Autoimmunity as a prognostic factor in melanoma patients treated with adjuvant low‐dose interferon alpha

Abstract

Interferon alpha is used for the adjuvant treatment of malignant melanoma at different dosages (high-, intermediate-, low-dose therapy). Only a minority of patients might benefit from this therapy, and markers to identify such patients are missing. A recent study suggested that melanoma patients developing autoantibodies or clinical manifestations of autoimmunity during adjuvant highdose interferon alpha treatment had a significant survival benefit. We retrospectively reviewed 134 melanoma patients from our institution treated with adjuvant low-dose interferon alpha therapy and correlated the development of autoimmune diseases with prognosis. Interferon (IFN) therapy was routinely monitored by history, physical examination and laboratory tests before, after the first month and then after every 3 months of therapy. During a median follow up of 46.0 months (8.5-79.0 months) 28 patients (20.9%) suffered from recurrences and melanoma related deaths occurred in 16 patients (11.9%). In 20 patients (14.9%) autoimmune thyroiditis (AIT) was diagnosed during IFN therapy, one of these 20 patients developed rheumatoid arthritis later while continuing IFN therapy. Other autoimmune diseases were not observed. In 2 patients (one with AIT and one with arthritis) the autoimmune disease led to discontinuation of IFN therapy, in the other patients AIT remained subclinical or responded well to treatment while IFN therapy was continued. Kaplan-Meier analyses revealed a significant better recurrence free survival and a trend for a better overall survival for patients with AIT. Thus, autoimmunity triggered by low-dose IFN therapy appears to indicate an improved prognosis and should encourage continuation of IFN therapy. ' 2007 Wiley-Liss, Inc.

Autoimmunity and treatment outcome in melanoma

“…Landmark analyses at 3 and 12 months showed a persistently strong association between autoimmune manifestations and RFS and OS (all P < 0.001). Analyzing the effects of autoimmunity in patients treated with low-dose interferon (LDI), Satzger et al [27] showed that the occurrence of autoimmune thyroid disease in 20 out of 134 patients (14.9%) correlated with a significantly better RFS (P ¼ 0.048) and a trend towards improved OS (P ¼ 0.065). The results of abovementioned trials appeared promising; however, since both studies analyzed the effects of autoimmunity on outcome in patients all receiving IFN treatment, the conclusion that autoimmunity could serve as a predictive marker for treatment response could not be drawn.…”

“…Satzger et al [27] did not use any statistical tests to correct for guarantee-time bias and therefore the observation that autoimmunity is beneficial in patients treated with LDI is difficult to interpret. The other abovementioned studies performed landmark analyses and time-dependent Cox model analyses to correct for guarantee-time bias.…”

Adjuvant interferon therapy and rheumatoid arthritis – a contraindication?

“…In a larger study about side effects of IFN treatment in hepatitis C, the rate of newly diagnosed RA after IFN start was 0.3% (2 of 677 patients) [10] while the prevalence of RA in the general population is 8/1000 [13]. This is in marked contrast to the frequent appearance of autoimmune thyroid antibodies under IFN treatment (26% according to the study by Gogas and coworkers [14]) and the high rate of clinical onset of autoimmune thyroid disease (15% according to the study by Satzger and coworkers [15]). …”

“…In the apparently unlikely event that RA is induced or exacerbated by IFN there is a good chance to control the disease by antirheumatic substances, although inhibitors of TNF are banned for use in patients with malignancies. In this context it is noteworthy that in melanoma the induction of exacerbation of RA under adjuvant IFN therapy may present a positive sign because the appearance of autoantibodies or clinical manifestations of autoimmunity during treatment with IFNa has been shown to be of significant improvement in PFS and OS [14,15].…”

The Adjuvant Effect in Infection and Autoimmunity

“…For example, patients receiving type I IFN for treatment of malignancy show a significant increase in autoimmune thyroid disease [9]. In contrast, treatment of NOD mice with complete Freund adjuvant prevents the development of insulitis and autoimmune diabetes [10].…”