Inequity of care provision and outcome disparity in autoimmune hepatitis in the United Kingdom

Summary Background Treatment paradigms in autoimmune hepatitis (AIH) have remained largely unchanged for decades. Studies report ≤20% of patients have sub‐optimal treatment response with most requiring long‐term therapy. Aim The United Kingdom Autoimmune Hepatitis (UK‐AIH) study was established to evaluate current treatment practice and outcomes, determine the unmet needs of patients, and develop and implement improved treatment approaches. Methods The United Kingdom Autoimmune Hepatitis study is a cross‐sectional cohort study examining secondary care management of prevalent adult patients with a clinical diagnosis of autoimmune hepatitis. Enrolment began in March 2014. Prevalent cases were defined as having been diagnosed and treated for >1 year. Demographic data, biochemistry, treatment history and response, and care location were collected. Results In total, 1249 patients were recruited; 635 were cared for in transplant units and 614 in non‐transplant centres (81% female with median age at diagnosis 50 years). Overall, 29 treatment regimens were reported and biochemical remission rate was 59%. Remission rates were significantly higher in transplant compared to non‐transplant centres (62 vs 55%, P = 0.028). 55% have ongoing corticosteroid exposure; 9% are receiving prednisolone monotherapy. Those aged ≤20 years at diagnosis were more likely to develop cirrhosis and place of care was associated with an aggressive disease phenotype. Conclusions There are significant discrepancies in the care received by patients with autoimmune hepatitis in the UK. A high proportion remains on corticosteroids and there is significant treatment variability. Patients receiving care in transplant centres were more likely to achieve and maintain remission. Overall poor remission rates suggest that there are significant unmet therapeutic needs for patients with autoimmune hepatitis.


| INTRODUCTION
Autoimmune hepatitis (AIH) is a progressive inflammatory condition of the liver that may present in either acute or chronic forms. 1-3 If not effectively treated it can progress rapidly to acute liver failure or the development of cirrhosis. With a prevalence of approximately 17 per hundred thousand in Northern European populations the disease affects both adults and children. 4,5 Treatment paradigms established in the 1970s and 1980s utilising corticosteroids and azathioprine to achieve and sustain remission have remained largely unchanged over several decades. 1 Although case series of patients treated in specialist centres suggest that disease remission (even using the current definition of normalised transaminase and immunoglobulin G [IgG] levels) can be achieved in up to 80% of patients, 6 there is concern that real world disease outcomes in patients treated across the spectrum of health care settings may be substantially worse. 7 This leaves patients at risk of progression to end-stage disease for which liver transplantation is the only effective therapy. [8][9][10] International treatment guidelines have defined initial management and ongoing treatment models in AIH. [8][9][10] All recommend corticosteroids in the form of prednis(ol)one or budesonide with azathioprine. The goals of treatment for patients are biochemical and histological remission, with effective control of symptoms, followed by long-term maintenance of the remission state. Ideally, this should be achieved with minimisation of the dose of corticosteroid with full withdrawal being the goal. Maintenance with azathioprine monotherapy where possible is advised in UK and European Guidelines to minimise corticosteroid side effects and their impact on quality of life. The majority of patients require long-term therapy to prevent relapse 7,11 and increasing numbers of patients suffer with unpleasant side-effects, poorly controlled disease and a life-long immunosuppression burden. [12][13][14][15] The evidence base for management of patients who are nonresponders to conventional immunosuppression is limited. Alternative immunotherapy, whilst recommended as second-and third-line treatment in patients intolerant of azathioprine, can be variable in efficacy and tolerability. [16][17][18][19][20] In AIH, the majority of data relating to treatment outcomes is derived from large referral centres. 12,21 Even amongst these expert centres, significant differences exist in relation to approach to treatment. 22 In recent years, there has been a growing awareness of inadequacies in service provision for many common liver diseases and attention focused on the public health issues pertaining to the burden of liver disease in the UK. [23][24][25] To date, however, little attention has been given to rarer liver diseases such as primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and AIH in these documents and the unmet needs and requirements of these patient groups, whilst known, have never been properly quantified. 26,27 Since the majority of data defining outcome and treatment of AIH are derived from tertiary centres which may not accurately reflect the full spectrum of care delivery we set out to derive a national cohort of patients representing multiple hospital practice settings in the UK. The intention of the United Kingdom Autoimmune Hepatitis (UK-AIH) consortium is to use this platform to define current "real world" practice in the management of AIH within the UK, and to develop, evaluate and implement improved approaches to treatment. The goals of this study are to evaluate current treatment practice and remission rates and determine the real-life unmet clinical needs of patients with AIH.

| METHODS
The UK-AIH platform is a UK-wide cross-sectional cohort developed to evaluate the management and outcome of adult patients with AIH in the UK and to facilitate the development, evaluation and implementation of improved therapy. A key aim is to determine the unmet needs of patients with AIH. The UK-AIH patient cohort is comprised of patients 16   proportions were analysed using the Z test. Logistic regression was performed to assess risk factors for cirrhosis development. All P values reported are two-sided, and P < 0.05 was considered statistically significant.  Despite treatment guidelines recommending that maintenance corticosteroids not be used, 653 of 1198 patients (55%) were taking long-term corticosteroid therapy as part of their treatment regimen.

| Immunosuppression regimens
T A B L E 1 Baseline characteristics of patients at time of study entry (n = 1249) and patient-reported presence of other autoimmune conditions (n = 1192, 596 in both types of unit)

| Development of cirrhosis (includes transplanted patients)
Prevention of the development of cirrhosis in AIH is a major goal of

| DISCUSSION
In this large, nationwide study of "real world" clinical practice in AIH we have demonstrated both significant limitations in the effectiveness of care for AIH and a high degree of variability in practice and quality between unit types. Our first key observation is that the remission rate using standard criteria is only 59%; a figure falling far short of the benchmark figure of 80% demonstrated to be achievable in specialist centres with a specific interest in disease management and structures in place to deliver optimised care. 6  children with AIH, particularly, Type 2 AIH associated with detectable anti-Liver Kidney Microsomal (LKM) antibodies in serum. 38 The rate of corticosteroid use was high in our cohort with 55% of patients remaining on either prednisolone or budesonide. Recently published data from the UK-AIH study show that the use of corticosteroids is strongly associated with decreased health-related quality of life that is independent of biochemical remission status. 39  However, we know from published data that an azathioprine dose of up to 2 mg/kg/d can result in enhanced long-term remission rates in AIH with a concomitant ability to withdraw corticosteroids entirely from the treatment regimen for the majority of patients. 40 The approach to management of AIH was different between transplant and nontransplant centres. While the overall number of treatment regimens used in transplant compared to nontransplant units was similar (26 vs 27), there was a greater likelihood of patients being exposed to an expanded range of novel treatment options in AIH management (eg, CNIs, three drug regimens or biological agents). This more nuanced and individualised approach to care in the transplant centres appears to translate to less fluctuation in the disease, with more patients in biochemical remission, and consequently is likely to be protective in relation to hepatic outcomes. 6 This "real world" study of patients with AIH demonstrates and quantifies the therapeutic challenges that have been discussed in the literature. 22 In conclusion, despite its limitations the UK-AIH cohort demonstrates significant discrepancies in care delivery for patients with AIH. It outlines, in particular, the contrast between real world outcomes for a rare disease cohort and the outcomes achieved in clinical trials. It also suggests that the medical community seems comfortable in accepting both suboptimal patient outcomes and largely outmoded therapeutics for the disorder. This cohort provides evidence of the need to enhance adherence to optimal treatment approaches identified in clinical practice guidelines (through education of both clinicians and patients) and a need for more potent, and patient-acceptable, therapies for this important condition. Both areas should be research priorities moving forward.