Con: Steroids Should Not Be Withdrawn in Transplant Recipients With Autoimmune Hepatitis

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1 CONTROVERSIES IN LIVER TRANSPLANTATION THEOCHARIDOU AND HENEGHAN Con: Steroids Should Not Be Withdrawn in Transplant Recipients With Autoimmune Hepatitis Eleni Theocharidou and Michael A. Heneghan Institute of Liver Studies, King s College Hospital National Health Service Foundation Trust, London, United Kingdom Autoimmune liver diseases (AILDs) can recur following liver transplantation (LT) despite immunosuppressive therapy, with implications for graft survival. Although the evidence is not robust, disease recurrence seems to occur in the presence of less intense and/or steroid-free immunosuppression (IS) in particular in the case of autoimmune hepatitis (AIH). The main risk factor for AIH recurrence is the severity of disease activity in the explant and potential donor/recipient human leukocyte antigen D-related 3 (DR3) mismatch. The treatment for AIH recurrence includes reintroduction or increase in the dose of steroids with or without the addition of azathioprine. T cell mediated rejection episodes are also more common in AILD. Steroid withdrawal is the common practice in LT for non-aild, eliminating the risks associated with longterm exposure to steroids. In AILD, maintenance of steroids at a low dose in the long term may reduce the risk of disease recurrence and rejection. This strategy is safe when there is vigilance for steroid-related adverse effects. Alternatively, identifying patients who are at the greatest risk for disease recurrence and who would benefit from intensified IS might be an option. Liver Transplantation AASLD. Received April 25, 2018; accepted May 15, Following the introduction of calcineurin inhibitor (CNI) based immunosuppression (IS) in liver transplantation (LT), management has evolved toward steroid-free therapy. The benefits of this strategy include an improved metabolic profile (lower incidence of hypertension, hyperlipidemia, and diabetes mellitus) Abbreviations: ACR, acute cellular rejection; AIH, autoimmune hepatitis; AILD, autoimmune liver disease; AZA, azathioprine; CNI, calcineurin inhibitor; CsA, cyclosporine A; HLA, human leukocyte antigen; HR, hazard ratio; IgG, immunoglobulin G; IL, interleukin; IS, immunosuppression; LT, liver transplantation; MMF, mycophenolate mofetil; N/A, not assessed; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; SL, sirolimus; SW, steroid withdrawal; TAC, tacrolimus. Address reprint requests to Michael Heneghan, Professor in Hepatology, Institute of Liver Studies, King s College Hospital National Health Service Foundation Trust, Denmark Hill, London SE5 9RS, United Kingdom. Telephone: +44(0) ; michael. heneghan@nhs.net Copyright 2018 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI /lt Potential conflict of interest: Nothing to report. without an increase in the risk of rejection. (1,2) In view of its feasibility and safety, this approach has been adopted by the majority of LT centers. In the case of autoimmune liver diseases (AILDs), ie, autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC), a significant proportion of centers continue to have a more conservative approach with longterm steroid maintenance. The rationale for this approach reflects concerns about rejection and recurrence of primary disease in the graft. The Case for Steroid Maintenance in AIH AIH is a chronic liver disease characterized by the loss of immunological tolerance to liver-specific autoantigens in the context of immune dysregulation, genetic predisposition (such as human leukocyte antigen [HLA] DRB1*0301 and DRB1*0401), and environmental triggers. LT is associated with the removal of the autoantigens with the native liver but cannot alter the abnormal immunological responses and the genetic factors that predispose a patient to the development of CONTROVERSIES IN LIVER TRANSPLANTATION 1113

2 Theocharidou and Heneghan Liver Transplantation, August 2018 AIH. Antigen-sensitized recipient T memory cells can precipitate alloimmune reactions against homologous antigens in the donor liver, or alternatively autoantigens in the donor liver presented by recipient antigenpresenting cells that populate the allograft can sensitize naive T lymphocytes and precipitate an autoimmune response. (3) An interplay between the alloimmune and autoimmune responses has been also proposed. (4) AIH recurrence in the donor liver has been documented on the basis of biochemical, serological, and histological features similar to those used to diagnose classical AIH, although some of these features may be altered by concurrent immunosuppressive therapy. A meta-analysis of published cases and case series identified high-grade inflammation in the native liver and a HLA-D-related 3 (DR3)-positive recipient mismatched with a HLA-DR3 negative donor as the main risk factors for recurrence. (5) This finding reflects the significance of the intensity of the intrinsic immunological dysregulation that triggered the disease in the native liver and that can drive the recurrence in the allograft in a genetically predisposed recipient. Patients transplanted for acute liver failure due to AIH seem to have a lower risk of recurrence as opposed to patients with end-stage liver failure. (3) A potential explanation for this difference is the limited expansion of the T memory cells due to the shorter course of the disease. Timing and Implications of Recurrence The incidence of recurrent AIH increases with time and has been estimated at 18% at 5 years and 32% at 10 years after LT. (6) This, however, might be an underestimation of the actual incidence because histological features of recurrence may precede abnormalities of the liver biochemistry for several years. (7) Moreover, the lack of protocol biopsies limits accurate assessment of the true incidence of AIH recurrence. Sequential histological data in patients with recurrent AIH are scarce, but they demonstrate progression to advanced fibrosis/ cirrhosis in a small proportion of patients. (8) Although initial studies showed no significant impact on patient and graft survival, (9 11) graft loss has been reported in 6.2%, (12) and recurrence following retransplantation has also been demonstrated. (13) The risk of graft loss due to recurrent disease was estimated to be higher in AIH compared with PBC (hazard ratio [HR], 4.1), as well as the risk of overall graft loss (HR, 1.6). (12) It is noteworthy that AIH recurrence is recognized even in the presence of IS adequate to prevent rejection episodes. CNIs have been the cornerstone of immunosuppressive strategies having significantly improved patient and graft survival. AIH is characterized by imbalance between liverspecific T regulatory cells and effectors cells of liver damage. It has been hypothesized that CNIs can have a paradoxical effect on immune regulation with inhibition of liver-specific T regulatory cells resulting in impaired control over effector cells and loss of immunological tolerance. (4) This may provide an explanation for AIH recurrence on a background of CNIbased IS. Steroids attenuate autoimmune responses by the inhibition of T lymphocyte proliferation and the recruitment of inflammatory cells. They are the mainstay of AIH treatment and have been effectively used to treat recurrent disease in the graft with or without azathioprine (AZA). Steroid Withdrawal and Recurrence The first reported cases of AIH recurrence following LT occurred during weaning of steroid therapy, (14) after steroid withdrawal (SW), (15) or on a background of longterm CNI monotherapy. (16) All patients showed biochemical and histological remission following reintroduction or increase in the dose of steroids in combination with AZA. A subsequent patient series (27 patients) that investigated the role of baseline IS in the risk of recurrence found that patients with recurrence were less likely to be on triple IS (CNI/AZA/ steroid) as opposed to those with no recurrence. (11) A further study (46 patients) found no association of AIH recurrence with type of IS or longterm steroid maintenance. (6) Choice of CNI (cyclosporine A [CsA] or tacrolimus [TAC]) and previous acute rejection episodes do not seem to have an impact on AIH recurrence. (5) Type II Error and Bias Toward SW in Literature Several studies, mainly with a small number of patients and variable baseline IS, have addressed the feasibility 1114 CONTROVERSIES IN LIVER TRANSPLANTATION

3 Liver Transplantation, Vol. 24, No. 8, 2018 Theocharidou and Heneghan TABLE 1. Studies on SW After LT for AIH References Number of Patients IS SW Rejection AIH Recurrence Graft/Patient Survival Trouillot et al. 19 (1999) 25 CsA (20) 68% 33% N/A N/A TAC (5) Adams et al. 17 (2001) CsA 37% N/A N/A N/A CsA/AZA 62% Heffron et al. 10 (2002) % 50% 17.3% No impact Jain et al. 18 (2002) 25 70% N/A 30% N/A Khalaf et al. 20 (2007) 16 TAC 0% N/A 18.7% N/A Campsen et al. 9 (2008) 66 CsA/AZA 55% N/A 34.8% No impact TAC/MMF SL/CNI of steroid withdrawal (SW) in cohorts transplanted for AIH (Table 1). SW was deemed feasible in 29%- 70%, 9,10,17-19 although a single study reported that SW was not successful in any of their patients. (20) One study reported a higher SW rate with a CsA/ AZA combination compared with CsA monotherapy. (17) In another study, SW was associated with higher CsA levels. (9) The AIH recurrence rate in these studies was 19%-35% depending on the length of follow-up. In a large cohort of LT recipients for different indications, SW was achieved in 97%, but reintroduction was required in 24%. (21) The reasons for the latter were rejection (37%), recurrence of AILD (22%), CNI-sparing IS due to nephrotoxicity (20%), and concomitant disease requiring steroid therapy (13%). The main limitation in the interpretation of these studies is the small number of AIH patients, the variability of the baseline IS, the variable length of follow-up, and the lack of sequential protocol allograft biopsies. PBC and PSC Recurrence and SW PBC and PSC can also recur in the donor liver. PBC recurrence has been reported in 21%-37% at 10 years and 43% at 15 years. (22) CsA as opposed to TAC might exert a protective effect in terms of PBC recurrence. (23) The presence of the interleukin (IL) 12A locus that is associated with altered IL12 signaling has been shown to predispose a patient to recurrence. (24) Although the data are very limited, SW does not seem to be associated with PBC recurrence. (25) Graft loss secondary to PBC recurrence is uncommon and has been reported in 1.3%. (12) PSC recurrence has been reported in 10%-27% from 6 months to 5 years after LT. (22) The diagnosis of recurrent PSC requires the exclusion of other causes of cholangiopathy after LT, such as hepatic artery thrombosis or ischemia/reperfusion injury. The role of inflammatory bowel diseases and the presumed protective role of colectomy on recurrence remains equivocal. (26,27) Acute rejection episodes may cause damage of the biliary epithelium exposing biliary antigenic epitopes that can trigger autoimmune reactions increasing the risk of recurrent cholangiopathy. (28) Recurrent PSC can have a negative impact on graft survival with graft loss up to 8.4%. (12) The risk of graft loss due to recurrent disease was higher in PSC compared with PBC (HR, 6), as well as the risk of overall graft loss (HR, 1.6). (12) Variant forms of overlapping AIH/PSC or AIH/PBC are associated with increased risk of recurrence and shorter interval to recurrence compared with a single AILD. (29) Graft loss, although not common, can occur secondary to disease recurrence. (30) SW and Immune Reactivation The initial studies of SW following LT either did not include a separate analysis for patients with AILD or excluded such patients because of concerns regarding rejection. Indeed, patients with AILD are at increased risk of developing acute cellular rejection (ACR) compared with patients transplanted for nonautoimmune etiologies. ACR occurred in 81% of AILD patients compared with 47% of patients transplanted for alcohol-related liver disease, who received either CsA/ prednisolone or TAC/prednisolone IS. (31) ACR was CONTROVERSIES IN LIVER TRANSPLANTATION 1115

4 Theocharidou and Heneghan Liver Transplantation, August 2018 TABLE 2. Patient Selection for Steroid Continuation or Withdrawal in LT for AIH Candidates for Steroid Continuation less common with TAC-based regimens but still higher in the AILD group (50% versus 25%). Multiple episodes of ACR (29% versus 13%) and steroid-resistant ACR (38% versus 13%) were also more common in AILD, although there were no differences in patient and graft survival. A subsequent study confirmed these observations. (13) Patients transplanted for AILD maintained on triple IS with CsA/AZA/prednisolone had an ACR rate of 50% at 1 year, which is higher than those transplanted for alcohol (29%) or hepatitis B related disease (21%). (13) The risk of chronic rejection is also higher in patients (14%-17%) transplanted for AILD compared with non-aild indications (2%-8%). (32 34) Strategy of Steroid Maintenance Candidates for SW Recurrent ACR/chronic rejection Low risk of AIH recurrence High risk of AIH recurrence Optimally controlled activity before LT Severe disease activity in Acute severe presentation explant HLA-DR3 mismatch Poorly controlled diabetes mellitus, Variant forms (overlap hyperlipidemia, or hypertension syndromes) High risk of osteoporosis/osteoporotic fractures Recurrent severe infections Longterm maintenance with low-dose steroids (5-10 mg) in AILD remains the norm in many programs, although this approach is not supported by high-quality evidence. (35) The outcomes of LT for AILD in Europe and North America are excellent with a 5-year survival rate of 85%. (30) It should be taken into consideration that steroid maintenance strategies may have altered the longterm post-lt outcomes. The risk of ACR is twice as high in AILD, than in non-aild, supporting the strategy of intensified IS. ACR episodes are usually responsive to standard therapy, but occasionally can be steroid-resistant and rarely result in chronic rejection and graft loss. In the case of PSC, there is the additional concern that ACR episodes per se may trigger disease recurrence. Longterm Graft Outcomes With the improvement in outcomes in patients transplanted for hepatitis C, an unmet need in LT is now improving outcomes in AILD. The risk of disease recurrence is likely more relevant in AILD as recurrence will occur in at least one-third of patients. Aggressive recurrence can occur following retransplantation. CNI IS is not always protective against AIH recurrence and can paradoxically enhance alloimmune/autoimmune responses. Steroids with or without AZA remain the mainstay of AIH treatment both in the native liver and in the allograft, although it must be acknowledged that there exists a therapeutic deficit in AIH generally. A preventive strategy, therefore, would incorporate either or both these drugs. As yet, no randomized controlled studies have been performed comparing longterm steroid maintenance with steroid-free IS in these patients in terms of risk of recurrence, risk of rejection, and impact on patient and graft loss. Risk Profile of Steroids The strategy of longterm steroid continuation entails the well-demonstrated risks of hyperglycemia, hyperlipidemia, and hypertension that require vigilance and prompt intervention. The risk of infections is of concern in immunosuppressed post-lt populations, and rapid bone loss has been demonstrated in the first 3-6 months following LT. (36,37) The use of longterm lowdose steroids does not seem to increase these risks, as the incidence of septic episodes (33%) and osteoporosis (22%) in a cohort of patients transplanted for AIH and maintained on steroids was similar to that reported in historic cohorts. (38) In conclusion, longterm steroid maintenance in LT for AILD is safe and may reduce the risk of disease recurrence and rejection although the evidence to support this approach is not robust. An alternative approach would include a careful selection of patients who are at a higher risk of recurrence and who would theoretically benefit most from intensified IS following LT (Table 2; Fig. 1). Patients with severe disease activity in the explant, those with HLA-DR3 mismatch (recipient positive/donor negative), and patients with variant forms would be candidates for longterm steroid maintenance CONTROVERSIES IN LIVER TRANSPLANTATION

5 Liver Transplantation, Vol. 24, No. 8, 2018 Theocharidou and Heneghan Steroid withdrawal Optimally controlled activity before LT Acute severe presentation Low risk of AIH recurrence Poorly controlled diabetes mellitus, hyperlipidemia, or hypertension High risk of osteoporosis/osteoporotic fractures Recurrent severe infections Longterm steroid continuation High risk of AIH recurrence Recurrent ACR/chronic rejection Severe disease activity in explant High IgG before LT HLA-DR3 mismatch Variant forms (overlap syndromes) FIG. 1. Parameters favoring steroid continuation or withdrawal in LT for AIH. As to whether AZA can replace low-dose steroids in this preemptive strategy is unknown because both options are associated with different safety issues in the long term. When the risks associated with longterm steroid therapy (poorly controlled metabolic risk factors, preexisting osteoporosis/osteoporotic fractures) counterbalance the risks of rejection/disease recurrence, SW could be attempted in a very gradual manner with close monitoring and after a protracted period of normal graft function. In case features of recurrence emerge, steroids with or without AZA should be reintroduced. REFERENCES 1) Everson GT, Trouillot T, Wachs M, Bak T, Steinberg T, Kam I, et al. Early steroid withdrawal in liver transplantation is safe and beneficial. Liver Transpl Surg 1999;5(suppl 1):S48-S57. 2) Moench C, Barreiros AP, Schuchmann M, Bittinger F, Thiesen J, Hommel G, et al. Tacrolimus monotherapy without steroids after liver transplantation a prospective randomized double-blinded placebo-controlled trial. Am J Transplant 2007;7: ) Czaja AJ. Diagnosis, pathogenesis, and treatment of autoimmune hepatitis after liver transplantation. Dig Dis Sci 2012;57: ) Kerkar N, Yanni G. De novo and recurrent autoimmune hepatitis after liver transplantation: a comprehensive review. J Autoimmun 2016;66: ) Gautam M, Cheruvattath R, Balan V. Recurrence of autoimmune liver disease after liver transplantation: a systematic review. Liver Transpl 2006;12: ) Montano-Loza AJ, Mason AL, Ma M, Bastiampillai RJ, Bain VG, Tandon P. Risk factors for recurrence of autoimmune hepatitis after liver transplantation. Liver Transpl 2009;15: ) Duclos-Vallée JC, Sebagh M, Rifai K, Johanet C, Ballot E, Guettier C, et al. A 10 year follow up study of patients transplanted for autoimmune hepatitis: histological recurrence precedes clinical and biochemical recurrence. Gut 2003;52: ) Puustinen L, Boyd S, Arkkila P, Isoniemi H, Arola J, Färkkilä M. Histologic surveillance after liver transplantation due to autoimmune hepatitis. Clin Transplant doi: / ctr ) Campsen J, Zimmerman MA, Trotter JF, Wachs M, Bak T, Steinberg T, et al. Liver transplantation for autoimmune hepatitis and the success of aggressive corticosteroid withdrawal. Liver Transpl 2008;14: ) Heffron TG, Smallwood GA, Oakley B, Pillen T, Welch D, Martinez E, et al. Autoimmune hepatitis following liver transplantation: relationship to recurrent disease and steroid weaning. Transplant Proc 2002;34: ) Prados E, Cuervas-Mons V, de la Mata M, Fraga E, Rimola A, Prieto M, et al. Outcome of autoimmune hepatitis after liver transplantation. Transplantation 1998;66: ) Rowe IA, Webb K, Gunson BK, Mehta N, Haque S, Neuberger J. The impact of disease recurrence on graft survival following liver transplantation: a single centre experience. Transpl Int 2008;21: ) Ratziu V, Samuel D, Sebagh M, Farges O, Saliba F, Ichai P, et al. Long-term follow-up after liver transplantation for autoimmune hepatitis: evidence of recurrence of primary disease. J Hepatol 1999;30: CONTROVERSIES IN LIVER TRANSPLANTATION 1117

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