Opportunistic infections and biologic therapies in immune-mediated inflammatory diseases: consensus recommendations for infection reporting during clinical trials and postmarketing surveillance

Abstract

No consensus has previously been formed regarding the types and presentations of infectious pathogens to be considered as 'opportunistic infections' (OIs) within the setting of biologic therapy. We systematically reviewed published literature reporting OIs in the setting of biologic therapy for inflammatory diseases. The review sought to describe the OI definitions used within these studies and the types of OIs reported. These findings informed a consensus committee (infectious diseases and rheumatology specialists) in deliberations regarding the development of a candidate list of infections that should be considered as OIs in the setting of biologic therapy. We reviewed 368 clinical trials (randomised controlled/long-term extension), 195 observational studies and numerous case reports/series. Only 11 observational studies defined OIs within their methods; no consistent OI definition was identified across studies. Across all study formats, the most numerous OIs reported were granulomatous infections. The consensus group developed a working definition for OIs as 'indicator' infections, defined as specific pathogens or presentations of pathogens that 'indicate' the likelihood of an alteration in host immunity in the setting of biologic therapy. Using this framework, consensus was reached upon a list of OIs and case-definitions for their reporting during clinical trials and other studies. Prior studies of OIs in the setting of biologic therapy have used inconsistent definitions. The consensus committee reached agreement upon an OI definition, developed case definitions for reporting of each pathogen, and recommended these be used in future studies to facilitate comparison of infection risk between biologic therapies.

Long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to 8.5 years: integrated analysis of data from the global clinical trials

“…37 Rates of fungal and viral OIs were similar to those previously reported, 20 suggesting OIs are a risk with tofacitinib, although it is unclear whether risk differs from that associated with bDMARDs. Precise estimations of differences in OI risk among RA therapies are limited by heterogeneous definitions of OIs, 38 geographical variability and lack of head-to-head studies with sufficient power to detect differences. A higher incidence of TB has been observed in patients with RA versus the general population, and in those receiving TNFi.…”

Risk of Herpes Zoster in Individuals on Biologics, Disease-Modifying Antirheumatic Drugs, and/or Corticosteroids for Autoimmune Diseases: A Systematic Review and Meta-Analysis

“…Numerous meta-analyses have evaluated the general risk of serious infections or opportunistic infections, defined as development of a mycobacterial, fungal, or viral infection, during treatment with biologics and/or nbDMARDs. These studies have shown a clear risk of granulomatous infections, such as tuberculosis with biologics, but not necessarily for viral infections, although this may be related to lack of standardized reporting in RCTs [8, 76, 78, 79]. There were insufficient RCT data to enable us to examine HZ risk according to specific biological agents, but we did stratify our analysis according to the type of biologic and found evidence of a greater risk of HZ with non-TNF biologics.…”

“…This may be due to the RCTs being underpowered to detect differences in rare AEs such as HZ [79]. The types of nbDMARD used in the trials and clinical practice vary considerably, and our meta-analysis studies included 8 different nbDMARDs, because such we were not able to stratify results by drug, other than tofacitinib, which had enough RCTs for us to pool the results.…”

Opportunistic infections in patients with idiopathic inflammatory myopathies

“…Data regarding OIs were retrieved from the patients’ medical records and were defined in accordance with a recently published consensus document describing the specific pathogens and clinical presentations that ‘indicate’ the likelihood of a host immune abnormality in the setting of immunosuppressive therapy …”

“…Data regarding OIs were retrieved from the patients' medical records and were defined in accordance with a recently published consensus document describing the specific pathogens and clinical presentations that 'indicate' the likelihood of a host immune abnormality in the setting of immunosuppressive therapy. 16 The standard treatment in our DM/PM patients includes administration of glucocorticoids (1 mg/kg/ day) plus at least one of the following immunosuppressive drugs: azathioprine, methotrexate, cyclosporine, tacrolimus, cyclophosphamide (pulses) and mycophenolate mofetil. Various therapeutic approaches are used in refractory myositis patients: switching from one drug to another, adding another immunosuppressive drug to the first one, and/or use of biological therapy with infliximab, adalimumab, etanercept or rituximab.…”