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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Adalimumab

, MD.

Author Information and Affiliations

Last Update: February 10, 2026.

OVERVIEW

Introduction

Adalimumab is a monoclonal antibody to human tumor necrosis factor (TNF) alpha which has potent antiinflammatory activity and is used in the therapy of severe rheumatoid arthritis and inflammatory bowel disease. Adalimumab has been linked to rare instances of idiosyncratic acute liver injury and is a potential cause of reactivation of hepatitis B.

Background

Adalimumab (ay" da lim' ue mab) is a human recombinant monoclonal immunoglobulin G1 antibody to TNF alpha which binds avidly to serum and tissue-bound TNF, causing its inactivation and degradation. Inhibition of TNF alpha activity leads to modulation of the inflammatory and pain pathways activated by this cytokine which is found in elevated levels in several autoimmune and inflammatory conditions. Adalimumab was approved in the United States for use in rheumatoid arthritis in 2002, and subsequently its indications have been extended to ankylosing spondylitis, juvenile idiopathic (rheumatoid) arthritis, severe psoriasis and psoriatic arthritis, Crohn disease, ulcerative colitis, hidradenitis suppurative, and uveitis. It is used off-label for treatment of other autoimmune conditions including autoimmune hepatitis and immune-mediated drug-induced liver injury. Adalimumab is considered a disease modifying antirheumatic drug (DMARD), and has been shown to improve symptoms as well as joint and cartilage damage in the inflammatory arthritidies. Adalimumab is available in prefilled syringes or pens in various concentrations, most frequently 40 or 80 mg in 0.8 mL, generically and under the brand name of Humira. The typical maintenance dose of adalimumab in adults is 40 mg subcutaneously every other week. Common side effects include injection site reactions, headache, nausea, abdominal discomfort, diarrhea, skin rash and fever. Rare but potentially severe side effects include bone marrow suppression, demyelinating disorder, severe infections, lymphoma and other malignances, worsening of congestive heart failure, and hypersensitivity reactions. TNF alpha antagonists are also capable of causing immune suppression, resulting in reactivation of microbial infections including tuberculosis and hepatitis B.

Hepatotoxicity

Adalimumab has been associated with a low rate of serum aminotransferase elevations during therapy, but these have been transient, mild and asymptomatic, and have rarely required dose modification. ALT levels above 3 times ULN have been reported in 1.0% to 3.5% of adalimumab recipients compared to 0.9% to 1.8% of controls. Rare instances of clinically apparent liver injury have been reported with adalimumab, resembling the hepatic injury that has been described with infliximab therapy. The onset of injury is usually within 3 months and the pattern of serum enzyme elevations hepatocellular. The injury was usually mild and anicteric and resolves promptly on stopping adalimumab. In some instances, however, the injury persists and resembles autoimmune hepatitis requiring corticosteroid therapy (Case 1). In reports with adequate follow up, most patients are able to discontinue immunosuppressive therapy. Liver injury from adalimumab appears to be less frequent and less severe than similar injury from infliximab. The reasons for these differences are not clear. Infliximab is a chimeric monoclonal antibody (mouse-human) while adalimumab is a fully human monoclonal antibody. While infliximab has been associated with cases of severe liver injury and death from liver failure, adalimumab has not. In many instances patients with infliximab induced liver injury have subsequently tolerated adalimumab therapy without recurrence and those with adalimumab induced liver injury have tolerated other TNF antagonists.

Like infliximab, adalimumab has been linked to cases of reactivation of hepatitis B. Reactivation typically occurs in patients who are inactive HBsAg carriers, with normal serum aminotransferase levels and no or only low levels of HBV DNA in serum. The immune suppression caused by the immunomodulatory agent leads to an increase in HBV replication and rise in serum HBV DNA levels. With stopping the immunosuppression (or between cycles of therapy), restoration of immune function leads to an acute immunological response to the heightened viral replication and an flare of hepatitis, that can be severe and can result in hepatic failure and death. Reactivation in patients with anti-HBc without HBsAg (serologic pattern of previous HBV infection) has been reported in rare patients treated with anti-TNF antagonists, and is more common after therapy with rituximab or bone marrow transplantation. The anti-TNF inhibitors have little or no effect on hepatitis C virus levels and have been used safely in patients with chronic hepatitis C.

Likelihood score: B (highly likely but rare cause of clinically apparent liver injury due to an autoimmune hepatitis-like injury or reactivation of hepatitis B).

Mechanism of Injury

The mechanism of liver injury due to adalimumab and other TNFα antagonists is not known, but is likely caused by immune modulation and induction of autoimmunity.

Outcome and Management

Most published cases of hepatotoxicity of adalimumab have been mild and self-limiting, less frequent and less severe than that reported with infliximab. Patients who are to start adalimumab therapy should be screened for evidence of hepatitis B, and those with preexisting HBsAg in serum should be offered prophylaxis with an potent oral antiviral agent such as tenofovir or entecavir. Patients with anti-HBc without HBsAg in serum should receive antiviral therapy as prophylaxis or be monitored carefully with testing for HBV DNA in serum and started on antiviral therapy if HBV DNA arises, an early indicator of HBV reactivation.

Patients who develop an autoimmune hepatitis-like syndrome during adalimumab therapy may not recover promptly with stopping the TNF antagonist and may require corticosteroid therapy. In this event, the corticosteroid dose should be kept to a minimum to control the disease and, ultimately, attempts should be made to withdraw immunosuppression (or decrease to levels used to treat the underlying condition before administration of adalimumab).

Rechallenge with adalimumab can result in recurrence, while switching to other monoclonal anti-TNF such as infliximab, certolizumab, or golimumab may be safe from occurrence of liver injury but should be done with caution and careful monitoring. There does not appear to be cross reactivity in hepatic injury between adalimumab and etanercept, which is not a monoclonal antibody but rather a modified form of the TNFα receptor.

Drug Class: Antirheumatic Agents; Dermatologic Agents; Gastrointestinal Agents, Inflammatory Bowel Disease Agents

Other Drugs in the Subclass, Tumor Necrosis Factor Antagonists: Certolizumab, Etanercept, Golimumab, Infliximab

CASE REPORTS

Case 1. Hepatitis with jaundice due to adalimumab.(1)

A 44 year old woman with long standing Crohn disease was started on adalimumab in a dose of 40 mg subcutaneously every two weeks. She tolerated therapy well and her bowel symptoms improved. After 3 months of treatment she was found to have elevations in serum aminotransferase levels. Because of the success of therapy and her lack of symptoms, treatment was continued. After 11 months of treatment when she had the onset of fatigue, nausea and vomiting, abdominal pain, dark urine, and jaundice. Her past medical history included a cholecystectomy and two bowel resections for Crohn disease. She drank alcohol only occasionally and had no history of liver disease, risk factors for viral hepatitis, or drug allergies. Her other medications included amitriptyline for depression, omeprazole for gastrointestinal upset, and zolpidem for sleep. On examination she was jaundiced but had no rash, fever, or signs of liver failure. Serum bilirubin was 18.0 mg/dL, ALT 532 U/L, AST 932 U/L, Alk P 158 U/L, serum albumin 2.5 g/dL, and INR 3.2. Tests for hepatitis A, B and C were negative as was antinuclear antibody (ANA). A liver biopsy showed marked cholestasis and liver cell injury with ballooning degeneration without fibrosis. Imaging of the liver was unremarkable, and endoscopic retrograde cholangiopancreatography (ERCP) showed no biliary obstruction, or evidence of sclerosing cholangitis. Adalimumab had been stopped on admission and prednisone started. Her blood tests improved slowly and she was discharged after 4 weeks, still jaundiced but feeling better. When seen 2 months later liver tests were near normal, bilirubin having fallen to 0.7 mg/dL and INR improved at 1.2. Prednisone doses were tapered, and immunosuppressive therapy was discontinued 2 months later. In follow up all liver tests were normal except for intermittent mild elevations in alkaline phosphatase.

Key Points

Medication:Adalimumab (40 mg subcutaneously every 2 weeks)
Pattern:Hepatocellular (R=13.2)
Severity:Severe, 4+ (jaundice, hospitalization, INR > 1.5)
Latency:3 months to onset of ALT elevations, 11 months to jaundice
Recovery:2 to 3 months
Other medications:Chronically, amitriptyline, omeprazole, zolpidem

Laboratory Values

Time After
Starting		Time After
Stopping		ALT
(U/L)		Alk P
(U/L)		Bilirubin
(mg/dL)		Other
PrePre391140.4Shortly before therapy
3 monthsPre1651880.6
8 monthsPre1811810.7
11 months0 days52315818.0Drug stopped, Pred started, INR 3.5
1 week21817212.6Liver biosy, INR 1.8
2 weeks15313213.4INR 1.6
3 weeks13912714.7ERCP
12 months1 month14811516.4Discharged, INR 1.4
3 months511510.7INR 1.1
16 months4 months181030.5
5 months351210.5Prednisone stopped
8 months511510.7
23 months12 months311220.5INR 1.0
Normal values <45 <120 <1.2

Comment

A dramatic example of an autoimmune-like hepatitis arising in a patient with adalimumab induced liver injury. Serum aminotransferase elevations arose within 3 months of starting therapy but adalimumab was continued despite the ALT levels being above 3 times the ULN. The absence of symptoms and normal bilirubin are typical of the aminotransferase elevations that occur with anti-TNF therapy. Stopping therapy and restarting with careful monitoring might have been a more appropriate approach. The liver injury that arose after 11 months of treatment and eight months of abnormal liver tests was severe, with marked jaundice, prolongation of INR, and fall of serum albumin levels. Despite this, the patient recovered with little evidence of persistent liver injury.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Adalimumab – Humira®

DRUG CLASS

Antirheumatic Agents; Dermatologic Agents; Gastrointestinal Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Adalimumab 331731-18-1 Monoclonal antibodyNot available

CITED REFERENCE

1.
Ghabril M, Bonkovsky HL, Kum C, Davern T, Hayashi PH, Kleiner DE, Serrano J, et al; U.S. Drug-Induced Liver Injury Network. Liver injury from tumor necrosis factor-α antagonists: analysis of thirty-four cases. Clin Gastroenterol Hepatol 2013; 11: 558-64. [PMC free article: PMC3865702] [PubMed: 23333219]

ANNOTATED BIBLIOGRAPHY

References updated: 10 February 2026

Abbreviations Used: TNF, tumor necrosis factor alpha; anti-TNF, antibody to TNF; ANA, anti-nuclear antigen; dsDNA, double stranded DNA; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; anti-HBs, antibody to HBsAg; anti-HBc, antibody to hepatitis B core antigen; HBeAg, hepatitis B e antigen; anti-HBe, antibody to HBeAg; HCV, hepatitis C virus, anti-HCV, antibody to HCV.

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    (21 patients with rheumatic conditions who had anti-HBc without HBsAg in serum and were monitored during 7-56 months of therapy with infliximab [4], etanercept [14] or adalimumab [2]; anti-HBs titers decreased minimally, and no patient developed HBV DNA or HBsAg or features of reactivation).
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    (7 patients with rheumatoid arthritis and chronic hepatitis C were treated with cyclosporine and either etanercept or adalimumab and had clinical improvements with no worsening of liver disease, but instead mild decreases in ALT [38 to 26 U/L] and HCV RNA levels [7.1 to 2.3 million IU/mL]).
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    (66 year old man with psoriasis was treated with efalizumab [anti-CD11a] and then adalimumab [anti-TNF] and 11 days later developed jaundice and severe hepatitis [bilirubin 9.1 rising to 52 mg/dL, ALT 549 U/L, Alk P 131 U/L], with HBsAg being detected and slow, but eventual recovery).
  • Shale MJ, Seow CH, Coffin CS, Kaplan GG, Panaccione R, Ghosh S. Review article: chronic viral infection in the anti-tumour necrosis factor therapy era in inflammatory bowel disease. Aliment Pharmacol Ther 2010; 31: 20-34. [PubMed: 19681818]
    (Extensive review of literature on effects of anti-TNF therapies on underlying chronic hepatitis B and C; among 28 HBV-infected patients, reactivation was common in those not on antiviral therapy, more frequent with monoclonal antibodies than etanercept; among 110 HCV-infected patients, little evidence of worsening of disease and in some instances a decrease in HCV RNA levels).
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    (Retrospective analysis of ALT and AST elevations among 6861 patients with rheumatoid arthritis enrolled in a North American database receiving TNF inhibitors followed for an average of 1.5 years with ~1.7 determinations yearly; any elevation of ALT or AST occurred in 5.4% of visits, >2 times ULN in 0.6%, >5 times ULN in 0.1%; rates slightly higher for those on infliximab alone or combined with methotrexate and leflunomide).
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  • Cravo M, Silva R, Serrano M. Autoimmune hepatitis induced by infliximab in a patient with Crohn's disease with no relapse after switching to adalimumab. BioDrugs 2010; 24 Suppl 1:25-7. [PubMed: 21175232]
    (38 year old woman with Crohn disease, was on and off infliximab for 8 years, developed abnormal liver tests [bilirubin normal, ALT 191 U/L, ANA 1:640], responding to prednisolone and azathioprine within 12 weeks and later treated with adalimumab without worsening of liver disease, but while on long term azathioprine [50 mg/day]).
  • Katsanos KH, Tsianos VE, Zois CD, Zioga H, Vagias I, Zervou E, Christodoulou DK, et al.; Northwest Greece IBD Study Group. Inflammatory bowel disease and hepatitis B and C in Western Balkans: a referral centre study and review of the literature. J Crohns Colitis 2010; 4: 450-65. [PubMed: 21122543]
    (Among 482 patients with inflammatory bowel disease, 11 had HBV and 4 HCV, antiviral therapy for which did not worsen the underlying bowel disease).
  • Hagel S, Bruns T, Theis B, Herrmann A, Stallmach A. Subacute liver failure induced by adalimumab. Int J Clin Pharmacol Ther. 2011;49:38-40. [PubMed: 21176723]
  • (44 year old woman with psoriasis developed jaundice 4 months after starting adalimumab that progressed to subacute liver failure [peak bilirubin 3.5 mg/dL, ALT 15 times ULN, resolving slowly but completely after discontinuation) .
  • Fotiadou C, Lazaridou E, Ioannides D. Safety of anti-tumour necrosis factor-α agents in psoriasis patients who were chronic hepatitis B carriers: a retrospective report of seven patients and brief review of the literature. J Eur Acad Dermatol Venereol 2011; 25: 471-4. [PubMed: 20561122]
    (Seven patients with psoriasis and HBsAg carrier state were treated with adalimumab, etanercept or infliximab for 6-24 months with lamivudine prophylaxis and none suffered reactivation, HBV DNA being undetectable or present at low levels).
  • Carroll MB, Forgione MA. Use of tumor necrosis factor alpha inhibitors in hepatitis B surface antigen-positive patients: a literature review and potential mechanisms of action. Clin Rheumatol 2010; 29: 1021-9. [PubMed: 20556450]
    (Review of literature on anti-TNF therapy in patients with hepatitis B identified 35 cases, 7 cases of reactivation occurred, including 7 of 17 on infliximab, but none of 12 on etanercept or 6 on adalimumab; 18 received lamivudine, but only 7 as prophylaxis).
  • Caporali R, Bobbio-Pallavicini F, Atzeni F, Sakellariou G, Caprioli M, Montecucco C, Sarzi-Puttini P. Safety of tumor necrosis factor alpha blockers in hepatitis B virus occult carriers (hepatitis B surface antigen negative/anti-hepatitis B core antigen positive) with rheumatic diseases. Arthritis Care Res (Hoboken) 2010; 62: 749-54. [PubMed: 20535784]
    (Among 732 patients treated with anti-TNF agents, 5 had HBsAg and were given prophylaxis with lamivudine and 67 had anti-HBc without HBsAg [25 on infliximab, 23 etanercept, 19 adalimumab], none of whom developed HBsAg or reactivation during an average follow up of 3.5 years).
  • Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]
    (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, but none were attributed to a TNF antagonist).
  • Ferrajolo C, Capuano A, Verhamme KM, Schuemie M, Rossi F, Stricker BH, Sturkenboom MC. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol 2010; 70: 721-8. [PMC free article: PMC2997312] [PubMed: 21039766]
    (Worldwide pharmacovigilance database containing 9036 hepatic adverse drug reactions in children, included 60 due to infliximab making it rank 18th in frequency; no other TNF antagonist had more than 30 cases).
  • Vassilopoulos D, Apostolopoulou A, Hadziyannis E, Papatheodoridis GV, Manolakopoulos S, Koskinas J, Manesis EK, et al. Long-term safety of anti-TNF treatment in patients with rheumatic diseases and chronic or resolved hepatitis B virus infection. Ann Rheum Dis 2010; 69: 1352-5. [PubMed: 20472596]
    (Among 131 patients with rheumatic conditions treated with anti-TNF, 14 had HBsAg [all were given prophylactic anti-HBV therapy], 19 had anti-HBs alone [from vaccination] and 19 anti-HBc [from previous infection]; during an average of 2 years of therapy, one patient with HBsAg on lamivudine developed rising titers of HBV DNA and was successfully treated with tenofovir, while all others had no change in serologic status or ALT levels).
  • Kim YJ, Bae SC, Sung YK, Kim TH, Jun JB, Yoo DH, Kim TY, et al. Possible reactivation of potential hepatitis B virus occult infection by tumor necrosis factor-alpha blocker in the treatment of rheumatic diseases. J Rheumatol 2010; 37: 346-50. [PubMed: 20008922]
    (Among 266 Korean patients with rheumatic conditions receiving anti-TNF therapy, 8 had HBsAg and 88 anti-HBc without HBsAg; 2 of the 8 HBsAg-positive patients developed reactivation and ALT elevations were more common in the anti-HBc-positive group [16%] than the antibody-negative group [6%], but reactivation was not demonstrated and clinical features were not given).
  • Féau S, Causse X, Corondan A, Michenet P, Autret-Leca E. [Acute drug-induced hepatitis during adalimumab and ibuprofen treatment]. Gastroenterol Clin Biol 2010; 34: 420-2. French. PMID: 20494537 [PubMed: 20494537]
    (61 year old man with rheumatoid arthritis on adalimumab for 15 months and occasional ibuprofen developed hepatitis [bilirubin 2.9 mg/dL, ALT 2491 U/L, Alk P 292 U/L, ANA negative], resolving within 4 months of stopping medications and increasing prednisone dose)
  • Adar T, Mizrahi M, Pappo O, Scheiman-Elazary A, Shibolet O. Adalimumab-induced autoimmune hepatitis. J Clin Gastroenterol 2010; 44: e20-2. [PubMed: 19593165]
    (36 year old woman with psoriasis and Crohn disease developed nausea after starting adalimumab, and after 3 months liver tests were found to be abnormal [bilirubin 0.7 mg/dL, ALT 1265 U/L, Alk P 102 U/L, ANA 1:80], resolving within 2 months of stopping therapy and starting prednisone and azathioprine).
  • Björnsson E, Talwalkar J, Treeprasertsuk S, Kamath PS, Takahashi N, Sanderson S, Neuhauser M, Lindor K. Drug-induced autoimmune hepatitis: clinical characteristics and prognosis. Hepatology 2010; 51: 2040-8. PubMed Citation20512992 [PubMed: 20512992]
    (Among 261 cases of autoimmune hepatitis seen at the Mayo Clinic between 1997 and 2007, 24 were attributed to drugs, 11 to minocycline, 11 to nitrofurantoin, but none due to anti-TNF agents; all responded to corticosteroid therapy and did not relapse when withdrawn).
  • Stine JG, Bass M, Ibrahim D, Khokhar OS, Lewis JH. Dermatologists' awareness of and screening practices for hepatitis B virus infection before initiating tumor necrosis factor-α inhibitor therapy. South Med J 2011; 104: 781-8. [PubMed: 22089354]
    (Results of email questionnaire sent to 1,000 US dermatologists found that 52% of 62 respondents were aware of guidelines for screening for HBV before using anti-TNF agents, but only 42% routinely screened patients and none of the 62 had ever seen a case of HBV reactivation).
  • Pérez-Alvarez R, Díaz-Lagares C, García-Hernández F, Lopez-Roses L, Brito-Zerón P, Pérez-de-Lis M, Retamozo S, et al.; BIOGEAS Study Group. Hepatitis B virus (HBV) reactivation in patients receiving tumor necrosis factor (TNF)-targeted therapy: analysis of 257 cases. Medicine (Baltimore) 2011; 90: 359-71. [PubMed: 22033451]
    (Systematic review of literature identified 257 patients with preexisting HBV markers who received anti-TNF therapy, reactivation occurred in 39% of 89 patients with HBsAg [5 had acute liver failure and 4 died], but only 5% of 168 with anti-HBc without HBsAg [1 died]; lamivudine prophylaxis decreased, but did not eliminate reactivation [62% vs 23% in HBsAg carriers]).
  • Brunasso AM, Puntoni M, Gulia A, Massone C. Safety of anti-tumour necrosis factor agents in patients with chronic hepatitis C infection: a systematic review. Rheumatology (Oxford) 2011; 50: 1700-11. [PubMed: 21690185]
    (Systematic review of literature identified 153 patients with chronic hepatitis C treated with anti-TNF agents, mostly etanercept, with only 1 with definite worsening of disease on treatment).
  • Goldfeld DA, Verna EC, Lefkowitch J, Swaminath A. Infliximab-induced autoimmune hepatitis with successful switch to adalimumab in a patient with Crohn's disease: the index case. Dig Dis Sci 2011; 56: 3386-8. [PubMed: 21597977]
    (58 year old woman with Crohn disease developed ALT elevations [6 times ULN] 6 months after starting infliximab [peak ALT 210 U/L, ANA 1:2560], resolving within 4 months of stopping and later tolerating adalimumab without recurrence).
  • Manzano-Alonso ML, Castellano-Tortajada G. Reactivation of hepatitis B virus infection after cytotoxic chemotherapy or immunosuppressive therapy. World J Gastroenterol 2011; 17: 1531-7. [PMC free article: PMC3070121] [PubMed: 21472116]
    (Review of reactivation of hepatitis B with chemotherapy or immune suppression discusses 11 cases attributed to infliximab and 7 to etanercept).
  • Aithal GP. Hepatotoxicity related to antirheumatic drugs. Nat Rev Rheumatol 2011; 7: 139-50. [PubMed: 21263458]
    (Review of liver injury due to antirheumatic drugs discusses ALT elevations caused by anti-TNF agents and autoimmune hepatitis due to infliximab).
  • Abramson A, Menter A, Perrillo R. Psoriasis, hepatitis B, and the tumor necrosis factor-alpha inhibitory agents: a review and recommendations for management. J Am Acad Dermatol 2012; 67: 1349-61. [PubMed: 22727462]
    (Systematic review of the literature on risk of reactivation of hepatitis B in patients with psoriasis on anti-TNF therapy found considerable risk in patients with HBsAg who do not receive antiviral prophylaxis, but no reported cases of reactivation among patients with anti-HBc without HBsAg).
  • Titos Arcos JC, Hallal H, Robles M, Andrade RJ. Recurrent hepatotoxicity associated with etanercept and adalimumab but not with infliximab in a patient with rheumatoid arthritis. Rev Esp Enferm Dig 2012; 104: 282-4. [PubMed: 22662786]
    (47 year old woman with rheumatoid arthritis was found to have abnormal liver tests 2 years after starting etanercept [ALT 13 times ULN, ANA positive], resolving within 80 days of stopping and recurring 2 months after starting adalimumab [ALT 4 times ULN], but not after switching to infliximab).
  • Viganò M, Degasperi E, Aghemo A, Lampertico P, Colombo M. Anti-TNF drugs in patients with hepatitis B or C virus infection: safety and clinical management. Expert Opin Biol Ther 2012; 12: 193-207. [PubMed: 22188392]
    (Systematic review of effects of anti-TNF agents on hepatitis B and C, concluding that patients with hepatitis B should receive antiviral prophylaxis whereas those with hepatitis C need not).
  • Grasland A, Sterpu R, Boussoukaya S, Mahe I. Autoimmune hepatitis induced by adalimumab with successful switch to abatacept. Eur J Clin Pharmacol 2012; 68: 895-8. d PMID: 22205272 [PubMed: 22205272]
    (35 year old woman with rheumatoid arthritis developed liver enzyme elevations 2 months after switching from etanercept to adalimumab [bilirubin normal, ALT 266 U/L, Alk P normal, ANA 1:80, SMA 1:320], resolving after stopping and increasing dose of prednisone; later tolerating abatacept [anti-CTLA4]).
  • Di Minno MN, Iervolino S, Peluso R, Russolillo A, Lupoli R, Scarpa R, Di Minno G, et al; CaRRDS Study Group. Hepatic steatosis and disease activity in subjects with psoriatic arthritis receiving tumor necrosis factor-α blockers. J Rheumatol 2012; 39: 1042-6. [PubMed: 22422493]
    (48 patients with psoriatic arthritis and hepatic steatosis by ultrasound were monitored prospectively during anti-TNF treatment; steatosis increased in 47% of anti-TNF treated patients, but only 19% of controls).
  • Anelli MG, Scioscia C, Grattagliano I, Lapadula G. Old and new antirheumatic drugs and the risk of hepatotoxicity. Ther Drug Monit 2012; 34: 622-8. [PubMed: 23128910]
    (Review of hepatotoxicity of antirheumatic agents).
  • Park SH, Yang SK, Lim YS, Shim JH, Yang DH, Jung KW, et al. Clinical courses of chronic hepatitis B virus infection and inflammatory bowel disease in patients with both diseases. Inflamm Bowel Dis 2012; 18: 2004-10. [PubMed: 22337144]
    (Among 4153 Korean patients with inflammatory bowel disease, 134 [3.2%] had HBsAg but only 23 [17%] had abnormal liver tests, but mortality rate was higher in HBsAg-positive than -negative group [5.2% vs 0.4%], with 2 deaths from liver failure and 3 liver cancer).
  • Efe C. Drug induced autoimmune hepatitis and TNF-α blocking agents: is there a real relationship? Autoimmun Rev 2013; 12: 337-9. [PubMed: 22841985]
    (Review of evidence that anti-TNF agents induced autoimmune hepatitis commenting on the rarity of clinically apparent liver injury and the underlying autoimmune diathesis of most treated patients).
  • Lin MV, Blonski W, Buchner AM, Reddy KR, Lichtenstein GR. The influence of anti-TNF therapy on the course of chronic hepatitis C virus infection in patients with inflammatory bowel disease. Dig Dis Sci 2013; 58: 1149-56. [PubMed: 23179145]
    (Among 4274 patients with inflammatory bowel disease and 3523 with hepatitis C seen in a single health care system, 37 had both, 5 of whom received anti-TNF, none of whom developed flares of hepatitis C during therapy).
  • Ghabril M, Bonkovsky HL, Kum C, Davern T, Hayashi PH, Kleiner DE, Serrano J, et al; U.S. Drug-Induced Liver Injury Network. Liver injury from tumor necrosis factor-α antagonists: analysis of thirty-four cases. Clin Gastroenterol Hepatol 2013; 11: 558-64. [PMC free article: PMC3865702] [PubMed: 23333219]
    (Description of 6 cases of liver injury attributed to anti-TNF agents [3 infliximab, 2 etanercept, 1 adalimumab] in 5 women and 1 man, mean age 32 years with time to onset of 2 to 52 weeks; 3 were ANA positive and 5 were treated with prednisone; all resolved; review of 28 cases described in the literature, most due to infliximab [26], one resulting in liver transplant).
  • Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. [PubMed: 23419359]
    (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, including 4 [1 with jaundice] attributed to infliximab [ranking 3rd], for an estimated incidence of 1 per 148 persons exposed but none attributed to adalimumab).
  • Pompili M, Biolato M, Miele L, Grieco A. Tumor necrosis factor-α inhibitors and chronic hepatitis C: a comprehensive literature review. World J Gastroenterol 2013; 19: 7867-73. [PMC free article: PMC3848134] [PubMed: 24307780]
    (Systematic review of the literature on the safety of TNF antagonists in patients with chronic HCV infection identified reports on a total of 216 patients, and only rare instances of worsening of liver disease during therapy).
  • Kim E, Bressler B, Schaeffer DF, Yoshida EM. Severe cholestasis due to adalimumab in a Crohn's disease patient. World J Hepatol 2013; 5: 592-5. [PMC free article: PMC3812463] [PubMed: 24179620]
    (39 year old woman with Crohn disease developed jaundice and itching 7 months after adding adalimumab to azathioprine [bilirubin 9.8 mg/dL, ALT 15 U/L, Alk P 183 U/L, ANA negative], biopsy showing bland cholestasis and injury, resolving 10 weeks after stopping both drugs, but later tolerating azathioprine alone).
  • Italian Group for the Study of Inflammatory Bowel Disease, Armuzzi A, Biancone L, Daperno M, Coli A, Pugliese D, Annese V, Aratari A, et al. Adalimumab in active ulcerative colitis: a "real-life" observational study. Dig Liver Dis 2013; 45: 738-43. [PubMed: 23683530]
    (Retrospective analysis of the efficacy and safety of adalimumab in ulcerative colitis from 22 Italian centers identified 88 patients; side effects were reported in 12 patents, but none were due to liver injury).
  • Carvalheiro J, Mendes S, Sofia C. Infliximab induced liver injury in Crohn's disease: A challenging diagnosis. J Crohns Colitis 2013 Nov 29. [Epub ahead of print] [PubMed: 24291019]
    (24 year old man with Crohn disease developed serum enzyme elevations after a 2nd infusion of infliximab, which increased over the next 5 months [bilirubin not given, peak ALT 211 U/L, Alk P 388 U/L] and then fell back into the normal range 8 months after switching to adalimumab).
  • Rossi RE, Parisi I, Despott EJ, Burroughs AK, O'Beirne J, Conte D, Hamilton MI, Murray CD. Anti-tumour necrosis factor agent and liver injury: literature review, recommendations for management. World J Gastroenterol 2014; 20: 17352-9. [PMC free article: PMC4265593] [PubMed: 25516646]
    (Review of the literature on liver injury during anti-TNF therapy stresses that most ALT elevations are mild-to-moderate and self-limiting even with continuation of therapy).
  • Carvalheiro J, Mendes S, Sofia C. Infliximab induced liver injury in Crohn's disease: a challenging diagnosis. J Crohns Colitis 2014; 8: 436-7. [PubMed: 24291019]
    (24 year old man with Crohn disease developed liver enzyme elevations after a second infusion of infliximab [bilirubin not given, ALT 211 U/L, Alk P 388 U/L], biopsy showing chronic hepatitis and cholestasis, improving slowly after switching to adalimumab).
  • Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]
    (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, the most common implicated agents being nimesulide [n=53: 30%], cyproterone [n=18], nitrofurantoin [n=17], antituberculosis drugs [n=13] and flutamide [n=12: 7%]; none were attributed to a TNF antagonist).
  • Shelton E, Chaudrey K, Sauk J, Khalili H, Masia R, Nguyen DD, Yajnik V, et al. New onset idiosyncratic liver enzyme elevations with biological therapy in inflammatory bowel disease. Aliment Pharmacol Ther 2015; 41: 972-9. [PubMed: 25756190]
    (Among 1753 patients with inflammatory bowel disease receiving anti-TNF therapies between 2009 and 2013, 102 developed ALT elevations but half could be attributed to another cause and the 48 attributed to infliximab [45 of 1170: 3%] or adalimumab [3 of 575: 0.5%], 34 patients [71%] recovering despite continuation of therapy, 4 stopping therapy and 10 switching to an alternative agent without suffering recurrence).
  • Di Bisceglie AM, Lok AS, Martin P, Terrault N, Perrillo RP, Hoofnagle JH. Recent US Food and Drug Administration warnings on hepatitis B reactivation with immune-suppressing and anticancer drugs: just the tip of the iceberg? Hepatology 2015; 61: 703-11. [PMC free article: PMC5497492] [PubMed: 25412906]
    (Review of the pathogenesis, clinical course, treatment and prevention of HBV reactivation in patients receiving immunosuppressive or anticancer therapies, with particular focus on rituximab and ofatumumab).
  • Capkin E, Karkucak M, Cosar AM, Ak E, Karaca A, Gokmen F, Budak BS, Tosun M. Treatment of ankylosing spondylitis with TNF inhibitors does not have adverse effect on results of liver function tests: a longitudinal study. Int J Rheum Dis 2015; 18: 548-52. [PubMed: 24612551]
    (Among 94 patients with ankylosing spondylitis treated with infliximab [n=28], adalimumab [n=32] or etanercept [n=34], there was no change in mean ALT levels after 3 and 6 months of therapy).
  • Petríková J, Jarčuška P, Svajdler M, Pella D, Macejová Z. Autoimmune hepatitis triggered by adalimumab and allergic reactions after various anti-TNFα therapy agents in a patient with rheumatoid arthritis. Isr Med Assoc J 2015; 17: 256-8. [PubMed: 26040057]
    (33 year old woman with rheumatoid arthritis developed fatigue after 3 doses of adalimumab [bilirubin not given, ALT 888 U/L, Alk P 348 U/L, ANA positive], biopsy showing interface hepatitis, resolving with prednisolone; later having allergic reactions to etanercept and certolizumab, but responding to anakinra).
  • Shelton E, Chaudrey K, Sauk J, Khalili H, Masia R, Nguyen DD, Yajnik V, Ananthakrishnan AN. New onset idiosyncratic liver enzyme elevations with biological therapy in inflammatory bowel disease. Aliment Pharmacol Ther 2015; 41: 972-9. [PubMed: 25756190]
    (Among 1753 patients with inflammatory bowel disease treated with anti-TNF agents, 102 [6%] developed ALT elevations, but half could be attributed to other causes; among 48 with suspected anti-TNF injury [45 infliximab, 3 adalimumab], 34 resolved spontaneously and were able to continue therapy, 10 switched to another agent without recurrence, 4 were treated with corticosteroids).
  • Rodrigues S, Lopes S, Magro F, Cardoso H, Horta e Vale AM, Marques M, Mariz E, et al. Autoimmune hepatitis and anti-tumor necrosis factor alpha therapy: A single center report of 8 cases. World J Gastroenterol 2015; 21: 7584-8. [PMC free article: PMC4481456] [PubMed: 26140007]
    (Among more than 600 patients treated with anti-TNF agents over a 7 year period, 8 developed autoimmune hepatitis [7 on infliximab, 1 adalimumab]; 3 men, 5 women, most with ANA, 2 symptomatic, no mention of jaundice; all responding to corticosteroids, 2 requiring long term therapy).
  • Björnsson ES, Gunnarsson BI, Gröndal G, Jonasson JG, Einarsdottir R, Ludviksson BR, Gudbjörnsson B, Olafsson S. Risk of drug-induced liver injury from tumor necrosis factor antagonists. Clin Gastroenterol Hepatol 2015; 13: 602-8. [PubMed: 25131534]
    (Among 11 cases of liver injury from anti-TNF agents identified over a 5 year period in Iceland, 9 were due to infliximab [among 1076 patients treated=1:120], 1 adalimumab [270 treated] and 1 etanercept [430 treated]; 8 women, 3 men; latency 1 to 6 months; 5 were jaundiced [peak bilirubin 0.6-7.6 mg/dL, ALT 169-1658 U/L, Alk P 71-916 U/L], 8 hepatocellular, 2 cholestatic and 1 mixed injury; 8 had ANA, 5 were treated with corticosteroids [only 1 long term], 8 were switched to another anti-TNF agent without recurrence).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 6 cases [0.7%] were attributed to a tumor necrosis factor antagonist, including 3 to infliximab, 2 etanercept and 1 adalimumab, but none to certolizumab or golimumab).
  • Chiu YM, Tang CH, Hung ST, Yang YW, Fang CH, Lin HY. A real-world risk analysis of biological treatment (adalimumab and etanercept) in a country with a high prevalence of tuberculosis and chronic liver disease: a nationwide population-based study. Scand J Rheumatol 2017:46:236-40. 27766916 [PubMed: 27766916]
    (Nationwide population-based data on use of adalimumab [n=4049] and etanercept [n=5117] between 2007 and 2011, identified higher rates of serious hepatic events for adalimumab vs etanercept [0.75 vs 0.39 per 100 person years] as well as higher rates of tuberculosis [1.62 vs 0.57 per 100 person-years]).
  • Koller T, Galambosova M, Filakovska S, Kubincova M, Hlavaty T, Toth J, Krajcovicova A, et al. Drug-induced liver injury in inflammatory bowel disease: 1-year prospective observational study. World J Gastroenterol. 2017;23:4102-4111. [PMC free article: PMC5473129] [PubMed: 28652663]
    (Among 251 patients with inflammatory bowel disease enrolled in a prospective study with liver test monitoring every 3 months, 66 [22%] had ALT elevations that were usually transient and mild, and of 33 patients on adalimumab, only 2 had elevations above twice normal, none of which were persistent and none had elevations above 3 times normal).
  • Kok B, Lester ELW, Lee WM, Hanje AJ, Stravitz RT, Girgis S, Patel V, et al; United States Acute Liver Failure Study Group. Acute liver failure from tumor necrosis factor-α antagonists: report of four cases and literature review. Dig Dis Sci. 2018;63:1654-1666. [PubMed: 29564668]
    (Among more than 2500 cases of acute liver failure enrolled in a prospective US database between 1998 and 2014, 4 were attributed to infliximab induced liver injury, but none were attributed to adalimumab or other TNF antagonists).
  • Drugs for psoriatic arthritis. Med Lett Drugs Ther. 2019;61(1588):203-210. [PubMed: 31999665]
    (Concise review of the mechanism of action, efficacy, safety, and costs of drugs for psoriatic arthritis, mentions that five TNF antagonists are approved for this condition and appear to have similar efficacy and their adverse events include reactivation of hepatitis B; does not mention the risk of hepatotoxicity).
  • Bruno CD, Fremd B, Church RJ, Daly AK, Aithal GP, Björnsson ES, Larrey D, et al. HLA associations with infliximab-induced liver injury. Pharmacogenomics J. 2020;20:681-686. [PubMed: 32024945]
    (Amng 16 European patients with infliximab-induced liver injury compared to 60 matched controls, genome-wide association studies showed no apparent gene differences but imputation of HLA alleles found a higher carrier rate of B*39:01 in cases [n=4, carrier rate 25%] vs controls [none, predicted estimate 2%).
  • Drugs for rheumatoid arthritis. Med Lett Drugs Ther. 2021;63(1637):177-184. [PubMed: 35085210]
    (Concise review of the mechanism of action, efficacy, safety, and costs of drugs for rheumatoid arthritis, mentions that five TNF antagonists are indicated for rheumatoid arthritis if maximal tolerated doses of methotrexate are not adequately effective; description of adverse events mentions reactivation of hepatitis B and induction of autoimmune conditions but not hepatotoxicity).
  • Björnsson HK, Gudbjornsson B, Björnsson ES. Infliximab-induced liver injury: clinical phenotypes, autoimmunity and the role of corticosteroid treatment. J Hepatol. 2022;76:86-92. [PubMed: 34487751]
    (Among 36 Icelandic patients who developed elevated enzymes after starting infliximab therapy between 2009 and 2020, median age was 46 years, 78% were women, only 4 with jaundice, 2 hospitalized, 67% with ANA [half were positive before therapy], infliximab stopped in all but ALT elevations frequently persisted, 17 [47%] were treated with corticosteroids which led to rapid resolution [45 vs 79 days without corticosteroids], and all eventually stopped corticosteroid without relapse even when treated with other TNF antagonists).
  • Núñez F P, Quera R, Bay C, Castro F, Mezzano G. Drug-induced liver injury used in the treatment of inflammatory bowel disease. J Crohns Colitis. 2022;16:1168-1176. [PubMed: 35044449]
    (Review of the hepatic adverse events that occur with therapies of inflammatory bowel disease such as sulfasalazine, thiopurines, methotrexate, TNF antagonists, newer monoclonal and small molecule inhibitors, and sphingosine-1-phosphate modulators).
  • Akyol L, Balcı MA. Influence of anti-TNF-α treatment on liver and kidney functions in patients with ankylosing spondylitis: a retrospective longitudinal study. Eur J Rheumatol. 2022;9:31-35. [PMC free article: PMC10089139] [PubMed: 34101575]
    (Among 148 patients with ankylosing spondylitis treated with TNF antagonists [golimumab 68, certolizumab 33, etanercept 23, adalimumab 18 and infliximab 1] for at least one year, mean ALT and AST levels remained within the normal range).
  • Björnsson ES, Stephens C, Atallah E, Robles-Diaz M, Alvarez-Alvarez I, Gerbes A, Weber S, et al. A new framework for advancing in drug-induced liver injury research. The Prospective European DILI Registry. Liver Int. 2023;43:115-126. [PMC free article: PMC7614006] [PubMed: 35899490]
    (Initial results from the prospective European multi-national drug-induced liver injury registry [UK, Spain, Germany, Switzerland, Portugal, Iceland] describes 246 cases, the most frequent implicated agents being amoxicillin-clavulanate [12%], flucloxacillin [11%] atorvastatin [8%], nivolumab/ipilimumab [8%], infliximab [5%], nitrofurantoin [4.5%], disulfiram [2%], ibuprofen [2%], and HDS products [7.3%]; adalimumab and other TNF antagonists not mentioned).
  • Drugs for inflammatory bowel disease. Med Lett Drugs Ther. 2023;65(1680):105-112. [PubMed: 37418329]
    (Concise review of the mechanism of action, efficacy, safety, and costs of drugs for ulcerative colitis and Crohn disease, mentions that the monoclonal antibodies to TNF are effective in induction and maintenance of remissions, infliximab and adalimumab being approved for both forms, certolizumab for ulcerative colitis only and golimumab for Crohn disease only; discussion of adverse events mentions reactivation of hepatitis B and induction of autoimmune conditions but without mention of hepatotoxicity).
  • Drugs for plaque psoriasis. Med Lett Drugs Ther. 2024;66(1712):153-160. [PubMed: 39302348]
    (Concise review of the mechanism of action, efficacy, safety, and costs of drugs for psoriasis, mentions that four TNF antagonists are approved for moderate-to-severe plaque psoriasis and that adverse events include reactivation of hepatitis B but does not mention hepatotoxicity).
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    (Review of the literature identified 12 reports of severe acute liver injury due to infliximab but only one due to adalimumab [Hagel 2011] in a patient who ultimately recovered).
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    (Review of the clinical features, causes, diagnosis, and management of drug-induced autoimmune-like hepatitis and comparison to spontaneous autoimmune hepatitis mentions the most common causes as minocycline, nitrofurantoin, hydralazine, methyldopa, infliximab, adalimumab, statins, interferon, and imatinib).
  • Algarzae NK, Alotaibi HM, Alajlan AH, AlSaleh MR, Alsalman AA. Hepatotoxicity induced by adalimumab in chronic plaque psoriasis patient: a case report. Int Med Case Rep J. 2025;18:877-881. [PMC free article: PMC12256697] [PubMed: 40662078]
    (24 year old woman with psoriasis developed abnormal liver tests 6 months after starting adalimumab [bilirubin 1.2 mg/dL, ALT 152 U/L, Alk P not provided) which fell into the normal range within 6 weeks of stopping, later tolerating Risankizumab [IL-23 inhibitor]).
  • Caballero-Linares CF, Cei B, Alfageme F. Hepatotoxicity associated with adalimumab in hidradenitis suppurativa: a report of two cases of drug-induced liver injury. Dermatol Pract Concept. 2025;15:5320. [PMC free article: PMC12339123] [PubMed: 40790407]
    (Two women, ages 47 and 56 years, with hidradenitis suppurative developed liver test abnormalities the first after receiving adalimumab for 4 years [laboratory data not given] and the second after 3 days of an initial dose [ALT 1595 U/L, GGT 556 U/L, bilirubin not provided] both resolving after discontinuation).
  • Abdulhameed NM, Banama M, Alsayed AlMarzooqi E. Adalimumab-induced hepatocellular injury in a young male with hidradenitis suppurativa and underlying metabolically dysfunctional liver disease: a case report. Cureus. 2025;17:e100354. [PMC free article: PMC12851511] [PubMed: 41613664]
    (20 year old man with hidradenitis suppurativa developed gradually rising ALT levels after starting adalimumab [ALT 40 to 67 to 139 U/L], ultrasound demonstrating probable steatosis said to be due to the combination of nonalcoholic steatohepatitis and adalimumab induced liver injury but no follow up provided).
  • Bessone F, Hernandez N, Medina-Caliz I, García-Cortés M, Schinoni MI, Mendizabal M, Chiodi D, et al. Drug-induced liver injury in Latin America: 10-year experience of the Latin American DILI (LATINDILI) Network. Clin Gastroenterol Hepatol. 2025;23:89-102.. [PubMed: 38992407]
    (Among 483 cases of drug-induced liver injury enrolled in a prospective Latin American database, 1 was attributed to infliximab and none to adalimumab).
  • Kuo MH, Tseng CW, Tseng KC, Lu MC, Tung CH, Chen NT, Huang KY, et al. The relationship between TNF-α inhibitor potency and HBV reactivation in patients with rheumatic disorders. Liver Int. 2025;45:e70152.. [PubMed: 40418092]
    (Among 72 HBsAg positive patients treated with anti-TNF without prophylaxis, 21 [29%] developed reactivation vs 2 of 39 [5%] with prophylaxis, and 28 of 600 [5%] with anti-HBc without HBsAg and without prophylaxis, reactivation being more frequent with adalimumab that with etanercept or golimumab).
  • Chen H, Jiang S, Wang J, Zhang A, Zhu L. Hepatobiliary disorders associated with TNF-α inhibitors: a pharmacovigilance analysis of FAERS and JADER. Front Immunol. 2026;16:1739631. [PMC free article: PMC12832726] [PubMed: 41601665]
    (Analysis of the US FDA adverse event reporting system [FAERS] between 2004 and 2025 for TNF antagonists found 19,083 reports of hepatobiliary events, 9501 for adalimumab, 3979 infliximab, 3949 etanercept, 1012 certolizumab pegol, and 642 golimumab).

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