Infection Risk and Biologics: Current Update
Infection Risk and Biologics: Current Update
Tumour necrosis factor (TNF) plays an essential part in the host immune system. Early randomized controlled trials of the TNF inhibitors (TNFi) etanercept, infliximab and adalimumab did not report a higher rate of infection in the treatment groups than in the placebo groups, but subsequent observational studies, meta-analyses and reviews have raised concerns about infection. However, the data are inconsistent. Differing inclusion criteria, along with an increasing awareness of the risk of infection, which affected patient selection for biologic treatment, have made it difficult to compare data from different biologic registries. Although there is no head-to-head comparison of the anti-TNF agents with regard to infection risk, recent observational data from 2356 patients in the Dutch RA registry have identified a trend for lower risk of infection for etanercept than with infliximab or adalimumab. This might partly be explained by the different mode of action of etanercept, which is a soluble TNF receptor fusion protein, as compared with the monoclonal antibodies. The unadjusted incidence rate of a first serious infection per 100 patient year was 1.66 for etanercept, 2.61 for adalimumab and 3.86 for infliximab. The adjusted model confirmed a lower infection rate for etanercept. However, patients were not randomly assigned to treatments, and the risk of infection at baseline may have differed in the three groups.
A recent retrospective cohort study (Safety Assessment of Biologic Therapy) used four administrative data systems in the United States to investigate nonviral opportunistic infections in RA, inflammatory bowel disease and spondylitis. In RA, 24 384 new users of TNFi were compared with 11 828 patients treated with traditional DMARDs. The adjusted risk of nonviral opportunistic infection was not increased significantly in new users of TNFi, although infliximab was associated with an increased risk when compared with either traditional DMARDs or etanercept. Pneumocystis and mycobacterial infections accounted for almost half of the opportunistic infections occurring among new users of TNFi and most occurred within 6 months of TNFi initiation. The study relied on the use of administrative databases, which could result in misclassification of outcomes (for example, active TB versus latent TB) and underreporting of events, but these errors are likely to be seen across all treatment groups and probably do not affect the conclusions.
Skin and soft tissue infections have been reported to occur three times more frequently in RA patients than in the general population. The German biologics register (Rheumatoid Arthritis Observation of Biologic Therapy, RABBIT) identified a trend for increased rates of herpes zoster (shingles) infection with TNFi compared with traditional DMARDs, whereas the Spanish Registry of adverse events to biological therapy in rheumatic diseases (BIOBADASER) registry found that RA patients on TNFi were more likely to be hospitalized for chickenpox and shingles than patients on DMARDs. Most recently, a report from the British Society for Rheumatology Biologics Registers (BSRBR) demonstrated a significantly increased risk of shingles in TNFi-treated patients (1.6 per 100 patient year) compared with the DMARD cohort (0.8 per 100 patient year). The hazard risk for serious skin and soft tissue infections and for shingles varied over time, with a higher risk early on in therapy. However, this analysis did not include steroid use, and there were important differences between the biologic and DMARD-treated groups, with biologic-treated patients having higher disease activity.
Tumour Necrosis Factor Inhibitors in Rheumatoid Arthritis
Tumour necrosis factor (TNF) plays an essential part in the host immune system. Early randomized controlled trials of the TNF inhibitors (TNFi) etanercept, infliximab and adalimumab did not report a higher rate of infection in the treatment groups than in the placebo groups, but subsequent observational studies, meta-analyses and reviews have raised concerns about infection. However, the data are inconsistent. Differing inclusion criteria, along with an increasing awareness of the risk of infection, which affected patient selection for biologic treatment, have made it difficult to compare data from different biologic registries. Although there is no head-to-head comparison of the anti-TNF agents with regard to infection risk, recent observational data from 2356 patients in the Dutch RA registry have identified a trend for lower risk of infection for etanercept than with infliximab or adalimumab. This might partly be explained by the different mode of action of etanercept, which is a soluble TNF receptor fusion protein, as compared with the monoclonal antibodies. The unadjusted incidence rate of a first serious infection per 100 patient year was 1.66 for etanercept, 2.61 for adalimumab and 3.86 for infliximab. The adjusted model confirmed a lower infection rate for etanercept. However, patients were not randomly assigned to treatments, and the risk of infection at baseline may have differed in the three groups.
A recent retrospective cohort study (Safety Assessment of Biologic Therapy) used four administrative data systems in the United States to investigate nonviral opportunistic infections in RA, inflammatory bowel disease and spondylitis. In RA, 24 384 new users of TNFi were compared with 11 828 patients treated with traditional DMARDs. The adjusted risk of nonviral opportunistic infection was not increased significantly in new users of TNFi, although infliximab was associated with an increased risk when compared with either traditional DMARDs or etanercept. Pneumocystis and mycobacterial infections accounted for almost half of the opportunistic infections occurring among new users of TNFi and most occurred within 6 months of TNFi initiation. The study relied on the use of administrative databases, which could result in misclassification of outcomes (for example, active TB versus latent TB) and underreporting of events, but these errors are likely to be seen across all treatment groups and probably do not affect the conclusions.
Skin and soft tissue infections have been reported to occur three times more frequently in RA patients than in the general population. The German biologics register (Rheumatoid Arthritis Observation of Biologic Therapy, RABBIT) identified a trend for increased rates of herpes zoster (shingles) infection with TNFi compared with traditional DMARDs, whereas the Spanish Registry of adverse events to biological therapy in rheumatic diseases (BIOBADASER) registry found that RA patients on TNFi were more likely to be hospitalized for chickenpox and shingles than patients on DMARDs. Most recently, a report from the British Society for Rheumatology Biologics Registers (BSRBR) demonstrated a significantly increased risk of shingles in TNFi-treated patients (1.6 per 100 patient year) compared with the DMARD cohort (0.8 per 100 patient year). The hazard risk for serious skin and soft tissue infections and for shingles varied over time, with a higher risk early on in therapy. However, this analysis did not include steroid use, and there were important differences between the biologic and DMARD-treated groups, with biologic-treated patients having higher disease activity.
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