Autoimmune hepatitis in the context of systemic lupus erythematosus: A narrative review of overlap syndrome and lupus-associated hepatitis

Table 1 Differential diagnosis of liver function test abnormalities in patients with systemic lupus erythematosus

Aetiology	Typical ALT level	Frequency in SLE	Key distinguishing features	Management approach
Lupus hepatitis	1-5 × ULN (95.7% of cases)	20%-30%	Correlates with SLEDAI; hypocomplementaemia; anti-ribosomal P positive in approximately 69%; responds to corticosteroids	Optimise SLE therapy; corticosteroids if active flare
DILI	Variable; often > 10 × ULN in severe DILI	30% of LFT cases	Temporal drug exposure; acute onset; resolves on withdrawal; HCQ: LiverTox score D	Identify offending drug; withdraw if possible
AIH	Often > 5 × ULN; can exceed 10 × ULN	0.6%-5% biopsy-confirmed	Anti-SMA (VG/VGT pattern); anti-SLA/LP (99% specific); IgG > 2 × ULN; interface hepatitis; portal plasma cells; fibrosis	Corticosteroids + azathioprine or MMF; liver biopsy mandatory
MASLD/fatty liver	1-3 × ULN	17.9%	Metabolic risk factors; steatosis on imaging; no AIH-specific autoantibodies	Metabolic risk factor modification
PBC	ALP/GGT predominant	2.4%	AMA positive; florid bile duct lesions on biopsy; Paris criteria for AIH-PBC overlap	Ursodeoxycholic acid ± immunosuppression for overlap
Vascular liver disease (Budd-Chiari, PVT, NRH)	Mild; ALP may predominate in NRH	Antiphospholipid antibodies in 30%-40% of SLE	Antiphospholipid antibodies; Doppler ultrasound; portal hypertension	Anticoagulation; TIPS; portal hypertension management
Macrophage activation syndrome	Markedly elevated (hyperinflammation)	0.9%-4.6% of SLE	Fever; splenomegaly; cytopenias; hyperferritinaemia; fibrinogen ↓; HScore ≥ 169	High-dose corticosteroids; anakinra; ciclosporin; haematology

ALT: Alanine aminotransferase; SLE: Systemic lupus erythematosus; ULN: Upper limit of normal; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index; DILI: Drug-induced liver injury; LFT: Liver function test; HCQ: Hydroxychloroquine; AIH: Autoimmune hepatitis; SMA: Smooth muscle antibody; SLA: Soluble liver antigen; LP: Liver-pancreas; IgG: Immunoglobulin G; MMF: Mycophenolate mofetil; MASLD: Metabolic dysfunction-associated steatotic liver disease; PBC: Primary biliary cholangitis; ALP: Alkaline phosphatase; GGT: gamma-glutamyl transferase; AMA: Antimitochondrial antibody; PVT: Portal vein thrombosis; NRH: Nodular regenerative hyperplasia; TIPS: Transjugular intrahepatic portosystemic shunt.

Table 2 Treatment agents for autoimmune hepatitis-systemic lupus erythematosus overlap syndrome: Doses, evidence levels, and overlap-specific considerations

Agent	Dose/regimen	Level of evidence	Role in SLE	AIH-SLE overlap considerations
First-line therapy
Prednisone/prednisolone	40-60 mg/day induction; taper over 4-6 months	RCTs; guideline-recommended (AASLD 2019, EASL 2025)	Used for SLE flares (lower doses)	AIH induction doses (0.5-1 mg/kg/day) exceed typical SLE doses; dual-purpose in overlap
Azathioprine	1-2 mg/kg/day; introduce after 2-week steroid trial	RCTs; guideline-recommended	Steroid-sparing for SLE	TPMT genotyping mandatory before initiation. Standard dual-purpose steroid-sparing agent. Safe in pregnancy (limited teratogenicity data in humans)
MMF	2-3 g/day	First-line AIH: RCT (Snijders et al[32], 2024); meta-analysis (2025). First-line lupus nephritis: Multiple RCTs	First-line for lupus nephritis (class III-V); widely used for SLE	Preferred dual-purpose agent: Superior to azathioprine for AIH remission induction (CBR OR: 2.56; SAE OR: 0.15). Absolutely contraindicated in pregnancy (category X)
Budesonide	9 mg/day + azathioprine	RCT (HIBI trial)	Not used in SLE	Alternative to prednisone for non-cirrhotic patients; reduced systemic side effects. Contraindicated in cirrhosis
Second-line/rescue therapy
Tacrolimus	1-3 mg twice daily; trough 3-5 ng/mL	Retrospective cohorts; meta-analyses	Off-label SLE	Aminotransferase normalisation in 73%-92%. Side effects (approximately 25%): Tremors, headaches, nephrotoxicity. Monitor renal function in concurrent lupus nephritis
Ciclosporin A	2-5 mg/kg/day in divided doses	Retrospective cohorts	Off-label SLE	May be preferred over tacrolimus in diabetic patients. Higher risk of hypertension and nephrotoxicity with long-term use
Voclosporin	23.7 mg twice daily + MMF	FDA-approved for lupus nephritis (AURORA trials); no AIH data	FDA-approved for active lupus nephritis	Theoretically attractive dual-purpose calcineurin inhibitor for AIH-SLE overlap. No data in AIH. Expert opinion only
6-mercaptopurine	0.75-1.5 mg/kg/day	Retrospective multicenter cohort	Off-label	Alternative in azathioprine-intolerant patients (gastrointestinal intolerance); comparable complete biochemical response to MMF but lower tolerability (67% vs 89%)
Biologic and experimental therapies
Rituximab (anti-CD20)	375 mg/m2 × 4 or 1000 mg × 2	Systematic review (n = 80, 27 studies; 2025)	Refractory SLE (off-label; EXPLORER/LUNAR trials did not meet primary endpoints)	Complete remission in 55%; partial remission in 11% in refractory AIH. AASLD: Insufficient evidence for second-line use. Infectious complications in approximately 8%
Belimumab (anti-BAFF)	10 mg/kg IV monthly or 200 mg SC weekly	FDA-approved for SLE/lupus nephritis; case series for AIH	FDA-approved for active SLE and lupus nephritis	Case series suggest laboratory improvement in AIH. Anti-BAFF mechanism targets shared B-cell pathway. No hepatotoxicity in SLE trials. No prospective data in AIH-SLE overlap
Anifrolumab (anti-IFNAR1)	300 mg IV every four weeks	FDA-approved for SLE (TULIP-1/2 trials); no AIH data	FDA-approved for moderate-to-severe SLE	Targets type I IFN pathway (dominant in SLE, not in AIH). Theoretical risk of impaired innate antiviral liver immunity. No data in AIH-SLE overlap. Monitor liver function tests
Hydroxychloroquine	200-400 mg/day	EULAR 2023 grade A for all SLE patients	Cornerstone SLE therapy: Reduces flares, organ damage, thrombosis	Continue in all AIH-SLE overlap patients. LiverTox score D: Rare cause of toxic hepatitis. Document temporal withdrawal response if DILI suspected
Low-dose IL-2	0.5-3 × 106 IU SC every five days (investigational)	Phase I trials; case series	Investigational for SLE (regulatory T-cell expansion)	Selectively expands regulatory T cells; laboratory improvement in small refractory AIH cohorts. Mechanistically rational for overlap given profound regulatory T-cell impairment documented in AIH-SLE

AIH: Autoimmune hepatitis; SLE: Systemic lupus erythematosus; RCT: Randomised controlled trial; HIBI: Hepatology Inflammatory Bowel Disease (trial); AASLD: American Association for the Study of Liver Diseases; EASL: European Association for the Study of the Liver; TPMT: Thiopurine methyltransferase; MMF: Mycophenolate mofetil; CBR: Complete biochemical response; OR: Odds ratio; SAE: Serious adverse event; FDA: Food and Drug Administration; AURORA: A Study of Voclosporin in Lupus Nephritis; BAFF: B-cell activating factor; EXPLORER: Exploratory Phase II/III SLE Evaluation of Rituximab; LUNAR: Lupus Nephritis Assessment with Rituximab; IV: Intravenous; SC: Subcutaneous; IFNAR1: Interferon-α/β receptor 1; TULIP: Treatment of Uncontrolled Lupus via the Interferon Pathway; IFN: Interferon; EULAR: European League Against Rheumatism; DILI: Drug-induced liver injury; LN: Lupus nephritis.

Table 3 Summary of key published studies on lupus hepatitis and autoimmune hepatitis-systemic lupus erythematosus overlap syndrome

Ref.	Country	Design	n	Diagnostic criteria	Key clinical/serological findings	Treatment	Outcomes
Liu et al[1], 2015	United States	Prospective cohort	435	≥ 2-fold AST/ALT elevation	Liver disease in 20.7%; correlated with SLEDAI	SLE-directed therapy	Improved with SLE disease control
Takahashi et al[11], 2013	Japan	Retrospective cohort	206	Clinical/biochemical	Liver dysfunction 59.7% (DILI: 30.9%, SLE: 28.5%, fatty liver: 17.9%, AIH: 4.9%, PBC: 2.4%)	Etiology-directed	Variable by cause
Piga et al[12], 2010	Italy	Retrospective cohort	242	Clinical/biochemical	LFT abnormalities 18.6%; lupus hepatitis 5.8%	SLE-directed therapy	Not specified
Heijke et al[3], 2021	Sweden	Retrospective cohort	287	Simplified IAIHG criteria	2.8% biopsy-confirmed AIH; 13.9% met probable AIH criteria serologically	Immunosuppression per AIH diagnosis	Highlights poor IAIHG specificity in SLE
Efe et al[4], 2011	Türkiye	Retrospective cohort	147	Simplified IAIHG criteria + biopsy	72.3% met serologic IAIHG criteria; only 13.8% biopsy-confirmed AIH	Immunosuppression if biopsy-confirmed	Underscores need for histologic confirmation
Wang et al[19], 2024	Taiwan (hospitalized cohort)	Retrospective cohort	805	Clinical + biopsy where available	AIH overlap in 0.6%	Standard AIH therapy	Rare true overlap in hospitalized SLE
Beisel et al[5], 2014	Germany	Case series + literature review	Case series	Clinical, serological, histological	Reviewed reported AIH-SLE overlap cases	Glucocorticoids ± immunosuppressants	Generally favorable with treatment
Adiga and Nugent[6], 2017	United States	Narrative review	Review	Historical/clinical	Clarified “lupoid hepatitis” nomenclature confusion	N/A	Conceptual framework for overlap vs lupus hepatitis

AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index; SLE: Systemic lupus erythematosus; DILI: Drug-induced liver injury; AIH: Autoimmune hepatitis; PBC: Primary biliary cholangitis; LFT: Liver function test; IAIHG: International Autoimmune Hepatitis Group; N/A: Not applicable.

Table 4 Mechanistic and clinical distinctions between autoimmune hepatitis and lupus hepatitis

Feature	Autoimmune hepatitis	Lupus hepatitis
Pathomechanism
Primary mechanism	Cell-mediated; CD4+ Th1/Th17 and CD8+ CTL-driven hepatocyte injury via perforin/granzyme and Fas/FasL	Humoral; immune complex deposition → complement activation → Kupffer cell/macrophage/NK cell recruitment
Type I IFN signature	Absent; NLRP3 inflammasome dominates	Prominent; pDC activation via TLR7/9 → IFN-α
Treg function	Moderately impaired; ↓ CD39+ Tregs; defective AHR signalling; failed IL-17 suppression	Moderately impaired; overlap group shows most severe impairment (↓ FOXP3, ↑ IFN-γ+, Th1 skewing)
Serological markers
ANA	80% positive; not discriminatory	95%-99% positive; not discriminatory
Anti-SMA (VG/VGT)	63% positive; VG/VGT pattern strongly favours AIH	Approximately 4.4% positive; low
Anti-SLA/LP	14%-20%; 99% specific for AIH	Not reported in lupus hepatitis
Anti-ribosomal P	0% in primary AIH	68.8% in lupus hepatitis; OR approximately 5.4 for hepatic SLE involvement
Serum C3/C4	Normal or elevated	Consumed (hypocomplementaemia)
Histological features
Hallmark pattern	Interface hepatitis; portal lymphoplasmacytic infiltrate; plasma cells (66%); hepatocyte rosettes; emperipolesis	Non-specific mild lobular hepatitis; no plasma cell predominance; minimal portal inflammation
C1q immunofluorescence	Negative (0%)	Positive in 70% of biopsies (P = 0.011 vs non-lupus controls)
Fibrosis	Common: F3/F4 in 28%-33% at presentation	Rare; cirrhosis essentially absent in isolated disease
Clinical features and outcomes
Typical ALT level	Often > 5 × ULN	1-5 × ULN (95.7% of cases)
Response to corticosteroids	Dramatic but incomplete without steroid-sparing agent; relapse common on withdrawal	Typically rapid and complete; steroid-sparing agent not required
Long-term prognosis	Cirrhosis in 28%-33%; SMR: 1.63; liver transplantation possible	Excellent; liver-related mortality essentially absent

CTL: Cytotoxic T lymphocyte; NK: Natural killer; IFN: Interferon; LRP3: NLR family pyrin domain containing 3; pDC: Plasmacytoid dendritic cell; TLR: Toll-like receptor; AHR: Aryl hydrocarbon receptor; IL: Interleukin; FOXP3: Forkhead box P3; ANA: Antinuclear antibody; SMA: Smooth muscle antibody; AIH: Autoimmune hepatitis; SLA: Soluble liver antigen; LP: Liver-pancreas; OR: Odds ratio; SLE: Systemic lupus erythematosus; ALT: Alanine aminotransferase; ULN: Upper limit of normal; SMR: Standardised mortality ratio; Th: T helper; Treg: Regulatory T cell.

Table 5 Autoantibody profile and discriminatory value in the diagnosis of autoimmune hepatitis vs lupus hepatitis in patients with systemic lupus erythematosus

Autoantibody	Sensitivity in AIH	Specificity for AIH	Prevalence in SLE	Discriminatory value in AIH-SLE	Clinical notes
ANA	80%	Low	95%-99%	None	Intrinsic to SLE; not useful for discrimination
Anti-SMA (VG/VGT)	63%	Moderate	Approximately 4.4%	High	VG/VGT immunofluorescence pattern strongly favours AIH; anti-F-actin ELISA: AUROC 0.88
Anti-SLA/LP	14%-20%	99%	Not reported	Very high	Only AIH-specific autoantibody; sole marker in 14%-20% of AIH; associated with higher biochemical response rates; target antigen: SepSecS
Anti-LKM1	3% (type 2 AIH)	High	Rare	High if present	Marker of type 2 AIH; predominantly paediatric; target antigen: CYP2D6
Anti-ribosomal P	0%	High for lupus hepatitis	10%-40%	High-favours lupus hepatitis	Present in 68.8% of lupus hepatitis vs 0% of primary AIH; OR approximately 5.4 for hepatic SLE involvement (meta-analysis)
Polyreactive IgG	75%-88% (including seronegative AIH)	High	Not studied	Potentially high	25%-14% higher specificity than ANA/SMA; present in 88% of seronegative AIH; returns to baseline on treatment; not studied in SLE-AIH overlap
Anti-MRPS27	61.8%	87.1%	Not studied	Unknown	Novel biomarker identified by human proteome microarray; titres unchanged with treatment; role in AIH-SLE overlap unexplored

AIH: Autoimmune hepatitis; SLE: Systemic lupus erythematosus; SMA: Smooth muscle antibody; ELISA: Enzyme-linked immunosorbent assay; AUROC: Area under the receiver operating characteristic curve; SLA: Soluble liver antigen; LP: Liver-pancreas; SepSecS: O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase; CYP2D6: Cytochrome P450 2D6; LKM1: Liver kidney microsomal antibody type 1; OR: Odds ratio; IgG: Immunoglobulin G; ANA: Antinuclear antibody; SMA: Smooth muscle antibody; MRPS27: Mitochondrial ribosomal protein S27.

Table 6 International Autoimmune Hepatitis Group simplified scoring system for autoimmune hepatitis with systemic lupus erythematosus-specific caveats

Parameter	Criterion	Score	Caveat in SLE patients
Autoantibodies (maximum 2 points)
ANA or anti-SMA	≥ 1:40	+1	ANA is present in ≥ 95% of SLE patients → virtually all SLE patients score ≥ 1 point by default, inflating the score
ANA or anti-SMA	≥ 1:80	+2	High-titre ANA is the rule in SLE; assigns 2 points without discriminatory value
Anti-LKM1	≥ 1:40	+2	Rare in SLE; if present, strongly favours type 2 AIH
Anti-SLA/LP	Positive	+2	Not reported in SLE without concurrent AIH; high discriminatory value if present
IgG (maximum 2 points)
IgG	> ULN	+1	Hypergammaglobulinaemia is common in SLE (approximately 50%); not discriminatory
IgG	> 1.1 × ULN	+2	IgG > 2 × ULN is associated with cirrhosis risk in SLE-AIH overlap (OR: 11.0; 95%CI: 1.42-85.2) and may serve as a red flag, but is not specific to AIH
Liver histology (maximum 2 points)
Histology	Compatible with AIH	+1	Lupus hepatitis shows non-specific lobular hepatitis that may score +1 despite absence of true AIH; biopsy with C1q immunofluorescence is essential
Histology	Typical of AIH	+2	Interface hepatitis with portal plasma cells is typical of AIH; high discriminatory value in SLE context
Viral hepatitis excluded (maximum 2 points)
Hepatitis A, B, C negative	Yes	+2	SLE patients are generally seronegative for viral hepatitis → all SLE patients score +2 by default, further inflating the score
Score interpretation and SLE-specific problems
≥ 7: Definite AIH			In SLE: ANA (+2) + elevated IgG (+2) + viral hepatitis excluded (+2) = 6 points before histology is assessed; minimal histological abnormality tips to ‘definite AIH’ falsely
6: Probable AIH			In Swedish SLE cohort, 13.9% met ‘probable AIH’ serologically; biopsy-confirmed AIH was only 2.8% - over-diagnosis by > 5-fold

Per American Association for the Study of Liver Diseases 2019 and European Association for the Study of the Liver 2025 guidelines, neither the revised nor the simplified International Autoimmune Hepatitis Group scoring systems should be used for diagnosing overlap syndromes. In systemic lupus erythematosus, antinuclear antibody and hypergammaglobulinaemia inflate the score independently of hepatic autoimmune hepatitis activity, leading to systematic over-diagnosis. In a Swedish systemic lupus erythematosus cohort, 13.9% met ‘probable autoimmune hepatitis’ serologically, while biopsy-confirmed autoimmune hepatitis was only 2.8%. Liver biopsy with C1q immunofluorescence remains mandatory for definitive diagnosis. SLE: Systemic lupus erythematosus; ANA: Antinuclear antibody; SMA: Smooth muscle antibody; LKM1: Liver kidney microsomal antibody type 1; AIH: Autoimmune hepatitis; SLA: Soluble liver antigen; LP: Liver-pancreas; IgG: Immunoglobulin G; ULN: Upper limit of normal; OR: Odds ratio; CI: Confidence interval.