Patient selection based on treatment duration and liver biochemistry increases success rates after treatment withdrawal in autoimmune hepatitis

Hartl, Johannes; Ehlken, Hanno; Weiler‐Normann, Christina; Sebode, Marcial; Kreuels, Benno; Pannicke, Nadine; Zenouzi, Roman; Glaubke, C; Lohse, Ansgar W.; Schramm, Christoph

doi:10.1016/j.jhep.2014.10.018

Cited by 91 publications

(99 citation statements)

References 25 publications

(60 reference statements)

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“…It should be noted, however, that a normal liver biopsy prior to treatment termination does not preclude a relapse, since 92% of patients did have a relapse despite the histological resolution of disease [42] . Similarly, in the recently published study by Hartl et al [43] , the relapse rate was not different between patients with proven histological remission and those without biopsy prior to treatment cessation.…”

Section: Is Liver Biopsy Necessary Before Drug Withdrawal?supporting

confidence: 53%

“…Combination therapy at the beginning of drug withdrawal was one of the factors associated with a higher risk of relapse, and indeed according to a very recent study, the likelihood for a sustained remission may be somewhat more optimistic when biochemical remission is maintained for at least 2 years under immunosuppressive monotherapy. Nevertheless, even under these strict conditions, 46% of patients had a relapse [43] .…”

Section: Available Data On Drug Withdrawalmentioning

confidence: 93%

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Treatment Withdrawal in Autoimmune Hepatitis

Bouma

Nieuwkerk²

2015

Dig Dis

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Background: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disorder of unknown aetiology, which when left untreated can lead to liver cirrhosis and hepatic failure. Current treatment strategies include long-term treatment with corticosteroids and/or azathioprine. Most patients respond well to immunosuppressive therapy and treatment usually results in an asymptomatic course of AIH in remission. Nevertheless, both drugs are associated with serious side effects that can sometimes be severe and may necessitate drug withdrawal. Whether or not treatment in patients who are in longstanding remission can be discontinued is unknown. Key Messages: Available data rely on retrospective data sets and are not conclusive. Some studies indicate that a sustained remission after treatment withdrawal is feasible, whereas other studies have found relapse rates in up to 90% of patients, even in patients with established histological remission. Patients who relapse after drug withdrawal have a high probability for a re-relapse to occur. Life-long maintenance therapy should be strongly considered in these patients, since patients who have multiple relapses are more likely to progress to cirrhosis, liver transplantation and death from liver failure. Conclusion: For a majority of patients, AIH is a lifelong disease requiring permanent treatment. Patients in longstanding clinical remission on monotherapy, with complete normalisation of aminotransferases and IgG could be offered one attempt of drug withdrawal. The risk of disease progression after a single relapse appears low, while a patient's realization that infinite maintenance therapy is mandatory may improve drug adherence.

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Section: Is Liver Biopsy Necessary Before Drug Withdrawal?supporting

confidence: 53%

Section: Available Data On Drug Withdrawalmentioning

confidence: 93%

Treatment Withdrawal in Autoimmune Hepatitis

Bouma

Nieuwkerk²

2015

Dig Dis

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“…We believe that treatment withdrawal should be offered to patients with complete biochemical remission (normal transaminases and normal immunoglobulin G) for >2 years under immunosuppressive monotherapy with azathioprine, 11 keeping in mind that in most patients, AIH will require lifelong treatment. 12 Alternative medical treatment is available due to promising results of, for example, mycophenolatemofetil, which was shown to be an effective first-line therapy in an uncontrolled trial.…”

Section: Discussionmentioning

confidence: 99%

Two Cases of Hepatosplenic T-Cell Lymphoma in Adolescents Treated for Autoimmune Hepatitis

Brinkert

Arrenberg

Krech³

et al. 2016

Pediatrics

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We report the first 2 cases of hepatosplenic T-cell lymphoma in adolescents diagnosed with autoimmune hepatitis under long-term treatment with azathioprine. Patients presented with fatigue, hepatosplenomegaly, and pancytopenia. The diagnosis could be confirmed performing biopsies of liver and spleen or bone marrow, which demonstrated infiltration of neoplastic T lymphocytes with the typical phenotype with both markers, CD56+ and TCRγδ+. Thus, these cases emphasize the need to constantly reevaluate the administered dose and duration of thiopurines for autoimmune hepatitis, especially in adolescents.

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“…Indeed, some evidence suggests that the lower the transaminase level achieved by treatment the better it is. Patients in whom levels fell to the lower (compared to the upper) half of the normal range had lower off-treatment relapse rates [11] and lower 10-year mortality after 10 years [18] .…”

Section: An Optimal Treatment Endpoint?mentioning

confidence: 93%

“…A recent study indicates that quality of life (in particular, the mental well-being) is not normal in patients treated for AIH [7] . Five to fifteen per cent of patients do not respond to treatment and even in those who do, disease relapse occurs in almost 20% of patients despite ongoing treatment [8] and in 45-70% if treatment is stopped [9][10][11] . Most patients with AIH have some degree of liver fibrosis and about 30% have cirrhosis at presentation [12][13][14] .…”

mentioning

confidence: 99%

Standard Treatment in Adults: Which Steroid? Or without Steroids?

Gleeson¹

2015

Dig Dis

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Key Messages: (1) Standard treatment of autoimmune hepatitis in adults should be steroid based. In early trials, prednisolone +/- azathioprine was superior to the azathioprine mono-therapy (which was not significantly better than placebo). Prednisolone plus azathioprine has similar efficacy to, but is better tolerated than a higher-dose of prednisolone alone and therefore has become standard therapy. (2) In most treated patients, serum transaminases and globulin/IgG fall, but percentage attaining normal values within 6 months varies between 10 and 90%. Patients failing to do so have a worse longer-term outcome. (3) A higher initial prednisolone dose (1 mg/kg/day) plus azathioprine achieved 76% serum transaminase normalisation after 6 months but needs longer-term evaluation. (4) Histological remission (minimal hepatitis on re-biopsy) lags behind transaminase normalisation by 6-12 months and is achieved in 55-70% of patients after 24-36 months prednisolone. This lag and the inefficacy of azathioprine mono-therapy justifies continuing prednisolone (5-10 mg/day), even after transaminase normalisation, for a total of >2 years. (5) Repeat biopsy should be considered because 40-60% of patients still have (usually mild) persisting inflammation, despite normal serum transaminases and IgG. In such patients, fibrosis is less likely to regress and long-term mortality is higher. (6) In a large trial, non-cirrhotic treatment-naïve patients given budesonide (9 mg/day) plus azathioprine were more likely to achieve normal serum ALT after 6 months than those receiving prednisolone plus azathioprine and had less side effects. This trial was short term in nature and lacked follow-up histology. Budesonide is recommended in non-cirrhotic patients who develop prednisolone-related side effects. In an open study of mycophenolate plus prednisolone, 88% of treatment-naïve patients achieved normal serum transaminases. However, half relapsed during or after steroid withdrawal and only one of eight re-biopsied patients achieved histological remission. Mycophenolate is teratogenic, limiting its use in younger women. Conclusion: Despite its limitations, no regime has yet been shown clearly to be better than prednisolone and azathioprine-based therapy.

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Patient selection based on treatment duration and liver biochemistry increases success rates after treatment withdrawal in autoimmune hepatitis

Cited by 91 publications

References 25 publications

Treatment Withdrawal in Autoimmune Hepatitis

Treatment Withdrawal in Autoimmune Hepatitis

Two Cases of Hepatosplenic T-Cell Lymphoma in Adolescents Treated for Autoimmune Hepatitis

Standard Treatment in Adults: Which Steroid? Or without Steroids?

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