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Successful Treatment of Refractory AutoimmuneHepatitis With Rituximab

abstractAutoimmune hepatitis is a severe liver disease in which 10% ofpatients do not respond to standard treatment. We describe a newrescue therapy using anti-CD20 monoclonal antibodies (rituximab).Complete remission was obtained and maintained by using lowdoses of immunosuppressive drugs with repeated anti-CD20 infu-sions. Pediatrics 2013;132:e526e530

AUTHORS:

Daniel D

Agostino, MD,

a

Alejandro Costaguta,MD,b and Fernando lvarez, MDc

aPediatric Gastroenterology-Hepatology Division, Hospital Italiano

de Buenos Aires, Buenos Aires, Argentina; bUnidad de Hgado y

Trasplante Heptico, Sanatorio de Nios, Rosario, Argentina; andcPdiatrie, CHU Sainte-Justine Universit de Montral, Montreal,

Canada

KEY WORDS

autoimmune hepatitis, children, treatment, rituximab

ABBREVIATIONS

AIHautoimmune hepatitisALTalanine aminotransferaseASTaspartate aminotransferaseIgGimmunoglobulin G

MMFmycophenolate mofetyl

Dr DAgostino participated actively in the design and criticalrevision of the manuscript, and analysis of data; Dr lvarezcontributed to the design and conception, analyzed the data, andcritically revised the manuscript; Dr Costaguta contributed tothe design and conception, analyzed the data, and drafted andreviewed the manuscript; and all authors approved the nalversion 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 deHgado y Trasplante Heptico, Sanatorio de Nios, Alvear 863(2000) Rosario, Santa Fe, Argentina. E-mail: [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 nancial relationships relevant to this article to disclose.

FUNDING:No external funding.

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aminotransferase (AST) 1366 (normal,35 IU/mL), total bilirubin 6.1 mg/dL(normal ,1 mg/dL), gammaglutamyl-transferase 135 IU/mL (normal,30 IU/mL), international normalized ratio =

1.8, and serum albumin 2.8 mg/dL

(normal .3.2 mg/dL). Antinuclearantibodies and smooth muscle anti-bodies were positive at titers of 1/1280and 1/160, respectively, and circulatingimmunoglobulin G (IgG) levels werevery high, at 5500 mg/dL.

Triple therapy with mycophenolatemofetyl (MMF), cyclosporine, and pred-nisone was begun, but MMF had tobe discontinued because of gastroin-testinal complaints. Eighteen months

after the beginning of treatment, thepatient developed a Coombs-positiveautoimmune hemolytic anemia, andsirolimus was added (serum levels of510 ng/mL). In spite of achieving goodcontrol of the anemia, persistence ofthe liver disease (inammatory activitygrade 4, brosis stage 3) and thepresence of severe side effects from

calcineurin inhibitors led us to replacethis regimen by rituximab at the dos-

age of 375 mg/m2

weekly for 4 doses.Aminotransferases and IgG levels rap-idly dropped, and normalized 8 monthslater (Fig 1). Complete normalization ofALT and ASTwas maintained with smalldoses of prednisone (6 mg per day)and azathioprine (1 mg/kg per day).Furtherinfusions (1 dose of 375 mg/m2)every 4 months were arbitrarily ad-ministered to maintain remission. Aftera period of 26 months since the rst

dose of rituximab, no adverse eventwas observed (Fig 2). She moved toa foreign country, and was lost tofurther follow-up.

Case 2

A 13-year-old girl was referred to uswith a 15-day history of jaundice, darkurine,asthenia,andpruritus.SerumALTand ASTwere very high (ALT 1872 IU/mL;AST 1913 IU/mL). Total bilirubin was 4.3

mg%. Albumin and international nor-malized ratio were normal. Serological

tests for hepatitis A virus, hepatitis B

virus, hepatitis C virus, cytomegalo-

virus, and Epstein-Barr virus were

negative. She tested positive for anti-

nuclear antibodies (Titer 1/2560) andsmooth muscle antibodies (1/160) and

the IgG level was 2468 mg/dL. Liver

histology supported the diagnosis ofType1 AIH, with inammation and -

brosis at Grade 2 and Stage 1, re-

spectively (Fig 3). The patient wasstarted on steroids (prednisone 40 mg

per day) with normalization of ALT and

AST at 4 weeks. Tapering was un-

dertaken, but at the dosage of 20 mg

per day she showed an asymptomaticrise 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 re-

mained very high (Fig 1), without im-

provement after replacement ofazathioprine by MMF at 1.5 g per day.

Three months later, a second liver

biopsy conrmed the worsening of

inammatory activity to Grade 4, andbrosis to Stage 2. Treatment withcyclosporin was not offered in view ofpositivity for Epstein-Barr virus DNAfound in liver tissue from the secondbiopsy, not seen in therst. Instead, we

decided to use rituximab 375 mg/m2

weekly for 4 doses. Three months later,the level of serum aminotransferasesnormalized (Fig 1), and serum IgG lev-els also returned to normal values(Fig 2). Prednisone 4 mg per day wasmaintained. Twenty-three months later,a are of necroinammatory activity,evidenced by high levels of serumaminotransferases (ALT 902 IU/mL, AST353 IU/mL), was controlled with a newsingle dose of rituximab. Further infu-sions were then indicated every 6months to maintain successful clinicaland biochemical remission during thefollowing 12 months, keeping predni-sone at 4 mg per day and azathioprineat 1 mg/kg per day.

DISCUSSION

B cells are involved in the etiology ofmany autoimmune diseases in several

FIGURE 2

Serum IgG levels after rituximab treatment.

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ways4: rst, through their secretion ofautoantibodies; second, as antigen-

presenting cells, inducing the activa-tion of autoreactive T cells; third, bysecretion of cytokines, such as in-terleukin-2, interferon-g, tumor ne-crosis factor-a(Th1), or interleukin-6,and transforming growth factor-b(Th17). AIH is considered to be a T-cellmediated disease; however, numerous

observations would suggest thatB cells are also involved in its patho-

genesis: (1) immunoglobulin-secretingplasma cells are abundantly present inthe liver lymphocyte inltrates3; (2) thelevel of specic autoantibodies andtotal IgG in sera have been found tocorrelate with disease activity5,6; (3) intype 2 AIH, the CD4+ and CD8+ T-cellresponses target the same antigen as

B cells, and an overlap of B- and T-cellepitopes has been shown7; and (4)plasma exchange has been shown tobe effective for the management ofrefractory systemic autoimmune dis-eases.8 Finally, there are other pub-

lished cases of patients who respondedto rituximab treatment.911

The 2 cases reported inthis article showthatanti-CD20monoclonalantibodyis aneffective therapy. Remission of the dis-ease probably needs a complete pro-tocol of 4 weekly doses, and repeateddoses at variable periods of time couldbe necessary in some patients despitepersistent administration of usual main-tenance doses of other drugs, such as

prednisone or azathioprine.After more than 10 years of use, ritux-imab hasproven to be remarkably safe;however, side effects described inpatients treated with anti-CD20 includea slight increase in the incidence ofinfectious diseases. Recently, a moresevere complication consisting of a pro-gressive, multifocal, eventually lethalencephalitis caused by the polyoma-virus John Cunningham virus, has been

described months or years after thebeginning of the treatment.12

Altogether, according to previous clin-ical and experimental results and thecasespresentedhere,rituximabmaybeconsidered as a rescue therapy inpatients with AIH not responding to theusual immunosuppressive regimen.

REFERENCES

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FIGURE 3

Liver biopsy ndings from patients. Case 1: A, foci of lobular mononuclear in ltrates and conuentnecrosis. At higher magnication (B), perivenular necrosis with lymphoplasmacytic inltrates andhepatocyte drop-out is clearly seen. Case 2: C, dense portal and panlobular lymphoplasmacytic inl-

trates with rosette formation. D, Centrilobular changes similar to case 1, with hepatocyte swelling.Hematoxylin-eosin. H&E 110x magnication (A), 450x magnication (B to D).

CASE REPORT

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10. Shores D, Kobak G, Pegram LD, WhitingtonPF, Shneider BL. Giant cell hepatitis andimmune thrombocytopenic purpura: re-versal of liver failure with rituximab ther-apy. J Pediatr Gastroenterol Nutr. 2012;55(4):e128e130

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term outcome in 16 children. J Pediatr.2011;159(1):127132.e1

12. Carson KR, Focosi D, Major EO, et al.Monoclonal antibody-associated progres-sive multifocal leucoencephalopathy in pa-

tients treated with rituximab, natalizumab,and efalizumab: a Review from the Researchon Adverse Drug Events and Reports (RADAR)Project. Lancet Oncol. 2009;10(8):816824

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DOI: 10.1542/peds.2011-1900; originally published online July 1, 2013;2013;132;e526Pediatrics

Daniel D'Agostino, Alejandro Costaguta and Fernando lvarezSuccessful Treatment of Refractory Autoimmune Hepatitis With Rituximab

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DOI: 10.1542/peds.2011-1900; originally published online July 1, 2013;2013;132;e526Pediatrics

Daniel D'Agostino, Alejandro Costaguta and Fernando lvarezSuccessful Treatment of Refractory Autoimmune Hepatitis With Rituximab

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