Successful Treatment of Refractory Autoimmune Hepatitis With

Successful Treatment of Refractory Autoimmune Hepatitis With Rituximab AUTHORS: Daniel D’Agostino, MD,a Alejandro Costaguta, MD,b and Fernando Álvarez, MDc

abstract Autoimmune hepatitis is a severe liver disease in which ∼10% of patients do not respond to standard treatment. We describe a new rescue therapy using anti-CD20 monoclonal antibodies (rituximab). Complete remission was obtained and maintained by using low doses of immunosuppressive drugs with repeated anti-CD20 infusions. Pediatrics 2013;132:e526–e530

aPediatric Gastroenterology-Hepatology Division, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; bUnidad de Hígado y Trasplante Hepático, Sanatorio de Niños, Rosario, Argentina; and cPédiatrie, CHU Sainte-Justine Université de Montréal, Montreal, Canada

KEY WORDS autoimmune hepatitis, children, treatment, rituximab ABBREVIATIONS AIH—autoimmune hepatitis ALT—alanine aminotransferase AST—aspartate aminotransferase IgG—immunoglobulin G MMF—mycophenolate mofetyl Dr D’Agostino participated actively in the design and critical revision of the manuscript, and analysis of data; Dr Álvarez contributed to the design and conception, analyzed the data, and critically revised the manuscript; Dr Costaguta contributed to the design and conception, analyzed the data, and drafted and reviewed the manuscript; and all authors approved the final version of the manuscript. www.pediatrics.org/cgi/doi/10.1542/peds.2011-1900 doi:10.1542/peds.2011-1900 Accepted for publication Mar 27, 2013 Address correspondence to Alejandro Costaguta, MD, Unidad de Hígado y Trasplante Hepático, Sanatorio de Niños, Alvear 863 (2000) Rosario, Santa Fe, Argentina. E-mail: alejandro. [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2013 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: No external funding.

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CASE REPORT

Autoimmune hepatitis (AIH) is a disease of unknown etiology, characterized by a loss of tolerance against liver antigens, resulting in a progressive destruction of the hepatic parenchyma.1–3 Absence of response to standard immunosuppression or repeated relapses can lead to cirrhosis and liver failure.3 End-stage liver disease may occur in 10% to 20% of cases and liver transplantation may be necessary.3

AIH is considered a T-cell–mediated autoimmune disease.1 Because B cells have been shown to play a significant role in several T-cell–mediated autoimmune diseases, some of these disorders could respond to anti-CD20 monoclonal antibodies (rituximab). Such a treatment would be of interest for a particular subset of patients with AIH refractory to other treatments, and contribute to diminish the number of patients eventually needing liver transplantation.

PATIENTS Case 1 A 12-year-old girl was referred to our hospital with a 2-year history of jaundice associated with biological and histologic hallmarks of Type1 AIH. Despite treatment with prednisone over 12 months, her liver tests remained very abnormal with serum alanine aminotransferase (ALT) value of 531 IU/mL (normal ,33 IU/mL), aspartate

FIGURE 1 Serum levels of aminotransferases before and after rituximab treatment in patients 1 (A) and 2 (B).

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aminotransferase (AST) 1366 (normal ,35 IU/mL), total bilirubin 6.1 mg/dL (normal ,1 mg/dL), gammaglutamyltransferase 135 IU/mL (normal ,30 IU/ mL), international normalized ratio = 1.8, and serum albumin 2.8 mg/dL (normal .3.2 mg/dL). Antinuclear antibodies and smooth muscle antibodies were positive at titers of 1/1280 and 1/160, respectively, and circulating immunoglobulin G (IgG) levels were very high, at 5500 mg/dL. Triple therapy with mycophenolate mofetyl (MMF), cyclosporine, and prednisone was begun, but MMF had to be discontinued because of gastrointestinal complaints. Eighteen months after the beginning of treatment, the patient developed a Coombs-positive autoimmune hemolytic anemia, and sirolimus was added (serum levels of 5–10 ng/mL). In spite of achieving good control of the anemia, persistence of the liver disease (inflammatory activity grade 4, fibrosis stage 3) and the presence of severe side effects from calcineurin inhibitors led us to replace this regimen by rituximab at the dosage of 375 mg/m2 weekly for 4 doses. Aminotransferases and IgG levels rapidly dropped, and normalized 8 months later (Fig 1). Complete normalization of ALT and AST was maintained with small doses of prednisone (6 mg per day) and azathioprine (1 mg/kg per day). Further infusions (1 dose of 375 mg/m2) every 4 months were arbitrarily administered to maintain remission. After a period of 26 months since the first dose of rituximab, no adverse event was observed (Fig 2). She moved to a foreign country, and was lost to further follow-up. Case 2 A 13-year-old girl was referred to us with a 15-day history of jaundice, dark urine, asthenia, and pruritus. Serum ALT and ASTwere very high (ALT 1872 IU/mL; AST 1913 IU/mL). Total bilirubin was 4.3 e528

FIGURE 2 Serum IgG levels after rituximab treatment.

mg%. Albumin and international normalized ratio were normal. Serological tests for hepatitis A virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, and Epstein-Barr virus were negative. She tested positive for antinuclear antibodies (Titer 1/2560) and smooth muscle antibodies (1/160) and the IgG level was 2468 mg/dL. Liver histology supported the diagnosis of Type1 AIH, with inflammation and fibrosis at Grade 2 and Stage 1, respectively (Fig 3). The patient was started on steroids (prednisone 40 mg per day) with normalization of ALT and AST at 4 weeks. Tapering was undertaken, but at the dosage of 20 mg per day she showed an asymptomatic rise of serum ALT and AST values. She was put back on 40 mg of prednisone, and azathioprine 50 mg per day was started. During the following months, serum aminotransferase level remained very high (Fig 1), without improvement after replacement of azathioprine by MMF at 1.5 g per day. Three months later, a second liver biopsy confirmed the worsening of

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inflammatory activity to Grade 4, and fibrosis to Stage 2. Treatment with cyclosporin was not offered in view of positivity for Epstein-Barr virus DNA found in liver tissue from the second biopsy, not seen in the first. Instead, we decided to use rituximab 375 mg/m2 weekly for 4 doses. Three months later, the level of serum aminotransferases normalized (Fig 1), and serum IgG levels also returned to normal values (Fig 2). Prednisone 4 mg per day was maintained. Twenty-three months later, a flare of necroinflammatory activity, evidenced by high levels of serum aminotransferases (ALT 902 IU/mL, AST 353 IU/mL), was controlled with a new single dose of rituximab. Further infusions were then indicated every 6 months to maintain successful clinical and biochemical remission during the following 12 months, keeping prednisone at 4 mg per day and azathioprine at 1 mg/kg per day.

DISCUSSION B cells are involved in the etiology of many autoimmune diseases in several

CASE REPORT

B cells, and an overlap of B- and T-cell epitopes has been shown7; and (4) plasma exchange has been shown to be effective for the management of refractory systemic autoimmune diseases.8 Finally, there are other published cases of patients who responded to rituximab treatment.9–11 The 2 cases reported in this article show that anti-CD20 monoclonal antibody is an effective therapy. Remission of the disease probably needs a complete protocol of 4 weekly doses, and repeated doses at variable periods of time could be necessary in some patients despite persistent administration of usual maintenance doses of other drugs, such as prednisone or azathioprine.

FIGURE 3

Liver biopsy findings from patients. Case 1: A, foci of lobular mononuclear infiltrates and confluent necrosis. At higher magnification (B), perivenular necrosis with lymphoplasmacytic infiltrates and hepatocyte drop-out is clearly seen. Case 2: C, dense portal and panlobular lymphoplasmacytic infiltrates with rosette formation. D, Centrilobular changes similar to case 1, with hepatocyte swelling. Hematoxylin-eosin. H&E 110x magnification (A), 450x magnification (B to D).

ways4: first, through their secretion of autoantibodies; second, as antigenpresenting cells, inducing the activation of autoreactive T cells; third, by secretion of cytokines, such as interleukin-2, interferon-g, tumor necrosis factor-a (Th1), or interleukin-6, and transforming growth factor-b (Th17). AIH is considered to be a T-cell– mediated disease; however, numerous

observations would suggest that B cells are also involved in its pathogenesis: (1) immunoglobulin-secreting plasma cells are abundantly present in the liver lymphocyte infiltrates3; (2) the level of specific autoantibodies and total IgG in sera have been found to correlate with disease activity5,6; (3) in type 2 AIH, the CD4+ and CD8+ T-cell responses target the same antigen as

After more than 10 years of use, rituximab has proven to be remarkably safe; however, side effects described in patients treated with anti-CD20 include a slight increase in the incidence of infectious diseases. Recently, a more severe complication consisting of a progressive, multifocal, eventually lethal encephalitis caused by the polyomavirus John Cunningham virus, has been described months or years after the beginning of the treatment.12 Altogether, according to previous clinical and experimental results and the cases presented here, rituximab may be considered as a rescue therapy in patients with AIH not responding to the usual immunosuppressive regimen.

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atitis. Gastroenterology. 1999;116(3):643– 649 7. Ma Y, Bogdanos DP, Hussain MJ, et al. Polyclonal T-cell responses to cytochrome P450IID6 are associated with disease activity in autoimmune hepatitis type 2. Gastroenterology. 2006;130(3):868–882 8. Santos ES, Arosemena LR, Raez LE, O’Brien C, Regev A. Successful treatment of autoimmune hepatitis and idiopathic thrombocytopenic purpura with the monoclonal

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10. Shores D, Kobak G, Pegram LD, Whitington PF, Shneider BL. Giant cell hepatitis and immune thrombocytopenic purpura: reversal of liver failure with rituximab therapy. J Pediatr Gastroenterol Nutr. 2012;55 (4):e128–e130 11. Maggiore G, Sciveres M, Fabre M, et al. Giant cell hepatitis with autoimmune hemolytic anemia in early childhood: long-

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term outcome in 16 children. J Pediatr. 2011;159(1):127–132.e1 12. Carson KR, Focosi D, Major EO, et al. Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: a Review from the Research on Adverse Drug Events and Reports (RADAR) Project. Lancet Oncol. 2009;10(8):816–824

Successful Treatment of Refractory Autoimmune Hepatitis With Rituximab Daniel D'Agostino, Alejandro Costaguta and Fernando Álvarez Pediatrics 2013;132;e526; originally published online July 1, 2013; DOI: 10.1542/peds.2011-1900 Updated Information & Services

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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2013 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.


Successful Treatment of Refractory Autoimmune Hepatitis With Rituximab Daniel D'Agostino, Alejandro Costaguta and Fernando Álvarez Pediatrics 2013;132;e526; originally published online July 1, 2013; DOI: 10.1542/peds.2011-1900

The online version of this article, along with updated information and services, is located on the World Wide Web at: /content/132/2/e526.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2013 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
