• Adalimumab
• Autoimmune hepatitis
• Basiliximab
• Belimumab
• Biological therapies
• Infliximab
• Rituximab

• GI bleeding
• General surgery

• Female
• Humans
• Gallbladder/diagnostic imaging
• Choledocholithiasis/complications
• Choledocholithiasis/diagnostic imaging
• Choledocholithiasis/surgery
• Cholecystitis/complications
• Cholecystitis/surgery
• Gallbladder Diseases/complications
• Hemorrhage/complications

• Crohn’s disease
• Drug-induced liver damage
• hepatotoxicity
• inflammatory bowel disease
• ulcerative colitis

• Biological Products/adverse effects
• Chemical and Drug Induced Liver Injury/drug therapy
• Chemical and Drug Induced Liver Injury/etiology
• Humans
• Immunosuppressive Agents/therapeutic use
• Inflammatory Bowel Diseases/chemically induced
• Inflammatory Bowel Diseases/drug therapy
• Infliximab/therapeutic use
• Tumor Necrosis Factor Inhibitors
• Tumor Necrosis Factor-alpha

B cells are central for the adaptive immune system to mount successful immune responses not only as antibody producers but also as regulators of cellular immunity. These multifaceted features are also reflected in autoimmunity where autoreactive B cells can fuel disease by production of cytotoxic autoantibodies, presentation of autoantigens to autoreactive T cells, and secretion of cytokines and chemokines that either promote detrimental immune activation or impair regulatory T and B cells. The role of B cells and autoantibodies in autoimmune hepatitis (AIH) have been controversially discussed, with typical autoantibodies and hypergammaglobulinemia indicating a key role, while strong HLA class II association suggests T cells as key players. In this review, we summarize current knowledge on B cells in AIH and how different B cell subpopulations may drive AIH progression beyond autoantibodies. We also discuss recent findings of B cell-directed therapies in AIH.

• Antigen presentation
• Autoantibody
• Autoimmune hepatitis
• B cell
• Cytokine
• Depletion therapy

Inflammatory bowel diseases (IBD) are associated with various hepatobiliary disorders. They can occur at any moment in the course of the disease or associated with the treatment. The prevalence of liver dysfunction can reach up to 50% in different studies. Nonalcoholic fatty liver disease is considered the most common hepatobiliary complication in IBD, while primary sclerosing cholangitis is the most specific. Management of hepatic manifestations in IBD involves a multidisciplinary approach that includes a high index of suspicion and joint management with hepatologists. The medical confrontation with abnormal liver tests must include an exhaustive study to determine if these patterns can be related to IBD, associated diseases or to the therapies used.

• Extraintestinal manifestations
• Inflammatory bowel disease
• Sclerosing primary cholangitis
• Hepatic steatosis
• Liver toxicity

• Crohn’s disease (CD)
• Drug-induced liver injury (DILI)
• Hepatotoxicity
• Inflammatory bowel disease (IBD)
• Ulcerative colitis (UC)

Biologics are among the most commonly prescribed medications for several chronic inflammatory diseases. Tumor necrosis factor alpha inhibitors, more so than other agents, have been observed to cause drug‐induced liver injury. Additionally, because the approval and popularity of checkpoint inhibitors have grown, similar patterns of liver injury have been documented, with a majority of cases describing immune‐mediated hepatitis. Although the exact mechanism of injury is unknown, various host and medication characteristics play a role in the outcome of the molecular cascade invoked by biologics. Prognosis is usually favorable with cessation of the offending agent, but cases of acute liver failure requiring liver transplantation have also been observed. Therefore, algorithms have been created to assist clinicians in treating drug‐induced autoimmune hepatitis, mostly with corticosteroids. Additionally, case reports have documented successfully rechallenging patients with a different biologic without recurrence of liver injury, but data are limited. Further investigation is warranted regarding the potential for cross‐reactivity and mechanism of injury to develop guidelines to aid clinicians in further management of these patients.

• Autoimmune hepatitis
• Drug-induced liver injury
• Hepatitis B reactivation
• Hepatobiliary disorders
• Inflammatory bowel disease
• Nonalcoholic fatty liver disease
• Primary sclerosing cholangitis

• Bile Duct Neoplasms/epidemiology
• Chemical and Drug Induced Liver Injury/etiology
• Cholangiocarcinoma/epidemiology
• Cholangitis, Sclerosing/diagnosis
• Cholangitis, Sclerosing/etiology
• Cholangitis, Sclerosing/therapy
• Hepatitis, Autoimmune/etiology
• Hepatitis, Viral, Human/epidemiology
• Humans
• Inflammatory Bowel Diseases/complications
• Inflammatory Bowel Diseases/drug therapy
• Liver Diseases/epidemiology
• Liver Diseases/etiology

• Adalimumab
• Autoimmune hepatitis
• Biologics
• Etanercept
• Hepatitis
• Infliximab
• TNF alpha inhibitors

• Animals
• Chemical and Drug Induced Liver Injury/diagnosis
• Chemical and Drug Induced Liver Injury/metabolism
• Etanercept/adverse effects
• Humans
• Infliximab/adverse effects
• Tumor Necrosis Factor-alpha/antagonists & inhibitors
• Tumor Necrosis Factor-alpha/metabolism

• R15 HL117199 NHLBI NIH HHS
• U01 DK065201 NIDDK NIH HHS
• U01 DK065211 NIDDK NIH HHS
• U54 DK083909 NIDDK NIH HHS

• Adverse drug reactions
• Crohn’s disease
• Drug induced liver injury
• Hepatotoxicity
• Inflammatory bowel disease
• Ulcerative colitis

• Acute Liver Failure
• Autoimmune Hepatitis
• Hepatocellular Carcinoma

• ANA
• Autoimmune Hepatitis
• Liver Disease
• TNF-α
• Toxicity

Autoimmune hepatitis (AIH) is an unresolving progressive liver disease of unknown etiology characterized by hypergammaglobulinemia, autoantibodies detection and interface hepatitis. Due to the absence of specific diagnostic markers and the large heterogeneity of its clinical, laboratory and histological features, AIH diagnosis may be potentially difficult. Therefore, in this in-depth review we summarize the substantial progress on etiopathogenesis, clinical, serological and histological phenotypes of AIH. AIH has a global distribution affecting any age, both sexes and all ethnic groups. Clinical manifestations vary from asymptomatic to severe or rarely fulminant hepatitis. Hypergammaglobulinemia with selective elevation of IgG is found in most cases. Autoimmune attack is perpetuated, possibly via molecular mimicry, and favored by the impaired control of T-regulatory cells. Histology (interface hepatitis, emperipolesis and hepatic rosette formation) and autoantibodies detection although not pathognomonic, are still the hallmark for a timely diagnosis. AIH remains a major diagnostic challenge. AIH should be considered in every case in the absence of viral, metabolic, genetic and toxic etiology of chronic or acute hepatitis. Laboratory personnel, hepato-pathologists and clinicians need to become more familiar with disease expressions and the interpretation of liver histology and autoimmune serology to derive maximum benefit for the patient.

• Autoimmune hepatitis
• Liver autoimmunity
• Liver-related autoantibodies
• Non-organ specific autoantibodies
• Overlap syndromes

• Animals
• Autoantibodies/blood
• Biomarkers/blood
• Hepatitis, Autoimmune/blood
• Hepatitis, Autoimmune/classification
• Hepatitis, Autoimmune/diagnosis
• Hepatitis, Autoimmune/epidemiology
• Hepatitis, Autoimmune/immunology
• Hepatitis, Autoimmune/therapy
• Humans
• Liver/immunology
• Liver/pathology
• Phenotype
• Prognosis
• Risk Factors

• Adalimumab
• Anti-tumor necrosis factor
• Autoimmune disease
• Certolizumab pegol
• Complications
• Golimumab
• Infliximab
• Infusion reactions

• Antibodies, Monoclonal/adverse effects
• Autoimmune Diseases/chemically induced
• Autoimmune Diseases/therapy
• Biological Products/adverse effects
• Chemical and Drug Induced Liver Injury/etiology
• Drug Hypersensitivity/epidemiology
• Drug Hypersensitivity/etiology
• Drug Hypersensitivity/therapy
• Heart Diseases/chemically induced
• Hematologic Diseases/chemically induced
• Humans
• Immunosuppressive Agents/adverse effects
• Inflammatory Bowel Diseases/drug therapy
• Infliximab
• Infusions, Intravenous
• Lung Diseases/chemically induced
• Nervous System Diseases/chemically induced
• Skin Diseases/chemically induced
• Skin Diseases/therapy
• Tumor Necrosis Factor-alpha/antagonists & inhibitors

Elevation of liver biochemistry has been reported with anti-tumor necrosis factor agents, but overt liver failure rarely reported. Autoimmune hepatitis has been more commonly reported with infliximab than adalimumab (ADA). Our case, however, describes the first reported case of ADA-associated severe cholestatic injury. A 39-year-old female with Crohn’s disease developed severe jaundice after initiation of ADA. All serologic tests and imaging studies were normal. Liver biopsy showed prominent pericentral canalicular cholestasis, without features of steatosis or sclerosing cholangitis, consistent with drug-induced cholestasis. The serum total bilirubin peaked at 280 μmol/L, and improvement was seen after 5 wk with eventual normalization of liver enzymes at 10 wk. Our case describes the first reported case of ADA-associated severe cholestatic liver disease and the first histopathologic examination of this adverse drug effect. Clinicians need to be aware of this potential drug-induced liver injury when prescribing this commonly used biologic medication.

• Crohn’s disease
• Cholestasis
• Adalimumab
• Anti-tumor necrosis factor agents
• Drug-induced liver injury

• Antibodies, Monoclonal/therapeutic use
• Female
• Hepatitis, Autoimmune/drug therapy
• Humans
• Male
• Tumor Necrosis Factor-alpha/antagonists & inhibitors

Immunomodulatory biologics are a class of biotechnology-derived therapeutic products that are designed to engage immune-relevant targets and are indicated in the treatment and management of a range of diseases, including immune-mediated inflammatory diseases and malignancies.

Owing to their specificity, immunomodulatory biologics generally have better safety profiles than small-molecule drugs. However, adverse effects such as an increased risk of infections or cytokine release syndrome are of concern. Here, Park and colleagues discuss the current strategies used to predict and mitigate these adverse effects and consider how they can be used to inform the development of safer immunomodulatory biologics.

Immunomodulatory biologics, which render their therapeutic effects by modulating or harnessing immune responses, have proven their therapeutic utility in several complex conditions including cancer and autoimmune diseases. However, unwanted adverse reactions — including serious infections, malignancy, cytokine release syndrome, anaphylaxis and hypersensitivity as well as immunogenicity — pose a challenge to the development of new (and safer) immunomodulatory biologics. In this article, we assess the safety issues associated with immunomodulatory biologics and discuss the current approaches for predicting and mitigating adverse reactions associated with their use. We also outline how these approaches can inform the development of safer immunomodulatory biologics.

• drug-induced liver injury
• tumor necrosis factor
• tnf-α antagonists
• hepatotoxicity
• autoimmunity

• Adalimumab
• Adult
• Antibodies, Monoclonal/administration & dosage
• Antibodies, Monoclonal/adverse effects
• Antibodies, Monoclonal, Humanized/administration & dosage
• Antibodies, Monoclonal, Humanized/adverse effects
• Autoimmune Diseases/chemically induced
• Chemical and Drug Induced Liver Injury
• Cholestasis/chemically induced
• Etanercept
• Female
• Humans
• Immunoglobulin G/administration & dosage
• Immunoglobulin G/adverse effects
• Immunologic Factors/administration & dosage
• Immunologic Factors/adverse effects
• Infliximab
• Liver/pathology
• Male
• Receptors, Tumor Necrosis Factor/administration & dosage
• Severity of Illness Index
• Tumor Necrosis Factor-alpha/antagonists & inhibitors
• United States

• U01 DK065211 NIDDK NIH HHS
• 1U01DK065238 NIDDK NIH HHS
• 1U01DK065021 NIDDK NIH HHS
• U01DK065193 NIDDK NIH HHS
• U01 DK083027 NIDDK NIH HHS
• U01 DK083020 NIDDK NIH HHS
• U01 DK065201 NIDDK NIH HHS
• U01 DK065238 NIDDK NIH HHS
• U01 DK065193 NIDDK NIH HHS
• 1U01DK065201 NIDDK NIH HHS
• U01 DK065176 NIDDK NIH HHS
• U01 DK083023 NIDDK NIH HHS
• 1U01DK065176 NIDDK NIH HHS
• U01 DK082992 NIDDK NIH HHS
• 1U01DK065193 NIDDK NIH HHS
• 1U01DK065211 NIDDK NIH HHS
• 1U01DK065184 NIDDK NIH HHS
• U01 DK065184 NIDDK NIH HHS

• AUTOIMMUNE HEPATITIS
• AUTOIMMUNE LIVER DISEASE
• CIRRHOSIS
• HEPATOCELLULAR CARCINOMA