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Editorial

Use of Immunomodulary Agents is Difficult in Treating Autoimmune Hepatitis Patients

Gordon, Fredric D MD; Simpson, MaryAnn PhD

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Journal of Clinical Gastroenterology: October 2004 - Volume 38 - Issue 9 - p 729-730
doi: 10.1097/01.mcg.0000139177.33502.47
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Autoimmune hepatitis (AIH) is a common condition affecting 11% to 23% of patients with chronic liver disease in the United States.1 Its manifestations may be occult, presenting with mildly abnormal transaminases or fulminant with jaundice, coagulopathy, and encephalopathy. Fortunately, AIH is usually responsive to immunosuppressive therapy and life expectancy can be similar to a healthy aged-matched population. Biochemical response is expected in 80% of patients; however, relapse is common. Even among biochemical responders, histology may progress toward cirrhosis. The effectiveness of the standard treatment regimen (prednisolone with or without azathioprine [AZA]) may be limited by patient intolerance of side effects.

In this issue of The Journal of Clinical Gastroenterology, Aqel et al2 analyze a group of patients with AIH unresponsive to standard immunosuppression treated with a more aggressive immunosuppression regimen. Eleven patients with steroid refractory AIH were treated with tacrolimus as the primary immunosuppressive agent, allowing dose reductions or discontinuation of the standard immunosuppressants. All subjects met the diagnostic criteria set forth by the International AIH Group.3 After a median 25-month duration of therapy and 16 month follow-up period, clinical and biochemical remission was achieved in 91%. Importantly, histologic improvement was also noted.

In evaluating the effectiveness of treatment in a “difficult-to-treat” group of patients it is necessary to establish a rigorous definition of “refractory.” Aqel et al2 defined “steroid-refractory” as persistent elevation of the transaminases greater than 2 times the upper limit of normal and intolerance of steroids necessary to induce a biochemical remission. Although these are reasonable definitions of “refractory,” the result may be 2 distinct groups of patients, specifically those in whom steroids are truly ineffective and those who would have been successfully treated but were intolerant due to adverse reactions. The latter group may not actually be more “difficult-to-treat” biasing the data toward a successful outcome. Additionally it would have been interesting to know the serologic autoimmune marker status of the subjects as it is known that patients with anti-LKM antibodies can have a more aggressive course of disease.4

Numerous papers have been published evaluating the efficacy of other immunomodulatory agents for those patients who have failed standard therapy. These drugs include cyclosporine, budesonide, mycophenolate mofetil, cyclophosphamide, and methotrexate.5 Although the published clinical experience is still quite limited, cyclosporine has been the most extensively evaluated and shares many features with tacrolimus. Studies looking at cyclosporine treated AIH patients range in size from 1–19 subjects. All have shown improvement in biochemical parameters and histologic features (when evaluated) and acceptable side effect profiles. However, discontinuation of the drug often resulted in relapse suggesting that ongoing immunosuppression in these refractory patients is necessary.6 In their study relapse did not occur during a relatively short median follow-up period of 16 months.

Given the extensive use of interleukin-2 blockers in the transplant population there are likely lessons to be learned from patients transplanted for AIH-related liver failure. Tacrolimus is a potent immunosuppressive; its immediate action is the inhibition of the calcineurin complex while its immunologically relevant action is the suppression of IL-2 production. IL-2 is arguably the most important of the cytokines in terms of its role as orchestrator of immune activation. There is extensive experimental evidence documenting the requirement for IL-2 for maximal response to both auto- and allo-antigens. From this point of view, the use of tacrolimus to treat autoimmune hepatitis is sound. However, as AIH can and does occur in the setting of liver transplant patients who are already imunosuppressed with tacrolimus, other mechanisms must be considered. IL-2 is a member of a cytokine group called the “gamma-chain receptor” family. They share a common receptor chain and several biologic activities. IL-7, IL-21, and in particular, IL-15 can by-pass suppression of IL-2 activity and support the maintenance of lymphocyte clones as well as the specific activities of lymphocyte activation and clonal expansion. They tend to be less efficient at these activities than IL-2 when measured in vitro, but are able to produce significant biologic effects when administered to animals receiving IL-2 blockade. IL-15 is also elevated in liver transplant patients undergoing rejection.7

Tacrolimus has had overall success, in the prevention of rejection after liver transplantation, but it has not eliminated posttransplantation AIH. Ayata et al,8 demonstrated that in 12 patients transplanted for cirrhosis caused by AIH, there was a histologic recurrence rate of 41.9%. Among those with recurrence, 100% were treated with tacrolimus as the primary immunosuppressive agent. In the non-recurrent group, only 28.6% were treated with tacrolimus (P < 0.05). Similarly, others have shown recurrence while under tacrolimus immunosuppression.9–11 This suggests that tacrolimus may not be adequately protective against AIH, especially for the long-term perhaps for the reasons detailed above. Another point of emphasis by the authors is that tacrolimus allows the avoidance of acute and chronic side effects of steroids, including cushingoid features, osteopenia, and diabetes. This is certainly desirable, but tacrolimus use is associated with renal failure, hypertension, and diabetes. Lastly both the direct and indirect costs of tacrolimus therapy far surpass the costs associated with standard therapy.

The responsiveness of AIH to prednisolone and AZA has been studied and verified for over 30 years. The algorithm for AIH treatment should continue to include these medications as first line agents. In the minority of patients who either fail to adequately respond or are truly intolerant to standard therapy, other immunosuppressive agents may be considered. Because these alternative therapies, including tacrolimus, can result in other complications and costs, comparative histologic assessment should be a necessary component of the definition of failure.

Several new immunosuppressant agents have become commercially available in the past 5 years. Many of these have demonstrated reduced nephrotoxicity (such as sirolimus) and longer duration of effect (such as daclizumab and basiliximab). There will certainly be temptation to add these drugs and immunosuppressants-in-development to the AIH treatment armamentarium, not only in the hope of increasing efficacy but also to reduce toxicity. To properly determine the role of currently available and future immunosuppressant agents in the treatment of AIH, controlled trials with strict inclusion criteria and rigorous definitions of success are needed. The most prudent course of clinical action is to have available several types of immunosuppressive agents minimizing the chance of being circumvented by the redundancy of the immune system.

REFERENCES

1. Rakela J, Czaja AJ. Clinical, biochemical, and histologic features of HbsAg-negative chronic active hepatitis. In: Czaja AJ, Dickson ER, eds. Chronic Active Hepatitis: The Mayo Clinic Experience. New York: Marcel Dekker; 1986:69–82.
2. Aqel BA, Machicao V, Harnois DM, et al. Efficacy of tacrolimus in the treatment of steroid refractory autoimmune hepatitis. J Clin Gastro. 2004.
3. Alvarez F, Berg PA, Bianchi FB, et al. International autoimmune hepatitis group report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999;31:929–938.
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8. Ayata G, Gordon FD, Lewis WD, et al. Liver transplantation for autoimmune hepatitis: A long-term pathologic study. Hepatology. 2002;32:185–192.
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11. Gotz G, Neuhaus R, Bechstein WO, et al. Recurrence of autoimmune hepatitis after liver transplantation. Transplant Proc. 1999;31:430–431.
© 2004 Lippincott Williams & Wilkins, Inc.