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The use of therapy targeting immunoregulatory cytokines or immune cells (“biologic response modifiers” or “biologics”) has become commonplace in the treatment of certain autoimmune disorders. Common nonmalignant diseases treated with biologics include rheumatoid arthritis (RA), psoriasis, inflammatory bowel disease, and multiple sclerosis (MS). It follows that when immune regulatory molecules or cells are targeted and their function is inhibited, infectious or malignant complications resulting from a deficient immune system might arise. Redundancy in our immune system tends to mitigate against a high rate of such complications, so reaching conclusions about infection risk requires large numbers of patients for study.
Registries of patients receiving biologics have been most useful in this regard, but registries include all comers, with patients having wide-ranging demographics, severities of illness, concomitant therapies, and comorbidities, so drawing conclusions can be problematic. Also, registries mostly represent the oldest biologics, such as the tumor necrosis factor (TNF) inhibitors etanercept, adalimumab, and infliximab, as the newer agents have been used in far fewer patients. Controlled trials may be much smaller and may exclude important groups of patients because of strict enrollment criteria. Meta-analyses, in an effort to make sense of small uncontrolled and controlled trials, overcome some of the problems of registries but maintain others. Not to be ignored, infection may be associated with the inflammatory disease itself, further complicating the ability to draw conclusions about treatment-associated infection risk.
It is useful to start by understanding which biologics are approved for which diseases, and what immune functions are being inhibited. The TNFα inhibitors etanercept, adalimumab, infliximab, golimumab, and certolizumab pegol are approved for the treatment of RA, as well as psoriatic arthritis and ankylosing spondylitis. All are monoclonal antibodies except etanercept, which is a fusion protein of the TNF receptor with an immunoglobulin G1 antibody.1 Other monoclonal antibodies approved for the treatment of RA include rituximab, which is an anti-CD20 monoclonal antibody that triggers B-cell death, and 2 anti-interleukin (IL)-6 receptor antagonists, tocilizumab and sarilumab, with the latter having received approval by the US Food and Drug Administration in May 2017.
Anakinra, an anti-IL-1 receptor antagonist; abatacept, which inhibits T-cell activation; and tofacitinib, a Janus kinase inhibitor, are also approved for the treatment of RA but are not monoclonal antibodies. Along with the TNFα inhibitors etanercept, adalimumab, and infliximab, several monoclonal antibodies are approved for the treatment of psoriasis: ustekinumab, which binds to the p40 subunit of IL-12 and IL-23 to inhibit the binding of these cytokines to their receptors on NK and T cells,2 and secukinumab and ixekizumab, which are anti-IL-17A monoclonal antibodies. The TNFα inhibitors adalimumab, infliximab, and certolizumab pegol are approved for the treatment of Crohn’s disease, and infliximab and golimumab are approved for the treatment of ulcerative colitis. The monoclonal antibodies natalizumab and vedolizumab are also approved for use in inflammatory bowel disease (natalizumab for Crohn’s disease and vedolizumab for Crohn’s disease and ulcerative colitis); these antibodies bind to α4 integrins, cell adhesion molecules on leukocytes involved in their movement through cell barriers.3 Natalizumab is also approved for use in patients with MS. Alemtuzumab, an anti-CD52 monoclonal antibody; daclizumab, an anti-IL-2 receptor monoclonal antibody; and ocrelizumab, an anti-CD20 monoclonal antibody just approved in March 2017, are also approved to treat MS.
Studies make the distinction between opportunistic infections associated with biologics and “routine” infections, and also classify infections as serious infections or not. A serious infection is usually defined as an infection that results in death, hospitalization, or intravenous antibiotic use.4 The definition of opportunistic infection, as it applies to biologics, is not as well worked out as it is for HIV infection; after all, any infection, be it more routine or more unusual, is opportunistic if it would not have occurred in the absence of the biologic treatment.
TNFα Inhibitors
TNFα is an inflammatory cytokine produced by macrophages and T lymphocytes that plays a role in cell differentiation, proliferation, and recruitment.5 Elevated levels of TNFα are measurable in infections and inflammatory diseases, implicating the cytokine in host response, and potentially pathogenesis.5 TNFα has been shown to be important in granuloma formation and maintenance of granulomas,6 so it follows that patients receiving a TNFα inhibitor would be at increased risk for infections caused by organisms that are controlled by granuloma formation.
