Positive Autoantibodies but Without Symptoms of Autoimmune Disorders

The presence of serum autoantibodies is essential for the diagnosis of an autoimmune disorder, but no one marker is pathognomonic for a certain autoimmune condition. In addition, many healthy persons carry "silent" autoantibodies, and they remain asymptomatic throughout their lives. These autoantibodies may represent a subclinical autoimmune dysregulation state, which may become manifest when a trigger, such as HCV or IFN, affects the subject. The presence of these autoantibodies ultimately does not compromise the host's immunologic response to pathogens, compared to the general population, and the literature suggests that these individuals have an acceptable response to IFN therapy. Nevertheless, these patients appear to be at a higher risk for the development of autoimmune complications during IFN therapy.

The report by Okanoue et al. (28), which followed 677 patients with chronic hepatitis C virus during therapy, found that autoimmune side effects were more frequent among those individuals who had pre-existing autoantibodies. Of 24 patients with pretreatment antimicrosomal antibodies, for example, four individuals (16%) developed hypothyroidism during therapy, compared to 2/653 (0.32%) without antimicrosomal antibodies, who developed this problem. Likewise, Custro et al. (29) found that HCV patients with pretreatment thyroid autoantibodies (antimicrosomal thyroid peroxidase and antithyroglobulin antibodies) were 3x more likely to develop hypothyroidism during therapy than HCV patients who were seronegative. Bell et al. (30) studied a group of patients with HCV hepatitis, including 20 patients who had one or more pre-existing autoantibody, and 20 patients without any pre-existing autoantibodies. During treatment with IFN-a, 6/20 patients (30%) with autoantibodies developed new immune-mediated disorders (hypothyroidism in two patients, hyperthyroidism in one patient, arthropathy in one patient, and psoriasis in one patient). In 20 patients without pretreatment autoantibodies, treatment with IFN did not result in any autoimmune complications. These authors concluded that patients with no detectable autoantibodies have a low risk for developing autoimmune complications during treatment of IFN-a, but patients with circulating antibodies are at significant risk for the development of such complications.

Patients with circulating autoantibodies appear to have an adequate viral response to IFN therapy, which is comparable to the response of the general population. Clifford et al. (31), in a retrospective review of 244

patients with HCV hepatitis, compared the viral response of patients who were positive for autoimmune markers (antinuclear antibody [ANA] antismooth muscle antibody, rheumatoid factor, and anti-liver-kidney microsome [LKM] antibodies), and the response of patients who were seronegative. The two groups of patients were similar in age, gender, and severity of disease, and had no significant differences in their response to IFN therapy (as defined by normalization of aminotransferase) during the therapy. Similarly, Bayraktar et al. (32) found no significant differences in the response to IFN, as defined by both HCV RNA negativity and normalization of serum alanine aminotransferase levels, between patients who were positive for autoantibodies and those who were not. A report by Van Thiel et al. (33) found similar results. In a well-designed prospective study, those investigators used IFN-a to treat chronic hepatitis C virus hepatitis patients with positive autoimmune "dysregulation" markers. The antiviral response rate was not affected by the presence of these autoantibodies. Likewise, Wada et al. (34) suggested that the presence of autoimmune markers in HCV patients does not necessarily predict a poor response to IFN-a therapy.

Two studies evaluated the antiviral response among patients with HCV, who were positive for the anti-LKM antibody. Todros et al. (35), from Italy, in 1995, treated 92 HCV patients with IFN-a2b, including 12 patients who were anti-LKM positive. Those investigators found that the virologic response to the therapy, and the side effects, were similar in the two groups. Similarly, Duclos-Vallee et al. (36) studied 5 HCV patients who were positive for anti-LKM, and each was treated with IFN-a2b. Side effects and viral response were similar to the autoantibody-seronegative population.

The above studies indicate that HCV patients with underlying anti-LKM autoantibody may be successfully treated with IFN-a2b; in most cases, the virologic response is not affected by the presence of underlying autoantibodies. Should IFN induce a clinical autoimmune syndrome in an asymptomatic carrier of autoantibodies, this phenomenon appears to be reversible after the cessation of IFN. Based on reported experience, asymptomatic patients with autoantibodies should not be excluded from treatment programs.

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