Use of TNFα antagonists in refractory AIH: Revealing the unforeseen

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SUMMARY BackgroundAutoimmune hepatitis (AIH) is a disease of unknown aetiology characterised by interface hepatitis, hypergammaglobulinaemia, circulating autoantibodies and a favourable response to immunosuppression. AimTo review recent advancements in understanding aetiopathogenesis, clinical, serological and histological features, diagnostic criteria and treatment strategies of AIH. MethodsPublished studies on AIH extracted mainly from PubMed during the last 15 years. ResultsAutoimmune hepatitis has a global distribution affecting any age, both sexes and all ethnic groups. Clinical manifestations are variable ranging from no symptoms to severe acute hepatitis and only seldom to fulminant hepatic failure. Autoimmune attack is perpetuated, possibly via molecular mimicry mechanisms, and favoured by the impaired control of regulatory T-cells. A typical laboratory finding is hypergammaglobulinaemia with selective elevation of IgG, although in 15-25% of patients -particularly children, elderly and acute cases -IgG levels are normal. Liver histology and autoantibodies, although not pathognomonic, still remain the hallmark for diagnosis. Immunosuppressive treatment is mandatory and life-saving; however, to meet strict response criteria, the conventional therapy with prednisolone with or without azathioprine is far from ideal. ConclusionsAutoimmune hepatitis remains a major diagnostic and therapeutic challenge. The clinician, the hepato-pathologist and the laboratory personnel need to become more familiar with different expressions of the disease, interpretation of liver histology and autoimmune serology. According to the strict definition of treatment response issued by the 2010 AASLD guidelines, many patients are nonresponders to conventional treatment. Newer immunosuppressive agents targeting pathogenetic mechanisms can improve patient management, which needs to be tailored on a case-by-case basis.

Section: Management and Outcomementioning

confidence: 99%

Review article: autoimmune hepatitis - current management and challenges

Zachou

Muratori

Koukoulis³

et al. 2013

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“…Both interventions may affect the production of cytokines and chemokines, and each has been effective in small observational studies of patients with steroid‐refractory autoimmune hepatitis or steroid‐intolerance . Therapeutic manipulations of key counter‐regulatory homoeostatic mechanisms such as the cytokine pathways also have risks, and these risks include systemic infection and altered immune reactivity . Infliximab has been implicated in the production of a clinical syndrome that resembles autoimmune hepatitis, and experiences with this drug indicate the hazards that may be encountered when manipulating complex interactive pathways that can affect host defence mechanisms …”

Section: Chemokine‐directed Therapymentioning

confidence: 99%

Review article: chemokines as orchestrators of autoimmune hepatitis and potential therapeutic targets

Czaja

2014

Summary Background Chemokines contribute to the pathogenesis of autoimmune hepatitis by directing the migration and positioning of inflammatory and immune cells within the liver. Aim Describe the liver‐infiltrating effector cell populations in autoimmune hepatitis, indicate the chemokines that influence their migration, describe the role of chemokines in hepatic fibrosis and identify chemokine‐directed treatment opportunities. Methods Studies cited in Pub Med from 1972 to 2014 for autoimmune hepatitis, chemokines in liver disease, pathogenesis of autoimmune hepatitis and chemokine therapy were selected. Results T helper type 17 lymphocytes expressing CXCR3 and CCR6 are attracted to the liver by the secretion of CXCL9, CXCL10 and CXCL11. These cells recruit pro‐inflammatory T helper type 1 lymphocytes expressing CXCR3 and CCR5 by secreting CXCL10. Resident natural killer T cells expressing CXCR6 migrate in response to the local secretion of CXCL16, and they modulate the inflammatory response. T helper type 2 lymphocytes expressing CCR4 are attracted by CCL17 and CCL22, and they dampen the expansion of pro‐inflammatory cells. Regulatory T cells expressing CXCR3 are attracted by the secretion of CXCL9, and they help dampen the pro‐inflammatory responses. CCL2, CCL3, CCL5, CXCL4, CXCL10 and CXCL16 promote fibrosis by activating or attracting hepatic stellate cells, and CX3CL1 may prevent fibrosis by affecting the apoptosis of monocytes. Conclusions Chemokines are requisites for mobilising, directing and positioning the effector cells in immune‐mediated liver disease. They are feasible therapeutic targets in autoimmune hepatitis, and the evaluation of monoclonal antibodies that neutralise the pro‐inflammatory ligands or designer peptides that block receptor activity are investigational opportunities.

“…The emergence of pharmacological, molecular and cellular interventions promises to improve the opportunity for a treatment‐free state by having greater immunosuppressive and anti‐inflammatory effects than current treatments and by interrupting specific sites in the critical pathogenic pathways that sustain the disease (Table ) . These interventions have had limited experience in animal models and selected patients with autoimmune hepatitis, and their safety profile and target population have not been defined . Furthermore, human experiences with these interventions in autoimmune hepatitis have yet to demonstrate a durable treatment‐free state .…”

Section: Strategies To Induce Treatment‐free Autoimmune Hepatitismentioning

confidence: 99%

Review article: permanent drug withdrawal is desirable and achievable for autoimmune hepatitis

Czaja

2014

Summary Background Autoimmune hepatitis can be rendered treatment‐free, but the difficulty, frequency and risks associated with the pursuit of this outcome are unclear. Aim To describe the frequency that autoimmune hepatitis can be rendered treatment‐free, identify the features that characterise these patients, examine the pathogenic pathways that may sustain or terminate the disease and indicate management protocols that can obtain this result. Methods Studies cited in Pub Med from 1972–2014 for autoimmune hepatitis, treatment, relapse, remission and outcome were selected. Results The frequency of a treatment‐free state varies from 19% to 40% in patients observed for ≥3 years after drug withdrawal. Complete laboratory resolution and reversion to normal liver tissue prior to drug withdrawal favours this response. The development of cirrhosis during therapy may increase treatment‐dependence. Persistent liver damage and the generation of neo‐antigens during the apoptosis of hepatocytes may perpetuate the disease. Genetic and age‐related effects on the vigour of the immune response may also contribute. Reversion to normal liver tissue is achieved in only 22% of patients during conventional corticosteroid therapy, and the emerging pharmacological and biological interventions may improve this frequency. A management strategy designed to achieve a treatment‐free state accommodates all candidates for this outcome, and it can be modified to a long‐term maintenance strategy as warranted by the clinical response. Conclusions Permanent drug withdrawal is a treatment outcome that is desirable and achievable in patients with autoimmune hepatitis. Normalisation of liver tests and liver tissue during treatment enhances this occurrence.