Autoimmune liver diseases in systemic rheumatic diseases

Table 1 Hepatic abnormalities associated with common medications used in systemic rheumatic diseases

Medications	Hepatic abnormalities	2Likelihood score category in DILI
NSAIDs	LEE, cholestasis, acute liver failure, VBDS	A for diclofenac, ibuprofen, sulindac
Glucocorticoids	LEE, NAFLD, acute liver failure, HBV reactivation	A in high dosages
Immunosuppressive agents
Azathioprine	LEE, cholestasis, NRH, peliosis hepatis, VOD	A
Mycophenolate mofetil	LEE	D
Cyclophosphamide	LEE, VOD	B
Cyclosporine	LEE, cholelithiasis	C
Tacrolimus	LEE	C
Conventional SDMARDs
Hydroxychloroquine	LEE	C
Leflunomide	LEE, acute liver failure, HBV reactivation	B
Methotrexate	LEE, NAFLD, HBV reactivation, fibrosis, cirrhosis	A
Penicillamine	LEE, cholestasis	A
Sulfasalazine	LEE, cholestasis, DRESS	A
Biologic/targeted SDMARDs
Abatacept	LEE, HBV reactivation	C
Anakinra	LEE	C
Apremilast	Unlikely liver injury	E
Belimumab	Unlikely liver injury	E
Mepolizumab	Unlikely liver injury	E
Rituximab	LEE, HBV reactivation	A
TNF blockers1	LEE, cholestasis, HBV reactivation, AIH	A for infliximab
Tocilizumab	LEE, HBV reactivation	C
Tofacitinib	Suspected liver injury, potential HBV reactivation	E’
Ustekinumab	Suspected liver injury, possible HBV reactivation	E’

¹TNF blockers including adalimumab, certolizumab, etanercept, golimumab and infliximab.

²Categorization of Likelihood Score in drug-induced liver injury. A: Definite; B: Highly likely; C: Probable, D: Possible, E: Unlikely; E’: Suspected.

NSAIDs: Non-steroidal anti-inflammatory drugs; HBV: Hepatitis virus B; DILI: Drug-induced liver injury; DRESS: Drug rash with eosinophilia and systemic symptoms; LEE: Liver enzyme elevation; NAFLD: Nonalcoholic fatty liver disease; NRH: Nodular regenerative hyperplasia; SDMARDs: Synthetic disease-modifying antirheumatic drugs; SRDs: Systemic rheumatic disease; VBDS: Vanishing bile duct syndrome; VOD: Veno-occlusive disease.

Table 2 Demographic, clinical, laboratory, pathological, therapeutic and prognostic profiles in three common autoimmune liver diseases

Category	AIH	PBC	PSC
Demographic
Sex	Predominant F, 4:1	Predominant F, 10:1	Predominant M, 2:1
Age	Any, median 45 yr	Common above 40 yr	Any, typical 30-50 yr
Prevalence	Rare, 4-25 per 100000	Rare, 2-40 per 100000	Rare, 4-16 per 100000
Laboratory
Abnormal LFT	Majorly AST/ALT	Majorly ALP/GGT	Majorly ALP/GGT
Serum Ig	Elevated IgG	Elevated IgM	Elevated IgG, IgM
Autoantibody	I: ANA, ASMA; II: anti-LKM, -LC	ANA, AMA	ANCA
HLA-DR	DR3, DR4	DR8	DR52
Liver biopsy
Interface HA	Typical finding	Occasional	Occasional
Portal infiltrate	Lymphoplasmacytic	Lymphocytic	Lymphocytic
Bile duct lesion	Occasional	Florid duct lesion	Obliterative duct
Granuloma	Rare	Typical finding	Rare
Diagnosis	AIH score for definite diagnosis	AMA, liver biopsy, Cholestatic LFT	Cholangiography, Cholestatic LFT
Coexistent SRD
SLE	0.7%-2.8%	1.3%-3.7%	1.70%
SS	1.4%-35%	3.5%-38%	CR
SSc	0.80%	2.3%-12%	CR
RA	1.6%-5.4%	1.8%-13%	1.2%-3.4%
IIM	CR	0.6%-3.1%	CR
MCTD	CR	0.60%	NA
SV	1.60%	2.20%	CR
Sarcoidosis	0.60%	2.70%	0.80%
First-line Tx	CS or CS plus AZA	UDCA	No effective therapy
Prognosis	Generally responsive to IS, poor prognosis if untreated	Excellent prognosis if responsive to UDCA	Median survival without LT 12-16 yr after diagnosis

AIH: Autoimmune hepatitis; ALP: Alkaline phosphatase ALT: Alanine aminotransferase; AMA: Antimitochondrial autoantibody; ANA: Anti-nuclear antibody; ANCA: Perinuclear antineutrophil cytoplasmic antibody; APS: Antiphospholipid syndrome; ASMA: Anti-smooth muscle antibody; AST: Aspartate aminotransferase; AZA: Azathioprine; CR: Case report; CS: Corticosteroids; EHAID: Extra-hepatic autoimmune disease; HA: Hepatitis; Ig: Immunoglobulin; IIM: Idiopathic inflammatory myopathies; IS: Immunosuppressants; GGT: Gamma-glutamyl transferase; LC: Liver cytosol; LKM: Liver kidney microsomal; LFT: Liver function test; LT: Liver transplantation; MCTD: Mixed connective tissue disease; NA: Not available; PBC: Primary biliary cholangitis; PSC: Primary sclerosing cholangitis; RA: Rheumatoid arthritis; SLE: Systemic lupus erythematosus; SS: Sjögren syndrome; SSc: Systemic sclerosis; Tx: Treatment; UDCA: Ursodeoxycholic acid.

Table 3 Reported prevalence of concomitant autoimmune liver diseases in different systemic rheumatic diseases

Category	AIH	PBC	PSC	AIH/PBC OS
SLE	1.6%-15%	2.2%-7.5%	CR	CR
SS	0.4%-4.4%	3.4%-8.9%	CR	CR
SSc	CR	0.8%-3.3%	CR	CR
RA	1.3%	3.8%-6.3%	CR	CR
IIM	CR	0.7%	CR	CR
MCTD	1.6%	CR	NA	NA

AIH: Autoimmune hepatitis; APS: Antiphospholipid syndrome; CR: Case report; IIM: Idiopathic inflammatory myopathies; NA: Not available; OS: Overlap syndrome; PBC: Primary biliary cholangitis; PSC: Primary sclerosing cholangitis; RA: Rheumatoid arthritis; SLE: Systemic lupus erythematosus; SS: Sjögren syndrome; SSc: Systemic sclerosis.

Table 4 Clinical, laboratory, therapeutic and outcome data in 3 patients with systemic lupus erythematosus-autoimmune hepatitis overlap disease¹

Patient number	1	2	3
Sex	Female	Female	Female
SLE Dx age	19	50	20
ACR criteria	8/11	7/11	8/11
AIH Dx age	26	37	22
IAIHG score	Definite	Definite	Definite
Clinical
SLE	Skin, joint, renal, hematology, neurology	Skin, joint, renal, hematology, serositis	Skin, joint, renal, hematology, serositis
AILD complication	Jaundice, malaise LC with PH	Jaundice, pruritus hepatosplenomegaly	Jaundice, anorexia
Coexistent AID	Nil	PBC, SS	Nil
Laboratory
Hemogram	HA, TP	HA, TP, leukopenia	TP, leukopenia
Proteinuria autoantibody	2 g/d	2.5 g/d	1 g/d
SLE-related	ANA, anti-dsDNA/Sm	ANA, anti-dsDNA/Sm	ANA, anti-dsDNA
AILD-related	ASMA	AMA, ASMA	ASMA
Others	ARPA, ANCA	ARPA, anti-Ro/La	ARPA
2IgG (mg/dL)	2130	2520	1615
2AST (IU/L)	1563	116	97
2ALT (IU/L)	1093	217	177
2Bil (mg/dL)	23.8	3.7	2.4
2ALP (IU/L)	432	621	344
HLA-DR	DR8, DR15	DR4, DR15	DR4, DR7
VH	No 3HHV/CMV/EBV	No HHV/CMV/EBV	No HHV/CMV/EBV
Treatment	CS/AZA, LDLT and low-dose CS/FK506 after OP	CS/AZA, UDCA RTX and low-dose CS for maintenance	CS/AZA, AZA for maintenance
Outcome	Stabilized LFT and low SLEDAI	Normalized LFT and low SLEDAI	Normalized LFT and low SLEDAI

¹Enrollment from 2018 July to 2021 June.

²Peak levels during autoimmune hepatitis.

³Human hepatitis viruses including hepatitis A virus, hepatitis B virus and hepatitis C virus.

AID: Autoimmune disease; AIH: Autoimmune hepatitis; ALP: Alkaline phosphatase ALT: Alanine aminotransferase; AMA: Antimitochondrial autoantibody; ANCA: Antineutrophil cytoplasmic antibody; ARPA: Anti-ribosomal-P antibody; ASMA: Anti-smooth muscle antibody; AST: Aspartate aminotransferase; AZA: Azathioprine; Bil: Bilirubin; CMV: Cytomegalovirus; CS: Corticosteroids; Dx: Diagnosis; EBV: Epstein-Barr virus; IAIHG: International Autoimmune Hepatitis Group; HA: Hemolytic anemia; HHV: Human hepatitis viruses; LC: Liver cirrhosis; LDLT: Living donor liver transplantation; LFT: Liver function test; OP: Operation; PBC: Primary biliary cholangitis; PH: Portal hypertension; RTX: Rituximab; SLEDAI: SLE disease activity index; SS: Sjögren syndrome; TP: Thrombocytopenia; UDCA: Ursodeoxycholic acid; VH: Viral hepatitis.