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Original Investigation |

Immunogenicity of Monoclonal Antibodies Against Tumor Necrosis Factor Used in Chronic Immune-Mediated Inflammatory Conditions:  Systematic Review and Meta-analysis

Jose Ramon Maneiro, MD1; Eva Salgado, MD1; Juan Jesus Gomez-Reino, PhD1,2
[+] Author Affiliations
1Rheumatology Unit, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago, Spain
2Department of Medicine, Medical School, Universidad de Santiago, Santiago, Spain
JAMA Intern Med. 2013;173(15):1416-1428. doi:10.1001/jamainternmed.2013.7430.
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Importance  Knowledge of the immunogenicity of biologic agents may be helpful for the development of strategies for treatment of chronic immune-mediated inflammatory diseases.

Objective  To summarize the influence of antibodies against biologic agents (AABs [seropositivity]) on efficacy and safety in immune-mediated inflammatory diseases.

Data Sources  MEDLINE, EMBASE, Cochrane Library, and the Web of Knowledge were searched for articles published in English, Spanish, French, Italian, or Portuguese between 2000 and March 2012. The search strategy focused on synonyms of diseases, immunogenicity, and biologic agents. Abstracts from 2001 to 2011 of the European League Against Rheumatism and American College of Rheumatology congresses were also included.

Study Selection  The selection criteria were (1) observational or interventional studies in rheumatoid arthritis, juvenile idiopathic arthritis, inflammatory bowel disease, spondyloarthritis, and psoriasis; (2) studies including patients who received biologic agents; and (3) studies collecting data on AABs.

Data Extraction and Synthesis  Data collected included publication details, study design, characteristics of patients and treatments, presence of antibodies, and definition of response.

Main Outcomes and Measures  The primary end point was the association of AABs with response to treatment. Secondary end points were the association of AABs with safety, the association of AABs with concentration of the drug, and the influence of use of concomitant immunosuppressive therapy in the formation of AABs.

Results  The search captured 10 728 articles and abstracts. By hand and reverse search, 31 articles were additionally included. After evaluation of the full reports, 60 references were selected. They included 59 studies of anti–tumor necrosis factor monoclonal antibodies: 1 with etanercept, 2 with rituximab, and 2 with abatacept. In rheumatoid arthritis but not in inflammatory bowel disease or spondyloarthritis, seropositive patients presented worse clinical response at 6 months or less (odds ratio [OR], 0.03; 95% CI, 0.01-0.21), and at 6 months or more (0.03; 0.00-0.30) by meta-analysis. In rheumatoid arthritis, discontinuation of the biologic agent for all reasons was more common in seropositive patients (OR, 3.53; 95% CI, 1.60-7.82). In all conditions, seropositive patients had a higher risk of hypersensitivity reactions (OR, 3.97; 95% CI, 2.36-6.67). Overall, concomitant treatment with disease-modifying antirheumatic drugs, including azathioprine, decreased the risk of seropositivity (OR, 0.32; 95% CI, 0.25-0.42).

Conclusions and Relevance  Presence of antibodies against anti–tumor necrosis factor monoclonal antibodies confers a risk of discontinuation of treatment in rheumatoid arthritis and a risk of development of hypersensitivity reactions in all immune-mediated inflammatory diseases. The combined use of anti–tumor necrosis factor monoclonal antibodies and disease-modifying antirheumatic drugs reduces the development of antibodies and subsequent risks. Information on other biologic agents is fragmentary.

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Figure 1.
Meta-analysis of Association of Antibodies Against Biological Therapies (AABs) With Efficacy

Size of the data marker corresponds to the relative weight assigned in the pooled analysis using random-effects analysis. A, Association with European League Against Rheumatism (EULAR) response at 6 months or less. B, Association with EULAR response at 6 months or more. C, Association with Assessment in AS International Working Group response. D, Association with clinical response in inflammatory bowel disease. AAB– indicates seronegative patients; AAB+, seropositive patients; ACT, Active Ulcerative Colitis Trial; ADA, adalimumab; IFX, infliximab; OR, odds ratio.

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Figure 2.
Meta-analysis of Association of Antibodies Against Biological Therapies (AABs) With Hypersensitivity Reactions

Size of the data marker corresponds to the relative weight assigned in the pooled analysis using random-effects analysis. AAB– indicates seronegative patients; AAB+, seropositive patients; ACT, Active Ulcerative Colitis Trial; OBS, observational study; OR, odds ratio.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.
Meta-analysis of Concomitant Treatment Influence in Development of Antibodies Against Biological Therapies

Size of the data marker corresponds to the relative weight assigned in the pooled analysis using random-effects analysis. ACT indicates Active Ulcerative Colitis Trial; ADA, adalimumab; CTZ, certolizumab; INF, infliximab; OR, odds ratio.

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