http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; 24(5): 874–876 © 2014 Japan College of Rheumatology DOI: 10.3109/14397595.2013.844399
LETTER
Rheumatoid arthritis complicated with severe liver injury during treatment with abatacept Nozomi Iwanaga1, Tomoki Origuchi2,3, Kaoru Terada1, Yukitaka Ueki1, Yasuhiro Kamo4, Noboru Kinoshita4, Nobuhisa Yonemitsu5, Shin-Ya Kawashiri2, Kunihiro Ichinose2, Mami Tamai2, Hideki Nakamura2, and Atsushi Kawakami2 1Department of Rheumatology, Sasebo Chuo Hospital, Sasebo, Japan, 2Department of Rheumatology, 3Department of Rehabilitation Sciences,
Unit of Translational Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan, 4Department of Gastroenterology, Sasebo Chuo Hospital, Sasebo, Japan, and 5Department of Pathology, Sasebo Chuo Hospital, Sasebo, Japan
To the Editor, Liver dysfunction is sometimes experienced in the clinical course of rheumatoid arthritis (RA). It is caused by viral hepatitis, autoimmune hepatitis, fatty liver disease and drug-induced liver disease. Reactivation of hepatitis B virus (HBV) in RA patients undergoing immunosuppressive therapy, including biologic agents, is a fairly common clinical complication [1–5]. Abatacept (ABT), a biologic agent of recombinant fusion protein-cytotoxic T-lymphocyte-associated antigen 4-IgG1, binds to CD80 and CD86 on antigen-presenting cells, blocking the engagement of CD28 on T cells and preventing T-cell activation [6]. A recent analysis of ABT from clinical trials showed not only therapeutic benefits but also lower rates of serious adverse events and serious infections compared with most other biologics in individuals with RA in both Western and Asian populations [6–11]. Nevertheless, we encountered an RA patient complicated with severe liver injury during treatment with ABT. To our knowledge, the occurrence of severe liver injury in an ABT-treated RA patient without reactivation of HBV has not been reported previously. A 61-year-old female suffered from keratoconjunctivitis sicca and xerostomia. She presented at another institution in 2004. Both anti-Sjogren’s syndrome antigen A (anti-SS-A) antibody and antiSjogren’s syndrome antigen B (anti-SS-B) antibody were positive. Lymphocyte infiltration was seen in the specimen of a lip biopsy, and the patient was diagnosed as having Sjögren’s syndrome by the revised criteria proposed by the American–European Consensus Group in 2004 [12]. She also suffered from symmetrical polyarthralgia with positive rheumatoid factor and abnormal radiological changes of both fingers, and in March 2009 she was diagnosed as having RA according to the American Rheumatism Association 1987 revised criteria for the classification of RA [13]. We started methotrexate (MTX; 8 mg/week), and infliximab was added in August 2009. The infliximab was switched to tocilizumab in November 2009 because the patient’s serum transaminase levels were increased. However, the tocilizumab was discontinued because thrombocytopenia developed, and adalimumab and tacrolimus were used instead. In January 2010 the patient’s treatment was revised again, replacing the adalimumab and tacrolimus with ABT (500 mg) because of her high RA disease activity. Her disease activity score Correspondence to: Dr. Tomoki Origuchi, Department of Rehabilitation Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8520, Japan. Tel: ⫹ 81-95-819-7921. Fax: ⫹ 81-95-849-7270. E-mail: [email protected]
History Received 27 May 2013 Accepted 9 August 2013 Published online 6 March 2014
28 -erythrocyte sedimentation rate (ESR) was 6.07 and her simplified disease activity index was 36.1. We classified the patient’s RA as Stage II and Class 2 according to the Steinbrocker disease stage score and classification system, respectively. After the fourth infusion of ABT the patient complained of epigastralgia, general fatigue and appetite loss, and she was admitted to our hospital. At that time she was not being treated with nor was she taking any medicine other than the ABT; neither methotrexate, tacrolimus, Chinese herbs, over-the-counter drugs, nor alcohol. On admission, a physical examination revealed jaundice and tenderness of her epigastric region. She had not developed hepatosplenomegaly. Her initial laboratory studies revealed a white blood cell count of 6100/μL (46.0% neutrophils, 3.0% eosinophils, 37.0% lymphocytes and 13.0% monocytes), hemoglobin of 12.6 g/dL, platelet count of 131,000/ μL, ESR of 18 mm/H and C-reactive protein of 1.3 mg/dL. Total bilirubin and direct bilirubin were 15.2 mg/dL and 12.1 mg/dL, respectively. Serum aspartate aminotransferase (AST) was 4310 IU/L, serum alanine aminotransferase (ALT) was 2217 IU/L, serum alkaline phosphatase was 1388 IU/L, lactate dehydrogenase was 1368 IU/L, cholinesterase was 169 IU/L, NH3 was 133 μg/dL, and prothrombin activity (PT) and activated partial thromboplastin time were 49.5% and 42 s, respectively. Rheumatoid factor and anti-CCP antibody were 56.8 IU/mL and 253 U/mL, respectively. Anti-nuclear antibody was 1,280 ⫻ positive (speckled pattern), and antimitochondrial M2 (anti-M2) and anti-smooth-muscle (anti-Sm) antibodies were negative. Anti-double stranded DNA and anti-Sm antibodies were also negative. Anti-SS-A/Ro antibody was ⬎ 240 U/mL and anti-SS-B/La antibody was ⬎ 320 U/mL. Total serum hemolytic complement activity (CH50) was 28.6 mg/dL, complement C3 was 59.7 mg/dL and complement C4 was 12.6 mg/dL. Immunoglobulin (IgG) was 2.030 mg/dL, IgA was 449 mg/dL and IgM was 205 mg/dL. IgM-hepatitis A virus antibody was negative. Hepatitis B surface antigen and hepatitis B core antibody were negative. HBV-DNA was under the detection level. Anti-hepatitis C virus antibody was negative, Epstein–Barr virus (EBV) viral-capsid antigen (VCA) IgM was negative, EBV VCA IgG was positive (9⫻) and Epstein Barr Virus nuclear antigen (EBV EBNA) IgG was positive (4.3⫻). Cytomegalovirus (CMV) IgM was negative and CMV IgG was positive. Based on the above data, we ruled out viral hepatitis as a potential cause for her liver dysfunction.
DOI 10.3109/14397595.2013.844399
Letter
875
Figure 1. Clinical course of the patient, a 61-year-old female with RA complicated with severe liver injury during treatment with ABT.
We treated the patient with intravenous pulse of methylprednisolone (mPSL; 1,000 mg/day, 3 days) and plasma exchange therapy. Despite these treatments, her liver atrophy rapidly progressed and hepatic coma with ascites appeared (Figure. 1). Although we planned a liver transplantation to save her, her symptoms improved along with decreases in AST and ALT levels after a while. After obtaining the patient’s consent, we performed a liver biopsy on the 73rd hospital day (in April 2011), which revealed moderate fibrosis and a moderate infiltration of neutrophils and plasma cells and lymphocytes in portal areas. Some spotty necrosis of hepatocytes was noted with an infiltration of neutrophils and lymphocytes. Cholestasis of the bile ducts is not a typical finding of drug-induced liver damage, and lymphoplasmacytic infiltration intermingled with neutrophils and spotty necrosis suggests drug-induced hepatitis (Figure. 2). We thus suspected that the patient’s liver dysfunction was induced by the abatacept. After cessation of abatacept, the patient’s RA activity increased and we treated her with leukocytapheresis. Liver dysfunction in RA patients who are receiving biologics has been reported in post-marketing surveillance in Japan [14–17]. Although the incidence is very low, severe liver injury in biologic agent-treated Japanese RA patients as judged by the physicians has occurred in 4 cases (0.1%) with ABT, 0 cases (0.0%) with infliximab (IFX), 4 cases (0.1%) with adalimumab , 15 cases (0.1%) with etanercept and 12 cases (0.3%) with tocilizumab (TCZ) treatment. Almost all of these cases were associated with HBV reactivation, but reactivation of HBV was not found in the present patient. The mechanism underlying liver injury due to ABT has not been identified. However, the investigators of the Consortium of Rheumatology Researchers of North America (CORRONA) described a possible mechanism: fragment crystallizable (Fc) receptormediated hepatotoxicity due to tumor necrosis factor (TNF) inhibitors [18]. Hepatic sinusoids bind IgG immune complexes via Fc receptor-mediated interactions, and then Kupffer cells are activated to produce reactive oxygen metabolites, followed by hepatocyte damage and release of liver enzymes. Mahamid et al. reported histological changes in a case of acute liver injury due to TCZ [19]. The histological changes included focal necrosis with perisinusoidal fibrosis and steatosis, without
cellular infiltrates. Mahamid et al. suggested that severe liver injury was induced by promoting apoptosis of the hepatocytes and inhibiting liver regeneration.
Figure 2. Histological findings of our patient’s liver biopsy: cholestasis in bile ducts and moderate infiltration of neutrophils, plasma cells and lymphocytes and moderate fibrosis in the portal area and spotty necrosis (H.E. stain ⫻ 100 and ⫻ 400).
876
N. Iwanaga et al.
Our patient’s case was complicated with Sjögren’s syndrome. Autoimmune hepatitis (AIH) might therefore be speculated to be the cause of her liver dysfunction. The BIOGEAS project (a Spanish registry collecting data on the use of biological agents in adults with systemic autoimmune diseases) has reported more than 800 cases of autoimmune diseases secondary to TNF-targeted therapies, mostly lupus, vasculitis and optic neuritis [20]. AIH cases are rare, representing less than 2% of all autoimmune-disorder cases related to anti-TNF agents [20]. With the use of anti-TNFα agents, the incidence of drug-induced AIH as a complication of treatment has increased. Although 11 cases of AIH due to anti-TNFα agents were reported between 2001 and 2010 [21], it has not been reported in any case of ABT, to our knowledge. In our patient’s case, ANA was positive and the IgG titer was elevated. However, anti-M2 antibody and anti-Sm antibody were negative, and the liver biopsy did not indicate AIH pathologically since AIH is associated with a chronic hepatitis pattern in liver biopsy. In addition, the patient’s autoimmune score of 9 prior to treatment did not meet the international diagnostic criteria for AIH (definite AIH, ⬎ 15; probable AIH, 10 to 15) [22]. Sjögren’s syndrome patients often develop drug allergies. Our patient had developed liver dysfunction due to IFX and thrombocytopenia due to TCZ; therefore, she fit the profile of a patient who is susceptible to drug allergy, and her liver dysfunction was suspected to be due to a drug-induced hepatic injury caused by ABT. We have reported for the first time an RA patient whose case was complicated with severe liver injury during treatment with ABT. Although almost all cases in which severe liver injury or fulminant hepatitis developed during treatment with biologic agents were due to HBV reactivation, we think that this RA patient was an extraordinary case who had anti-SS-B/La antibody positive Sjögren’s syndrome and had experienced some adverse effects, and the liver injury was induced by ABT. Physicians should recognize the possibility of severe liver dysfunction developing in RA patients receiving ABT even if the patients do not have an HBV infection or AIH.
Conflict of interest AK has received lecture fees and/or research grants from BristolMyers Squibb, Mitsubishi Tanabe Pharma Co., Takeda Pharmaceutical Company, Pfizer Japan, Abbvie GK, Eisai Co., Chugai Pharmaceutical Co. and Astellas Pharma Inc. TO has received a research grant from Mitsubishi Tanabe Pharma Co.
References 1. Chung SJ, Kim JK, Park MC, Park YB, Lee SK. Reactivation of hepatitis B viral infection in inactive HBsAg carriers following anti-tumor necrosis factor-alpha therapy. J Rheumatol. 2009;36(11):2416–20. 2. Lan JL, Chen YM, Hsieh TY, Chen YH, Hsieh CW, Chen DY, et al. Kinetics of viral loads and risk of hepatitis B virus reactivation in hepatitis B core antibody-positive rheumatoid arthritis patients undergoing anti-tumour necrosis factor alpha therapy. Ann Rheum Dis. 2011;70(10):1719–25. 3. Tanaka E, Urata Y. Risk of hepatitis B reactivation in patients treated with tumor necrosis factor-α inhibitors. Hepatol Res. 2012;42(4):333–9. 4. Viganò M, Degasperi E, Aghemo A, Lampertico P, Colombo M. AntiTNF drugs in patients with hepatitis B or C virus infection: safety and clinical management. Expert Opin Biol Ther. 2012;12(2):193–207. 5. Lee YH, Bae SC, Song GG. Hepatitis B virus (HBV) reactivation in rheumatic patients with hepatitis core antigen (HBV occult carriers) undergoing anti-tumor necrosis factor therapy. Clin Exp Rheumatol. 2013;31(1):118–21.
Mod Rheumatol, 2014; 24(5): 874–876
6. Kremer JM, Westhovens R, Leon M, Di Giorgio E, Alten R, Steinfeld S, et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med. 2003;349(20):1907–15. 7. Nash P, Nayiager S, Genovese MC, Kivitz AJ, Oelke K, Ludivico C, et al. Immunogenicity, safety and efficacy of abatacept administered subcutaneously with or without background methotrexate in patients with rheumatoid arthritis: Results from accompany, a phase III study. Arthritis Care Res (Hoboken) 2013;65(5):718–28. 8. Schiff M, Keiserman M, Codding C, Songcharoen S, Berman A, Nayiager S, et al. Clinical response and tolerability to abatacept in patients with rheumatoid arthritis previously treated with infliximab or abatacept: open-label extension of the ATTEST Study. Ann Rheum Dis. 2011;70(11):2003–7. 9. Kremer JM, Russell AS, Emery P, Abud-Mendoza C, Szechinski J, Westhovens R, et al. Long-term safety, efficacy and inhibition of radiographic progression with abatacept treatment in patients with rheumatoid arthritis and an inadequate response to methotrexate: 3-year results from the AIM trial. Ann Rheum Dis. 2011;70(10):1826–30. 10. Takeuchi T, Matsubara T, Nitobe T, Suematsu E, Ohta S, Honjo S, et al. Japan Abatacept Study Group. Phase II dose-response study of abatacept in Japanese patients with active rheumatoid arthritis with an inadequate response to methotrexate. Mod Rheumatol. 2013;23(2):226–35. 11. Singh JA, Wells GA, Christensen R, Tanjong Ghogomu E, Maxwell L, Macdonald JK, et al. Adverse effects of biologics: a network metaanalysis and Cochrane overview. Cochrane Database Syst Rev. 2011; doi: 10.1002/14651858. 12. Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, et al. Classification criteria for Sjögren’s syndrome: a revised version of the European criteria proposed by the AmericanEuropean Consensus Group. Ann Rheum Dis. 2002;61(6):554–8. 13. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315–24. 14. Takeuchi T, Tatsuki Y, Nogami Y, Ishiguro N, Tanaka Y, Yamanaka H, et al. Postmarketing surveillance of the safety profile of infliximab in 5000 Japanese patients with rheumatoid arthritis. Ann Rheum Dis. 2008;67(2):189–94. 15. HUMIRA Information Network, http://db.e-humira.jp/dra/report/ download.php/224/%E9%81%A9%E6%AD%A3%E4%BD%BF%E7 %94%A8%E6%83%85%E5%A0%B1%20Vol.5.pdf#search ⫽ ‘%E3% 83%92%E3%83%A5%E3%83%9F%E3%83%A9⫹%E8%82%9D%E 9%9A%9C%E5%AE%B3 ⫹ 3084’. 16. Koike T, Harigai M, Inokuma S, Ishiguro N, Ryu J, Takeuchi T, et al. Postmarketing surveillance of safety and effectiveness of etanercept in Japanese patients with rheumatoid arthritis. M. Mod Rheumatol. 2011;21(4):343–51. 17. Koike T, Harigai M, Inokuma S, Ishiguro N, Ryu J, Takeuchi T, et al. Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: interim analysis of 3881 patients. Ann Rheum Dis. 2011;70(12):2148–51. 18. Sokolove J, Strand V, Greenberg JD, Curtis JR, Kavanaugh A, Kremer JM, et al.; CORRONA Investigators. Risk of elevated liver enzymes associated with TNF inhibitor utilisation in patients with rheumatoid arthritis. Ann Rheum Dis. 2010;69(9):1612–7. 19. Mahamid M, Paz K, Reuven M, Safadi R. Hepatotoxicity due to tocilizumab and anakinra in rheumatoid arthritis: two case reports. Int J Gen Med. 2011;4:657–60. 20. Ramos-Casals M, Roberto-Perez-Alvarez, Diaz-Lagares C, Cuadrado MJ, Khamashta MA; BIOGEAS Study Group. Autoimmune diseases induced by biological agents: a double-edged sword? Autoimmun Rev. 2010;9(3):188–93. 21. Efe C, Purnak T, Ozaslan E, Wahlin S. Drug-induced autoimmune hepatitis caused by anti-tumor necrosis factor α agents. Hepatology. 2010;52(6):2246–7. 22. Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Candcado EL. International autoimmune hepatitis group report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol, 1999;31(5):929–38.
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LETTER
Rheumatoid arthritis complicated with severe liver injury during treatment with abatacept Nozomi Iwanaga1, Tomoki Origuchi2,3, Kaoru Terada1, Yukitaka Ueki1, Yasuhiro Kamo4, Noboru Kinoshita4, Nobuhisa Yonemitsu5, Shin-Ya Kawashiri2, Kunihiro Ichinose2, Mami Tamai2, Hideki Nakamura2, and Atsushi Kawakami2 1Department of Rheumatology, Sasebo Chuo Hospital, Sasebo, Japan, 2Department of Rheumatology, 3Department of Rehabilitation Sciences,
Unit of Translational Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan, 4Department of Gastroenterology, Sasebo Chuo Hospital, Sasebo, Japan, and 5Department of Pathology, Sasebo Chuo Hospital, Sasebo, Japan
To the Editor, Liver dysfunction is sometimes experienced in the clinical course of rheumatoid arthritis (RA). It is caused by viral hepatitis, autoimmune hepatitis, fatty liver disease and drug-induced liver disease. Reactivation of hepatitis B virus (HBV) in RA patients undergoing immunosuppressive therapy, including biologic agents, is a fairly common clinical complication [1–5]. Abatacept (ABT), a biologic agent of recombinant fusion protein-cytotoxic T-lymphocyte-associated antigen 4-IgG1, binds to CD80 and CD86 on antigen-presenting cells, blocking the engagement of CD28 on T cells and preventing T-cell activation [6]. A recent analysis of ABT from clinical trials showed not only therapeutic benefits but also lower rates of serious adverse events and serious infections compared with most other biologics in individuals with RA in both Western and Asian populations [6–11]. Nevertheless, we encountered an RA patient complicated with severe liver injury during treatment with ABT. To our knowledge, the occurrence of severe liver injury in an ABT-treated RA patient without reactivation of HBV has not been reported previously. A 61-year-old female suffered from keratoconjunctivitis sicca and xerostomia. She presented at another institution in 2004. Both anti-Sjogren’s syndrome antigen A (anti-SS-A) antibody and antiSjogren’s syndrome antigen B (anti-SS-B) antibody were positive. Lymphocyte infiltration was seen in the specimen of a lip biopsy, and the patient was diagnosed as having Sjögren’s syndrome by the revised criteria proposed by the American–European Consensus Group in 2004 [12]. She also suffered from symmetrical polyarthralgia with positive rheumatoid factor and abnormal radiological changes of both fingers, and in March 2009 she was diagnosed as having RA according to the American Rheumatism Association 1987 revised criteria for the classification of RA [13]. We started methotrexate (MTX; 8 mg/week), and infliximab was added in August 2009. The infliximab was switched to tocilizumab in November 2009 because the patient’s serum transaminase levels were increased. However, the tocilizumab was discontinued because thrombocytopenia developed, and adalimumab and tacrolimus were used instead. In January 2010 the patient’s treatment was revised again, replacing the adalimumab and tacrolimus with ABT (500 mg) because of her high RA disease activity. Her disease activity score Correspondence to: Dr. Tomoki Origuchi, Department of Rehabilitation Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8520, Japan. Tel: ⫹ 81-95-819-7921. Fax: ⫹ 81-95-849-7270. E-mail: [email protected]
History Received 27 May 2013 Accepted 9 August 2013 Published online 6 March 2014
28 -erythrocyte sedimentation rate (ESR) was 6.07 and her simplified disease activity index was 36.1. We classified the patient’s RA as Stage II and Class 2 according to the Steinbrocker disease stage score and classification system, respectively. After the fourth infusion of ABT the patient complained of epigastralgia, general fatigue and appetite loss, and she was admitted to our hospital. At that time she was not being treated with nor was she taking any medicine other than the ABT; neither methotrexate, tacrolimus, Chinese herbs, over-the-counter drugs, nor alcohol. On admission, a physical examination revealed jaundice and tenderness of her epigastric region. She had not developed hepatosplenomegaly. Her initial laboratory studies revealed a white blood cell count of 6100/μL (46.0% neutrophils, 3.0% eosinophils, 37.0% lymphocytes and 13.0% monocytes), hemoglobin of 12.6 g/dL, platelet count of 131,000/ μL, ESR of 18 mm/H and C-reactive protein of 1.3 mg/dL. Total bilirubin and direct bilirubin were 15.2 mg/dL and 12.1 mg/dL, respectively. Serum aspartate aminotransferase (AST) was 4310 IU/L, serum alanine aminotransferase (ALT) was 2217 IU/L, serum alkaline phosphatase was 1388 IU/L, lactate dehydrogenase was 1368 IU/L, cholinesterase was 169 IU/L, NH3 was 133 μg/dL, and prothrombin activity (PT) and activated partial thromboplastin time were 49.5% and 42 s, respectively. Rheumatoid factor and anti-CCP antibody were 56.8 IU/mL and 253 U/mL, respectively. Anti-nuclear antibody was 1,280 ⫻ positive (speckled pattern), and antimitochondrial M2 (anti-M2) and anti-smooth-muscle (anti-Sm) antibodies were negative. Anti-double stranded DNA and anti-Sm antibodies were also negative. Anti-SS-A/Ro antibody was ⬎ 240 U/mL and anti-SS-B/La antibody was ⬎ 320 U/mL. Total serum hemolytic complement activity (CH50) was 28.6 mg/dL, complement C3 was 59.7 mg/dL and complement C4 was 12.6 mg/dL. Immunoglobulin (IgG) was 2.030 mg/dL, IgA was 449 mg/dL and IgM was 205 mg/dL. IgM-hepatitis A virus antibody was negative. Hepatitis B surface antigen and hepatitis B core antibody were negative. HBV-DNA was under the detection level. Anti-hepatitis C virus antibody was negative, Epstein–Barr virus (EBV) viral-capsid antigen (VCA) IgM was negative, EBV VCA IgG was positive (9⫻) and Epstein Barr Virus nuclear antigen (EBV EBNA) IgG was positive (4.3⫻). Cytomegalovirus (CMV) IgM was negative and CMV IgG was positive. Based on the above data, we ruled out viral hepatitis as a potential cause for her liver dysfunction.
DOI 10.3109/14397595.2013.844399
Letter
875
Figure 1. Clinical course of the patient, a 61-year-old female with RA complicated with severe liver injury during treatment with ABT.
We treated the patient with intravenous pulse of methylprednisolone (mPSL; 1,000 mg/day, 3 days) and plasma exchange therapy. Despite these treatments, her liver atrophy rapidly progressed and hepatic coma with ascites appeared (Figure. 1). Although we planned a liver transplantation to save her, her symptoms improved along with decreases in AST and ALT levels after a while. After obtaining the patient’s consent, we performed a liver biopsy on the 73rd hospital day (in April 2011), which revealed moderate fibrosis and a moderate infiltration of neutrophils and plasma cells and lymphocytes in portal areas. Some spotty necrosis of hepatocytes was noted with an infiltration of neutrophils and lymphocytes. Cholestasis of the bile ducts is not a typical finding of drug-induced liver damage, and lymphoplasmacytic infiltration intermingled with neutrophils and spotty necrosis suggests drug-induced hepatitis (Figure. 2). We thus suspected that the patient’s liver dysfunction was induced by the abatacept. After cessation of abatacept, the patient’s RA activity increased and we treated her with leukocytapheresis. Liver dysfunction in RA patients who are receiving biologics has been reported in post-marketing surveillance in Japan [14–17]. Although the incidence is very low, severe liver injury in biologic agent-treated Japanese RA patients as judged by the physicians has occurred in 4 cases (0.1%) with ABT, 0 cases (0.0%) with infliximab (IFX), 4 cases (0.1%) with adalimumab , 15 cases (0.1%) with etanercept and 12 cases (0.3%) with tocilizumab (TCZ) treatment. Almost all of these cases were associated with HBV reactivation, but reactivation of HBV was not found in the present patient. The mechanism underlying liver injury due to ABT has not been identified. However, the investigators of the Consortium of Rheumatology Researchers of North America (CORRONA) described a possible mechanism: fragment crystallizable (Fc) receptormediated hepatotoxicity due to tumor necrosis factor (TNF) inhibitors [18]. Hepatic sinusoids bind IgG immune complexes via Fc receptor-mediated interactions, and then Kupffer cells are activated to produce reactive oxygen metabolites, followed by hepatocyte damage and release of liver enzymes. Mahamid et al. reported histological changes in a case of acute liver injury due to TCZ [19]. The histological changes included focal necrosis with perisinusoidal fibrosis and steatosis, without
cellular infiltrates. Mahamid et al. suggested that severe liver injury was induced by promoting apoptosis of the hepatocytes and inhibiting liver regeneration.
Figure 2. Histological findings of our patient’s liver biopsy: cholestasis in bile ducts and moderate infiltration of neutrophils, plasma cells and lymphocytes and moderate fibrosis in the portal area and spotty necrosis (H.E. stain ⫻ 100 and ⫻ 400).
876
N. Iwanaga et al.
Our patient’s case was complicated with Sjögren’s syndrome. Autoimmune hepatitis (AIH) might therefore be speculated to be the cause of her liver dysfunction. The BIOGEAS project (a Spanish registry collecting data on the use of biological agents in adults with systemic autoimmune diseases) has reported more than 800 cases of autoimmune diseases secondary to TNF-targeted therapies, mostly lupus, vasculitis and optic neuritis [20]. AIH cases are rare, representing less than 2% of all autoimmune-disorder cases related to anti-TNF agents [20]. With the use of anti-TNFα agents, the incidence of drug-induced AIH as a complication of treatment has increased. Although 11 cases of AIH due to anti-TNFα agents were reported between 2001 and 2010 [21], it has not been reported in any case of ABT, to our knowledge. In our patient’s case, ANA was positive and the IgG titer was elevated. However, anti-M2 antibody and anti-Sm antibody were negative, and the liver biopsy did not indicate AIH pathologically since AIH is associated with a chronic hepatitis pattern in liver biopsy. In addition, the patient’s autoimmune score of 9 prior to treatment did not meet the international diagnostic criteria for AIH (definite AIH, ⬎ 15; probable AIH, 10 to 15) [22]. Sjögren’s syndrome patients often develop drug allergies. Our patient had developed liver dysfunction due to IFX and thrombocytopenia due to TCZ; therefore, she fit the profile of a patient who is susceptible to drug allergy, and her liver dysfunction was suspected to be due to a drug-induced hepatic injury caused by ABT. We have reported for the first time an RA patient whose case was complicated with severe liver injury during treatment with ABT. Although almost all cases in which severe liver injury or fulminant hepatitis developed during treatment with biologic agents were due to HBV reactivation, we think that this RA patient was an extraordinary case who had anti-SS-B/La antibody positive Sjögren’s syndrome and had experienced some adverse effects, and the liver injury was induced by ABT. Physicians should recognize the possibility of severe liver dysfunction developing in RA patients receiving ABT even if the patients do not have an HBV infection or AIH.
Conflict of interest AK has received lecture fees and/or research grants from BristolMyers Squibb, Mitsubishi Tanabe Pharma Co., Takeda Pharmaceutical Company, Pfizer Japan, Abbvie GK, Eisai Co., Chugai Pharmaceutical Co. and Astellas Pharma Inc. TO has received a research grant from Mitsubishi Tanabe Pharma Co.
References 1. Chung SJ, Kim JK, Park MC, Park YB, Lee SK. Reactivation of hepatitis B viral infection in inactive HBsAg carriers following anti-tumor necrosis factor-alpha therapy. J Rheumatol. 2009;36(11):2416–20. 2. Lan JL, Chen YM, Hsieh TY, Chen YH, Hsieh CW, Chen DY, et al. Kinetics of viral loads and risk of hepatitis B virus reactivation in hepatitis B core antibody-positive rheumatoid arthritis patients undergoing anti-tumour necrosis factor alpha therapy. Ann Rheum Dis. 2011;70(10):1719–25. 3. Tanaka E, Urata Y. Risk of hepatitis B reactivation in patients treated with tumor necrosis factor-α inhibitors. Hepatol Res. 2012;42(4):333–9. 4. Viganò M, Degasperi E, Aghemo A, Lampertico P, Colombo M. AntiTNF drugs in patients with hepatitis B or C virus infection: safety and clinical management. Expert Opin Biol Ther. 2012;12(2):193–207. 5. Lee YH, Bae SC, Song GG. Hepatitis B virus (HBV) reactivation in rheumatic patients with hepatitis core antigen (HBV occult carriers) undergoing anti-tumor necrosis factor therapy. Clin Exp Rheumatol. 2013;31(1):118–21.
Mod Rheumatol, 2014; 24(5): 874–876
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