Immunosuppressive Treatment Regimens in Autoimmune Hepatitis: Systematic Reviews and Meta‐Analyses Supporting American Association for the Study of Liver Diseases Guidelines

Vierling, John M.; Kerkar, Nanda; Czaja, Albert J.; Mack, Cara L.; Adams, David H.; Assis, David N.; Manns, Michael P.; Mayo, Marlyn J.; Nayfeh, Tarek; Majzoub, Abdul M.; Alzuabi, Muayad; Ding, Jingyi Francess; Haffar, Samir; Murad, Mohammad Hassan; Alsawas, Mouaz

doi:10.1002/hep.31407

Cited by 34 publications

(35 citation statements)

References 47 publications

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“…1 With an accompanying systemic review and meta-analysis, the AASLD demonstrated a higher rate of biochemical remission in the budesonide + AZA group compared to the prednisone + AZA group (odds ratio, 2.19; 95% CI, 1.30-3.67), and they described this finding as highgrade evidence. 57 Accordingly, the AASLD suggests budesonide in combination with AZA as a first-line therapy for child and adult AIH patients who do not have cirrhosis or acute severe AIH; 1 patients with cirrhosis are contraindicated for budesonide because portosystemic shunting may reduce the drug's efficacy.…”

Section: First-line Treatmentsmentioning

confidence: 99%

Recent updates on the management of autoimmune hepatitis

Komori

2021

Clin Mol Hepatol

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Autoimmune hepatitis (AIH) is an immunoinflammatory chronic liver disease with dynamic and rather heterogeneous disease manifestations. A trend of increasing prevalence of AIH has been observed worldwide, along with a relative increase in the percentage of male patients. AIH is characterized and diagnosed based on serum biochemistry and liver histology: elevated aminotransferases and serum immunoglobulin G (IgG), the presence of serum anti-nuclear antibody or anti-smooth muscle antibody, and interface lympho-plasmacytic hepatitis. Clinical manifestations differ among disease subtypes with distinct time-frames, i.e., AIH with a chronic insidious onset, and acute-onset AIH (the diagnosis of which is often challenging due to the lack of typical serum findings). The absence of disease-specific biomarkers or histological findings may expand the disease phenotype into drug-induced AIH-like liver injury. Corticosteroids and azathioprine are recommended first-line treatments for AIH. The complete normalization of aminotransferases and serum IgG is an essential treatment response to ensure long-term overall survival. An incomplete response or intolerance to these drugs is considered an indication for second-line treatment, especially with mycophenolate mofetil. Life-long maintenance treatment is required for the majority of patients, but the few who achieve prolonged and stringent biochemical remission with lower alanine aminotransferase and IgG within the normal range may be able to discontinue the medications. In the future, the quality of life of AIH patients should be managed by personalized medicine, including the appropriate selection and dosing of first-line therapy and perhaps alternating with potential therapeutics, and the prediction of the success of treatment withdrawal.

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Section: First-line Treatmentsmentioning

confidence: 99%

Recent updates on the management of autoimmune hepatitis

Komori

2021

Clin Mol Hepatol

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“…An unmet need in autoimmune hepatitis is to identify interventions that can supplement or replace current regimens, reduce or eliminate the need for glucocorticoids, and rescue patients with refractory disease or drug intolerance [9,46,273]. Preliminary studies in diverse autoimmune diseases [70-72, 74, 77-79] and in autoimmune hepatitis [80] suggest that low-dose recombinant IL-2 therapy is a candidate to satisfy this unmet clinical need.…”

Section: Overviewmentioning

confidence: 99%

Exploring the Pathogenic Role and Therapeutic Implications of Interleukin 2 in Autoimmune Hepatitis

Czaja

2020

Dig Dis Sci

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Interleukin 2 is essential for the expansion of regulatory T cells, and low-dose recombinant interleukin 2 has improved the clinical manifestations of diverse autoimmune diseases in preliminary studies. The goals of this review are to describe the actions of interleukin 2 and its receptor, present preliminary experiences with low-dose interleukin 2 in the treatment of diverse autoimmune diseases, and evaluate its potential as a therapeutic intervention in autoimmune hepatitis. English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Interleukin 2 is critical for the thymic selection, peripheral expansion, induction, and survival of regulatory T cells, and it is also a growth factor for activated T cells and natural killer cells. Interleukin 2 activates the signal transducer and activator of transcription 5 after binding with its trimeric receptor on regulatory T cells. Immune suppressor activity is increased; anti-inflammatory interleukin 10 is released; pro-inflammatory interferon-gamma is inhibited; and activation-induced apoptosis of CD8 + T cells is upregulated. Preliminary experiences with cyclic injections of low-dose recombinant interleukin 2 in diverse autoimmune diseases have demonstrated increased numbers of circulating regulatory T cells, preserved regulatory function, improved clinical manifestations, and excellent tolerance. Similar improvements have been recognized in one of two patients with refractory autoimmune hepatitis. In conclusion, interferon 2 has biological actions that favor the immune suppressor functions of regulatory T cells, and low-dose regimens in preliminary studies encourage its rigorous investigation in autoimmune hepatitis.

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“…Ranges of 6‐TGN levels that ensure a complete clinical response, indicate treatment failure and predict leucopenia or thiopurine intolerance are unmet clinical needs in the management of IBD 169 . They also align with the unmet clinical needs in autoimmune hepatitis 35,170,171 …”

Section: Investigational Opportunities To Improve Primary Treatment Omentioning

confidence: 99%

“…Its disadvantages are its frequency of major side effects in 3%‐34% of patients, including leucopenia, 188,189,231,232 its expense, 10,233 established teratogenicity, 234,235 and inability to monitor or adjust its actions by established metrics. Furthermore, systematic review and meta‐analysis of the clinical evidence has justified only a conditional recommendation of low certainty for its use as a second‐line treatment in autoimmune hepatitis 171 . Similarly, the calcineurin inhibitors (tacrolimus and ciclosporin) have acquired a role in refractory autoimmune hepatitis 10,188‐190,236 despite clinical evidence that has also been judged insufficient to generate a recommendation with certainty for their use as a second‐line regimen 171 .…”

Section: Overviewmentioning

confidence: 99%

Review article: opportunities to improve and expand thiopurine therapy for autoimmune hepatitis

Czaja

2020

Aliment Pharmacol Ther

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Background: Thiopurines in combination with glucocorticoids are used as first-line, second-line and maintenance therapies in autoimmune hepatitis and opportunities exist to improve and expand their use. Aims:To describe the metabolic pathways and key factors implicated in the efficacy and toxicity of the thiopurine drugs and to indicate the opportunities to improve outcomes by monitoring and manipulating metabolic pathways, individualising dosage and strengthening the response.Methods: English abstracts were identified in PubMed by multiple search terms. Fulllength articles were selected for review, and secondary and tertiary bibliographies were developed.Results: Thiopurine methyltransferase activity and 6-tioguanine (6-thioguanine) nucleotide levels influence drug efficacy and safety, and they can be manipulated to improve treatment response and prevent myelosuppression. Methylated thiopurine metabolites are associated with hepatotoxicity, drug intolerance and nonresponse and their production can be reduced or bypassed. Universal pre-treatment assessment of thiopurine methyltransferase activity and individualisation of dosage to manipulate metabolite thresholds could improve outcomes. Early detection of thiopurine resistance by metabolite testing, accurate estimations of drug onset and strength by surrogate markers and adjunctive use of allopurinol could improve the management of refractory disease. Dose-restricted tioguanine (thioguanine) could expand treatment options by reducing methylated metabolites, increasing the bioavailability of 6-tioguanine nucleotides and ameliorating thiopurine intolerance or resistance. Conclusions:The efficacy and safety of thiopurines in autoimmune hepatitis can be improved by investigational efforts that establish monitoring strategies that allow individualisation of dosage and prediction of outcome, increase bioavailability of the active metabolites and demonstrate superiority to alternative agents.

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Immunosuppressive Treatment Regimens in Autoimmune Hepatitis: Systematic Reviews and Meta‐Analyses Supporting American Association for the Study of Liver Diseases Guidelines

Cited by 34 publications

References 47 publications

Recent updates on the management of autoimmune hepatitis

Recent updates on the management of autoimmune hepatitis

Exploring the Pathogenic Role and Therapeutic Implications of Interleukin 2 in Autoimmune Hepatitis

Review article: opportunities to improve and expand thiopurine therapy for autoimmune hepatitis

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