Systematic reviews and meta-analyses
Effects of Combination Therapy With Immunomodulators on Trough Levels and Antibodies Against Tumor Necrosis Factor Antagonists in Patients With Inflammatory Bowel Disease: A Meta-analysis

https://doi.org/10.1016/j.cgh.2017.02.005Get rights and content

Background & Aims

It is not clear whether combination therapy with immunomodulators affects the immunogenicity of tumor necrosis factor (TNF) antagonists in patients with inflammatory bowel disease. We performed a meta-analysis to quantify the effects of combined immunomodulator therapy on the presence of antibodies against TNF antagonists (antidrug antibodies [ADAs]) and trough levels of anti-TNF agents.

Methods

We systematically searched publication databases for studies that reported prevalence of ADAs in patients who received anti-TNF agents. Raw data from studies that met the inclusion criteria were pooled to determine effect estimates. We performed subgroup and metaregression analyses to determine the level of heterogeneity among study outcomes.

Results

We analyzed findings from 35 studies that met inclusion criteria (results reported from 6790 patients with inflammatory bowel disease). The pooled risk ratio for formation of ADAs in patients receiving combined therapy with immunomodulators, versus that of patients receiving anti-TNF monotherapy, was 0.49 (95% confidence interval, 0.41–0.59; P < .001). However, the pooled analysis did not demonstrate a significant difference in trough levels of anti-TNF agents between patients with versus without concurrent use of immunomodulators (standardized mean difference, 0.11; 95% confidence interval, 0.19–0.41; P = .47). Subgroup analyses of patients treated with different TNF antagonists revealed no difference in the formation of ADAs (P = .50 for interaction); the protective effect of immunomodulators did not differ with type of drug patients were given (methotrexate vs thiopurines), or assay for ADA. We observed heterogeneity only among studies of patients with ulcerative colitis (I2 = 76%). Funnel plot and Egger test analyses indicated publication bias in the studies (P = .001).

Conclusions

In a meta-analysis of published studies, we associated combined treatment with immunomodulators with reduced risk of formation of antibodies against TNF antagonists in patients with inflammatory bowel disease.

Section snippets

Methods

The study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.9

Study Characteristics

Figure 1 depicts the study selection process. Of the 3478 references identified from database searches, 235 articles were selected for full text review. After reviewing the full text, 154 articles were excluded. Of the remaining 81 articles, 46 articles were excluded for the reasons detailed in Supplementary Table 1, and 35 studies5, 6, 7, 8, 12, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 that reported results in 6790

Discussion

Several observational studies and randomized controlled trials have examined the association between concurrent use of immunomodulators and ADAs formation in treatment of patients with IBD. To the best of our knowledge, the present study is the first meta-analysis to investigate the pooled impact of concomitant immunomodulators on immunogenicity of all approved anti-TNFs including IFX, adalimumab, certolizumab, and golimumab in patients with IBD. Overall, patients with IBD who are on anti-TNF-α

References (54)

  • J.F. Colombel et al.

    Infliximab, azathioprine, or combination therapy for Crohn's disease

    N Engl J Med

    (2010)
  • E.A. Maser et al.

    Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn's disease

    Clin Gastroenterol Hepatol

    (2006)
  • B. Pariente et al.

    Trough levels and antibodies to infliximab may not predict response to intensification of infliximab therapy in patients with inflammatory bowel disease

    Inflamm Bowel Dis

    (2012)
  • H. Imaeda et al.

    Relationship between serum infliximab trough levels and endoscopic activities in patients with Crohn's disease under scheduled maintenance treatment

    J Gastroenterol

    (2014)
  • D. Moher et al.

    Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

    Ann Intern Med

    (2009)
  • J.P. Higgins et al.

    The Cochrane Collaboration's tool for assessing risk of bias in randomised trials

    BMJ

    (2011)
  • A. Stang

    Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses

    Eur J Epidemiol

    (2010)
  • B.E. Sands et al.

    Infliximab maintenance therapy for fistulizing Crohn's disease

    N Engl J Med

    (2004)
  • M.E. Buyse

    Analysis of clinical trial outcomes: some comments on subgroup analyses

    Control Clin Trials

    (1989)
  • B. Schneider

    Analysis of clinical trial outcomes: alternative approaches to subgroup analysis

    Control Clin Trials

    (1989)
  • L. Peyrin-Biroulet et al.

    Defining disease severity in inflammatory bowel diseases: current and future directions

    Clin Gastroenterol Hepatol

    (2016)
  • W.L. Baker et al.

    Understanding heterogeneity in meta-analysis: the role of meta-regression

    Int J Clin Pract

    (2009)
  • M. Egger et al.

    Bias in meta-analysis detected by a simple, graphical test

    BMJ

    (1997)
  • S.P. Hozo et al.

    Estimating the mean and variance from the median, range, and the size of a sample

    BMC Med Res Methodol

    (2005)
  • J.P. Higgins et al.

    Quantifying heterogeneity in a meta-analysis

    Stat Med

    (2002)
  • F. Baert et al.

    Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease

    N Engl J Med

    (2003)
  • E. Miele et al.

    Human antichimeric antibody in children and young adults with inflammatory bowel disease receiving infliximab

    J Pediatr Gastroenterol Nutr

    (2004)

    • Cited by (48)

    • The efficacy of adalimumab in treating patients with central multifocal choroiditis

      2020, American Journal of Ophthalmology Case Reports
      Citation Excerpt :

      In most cases, though not all, adalimumab was reported to be effective, which is in line with the results of our study. All patients were concomitantly treated with IMT for synergistic effect as well as prohibition of the formation of anti-drug antibodies to adalimumab, though literature is conflicting concerning the latter indication.27 In our study, intravitreal anti-VEGF injections were extended and discontinued after the initiation of treatment with adalimumab.

    • AGA Technical Review on the Management of Moderate to Severe Ulcerative Colitis

      2020, Gastroenterology
      Citation Excerpt :

      First, immunomodulators have their independent efficacy in patients with UC, which may add to the benefits observed with biologics. Second, immunomodulators have been consistently shown to decrease the risk of immunogenicity to biologic agents and may increase trough concentrations of these agents.98 However, direct comparison with drugs other than infliximab are lacking, and the rates of immunogenicity with adalimumab, golimumab, vedolizumab, and ustekinumab are lower than with infliximab.

    • Chinese clinical practice guideline on the management of Crohn′s disease (2023, Guangzhou)

      2024, Chinese Journal of Inflammatory Bowel Diseases

    • Controversies in the management of anti-TNF therapy in patients with Crohn's disease: a Delphi consensus

      2024, BMJ Open Gastroenterology

    • Methotrexate is the re-discovered drug for Crohn’s disease

      2024, Gastroenterologie a Hepatologie

    • Oral Versus Subcutaneous Methotrexate in Immune-Mediated Inflammatory Disorders: an Update of the Current Literature

      2023, Current Rheumatology Reports
    View all citing articles on Scopus

    Conflicts of interest The authors disclose no conflicts.

    Funding This study was financially supported by the National Natural Science Foundation of China (grants 81470821, 81670498, 81630018, and 81500501).

    a

    Authors share co-first authorship.

    View full text
    © 2017 by the AGA Institute