Abatacept is a recombinant fusion protein of the cell surface marker CTLA-4 and immunoglobulin that acts by interfering with T cell activation and is used to treat rheumatoid arthritis. Abatacept has been linked to a low rate of serum enzyme elevations during therapy, but has not been linked to cases of idiosyncratic, clinically apparent liver injury with jaundice. Because abatacept is a potent inhibitor of lymphocyte function, it may cause reactivation of chronic hepatitis B in susceptible patients.
Abatacept (a bat' a sept) is a recombinant fusion protein that combines the extracellular domain of the cytotoxic T lymphocyte associated antigen-4 (CTLA-4) with the heavy chain fragment of immunoglobulin G. Abatacept blocks the actions of CTLA-4, which is important in the co-stimulatory pathway of activation of T cells. Blocking CTLA-4 inhibits maturation and activation of T cells, T cell proliferation and production of proinflammatory cytokines, such as tumor necrosis factor (TNF), interferon gamma and interleukin 2. Abatacept has been evaluated in several autoimmune inflammatory conditions, including rheumatoid and psoriatic arthritis, lupus erythematosis and inflammatory bowel disease. Abatacept was approved for use in the United States in 2005, but current formal indications are limited to rheumatoid arthritis and juvenile idiopathic arthritis. Abatacept is available under the brand name Orencia as a lyophilized power for intravenous administration in single use vials of 250 mg and as a solution for subcutaneous administration in single use syringes of 125 mg/mL. In adults, abatacept may be given subcutaneously (every week) or intravenously (at weeks 0, 2, 4 and then every 4 weeks) in doses based upon body weight ranging from 500 to 1000 mg. The dose in children is 10 mg/kg intravenously at weeks 0, 2, 4 and then every 4 weeks. Common side effects include infusion reactions of chills, fever and hypertension and nonspecific symptoms of headache, dizziness, body pain and rash. Acute hypersensitivity reactions occur in <1% of patients and anaphylaxis in <0.1%. Less common, but potentially severe side effects include an increased risk of infections and possibly reactivation of tuberculosis or hepatitis B.
In prelicensure controlled trials, serum ALT elevations occurred in 2% to 3% of abatacept and a similar proportion of placebo treated subjects. The elevations were usually mild-to-moderate in severity, asymptomatic and self-limited in course. ALT elevations above 5 times the upper limit of normal (ULN) occurred <1% of abatacept recipients, and only rare patients had to stop therapy because of serum enzyme elevations. Clinically apparent liver injury is not listed as a potential side effect in the product label for abatacept, but there has been at least one case report of acute liver injury with symptoms or jaundice attributed to abatacept: a case of severe acute hepatitis accompanied by ANA positivity and a response to corticosteroid therapy (Case 1). Thus, abatacept may precipitate an acute autoimmune hepatitis but this is quite rare.
Abatacept is a potent immunosuppressive agent and reactivation of hepatitis B in susceptible patients is theoretically possible, but has not been reported despite considerable experience with its use in patients with inactive or resolved hepatitis B. Reactivation of hepatitis B typically occurs in patients who are HBsAg carriers with inactive liver disease. During early stages of the immunosuppressive therapy, levels of HBV DNA rise, followed by increases in serum ALT and AST and then symptoms and jaundice. The onset of liver injury is usually after 3 to 6 monthly injections of the immunomodulatory agent. Nevertheless, there have been no clear instances of reactivation of hepatitis B attributed to abatacept, and routine screening for hepatitis B and prophylaxis against reactivation is not recommended.
Likehood score: D (possible but rare cause of clinically apparent liver injury).
Mechanism of Injury
Abatacept is a recombinant human protein and as such is unlikely to be intrinsically hepatotoxic. Because it has immunomodulatory actions, it may cause reactivation of hepatitis B or induce an autoimmune liver reaction.
Outcome and Management
Abatacept has been linked to minor serum enzyme elevations and to rare instances of acute liver injury with jaundice. Discontinuation for serum enzyme elevations is rarely necessary, but should be done if the elevations are accompanied by symptoms or jaundice or for persistent ALT elevations of more than 5 times ULN. There is no information on cross sensitivity to liver injury between abatacept and other immunomodulatory cytokines.
Case 1. Acute liver injury attributed to abatacept therapy.
[Modified from: Iwanaga N, Origuchi T, Terada K, Ueki Y, Kamo Y, Kinoshita N, Yonemitsu N, et al. Rheumatoid arthritis complicated with severe liver injury during treatment with abatacept. Mod Rheumatol 2014; 24: 874-6. PubMed Citation]
A 61 year old Japanese woman with
Sjögren syndrome and rheumatoid arthritis developed epigastric pain and nausea after four infusions of abatacept. She had been treated previously with methotrexate, infliximab, adalimumab, tacrolimus and tocilizumab without a lasting response. She had no history of liver disease, drug allergies, risk factors for viral hepatitis or alcohol abuse. Physical examination showed jaundice and epigastric tenderness. Laboratory tests show a total bilirubin of 15.2 mg/dL (12.1 mg/dL direct) with an ALT of 2217 U/L, AST 4310 U/L, alkaline phosphatase 1388 U/L and prothrombin time index 50%. Tests for hepatitis A, B (including HBV DNA) and C were negative, as were IgM antibodies to cytomegalovirus and Epstein Barr virus. The ANA was positive (1:1280), IgG was elevated (2,030 mg/dL) and rheumatoid factor was present (56.8 IU/mL), but SMA and AMA were negative. Over the next few weeks, she worsened with serum bilirubin rising to 24 mg/dL, prothrombin activity falling to 40% and appearance of hepatic encephalopathy and ascites. She was treated with high doses of methylprednisolone and plasma exchange. She was evaluated for emergency liver transplantation, but then began to improve spontaneously. Over the next several months, liver tests improved and were normal 6 months later.
|Medication:||Abatacept (500 mg, four intravenous infusions)|
|Pattern:|| Mixed (R=4.6)|
|Severity:||4+ (jaundice, hospitalization, abnormal INR, hepatic coma)|
|Other medications:||None concurrently|
This case is an example of an acute hepatitis with a "mixed" pattern of serum enzyme elevations and severe course arising after 4 to 6 weeks of abatacept therapy of rheumatoid arthritis. Other common causes of acute liver injury were excluded. Tests for hepatitis B documented that the hepatitis was not due to reactivation. Autoimmune features were present, including high titers of ANA and elevations in IgG levels, but these might also have been present because of the underlying disease. Nonetheless, the course and outcome are most compatible with an autoimmune hepatitis induced by the immunomodulatory agent. This reaction must be quite rare.
REPRESENTATIVE TRADE NAMES
Abatacept – Orencia®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NO.
References updated:10 January 2016
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