Improving Corticosteroid Therapy: Type 1 Autoimmune Hepatitis
Improving Corticosteroid Therapy: Type 1 Autoimmune Hepatitis
Objective: Relapse of autoimmune hepatitis may reflect incomplete suppression of disease activity prior to corticosteroid withdrawal, and liver tissue examination prior to the termination of therapy may be insufficient to predict subsequent course. Our goal was to refine treatment end point criteria so as to reduce the frequency of relapse after drug withdrawal.
Methods: One hundred thirty-two patients with definite type 1 autoimmune hepatitis who fulfilled clinical, laboratory, and histological criteria for remission were evaluated. The degree of laboratory improvement at the termination of treatment was correlated with subsequent clinical course in patients who had improved to normal or near-normal histological findings during corticosteroid therapy.
Results: Serum aspartate aminotransferase (AST) levels at the end of treatment were higher in patients who subsequently relapsed than in those who sustained remission (32 ± 2 U/L vs 25 ± 2 U/L, P = 0.04). Serum γ-globulin (1.4 ± 0.1 g/dL vs 1.2 ± 0.1 g/dL, P = 0.03) and immunoglobulin G (IgG) (1,416 ± 55 mg/dL vs 1,079 ± 57 mg/dL, P = 0.001) levels were also higher in these patients prior to termination of therapy. The frequencies of abnormal serum AST (40% vs 13%, P = 0.008), γ-globulin (25% vs 3%, P = 0.009), and IgG levels (36% vs 4%, P = 0.001) at treatment withdrawal were also greater in the patients who subsequently relapsed.
Conclusions: Patients who are treated to normal serum AST, γ-globulin, and IgG levels have a lower frequency of relapse than others despite comparable histological findings.
Prednisone alone or a lower dose in combination with azathioprine induces clinical, laboratory, and histological remission in 65% of patients with type 1 autoimmune hepatitis within 18 months and 80% within 3 yr. Remission, however, is difficult to sustain long term as discontinuation of medication is followed by relapse in 50-86% of patients within 1 yr. The high frequency of relapse has generated various management strategies that have included continuous treatment with doses adjusted periodically by laboratory behavior and fixed drug schedules that are administered long term. These schedules assume that the disease is either unlikely to sustain remission or that the treatment response is constant in all patients and requires a fixed interval of at least 2 yr to achieve.
Twenty-one percent of patients treated with standard corticosteroid regimens become inactive long term after initial therapy. The mean duration of remission in these patients exceeds 10 yr, and the period of inactivity extends as long as the follow-up period. Furthermore, some patients can achieve this outcome with less than 2 yr of treatment. Management strategies that discount the opportunity for sustained long-term remission or require uniform rigid treatment intervals may needlessly or excessively treat some patients and subject them to the consequences of drug-related side effects. An ideal approach would be to monitor indices of response that predict outcome after drug withdrawal and to individualize treatment regimens to account for the behavior of these indices.
The pathogenic mechanisms for relapse are uncertain, but earlier studies have shown that premature withdrawal of medication may be a factor. Patients treated to histological resolution of inflammatory activity have fared better than those with interface hepatitis or portal plasma cell infiltration at termination of treatment. These studies have emphasized that the histological findings are the important determinants of the treatment end point, and they have justified the recommendation that liver biopsy be performed prior to cessation of therapy. Histological improvement to normal or near-normal features, however, has not precluded relapse after drug withdrawal, and adjunctive indices are needed to optimize the treatment outcome. The value of the laboratory response in predicting sustained remission remains uncertain, especially since complete resolution of these indices has not been a requisite before drug withdrawal.
In this retrospective analysis of prospectively acquired data, we evaluate the laboratory findings immediately prior to termination of corticosteroid therapy in patients with type 1 autoimmune hepatitis who had satisfied histological criteria for remission. We correlate the laboratory findings with the subsequent clinical behavior, and in this fashion, we determine if the laboratory response can complement the histological findings in defining a treatment end point associated with long-term remission. Our goal was to refine treatment end point criteria so as to reduce the frequency of relapse after drug withdrawal.
Abstract and Introduction
Abstract
Objective: Relapse of autoimmune hepatitis may reflect incomplete suppression of disease activity prior to corticosteroid withdrawal, and liver tissue examination prior to the termination of therapy may be insufficient to predict subsequent course. Our goal was to refine treatment end point criteria so as to reduce the frequency of relapse after drug withdrawal.
Methods: One hundred thirty-two patients with definite type 1 autoimmune hepatitis who fulfilled clinical, laboratory, and histological criteria for remission were evaluated. The degree of laboratory improvement at the termination of treatment was correlated with subsequent clinical course in patients who had improved to normal or near-normal histological findings during corticosteroid therapy.
Results: Serum aspartate aminotransferase (AST) levels at the end of treatment were higher in patients who subsequently relapsed than in those who sustained remission (32 ± 2 U/L vs 25 ± 2 U/L, P = 0.04). Serum γ-globulin (1.4 ± 0.1 g/dL vs 1.2 ± 0.1 g/dL, P = 0.03) and immunoglobulin G (IgG) (1,416 ± 55 mg/dL vs 1,079 ± 57 mg/dL, P = 0.001) levels were also higher in these patients prior to termination of therapy. The frequencies of abnormal serum AST (40% vs 13%, P = 0.008), γ-globulin (25% vs 3%, P = 0.009), and IgG levels (36% vs 4%, P = 0.001) at treatment withdrawal were also greater in the patients who subsequently relapsed.
Conclusions: Patients who are treated to normal serum AST, γ-globulin, and IgG levels have a lower frequency of relapse than others despite comparable histological findings.
Introduction
Prednisone alone or a lower dose in combination with azathioprine induces clinical, laboratory, and histological remission in 65% of patients with type 1 autoimmune hepatitis within 18 months and 80% within 3 yr. Remission, however, is difficult to sustain long term as discontinuation of medication is followed by relapse in 50-86% of patients within 1 yr. The high frequency of relapse has generated various management strategies that have included continuous treatment with doses adjusted periodically by laboratory behavior and fixed drug schedules that are administered long term. These schedules assume that the disease is either unlikely to sustain remission or that the treatment response is constant in all patients and requires a fixed interval of at least 2 yr to achieve.
Twenty-one percent of patients treated with standard corticosteroid regimens become inactive long term after initial therapy. The mean duration of remission in these patients exceeds 10 yr, and the period of inactivity extends as long as the follow-up period. Furthermore, some patients can achieve this outcome with less than 2 yr of treatment. Management strategies that discount the opportunity for sustained long-term remission or require uniform rigid treatment intervals may needlessly or excessively treat some patients and subject them to the consequences of drug-related side effects. An ideal approach would be to monitor indices of response that predict outcome after drug withdrawal and to individualize treatment regimens to account for the behavior of these indices.
The pathogenic mechanisms for relapse are uncertain, but earlier studies have shown that premature withdrawal of medication may be a factor. Patients treated to histological resolution of inflammatory activity have fared better than those with interface hepatitis or portal plasma cell infiltration at termination of treatment. These studies have emphasized that the histological findings are the important determinants of the treatment end point, and they have justified the recommendation that liver biopsy be performed prior to cessation of therapy. Histological improvement to normal or near-normal features, however, has not precluded relapse after drug withdrawal, and adjunctive indices are needed to optimize the treatment outcome. The value of the laboratory response in predicting sustained remission remains uncertain, especially since complete resolution of these indices has not been a requisite before drug withdrawal.
In this retrospective analysis of prospectively acquired data, we evaluate the laboratory findings immediately prior to termination of corticosteroid therapy in patients with type 1 autoimmune hepatitis who had satisfied histological criteria for remission. We correlate the laboratory findings with the subsequent clinical behavior, and in this fashion, we determine if the laboratory response can complement the histological findings in defining a treatment end point associated with long-term remission. Our goal was to refine treatment end point criteria so as to reduce the frequency of relapse after drug withdrawal.