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. 2019 Oct 17;7(10):1285–1303. doi: 10.1177/2050640619883566

Efficacy and safety of biologic agents and tofacitinib in moderate-to-severe ulcerative colitis: A systematic overview of meta-analyses

Katerina Pantavou 1, Anneza I Yiallourou 1, Daniele Piovani 2,3, Despo Evripidou 1, Silvio Danese 2,3, Laurent Peyrin-Biroulet 4, Stefanos Bonovas 2,3, Georgios K Nikolopoulos 1,✉
PMCID: PMC6894001  PMID: 31839954

Abstract

Background

Ulcerative colitis (UC) is an inflammatory disease of the colon and rectum. Treatment options include biologics and tofacitinib.

Objectives

We aim to summarize the evidence on efficacy and safety of biologics and tofacitinib in moderate-to-severe UC.

Methods

PubMed, Embase, Scopus, and the Cochrane Library were systematically searched to identify meta-analyses of randomized controlled trials assessing adalimumab, golimumab, infliximab, vedolizumab, and tofacitinib in UC. Efficacy outcomes included induction and maintenance of clinical response, clinical remission and mucosal healing. Safety outcomes included adverse events and serious adverse events.

Results

The overview involved 31 meta-analyses. All four biologics and tofacitinib were superior to placebo regarding efficacy. Indirect comparisons suggested that infliximab may be better than adalimumab and golimumab to induce clinical response and mucosal healing. Safety analyses indicated no increased rates of adverse events, except for infliximab.

Conclusions

Biologics and tofacitinib are efficacious and safe for treating UC. These findings can support clinical decision-making.

Keywords: anti-TNF, small molecule, inflammatory bowel disease, efficacy, adverse effect, serious adverse effect, ulcerative colitis

Introduction

Ulcerative colitis (UC) is an inflammatory disease of the colon and rectum with remissions and relapses. Although the causes of UC have not been fully elucidated yet, its etiology comprises genetic and environmental factors.1 UC is globally spread2 with a high economic burden, which necessitates further research on its etiology and treatment. For instance, in the United States, where the prevalence of UC is 286 per 100,000 persons,2 the total annual cost of the disease is between $8.1 and $14.9 billion.3 The highest prevalence of UC has been observed in a European setting (Norway: 505 per 100,000). The cost of UC in Europe ranges between €12.5 and €29.1 billion.3 UC is related with worsened quality of life, substantial morbidity and increased cancer risk.4

Biologic therapies that include tumor necrosis factor (TNF) antagonists (adalimumab, ADA; golimumab, GLM; infliximab, IFX) and anti-a4b7 antibody (vedolizumab, VDZ) have improved the management of UC patients5 compared with the conventional therapeutic approaches of 5-aminosalicylates, glucocorticoids and immunomodulators. Meanwhile, new treatment options are emerging. Tofacitinib (TFB), an orally administered small-molecule Janus kinase inhibitor, is a promising new medicine that has recently been approved by the regulatory authorities.

This work aims to systematically summarize the available evidence and provide an efficient overview of published meta-analyses (MAs) of randomized controlled trials (RCTs) on efficacy and safety of biologic agents and TFB, and hopefully to support clinical decision-making.

Materials and methods

Literature search

PubMed, Embase, Scopus and the Cochrane Library were systematically searched through December 2018. Search terms included: adalimumab, golimumab, infliximab, vedolizumab, tofacitinib, biologic(s), biologic(al) agent(s), ulcerative colitis and meta-analysis. Medical subject headings (MeSH) terms were also included. The search was limited to papers published in English and in international scientific journals. Conference abstracts were excluded as they usually present results of preliminary analyses, which later appear as full-text publications. The reference lists of the included MAs were screened to identify additional eligible publications that might have been missed by the electronic search.

Study selection

Eligible articles were MAs of RCTs that examined the efficacy and/or safety of biologic agents and TFB versus placebo for treatment of moderate-to-severe UC. MA should have reported the effect estimates for at least one of the efficacy outcomes, that is, clinical response, clinical remission, and mucosal healing and/or assessed safety based on any adverse event (AE) and serious adverse event (SAE), as defined in each MA. Both induction and maintenance phases were considered.

MAs of observational studies were not included as they provide a lower level of evidence than MAs of RCTs. As mentioned above, articles written in language other than English and conference abstracts were excluded.

Data selection and extraction

Two reviewers (KP and DE) independently screened titles and abstracts to identify potentially eligible MAs. Disagreements were resolved by consensus with a third reviewer (DP). Two reviewers (KP and DE) extracted the data from MAs; a third reviewer (AY) verified their accuracy. First author’s last name, journal, year of publication, PROSPERO ID, type of agent and doses, patients’ characteristics, outcomes examined, numbers of included RCTs and participants, estimated summary effect sizes along with the corresponding 95% confidence intervals (CI) or credible intervals (CrI), heterogeneity statistics, and statistics about small-study effects (p-value) were extracted from each MA. An I-square < 50% and Cochran’s Q statistic p > 0.10 were considered as evidence of no substantial heterogeneity. The conduct of tests for small-study effects requires that at least 10 studies are included in a MA.6,7 Nevertheless, if tests for small-study effects were performed in MAs that had involved fewer than 10 studies, we presented their associated p-values. A p < 0.10 indicated the presence of small-study effects. In all other cases, a p < 0.05 was considered as statistically significant.

Quality of meta-analyses

Two reviewers (KP and AY) assessed the methodologic quality of each MA included in this overview based on AMSTAR 2.8 AMSTAR 2 is an appraisal tool to assess systematic reviews of randomized trials and includes 16 items that combine several published guidelines on this issue (e.g. PRISMA, MOOSE). The AMSTAR 2 tool rates the overall confidence in a systematic review as high, moderate, low or critically low.

Results

Search results

The literature search yielded 766 records. In total, 31 MAs9–39 met the eligibility criteria (Figure 1). MAs of head-to-head trials were unavailable, hence we included network MAs presenting evidence from indirect comparisons. One study was in Chinese and excluded from the overview.40 All eligible MAs were published after 2006.14 Most MAs involved adult patients (≥18 years old) and patients naive to anti-TNF agents (Supplementary Table S1).

Figure 1.

Figure 1.

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Summary of the evidence search and selection process (flow chart).

The efficacy of biologic therapies in terms of clinical response, clinical remission and mucosal healing was studied in 28 MAs (Supplementary Table S1). Two MAs presented data only for safety.23,26 Four MAs9,20,29,38 examined the combined effect of biologics. Induction therapy was examined in 25 MAs, maintenance therapy in 19 MAs, and the combination of induction and maintenance phases in three.11,16,30 Primary maintenance studies considered in the included MAs that examined the efficacy and/or safety of golimumab and vedolizumab were restricted to induction responders who were re-randomized at the beginning of the study. This was not the case for adalimumab and infliximab trials.

Results of indirect comparisons between biologics were presented in 11 articles.9,10,15,17,22,24,29,31,34,35,39 These articles provided efficacy estimates for indirect comparisons for the induction phase, while nine articles9,10,15,17,22,29,31,34,39 did so also for the maintenance phase. AE were examined in 14 MAs and SAE in 19 MAs. Network MAs were reported in six articles.15,22–24,31,34

Tofacitinib was examined in four MAs12,24,31,34 (Supplementary Table S1). Clinical response was studied only when it was used as induction therapy.12,24

Most comparisons evaluated treatment effects using the odds ratio (OR) as the metric of choice. Relative risk (ReR) or Risk ratio (RiR) were also reported. One study17 used a probit link function to estimate the treatment effect based on the change of the probit score of the control arm.

Quality assessment of meta-analyses

The quality of the included MAs was assessed as low (eight MAs, 25.8%) and critically low (23 MAs, 74.2%) (Supplementary Table S2). Main critical flaws were the absence of a registered protocol for the MA (24 MAs, 77.4%) and of a list of the excluded studies with justification why these studies were not included in the MA (21 MAs, 67.7%).

Efficacy of biologics

Efficacy of biologics as induction therapy

Clinical response

Meta-analyses20,29 examining ADA, GLM, and IFX together in a direct comparison with placebo concluded that biologics were superior to placebo (Table 1A).

Table 1.

Characteristics of meta-analyses that studied the efficacy (compared with placebo) of biologic therapies, that is, adalimumab, golimumab, infliximab and vedolizumab, as induction therapy, in ulcerative colitis. Significant estimates (p < 0.05) are presented in bold.

Outcome/ Biologic therapy Subjects (n) Intervention group (n) Estimates and 95% CI Heterogeneity (I2 or p-value) Small- study effects
Author, year Dosage Trials (n)
A
Clinical response
ADA, GLM, IFX Lopez et al.,20 2015 ADA 160/80, 80/40 mg; GLM 400/200, 200/100, 100/50 mg; IFX 5 or 10 mg/kg 5 3637 1683 ReR, 1.54 (1.35–1.72) I2 = 70%, p = 0.0005 NA
Stidham et al.,29 2014 ADA 160/80/40 mg, GLM 200/100 mg, IFX 5 mg 5 1780 888 ReR, 1.65 (1.37–1.99) I2 = 64%, p = 0.025 p = 0.64
ADA Bonovas et al.,24 2018 160/80/40 mg 4 927 463 OR, 1.77 (1.36–2.29) I2 = 0%, p = 0.51 NA
Trigo-Vicente et al.,34 2018 160/80/40 mg 3 580 305 OR, 1.98 (1.43–2.76) NR NA
Chen et al.,36 2016 160/80 mg 3 940 468 RiR, 1.37 (1.19–1.59) I2 = 0%, p = 0.56 NA
Chen et al.,36 2016 80/40 mg 2 443 217 RiR, 1.17 (0.95-1.44) I2 = 0%, p = 0.86 NA
Vickers et al.,39 2016 160/80/40 mg 3 741 370 OR, 1.89 (1.41–2.50) a NR NA
Vickers et al.,39 2016 160/80/40 mg 1 199 98 OR, 1.43 (0.79–2.64)a,b NA NA
Zhang et al.,16 2016 160/80 or 80/40 mg 3 1157 685 ReR, 1.33 (1.16-1.52) I2 = 0%, p = 0.43 NA
Galván-Banqueri et al.,10 2015 160/80/40 mg 2 555 280 RiR, 1.37 (1.15–1.63) NR NA
Lopez et al.,20 2015 160/80 mg 2 754 378 ReR, 1.28 (1.14–1.47) I2 = 0%, p = 0.59 NA
Lopez et al.,20 2015 80/40 mg 1 260 130 ReR, 1.14 (0.90–1.45) NA NA
Mei et al.,22 2015 c 160/80 or 80/40 mg 3 1157 685 OR, 1.61 (1.22–2.07) NR NA
Yang et al.,19 2015 160/80 mg 2 754 378 RiR, 1.40 (1.19–1.65) I2 = 0%, p = 0.54 NA
Danese et al.,35 2014 160/80/40 mg 4 928 NR OR, 1.76 (1.19–2.56) a NR NA
Stidham et al.,29 2014 160/80/40 mg 2 778 388 ReR, 1.36 (1.13–1.64) I2 = 24.1%, p = 0.25 NA
Thorlund et al.,15 2014 160/80, or 160 mg 2 685 410 OR, 1.87 (1.18–2.97) a NR NA
GLM Bonovas et al.,24 2018 200/100 mg 3 644 324 OR, 2.13 (1.54–2.95) I2 = 1%, p = 0.37 NA
Trigo-Vicente et al.,34 2018 200/100 mg 1 761 510 OR, 2.59 (1.89–3.57) NA NA
Vickers et al.,39 2016 200/100 mg 1 513 257 OR, 2.54 (1.79–3.70) a NA NA
Galván-Banqueri et al.,10 2015 200/100 mg 1 513 257 RiR, 1.74 (1.40–2.18) NA NA
Lopez et al.,20 2015 400/200 mg 1 645 325 ReR, 1.49 (1.30–1.70) NA NA
Lopez et al.,20 2015 200/100 mg 1 645 325 ReR, 1.35 (1.09–1.54) NA NA
Lopez et al.,20 2015 100/50 mg 1 361 41 ReR, 1.56 (1.19–2.22) NA NA
Mei et al.,22 2015c 50, 100, 200/100 or 400/200, mg 2 1457 970 OR, 2.59 (1.83–3.73) NR NA
Danese et al.,35 2014 200/100 mg 3 662 NR OR, 2.11 (1.18–3.28) a NR NA
Kawalec et al.,25 2014 NR 2 1057 728 RiR, 1.69 (1.41–2.03) I2 = 38%, p = 0.20 NA
Stidham et al.,29 2014 200/100 mg 1 516 258 ReR, 1.75 (1.40–2.19) NA NA
IFX Bonovas et al.,24 2018 5 mg/kg 4 776 387 OR, 3.62 (2.46–5.33) I2 = 37%, p = 0.19 NA
Trigo-Vicente et al.,34 2018 3.5 mg/kg 3 568 283 OR, 4.07 (1.76–9.81) NR NA
Trigo-Vicente et al.,34 2018 5 mg/kg 1 82 41 OR, 4.15 (2.96–5.84) NA NA
Vickers et al.,39 2016 5 mg/kg 2 486 242 OR, 4.11 (2.84–6.10) a NR NA
Galván-Banqueri et al.,10 2015 5 mg/kg 2 486 242 RiR, 2.00 (1.64–2.44) NR NA
Mei et al.,22 2015c 5 or 10 mg/kg 2 728 484 OR, 3.96 (2.85–5.52) NR NA
Lopez et al.,20 2015 5 mg/kg 2 486 242 ReR, 2.00 (1.67–2.44) I2 = 0%, p = 0.88 NA
Lopez et al.,20 2015 10 mg/kg 2 486 242 ReR, 1.92 (1.37–2.70) I2 = 66%, p = 0.09 NA
Danese et al.,35 2014 5 mg/kg 2 486 NR OR, 4.13 (2.39–7.16) a NR NA
Stidham et al.,29 2014 5 mg/kg 2 486 242 ReR, 2.00 (1.64–2.44) I2 = 0%, p = 0.417 NA
Thorlund et al.,15 2014 5 or 10 mg 2 728 484 OR, 4.15 (2.53–6.82) a NR NA
Gisbert et al.,21 2007 5 or 10 mg/kg 4 782 515 OR, 3.60 (2.67–4.85) I2 = 17.6%, p = 0.30 NA
Gisbert et al.,21 2007 5 mg/kg 4 535 268 OR, 3.64 (2.59–5.11) I2 = 0%, p = 0.42 NA
Gisbert et al.,21 2007 10 mg/kg 3 492 245 OR, 3.61 (2.54–5.15) I2 = 35.1%, p = 0.21 NA
Lawson et al.,14 2006 5 or 10 mg/kg 2 728 484 RiR, 1.98 (1.54–2.56) I2 = 44.7%, p = 0.18 NA
VDZ Bonovas et al.,24 2018 300 mg 1 206 130 OR, 3.17 (1.71–5.86) NA NA
Trigo-Vicente et al.,34 2018 300 mg 1 374 225 OR, 2.63 (1.66–4.16) NA NA
Vickers et al.,39 2016 300 mg 1 206 130 OR, 3.17 (1.72–6.16) a NA NA
Vickers et al.,39 2016 300 mg 1 145 82 OR, 2.51 (1.18–5.48) a,b NA NA
Jin et al.,32 2015 0.5-10 mg/kg or 300 mg 3 1122 901 OR, 2.69 (1.94–3.74) I2 = 0%, p = 0.94 NA
Jin et al.,32 2015 2 mg/kg 2 144 72 OR, 2.25 (1.14–4.42) I2 = 0%, p = 0.89 NA
Jin et al.,32 2015 6 mg/kg 2 918 760 OR, 2.64 (1.79–3.88) I2 = 0%, p = 0.76 NA
Mei et al.,22 2015c 300 mg 1 895 746 OR, 2.64 (1.49–4.57) NA NA
Mosli et al.,27 2015 NR 3 601 380 RiR, 0.68 (0.59–0.78) d I2 = 0%, p = 0.64 NA
Danese et al.,35 2014 300 mg 1 206 NR OR, 3.23 (1.42–7.42) a NA NA
Kawalec et al.,25 2014 NR 2 555 343 RiR, 1.82 (1.43–2.31) I2 = 0%, p = 0.88 NA
Wang et al.,13 2014 0.5, 2, 6, 10 mg/kg or 300 mg 2 555 343 ReR, 1.82 (1.43–2.31) I2 = 0%, p = 0.88 NA
B
Clinical remission
ADA, GLM, IFX Lopez et al.,20 2015 ADA 160/80 or 80/40 mg; GLM 400/200, 200/100 or 100/50 mg; IFX 5 or 10 mg/kg 5 3914 1776 ReR, 1.18 (1.11–1.24) I2 = 76%, p < 0.0001 NA
Stidham et al.,29 2014 ADA 160/80/40 mg; GLM 200/100 mg; IFX 5 mg/kg 6 1823 911 ReR, 2.45 (1.72–3.47) I2 = 50.7%, p = 0.071 P = 0.44
ADA Bonovas et al.,24 2018 160/80/40 mg 4 927 463 OR, 1.89 (1.19–3.00) I2 = 19%, p = 0.30 NA
Singh et al.,31 2018 160/80/40 mg 3 741 370 OR, 1.80 (1.78–2.76) I2 = 35%, p = 0.21 NA
Singh et al.,31 2018 160/80/40 mg 1 199 98 OR, 1.36 (0.49–3.80)b NA NA
Trigo-Vicente et al.,34 2018 160/80/40 mg 4 766 395 OR, 1.95 (1.29–2.96) NR NA
Chen et al.,36 2016 160/80 mg 3 940 468 RiR, 1.62 (1.15–2.29) I2 = 25%, p = 0.27 NA
Chen et al.,36 2016 80/40 mg 2 443 217 RiR, 1.14 (0.67–1.94) I2 = 0%, p = 0.85 NA
Vickers et al.,39 2016 160/80/40 mg 3 741 370 OR, 1.82 (1.19–2.83) a NR NA
Vickers et al.,39 2016 NR 1 199 98 OR 1.37 (0.47–4.03)a,b NA NA
Zhang et al.,16 2016 160/80 or 80/40 mg 3 1157 685 ReR, 1.50 (1.08–2.09) I2 = 0%, p = 0.45 NA
Galván-Banqueri et al.,10 2015 160/80/40 mg 2 555 280 RiR, 1.96 (1.29–2.99) NR NA
Lopez et al.,20 2015 160/80 mg 2 939 471 ReR, 1.10 (1.04–1.15) I2 = 0%, p = 0.78 NA
Lopez et al.,20 2015 80/40 mg 1 352 130 ReR, 1.03 (0.96–1.10) NA NA
Mei et al.,22 2015d 160/80 or 80/40 mg 3 1157 685 OR, 1.50 (0.93–2.37) NR NA
Yang et al.,19 2015 160/80 mg 2 754 378 RiR, 1.85 (1.26–2.72) I2 = 0%, p = 0.76 NA
Danese et al.,35 2014 160/80/40 mg 4 928 NR OR, 1.91 (0.98–3.72)a NR NA
Stidham et al.,29 2014 160/80/40 mg 2 778 388 ReR, 1.87 (1.27–2.75) I2 = 0%, p = 0.794 NA
Thorlund et al.,15 2014 160/80 or 160 mg 2 685 410 OR, 2.22 (1.23–3.98) a NR NA
GLM Bonovas et al.,24 2018 200/100 mg 3 644 324 OR, 2.80 (1.67–4.67) I2 = 0%, p = 0.72 NA
Singh et al.,31 2018 200/100 mg 2 644 324 OR, 2.81 (1.69–4.69) I2 = 0%, p = 0.42 NA
Trigo-Vicente et al.,34 2018 200/100 mg 1 761 510 OR, 3.24 (1.80–6.06) NA NA
Vickers et al.,39 2016 200/100 mg 1 513 257 OR, 3.54 (2.00–6.56) a NA NA
Galván-Banqueri et al.,10 2015 200/100 mg 1 513 257 RiR, 2.99 (1.74–5.12) NA NA
Lopez et al.,20 2015 400/200 mg 1 645 325 ReR, 1.15 (1.09–1.24) NA NA
Lopez et al.,20 2015 200/100 mg 1 645 325 ReR, 1.12 (1.06–1.20) NA NA
Lopez et al.,20 2015 100/50 mg 1 361 41 ReR, 1.12 (0.97–1.28) NA NA
Mei et al.,22 2015c 50, 100, 200/100, or 400/200 mg 2 1457 685 OR, 3.24 (1.720–6.28) NR NA
Danese et al.,35 2014 200/100 mg 3 662 NR OR, 2.90 (1.19–6.54) a NR NA
Kawalec et al.,25 2014 NR 2 1057 728 ReR, 1.95 (0.81–4.68) I2 = 74%, p = 0.05 NA
Stidham et al.,29 2014 200/100 mg 1 516 258 ReR, 3.00 (1.75–5.14) NA NA
IFX Motaghi et al.,37 2019 3.5 or 5 mg/kg 5 858 428 OR, 3.99 (2.80–5.68) I2 = 28%, p = 0.24 NA
Bonovas et al.,24 2018 5 mg/kg 4 776 387 OR, 3.97 (2.32–6.79) I2 = 46%, p = 0.14 NA
Singh et al.,31 2018 5 mg/kg 4 667 333 OR, 4.22 (2.80–6.35) I2 = 30%, p = 0.23 NA
Trigo-Vicente et al.,34 2018 3.5 mg/kg 3 82 41 OR, 4.02 (1.79–9.20) NR NA
Trigo-Vicente et al.,34 2018 5 mg/kg 1 593 308 OR, 4.59 (3.06–6.98) NA NA
Vickers et al.,39 2016 5 mg/kg 2 486 242 OR, 5.12 (3.18–8.58) a NR NA
Lopez et al.,20 2015 5 mg/kg 2 486 242 ReR, 1.41 (1.26–1.56) I2 = 0%, p = 0.82 NA
Lopez et al.,20 2015 10 mg/kg 2 486 242 ReR, 1.28 (1.16–1.41) I2 = 0%, p = 0.68 NA
Galván-Banqueri et al.,10 2015 5 mg/kg 2 486 242 RiR, 3.30 (2.19–4.96) NR NA
Mei et al.,22 2015d 5 or 10 mg/kg 2 728 484 OR, 4.48 (2.85–7.54) NR NA
Danese et al.,35 2014 5 mg/kg 2 486 NR OR, 5.33 (2.28–13.63) NR NA
Stidham et al.,29 2014 5 mg/kg 3 529 265 ReR, 2.76 (1.29–5.90) I2 = 72.8%, p = 0.025 NA
Thorlund et al.,15 2014 5 or 10 mg/kg 2 728 484 OR, 5.26 (2.94–9.99) a NR NA
Nikfar et al.,33 2011 5 or 10 mg/kg 5 827 292 ReR, 1.93 (1.62–2.30) NR, p = 0.410 NA
Ford et al.,18 2011 NR 5 827 539 ReR, 1.39 (1.10–1.75) I2 = 70%, p = 0.009 NA
Gisbert et al.,21 2007 5 or 10 mg/kg 2 728 484 OR, 4.56 (1.98–10.52) I2 = 65.5%, p = 0.09 NA
Gisbert et al.,21 2007 5 mg/kg 2 486 242 OR, 5.28 (2.30–12.09) I2 = 60.3%, p = 0.11 NA
Gisbert et al.,21 2007 10 mg/kg 2 486 244 OR, 3.90 (1.70–8.93) I2 = 59.2%, p = 0.12 NA
Lawson et al.,14 2006 5 or 10 mg/kg 2 728 484 ReR, 3.40 (1.51–7.67) I2 = 72%, p = 0.06 NA
Lawson et al.,14 2006 5 mg/kg 2 486 242 ReR, 3.54 (2.36, 5.31) NR NA
Lawson et al.,14 2006 5 or 10 mg/kg 1 45 24 RiR, 2.63 (0.59–11.64) at 3 months NA NA
Lawson et al.,14 2006 5 or 10 mg/kg 1 43 23 ReR, 1.30 (0.56, 3.03) at 6 weeks NA NA
VDZ Bonovas et al.,24 2018 300 mg 1 206 130 OR, 4.26 (1.58–11.52) NA NA
Lasa et al.,28 2018 0.5, 2 mg/kg or 300 mg 2 555 343 ReR, 0.85 (0.77–0.94) d I2 = 35%, p = 0.22 NA
Singh et al.,31 2018 300 mg 1 206 130 OR, 4.26 (1.58–11.52) NA NA
Singh et al.,31 2018 300 mg 1 145 82 OR, 3.30 (0.68–16.11)b NA NA
Trigo-Vicente et al.,34 2018 300 mg 1 374 225 OR, 3.72 (1.76–9.06) NA NA
Vickers et al.,39 2016 300 mg 1 206 130 OR, 4.42 (1.72–14.00) a NA NA
Vickers et al.,39 2016 NR 1 145 82 OR, 3.66 (0.87–27.98)a,b NA NA
Jin et al.,32 2015 0.5-10 mg/kg or 300 mg 3 1122 901 OR, 2.72 (1.76–4.19) I2 = 14.4%, p = 0.31 NA
Mei et al.,22 2015c 300 mg 1 895 746 OR, 3.72 (1.31–11.19) NA NA
Mosli et al.,27 2015 NR 4 606 382 RiR, 0.86 (0.80–0.91) d I2 = 0%, p = 0.57 NA
Danese et al.,35 2014 300 mg 1 206 NR OR, 4.51 (1.13–20.76) NA NA
Kawalec et al.,25 2014 NR 2 555 343 ReR, 2.66 (1.63–4.34) I2 = 0%, p = 0.51 NA
Wang et al.,13 2014 0.5, 2, 6, 10 mg/kg or 300 mg 3 578 362 ReR, 2.23 (1.35–3.68) I2 = 19%, p = 0.29 NA
C
Clinical response/remission
ADA Archer et al.,17 2016 160/80 mg 2 1274 788 PS, –0.40 (–0.76 to –0.04) a NR NA
GLM Archer et al.,17 2016 200/100 mg 1 404 73 PS, –0.49 (–0.97 to –0.01) a NA NA
IFX Archer et al.,17 2016 5 mg/kg 3 956 506 PS, –0.92 (–1.27 to –0.56) a NR NA
D
Mucosal healing
ADA, GLM, IFX, VDZ Cholapranee et al.,9 2017 Commonly used in clinical practice or approved by FDA 7 2304 1188 OR, 1.99 (1.53–2.58) I2 = 53.7%, p = 0.044 NA
ADA, GLM, IFX Lopez et al.,20 2015 ADA 160/80, 80/40 mg; GLM 400/200, 200/100, 100/50 mg; IFX 5, 10 mg/kg 5 3637 1683 ReR, 1.33 (1.19–1.52) I2 = 75%, p < 0.0001 NA
ADA Bonovas et al.,24 2018 160/80/40 mg 4 927 463 OR, 1.63 (1.25–2.13) I2 = 0%, p = 0.64 NA
Singh et al.,31 2018 160/80/40 mg 3 741 370 OR, 1.58 (1.18–2.12) I2 = 0%, p = 0.48 NA
Singh et al.,31 2018 160/80/40 mg 1 199 98 OR, 1.10 (0.59–2.04)b NA NA
Thorlund et al.,15 2014 160/80 or 160 mg 2 685 410 OR, 1.51 (0.96–2.39)a NR NA
Trigo-Vicente et al.,34 2018 160/80/40 mg 3 580 305 OR, 1.61 (1.16–2.23) NR NA
Cholapranee et al.,9 2017 Commonly used in clinical practice or approved by FDA 3 940 468 OR, 1.49 (1.04–2.16) NR NA
Chen et al.,36 2016 160/80 mg 3 940 468 RiR, 1.27 (1.08–1.50) I2 = 0%, p = 0.52 NA
Chen et al.,36 2016 80/40 mg 2 443 217 RiR, 1.04 (0.82–1.32) I2 = 48%, p = 0.17 NA
Vickers et al.,39 2016 160/80/40 mg 3 741 370 OR, 1.53 (1.14–2.07) a NR NA
Vickers et al.,39 2016 160/80/40 mg 1 199 98 OR, 1.09 (0.60–2.10)a,b NA NA
Zhang et al.,16 2016 160/80 or 80/40 mg 3 1157 685 ReR, 1.21 (1.04–1.41) I2 = 27%, p = 0.25 NA
Galván-Banqueri et al.,10 2015 160/80/40 mg 2 555 280 RiR, 1.26 (1.04–1.53) NR NA
Lopez et al.,20 2015 160/80 mg 2 754 378 ReR, 1.15 (1.02–1.28) I2 = 0%, p = 0.69 NA
Lopez et al.,20 2015 80/40 mg 1 260 130 ReR, 1.07 (0.88–1.30) NA NA
Mei et al.,22 2015 80/40 or 160/80 mg 3 1157 685 OR, 1.33 (1.02–1.74) NR NA
Yang et al.,19 2015 160/80 mg 2 754 378 RiR, 1.23 (1.03–1.47) I2 = 0%, p = 0.45 NA
Danese et al.,35 2014 160/80/40 mg 4 928 NR OR, 1.64 (1.18–2.31) a NR NA
GLM Bonovas et al.,24 2018 200/100 mg 3 644 324 OR, 1.74 (1.25–2.42) I2 = 0%, p = 0.84 NA
Singh et al.,31 2018 200/100 mg 2 644 324 OR, 1.74 (1.25–2.41) I2 = 0%, p = 0.60 NA
Trigo-Vicente et al.,34 2018 200/100 mg 1 761 510 OR, 1.94 (1.40–2.70) NA NA
Cholapranee et al.,9 2017 Commonly used in clinical practice or approved by FDA 1 504 253 OR, 1.83 (1.05–3.20) NA NA
Vickers et al.,39 2016 200/100 mg 1 513 257 OR, 1.91 (1.33–2.73) a NA NA
Galván-Banqueri et al.,10 2015 200/100 mg 1 513 257 RiR, 1.51 (1.19–1.92) NA NA
Lopez et al.,20 2015 400/200 mg 1 645 325 ReR, 1.30 (1.15–1.47) NA NA
Lopez et al.,20 2015 200/100 mg 1 645 325 ReR, 1.22 (1.09–1.37) NA NA
Lopez et al.,20 2015 100/50 mg 1 361 41 ReR, 1.32 (0.98–1.75) NA NA
Mei et al.,22 2015d 50, 100, 200/100 or 400/200, mg 2 1457 685 OR, 1.94 (1.37–2.77) NR NA
Danese et al.,35 2014 200/100 mg 3 662 NR OR, 1.84 (1.18–2.81) a NR NA
Kawalec et al.,25 2014 NR 1 771 515 ReR, 1.55 (1.25–1.93) NA NA
IFX Bonovas et al.,24 2018 5 mg/kg 4 776 387 OR, 3.05 (2.26–4.10) I2 = 0%, p = 0.59 NA
Singh et al.,31 2018 5 mg/kg 4 667 333 OR, 3.32 (2.39–4.59) I2 = 0%, p = 0.90 NA
Trigo-Vicente et al.,34 2018 3.5 mg/kg 3 82 41 OR, 3.36 (1.55–7.55) NA NA
Trigo-Vicente et al.,34 2018 5 mg/kg 1 593 308 OR, 3.24 (2.32–4.55) NA NA
Cholapranee et al.,9 2017 Commonly used in clinical practice or approved by FDA 2 486 242 OR, 3.34 (2.06–5.37) NR NA
Vickers et al.,39 2016 5 mg/kg 2 486 242 OR, 3.42 (2.00–5.94) a NR NA
Galván-Banqueri et al.,10 2015 5 mg/kg 2 486 242 RiR, 1.88 (1.53–2.32) NR NA
Lopez et al.,20 2015 5 mg/kg 2 486 242 ReR, 1.75 (1.45–2.08) I2 = 0%, p = 0.99 NA
Lopez et al.,20 2015 10 mg/kg 2 486 242 ReR, 1.69 (1.43–2.04) I2 = 0%, p = 0.54 NA
Mei et al.,22 2015c 5 or 10 mg/kg 2 728 484 OR, 3.24 (2.39–4.44) NR NA
Danese et al.,35 2014 5 mg/kg 2 486 NR OR, 3.31 (2.07–5.32) NR NA
Thorlund et al.,15 2014 5 or 10 mg 2 728 484 OR, 3.26 (2.21–0.84) a,e NR NA
VDZ Bonovas et al.,24 2018 300 mg 1 206 130 OR, 2.91 (1.56–5.42) NA NA
Lasa et al.,28 2018 0.5, 2 mg/kg or 300 mg 2 555 343 ReR, 0.84 (0.74–0.94) d NR NA
Singh et al.,31 2018 300 mg 1 206 130 OR, 2.91 (1.56–5.42) NA NA
Singh et al.,31 2018 300 mg 1 145 82 OR, 1.69 (0.78–3.64)b NA NA
Trigo-Vicente et al.,34 2018 300 mg 1 374 225 OR, 2.10 (1.35–3.34) NA NA
Cholapranee et al.,9 2017 NR 1 374 225 OR, 2.11 (1.14–3.93) NA NA
Vickers et al.,39 2016 300 mg 1 206 130 OR, 2.97 (1.59–5.37) a NA NA
Vickers et al.,39 2016 300 mg 1 145 82 OR, 1.70 (0.80–3.81)a,b NA NA
Mei et al.,22 2015c 300 mg 1 895 746 OR, 2.10 (1.21–3.71) NA NA
Kawalec et al.,25 2014 NR 2 555 343 ReR, 1.75 (1.29–2.37) I2 = 0%, p = 0.42 NA
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ADA and GLM were administered subcutaneously (SC) and IFX and VDZ intravenously (IV).

ADA: adalimumab; CI: confidence interval; FDA: United States Food and Drug Administration; GLM: golimumab; IFX: infliximab; NA: non-applicable; NR: not reported; OR: odds ratio; PS: probit score; ReR: relative risk; RiR: risk ratio; p, p-value; VDZ: vedolizumab.

a

CrI, credible interval.

b

Patients with prior exposure to anti-TNF agents.

c

The presented odds ratios in the study of Mei et al. 201522 are for the opposite associations (i.e. for example infliximab vs. placebo – not placebo vs. infliximab).

d

Failure to induce or maintain clinical response or remission.

e

The upper boundary of the credible interval is misprinted in the original publication.

ADA was individually examined in 12 MAs. The summary estimates showed that ADA is significantly better than placebo for dosages other than 80/40 mg subcutaneous (SC) (range of effect estimate: 1.28–1.98). Nine MAs studied the efficacy of GLM, 11 of IFX for intravenous use (IV), and nine of VDZ. All three biologics demonstrated superiority over placebo in all dosages (Table 1A). Most indirect comparisons did not reach statistical significance (Supplementary Table S3). However, the indirect comparisons in the included MAs showed that IFX was significantly better than ADA (range of effect estimate: 1.46–2.44) and GLM (range of effect estimate: 1.60–1.67) (Supplementary Table S3).

Clinical remission

ADA, GLM and IFX were examined together in two MAs.20,29 The results were statistically significant favoring these biologic agents over placebo (Table 1B).

The efficacy of ADA was investigated in 13 MAs. ADA administration improved clinical remission compared with placebo in most of these MAs (range of effect estimate: 1.10–2.22). Non-significant summary estimates were mainly obtained when only patients with prior exposure to anti-TNF agents were considered,31,39 the number of participants was low,20,31,36 or a dosage of 80/40 mg SC was administered.20,22,36

GLM attained significant improvements in remission rates compared with placebo in most of the 10 MAs (range of effect estimate: 1.12–3.54). Fifteen MAs examined the efficacy of IFX indicating superiority over placebo (range of effect estimate: 1.28–5.33). VDZ was also found to be more effective than placebo in 11 MAs, except for UC patients with prior exposure to biologics (range of effect estimate: 1.18–4.51). The highest magnitude of effect was observed for IFX (Table 1B). However, most indirect comparisons did not reach statistical significance (Supplementary Table S3). About half of the MAs showed that IFX was significantly better than ADA (range of effect estimate: 2.10–3.03).

Clinical response/remission

One MA17 examined the effect of ADA, GLM and IFX on clinical response and remission together. All three biologics were associated with beneficial treatment effects compared with placebo (Table 1C). The indirect comparisons did not show statistically significant differences (Supplementary Table S3).

Mucosal healing

Two MAs9,20 examined the efficacy of all biologics together, showing superiority over placebo (Table 1D). Summary effect estimates for ADA alone were reported in 13 MAs (17 comparisons). Of these, 12 comparisons showed that ADA was superior to placebo (range of effect estimate: 1.15–1.64). All comparisons in 10 MAs showed the superiority of GLM over placebo in terms of mucosal healing in the induction phase (range of effect estimate: 1.22–1.94), except for one comparison that was based on a dosage of 100/50 mg SC.20 IFX comparisons with placebo for dosages 5 or 10 mg/kg IV indicated the superiority of the active comparator (range of effect estimate: 1.69–3.42). VDZ was significantly better than placebo in eight of 10 comparisons presented in eight MAs (range of effect estimate: 1.19–2.97). The two non-significant comparisons31,39 considered only UC patients with prior exposure to anti-TNF agents.

Nine of the 10 indirect comparisons indicated the superiority of IFX over ADA and four of nine comparisons suggested that IFX was better than GLM (Supplementary Table S3).

Measures of heterogeneity and small-study effects

Several MAs9,13,14,16,18–20,24,25,27,29,31–33,35–39 provided heterogeneity assessment. Most comparisons versus placebo did not show substantial heterogeneity16,24,32,36 (Table 1A–D). In many cases, MAs included only one study or fewer than 10 studies, thus tests for small-study effects were not applicable.

Efficacy of biologics as maintenance therapy

Clinical response

MAs20,29 that examined biologics together found that biologics were superior to placebo (Table 2A).

Table 2.

Characteristics of meta-analyses that studied the efficacy (compared to placebo) of biologic therapies, i.e. adalimumab, golimumab, infliximab, and vedolizumab, as maintenance therapy, in ulcerative colitis. Significant estimates (p < 0.05) are presented in bold.

Outcome/ Biologic therapy Subjects (n) UC cases (n) Estimates and 95% CI Heterogeneity (I2 or p-value) Small- study effects
Author, year Dosage Trials (n)
A
Clinical response
ADA, IFX Lopez et al.,20 2015 NR 2 858 491 ReR, 1.30 (1.05–1.61) I2 = 83%, p = 0.02 NA
ADA, GLM, IFX Stidham et al.,29 2014 ADA 40 mg; GLM 100, mg; IFX 5 mg/kg 3 1070 533 ReR, 1.76 (1.46–2.14) I2 = 3.5%, p = 0.355 P = 0.27
ADA Bonovas et al.,24 2018 40 mg 2 481 240 OR, 1.91 (1.27–2.87) I2 = 0%, p = 0.74 NA
Chen et al.,36 2016 40 mg 2 767 425 RiR, 1.69 (1.29–2.21) I2 = 0%, p = 0.84 NA
Archer et al.,17 2016 160/80 mg 1 1379 1023 PS, –0.03(–0.76–0.68)a,b NA NA
Archer et al.,17 2016 160/80 mg NR NR NR PS, 0.31 (–0.58–1.27)a,c NR NA
Vickers et al.,39 2016 40 mg 2 261 171 OR, 1.33 (0.77–2.22)a,d NR NA
Vickers et al.,39 2016 40 mg 1 65 29 OR, 2.47 (0.90–6.99)a,e NA NA
Zhang et al.,16 2016 160/80 or 80/40 mg 2 767 425 ReR, 1.69 (1.29–2.21) I2 = 0%, p = 0.84 NA
Galván-Banqueri et al.,10 2015 40 mg 1 295 150 RiR, 1.52 (1.06–2.17) NA NA
Lopez et al.,20 2015 NR 1 NR NR ReR, 1.18 (1.06–1.30) NA NA
Mei et al.,22 2015f 40 mg 2 767 425 OR, 1.98 (1.22–3.23) NR NA
Danese et al.,35 2014 40 mg 2 NR NR OR, 1.90 (1.27–2.86) NR NA
Stidham et al.,29 2014 40 mg 1 518 258 ReR, 1.68 (1.21–2.33) NA NA
Thorlund et al.,15 2014 160/80 or 160 mg 1 295 150 OR, 1.81 (1.09–3.05) a NA NA
GLM Bonovas et al.,24 2018 100 mg 2 368 183 OR, 2.93 (1.28–6.71) I2 = 52%, p = 0.15 NA
Archer et al.,17 2016 50 mg NR NR NR PS, –0.31(–0.97–0.30)a,b NR NA
Archer et al.,17 2016 100 mg NR NR NR PS, –0.42 (–1.06–0.21)a,b NR NA
Archer et al.,17 2016 50 mg NR NR NR PS, –0.17 (–1.01–0.69)a,c NR NA
Archer et al.,17 2016 100 mg NR NR NR PS, 0.20 (–0.63–1.03)a,c NR NA
Vickers et al.,39 2016 100 mg 1 309 153 OR, 2.27 (1.39–3.60) a NA NA
Mei et al.,22 2015e 50 or 100 mg 1 464 308 OR, 2.08 (1.30–3.30) NA NA
Danese et al.,35 2014 100 mg 1 NR NR OR, 2.24 (1.41–3.56) NA NA
Kawalec et al.,25 2014 NR 1 463 307 ReR, 1.56 (1.20–2.01) NA NA
Stidham et al.,29 2014 100 mg 1 310 154 ReR, 1.61 (1.22–2.13) NA NA
IFX Bonovas et al.,24 2018 5 mg/kg 4 776 387 OR, 2.76 (1.90–4.00) I2 = 30%, p = 0.23 NA
Archer et al.,17 2016 5 mg/kg 3 956 712 PS, –0.24 (–0.78–0.29)a,b NR NA
Archer et al.,17 2016 5 mg/kg NR NR NR PS, –0.36 (–1.33–0.62)a,c NR NA
Vickers et al.,39 2016 5 mg/kg 1 129 84 OR, 1.66 (0.79–3.50)a NA NA
Galván-Banqueri et al.,10 2015 5 mg/kg 1 242 121 RiR, 2.29 (1.52–3.45) NA NA
Lopez et al.,20 2015 NR 1 NR NR ReR, 1.45 (1.26–1.67) NA NA
Mei et al.,22 2015f 5 or 10 mg/kg 2 728 484 OR, 3.33 (1.96–5.66) NR NA
Danese et al.,35 2014 5 mg/kg 2 NR NR OR, 2.89 (1.96–4.28) NR NA
Stidham et al.,29 2014 5 mg/kg 1 242 121 ReR, 2.29 (1.52–3.45) NA NA
Thorlund et al.,15 2014 5 or 10 mg/kg 1 364 243 OR, 3.39 (1.94–6.06) a NA NA
Gisbert et al.,21 2007 5 or 10 mg/kg 3 773 508 OR, 3.40 (2.52–4.59) I2 = 0%, p = 0.76 NA
Gisbert et al.,21 2007 5 mg/kg 3 531 266 OR, 2.92 (2.05–4.16) I2 = 0%, p = 0.62 NA
Gisbert et al.,21 2007 10 mg/kg 3 531 266 OR, 3.59 (2.52–5.10) I2 = 0%, p = 0.73 NA
VDZ Bonovas et al.,24 2018 300 mg 1 151 72 OR, 5.19 (2.59–10.42) NA NA
Vickers et al.,39 2016 300 mg 1 151 72 OR, 5.27 (2.68–11.00) a NA NA
Vickers et al.,39 2016 NR 1 81 43 OR, 4.89 (1.74–15.89) a,e NA NA
Mei et al.,22 2015f 300 mg 1 895 746 OR, 3.83 (2.34–6.52) NA NA
Mosli et al.,27 2015 NR 4 373 247 RiR, 2.73 (1.78–4.18) f NR NA
Danese et al.,35 2014 300 mg at 0 and 2 wk and every 8 wk thereafter 1 NR NR OR, 3.54 (1.79–6.99) NA NA
Danese et al.,35 2014 300 mg at 0 and 2 wk and every 4 wk thereafter 1 NR NR OR, 5.19 (2.59–10.42) NA NA
Wang et al.,13 2014 0.5, 2, 6 or 10 mg/kg, 300 mg 2 NR NR ReR, 2.22 (1.62–3.05) I2 = 0%, p = 0.65 NA
B
Clinical remission
ADA, IFX Lopez et al.,20 2015 NR 2 858 491 ReR, 1.18 (1.02–1.35) I2 = 77%, p = 0.04 NA
ADA, IFX Lv et al.,38 2014 160/80/40 mg; 5 or 10 mg/kg 3 1222 732 ReR, 2.29 (1.73–3.03) I2 = 0%, p = 0.57 NA
ADA, GLM, IFX Stidham et al.,29 2014 ADA 40 mg; GLM 100, mg; IFX 5 mg/kg 3 1070 533 ReR, 2.00 (1.52–2.62) I2 = 0%, p = 0.921 P = 0.59
ADA Bonovas et al.,24 2018 40 mg 2 481 240 OR, 2.31 (1.37–3.87) I2 = 0%, p = 0.41 NA
Singh et al.,31 2018 160/80/40 mg 2 568 327 OR, 2.59 (1.58–4.27) I2 = 34%, p = 0.22 NA
Trigo-Vicente et al.,34 2018 160/80/40 mg 2 680 338 OR, 2.35 (1.41–4.02) NR NA
Archer et al.,17 2016 160/80 mg NR NR NR PS, 0.19 (–0.75–1.09)a,b NR NA
Archer et al.,17 2016 160/80 mg NR NR NR PS, –1.04 (–1.93 to –1.02) a,c NR NA
Chen et al.,36 2016 40 mg 2 767 425 RiR, 2.38 (1.57–3.59) I2 = 0%, p = 0.33 NA
Vickers et al.,39 2016 40 mg 2 261 171 OR, 1.97 (1.13–3.50) a NR NA
Vickers et al.,39 2016 40 mg 1 65 29 OR, 3.60 (1.01–18.23) a,e NA NA
Zhang et al.,16 2016 160/80 or 80/40 mg 2 767 425 ReR, 2.38 (1.57–3.59) I2 = 0%, p = 0.33 NA
Galván-Banqueri et al.,10 2015 40 mg 1 295 150 RiR, 1.77 (1.05–3.00) NA NA
Mei et al.,22 2015f 40 mg 2 767 425 OR, 2.85 (0.93–9.47) NR NA
Lopez et al.,20 2015 NR 1 294 248 ReR, 1.11 (1.15–1.19) NR NA
Danese et al.,35 2014 40 mg 2 NR NR OR, 2.30 (1.37–3.86) NA NA
Lv et al.,38 2014 160/80/40 mg 1 494 248 ReR, 2.03 (1.24–3.32) NA NA
Stidham et al.,29 2014 40 mg 1 518 258 ReR, 2.06 (1.26–3.38) NA NA
Thorlund et al.,15 2014 160/80 or 160 mg 1 295 150 OR, 1.99 (1.08–3.89) a NA NA
GLM Bonovas et al.,24 2018 100 mg 2 368 183 OR, 4.44 (0.58–34.22) I2 = 84%, p = 0.01 NA
Singh et al.,31 2018 100 mg 2 373 186 OR, 2.89 (1.74–4.82) d I2 = 79%, p = 0.03
Trigo-Vicente et al.,34 2018 50 mg 1 519 334 OR, 1.75 (1.04–2.92) NA NA
Trigo-Vicente et al.,34 2018 100 mg 1 519 334 OR, 1.81 (1.10–3.00) NA NA
Archer et al.,17 2016 50 mg NR NR NR PS, –0.63 (–1.36–0.11)a,b NR NA
Archer et al.,17 2016 100 mg NR NR NR PS, –0.61 (–1.32–0.11)a,b NR NA
Archer et al.,17 2016 50 mg NR NR NR PS, 0.05 (–0.80–0.89)a,c NR NA
Archer et al.,17 2016 100 mg NR NR NR PS, –0.16 (–1.00– 0.69)a,c NR NA
Vickers et al.,39 2016 100 mg 1 309 153 OR, 1.79 (1.09–3.04) a NA NA
Galván-Banqueri et al.,10 2015 50 mg 1 305 154 RiR, 1.50 (1.03–2.18) NA NA
Galván-Banqueri et al.,10 2015 100 mg 1 305 154 RiR, 1.53 (1.06–2.22) NA NA
Mei et al.,22 2015e 50 or 100 mg 1 464 308 OR, 1.87 (0.59–5.79) NA NA
Danese et al.,35 2014 100 mg 1 NR NR OR, 1.81 (1.10–3.00) NA NA
Kawalec et al.,25 2014 NR 1 463 307 ReR, 1.51 (1.08–2.10) NA NA
Stidham et al.,29 2014 100 mg 1 310 154 ReR, 1.86 (1.19–2.90) NA P = 0.59
IFX Bonovas et al.,24 2018 5 mg/kg 4 776 387 OR, 2.37 (1.63–3.44) I2 = 8%, p = 0.35 NA
Singh et al.,31 2018 5 mg/kg 3 675 333 OR, 3.05 (2.07–4.49) I2 = 0%, p = 0.89 NA
Trigo-Vicente et al.,34 2018 5 mg/kg 1 242 121 OR, 2.72 (1.48–5.10) NA NA
Archer et al.,17 2016 5 mg/kg NR NR NR PS, –0.11 (–0.78–0.56)a,b NR NA
Archer et al.,17 2016 5 mg/kg NR NR NR PS, –0.24 (–1.21–0.75)a,c NR NA
Vickers et al.,39 2016 5 mg/kg 1 129 84 OR, 1.24 (0.61–2.67)a NA NA
Galván-Banqueri et al.,10 2015 5 mg/kg 1 242 121 RiR, 2.10 (1.31–3.36) NA NA
Lopez et al.,20 2015 NR 1 NR NR ReR, 1.28 (1.14–1.45) NA NA
Mei et al.,22 2015f 5 or 10 mg/kg 2 728 484 OR, 2.70 (0.86–8.43) NR NA
Danese et al.,35 2014 5 mg/kg 2 NR NR OR, 2.78 (1.75–4.41) NR NA
Stidham et al.,29 2014 5 mg/kg 1 242 121 ReR, 2.10 (1.31–3.36) NA NA
Thorlund et al.,15 2014 5 or 10 mg/kg 1 364 243 OR, 2.73 (1.50–5.14) a NA NA
Gisbert et al.,21 2007 5 or 10 mg/kg 2 728 484 OR, 2.72 (1.92–3.86) I2 = 0%, p = 0.59 NA
Gisbert et al.,21 2007 5 mg/kg 2 486 242 OR, 2.61 (1.69–4.03) I2 = 0%, p = 0.83 NA
Gisbert et al.,21 2007 10 mg/kg 2 486 242 OR, 3.22 (2.13–4.87) I2 = 22.7%, p = 0.26 NA
VDZ Bonovas et al.,24 2018 300 mg 1 151 72 OR, 3.61 (1.74–7.48) NA NA
Singh et al.,31 2018 300 mg 1 251 125 OR, 4.30 (2.38–7.79) e NA NA
Trigo-Vicente et al.,34 2018 300 mg 1 248 122 OR, 3.84 (2.13–7.15) NR NA
Vickers et al.,39 2016 300 mg 1 151 72 OR, 3.63 (1.75–7.72) a NA NA
Vickers et al.,39 2016 NR 1 81 43 OR, 12.14 (3.14–78.38) a,e NA NA
Mei et al.,22 2015f 300 mg 1 895 746 OR, 2.31 (0.71–7.04) NA NA
Danese et al.,35 2014 300 mg at 0 and 2 wk and every 8 wk thereafter 1 NR NR OR, 3.93 (1.90–8.12) NA NA
Danese et al.,35 2014 300 mg at 0 and 2 wk and every 4 wk thereafter 1 NR NR OR, 3.61 (1.74–7.48) NA NA
Kawalec et al.,25 2014 NR 1 373 247 ReR, 2.73 (1.78–4.18) NA NA
Wang et al.,13 2014 0.5, 2, 6, 10 mg/kg or 300 mg 2 NR NR ReR, 2.51 (1.70–3.72) I2 = 0%, p = 0.32 NA
C
Mucosal healing
ADA, GLM, IFX, VDZ Cholapranee et al.,9 2017 Commonly used in clinical practice or approved by FDA 5 1567 822 OR, 2.59 (1.84–3.66) I2 = 51.4%, p = 0.084 NA
ADA, IFX Lopez et al.,20 2015 NR 2 NR NR ReR, 1.30 (0.97–1.75) I2 = 92%, p = 0.005 NA
ADA, IFX Lv et al.,38 2014 160/80/40 mg; 5 or 10 mg/kg 3 1222 732 ReR, 1.89 (1.55–2.31) I2 = 37%, p = 0.20 NA
ADA Bonovas et al.,24 2018 40 mg 2 481 240 OR, 2.01 (1.31–3.08) I2 = 0%, p = 0.76 NA
Singh et al.,31 2018 160/80/40 mg 2 568 327 OR, 2.02 (1.34–3.05) I2 = 0%, p = 0.75 NA
Trigo-Vicente et al.,34 2018 160/80/40 mg 2 481 240 OR, 2.02 (1.31–3.13) NR NA
Cholapranee et al.,9 2017 Commonly used in clinical practice or approved by FDA 2 767 425 OR, 1.96 (1.12–3.49) NR NA
Chen et al.,36 2016 40 mg 2 767 425 RiR, 1.69 (1.29–2.28) I2 = 0%, p = 0.69 NA
Vickers et al.,39 2016 40 mg 2 261 171 OR, 1.49 (0.95–2.39)a NR NA
Vickers et al.,39 2016 40 mg 1 65 29 OR, 1.36 (0.50–3.91)a,e NA NA
Zhang et al.,16 2016 160/80 or 80/40 mg 2 767 425 ReR, 1.69 (1.26–2.28) I2 = 0%, p = 0.69 NA
Galván-Banqueri et al.,10 2015 40 mg 1 295 150 RiR, 1.62 (1.08–2.44) NA NA
Lopez et al.,20 2015 NR 1 294 248 ReR, 1.12 (1.03–1.23) NA NA
Mei et al.,22 2015f 40 mg 2 767 425 OR, 3.42 (1.18–11.03) NR NA
Thorlund et al.,15 2014 160/80 or 160 mg 1 295 150 OR, 1.91 (1.12–3.31) a NA NA
Danese et al.,35 2014 40 mg 2 NR NR OR, 1.99 (1.30–3.06) NR NA
Lv et al.,38 2014 160/80/40 mg 1 494 248 ReR, 1.62 (1.13–2.33) NA NA
GLM Bonovas et al.,24 2018 100 mg 2 368 183 OR, 3.77 (0.92–15.41) I2 = 80%, p = 0.03 NA
Singh et al.,31 2018 100 mg 2 373 186 OR, 2.53 (1.64–3.92) e I2 = 74%, p = 0.05 NA
Trigo-Vicente et al.,34 2018 50 mg 1 456 302 OR, 1.98 (1.22–3.21) NA NA
Trigo-Vicente et al.,34 2018 100 mg 1 456 302 OR, 2.04 (1.26–3.31) NA NA
Cholapranee et al.,9 2017 Commonly used in clinical practice or approved by FDA 1 310 154 OR, 1.99 (0.89–4.42) NA NA
Mei et al.,22 2015f 50 or 100 mg 1 464 308 OR, 2.01 (0.67–5.96) NA NA
Kawalec et al.,25 2014 NR 1 463 307 ReR, 1.58 (1.19–2.12) NA NA
IFX Bonovas et al.,24 2018 5 mg/kg 4 776 387 OR, 2.53 (1.68–3.81) I2 = 41%, p = 0.17 NA
Trigo-Vicente et al.,34 2018 5 mg/kg 1 242 121 OR, 3.81 (2.13–6.97) NA NA
Singh et al.,31 2018 5 mg/kg 3 675 333 OR, 2.67 (1.80–3.96) I2 = 24%, p = 0.27 NA
Cholapranee et al.,9 2017 Commonly used in clinical practice or approved by FDA 1 242 121 OR, 3.74 (1.60–9.12) NA NA
Vickers et al.,39 2016 5 mg/kg 1 129 84 OR, 1.98 (0.96–4.04)a NA NA
Galván-Banqueri et al.,10 2015 5 mg/kg 1 242 121 RiR, 2.50 (1.63–3.83) NA NA
Lopez et al.,20 2015 NR 1 NR NR ReR, 1.52 (1.32–1.75) NA NA
Mei et al.,22 2015f 5 or 10 mg/kg 2 728 484 OR, 3.90 (1.29–12.17) NR NA
Danese et al.,35 2014 5 mg/kg 2 NR NR OR, 2.65 (1.79–3.92) NR NA
Thorlund et al.,15 2014 5 or 10 mg/kg 1 364 243 OR, 3.77 (2.12–6.89) a NA NA
VDZ Bonovas et al.,24 2018 300 mg 1 151 72 OR, 4.68 (2.33–9.42) NA NA
Singh et al.,31 2018 300 mg 1 251 125 OR, 5.14 (2.93–9.02) NA NA
Trigo-Vicente et al.,34 2018 300 mg 1 248 122 OR, 4.35 (2.48–7.79) NA NA
Cholapranee et al.,9 2017 NR 1 248 122 OR, 4.39 (1.88–10.03) NA NA
Vickers et al.,39 2016 300 mg 1 151 72 OR, 4.79 (2.33–9.93) a NA NA
Vickers et al.,39 2016 NR 1 81 43 OR, 9.09 (2.74–40.06) a,e NA NA
Mei et al.,22 2015e 300 mg 1 895 746 OR, 4.78 (1.56–14.47) NA NA
Kawalec et al.,25 2014 NR 1 373 247 ReR, 2.92 (2.02–4.21) NA NA
Wang et al.,13 2014 0.5, 2, 6, 10 mg/kg or 300 mg 2 NR NR ReR, 2.55 (1.38–4.70) NR NA
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ADA and GLM were administered subcutaneously (SC) and IFX and VDZ intravenously (IV).

ADA: adalimumab; CI: confidence interval; FDA: United States Food and Drug Administration; GLM: golimumab; IFX: infliximab; NA: non-applicable; NR: not reported; OR: odds ratio; ReR: relative risk; RiR: risk ratio; p: p-value; PS: probit score; VDZ: vedolizumab.

a

CrI, credible interval.

b

Maintenance 8–32 weeks for patients starting in response.

c

Maintenance 32–52 weeks for patients starting in response.

d

Durable clinical response.

e

Patients with prior exposure to anti-TNF agents.

f

The presented odds ratios in the study of Mei et al. 201522 are for the opposite associations (i.e. for example infliximab vs. placebo—not placebo vs. infliximab).

Nine of 11 MAs for ADA and eight of 10 MAs for IFX showed a better clinical response over placebo in the maintenance phase. GLM and VDZ were also superior to placebo in all MAs except for one.17

A few articles reported data on indirect comparisons among biologics (Supplementary Table S4). Only one article39 suggested the superiority of VDZ over IFX (IFX vs. VDZ, OR: 0.31, 95% CrI: 0.11–0.88).

Clinical remission

Three MAs20,29,38 studied biologics together (Table 2B) and found that they were more effective than placebo. One MA38 included patients intolerant or refractory to conventional medical therapy but the superiority of biologics was confirmed.

Fourteen studies examined ADA individually. One22 failed to reach statistical significance. Seven of 10 MA found that GLM was superior to placebo (range of effect estimate: 1.50–2.89). IFX was more effective than placebo in nine of 12 MAs, and VDZ was better than placebo in seven of eight MAs (range of effect estimate: 2.51–12.14). VDZ performed better than IFX (IFX vs. VDZ, OR: 0.34, 95% CrI: 0.12–0.97) only in one study39 (Supplementary Table S4). No other indirect comparisons reached statistical significance.

Mucosal healing

The combination of ADA and IFX showed superiority over placebo in one of two MAs.20,38 The four biologic agents were significantly better than placebo in one MA9 (Table 2C). IFX was significantly better than placebo in nine of 10 MAs (range of effect estimate: 1.52–3.90) and VDZ was significantly better than placebo in all MAs (range of effect estimate: 2.55–9.09). ADA and GLM were significantly better than placebo in all (13 MAs and six MAs, respectively) but two MAs.

In indirect comparisons, two of five MAs suggested that VDZ may be superior to ADA, and one of six that it may be superior to GLM. The significant effect estimates for ADA versus VDZ ranged from 0.15 to 0.46, and for GLM versus VDZ from 0.45 to 0.47 (Supplementary Table S4).

Measures of heterogeneity and small-study effects

Heterogeneity assessments for comparisons evaluating the efficacy of biologics as maintenance therapy were lacking. For most comparisons, no evidence of substantial heterogeneity was found, except for ADA and IFX combined,20 and for GLM24,31 (Table 2A, B, and C).

In many cases, MAs included only one study, or fewer than 10 studies. Consequently, tests for small-study effects were not applicable.

Efficacy of biologics as induction/maintenance therapy

Induction and/or maintenance therapy was examined in three MAs.11,16,30 ADA, GLM and VDZ were more efficacious than placebo in most MAs (Table 3). Non-significant differences from placebo were observed when the ADA dosage of 80/40 mg SC was administered. None of the articles reported indirect comparisons.

Table 3.

Characteristics of meta-analyses that studied the efficacy (compared with placebo) of biologic therapies, i.e. adalimumab, golimumab, infliximab, and vedolizumab, as induction and/or maintenance therapy, in ulcerative colitis. Significant estimates (p < 0.05) are presented in bold.

Outcome/ Biologic therapy Subjects (n) UC cases (n) Estimates and 95% CI Heterogeneity (I2 or p-value) Small- study effects
Author, year Dosage Trials (n)
A
Clinical response
ADA Zhang et al.,16 2016 160/80 mg 3 940 468 ReR, 1.37 (1.19–1.59) I2 = 0%, p = 0.56 NA
Zhang et al.,16 2016 80/40 mg 2 443 217 ReR, 1.17 (0.95–1.44) I2 = 0%, p = 0.86 NA
Song and Zheng,30 2015 160/80 or 80/40 mg 3 1014 508 OR, 1.63 (1.27–2.09) I2 = 0%, p = 0.44 NA
GLM Song and Zheng,30 2015 NR 1 771 515 OR, 2.71 (1.97–3.73) NA NA
VDZ Bickston et al.,11 2014 0.5, 2, 6 or 10 mg/kg 3 601 380 RiR, 1.47 (1.28–1.69) I2 = 0%, p = 0.64 NA
B
Clinical remission NA
ADA Zhang et al.,16 2016 160/80 mg 3 940 468 ReR, 1.62 (1.15–2.29) I2 = 25%, p = 0.27 NA
Zhang et al.,16 2016 80/40 mg 2 443 217 ReR, 1.14 (0.67–1.94) I2 = 0%, p = 0.85 NA
VDZ Bickston et al.,11 2014 0.5, 2, 6 or 10 mg/kg 4 606 382 RiR, 1.16 (1.10–1.25) I2 = 0%, p = 0.57 NA
C
Mucosal healing NA
ADA Zhang et al.,16 2016 160/80 mg 3 940 468 ReR, 1.27 (1.08–1.50) I2 = 0%, p = 0.52 NA
Zhang et al.,16 2016 80/40 mg 2 443 217 ReR, 1.04 (0.82–1.32) I2 = 48%, p = 0.17 NA
Song and Zheng,30 2015 160/80 or 80/40 mg 3 1014 508 OR, 1.23 (0.96–1.59) I2 = 38%, p = 0.20 NA
GLM Song and Zheng,30 2015 NR 1 771 515 OR, 1.99 (1.44–2.75) NA NA
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ADA and GLM were administered subcutaneously (SC) and VDZ intravenously (IV).

ADA: adalimumab; CI: confidence interval; GLM: golimumab; IFX: infliximab; NA: non-applicable; NR: not reported; OR: odds ratio; ReR: relative risk; RiR: Risk ratio; p: p-value; VDZ: vedolizumab.

Efficacy of tofacitinib

Tofacitinib was more effective than placebo in terms of clinical remission and mucosal healing in both the induction and maintenance phases. For the dosage of 10 mg as maintenance therapy, which was examined in two MAs,31,34 the difference regarding clinical remission was non-significant in one MA31 (Table 4). One MA31 showed that TFB was better than ADA in terms of clinical response and mucosal healing in the induction phase, when patients with prior exposure to anti-TNF agents were considered (Supplementary Table S5). TFB also was found to perform better than ADA and GLM (dosages 50 or 100 mg) as maintenance therapy in one MA.34

Table 4.

Characteristics of meta-analyses that studied (A) the efficacy and (B) the safety of tofacitinib compared with placebo, as induction, maintenance, and induction and/or maintenance therapy, in ulcerative colitis. Significant estimates (p < 0.05) are presented in bold.

Outcome/TFB therapy Subjects (n) Intervention group (n) Estimates and 95% CI Heterogeneity (I2 or p-value) Small- study effects
Author, year Dosage Trials (n)
A
Efficacy
Induction therapy
Clinical response Bonovas et al.,24 2018 10 mg 2 577 440 OR, 2.42 (1.61–3.63) I2 = 0%, p = 0.61 NA
Paschos et al.,12 2018 10 mg 3 1220 938 OR, 2.95 (2.21–3.95) I2 = 0%, p = 0.77 NA
Paschos et al.,12 2018 10 mg 3 643 512 OR, 2.32 (1.57–3.43) a I2 = 0%, NR NA
Paschos et al.,12 2018 10 mg 3 669 526 OR, 3.43 (2.25–5.22) b I2 = 48%, NR NA
Clinical remission Bonovas et al.,24 2018 10 mg 3 577 440 OR, 2.47 (1.41–4.34) I2 = 0%, p = 0.46 NA
Paschos et al.,12 2018 10 mg 2 1220 938 OR, 3.84 (2.29–6.44) I2 = 41%, p = 0.18 NA
Paschos et al.,12 2018 10 mg 2 521 417 OR, 2.20 (1.18–4.10) a I2 = 0%, NR NA
Paschos et al.,12 2018 10 mg 2 618 488 OR, 12.15 (2.38–62.07) b I2 = 0%, NR NA
Singh et al.,31 2018 10 mg 2 520 417 OR, 2.17 (1.16–4.06) I2 = 0%, p = 0.42 NA
Singh et al.,31 2018 10 mg 2 623 488 OR, 12.57 (2.46–64.12) b I2 = 0%, p = 0.67 NA
Trigo-Vicente et al.,34 2018 10 mg 2 521 417 OR, 2.23 (1.23–4.43) c NR NA
Mucosal healing Bonovas et al.,24 2018 10 mg 2 521 417 OR, 2.06 (1.25–3.39) I2 = 0%, p = 0.60 NA
Paschos et al.,12 2018 10 mg 2 1139 905 OR, 2.70 (1.81–4.03) I2 = 0%, p = 0.62 NA
Paschos et al.,12 2018 10 mg 2 521 417 OR, 2.06 (1.25–3.40) a I2 = 0%, NR
Paschos et al.,12 2018 10 mg 2 618 488 OR, 4.53 (2.15–9.56) b I2 = 0%, NR
Singh et al.,31 2018 10 mg 2 520 417 OR, 2.04 (1.24–3.35) I2 = 0%, p = 0.57 NA
Singh et al.,31 2018 10 mg 2 623 488 OR, 4.71 (2.24–9.92) b I2 = 0%, p = 0.95 NA
Trigo-Vicente et al.,34 2018 10 mg 2 521 417 OR, 2.08 (1.29–3.53) c NR NA
Maintenance therapy
Clinical remission Singh et al.,31 2018 5 mg 1 396 198 OR, 4.18 (2.46–7.12) NR NA
Singh et al.,31 2018 10 mg NR NR NR OR, 5.42 (0.50–58.85) NR NR
Trigo-Vicente et al.,34 2018 10 mg 1 395 197 OR, 5.51 (3.31–9.56) c NR NA
Mucosal healing Singh et al.,31 2018 5 mg 1 396 198 OR, 3.95 (2.39–6.53) NA NR
Singh et al.,31 2018 10 mg NR NR NR OR, 5.56 (1.10–28.16) NR NR
Trigo-Vicente et al.,34 2018 10 mg 1 395 197 OR, 5.62 (3.51, 9.57) c NA NA
B
Safety
Adverse events
Induction therapy Paschos et al.,12 2018 10 mg NR NR NR OR, 0.93 (0.68–1.28) I2 = 0%, NR NA
Induction and/or maintenance therapy Bonovas et al.,24 2018 10 or 5 mg 4 1812 1332 OR, 0.97 (0.77–1.22) I2 = 0%, p = 0.87 NA
Serious adverse events
Induction therapy Paschos et al.,12 2018 10 mg NR NR NR OR, 0.63 (0.34–1.15) I2 = 0%, NR NA
Maintenance therapy Singh et al.,31 2018 5 mg 1 NR NR OR, 0.76 (0.32–1.77) NA NA
Singh et al.,31 2018 10 mg N NR NR OR, 0.85 (0.37–1.94) NA NA
Trigo-Vicente et al.,34 2018 10 mg 1 394 196 OR, 0.84 (0.36–1.93)c NA NA
Induction and/or maintenance therapy Bonovas et al.,24 2018 10 or 5 mg 4 1812 1332 OR, 0.69 (0.43–1.09) I2 = 0%, p = 0.84 NA
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NR: not reported; OR: odds ratio; p: p-value; TFB: tofacitinib.

a

anti-TNF naive.

b

Patients with prior exposure to anti-TNF agents.

c

Credible interval.

Safety

Safety of biologics

Most MAs indicated that the examined biologics are safe compared with placebo both in terms of AE and SAE (Supplementary Table S6). However, two comparisons for IFX (AE) reached statistical significance; one for the induction phase (OR: 1.52, 95% CI: 1.03–2.24)21 and one for the combined induction and/or maintenance phase (OR: 1.48, 95% CI: 1.00–2.19).24 ADA showed a slightly elevated occurrence of AE in the maintenance phase (RiR: 1.28, 95% CI: 1.06–1.54) in one MA. In terms of indirect comparisons, no significant difference was observed between the biologics (Supplementary Tables S3, S4, S7), except for a marginally significant difference in SAE between GLM and VDZ24 (Supplementary Table S7).

Safety of tofacitinib

All the MAs that examined TFB versus placebo have reported non-significant results (Table 4). Indirect comparisons between TFB with biologics also yielded non-significant results (Supplementary Table S5).

Discussion

This overview summarized and evaluated the evidence from 31 MAs on the efficacy and safety of four biologic therapies and of a small-molecule agent in moderate-to-severe UC. More MAs involved ADA and IFX than GLM and VDZ, evaluated clinical remission rather than clinical response or mucosal healing, and presented results for the induction phase rather than for the maintenance phase. In biologic-naive patients, the existing evidence suggested that biologics are more effective than placebo. The safety of biologics in patients with UC had been documented in another overview5 studying any infectious AEs, serious and opportunistic infections, tuberculosis and malignancies, concluding that treating UC patients with biologics is safe. Biologics were also found safe for treating UC in this overview. The only significant differences in terms of AEs (vs. placebo) were observed for IFX in the induction and induction/maintenance phases, and marginally for ADA in the maintenance phase.

Indirect comparisons suggested that IFX may be better than ADA and GLM to induce clinical response, better than ADA in clinical remission, and superior to ADA and GLM in mucosal healing. Some of the evidence indicated that VDZ could be better than ADA and GLM in maintaining mucosal healing. These results are confirmed by the first study directly comparing two biologic agents in UC.41 In this head-to-head comparison, VDZ was superior to ADA in achieving clinical remission and endoscopic mucosal healing at Week 52, while VDZ and ADA were both generally safe and well tolerated, in patients with moderate-to-severe UC.41

The accumulated evidence for TFB showed that it was more effective than placebo, and indirect comparisons suggested its superiority over ADA and GLM for maintenance of remission and mucosal healing. No evidence was found for indirect comparisons between TFB and IFX.

This overview revealed some weaknesses in the field. Many MAs have been conducted, although the primary RCTs are rather few. Therefore, some MAs are based on a limited number of RCTs, undermining a major objective of MAs, which is to test for heterogeneity and small-study effects. Differences in definitions of outcomes in the included MAs may exist and cause variation in their summary effect estimates. There were not head-to-head comparisons between biologics or between biologics and TFB in the primary RCTs included in the MAs of this overview. Thus, the evidence was based on indirect comparisons. Significant parameters for MAs including heterogeneity and small-study effects statistics were often not reported even when enough RCTs were included. It is well known that earlier trials enrolled a higher proportion of (or exclusively) biologic-naive patients. For this reason, the estimates presented in network MAs mixing naive and non-naive populations should be interpreted with great caution.42 Finally, many authors failed to register the protocol of their MA in advance and to provide a list of the primary studies excluded from MA and of the reasons why the authors did so.

In conclusion, this overview supports the efficacy and safety of biologics and TFB for the treatment of UC. IFX was superior than ADA and GLM for induction, and VDZ than ADA and GLM for maintaining mucosal healing. The superiority of VDZ over ADA was confirmed by a head-to-head trial.41 IFX was the only agent showing an increase of AEs. TFB seems to be better than ADA and GLM for maintenance of remission and mucosal healing. This overview, as an in-depth summary of the existing evidence on the comparative efficacy and safety of therapeutic options for patients with UC, can support clinical decision-making. More studies on therapy combinations, early effective intervention, and precision medicine approaches are still needed to improve the management of non-naive patients.42 More head-to-head trials are needed to confirm these findings and further support clinical decision-making.

Declaration of conflicting interests

Silvio Danese has served as a speaker, a consultant, and an advisory board member for AbbVie, Allergan, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Hospira, Johnson & Johnson, Merck, MSD, Takeda, Mundipharma, Pfizer, Sandoz, Tigenix, UCB Pharma, and Vifor. Laurent Peyrin-Biroulet has received consulting fees from AbbVie, Amgen, Biogaran, Biogen, Boerhinger-Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Ferring, Forward Pharma, Genentech, H.A.C. Pharma, Hospira, Index Pharmaceuticals, Janssen, Lycera, Merck, Lilly, Mitsubishi, Norgine, Pfizer, Pharmacosmos, Pilege, Samsung Bioepis, Sandoz, Takeda, Therakos, Tillots, UCB Pharma and Vifor, and lecture fees from AbbVie, Ferring, H.A.C. Pharma, Janssen, Merck, Mitsubishi, Norgine, Takeda, Therakos, Tillots, and Vifor. All other authors have no conflicts of interest to declare.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Guarantor of the article

Georgios K. Nikolopoulos

Specific author contributions

Conception and design: SD, LPB, SB, GN. Literature search and data collection: KP, DE, DP, AY Data interpretation: AY, DP, SD, LPB, SB, GN. Drafting of the manuscript: KP. Critical revision of the manuscript for important intellectual content: All the authors. Final approval of the version to be published including the authorship list: All the authors.

Supplemental Material

UEG883566 Supplemental Material - Supplemental material for Efficacy and safety of biologic agents and tofacitinib in moderate-to-severe ulcerative colitis: A systematic overview of meta-analyses
Click here for additional data file. (830.2KB, pdf)

Supplemental material, UEG883566 Supplemental Material for Efficacy and safety of biologic agents and tofacitinib in moderate-to-severe ulcerative colitis: A systematic overview of meta-analyses by Katerina Pantavou, Anneza I Yiallourou, Daniele Piovani, Despo Evripidou, Silvio Danese, Laurent Peyrin-Biroulet, Stefanos Bonovas and Georgios K Nikolopoulos in United European Gastroenterology Journal

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UEG883566 Supplemental Material - Supplemental material for Efficacy and safety of biologic agents and tofacitinib in moderate-to-severe ulcerative colitis: A systematic overview of meta-analyses
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Supplemental material, UEG883566 Supplemental Material for Efficacy and safety of biologic agents and tofacitinib in moderate-to-severe ulcerative colitis: A systematic overview of meta-analyses by Katerina Pantavou, Anneza I Yiallourou, Daniele Piovani, Despo Evripidou, Silvio Danese, Laurent Peyrin-Biroulet, Stefanos Bonovas and Georgios K Nikolopoulos in United European Gastroenterology Journal

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