34)0.58 (0.17, 2.01)1.11 (0.48, 2.51)1.03 (0.46, 2.29)0.18 (0.09, 0.36)TCZ0.76 (0.43, 1.35)
TCZ + MTX0.21 (0.06, 0.79)0.76 (0.35, 1.65)0.61 (0.24, 1.48)0.82 (0.40, 1.72)0.24 (0.14, 0.39)1.58 (0.46, 5.42)1.36 (0.64, 2.89)0.59 (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 + MTX

[i] PBO – placebo, MTX – 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.

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: 0.94–3.71). As for cDMARDs, it revealed worse efficacy than the other treatments except ABT, GOL and PBO. In addition, ETN + MTX, CZP + MTX and TCZ + MTX were superior to ETN for the efficacy of ACR50 (ETN + MTX: OR = 1.59, 95% CrI: 1.01–2.56; CZP + MTX: OR = 2.27, 95% CrI: 1.07–4.76; TCZ + MTX: OR = 2.10, 95% CrI: 1.06–4.01.

American College of Rheumatology 70% response rate (ACR70)

As shown in the lower panel of Table III, only cDMARDs (OR = 2.41, 95% CrI: 0.91–7.10) 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: 0.32–7.54), ADA (OR = 2.77, 95% CrI: 0.93–8.08) and GOL (OR = 2.69, 95% CrI: 0.37–10.3) Additionally, CZP enjoyed obvious superiority to ABT (OR = 0.05, 95% CrI: 0.01–0.62) and ADA (OR = 0.09, 95% CrI: 0.01–0.84).

Table III

Odds ratio estimates with 95% credible intervals of ACR70 and remission for each comparison

EndpointRemission
ACR70ABT + MTX0.30 (0.05, 1.60)ABT + MTX0.34 (0.02, 6.11)0.90 (0.12, 6.75)4.06 (1.03, 16.3)2.10 (0.20, 23.8)1.19 (0.18, 7.61)1.17 (0.09, 13.2)0.71 (0.12, 4.06)1.06 (0.20, 5.58)0.06 (0.01, 0.45)0.15 (0.03, 0.87)
ADA0.58 (0.17, 1.93)1.90 (0.55, 6.96)ADA2.69 (0.08, 107)12.1 (0.92, 185)6.17 (0.26, 183)3.53 (0.21, 70.1)3.49 (0.12, 104)2.14 (0.13, 38.1)3.16 (0.17, 68.7)0.17 (0.02, 1.39)0.46 (0.03, 6.42)
ADA + MTX0.30 (0.05, 1.55)0.97 (0.45, 2.12)0.51 (0.14, 1.73)ADA + MTX4.53 (0.39, 52.5)2.34 (0.10, 54.1)1.32 (0.08, 20.5)1.32 (0.05, 30.0)0.80 (0.05, 11.3)1.20 (0.09, 16.4)0.06 (0.01, 1.12)0.17 (0.01, 2.41)
cDMARDs1.60 (0.32, 7.54)5.26 (2.77, 10.4)2.77 (0.93, 8.08)5.42 (2.92, 10.5)cDMARDs0.52 (0.08, 3.63)0.29 (0.08, 0.98)0.29 (0.03, 2.10)0.18 (0.06, 0.50)0.26 (0.06, 1.09)0.02 (0.01, 0.07)0.04 (0.01, 0.11)
CZP0.05 (0.01, 0.62)0.18 (0.01, 1.97)0.09 (0.01, 0.84)0.18 (0.01, 2.05)0.03 (0.01, 0.34)CZP
CZP + MTX0.21 (0.04, 1.23)0.70 (0.25, 2.05)0.37 (0.10, 1.43)0.73 (0.26, 2.08)0.13 (0.06, 0.30)3.97 (0.34, 133)CZP + MTX
ETN0.49 (0.09, 2.34)1.62 (0.61, 4.06)0.85 (0.25, 2.53)1.65 (0.63, 4.06)0.31 (0.15, 0.58)9.03 (0.86, 276)2.29 (0.75, 6.36)ETN0.57 (0.12, 2.53)0.57 (0.03, 9.03)0.34 (0.04, 3.00)0.51 (0.04, 5.53)0.03 (0.01, 0.32)0.07 (0.01, 0.64)
ETN + MTX0.31 (0.06, 1.49)1.03 (0.44, 2.32)0.54 (0.16, 1.63)1.06 (0.46, 2.32)0.20 (0.11, 0.31)5.75 (0.55, 179)1.46 (0.53, 3.71)0.64 (0.36, 1.15)ETN + MTX1.00 (0.09, 10.2)0.61 (0.11, 3.06)0.90 (0.13, 5.87)0.05 (0.01, 0.34)0.13 (0.02, 0.65)
GOL0.59 (0.07, 4.71)1.97 (0.44, 8.94)1.04 (0.18, 5.81)2.01 (0.47, 9.03)0.37 (0.10, 1.42)11.4 (0.75, 424)2.80 (0.57, 13.3)1.22 (0.28, 5.75)1.90 (0.47, 8.41)GOL0.61 (0.09, 4.48)0.90 (0.08, 11.7)0.05 (0.01, 0.66)0.13 (0.01, 1.36)
GOL + MTX0.33 (0.05, 1.82)1.08 (0.40, 2.97)0.57 (0.15, 2.10)1.12 (0.41, 2.97)0.21 (0.09, 0.43)6.17 (0.52, 198)1.54 (0.50, 4.57)0.68 (0.25, 1.92)1.05 (0.43, 2.66)0.55 (0.15, 1.93)GOL + MTX1.48 (0.25, 9.30)0.08 (0.01, 0.55)0.22 (0.05, 0.98)
IFX + MTX0.36 (0.06, 1.86)1.19 (0.52, 2.66)0.62 (0.17, 2.12)1.21 (0.51, 2.86)0.22 (0.12, 0.41)6.69 (0.59, 211)1.67 (0.58, 4.66)0.73 (0.30, 1.86)1.14 (0.53, 2.59)0.60 (0.13, 2.56)1.08 (0.41, 2.86)IFX + MTX0.05 (0.01, 0.44)0.15 (0.02, 0.86)
PBO3.86 (1.07, 14.6)12.8 (4.01, 46.5)6.69 (3.35, 14.7)13.1 (4.14, 47.0)2.41 (0.91, 7.10)70.8 (9.49, 1900)18.0 (5.10, 69.4)7.92 (2.94, 26.1)12.3 (4.53, 40.4)6.49 (1.23, 37.3)11.7 (3.46, 45.6)10.8 (3.46, 38.8)PBO
TCZ0.39 (0.09, 1.70)1.30 (0.50, 3.67)0.68 (0.28, 1.75)1.32 (0.52, 3.71)0.24 (0.12, 0.53)7.32 (0.77, 217)1.82 (0.64, 5.64)0.80 (0.34, 2.27)1.25 (0.56, 3.25)0.65 (0.15, 3.16)1.19 (0.43, 3.63)1.09 (0.44, 3.03)0.10 (0.04, 0.24)TCZ2.66 (0.57, 13.5)
TCZ + MTX0.26 (0.05, 1.26)0.86 (0.36, 2.12)0.45 (0.15, 1.36)0.88 (0.38, 2.14)0.16 (0.09, 0.29)4.85 (0.48, 148)1.22 (0.45, 3.32)0.53 (0.23, 1.35)0.84 (0.41, 1.90)0.44 (0.10, 1.92)0.79 (0.31, 2.12)0.73 (0.32, 1.79)0.07 (0.02, 0.19)0.67 (0.32, 1.32)TCZ + MTX

[i] PBO – placebo, MTX – 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 + MTX were significantly better than ABT + MTX (OR = 0.06, 95% CrI: 0.01–0.45; OR = 0.15, 95% CrI: 0.03–0.87), cDMARDs (OR = 0.01, 95% CrI: 0.01–0.07; OR = 0.04, 95% CrI: 0.01–0.11), ETN (OR = 0.03, 95% CrI: 0.01–0.32; OR = 0.07, 95% CrI: 0.01–0.64), ETN + MTX (OR = 0.05, 95% CrI: 0.01–0.34; OR = 0.13, 95% CrI: 0.02–0.65), GOL + MTX (OR = 0.08, 95% CrI: 0.01–0.55; OR = 0.22, 95% CrI: 0.05–0.98) and IFX + MTX (OR = 0.05, 95% CrI: 0.01–0.44; OR = 0.15, 95% CrI: 0.02–0.86) in disease remission. However, there was no particular evidence to confirm which one of TCZ and TCZ + MTX was better. ABT + MTX (OR = 0.25, 95% CrI: 0.06–0.97), ETN + MTX (OR = 0.29, 95% CrI: 0.08–0.98) and GOL + MTX (OR = 0.18, 95% CrI: 0.06–0.50) also presented greater remission of pain compared to cDMARDs. Additionally, GOL (OR = 0.05, 95% CrI: 0.01–0.66) was less efficacious than TCZ.

Adverse events (AEs)

The safety outcomes are shown in Table IV. Statistically, ABT (OR = 1.86, 95% CrI: 1.03–3.42), ADA (OR = 2.10, 95% CrI: 1.32–3.25) and CZP (OR = 2.01, 95% CrI: 1.25–3.29) presented a higher risk of AEs than PBO. ADA was more likely to cause adverse events than ADA + MTX (OR = 2.10, 95% CrI: 1.02–4.48), cDMARDs (OR = 2.59, 95% CrI: 1.35–5.00), CZP + MTX (OR = 2.08, 95% CrI: 1.01–4.31), ETN + MTX (OR = 2.10, 95% CrI: 1.08–4.14), GOL (OR = 2.51, 95% CrI: 1.04–5.99) and PBO (OR = 2.10, 95% CrI: 1.32–3.25). In comparison with ETN + MTX (OR = 2.01, 95% CrI: 1.01–4.10) and GOL (OR = 2.44, 95% CrI: 1.00–5.81) 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: 0.20–0.79), ETN (OR = 0.62, 95% CrI: 0.43–0.87), IFX + MTX (OR = 0.73, 95% CrI: 0.52–0.98), TCZ (OR = 0.65, 95% CrI: 0.47–0.92) and TCZ + MTX (OR = 0.69, 95% CrI: 0.53–0.90).

Table IV

Odds ratio estimates with 95% credible intervals of AEs and SAEs for each comparison

EndpointSAEs
AEsABTABT3.71 (0.88, 16.9)2.39 (0.73, 8.67)2.94 (0.66, 13.5)2.94 (0.73, 12.3)0.60 (0.12, 3.03)1.82 (0.41, 8.76)1.88 (0.45, 7.92)2.29 (0.54, 9.49)2.61 (0.38, 17.6)1.31 (0.25, 6.55)2.69 (0.63, 12.2)2.36 (0.73, 8.41)1.84 (0.46, 7.92)2.12 (0.50, 9.49)
ABT + MTX1.77 (0.76, 4.26)ABT + MTX0.64 (0.24, 1.70)0.80 (0.45, 1.28)0.80 (0.51, 1.17)0.16 (0.04, 0.66)0.51 (0.24, 0.99)0.51 (0.25, 0.92)0.62 (0.32, 1.07)0.68 (0.17, 2.64)0.35 (0.14, 0.78)0.73 (0.41, 1.25)0.64 (0.25, 1.62)0.50 (0.24, 0.96)0.57 (0.30, 1.02)
ADA0.89 (0.48, 1.63)0.50 (0.23, 1.05)ADA1.23 (0.44, 3.42)1.25 (0.51, 2.94)0.26 (0.08, 0.74)0.78 (0.27, 2.25)0.79 (0.32, 1.79)0.96 (0.38, 2.27)1.07 (0.23, 5.00)0.55 (0.18, 1.67)1.13 (0.41, 2.97)0.99 (0.63, 1.60)0.76 (0.32, 1.80)0.88 (0.34, 2.25)
ADA + MTX1.86 (0.82, 4.48)1.05 (0.68, 1.65)2.10 (1.02, 4.48)ADA + MTX1 (0.6, 1.68)0.21 (0.05, 0.86)0.63 (0.29, 1.38)0.64 (0.31, 1.27)0.78 (0.39, 1.46)0.87 (0.21, 3.49)0.44 (0.17, 1.06)0.91 (0.48, 1.77)0.81 (0.31, 2.14)0.62 (0.30, 1.32)0.71 (0.36, 1.42)
cDMARDs2.29 (1.08, 5.10)1.28 (0.90, 1.90)2.59 (1.35, 5.00)1.23 (0.85, 1.75)cDMARDs0.21 (0.05, 0.78)0.63 (0.35, 1.12)0.64 (0.38, 1.02)0.78 (0.50, 1.14)0.86 (0.22, 3.13)0.44 (0.20, 0.89)0.91 (0.59, 1.39)0.80 (0.35, 1.88)0.63 (0.36, 1.06)0.71 (0.45, 1.12)
CZP0.92 (0.42, 1.99)0.52 (0.24, 1.13)1.05 (0.53, 1.97)0.50 (0.22, 1.05)0.40 (0.20, 0.79)CZP3.03 (0.72, 13.9)3.13 (0.81, 12.4)3.78 (0.97, 14.2)4.31 (0.66, 25.5)2.14 (0.45, 9.58)4.44 (1.09, 18.2)3.86 (1.48, 11.5)3.03 (0.82, 10.9)3.49 (0.89, 13.6)
CZP + MTX1.84 (0.81, 4.35)1.04 (0.64, 1.68)2.08 (1.01, 4.31)1.00 (0.61, 1.58)0.81 (0.58, 1.11)1.99 (0.93, 4.39)CZP + MTX1.01 (0.46, 2.14)1.22 (0.59, 2.46)1.38 (0.34, 5.53)0.70 (0.27, 1.75)1.45 (0.71, 3.00)1.28 (0.45, 3.49)0.98 (0.45, 2.20)1.13 (0.54, 2.39)
ETN1.42 (0.65, 3.16)0.80 (0.47, 1.30)1.60 (0.82, 3.10)0.76 (0.45, 1.23)0.62 (0.43, 0.87)1.54 (0.76, 3.06)0.77 (0.47, 1.21)ETN1.21 (0.76, 1.92)1.36 (0.33, 5.31)0.69 (0.28, 1.63)1.43 (0.75, 2.83)1.26 (0.57, 2.92)0.98 (0.49, 1.97)1.13 (0.58, 2.23)
ETN + MTX1.86 (0.86, 4.18)1.05 (0.68, 1.63)2.10 (1.08, 4.14)1.00 (0.64, 1.54)0.81 (0.64, 1.04)2.01 (1.01, 4.10)1.00 (0.68, 1.52)1.31 (0.96, 1.86)ETN + MTX1.13 (0.27, 4.35)0.57 (0.23, 1.32)1.19 (0.66, 2.20)1.03 (0.45, 2.51)0.80 (0.42, 1.57)0.92 (0.52, 1.73)
GOL2.23 (0.86, 5.81)1.26 (0.64, 2.46)2.51 (1.04, 5.99)1.20 (0.61, 2.27)0.97 (0.55, 1.68)2.44 (1.00, 5.81)1.21 (0.63, 2.27)1.57 (0.82, 3.03)1.20 (0.65, 2.18)GOL0.51 (0.15, 1.55)1.06 (0.27, 3.90)0.91 (0.21, 4.48)0.72 (0.18, 2.83)0.83 (0.21, 3.22)
GOL + MTX1.79 (0.79, 4.18)1.00 (0.63, 1.62)2.01 (0.99, 4.18)0.96 (0.59, 1.51)0.78 (0.58, 1.05)1.93 (0.92, 4.10)0.96 (0.63, 1.51)1.26 (0.80, 2.03)0.96 (0.66, 1.40)0.80 (0.47, 1.40)GOL + MTX2.08 (0.93, 4.95)1.80 (0.63, 5.58)1.42 (0.58, 3.53)1.63 (0.70, 3.86)
IFX + MTX1.65 (0.73, 3.94)0.94 (0.59, 1.45)1.86 (0.90, 3.90)0.90 (0.54, 1.39)0.73 (0.52, 0.98)1.79 (0.84, 3.82)0.90 (0.57, 1.40)1.17 (0.74, 1.88)0.90 (0.59, 1.31)0.75 (0.39, 1.40)0.93 (0.59, 1.40)IFX + MTX0.88 (0.35, 2.25)0.68 (0.34, 1.34)0.78 (0.43, 1.45)
PBO1.86 (1.03, 3.42)1.04 (0.57, 1.90)2.10 (1.32, 3.25)1.01 (0.54, 1.79)0.81 (0.50, 1.31)2.01 (1.25, 3.29)1.00 (0.56, 1.80)1.31 (0.80, 2.16)1.00 (0.60, 1.63)0.83 (0.40, 1.75)1.04 (0.58, 1.82)1.12 (0.63, 1.99)PBO0.77 (0.34, 1.70)0.89 (0.36, 2.12)
TCZ1.51 (0.73, 3.32)0.84 (0.52, 1.40)1.70 (0.91, 3.19)0.81 (0.50, 1.31)0.65 (0.47, 0.92)1.62 (0.86, 3.16)0.81 (0.52, 1.31)1.05 (0.70, 1.68)0.80 (0.57, 1.17)0.68 (0.36, 1.31)0.84 (0.54, 1.32)0.90 (0.58, 1.46)0.81 (0.53, 1.27)TCZ1.15 (0.66, 2.03)
TCZ + MTX1.58 (0.74, 3.60)0.89 (0.58, 1.42)1.80 (0.91, 3.53)0.85 (0.54, 1.32)0.69 (0.53, 0.90)1.72 (0.87, 3.49)0.85 (0.58, 1.31)1.12 (0.76, 1.73)0.85 (0.61, 1.19)0.71 (0.39, 1.34)0.90 (0.60, 1.32)0.95 (0.64, 1.46)0.85 (0.53, 1.43)1.06 (0.76, 1.48)TCZ + MTX

[i] PBO – placebo, MTX – 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.

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: 1.48–11.5) presented a worse performance than PBO (OR = 0.26, 95% CrI: 0.09–0.68), INF + MTX (OR = 0.23, 95% CrI: 0.06–0.91), cDMARDs (OR = 0.21, 95% CrI: 0.05–0.78), ADA + MTX (OR = 0.21, 95% CrI: 0.05–0.86), ADA (OR = 0.26, 95% CrI: 0.08–0.74) and ABT + MTX (OR = 0.16, 95% CrI: 0.04–0.66). In contrast, ABT + MTX was more efficacious in reducing the SAEs in comparison with CZP + MTX (OR = 0.51, 95% CrI: 0.24–0.99), ETN (OR = 0.51, 95% CrI: 0.25–0.92), GOL + MTX (OR = 0.35, 95% CrI: 0.14–0.78) and TCZ (OR = 0.50, 95% CrI: 0.24–0.96). Furthermore, cDMARDs (OR = 0.44, 95% CrI: 0.20–0.89) worked better than GOL + MTX in withdrawal due to SAEs.

Relative ranking analysis

Relative ranking of the treatments is assessed by SUCRA in Table V. Since CZP + MTX 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 + MTX as the optimal drug therapy. Another alternative was TCZ + MTX 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.

Table V

Relative ranking of the treatments assessed by surface under cumulative ranking curve area

TreatmentsACR20ACR50ACR70RemissionAEsSAEs
ABT0.1080.2390.2000.1480.172
ABT + MTX0.5100.5640.6050.4020.5490.852
ADA0.3920.3750.3260.6170.0770.551
ADA + MTX0.5540.7220.6200.4280.6060.693
cDMARDs0.1080.0840.0890.0500.8620.727
CZP0.8180.7960.8820.0990.051
CZP + MTX0.8330.8420.7510.6020.365
ETN0.3590.3070.3580.2200.2950.356
ETN + MTX0.6340.6110.5970.3640.5560.506
GOL0.3030.3320.3320.3600.7470.567
GOL + MTX0.5940.6600.5610.5010.5550.186
IFX + MTX0.5470.5460.5110.3850.4660.637
PBO0.0230.0040.0050.6130.545
TCZ0.5320.6090.4700.8900.3520.346
TCZ + MTX0.6850.8090.6930.7840.4070.445

[i] PBO – placebo, MTX – 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.

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 + MTX and cDMARDs (p = 0.015), as well as TCZ + MTX and TCZ (p = 0.019). On the other hand, no consistency between ETN + MTX and cDMARDs (p < 0.001), TCZ and ETN + MTX (p = 0.034), TCZ + MTX and ETN + MTX (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.

Table VI

Results of consistency analysis by node-splitting plot

EndpointComparisonDirect OR (95% CI)Indirect OR (95% CrI)Network OR (95% CrI)P-value
ACR20ADA + MTX vs. ABT + MTX1.10 (0.35, 3.50)1.10 (0.48, 2.70)1.10 (0.53, 2.10)0.899
cDMARDs vs. ABT + MTX0.34 (0.17, 0.68)0.29 (0.07, 1.10)0.31 (0.17, 0.56)0.819
cDMARDs vs. ADA + MTX0.29 (0.16, 0.52)0.31 (0.08, 1.10)0.29 (0.17, 0.49)0.928
ETN vs. cDMARDs2.50 (1.00, 6.10)2.40 (1.00, 5.90)2.50 (1.40, 4.60)0.963
ETN + MTX vs. cDMARDs3.80 (2.50, 5.70)4.70 (1.30, 15.0)3.80 (2.60, 5.70)0.723
ETN + MTX vs. ETN1.50 (0.86, 2.90)1.20 (0.27, 4.90)1.50 (0.89, 2.70)0.751
IFX + MTX vs. ABT + MTX0.72 (0.22, 2.40)1.30 (0.53, 3.20)1.10 (0.51, 2.30)0.425
IFX + MTX vs. cDMARDs3.50 (2.00, 5.80)3.90 (0.52, 26.0)3.50 (2.00, 5.60)0.933
IFX + MTX vs. ETN + MTX1.00 (0.15, 7.30)0.88 (0.46, 1.70)0.90 (0.47, 1.70)0.871
PBO vs. ADA0.22 (0.12, 0.38)0.41 (0.10, 1.70)0.23 (0.13, 0.40)0.423
PBO vs. ETN0.22 (0.10, 0.48)0.29 (0.08, 1.10)0.23 (0.13, 0.45)0.691
TCZ vs. ADA1.90 (0.53, 6.20)1.00 (0.34, 2.70)1.30 (0.62, 2.90)0.413
TCZ vs. cDMARDs3.40 (1.40, 8.50)3.30 (1.30, 8.40)3.30 (1.80, 6.40)0.950
TCZ vs. PBO3.50 (1.10, 11.0)7.70 (3.10, 18.0)5.60 (2.80, 12.0)0.274
TCZ + MTX vs. cDMARDs4.00 (2.40, 7.00)4.80 (1.10, 21.0)4.20 (2.50, 6.90)0.818
TCZ + MTX vs. TCZ1.40 (0.60, 3.20)0.94 (0.35, 2.90)1.30 (0.65, 2.50)0.574
ACR50ADA + MTX vs. ABT + MTX1.10 (0.42, 2.80)1.40 (0.59, 3.00)1.20 (0.63, 2.30)0.741
cDMARDs vs. ABT + MTX0.29 (0.16, 0.56)0.22 (0.07, 0.74)0.26 (0.15, 0.45)0.679
cDMARDs vs. ADA + MTX0.21 (0.12, 0.35)0.24 (0.08, 0.82)0.21 (0.13, 0.36)0.789
ETN vs. cDMARDs2.20 (0.96, 4.80)3.00 (1.40, 6.80)2.50 (1.50, 4.50)0.565
ETN + MTX vs. cDMARDs4.30 (2.90, 6.50)2.90 (0.92, 9.20)4.10 (2.80, 6.20)0.520
ETN + MTX vs. ETN1.50 (0.89, 2.60)1.80 (0.45, 7.00)1.60 (0.97, 2.60)0.834
IFX + MTX vs. ABT + MTX0.88 (0.30, 2.50)1.10 (0.45, 2.40)0.98 (0.51, 1.90)0.776
IFX + MTX vs. cDMARDs3.60 (2.10, 6.00)5.80 (0.84, 41.0)3.80 (2.40, 6.00)0.630
IFX + MTX vs. ETN + MTX1.40 (0.24, 9.40)0.87 (0.47, 1.60)0.93 (0.52, 1.60)0.606
PBO vs. ADA0.17 (0.09, 0.30)0.41 (0.10, 1.40)0.19 (0.11, 0.32)0.223
PBO vs. ETN0.21 (0.10, 0.47)0.20 (0.06, 0.64)0.21 (0.10, 0.40)0.920
TCZ vs. ADA2.40 (0.83, 6.90)0.98 (0.37, 2.60)1.50 (0.71, 3.00)0.199
TCZ vs. cDMARDs3.50 (1.50, 8.30)4.40 (1.90, 9.80)4.10 (2.30, 7.40)0.710
TCZ vs. PBO5.00 (1.90, 14.0)9.80 (4.40, 22.0)7.70 (4.00, 15.0)0.299
TCZ + MTX vs. cDMARDs4.60 ( 3.00, 7.20)9.10 (2.70, 33.0)5.30 (3.40, 8.30)0.299
TCZ + MTX vs. TCZ1.60 (0.84, 2.90)0.73 (0.29, 1.90)1.30 (0.71, 2.30)0.166
ACR70ADA + MTX vs. ABT + MTX0.95 (0.27, 2.90)1.10 (0.39, 3.20)1.00 (0.46, 2.20)0.800
cDMARDs vs. ABT + MTX0.19 (0.08, 0.42)0.16 (0.04, 0.69)0.19 (0.09, 0.37)0.809
cDMARDs vs. ADA + MTX0.18 (0.08, 0.36)0.22 (0.05, 0.92)0.18 (0.09, 0.35)0.755
ETN vs. cDMARDs2.60 (1.00, 8.00)4.40 (1.70, 13.0)3.30 (1.70, 6.60)0.463
ETN + MTX vs. cDMARDs5.20 (3.20, 9.50)6.80 (1.10, 46.0)5.00 (3.20, 8.90)0.770
ETN + MTX vs. ETN1.60 (0.83, 2.80)0.79 (0.07, 6.90)1.60 (0.88, 2.70)0.548
IFX + MTX vs. ABT + MTX1.20 (0.32, 4.30)0.58 (0.21, 1.60)0.85 (0.38, 1.90)0.355
IFX + MTX vs. cDMARDs3.90 (2.10, 7.70)5.30 (0.13, 230)4.50 (2.40, 8.70)0.856
IFX + MTX vs. ETN + MTX1.0 0(0.02, 33.0)0.86 (0.38, 2.00)0.89 (0.40, 1.80)0.901
PBO vs. ADA0.12 (0.05, 0.27)0.31 (0.07, 1.40)0.15 (0.08, 0.29)0.238
PBO vs. ETN0.08 (0.01, 0.38)0.17 (0.04, 0.64)0.13 (0.04, 0.34)0.478
TCZ vs. ADA2.20 (0.70, 7.10)0.85 (0.22, 3.60)1.50 (0.58, 3.60)0.299
TCZ vs. cDMARDs3.20 (1.10, 8.80)5.40 (1.50, 18.0)4.10 (1.90, 8.40)0.494
TCZ vs. PBO4.80 (1.50, 15.0)18.0 (6.30, 59.0)10.0 (4.10, 25.0)0.085
TCZ + MTX vs. cDMARDs5.60 (3.30, 9.60)7.70 (1.70, 30.0)6.10 (3.50, 11.0)0.661
TCZ + MTX vs. TCZ1.60 (0.83, 3.50)0.90 (0.30, 3.00)1.50 (0.73, 3.20)0.396
RemissionIFX + MTX vs. ABT + MTX1.10 (0.10, 11.0)0.66 (0.04, 13.0)0.94 (0.16, 5.00)0.749
TCZ vs. cDMARDs360 (73.0,1800)12.0 (2.60, 71.0)70.0 (13.0,380)0.013
TCZ + MTX vs. cDMARDs15.0 (7.10, 37.0)430 (47.0, 3500)26.0 (9.10, 78.0)0.015
TCZ + MTX vs. TCZ1.30 (0.34, 4.60)0.04 (0.01, 0.29)0.38 (0.07, 1.70)0.019
AEsADA + MTX vs. ABT + MTX0.84 (0.41, 1.60)1.00 (0.57, 1.80)0.95 (0.60, 1.50)0.628
cDMARDs vs. ABT + MTX0.83 (0.53, 1.30)0.65 (0.30, 1.50)0.77 (0.53, 1.10)0.611
cDMARDs vs. ADA + MTX0.78 (0.50, 1.20)0.96 (0.42, 2.20)0.81 (0.57, 1.20)0.635
ETN vs. cDMARDs2.00 (1.20, 3.50)1.30 (0.85, 2.20)1.60 (1.20, 2.40)0.236
ETN + MTX vs. cDMARDs1.00 (0.79, 1.30)2.70 (1.70, 4.30)1.20 (0.97, 1.60)< 0.001
ETN + MTX vs. ETN0.86 (0.55, 1.20)0.47 (0.24, 0.93)0.77 (0.53, 1.10)0.154
IFX + MTX vs. ABT + MTX1.20 (0.58, 2.30)0.99 (0.56, 1.80)1.10 (0.67, 1.70)0.679
PBO vs. ETN0.76 (0.37, 1.50)0.76 (0.35, 1.50)0.77 (0.45, 1.20)0.996
TCZ vs. cDMARDs1.60 (0.92, 2.70)1.40 (0.83, 2.20)1.50 (1.10, 2.10)0.708
TCZ vs. ETN + MTX0.68 (0.36, 1.30)1.50 (0.97, 2.40)1.20 (0.85, 1.80)0.034
TCZ vs. PBO1.20 (0.75, 2.20)1.20 (0.51, 2.80)1.20 (0.79, 2.00)0.996
TCZ + MTX vs. cDMARDs1.60 (1.20, 2.10)0.94 (0.54, 1.60)1.40 (1.10, 1.80)0.093
TCZ + MTX vs. ETN + MTX0.61 (0.30, 1.10)1.40 (0.99, 2.00)1.20 (0.84, 1.60)0.025
TCZ + MTX vs. TCZ0.86 (0.58, 1.30)1.00 (0.53, 1.90)0.95 (0.68, 1.30)0.619
SAEsADA + MTX vs. ABT + MTX1.20 (0.58, 2.40)1.30 (0.61, 3.70)1.20 (0.77, 2.20)0.919
cDMARDs vs. ABT + MTX1.30 (0.80, 2.30)1.20 (0.42, 3.00)1.20 (0.83, 1.90)0.885
cDMARDs vs. ADA + MTX0.97 (0.45, 1.90)1.00 (0.45, 2.60)0.99 (0.59, 1.70)0.936
ETN vs. ADA1.30 (0.32, 4.30)1.40 (0.43, 4.70)1.30 (0.53, 3.40)0.904
ETN vs. cDMARDs1.70 (0.92, 3.60)1.40 (0.55, 4.00)1.60 (0.97, 2.7)0.760
ETN + MTX vs. cDMARDs1.30 (0.88, 2.20)1.70 (0.26,11.0)1.30 (0.88,2.10)0.829
ETN + MTX vs. ETN0.81 (0.52, 1.30)0.82 (0.18, 4.60)0.82 (0.50, 1.30)1.000
IFX + MTX vs. ABT + MTX2.40 (0.96, 6.60)1.00 (0.56, 2.00)1.30 (0.82, 2.40)0.145
IFX + MTX vs. ETN + MTX1.30 (0.50, 3.80)1.30 (0.34, 4.90)1.30 (0.61, 3.30)0.989
PBO vs. ADA1.00 (0.62, 1.70)0.90 (0.16, 5.00)1.00 (0.61, 1.50)0.875
PBO vs. ETN0.61 (0.07, 4.30)0.82 (0.31, 2.10)0.76 (0.28, 1.70)0.780
TCZ vs. cDMARDs1.70 (0.81,3.50)1.40 (0.55,4.40)1.60 (0.93,2.80)0.839
TCZ vs. PBO0.85 (0.39, 1.80)0.91 (0.37, 2.30)0.88 (0.48, 1.50)0.910
TCZ + MTX vs. cDMARDs1.40 (0.87, 2.40)1.50 (0.35, 6.30)1.40 (0.90, 2.20)0.934

[i] PBO – placebo, MTX – 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.

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 + MTX, B – TCZ, C – PBO, D – IFX + MTX, E – GOL + MTX, F – GOL, G – ETN + MTX, H – ETN, I – CZP + MTX, J – CZP, K – cDMARDs, L – ADA + MTX, M – ADA, N – ABT + MTX, O – ABT.

https://www.archivesofmedicalscience.com/f/fulltexts/69683/AMS-15-31923-g003_min.jpg

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.

Figure 4

Publication bias of different outcomes

https://www.archivesofmedicalscience.com/f/fulltexts/69683/AMS-15-31923-g004_min.jpg

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 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.

Table VII

Jadad scale of 67 included studies

Author, yearRandomizedBlindedWithdrawal
Abe et al., 2006220
Bae et al., 2013200
Kim et al., 2012201
Combe et al., 2006221
Combe et al., 2016221
Dougados et al., 2013221
Kameda et al., 2014200
Jobanputra et al., 2012201
Kay et al., 2008220
Kim et al., 2007221
Kremer et al., 2011221
Kremer et al., 2006220
Lan et al., 2004220
Mathias et al., 2000220
Moreland et al., 1999221
Miyasaka et al., 2008221
Nishimoto et al., 2009221
O’Dell et al., 2013221
O’Dell et al., 2012221
Nishimoto et al., 2007211
Tanake et al., 2016220
Schiff et al., 2008220
Van Riel et al., 2006200
Van Riel et al., 2008201
Van Vollenhoven et al., 2011220
Weinblatt et al., 2003221
Weinblatt et al., 2006221
Westhovens et al., 2006210
Zhang et al., 2006221
Keystone et al., 2012221
Smolen et al., 2009221
Smolen et al., 2008221
Gabay et al., 2012220
Genovese et al., 2008221
Yamamoto et al., 2014221
Schiff et al., 2014210
Weinblatt et al., 2012221
Weinblatt et al., 2003221
Fleischmann et al., 2012221
Feischmann et al., 2009221
Choy et al., 2012221
Keystone et al., 2009220
Chen et al., 2009220
Keystone et al., 2008221
Maini et al., 2006221
Maini et al., 1999221
Vandeputte et al., 2004221
Vandeputte et al., 2003221
Klareskog et al., 2004220
Lipsky et al., 2000200
Kremer et al., 2003220
Chen et al., 2016221
Fleischmann et al., 2014220
Machado et al., 2014200
Kivitz et al., 2014221
Kivitz et al., 2013221
Hobbs et al., 2015220
Li et al., 2015221
Conaghan et al., 2013221
Keystome et al., 2004221
Defilippis et al., 2006220
Weinbaltt et al., 2003221
Weinbaltt et al., 1999221
Smolen et al., 2011221
Strand et al., 2011221
Moreland et al., 1997221
Furst et al., 2003221

[i] Each question was to be answered with either a yes or a no. Each yes would score a single point, each no zero points. Additional points were given if: The method of randomization was described in the paper, and that method was appropriate (1 extra point in the randomization part); the method of blinding was described, and it was appropriate (1 extra point in the blinding part).

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 recommend CZP + MTX as the best treatment due to it having the highest rankings in ACR20 (83.3%) and ACR50 (84.2%) response rates and relatively low risk of adverse events. TCZ + MTX is recommended as an alternative treatment due to its good performance in all efficacy and safety outcomes. ABT is considered as the worst therapy, and cDMARDs is also not recommended though its safety seemed to be superior.

Interestingly, among these 15 drug therapies, six are biologics and another six are different combinations of MTX and biologics, including comparisons between ABT and ABT + MTX, ADA and ADA + MTX, CZP and CZP + MTX, ETN and ETN + MTX, GOL and GOL + MTX as well as TCZ and TCZ + MTX. It is easy to find that in most cases the efficacy and safety of a biological agent plus MTX are superior to the corresponding biologic agent alone. For example, the SUCRAs of efficacy and safety outcomes for ABT are as follows: 10.8% (ACR20), 23.9% (ACR50), 20% (ACR70), 14.8% (AEs) and 17.2% (SAEs). By contrast, ABT + MTX is more efficacious and safer with corresponding SUCRAs of 51%, 56.4%, 60.5%, 54.9% and 85.2%. Previous researchers have also conducted direct comparisons between biologic monotherapy and a biological agent combined with MTX. For instance, Klareskog et al. demonstrated that the proportions of RA patients achieving ACR20, ACR50 and ACR70 were higher under the treatment of ETN + MTX than the ETN monotherapy. At week 52, about 85%, 69%, 43% and 35% of patients in the ETN + MTX group achieved ACR20, ACR50, ACR70 and remission compared with 76%, 48%, 24% and 16% in the ETN groups [81], which is in line with our results.

However, a closer observation reveals that there is an exception. GOL + MTX performs better in all efficacy outcomes than GOL as the other treatments of a biologic agent plus MTX, while it performed worse in AEs and SAEs. There are also studies which presented a different conclusion. Some studies published before presented no difference between two kinds of treatment groups. Patients with RA treated with ETN and those treated with ETN + MTX were similar in ACR20, ACR50 and ACR70 (71.0% vs. 67.1%, 41.9% vs. 40.1% and 17.4% vs. 18.4%, respectively). The rates of adverse events and serious adverse events were also similar [82]. Maini et al. arrived at the same conclusion in the comparison between TCZ + MTX and TCZ [83]. Thus, further research should be conducted to estimate whether MTX benefits biologic monotherapy or not.

Although we have made the study as comprehensive as possible, there are still some limitations. Firstly, despite the fact that the inclusion trials were all RCTs, the results of efficacy and safety comparisons among 15 drug therapies still showed some statistical inconsistency. Perhaps the RCTs with contradictions between direct and indirect evidence should be reconsidered. Secondly, though disease durations of these interventions ranged from 14 weeks to 54 weeks, 16 of them only had a follow-up time of less than 20 weeks. A short duration is not enough to judge the safety of treatment [1]. Thirdly, medication dose, treatment cost, patient compliance and other influential factors also affected trial homogeneity. To some extent, the improvement in patients with RA is related to the dose of drugs, which was neglected in this study [83]. Last but not least, different RCTs included in our research had different definitions of safety outcomes. There is still a shortage of clear definition of AEs and SAEs.

In conclusion, we regard CZP + MTX as the optimal choice for RA patients in clinical practice and TCZ + MTX as an alternative treatment. Conversely, both ABT and cDMARDs are not recommended. It is necessary to conduct long-term studies on patients with RA in order to provide a more complete assessment of diverse treatments and make a more judicious choice in clinical practice. In other words, we ought not only take into account clinical parameters such as ACR response rates and safety outcomes, but should also consider medication dose, treatment cost, patient compliance and so on. All efforts should be made to improve the life quality and health standard for patients with RA.