ETM Experimental and Therapeutic Medicine 1792-0981 1792-1015 D.A. Spandidos 10.3892/etm.2017.5003 ETM-0-0-5003 Articles Risk of infection in patients with spondyloarthritis and ankylosing spondylitis receiving antitumor necrosis factor therapy: A meta-analysis of randomized controlled trials XuZhigao 1 * XuPeipei 2 * FanWei 2 YangGui 3 WangJune 2 ChengQingyuan 2 YuMingxia 2 3 Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China Department of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China Correspondence to: Professor Mingxia Yu, Department of Clinical Laboratory, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, Hubei 430071, P.R. China, E-mail: dewrosy520@163.com

Contributed equally

 10 2017 22 08 2017 14 4 3491 3500 30092016 02062017 Copyright: © Xu et al. 2017 This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Antitumor necrosis factor (TNF) agents have been widely used for the treatment of spondyloarthritis (SpA) and ankylosing spondylitis (AS). However, these agents may increase the risk of infection due to suppressing the immune response. The present meta-analysis was performed to systematically investigate the risk of overall infection, serious infection and tuberculosis in patients with SpA and AS treated with anti-TNF agents. Medline, Embase and the Cochrane library were searched for randomized controlled trials (RCTs) published between January 1998 and December 2015 about infection in patients with SpA receiving anti-TNF therapy. Data were pooled to obtain relative risks (RRs) along with their 95% confidence intervals (CIs). A total of 25 RCTs investigating SpA, including 12 investigating AS specifically, were eligible for the meta-analysis. Similar risks of overall infection were reported in patients with SpA (RR, 1.03; 95% CI, 0.92–1.15) and AS (RR, 1.06; 95% CI, 0.91–1.24) treated with anti-TNF agents. The RR of serious infection for patients with SpA or AS receiving anti-TNF therapy compared with a placebo was 1.27 (95% CI, 0.67–2.38) and 1.57 (95% CI, 0.63–3.91), respectively. In addition, 4 RCTs with outcomes of tuberculosis in patients with SpA receiving anti-TNF agents were identified, all in infliximab-treated patients (RR, 2.52; 95% CI, 0.53–12.09). However, due to the limited number of RCTs, this finding should be interpreted with caution. The present meta-analysis did not find any significantly increased risk of infection associated with anti-TNF therapy in patients with SpA or AS. However, due to short duration of follow-up in the RCTs and the rarity of serious infections and tuberculosis, patients treated with anti-TNF agents still should be closely monitored in clinical practice.

 antitumor necrosis factor agents spondyloarthritis ankylosing spondylitis infection meta-analysis Introduction

Spondyloarthritis (SpA) is a group of chronic inflammatory rheumatic diseases with pathophysiological, clinical, radiological and genetic features of inflammatory back pain with or without peripheral arthritis, combined with certain features of extra-articular manifestations. Diseases in this category include ankylosing spondylitis (AS), reactive arthritis, psoriatic arthritis, arthropathy of inflammatory bowel disease, undifferentiated SpA and juvenile chronic arthritis (1–3). As SpA diseases progress they can develop into AS, which is the most severe and common subtype of SpA. The primary clinical symptoms of AS include pain, joint stiffness and loss of spinal mobility, which can result in severe impairment of function and a decrease in the patient's quality of life (4,5).

The primary treatments for patients with SpA include general drug treatments accompanied with physiotherapy. However, short-term corticosteroids, conventional non-steroidal anti-inflammatory drugs and disease modifying anti-rheumatic drugs, including methotrexate and sulfasalazine, have not proved to be particularly effective for the treatment of SpA while causing a high incidence of side effects (6–8). Tumor necrosis factor (TNF)-α, a pleiotropic cytokine that is produced during the inflammatory response, serves an important role in the pathogenesis of numerous chronic inflammatory and rheumatic diseases (9). The therapies used for the treatment of SpA have undergone a drastic revision since the development of anti-TNF agents, which inhibit and prevent TNF-α from promoting inflammation, and therefore are beneficial for alleviating the symptoms of SpA (10).

While anti-TNF biologics improve the function and quality of life of patients with SpA, suppressing the immune system makes patients more susceptible to infections. This is the most adverse effect of anti-TNF agent therapy, and has been demonstrated to be significantly higher in patients with SpA, particularly AS, treated with anti-TNF agents compared with those receiving non-biological treatments (11). Serious infection, whilst rare, is severe and thus the inhibitory effects of anti-TNF therapy on the immune response are important. Considering that anti-TNF agents usually require long-term application in patients with SpA and AS (10,12), a meta-analysis was performed to investigate whether the risk of serious infection, including tuberculosis, is increased in patients with SpA or AS treated with anti-TNF agents. In addition, the overall infection rate in patients with SpA or AS was investigated.

 Materials and methods <sec> <title>Data sources and search strategy

The design of the present meta-analysis was prepared in accordance with the preferred reporting items for systematic reviews and meta-analyses statement (13). Medline (http://www.ncbi.nlm.nih.gov), Embase (http://www.embase.com) and the Cochrane Library (http://www.cochranelibrary.com) were searched for publications from January 1998 to December 2015 with the following terms: ‘Spondyloarthritis’, ‘ankylosing spondylitis’, ‘psoriatic arthritis’ or ‘reactive arthritis’ combined with ‘biologics’, ‘anti-TNF agent’ or the names of specific biologic agents, including ‘etanercept’, ‘infliximab’, ‘adalimumab’, ‘certolizumab pegol’, ‘golimumab’, and combined with ‘adverse reaction’ and ‘infection’. Searches were restricted to English language publications and studies in humans. The search was supplemented by manual searches of the proceedings of the American College of Rheumatology (http://www.rheumatology.org) and the European League Against Rheumatism (http://www.eular.org). Meanwhile, to identify all relevant articles, the reference lists from associated reviews and meta-analyses were also searched manually.

 Study selection

Randomized controlled trials (RCTs) comparing anti-TNF agents with placebos (or other medications), alone or in combination, in patients with SpA were identified. The inclusion and exclusion criteria were as described below. i) Study design: The study must be an RCT; for trials with a cross-over design, a double-blind period followed by an open-label period was eligible for inclusion, while studies with a Jadad score <3 were excluded. ii) Participants: The enrolled patients must fulfill the assessment of SpA criteria for peripheral SpA and SpA in general (14), and patients who were suffering from chronic infections at the beginning of experiments were excluded. iii) Intervention: Studies comparing treatment with infliximab, etanercept, adalimumab, golimumab and certolizumab pegol, either alone or in combination with other medications, against a control group were included; trials using a single infusion or injection of an anti-TNF agent were excluded. Additionally, the duration of the placebo-controlled phases across trials were limited to short term. iv) Endpoints: All included articles must demonstrate the outcomes associated with infection. Studies were independently screened and selected by two investigators, and discrepancies were resolved through discussion.

 Data extraction and quality assessment

Using a preformed form, data were extracted by two independent investigators with any discrepancies resolved by discussion. In addition to general information, including the first author, publication year, study design, underlying disease, interventions, study duration, sample size and other specific circumstances, the present study focused on extracting outcomes of the events, including the occurrence of overall infection, serious infection and tuberculosis. For the studies that included a double-blind period and an open-labeled period, only the result of the double-blind period was extracted. Notably, in one trial of etanercept with administration of 25 mg twice a week or 50 mg once a week, the decision was made to present the combined results as these regimens were demonstrated to be equivalent in terms of benefit and safety (15). Selected studies were critically appraised for quality based on the Jadad scale (16).

 Statistical analysis

Extracted data were analyzed using the Mantel-Haenszel method with Review Manager software (version 5.2, The Cochrane Collaboration, Copenhagen, Denmark). The Q test and I2 statistics were used to evaluate the heterogeneity of the RCTs in accordance with the Cochrane Handbook (17). An I2 value of >50% accompanied with a P-value <0.05 for the Q test was determined to indicate the presence of significant heterogeneity. When there was no significant heterogeneity, a fixed effects model was used; otherwise a random effects model was applied. Forest plots were constructed to display relative risk (RR) estimates and 95% confidence intervals (CIs). Funnel plots were assessed for evidence of asymmetry, followed by possible publication bias or other small study effects. Subgroup analysis was performed to explore potential differences by stratifying different anti-TNF agents in patients with SpA and AS. For sparse data on serious infection, due to null values in either the intervention or control arms in several trials, either a crude analysis was performed by combining study results, or the studies were excluded, according to the methodological description by Bradburn et al (18). Sensitivity analysis was also performed to inspect the robustness of the data using Stata software (version 12.0, StataCorp LP, College Station, TX, USA).

 Results <sec> <title>Study selection and characteristics

A flow diagram depicting the process of searching and selecting RCTs was presented in Fig. 1. A total of 1,621 unique RCTs were obtained after removing duplicates from the initial search that identified 1,744 studies. Of these studies, 1,526 were excluded through reading the title and abstract. Via a detailed full-text review of the remaining 95 studies, 26 articles were retrieved for evaluation. With 1 study eliminated due to a Jaded score below the cutoff level of 3 (19), ultimately 25 articles were eligible for inclusion in the analysis (2,15,20–42). Notably, 2 trials (29,42) that were not double-blind were included in the primary analysis, though the quality of their Jadad scores was not particularly high. Among the 25 articles eligible for analysis, 12 studies were investigating patients with AS.

Table I listed the general characteristics of the 25 articles included in the present study. With regards to the anti-TNF agents utilized, 9 trials used etanercept, 7 used infliximab, 7 used adalimumab and 2 used golimumab. No RCTs investigating certolizumab pegol were eligible for analysis due to their inadequate presentation of infection outcomes (43–45). The quality of the eligible studies met the required standards, with a mean Jadad score of 5.80±1.04. The duration of placebo-controlled phases across trials ranged from 12 to 48 weeks. In addition, the dosages of the biologics used in these RCTs met US Food and Drug Administration standards.

 Overall infection rate of patients with SpA or AS receiving anti-TNF agents vs. a placebo

In the 25 studies identified, 564/2,534 patients with SpA (22.3%) who received anti-TNF agents and 369/1,685 patients with SpA (21.9%) who received a placebo experienced an infection. Thus, no significant difference was identified in the infection rate between patients with SpA treated with anti-TNF agents compared with those who received a placebo (RR, 1.03; 95% CI, 0.92–1.15; Fig. 2). The risk of overall infection was then stratified by the type of anti-TNF agent. No significant differences were observed in the infection rate between patients with SpA treated with a specific anti-TNF agent compared with a placebo. The individual results were as follows: Etanercept (RR, 0.97; 95% CI, 0.81–1.16); infliximab (RR, 1.11; 95% CI, 0.88–1.40); adalimumab (RR, 1.02; 95% CI, 0.84–1.24); and golimumab (RR, 3.00; 95% CI, 0.42–21.65) (Fig. 2).

Among the RCTs evaluated, 12 investigated patients with AS. The incidence of infection in these studies was similar between the groups treated with anti-TNF agents (374/1,618 patients; 23.1%) and the control (187/816 patients; 22.9%). There was no significant difference in the overall rate of infection between these groups (RR, 1.06; 95% CI, 0.91–1.24; Fig. 3). Subgroup analysis by the type of anti-TNF agent used also revealed no significant differences, with the following individual results: Etanercept (RR, 0.95; 95% CI, 0.77–1.19); infliximab (RR, 1.08; 95% CI, 0.81–1.44); adalimumab (RR, 1.27; 95% CI, 0.92–1.24); and golimumab (RR, 3.00; 95% CI, 0.42–21.65) (Fig. 3).

 Serious infection rate of patients with SpA or AS receiving anti-TNF agents vs. a placebo

A total of 19/2,534 patients with SpA (0.75%) treated with anti-TNF agents had a serious infection compared with 9/1,685 patients (0.53%) who received a placebo. By pooling the data crudely, the relative risk of serious infection in patients with SpA treated with anti-TNF agents compared with the control group was 1.40 (95% CI, 0.64–3.10). After discarding the null studies, 17 RCTs were evaluated. Compared with patients treated with a placebo, patients receiving anti-TNF agents did not have a significantly increased risk of serious infection (RR, 1.27; 95% CI, 0.67–2.38; Fig. 4). The subgroup analysis that stratified the studies based on the anti-TNF agent used did not identify any significant heterogeneity compared with the control group either. The results were as follows: Etanercept (RR, 1.33; 95% CI, 0.46–3.85); infliximab (RR, 2.27; 95% CI, 0.68–7.54); and adalimumab (RR, 0.67; 95% CI, 0.22–2.06) (Fig. 4).

Similarly, in the 12 RCTs investigating patients with AS, 12/1,618 patients (0.74%) who received anti-TNF agent therapy experienced serious infection compared with 3/816 patients (0.37%) in the control group. This crude pooled result demonstrated that anti-TNF agents did not significantly increase the risk of serious infection in patients with AS (RR, 2.02; 95% CI, 0.57–7.13). After the 4 null RCTs abandoned, 8 studies were eligible for further analysis. The meta-analysis demonstrated that anti-TNF agents resulted in a 1.57-fold higher risk of serious infection in patient with AS compared with the control group (RR, 1.57; 95% CI, 0.63–3.91; Fig. 5). Individually, etanercept resulted in a 2.23-fold higher likelihood of serious infection (RR, 2.23; 95% CI, 0.49–10.10) and infliximab in a 2.42-fold higher likelihood (RR, 2.42; 95%, CI, 0.27–21.24), while adalimumab reduced the risk of serious infection (RR, 0.87; 95% CI, 0.21–3.61) (Fig. 5). However, none of these results were statistically significant.

 Rate of tuberculosis infection in patients with SpA receiving anti-TNF agents vs. a placebo

In the 25 RCTs included in the present study, only 4 studies revealed incidences of tuberculosis, which all emerged in infliximab-treated patients with SpA (Fig. 6). Thus, infliximab treatment resulted in a 2.42-fold higher likelihood of tuberculosis in patients with SpA compared with the control group (RR, 2.42; 95% CI, 0.40–14.70); however, this result was not significant (Fig. 6). In addition, due to the limited number of RCTs, this finding should be interpreted with caution.

 Publication bias

Funnel plots were produced to assess the publication bias of the included studies. The shape of funnel plots revealed no obvious asymmetry (Fig. 7), indicating that there was no publication bias for the overall and serious infection outcomes identified in patients with SpA or AS.

 Sensitivity analysis

Sensitivity analysis was performed by omitting individual studies to evaluate the robustness of the data. The results revealed that the RR was not influenced meaningfully in each model (Fig. 8). Notably, the 2 studies that were not double-blinded trials did not influence the robustness of the present study.

 Discussion

Presently, there are five anti-TNF agents available for the treatment of SpA, which are divided into three categories (46,47). One category includes etanercept, a soluble receptor of the p75 TNF receptor/Fc fusion protein. Another category includes the monoclonal antibodies infliximab, adalimumab and golimumab. Infliximab is composed of a murine variable region and human constant region, while adalimumab and golimumab are human antibodies. The last category includes certolizumab pegol, a recombinant humanized antibody of the Fab region conjugated to polyethylene glycol. The use of these drugs is a double-edged sword, as suppressing the immune response improved the symptoms of patients with SpA but also increased the risk of infection (48–52). To the best of our knowledge, the present meta-analysis was the first and largest review examining the risk of infection in patients with SpA treated with anti-TNF agents in RCTs. In AS, a meta-analysis was published to assess serious infection in patients receiving TNF blockers in 2010 (53). Considering more single studies arising published after 2010 (21,35,38) and the absence of data identifying respective risk of different anti-TNF agents in the previous meta-analysis, an updated meta-analysis regarding serious infection with use of TNF inhibitors for AS was performed in the present study.

The results of the present study revealed that there was no increased risk of overall infection with the short-term use of anti-TNF agents for patients with SpA or AS. Among the studies identified, the majority of reported infections were minor, particularly upper respiratory tract infections. With regard to the risk of serious infection, the crude pooled result did not find an increased risk in patients with SpA or AS treated with anti-TNF agents. For the risk of serious infection in patients with AS, the result of the present study was in accordance with the previous meta-analysis (53). However, compared with the prior meta-analysis, the present study had certain advantages. Firstly, the estimates were based on the pooling of 12 RCTs with an overall population of 2,434 participants compared with the prior study's sample size of 1,496 patients. With the large number of patients and similar results to the previous meta-analysis, it was unlikely that new individual RCTs would affect the conclusion of the present analysis. In addition, the present study brought golimumab into the meta-analysis and performed a subgroup analysis to explore the individual risk of infection from each anti-TNF agent. Furthermore, since SpA may develop into AS, in the meta-analysis, we didn't simply limit to the disease of AS and severity of infection, which could lead to a more comprehensive understanding and comparison as diseases progresses. Overall, the present study provided further support to the existing observational data, and was an updated and extended meta-analysis with detailed outcomes for infection.

On account of its seriousness and infectivity, tuberculosis was also an outcome that the present study investigated in patients with SpA treated with anti-TNF agents. In the analysis conducted in the current study, only 4 incidences of tuberculosis were detected in anti-TNF agent-treated patients with SpA, with the anti-TNF agent being infliximab in all cases. Certain previous studies have demonstrated that the incidence of tuberculosis is 3–4 times higher in patients with SpA receiving monoclonal antibody anti-TNF agents compared with those receiving etanercept (54,55), which may be associated with the different mechanisms of tuberculosis infection. Saliu et al (56) reported that adalimumab and infliximab reduced the proportion of tuberculosis-responsive cluster of differentiation (CD)69+ CD4 cells by 50–70% and suppressed antigen-induced interferon γ production in an in vitro intracellular infection model; however, etanercept had no significant effect. A Markov model performed by Wallis (57) revealed that infliximab-associated tuberculosis occurred within a very short time after taking the medicine (12–21 weeks), whereas infection onset was 3–5 times later with etanecept. In addition, the risk of latent tuberculosis recurrence after infliximab was 12.1 times higher compared with etanecept (57). These results indicated that anti-TNF agents should be carefully selected and that tuberculosis should be screened for in a timely manner in the clinical practice of patients with SpA.

The present analysis had several limitations. The study search was limited to papers published in English, which may have excluded other relevant non-English language studies and affected the results. However, all large RCTs were included, so the exclusion of several small trials should not have altered the results. In addition, no publication bias was identified for any condition. Another limitation was that serious infection was determined according to each RCTs definition, which would increase heterogeneity to a certain extent. However, the sensitivity analysis performed would have minimized the role of such heterogeneity. In addition, due to the rarity of serious infection, and the short duration of treatment and follow-up, the present study did not assess the risk of serious infection stratified by follow-up time.

In conclusion, the results of the present meta-analysis suggest that there is not a significantly increased risk of infection in patients with SpA or AS receiving anti-TNF agent therapy. However, since anti-TNF agents typically need to be used for a long period of time, even lifelong, in patients with SpA, particularly AS, more long-term follow-up studies are required to confirm the findings of the present study, in addition to exploring the potential occurrence of tuberculosis.

 Acknowledgements

The present study was supported by the National Natural Science Funds (grant nos. 81472033 and 30901308), the National Science Foundation of Hubei Province (grant nos. 2013CFB233 and 2013CFB235), the Scientific and Technological Project of Wuhan City (grant no. 2014060101010045), and the Hubei Province Health and Family Planning Scientific Research Project (grant no. WJ2015Q021).

 References DougadosMBaetenDSpondyloarthritisLancet37721272137201110.1016/S0140-6736(11)60071-821684383 MeasePSieperJVan den BoschFRahmanPKarunaratnePMPanganALRandomized controlled trial of adalimumab in patients with nonpsoriatic peripheral spondyloarthritisArthritis Rheumatol67914923201510.1002/art.3900825545240 SmolenJSBraunJDougadosMEmeryPFitzgeraldOHelliwellPKavanaughAKvienTKLandewéRLugerTTreating spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, to target: Recommendations of an international task forceAnn Rheum Dis73616201410.1136/annrheumdis-2013-20341923749611 BraunJSieperJAnkylosing spondylitisLancet36913791390200710.1016/S0140-6736(07)60635-717448825 DavisJCvan der HeijdeDDougadosMWoolleyJMReductions in health-related quality of life in patients with ankylosing spondylitis and improvements with etanercept therapyArthritis Rheum53494501200510.1002/art.2133016082640 GuellecDNocturneGTatarZPhamTSellamJCantagrelASarauxAShould non-steroidal anti-inflammatory drugs be used continuously in ankylosing spondylitis?Joint Bone Spine81308312201410.1016/j.jbspin.2014.01.00324589253 VisserKvan der HeijdeDMRisk and management of liver toxicity during methotrexate treatment in rheumatoid and psoriatic arthritis: A systematic review of the literatureClin Exp Rheumatol2710171025200920149325 LateefOShakoorNBalkRAMethotrexate pulmonary toxicityExpert Opin Drug Saf4723730200510.1517/14740338.4.4.72316011450 TraceyDKlareskogLSassoEHSalfeldJGTakPPTumor necrosis factor antagonist mechanisms of action: A comprehensive reviewPharmacol Ther117244279200810.1016/j.pharmthera.2007.10.00118155297 MaxwellLJZochlingJBoonenASinghJAVerasMMGhogomuTanjong EJanduBenkhalti MTugwellPWellsGATNF-alpha inhibitors for ankylosing spondylitisCochrane Database Syst Rev18CD0054682015 Sampaio-BarrosPDvan der Horst-BruinsmaIEAdverse effects of TNF inhibitors in SpA: Are they different from RA?Best Pract Res Clin Rheumatol28747763201410.1016/j.berh.2014.10.00125488782 PoddubnyyDFedorovaAListingJHaibelHBaraliakosXBraunJSieperJPhysical function and spinal mobility remain stable despite radiographic spinal progression in patients with ankylosing spondylitis treated with TNF-α inhibitors for Up to 10 YearsJ Rheumatol4321422148201610.3899/jrheum.16059427803139 KnoblochKYoonUVogtPMPreferred reporting items for systematic reviews and meta-analyses (PRISMA) statement and publication biasJ Craniomaxillofac Surg399192201110.1016/j.jcms.2010.11.00121145753 RudwaleitMvan der HeijdeDLandewéRAkkocNBrandtJChouCTDougadosMHuangFGuJKirazliYThe assessment of SpondyloArthritis international society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in generalAnn Rheum Dis702531201110.1136/ard.2010.13364521109520 van der HeijdeDDa SilvaJCDougadosMGeherPvan der Horst-BruinsmaIJuanolaXOlivieriIRaemanFSettasLSieperJEtanercept 50 mg once weekly is as effective as 25 mg twice weekly in patients with ankylosing spondylitisAnn Rheum Dis6515721577200610.1136/ard.2006.05674716968715 JadadARMooreRACarrollDJenkinsonCReynoldsDJGavaghanDJMcQuayHJAssessing the quality of reports of randomized clinical trials: Is blinding necessary?Control Clin Trials17112199610.1016/0197-2456(95)00134-48721797 HigginsJPGreenSCochrane Handbook for Systematic Reviews of InterventionsNaunyn-Schmiedebergs Archiv für experimentelle Pathologie und Pharmakologie5S382011 BradburnMJDeeksJJBerlinJALocalioRussell AMuch ado about nothing: A comparison of the performance of meta-analytical methods with rare eventsStat Med265377200710.1002/sim.252816596572 WangJZhangYZhaoLLiZHShiZJThe efficacy and safety of infliximab used in patients with ankylosing spondylitis after unilateral total hip arthroplastyHip Int23406410201310.5301/hipint.500003323873508 DougadosMvan der HeijdeDSieperJBraunJMaksymowychWPCiteraGMiceli-RichardCWeiJCPedersenRBoninRSymptomatic efficacy of etanercept and its effects on objective signs of inflammation in early nonradiographic axial spondyloarthritis: A multicenter, randomized, double-blind, placebo-controlled trialArthritis Rheumatol6620912102201410.1002/art.3872124891317 BraunJvan der Horst-BruinsmaIEHuangFBurgos-VargasRVlahosBKoenigASFreundlichBClinical efficacy and safety of etanercept versus sulfasalazine in patients with ankylosing spondylitis: A randomized, double-blind trialArthritis Rheum6315431551201110.1002/art.3022321630245 DougadosMCombeBBraunJLandewéRSibiliaJCantagrelAFeydyAvan der HeijdeDLeblancVLogeartIA randomised, multicentre, double-blind, placebo-controlled trial of etanercept in adults with refractory heel enthesitis in spondyloarthritis: The HEEL trialAnn Rheum Dis6914301435201010.1136/ard.2009.12153320511606 MeasePJKivitzAJBurchFXSiegelELCohenSBOryPSalonenDRubensteinJSharpJTTsujiWEtanercept treatment of psoriatic arthritis: Safety, efficacy, and effect on disease progressionArthritis Rheum5022642272200410.1002/art.2033515248226 CalinADijkmansBAEmeryPHakalaMKaldenJLeirisalo-RepoMMolaEMSalvaraniCSanmartíRSanyJOutcomes of a multicentre randomised clinical trial of etanercept to treat ankylosing spondylitisAnn Rheum Dis6315941600200410.1136/ard.2004.02087515345498 DavisJCVan Der HeijdeDBraunJDougadosMCushJCleggDOKivitzAFleischmannRInmanRTsujiWEnbrel Ankylosing Spondylitis Study Group: Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: A randomized, controlled trialArthritis Rheum4832303236200310.1002/art.1132514613288 BrandtJKhariouzovAListingJHaibelHSörensenHGrassnickelLRudwaleitMSieperJBraunJSix-month results of a double-blind, placebo-controlled trial of etanercept treatment in patients with active ankylosing spondylitisArthritis Rheum4816671675200310.1002/art.1101712794835 GormanJDSackKEDavisJCJrTreatment of ankylosing spondylitis by inhibition of tumor necrosis factor alphaN Engl J Med34613491356200210.1056/NEJMoa01266411986408 SieperJLenaertsJWollenhauptJRudwaleitMMazurovVIMyasoutovaLParkSSongYYaoRChitkaraDEfficacy and safety of infliximab plus naproxen versus naproxen alone in patients with early, active axial spondyloarthritis: Results from the double-blind, placebo-controlled INFAST study, Part 1Ann Rheum Dis73101107201410.1136/annrheumdis-2012-20320123696633 BaranauskaiteARaffayováHKungurovNVKubanovaAVenalisAHelmleLSrinivasanSNasonovEVastesaegerNRESPOND investigators: Infliximab plus methotrexate is superior to methotrexate alone in the treatment of psoriatic arthritis in methotrexate-naive patients: The RESPOND studyAnn Rheum Dis71541548201210.1136/ard.2011.15222321994233 Marzo-OrtegaHMcGonagleDJarrettSHaugebergGHensorEO'connorPTanALConaghanPGGreensteinAEmeryPInfliximab in combination with methotrexate in active ankylosing spondylitis: A clinical and imaging studyAnn Rheum Dis6415681575200510.1136/ard.2004.02258215829577 van der HeijdeDDijkmansBGeusensPSieperJDeWoodyKWilliamsonPBraunJAnkylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy Study Group: Efficacy and safety of infliximab in patients with ankylosing spondylitis: Results of a randomized, placebo-controlled trial (ASSERT)Arthritis Rheum52582591200510.1002/art.2085215692973 AntoniCEKavanaughAKirkhamBTutuncuZBurmesterGRSchneiderUFurstDEMolitorJKeystoneEGladmanDSustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: Results from the infliximab multinational psoriatic arthritis controlled trial (IMPACT)Arthritis Rheum5212271236200510.1002/art.2096715818699 Van Den BoschFKruithofEBaetenDHerssensAde KeyserFMielantsHVeysEMRandomized double-blind comparison of chimeric monoclonal antibody to tumor necrosis factor alpha (infliximab) versus placebo in active spondylarthropathyArthritis Rheum46755765200210.1002/art.51111920412 BraunJBrandtJListingJZinkAAltenRGolderWGromnica-IhleEKellnerHKrauseASchneiderMTreatment of active ankylosing spondylitis with infliximab: A randomised controlled multicentre trialLancet35911871193200210.1016/S0140-6736(02)08215-611955536 HuangFGuJZhuPBaoCXuJXuHWuHWangGShiQAndhivarothaiNEfficacy and safety of adalimumab in Chinese adults with active ankylosing spondylitis: Results of a randomised, controlled trialAnn Rheum Dis73587594201410.1136/annrheumdis-2012-20253323475983 SieperJvan der HeijdeDDougadosMMeasePJMaksymowychWPBrownMAAroraVPanganALEfficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: Results of a randomised placebo-controlled trial (ABILITY-1)Ann Rheum Dis72815822201310.1136/annrheumdis-2012-20176622772328 ParamartaJEDe RyckeLHeijdaTFAmbarusCAVosKDinantHJTakPPBaetenDLEfficacy and safety of adalimumab for the treatment of peripheral arthritis in spondyloarthritis patients without ankylosing spondylitis or psoriatic arthritisAnn Rheum Dis7217931799201310.1136/annrheumdis-2012-20224523139265 HorneffGFitterSFoeldvariIMindenKKuemmerle-DeschnerJTzaribacevNThonABorteMGanserGTrauzeddelRHuppertzHIDouble-blind, placebo-controlled randomized trial with adalimumab for treatment of juvenile onset ankylosing spondylitis (JoAS): Significant short term improvementArthritis Res Ther14R230201210.1186/ar407223095307 van der HeijdeDKivitzASchiffMHSieperJDijkmansBABraunJDougadosMReveilleJDWongRLKupperHEfficacy and safety of adalimumab in patients with ankylosing spondylitis: Results of a multicenter, randomized, double-blind, placebo-controlled trialArthritis Rheum5421362146200610.1002/art.2191316802350 MeasePJGladmanDDRitchlinCTRudermanEMSteinfeldSDChoyEHSharpJTOryPAPerdokRJWeinbergMAAdalimumab Effectiveness in Psoriatic Arthritis Trial Study Group: Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: Results of a double-blind, randomized, placebo-controlled trialArthritis Rheum5232793289200510.1002/art.2130616200601 SieperJvan der HeijdeDDougadosMMaksymowychWPScottBBBoiceJABerdYBergmanGCurtisSTzontchevaAA randomized, double-blind, placebo-controlled, sixteen-week study of subcutaneous golimumab in patients with active nonradiographic axial spondyloarthritisArthritis Rheumatol6727022712201510.1002/art.3925726139307 MokCCLiOCChanKLHoLYHuiPKEffect of golimumab and pamidronate on clinical efficacy and MRI inflammation in axial spondyloarthritis: A 48-week open randomized trialScand J Rheumatol44480486201510.3109/03009742.2015.103830026271141 SieperJKivitzAvan TubergenADeodharACoteurGWolteringFLandewéRImpact of certolizumab pegol on patient-reported outcomes in patients with axial spondyloarthritisArthritis Care Res (Hoboken)6714751480201510.1002/acr.2259425832312 MeasePJFleischmannRDeodharAAWollenhauptJKhraishiMKielarDWolteringFStachCHoepkenBArledgeTvan der HeijdeDEffect of certolizumab pegol on signs and symptoms in patients with psoriatic arthritis: 24-week results of a Phase 3 double-blind randomised placebo-controlled study (RAPID-PsA)Ann Rheum Dis734855201410.1136/annrheumdis-2013-20369623942868 LandewéRBraunJDeodharADougadosMMaksymowychWPMeasePJReveilleJDRudwaleitMvan der HeijdeDStachCEfficacy of certolizumab pegol on signs and symptoms of axial spondyloarthritis including ankylosing spondylitis: 24-week results of a double-blind randomised placebo-controlled Phase 3 studyAnn Rheum Dis733947201410.1136/annrheumdis-2013-20423124013647 ThalayasingamNIsaacsJDAnti-TNF therapyBest Pract Res Clin Rheumatol25549567201110.1016/j.berh.2011.10.00422137924 TaylorPCPharmacology of TNF blockade in rheumatoid arthritis and other chronic inflammatory diseasesCurr Opin Pharmacol10308315201010.1016/j.coph.2010.01.00520172761 KimSYSolomonDHTumor necrosis factor blockade and the risk of viral infectionNat Rev Rheumatol6165174201010.1038/nrrheum.2009.27920142812 SolomonDHLuntMSchneeweissSThe risk of infection associated with tumor necrosis factor alpha antagonists: Making sense of epidemiologic evidenceArthritis Rheum58919928200810.1002/art.2339618383377 IsemanMDFischerATumor necrosis factor-alpha at the intersection of mycobacterial immunity and pathogenesis: An important new address in medicineClin Infect Dis4617411742200810.1086/58799018419423 Gomez-ReinoJJCarmonaLDescalzoAngel MBiobadaser Group: Risk of tuberculosis in patients treated with tumor necrosis factor antagonists due to incomplete prevention of reactivation of latent infectionArthritis Rheum57756761200710.1002/art.2276817530674 RoosJCOstorAJAnti-tumor necrosis factor alpha therapy and the risk of JC virus infectionArthritis Rheum54381382200610.1002/art.2168816385537 Fouque-AubertAJette-PaulinLCombescureCBaschATebibJGossecLSerious infections in patients with ankylosing spondylitis with and without TNF blockers: A systematic review and meta-analysis of randomised placebo-controlled trialsAnn Rheum Dis6917561761201010.1136/ard.2008.09882219640854 MarietteXGottenbergJERavaudPCombeBRegistries in rheumatoid arthritis and autoimmune diseases: Data from the French registriesRheumatology (Oxford)50222229201110.1093/rheumatology/keq36821148156 DixonWGHyrichKLWatsonKDLuntMGallowayJUstianowskiAB S R B R Control Centre Consortium, Symmons DP; BSR Biologics Register: Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: Results from the British society for rheumatology biologics register (BSRBR)Ann Rheum Dis69522528201010.1136/ard.2009.11893519854715 SaliuOYSoferCSteinDSSchwanderSKWallisRSTumor-necrosis-factor blockers: Differential effects on mycobacterial immunityJ Infect Dis194486492200610.1086/50543016845632 WallisRSMathematical modeling of the cause of tuberculosis during tumor necrosis factor blockadeArthritis Rheum58947952200810.1002/art.2328518383389

Flow diagram depicting the process of searching and selecting randomized controlled trials for the meta-analysis. AS, ankylosing spondylitis.

Meta-analysis of overall infection risk in patients with spondyloarthritis treated with anti-TNF agents. M-H, Mantel-Haenszel method; CI, confidence interval.

Meta-analysis of overall infection risk in patients with ankylosing spondylitis treated with anti-TNF agents. M-H, Mantel-Haenszel method; CI, confidence interval.

Meta-analysis of serious infection risk in patients with spondyloarthritis treated with anti-TNF agents. M-H, Mantel-Haenszel method; CI, confidence interval.

Meta-analysis of serious infection risk in patients with ankylosing spondylitis treated with anti-TNF agents. M-H, Mantel-Haenszel method; CI, confidence interval.

Meta-analysis of tuberculosis risk in patients with SpA treated with infliximab. M-H, Mantel-Haenszel method; CI, confidence interval.

Funnel plots for publication bias of the studies included in the present meta-analysis. Funnel plots for overall infection risk associated with anti-TNF agents in patients with (A) SpA and (B) AS. Funnel plots for serious infection risk associated with anti-TNF agents in patients with (C) SpA and (D) AS. SpA, spondyloarthritis; AS, ankylosing spondylitis; SE, standard error; RR, relative risk.

Sensitivity analysis. Sensitivity analysis was performed for overall infection associated with anti-TNF agents in patients with (A) SpA and (B) AS. Sensitivity analysis was also performed for serious infection associated with anti-TNF agents in patients with (C) SpA and (D) AS. SpA, spondyloarthritis; AS, ankylosing spondylitis; CI, confidence interval.

Characteristics of the studies included in the meta-analysis investigating the use of anti-TNF agents in patients with SpA or AS.

Anti-TNF group Control group
First author, year Type of disease Duration (weeks) Treatment P (n) I (n) SI (n) TB (n) Treatment P (n) I (n) SI (n) TB (n) (Refs.)
Dougados et al, 2014 axSpA 12 ETA 50 mg Qw 106 11 0 0 PBO 109 10 1 0 (20)
Braun et al, 2010 AS 16 ETA 50 mg Qw 379 43 0 0 SSZ 187 26 0 0 (21)
Dougados et al, 2010 SpA 12 ETA 50 mg Qw   12   5 1 0 PBO   12   1 0 0 (22)
van der Heijde et al, 2006 AS 12 ETA 50 mg Qw or 25 mg Biw 305 68 2 0 PBO   51 12 0 0 (15)
Mease et al, 2004 PsA 24 ETA 25 mg Biw 101 33 0 0 PBO 104 39 1 0 (23)
Calin et al, 2004 AS 12 ETA 25 mg Biw   45   0 0 0 PBO   39   0 0 0 (24)
Davis et al, 2003 AS 24 ETA 25 mg Biw 138 44 2 0 PBO 139 43 1 0 (25)
Brandt et al, 2003 AS 24 ETA 25 mg Biw   14   6 0 0 PBO   16   6 0 0 (26)
Gorman, 2002 AS 16 ETA 25 mg Biw   20 12 2 0 PBO   20 12 0 0 (27)
Sieper et al, 2013 axSpA 24 IFX 5 mg/kg+NPX 0, 2, 6, 12, 18, 24 w 105 27 1 1 PBO + NPX   52   9 0 0 (28)
Baranauskaite et al, 2011 PsA 16 IFX 5 mg/kg+MTX 0, 2, 6, 14 w   57   4 2 1 MTX   54   0 0 0 (29)
Marzo-Ortega et al, 2005 AS 30 IFX 5 mg/kg+MTX 0, 2, 6, 14, 22 w   28   6 0 0 PBO + MTX   14   2 0 0 (30)
van der Heijde et al, 2004 AS 24 IFX 5 mg/kg 0, 2, 6, 12, 18 w 201 86 2 0 PBO   78 27 0 0 (31)
Antoni et al, 2004 PsA 16 IFX 5 mg/kg 0, 2, 6, 14 w   52   9 1 0 PBO   51 16 1 0 (32)
Van Den Bosch et al, 2002 SpA 12 IFX 5 mg/kg 0, 2, 6 w   20   9 1 1 PBO   20   6 0 0 (33)
Braun et al, 2002 AS 12 IFX 5 mg/kg 0, 2, 6 w   34 12 1 1 PBO   35 18 0 0 (34)
Mease et al, 2015 npSpA 12 ADA 40 mg Eow   84 18 0 0 PBO   81 23 0 0 (2)
Huang et al, 2013 AS 12 ADA 40 mg Eow 229 25 1 0 PBO 115 12 0 0 (35)
Sieper et al, 2012 axSpA 12 ADA 40 mg Eow   91 28 0 0 PBO   94 28 0 0 (36)
Paramarta et al, 2012 SpA 12 ADA 40 mg Eow   20   4 0 0 PBO   20   8 1 0 (37)
Horneff et al, 2012 Jo-AS 12 ADA 40 mg Eow   17   6 2 0 PBO   15   6 1 0 (38)
van der Heijde et al, 2006 AS 24 ADA 40 mg Eow 208 66 0 0 PBO 107 23 1 0 (39)
Mease et al, 2005 PsA 24 ADA 40 mg Eow 151 36 1 0 PBO 162 41 2 0 (40)
Sieper et al, 2015 axSpA 16 GLM 50 mg Q4w   97   0 0 0 PBO 100   0 0 0 (41)
Mok et al, 2015 axSpA 48 GLM 50 mg Q4w   20   6 0 0 PAM   10   1 0 0 (42)

ETA, etanercept; IFX, infliximab; ADA, adalimumab; GLM, golimumab; PBO, placebo; MTX, methotrexate; NPX, naproxen; SSZ, sulfasalazine; PAM, pamidronate; P, participant; I, infection; SI, serious infection; TB, tuberculosis; n, number; w, week; Qw, once weekly; Biw, twice weekly; Eow, every other week; Q4w, every 4 weeks; SpA, spondyloarthritis; AS, ankylosing spondylitis; axSpA, axial SpA; PsA, psoriatic arthritis; npSpA, nonpsoriatic peripheral SpA; Jo-AS, juvenile onset AS.