Interferon alpha-induced lupus: proof of principle.

Abstract

In this month's issue of Journal of Clinical Rheumatology, Ho et al1 present a case of severe systemic lupus erythematosus (SLE) which developed during interferon alpha (IFN-α) therapy for chronic hepatitis C. This case of life-threatening SLE adds to a growing body of literature suggesting that exogenous IFN-α can induce severe systemic autoimmune disease in some individuals. IFN-α is a type I interferon that plays an important role in viral defense. Some of the physiologic functions of IFN-α include activation of dendritic cells and increased expression of major histocompatibility complex class I and II molecules, leading to increased antigen presentation.2 This suggests that IFN-α can bridge the innate and adaptive immune systems, and thus could play an important role in immunologic self-tolerance in both health and disease. High levels of circulating IFN-α have been described in SLE patients,3,4 and IFN-α present in SLE patient serum is capable of inducing differentiation and activation of antigen presenting cells in vitro.5 While these in vitro data suggest that IFN-α could play a role in SLE pathogenesis, cases of IFN-α-induced SLE such as the one presented in this issue of the journal provide an in vivo “proof of principle” that IFN-α can be sufficient to induce SLE in certain individuals. A number of other cases of IFN-α-induced SLE have been described, which reflect the diverse clinical spectrum of idiopathic SLE, including malar rash, nephritis, hypocomplementemia, and characteristic autoantibodies such as antidsDNA, anti-Ro, and anti-Sm.6,7 In many instances, SLE symptoms resolve after discontinuation of the IFN-α and a short course of immunosuppressive therapy, supporting the idea that IFN-α was causal.7 Some cases are not reversible, however, and the case presented in this issue of the journal demonstrates that IFN-α-induced SLE can be extremely severe and life threatening. Although clinical SLE is relatively rare during IFN-α therapy (<1% of patients treated with IFN-α),8 a greater number of patients develop a “lupus-like” syndrome, meeting fewer than 4 of the 11 formal criteria for SLE.9 Studies of patients receiving IFN-α for hepatitis C suggest that individuals with a positive antinuclear antibody test before therapy may be more likely to develop autoimmune complications while receiving IFN-α therapy.10 There are also reports of IFN-α therapy worsening pre-existing autoimmunity,11 and due to these reports autoimmune disease is listed as a relative contraindication to IFN-α treatment. In SLE patients, high levels of IFN-α are associated with particular clinical characteristics, including renal disease, low complement, double-stranded DNA antibodies, and antibodies to RNA-binding proteins such as Ro, La, Sm, and RNP.12 High serum IFN-α activity is also associated with increased disease activity in a number of studies.12,13 Approximately 50% of SLE patients show evidence of high serum IFN-α activity in large cross-sectional studies,4,14 and these patients represent a substantial subgroup within SLE who likely share a common pathogenesis related to IFN-α. In a disease as clinically heterogeneous as SLE, subclassifying patients may be useful for both prognosis and treatment. Anti-IFN-α antibody therapies are currently in early phase clinical trials in SLE, and eventually these therapies may be directed preferentially at the “high IFN-α” subgroup of SLE patients. Abnormally high levels of serum IFN-α are frequently found in healthy first degree relatives of SLE patients, and serum IFN-α activity levels in closely related individuals are well correlated, suggesting that high serum IFN-α is a heritable risk factor for SLE.14 Genetic polymorphisms in 2 genes in the IFN-α signaling pathway, IRF5 and Tyk2, have been associated with susceptibility to SLE.15,16 The association of IRF5 with SLE has been validated in large SLE cohorts, and risk at this locus has been mapped to a haplotype containing a number of functional variants.16,17 IRF5 is a transcription factor that can directly induce transcription of IFN-α. Recent work from our group has demonstrated that SLE patients carrying the IRF5 risk haplotype have higher serum IFN-α than SLE patients lacking the risk haplotype,18 supporting the idea that the IRF5 SLE-risk variant results in risk of SLE by predisposing to higher IFN-α production. Cases such as the one presented in this issue of the journal describe a highly unfortunate series of events, and remind us that serious immunologic consequences can accompany IFN-α therapy. Beyond their importance as cautionary tales, however, cases of IFN-α-induced SLE have inspired many of above referenced investigations which have shed light on the role of IFN-α in SLE pathogenesis. The finding that an exogenously administered agent can be sufficient to induce a complex systemic human autoimmune disease is striking, even when it is a rare event. Much insight has been gained regarding IFN-α as a causal factor for SLE in recent years, providing hope that we will have a better map of some of the early pathogenic events in SLE. This work could result in newer, more specific therapeutics or possibly even preventive agents targeting the IFN-α pathway in SLE.