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Effects of Tumor Necrosis Factor-alpha Inhibitors on the Incidence of Tuberculosis
Korean J Clin Pharm 2018;28(4):333-341
Published online December 31, 2018
© 2018 Korean College of Clinical Pharmacy.

Hyun Jin Park, Bo Yoon Choi, Minji Sohn, Na Young Han, In-Wha Kim, and Jung Mi Oh*

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
Correspondence to: Jung Mi Oh, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea Tel: +82-2-880-7997, Fax: +82-2-822-9560 E-mail: jmoh@snu.ac.kr
Received November 19, 2018; Revised December 4, 2018; Accepted December 11, 2018.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract

Objective:

Tumor necrosis factor-alpha (TNF-alpha) inhibitors are used as a treatment in various immune-mediated inflammatory diseases (IMIDs). Tuberculosis (TB) risk is reported in several meta-analyses in patients treated with TNF-alpha inhibitors. The purpose of this study is to collect, review, and evaluate the TB risk in TNF-alpha inhibitors according to IMIDs indications and between soluble-receptor TNF-alpha inhibitor and monoclonal-antibody TNF-alpha inhibitors.

Methods:

A systematic literature search on systematic reviews and meta-analyses was performed in PubMed, MEDLINE, Cochrane library, and EMBASE. We identified meta-analyses that evaluated TB infection risk of TNF-alpha inhibitors in IMIDs patients.

Results:

Thirteen meta-analyses including 41 study results were included in this umbrella review. IMIDs patients treated with TNF-alpha inhibitors had an increased risk of TB than control group (placebo with or without standard therapy patients) (relative risk ratio (RR) 2.057, 95% confidence interval (CI) 1.697 to 2.495). Among them, RA patients with TNF-alpha inhibitors had a higher risk of TB than control group (RR 1.847, 95% CI 1.385 to 2.464), and non-RA patients with TNF-alpha inhibitors had an increased risk of TB (RR 2.236, 95% CI 1.284 to 3.894). In subgroup analysis on TB risk between soluble-receptor TNF-alpha inhibitor and monoclonal-antibody TNF-alpha inhibitors in RA patients, the analysis indicated that monoclonal-antibody TNF-alpha inhibitors had higher risk of TB than solublereceptor TNF-alpha inhibitor (RR 2.880, 95% CI 1.730 to 4.792).

Conclusion:

This umbrella review confirms that the risk of TB is significantly increased in TNF-alpha inhibitor treated patients compared to control group.

Keywords : Tumor necrosis factor-alpha inhibitor, tuberculosis, immune-mediated inflammatory disease, rheumatoid arthritis, umbrella review
Introduction

Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic cytokine that has proinflammatory and immune-regulatory function.1) TNF-alpha has been the therapeutic target in immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD) ulcerative colitis (UC) and Crohn’s disease (CD), ankylosing spondylitis (AS), psoriasis (Ps), psoriatic arthritis (PsA), and spondyloarthritis (SpA).1) Although the exact mechanism of action of IMIDs is unknown, as IMIDs are all inflammatory diseases, they share some common pathological pathways.2) IMIDs commonly involve dysregulation of immune systems due to imbalance of inflammatory cytokines such as interleukin (IL)-12, IL-6, and TNF-alpha.2,3) Among these cytokines, TNFalpha has been recognized as a pivotal cytokine in the pathophysiology of IMIDs.4)

Since FDA’s first approval of TNF-alpha inhibitor, etanercept (ETA), to date, five TNF-alpha inhibitors have been approved for IMIDs: ETA, infliximab (IFX), adalimumab (ADA), golimumab (GOL), and certolizumab pegol (CZP).1) TNF-alpha inhibitors have been used in Korea since 2001 to treat RA and their use in other IMIDs has increased. Along with the increased use of TNF-alpha inhibitors, there are also increased safety concerns related to TNF-alpha inhibitors. Because these agents inhibit TNF-alpha from promoting inflammation, these agents suppress immune system in patients which in result cause patients become more susceptible to infections.5) Especially, tuberculosis (TB) infection risk associated with TNF-alpha inhibitors has been recognized in various studies including observational studies, administrative data studies, and metaanalyses. 6-22) Because TNF-alpha inhibitors play a major role in host defense mechanisms against Mycobacterium tuberculosis, reactivation of latent TB has become a major safety issue of these agents.23)

Several systematic reviews and meta-analyses have already examined the risk of TB of TNF-alpha inhibitors. However, already existing systematic reviews and meta-analyses examined TB risk in single TNF-alpha inhibitor or in single IMID indication rather than overall IMIDs.9-12,18-20) Also several existing meta-analyses evaluated an overall infection risk or adverse event risk in TNF-alpha inhibitors rather than TB infection risk in specific.10-16) Thus in this umbrella review, we aimed to integrate the existing meta-analyses data, examine the consistency of inferences from meta-analyses, and identify TB risk in IMIDs patients, RA patients, and non-RA patients and compared risk between soluble-receptor TNF-alpha inhibitor (ETA) and monoclonal-antibody TNF-alpha inhibitors (ADA, IFX, CZP, and GOL).

METHODS

Eligible criteria

Systematic reviews and meta-analyses of randomized controlled trials and observational studies that compared TB risk among TNF-alpha inhibitors (ADA, IFX, ETA, CZP, GOL) treated patients to placebo with or without standard therapy patients were included in the inclusion criteria.

These criteria were considered:

  • • Population: IMID patients such as RA, IBD (CD, UC), Ps, SpA, PsA, and AS

  • • Interventions: TNF-alpha inhibitors (ADA, IFX, ETA, CZP, and GOL)

  • • Comparison: placebo with or without standard treatment

  • • Outcome: TB infection

Exclusion criteria were: duplicated studies, reviews lacking meta-analysis statistical results, studies not including TB infection risk results.

Literature search

We searched PubMed, OVID MEDLINE, Cochrane Database of Systematic Reviews, and EMBASE databases to August 2018 for systematic review and meta-analyses. Search terms used were (adalimumab or humira or trudexa or certolizumab or cimzia or etanercept or Enbrel or golimumab or simponi or infliximab or remicade or remsima or inflectra) AND (tuberculosis or mycobacterium tuberculosis or TB) AND (meta-analysis or systematic review). Two independent researchers (HJ Park and BY Choi) conducted literature search. A third researcher, M Sohn, arbitrated any disagreement that could not be resolved by consensus.

Data extraction and Data analysis

Two independent researchers extracted relevant data from the selected meta-analyses. We extracted treatment indication, study group and control group treatment, outcome (TB), number of studies, number of events, total number of participants in each group in the study, relative effect, confidence interval, and heterogeneity value for each meta-analysis. For studies reporting both random and fixed relative effects, we extracted the random effects value. Data extraction table was reproduced based on the guidance on conducting overviews of reviews.24,25) Heterogeneity between studies was evaluated using I2 statistics, which assess variability among studies. I2 values from 0 to 40% might not be important; 30 to 60% may represent moderate heterogeneity; 50 to 90% may represent substantial heterogeneity; and 75 to 100% may represent considerable heterogeneity.26)

From the extracted data for each meta-analysis, we calculated relative risk ratio (RR) from each relative effect value (odds ratio (OR) and incidence rate ratio (IRR)) using OR to RR and IRR to RR conversion equation.27,28) We plotted pooled estimates from RR for the TB risk comparison. Comprehensive Meta-analysis software version 3 (Biostat, Englewood, NJ, USA) was used for analyses and plotting forest plot.

RESULTS

Search results

We searched a total of 748 articles in PubMed, MEDLINE, Cochrane, and EMBASE. After duplication exclusion, we screened titles, abstracts, and full texts for study exclusion which was narrowed down to 16 meta-analyses articles which met the inclusion criteria for this umbrella review. Three articles from those 16 articles were excluded because relevant data was not reported. Finally, we identified a total of 13 meta-analyses for final data extraction and data analysis.9-21) (Fig. 1). Table 1 listed the characteristics of 13 articles included in this study analyses (IMIDs 12 articles, RA 8 articles, non-RA 7 articles, and soluble-receptor vs monoclonal-antibody TNF-alpha inhibitors 2 articles). Most of the articles included in this umbrella review reported more than 1 RR result on TB infection risk.

Fig. 1.

Flow diagram of study selection. Abbreviation: IMIDs, immune-mediated inflammatory diseases; RA, rheumatoid arthritis; TNF, tumor necrosis factor


Characteristics of meta-analyses included

   Meta-analysisIndicationIntervention groupControl groupNo. of studiesRelative effect (95% CI)I2
RA
Ai et al. 20159)RATNF-alpha inhibitors (ADA, IFX, ETA, CZP, GOL)placebo w/ or w/o MTX4IRR 4.03 (2.36-6.88)45%
Cappogrosso et al. 201511)RACZP 200 mgplacebo or the same DMARD medications allowed for the intervention group12RR 2.83 (0.50-16.01)<40%
Cappogrosso et al. 201511)RACZP 400 mgplacebo or the same DMARD medications allowed for the intervention groupN/ARR 3.04 (0.37-25.22)<40%
Ruiz et al. 201715)RACZP overallplacebo w/ or w/o MTX7OR 1.91 (0.61-5.96)0%
Ruiz et al. 201715)RACZP 200 mgplacebo w/ or w/o MTX6OR 1.53 (0.40-5.77)0%
Ruiz et al. 201715)RACZP 400 mgplacebo w/ or w/o MTX3OR 3.52 (0.40-31.33)0%
Singh et al. 201016)RAGOL 50 mg q4wplacebo w/ MTX4RR 3.04 (0.12-74.01)NA
Singh et al. 201016)RAGOL 50 mg q4w, 50 mg q2w, 100 mg q4w, 100 mg q2wplacebo w/ MTX4RR 1.52 (0.06-37.08)NA
Souto et al. 201417)RATNF-alpha inhibitors (ADA, IFX, ETA, CZP, GOL)placebo w/ or w/o MTX or other therapy13OR 1.87 (0.76-4.60)0%
Wang et al. 201618)RAIFXplacebo w/ or w/o concomitant immuno-modulator therapy7OR 3.93 (0.91-16.91)0%
Xie et al. 201319)RAIFX, ADAplacebo w/ MTX7OR 1.85 (0.62-5.52)0%
Xie et al. 201319)RAIFXplacebo w/ MTX4OR 1.92 (0.50-7.47)0%
Xie et al. 201319)RAADAplacebo w/ MTX3OR 1.70 (0.26-10.87)0%
Xie et al. 201319)RAIFX, ADA clinical or low dose ADA 40 mg qow, IFX 3 mg/kg q8wplacebo w/ MTX6OR 1.73 (0.52-5.76)0%
Xie et al. 201319)RAIFX high dose 3 mg/kg q4w, 6 mg/kg q8w, 10 mg/kg q4w, q8wplacebo w/ MTX3OR 1.65 (0.28-9.56)0%
Zhang et al. 201721)RATNF-alpha inhibitors (ADA, IFX, ETA, CZP, GOL)placebo w/ or w/o standard care or standard care treatment alone17OR 2.29 (1.09-4.78)0%

Non-RA
Bonovas et al. 201610)IBDADAPlacebo2OR 3.22 (0.25-41.73)NA
Bonovas et al. 201610)IBDCZPPlacebo1OR 3.00 (0.12-74.69)NA
Bonovas et al. 201610)IBDGOLPlacebo1OR 0.25 (0.01-4.77)NA
Bonovas et al. 201610)IBDIFXPlacebo4OR 2.80 (0.50-15.60)NA
Cappogrosso et al. 201511)CDCZP 400 mgplacebo or the same DMARD medications allowed for the intervention groupNARR 2.94 (0.12-71.88)<40%
Cappogrosso et al. 201511)PsCZP 400 mgplacebo or the same DMARD medications allowed for the intervention groupNARR 3.05 (0.13-73.39)<40%
Ford et al. 201312)IBDTNF-alpha inhibitors (ADA, IFX, ETA, CZP, GOL)placebo22RR 2.52 (0.62-10.21)0%
Souto et al. 201417)AS, PsA, Ps, CD, UCTNF-alpha inhibitors (ADA, IFX, ETA, CZP, GOL)placebo w/ or w/o MTX or other therapy6OR 2.01 (0.54-7.50)NA
Wang et al. 201618)SpAIFXplacebo w/ or w/o concomitant immuno-modulator therapy8OR 2.46 (0.38-15.92)0%
Wang et al. 201618)IBDIFXplacebo w/ or w/o concomitant immuno-modulator therapy9OR 1.66 (0.26-10.57)0%
Xu et al. 201720)SpAIFXplacebo (or other medications)4RR 2.52 (0.53-12.09)0%
Zhang et al. 201721)ASTNF-alpha inhibitors (ADA, IFX, ETA, CZP, GOL)Placebo w/ or w/o standard care or standard care treatment alone3OR 2.43 (0.38-15.77)0%
RA + non-RA
Cappogrosso et al. 201511)RA, CD, SpA, PsA, PsCZP over allplacebo or the same DMARD medications allowed for the intervention group18RR 2.47 (0.64-9.56)<40%
Cappogrosso et al. 201511)RA, CD, SpA, PsA, PsCZP 200 mgplacebo or the same DMARD medications allowed for the intervention group12RR 2.83 (0.50-16.01)<40%
Cappogrosso et al. 201511)RA, CD, SpA, PsA, PsCZP 400 mgplacebo or the same DMARD medications allowed for the intervention group14RR 3.02 (0.65-14.12)<40%
Minozzi et al. 201614)RA, PsA, ASTNF-alpha inhibitors (ADA, IFX, ETA, CZP, GOL)placebo or no treatment19OR 3.29 (1.48-7.33)0%
Souto et al. 201417)RA, AS, PsA, Ps, UC, CDTNF-alpha inhibitors (ADA, IFX, ETA, CZP, GOL)placebo w/ or w/o MTX or other therapy18OR 1.92 (0.91-4.03)0%
Wang et al. 201618)RA, SpA, IBDIFXplacebo w/ or w/o concomitant immuno-modulator therapy24OR 2.86 (1.09-7.52)0%
Zhang et al. 201721)IMIDsTNF-alpha inhibitors (ADA, IFX, ETA, CZP, GOL)Placebo w/ or w/o standard care or standard care treatment alone29OR 1.94 (1.10-3.44)0%
Zhang et al. 201721)IMIDsIFXPlacebo w/ or w/o standard care or standard care treatment alone14OR 1.82 (0.82-4.06)0%
Zhang et al. 201721)IMIDsADAPlacebo w/ or w/o standard care or standard care treatment alone9OR 2.11 (0.73-6.12)0%
Zhang et al. 201721)IMIDsCZPPlacebo w/ or w/o standard care or standard care treatment alone3OR 2.38 (0.42-13.42)0%

Monoclonal-antibody vs. soluble-receptor TNF-alpha inhibitors
Ai et al. 20159)RAIFXETA10IRR 2.78 (2.10-3.69)46%
Ai et al. 20159)RAADAETA7IRR 3.88 (2.31-6.53)0%
Liao et al. 201713)RAIFX, ADAETA6RR 4.17 (1.52-11.11)0%

Abbreviation: CI, confidence interval; RA, rheumatoid arthritis; TNF-alpha, tumor necrosis factor-alpha; ADA, adalimumab; IFX, infliximab; ETA, etanercept; CZP, certolizumab pegol; GOL, golimumab; MTX, methotrexate; IRR, incidence rate ratio; DMARD, disease-modifying antirheumatic drug; RR, relative risk; N/A, not available; w/, with; w/o, without; OR, odds ratio; q4w, every 4 weeks; q2w, every 2 weeks; qow, every other week; q8w, every 8 weeks; IBD, inflammatory bowel disease; CD, Crohn’s disease; Ps, psoriasis; AS, ankylosing spondylitis; PsA, psoriatic arthritis; UC, ulcerative colitis; SpA, spondyloarthritis; IMID, immune-mediated inflammatory disease


TB risk associated with TNF-alpha inhibitors in IMID patients

We conducted meta-analysis on 38 study results from 12 articles on TB risk in TNF-alpha inhibitors treated IMIDs patients (Fig. 2A). Pooled analysis determined that treatment with TNF-alpha inhibitors in IMIDs patients was associated with an increased risk of TB compared to control group (RR 2.057, 95% CI 1.697 to 2.495) and this result was statistically significant.

Fig. 2A.

Tuberculosis risk associated with TNF-alpha inhibitors in immune-mediated inflammatory diseases patients. Abbreviations: CI, confidence interval; ADA, adalimumab; IFX, infliximab; ETA, etanercept; CZP, certolizumab pegol; GOL, golimumab; RA, rheumatoid arthritis; IBD, inflammatory bowel disease; CD, Crohn’s disease; SpA, spondyloarthritis; PsA, psoriatic arthritis; Ps, psoriasis; AS, ankylosing spondylitis; UC, ulcerative colitis; q4w, every 4 weeks; q2w, every 2 weeks; qow, every other week; q8w, every 8 weeks; IMID, immune-mediated inflammatory disease


TB risk associated with TNF-alpha inhibitors in RA patients

An analysis on 16 study results from 8 meta-analyses showed an increased incidence of TB in TNF-alpha inhibitor treated RA patients with a relative risk of 1.847 (RR 1.847, 95% CI 1.385 to 2.464) compared to control group. Fig. 2B shows the forest plot of the analysis performed on those 16 study results.

Fig. 2B.

Tuberculosis risk associated with TNF-alpha inhibitors in rheumatoid arthritis patients. Abbreviations: CI, confidence interval; ADA, adalimumab; IFX, infliximab; ETA, etanercept; CZP, certolizumab pegol; GOL, golimumab; q4w, every 4 weeks


TB risk associated with TNF-alpha inhibitors in non-RA patients

There was a total of 12 pooled estimates from 7 articles reported for TB risk in TNF-alpha inhibitor treated non-RA patients. TNF-alpha inhibitors in non-RA patients were consistently associated with a higher risk of TB infection compared to placebo (RR 2.236, 95% CI 1.284 to 3.894). Forest plot of this analysis is shown in Fig. 2C.

Fig. 2C.

Tuberculosis risk associated with TNF-alpha inhibitors in non-rheumatoid arthritis patients. Abbreviations: CI, confidence interval; ADA, adalimumab; IBD, inflammatory bowel disease; CZP, certolizumab pegol; GOL, golimumab; IFX, infliximab; CD, Crohn’s disease; Ps, psoriasis; ETA, etanercept; AS, ankylosing spondylitis; PsA, psoriatic arthritis; UC, ulcerative colitis; SpA, spondyloarthritis


TB risk associated with monoclonal-antibody TNF-alpha inhibitors vs. soluble-receptor TNF-alpha inhibitor in RA patients

In addition to overall TNF-alpha inhibitor-induced TB risk, we performed a subgroup analysis of TB risk between monoclonal-antibody TNF-alpha inhibitors and soluble-receptor TNF-alpha inhibitor specifically in RA patients. A total of 3 study results from 2 studies were included in this subgroup analysis. Compared to soluble-receptor TNF-alpha inhibitor, non-soluble monoclonal-antibody TNF-alpha inhibitors had increased TB risk with RR of 2.880 (RR 2.880, 95% CI 1.730 to 4.792). The results are shown in Fig. 3.

Fig. 3.

Tuberculosis risk associated with monoclonal-antibody vs. soluble-receptor TNF-alpha inhibitors in rheumatoid arthritis patients. Abbreviations: TNF-alpha, tumor necrosis factor-alpha; CI, confidence interval; IFX, infliximab; ETA, etanercept; ADA, adalimumab


DISCUSSION & CONCLUSION

To our knowledge, this study is the first umbrella review conducted in evaluating risk of TB in TNF-alpha inhibitors treated patients. With increasing number of systematic reviews and meta-analyses on tuberculosis risk associated with TNFalpha inhibitor treatment, this study conducted a methodology, umbrella review, to integrate, manage, and provide a comprehensive evidence on this safety issue.25,29)

Most meta-analyses included in this umbrella review demonstrated statistically insignificant TB risk associated with TNF-alpha inhibitors.9-21) In addition to statistically insignificant results, previous meta-analyses examined TB risk in single IMID indication in TNF-alpha inhibitor patients9,10,12,15,16,19,20) or analyzed overall infection risk or overall safety profile of TNF-alpha inhibitors10-16,19,20) rather than TB risk in specific. Also, among those meta-analyses, there were several studies that included single TNF-alpha inhibitor15,16,18), without integrating risk in TNF-alpha inhibitors in general. Thus, we aimed to synthesize and analyze those results to examine the trend and consistency compared to the existing studies on TB risk in TNF-alpha inhibitors treated IMIDs, RA, and non-RA patients, and between monoclonal-antibody TNF-alpha inhibitors and soluble-receptor TNF inhibitor as a subgroup analysis.

We identified 12 meta-analyses with 38 study results that examined the risk of TB in TNF-alpha inhibitors in IMIDs patients-including RA and non-RA IMID patients. Our study confirms the current knowledge on TB risk related to TNFalpha inhibitors.30) Compared to control group treatment, TNFalpha inhibitors were consistently associated with increased risk of TB across all therapeutic indications including IMIDs, RA, and non-RA patients.

Moreover, consistent with the known association, non-soluble monoclonal-antibody TNF-alpha inhibitors were more associated with the risk of TB than soluble-receptor TNF-alpha inhibitor. This significantly higher TB risk for monoclonal-antibody TNFalpha inhibitors than soluble-receptor TNF-alpha inhibitor might be explained by the different structures and mechanisms of action in TNF-alpha inhibitors.13,31) Monoclonal-antibody TNFalpha inhibitors bind to membrane-bound TNF as well as both active and inactive soluble TNF, which then form fixed complexes, lyse the TNF-expressed cells, and reduce host immune response. Different from monoclonal-antibody TNFalpha inhibitors, soluble-receptor TNF-alpha inhibitor binds to active soluble TNF and forms relatively unstable complexes allowing easier dissociation of TNF.32,33,34) This different mechanism of action between the two types of TNF-alpha inhibitors may explain the different TB risk between the two TNF-alpha inhibitor types.

Even though it is not on the exact same research question, Bonovas et al.35) conducted an umbrella review on the safety issue of biological therapies in patients with ulcerative colitis and evaluated TB risk results as one of the safety measurements in the study. However, this study examined overall safety issues in biological agents including ADA, GOL, IFX, along with vedolizumab which is not a TNF-alpha inhibitor and reported insignificant results for TB risk in biologics group. Also, Bonovas et al.35) performed a descriptive review of metaanalyses and did not perform a statistical analysis. Compared to Bonovas et al.35), our umbrella review has focused specifically on TB infection risk associated with TNF-alpha inhibitors extended from this Bonovas et al.35) study.

There are some limitations in this study that should be addressed. Since meta-analyses included in this umbrella review varied in their treatment follow up period, our study analysis was performed on varying study follow up period. In addition, because we did not directly analyze the raw data for each included study, we could not directly compare TB infection risk between TNF-alpha inhibitors treated RA patients and non-RA patients. Since RA patients tend to use marginally higher induction dose of TNF-alpha inhibitors for treatment than non-RA patients36-40), further research is needed to compare the TB risk between RA patients and non-RA patients.

In summary, this umbrella review provides an evidence-based synthesis of meta-analyses on TB risk in TNF-alpha inhibitors. This umbrella review could be an informative review which provides integrated results of the existing meta-analysis. Our results confirm that the risk of TB increases in TNF-alpha inhibitors treated IMIDs patients – including RA patients and non-RA patients. Therefore, in clinical settings, TNF-alpha inhibitors treated IMIDs patients should be carefully monitored of TB infection risk.

ACKNOWLEDGMENTS

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HC17C0069).

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