Antibodies to Infliximab Are Associated with Lower Infliximab Levels and Increased Likelihood of Surgery in Pediatric IBD

Zitomersky, Naamah; Atkinson, Benjamin J.; Fournier, Kerri; Mitchell, Paul D.; Stern, Julia Bender; Butler, Michael; Ashworth, Lori A.; Hauenstein, Scott; Heiner, Linda; Chuang, Emil; Singh, Sharat; Bousvaros, Athos

doi:10.1097/mib.0000000000000284

Cited by 47 publications

(41 citation statements)

References 32 publications

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“…Formation of antidrug antibodies has been linked to decreased serum drug concentrations and higher rates of loss of response 38 , 39 and surgery. 40 In our study, the prevalence of detectable antidrug antibodies was low. This could be expected because the study population consisted of long-term treatment responders, possibly leading to a selection of patients not developing antidrug antibodies.…”

Section: Discussioncontrasting

confidence: 51%

Subtherapeutic concentrations of infliximab and adalimumab are associated with increased disease activity in Crohn’s disease

Carlsen

Omdal

Leitao

et al. 2018

Therap Adv Gastroenterol

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Background:Low anti-tumor necrosis factor α (TNFα) serum concentrations may result in lack of treatment response in patients with inflammatory bowel disease. We determined the anti-TNFα drug concentrations in patients with inflammatory bowel disease and investigated whether or not subtherapeutic drug concentrations were associated with increased levels of disease activity.Methods:In a single-center cross-sectional study, we included patients with ulcerative colitis or Crohn’s disease who were receiving infliximab or adalimumab maintenance therapy. Demographic data, disease activity symptom scores (Partial Mayo Score, Harvey Bradshaw Index), inflammatory markers [C-reactive protein (CRP), fecal calprotectin], antidrug antibodies and serum drug concentrations were recorded. Therapeutic drug concentrations were defined as 3–8 mg/liter for infliximab and 5–12 mg/liter for adalimumab.Results:Of 210 patients included, 137 (65.2%) had Crohn’s disease. In the adalimumab group, subtherapeutic drug concentrations were measured in 16.7% of patients with ulcerative colitis and in 27.7% of patients with Crohn’s disease. In the infliximab group, subtherapeutic drug concentrations were found in 23% (ulcerative colitis) and 30.3% (Crohn’s disease) of patients. In Crohn’s disease, subtherapeutic adalimumab concentrations were associated with higher fecal calprotectin and CRP concentrations compared with therapeutic concentrations. Subtherapeutic infliximab concentrations in patients with Crohn’s disease were also associated with higher CRP concentrations compared with therapeutic concentrations.Conclusions:The prevalence of subtherapeutic drug levels ranged from 17% to 30%. In patients with Crohn’s disease, subtherapeutic serum drug concentrations were associated with significantly higher disease activity with both anti-TNFα agents. These findings were not observed in patients with ulcerative colitis. Clinicaltrials.gov identifier [NCT02134054]

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Section: Discussioncontrasting

confidence: 51%

Subtherapeutic concentrations of infliximab and adalimumab are associated with increased disease activity in Crohn’s disease

Carlsen

Omdal

Leitao

et al. 2018

Therap Adv Gastroenterol

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“…Differences in serum biologic concentrations between ADAb-positive and -negative patients were found to be statistically significant in studies of ADA [42–44, 47–50, 53–55, 57, 58, 61] and INF [54, 57, 58, 61, 87–91, 97, 98, 105, 107, 111, 113, 114] across chronic inflammatory diseases. In the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate, a 12-month observational prospective cohort study, ADAbs against ADA were detected in 31 of 160 (19%) ADA-treated patients and were significantly associated with lower ADA concentrations ( r s = −0.51; p < 0.0001) [44].…”

Section: Resultsmentioning

confidence: 99%

Immunogenicity of Biologics in Chronic Inflammatory Diseases: A Systematic Review

et al. 2017

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ObjectivesA systematic review was conducted to explore the immunogenicity of biologic agents across inflammatory diseases and its potential impact on efficacy/safety.MethodsLiterature searches were conducted through November 2016 to identify controlled and observational studies of biologics/biosimilars administered for treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), non-radiographic axial spondyloarthritis (nr-axSpA), psoriasis (Ps), Crohn’s disease, and ulcerative colitis.ResultsOf >21,000 screened publications, 443 were included. Anti-drug antibody (ADAb) rates varied widely among biologics across diseases (and are not directly comparable because of immunoassay heterogeneity); the highest overall rates were reported with infliximab (0–83%), adalimumab (0–54%), and infliximab biosimilar CT-P13 (21–52%), and the lowest with secukinumab (0–1%), ustekinumab (1–11%), etanercept (0–13%), and golimumab (0–19%). Most ADAbs were neutralizing, except those to abatacept and etanercept. ADAb+ versus ADAb− patients had lower rates of clinical response to adalimumab (RA, PsA, JIA, AS, Ps), golimumab (RA), infliximab (RA, PsA, AS, Ps), rituximab (RA), ustekinumab (Ps), and CT-P13 (RA, AS). Higher rates of infusion-related reactions were reported in infliximab- and CT-P13-treated ADAb+ patients. Background immunosuppressives/anti-proliferatives reduced biologic immunogenicity across diseases.ConclusionsBased on reviewed reports, biologic/biosimilar immunogenicity differs among agents, with the highest rates observed with infliximab and adalimumab. As ADAb formation in biologic-/biosimilar-treated patients may increase the risk of lost response, the immunogenicity of these agents is an important (albeit not the only) consideration in the treatment decision-making process.Electronic supplementary materialThe online version of this article (doi:10.1007/s40259-017-0231-8) contains supplementary material, which is available to authorized users.

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“…For studies included in this review in which serum levels of biologics were reported – ADM, CZP and IFX – ADAbs-positive patients had lower serum levels of the biologic than ADAbs-negative patients ( Table 2 ). 27 – 48 …”

Section: Resultsmentioning

confidence: 99%

Immunogenicity of biologics in inflammatory bowel disease

Vermeire

Gils

Accossato

et al. 2018

Therap Adv Gastroenterol

189

146

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Crohn’s disease and ulcerative colitis are chronic inflammatory disorders of the gastrointestinal tract. Treatment options include biologic therapies; however, a proportion of patients lose response to biologics, partly due to the formation of anti-drug antibodies (ADAbs). Concomitant immunosuppressive agents reduce the development of ADAbs. This review article aims to assess the immunogenicity of biologic therapies and their clinical implications. A comprehensive literature search was conducted for articles published January 2009 to August 2015 reporting immunogenicity to adalimumab (ADM), certolizumab pegol (CZP), golimumab, infliximab (IFX), ustekinumab, and vedolizumab in inflammatory bowel disease (IBD). Eligible articles were reviewed and quality assessed by independent reviewers. Overall, 122 publications reporting 114 studies were assessed. ADAbs were reported for all agents, but the percentage of patients developing ADAbs was extremely variable, with the highest (65.3%) being for IFX administration to patients with IBD. ADAb presence was frequently associated with a reduction in primary efficacy and a loss of response, and, for IFX, an increase in adverse events (AEs). Lower serum levels of ADM, CZP and IFX were seen in ADAbs-positive rather than ADAbs-negative patients; pharmacokinetic data were unavailable for other therapies. Little information was available regarding the timing of ADAb development; studies reported their detection from as early as 10–14 days up to months after treatment initiation. Biologic therapies carry an intrinsic risk of immunogenicity, although reported rates of ADAbs vary considerably. The clinical implications of immunogenicity are a concern for effective treatment; further research, particularly into the more recently approved biologics, is required.

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Antibodies to Infliximab Are Associated with Lower Infliximab Levels and Increased Likelihood of Surgery in Pediatric IBD

Cited by 47 publications

References 32 publications

Subtherapeutic concentrations of infliximab and adalimumab are associated with increased disease activity in Crohn’s disease

Subtherapeutic concentrations of infliximab and adalimumab are associated with increased disease activity in Crohn’s disease

Immunogenicity of Biologics in Chronic Inflammatory Diseases: A Systematic Review

Immunogenicity of biologics in inflammatory bowel disease

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