Letter to the Editor

Duration of immunosuppressive therapy in autoimmune hepatitis

Mortality rates for autoimmune hepatitis (AIH) vary. Data are lacking beyond 20 years follow-up.

Analysis of a consecutively recruited large AIH cohort from a single non-transplant tertiary centre in England and an overlapping cohort, already followed for ≥ 20 years.

We assessed 330 patients presenting 1987–2016 and 65 patients presenting 1971–96 already followed for 20 years.

Death/liver transplant rate was 51±4% (all-cause) and 21±4% (liver-related) over 20 years and was independently associated with: decompensation and lower serum ALT at diagnosis; and failure of serum ALT normalisation and higher relapse rate. There was excess mortality over the first year.

Patients (n = 65) already followed for twenty years had similar subsequent rates of relapse, disease progression and mortality, to those followed from diagnosis. Azathioprine-intolerant patients (n = 23) switching to Mycophenolate did not have higher mortality over 4(1–17) years, than patients continuing Azathioprine. Following immunosuppression withdrawal (n = 26), six (23% patients) relapsed with no liver-related deaths over 2.3(0–23.1) years.

In this consecutive autoimmune hepatitis cohort, mortality was similar to that in national registry studies, disease progression continued after 20 years, and immunosuppression withdrawal did not compromise survival.

Autoimmune liver diseases (AILDs) are complex conditions, which arise from the interaction between a genetic susceptibility and unknown environmental triggers. They represent a relevant cause of liver failure and liver transplantation worldwide. As a testimony of our progress in understanding the biology of AILDs and the disease progression is the overall median survival which has increased over the last decade. However, there are still major challenges such as the lack of therapies and surveillance strategies in primary sclerosing cholangitis (PSC), the management and treatment of non-responders to first-line therapies in primary biliary cholangitis (PBC) and the need for tailoring immunosuppressive drugs in autoimmune hepatitis (AIH). The different disease course and treatment response in patients with AILDs might be related to a heterogeneous genetic background between individuals which translates in a heterogeneous clinical phenotype. Thus, it becomes essential to personalise management and treatment based on specific risk profiles, e.g. low-risk and high-risk, based on genetic and molecular signatures.

It is now possible, thanks to the development of large-scale AILDs patient cohorts, that such diseases can be analysed using various high-throughput methods like gene expression profiling, next generation sequencing and other omics technologies to identify unique fingerprints based on which a personalised or tailor-made management and therapy can be developed. The final aim being to facilitate treatment decision-making that balances patient-specific risks and preferences. This is critical especially now with the current and forthcoming availability of more efficacious medications. To reach this point we need specific interventions such as creating bigger biobanks, sequencing more genomes and linking biological information to health-related data.

We have already identified subsets of patients with different risk profiles among patients with PBC, PSC and AIH by using clinical tools such as liver histology, laboratory investigation and non-invasive methods. In this manuscript, we review the clinical features and investigations that already enable us to individualize the care of PBC patients and that might support the development of precision medicine (PM) in AILDs.

En pediatría, la hepatitis autoinmune y la colangitis esclerosante son patologías de afección hepática cuyo mecanismo de daño es inmunológico.

La hepatitis autoinmune es una enfermedad de etiología desconocida, caracterizada por hepatitis de interfase, hipergammaglobulinemia, autoanticuerpos circulantes y una respuesta favorable a la inmunosupresión. Es una enfermedad eminentemente pediátrica, con una afección prevalente hacia mujeres jóvenes. La terapia debe ser instituida con prontitud para prevenir el deterioro rápido, promover la remisión de la enfermedad y la supervivencia a largo plazo. La falta persistente de respuesta o la falta de adherencia al tratamiento dan como resultado una enfermedad hepática terminal. Los pacientes que desarrollan esta patología, y aquellos con insuficiencia hepática fulminante en el momento del diagnóstico, requerirán trasplante hepático.

In pediatrics, autoimmune hepatitis and sclerosing cholangitis are liver disorders with an immunological damage mechanism.

Autoimmune hepatitis is a disease of unknown etiology characterized by interface hepatitis, hypergammaglobulinemia, circulating autoantibodies and a favorable response to immunosuppression. It is an eminently pediatric disease with a prevalent condition in young women. Therapy should be instituted promptly to prevent rapid deterioration, promote remission of disease and long-term survival. The persistent lack of response or lack of adherence to treatment results in terminal liver failure; these patients, and those with fulminant hepatic insufficiency at the time of diagnosis, will require liver transplantation.

In autoimmune hepatitis (AIH), relapse rates as high as 90% have been reported after treatment withdrawal. We therefore investigated, whether longer duration of treatment and proper patient selection could increase the long-term success rates after treatment withdrawal.

Following our previously published experience, treatment withdrawal was considered when biochemical remission was maintained under immunosuppressive monotherapy for at least 2 years. Remission was defined as repeatedly normal serum aminotransferase levels as well as normal IgG levels.

Out of 288 patients with well-defined AIH, 28 patients were included. Median duration of treatment was 48.5 months (range 35–179) and a sustained remission was observed for 45 months (range 24–111). All patients were in remission on immunosuppressive monotherapy for a minimum of 2 years before treatment was withdrawn. Using this strict approach, 15 patients (54%) remained in long-term remission after a median of 28 months follow-up (range 17–57) and 13 patients (46%) required reinstitution of treatment. Higher ALT and IgG levels – although within the normal range in all patients – were associated with the time to relapse. All patients who remained in remission had ALT levels less than half the ULN and IgG levels not higher than 12 g/L at the time of treatment withdrawal.

Proper patient selection including a sustained complete biochemical remission on immunosuppressive monotherapy for a minimum of 2 years can markedly improve the success rates of treatment withdrawal. The interpretation of aminotransferase and IgG levels within the normal range could aid in predicting the risk of relapse.