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

Abstract

Liver enzyme abnormalities of any etiology occur in 25%-60% of patients with systemic lupus erythematosus, a figure reflecting overall hepatic involvement rather than lupus hepatitis specifically, which accounts for only a minority of these cases. Hepatic manifestations remain absent from all major classification criteria, and true autoimmune hepatitis (AIH) co-exists with systemic lupus erythematosus in an estimated 0.6%-5% of cohorts. This overlap carries risk of progressive fibrosis, cirrhosis, and liver failure - outcomes essentially absent in lupus hepatitis alone - yet no validated diagnostic criteria or prospective trials exist. This narrative review synthesizes evidence on epidemiology, genetics, immunopathogenesis, diagnosis, management, and outcomes. The two entities are mechanistically distinct: AIH is a cell-mediated, organ-directed process targeting hepatocyte autoantigens, whereas lupus hepatitis is driven by humoral immune complex deposition with complement consumption. Key discriminators include anti-smooth muscle antibody, anti-soluble liver antigen/liver-pancreas, anti-ribosomal P antibodies, serum complement levels, and liver biopsy with C1q immunofluorescence. Infectious mimics warrant exclusion before escalating immunosuppression. Management follows standard AIH principles, with mycophenolate mofetil an attractive dual-purpose agent. The evidence base remains predominantly low quality; prospective registries, overlap-specific diagnostic algorithms, and trials of dual-purpose agents are the highest research priorities.

Key Words: Autoimmune hepatitis; Systemic lupus erythematosus; Overlap syndrome; Lupus hepatitis; autoantibodies; Liver biopsy; Immunopathogenesis

Core Tip: Liver enzyme abnormalities affect up to 60% of patients with systemic lupus erythematosus, yet true autoimmune hepatitis (AIH)-systemic lupus erythematosus overlap is rare and often over-diagnosed because antinuclear antibodies and hypergammaglobulinemia inflate International AIH Group scores. AIH is cell-mediated and can progress to cirrhosis, whereas lupus hepatitis is immune complex-mediated with complement consumption and an excellent prognosis. Liver biopsy with C1q immunofluorescence, anti-smooth muscle and anti-soluble liver antigen/liver-pancreas antibodies, and complement levels are key discriminators. Mycophenolate mofetil is the preferred dual-purpose agent; validated overlap-specific criteria remain needed.

INTRODUCTION

Justification and importance of the topic

Autoimmune hepatitis (AIH) and systemic lupus erythematosus (SLE) are two prototypical autoimmune diseases that share genetic susceptibility loci, immunological mechanisms, and serological markers, yet are managed by different subspecialties - hepatology/gastroenterology and rheumatology, respectively. Their co-occurrence creates a diagnostic and therapeutic challenge that is underrecognized in both fields. Liver function test (LFT) abnormalities are reported in 25%-60% of SLE patients - a figure that reflects all causes of hepatic dysfunction rather than lupus hepatitis specifically, which accounts for only a subset of these cases, yet hepatic involvement is absent from all major SLE classification criteria (American College of Rheumatology 1997, Systemic Lupus International Collaborating Clinics 2012, European League Against Rheumatism/American College of Rheumatology 2019)[1]. True biopsy-confirmed AIH-SLE overlap is rare (0.6%-5% of SLE cohorts), but when present, it carries the risk of progressive fibrosis, cirrhosis, and liver failure - outcomes essentially absent in lupus hepatitis alone[2-6]. The historical confusion with “lupoid hepatitis” - a term coined by Mackay in 1956 to describe AIH patients with lupus-like features, not SLE patients with liver disease - has perpetuated nosologically confusion for decades[6,7]. The differential diagnosis of LFT abnormalities in SLE is summarized in Table 1.

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.

The differential diagnosis of abnormal liver biochemistry in SLE is broad and should be considered systematically before invoking lupus hepatitis or AIH-SLE overlap (Table 1). In addition to these two entities, clinicians must exclude drug-induced liver injury (particularly non-steroidal anti-inflammatory drugs, azathioprine, methotrexate, and hydroxychloroquine), viral hepatitis (hepatitis B and C, and the infectious mimics discussed below), metabolic dysfunction-associated steatotic liver disease, vascular complications related to antiphospholipid antibodies (Budd-Chiari syndrome, portal vein thrombosis, and nodular regenerative hyperplasia), and other autoimmune liver diseases such as primary biliary cholangitis and primary sclerosing cholangitis. Lupus hepatitis and AIH-SLE overlap are distinguished from one another - and from these mimics - chiefly by the pattern and magnitude of enzyme elevation, autoantibody profile, and, when needed, liver histology; this framework underlies the diagnostic approach detailed later in this review.

Aims of the review

The aims of this narrative review are to: (1) Synthesize the current evidence on the epidemiology, genetics, and immunopathogenesis of AIH-SLE overlap and lupus-associated hepatitis; (2) Provide a clinically actionable diagnostic framework integrating autoantibody profiles, scoring systems, and liver biopsy findings; (3) Review management strategies including first-line immunosuppression, dual-purpose agents, and novel biologics (summarized in Table 2); (4) Address special populations including pregnancy, acute severe presentations, and liver transplantation; (5) Critically appraise the quality of available evidence; and (6) Identify gaps and propose research priorities. Throughout, the level of evidence supporting each statement is explicitly stated.

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.

LITERATURE SEARCH STRATEGY

A structured literature search was conducted in PubMed/MEDLINE, EMBASE, and the Cochrane Library from inception through May 2026. Search terms included combinations of “autoimmune hepatitis”, “systemic lupus erythematosus”, “lupus hepatitis”, “lupoid hepatitis”, “overlap syndrome”, “autoantibodies”, “liver biopsy”, “immunopathogenesis”, “regulatory T cells”, “gut-liver axis”, “liver transplantation”, “pregnancy”, and “biologic therapy”. Additional searches targeted specific agents [mycophenolate mofetil (MMF), rituximab, belimumab, anifrolumab, voclosporin] and biomarkers [anti-soluble liver antigen (SLA)/liver-pancreas, anti-ribosomal P, polyreactive immunoglobulin G (IgG)]. Reference lists of key guidelines and systematic reviews were manually screened. Publications from 2015 to 2026 were prioritized, though seminal earlier works were included where necessary. The search yielded more than 200 relevant publications. This review was conducted in accordance with the Scale for the Assessment of Narrative Review Articles criteria. Study selection followed an explicit process: Titles and abstracts identified by the search strategy above were screened by the corresponding author for relevance to AIH-SLE overlap, lupus hepatitis, or their clinical mimics and management; full texts were retrieved for all case series, cohort studies, systematic reviews, meta-analyses, and guidelines meeting this criterion, while isolated case reports were included selectively only where they illustrated a diagnostic or therapeutic point not otherwise represented in the larger series. Non-English-language publications and conference abstracts without full-text availability were excluded. A second author (Mohamed M) independently verified the final reference list for topical relevance and accuracy against the original source publications. Of the more than 200 publications identified, 65 were selected for citation based on methodological quality, relevance, and recency, with preference given to guidelines, systematic reviews, and larger cohort studies over smaller case series where both were available on the same point. All 2026-dated citations in this review were formally published or made available as peer-reviewed “Epub ahead of print” articles with an assigned digital object identifier at the time of manuscript preparation; no preprints were cited.

EPIDEMIOLOGY

Global epidemiology of AIH

A 2023 systematic review and meta-analysis encompassing more than 239 million participants and 55839 AIH patients from 18 countries found a global pooled incidence of 1.28 per 100000 inhabitant-years [95% confidence interval (CI): 1.01-1.63] and a prevalence of 15.65 per 100000 (95%CI: 13.42-18.24) [level of evidence (LoE): Systematic review/meta-analysis][8]. Prevalence has increased from 9.95 per 100000 (1970-1999) to 27.91 per 100000 (2015-2022)[8]. Female predominance occurs in adults (71%-95% women) and children (60%-76% girls)[9]. Alaskan Natives have the highest reported prevalence (42.9 per 100000)[9,10].

Liver involvement in SLE

In a longitudinal United States cohort of 435 SLE patients, liver disease [≥ 2-fold elevation of aspartate aminotransferase or alanine aminotransferase (ALT)] was present in 20.7%, correlating with higher SLE Disease Activity Index scores (LoE: Prospective cohort)[1]. A Japanese cohort (n = 206) found liver dysfunction in 59.7%, with causes including drug-induced injury (30.9%), SLE itself (28.5%), fatty liver (17.9%), AIH (4.9%), and primary biliary cholangitis (2.4%) (LoE: Retrospective cohort)[11]. An Italian cohort (n = 242) found liver enzyme abnormalities in 18.6%, of which only 5.8% were attributable to lupus hepatitis[12].

Prevalence of true AIH-SLE overlap

True biopsy-confirmed AIH-SLE overlap is rare (0.6%-5% of SLE cohorts), with the wide range reflecting differences in diagnostic stringency and biopsy rates: A Swedish cohort (n = 287) found 2.8% diagnosed with AIH, though 13.9% met “probable AIH” by simplified International AIH Group (IAIHG) criteria - illustrating the poor specificity of serological criteria in SLE (LoE: Cross-sectional)[3]. A Turkish cohort (n = 147) found that 72.3% of those with elevated liver enzymes fulfilled IAIHG criteria serologically, but only 13.8% had biopsy-confirmed AIH (LoE: Retrospective cohort)[4]. A Taiwanese hospitalized cohort (n = 805) identified AIH overlap in only 0.6% (LoE: Retrospective cohort)[5]. From the AIH perspective, SLE co-occurs in approximately 1%-3% of primary AIH cohorts (LoE: Case series/expert review)[13-15]. Key studies characterizing lupus hepatitis and AIH-SLE overlap across these and other populations are summarized in Table 3.

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.

GENETICS

Human leukocyte antigen associations

The primary genetic associations in AIH involve major histocompatibility complex loci within the conserved 8.1 ancestral haplotype: Non-human leukocyte antigen (HLA)-A1, Cw7, B8, DRB1*03:01, DRB1*04:01, DQA1*05:01, DQB1*02:01[9]. In pediatric autoimmune liver disease, homozygosity for DRB1*03 represents the strongest risk factor [odds ratio (OR): 8.8] (LoE: Case-control)[16].

Non-HLA genetic associations and shared susceptibility

HLA genetic associations include polymorphisms in cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), tumor necrosis factor-α, signal transducer and activator of transcription 4 (STAT4), transforming growth factor-β1, SH2 domain-containing adaptor protein 3, caspase recruitment domain-containing protein 10, and the interleukin-23 (IL-23) receptor[9]. Notably, SLE shares several of these risk loci, including HLA-DRB1*03:01, PTPN22, STAT4, TNFAIP3, and CTLA-4 polymorphisms, providing a genetic basis for co-occurrence (LoE: Genome-wide association studies)[2]. A C4A gene deletion within the 8.1 haplotype is found in young-onset AIH patients and is also a well-established risk factor for SLE, representing another shared genetic vulnerability (LoE: Genetic association studies)[17].

PATHOPHYSIOLOGY AND IMMUNOPATHOGENESIS

The mechanistic distinctions between AIH and lupus hepatitis - which have direct diagnostic implications - are summarised in Table 4 and illustrated in Figure 1.

Figure 1 Contrasting pathogenic mechanisms of autoimmune hepatitis vs lupus hepatitis. HLA: Human leukocyte antigen; MMF: Mycophenolate mofetil; SLE: Systemic lupus erythematosus.

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.

Shared immunological mechanisms

AIH and SLE share fundamental immunological features: Genetic susceptibility through HLA-DRB1*03:01, breakdown of self-tolerance, Th17/regulatory T-cell imbalance, and aberrant B-cell activation. A 2026 comprehensive review identified shared pathogenic mechanisms including defective immune tolerance, gut dysbiosis with increased intestinal permeability, and translocation of microbial products linking intestinal homeostasis to both systemic and hepatic autoimmunity (LoE: Narrative review)[2].

T-Cell dysregulation: The regulatory T-Cell/Th17 axis

In AIH, autoreactive CD4+ and CD8+ T cells break self-tolerance to hepatic autoantigens, and cytokine-mediated transformation of inducible regulatory T cells (Tregs) into pathogenic CD4+ Th17 cells promotes perpetuation of disease[18]. CD39-positive Tregs are decreased in frequency, exhibit limited ATP/ADP hydrolysis activity, and fail to suppress IL-17 production by effector CD4+ T cells (LoE: Translational study)[16]. A study by Longhi et al[19] directly comparing Tregs across AIH-SLE/mixed connective tissue disease overlap (n = 10), isolated AIH (n = 22), and SLE (n = 12) found that Tregs in the overlap group displayed the most profound impairment of suppressive function - more severe than in either disease alone (LoE: Translational study, small sample).

Mechanistic distinctions between AIH and lupus hepatitis

AIH is primarily a cell-mediated, organ-directed process. CD4+ T helper cells recognizing liver-specific autoantigens presented by HLA class II orchestrate the hepatic attack, while CD8+ cytotoxic T lymphocytes directly kill hepatocytes via perforin/granzyme and Fas/FasL pathways[2,13]. Serum complement levels (C3, C4) are typically normal or elevated[20].

Lupus hepatitis is primarily a humoral/immune complex-mediated process. Circulating immune complexes deposit in hepatic tissue, activating complement and recruiting Kupffer cells, macrophages, and natural killer cells[21]. C1q deposition by direct immunofluorescence was found in 70% of lupus hepatitis biopsies vs 0% of non-lupus liver disease controls (P = 0.011) (LoE: Case-control)[22]. Serum C3 and C4 are typically consumed (hypocomplementemia)[2,16]. SLE is defined by a prominent type I interferon signature driven by plasmacytoid dendritic cell activation via Toll-like receptor 7/9 sensing of nucleic acid-containing immune complexes, a signature not well-characterized in AIH[2].

Anti-ribosomal P antibodies as a pathogenic link

Anti-ribosomal P antibodies can bind hepatocyte surface P0 protein, penetrate living cells, and enhance proinflammatory cytokine production[23,24]. A meta-analysis confirmed the association of anti-ribosomal P with hepatic involvement in SLE (OR approximately 5.4, 95%CI: 2.56-11.2) (LoE: Meta-analysis)[24]. The autoantibody profile and its discriminatory value are detailed in Table 5.

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.

The gut-liver axis

SLE patients consistently present a lower Firmicutes/Bacteroidetes ratio, and Ruminococcus gnavus blooms correlate with SLE disease flares (LoE: Translational/observational)[15]. In AIH, gut dysbiosis and perturbations in microbial metabolites - including short-chain fatty acids, bile acids, and tryptophan derivatives - function as key mediators linking intestinal homeostasis to hepatic autoimmunity[2,16].

CLINICAL PRESENTATION

Spectrum of hepatic manifestations in SLE

The most common causes of LFT abnormalities in SLE are drug-induced liver injury (30.9%), SLE-related hepatitis (28.5%), and fatty liver (17.9%)[11]. Lupus hepatitis typically presents with mild transaminase elevations [95.7% have ALT 1-5 × upper limit of normal (ULN) lupus hepatitis itself - as opposed to drug-induced injury, steatosis, or other causes - accounts for roughly 20%-30% of SLE cohorts with any liver enzyme abnormality, underscoring that the frequently cited 25%-60% figure for overall hepatic involvement should not be equated with lupus hepatitis incidence (ULN)], correlates with active SLE, and responds to corticosteroids[1,22]. Vascular liver disease - including Budd-Chiari syndrome, portal vein thrombosis, and nodular regenerative hyperplasia - should be considered in SLE patients with antiphospholipid antibodies (present in 30%-40%)[25].

Features raising suspicion for AIH overlap

Clinical features that should raise suspicion for true AIH-SLE overlap include: Marked transaminase elevation (ALT > 5 × ULN), uncommon in lupus hepatitis. Persistent liver enzyme abnormalities despite adequate SLE treatment. Anti-smooth muscle antibody (SMA) positivity, particularly VG/VGT immunofluorescence pattern. Anti-SLA/liver-pancreas [anti-SLA/liver-pancreas (LP)] positivity (99% specificity for AIH). IgG elevation > 2 × ULN (associated with cirrhosis risk in SLE-AIH overlap: OR: 11.0; 95%CI: 1.42-85.2) (LoE: Retrospective cohort)[16]. Evidence of advanced fibrosis or cirrhosis, characteristic of AIH but extremely rare in lupus hepatitis[2-4,6].

Acute severe presentation

Infectious mimics of hepatitis in SLE: Several systemic viral infections can produce hepatitis that clinically and biochemically mimics both lupus hepatitis and AIH-SLE overlap, and appropriate virological testing should precede escalation of immunosuppressive therapy in SLE patients with new or worsening LFT abnormalities. Epstein-Barr virus and cytomegalovirus infection or reactivation are the most frequently implicated: Both are established triggers of SLE flares and can independently produce a hepatitis picture with modest transaminase elevation, atypical lymphocytosis, and, on occasion, autoantibody positivity (including antinuclear and anti-smooth muscle antibodies) that can be mistaken for AIH. Varicella-zoster virus and herpes simplex virus hepatitis are less common but carry a disproportionately high risk of fulminant hepatic failure in immunosuppressed SLE patients and should be considered in any patient on chronic immunosuppression who develops acute severe LFT derangement, particularly with fever or vesicular rash. Parvovirus B19 has also been associated with both hepatitis and cytopenias in SLE patients and can trigger disease flares that further confound the clinical picture. In practice, serologic or polymerase chain reaction testing for Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, herpes simplex virus, and parvovirus B19 - alongside standard hepatitis B and C screening - should be part of the initial evaluation of new LFT abnormalities in SLE, particularly in patients already on immunosuppressive therapy, before a presumptive diagnosis of lupus hepatitis or AIH-SLE overlap is made and before immunosuppression is escalated.

Acute presentation of AIH occurs in 22%-43% of all cases and represents a clinical spectrum ranging from acute AIH to acute liver failure[26]. Diagnosing acute presentation is particularly challenging due to frequent absence of classical serological signatures (autoantibodies and elevated IgG)[26]. In SLE-AIH overlap, an acute severe hepatic presentation may be misattributed to a lupus flare, drug toxicity, or macrophage activation syndrome.

DIAGNOSTIC APPROACH

The diagnostic algorithm for LFT abnormalities in SLE patients is illustrated in Figure 2.

Figure 2 Proposed diagnostic algorithm for the evaluation of liver enzyme abnormalities in patients with systemic lupus erythematosus. SLE: Systemic lupus erythematosus; HBV: Hepatitis B virus; HCV: Hepatitis C virus; EBV: Epstein-Barr virus; CMV: Cytomegalovirus; VZV: Varicella-zoster virus; HSV: Herpes simplex virus; MASLD: Metabolic dysfunction-associated steatotic liver disease; ANA: Antinuclear antibody; dsDNA: Double-stranded DNA; ALT: Alanine aminotransferase; ULN: Upper limit of normal; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index; AIH: Autoimmune hepatitis; IgG: Immunoglobulin G; SMA: Smooth muscle antibody; SLA: Soluble liver antigen; LP: Liver-pancreas; IAIHG: International Autoimmune Hepatitis Group.

Role of autoantibodies

Antinuclear antibody (ANA) are detected in 80% of white North American adults with AIH, SMA in 63%, and anti-liver kidney microsomal antibody type 1 in 3%[27]. Anti-SLA/LP is the only AIH-specific autoantibody (specificity 99%) and has been the sole marker of AIH in 14%-20% of patients[16]. Anti-ribosomal P antibody positivity favors lupus hepatitis (OR approximately 5.4 for hepatic involvement in SLE)[3,23,24]. SMA positivity, particularly with the VG/VGT pattern on immunofluorescence, strongly favors AIH; SMA prevalence is only approximately 4.4% in SLE, making it a high-value discriminatory marker[28]. The autoantibody discriminatory profiles are detailed in Table 5.

IAIHG scoring systems and their limitations in SLE

The 2008 IAIHG simplified scoring system has sensitivity 88% and specificity 97% in general hepatology populations[29]. However, per the American Association for the Study of Liver Diseases (AASLD) 2019 and European Association for the Study of the Liver 2025 guidelines, neither the revised nor the simplified IAIHG scoring systems should be used for assessing overlap syndromes (LoE: Guideline/expert consensus)[9,27]. The limitations of each scoring criterion in SLE patients are detailed in Table 6.

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.

Liver biopsy: Indications and histological features

Liver biopsy is considered essential for definitive diagnosis of AIH in SLE patients[3,4,6,9]. The hallmark histological pattern is interface hepatitis with a portal lymphoplasmacytic infiltrate. Plasma cells are prominent in 66%, lobular hepatitis in 47%, centrilobular necrosis in 29%, emperipolesis in 65%, and hepatocyte rosettes in 33%[9]. In contrast, lupus hepatitis shows non-specific histological changes; the most distinguishing feature is C1q deposition by direct immunofluorescence, found in 70% of lupus hepatitis biopsies vs 0% of non-lupus liver disease controls (P = 0.011)[22].

Non-invasive fibrosis assessment

Vibration-controlled transient elastography correlates strongly with histological fibrosis stage in AIH, but accuracy is impaired when performed within the first three months of treatment[30]. After six or more months of successful immunosuppressive therapy, vibration-controlled transient elastography can accurately diagnose cirrhosis with area under the receiver operating characteristic curve 0.95-1.0 at the optimal cutoff of 16 kPa[30]. Complete biochemical remission was the only independent predictor for histological fibrosis regression (relative risk: 3.66; 95%CI: 1.54-10.2; P = 0.001) (LoE: Prospective cohort)[31].

MANAGEMENT

Treatment agents, doses, evidence levels, and AIH-SLE overlap-specific considerations are summarized in Table 2. The treatment decision pathway for AIH-SLE overlap is illustrated in Figure 3.

Figure 3 Treatment decision pathway for autoimmune hepatitis-systemic lupus erythematosus overlap syndrome. AIH: Autoimmune hepatitis; SLE: Systemic lupus erythematosus; TPMT: Thiopurine methyltransferase; ALT: Alanine aminotransferase; IgG: Immunoglobulin G; ALF: Acute liver failure; ACLF: Acute-on-chronic liver failure.

Indications for treatment

Per the AASLD 2019 guidelines, treatment is indicated for patients with serum aspartate aminotransferase or ALT ≥ 10 × ULN, or ≥ 5 × ULN with IgG ≥ 2 × ULN, or histological evidence of bridging necrosis or multiacinar necrosis (LoE: Guideline)[9].

First-line immunosuppression

First-line AIH treatment consists of prednisone/prednisolone 40-60 mg/day with azathioprine (1-2 mg/kg/day) introduced after two weeks to confirm steroid responsiveness and assess thiopurine methyltransferase status [LoE: Guideline/randomized controlled trials (RCTs)][9,27]. Budesonide 9 mg/day plus azathioprine is an alternative for non-cirrhotic patients; budesonide is contraindicated in cirrhosis due to loss of first-pass hepatic metabolism (LoE: RCT)[9,27]. In AIH-SLE overlap, the corticosteroid component simultaneously addresses active SLE manifestations, though doses required for AIH induction (0.5-1 mg/kg/day) typically exceed those used for mild-to-moderate SLE.

MMF: A dual-purpose agent

MMF is an attractive agent for AIH-SLE overlap because it is effective in both diseases. A landmark open-label RCT (n = 70) comparing MMF plus prednisolone to azathioprine plus prednisolone as first-line induction therapy demonstrated that MMF achieved significantly higher complete biochemical response (CBR) at 24 weeks (56.4% vs 29.0%; P = 0.022) and higher CBR at six months (72.2% vs 32.3%; P = 0.004), with significantly fewer serious adverse events (LoE: RCT)[32]. A 2025 systematic review and meta-analysis (n = 512) confirmed that MMF-based first-line therapy significantly improved CBR (OR: 2.56; 95%CI: 1.18-5.55) with fewer serious adverse events (OR: 0.15; 95%CI: 0.07-0.34) (LoE: Systematic review/meta-analysis)[33]. MMF is also a cornerstone of SLE treatment for lupus nephritis (class III-V), making it an ideal dual-purpose agent. However, MMF is absolutely contraindicated in pregnancy (Food and Drug Administration category X)[34,35].

Calcineurin inhibitors

Tacrolimus has confirmed normalisation of serum aminotransferases in 73%-92% of cases, with side effects necessitating dose reduction or cessation in approximately 25% (LoE: Retrospective cohort/meta-analysis)[1]. Voclosporin - a novel calcineurin inhibitor Food and Drug Administration-approved for active lupus nephritis in combination with MMF - represents a theoretically attractive option for AIH-SLE overlap, though no data exist on its use in this context (LoE: Expert opinion)[8,9].

Response criteria and monitoring

The IAIHG consensus (2022) defines CBR as normalization of serum transaminases and IgG below the ULN, assessed at six months after treatment initiation (LoE: Expert consensus/Delphi)[10]. In SLE-AIH overlap, monitoring must address both hepatic and systemic disease activity: Liver enzymes, IgG, and complement levels (C3, C4) should be assessed at each visit, and SLE Disease Activity Index scoring performed concurrently. Vibration-controlled transient elastography should be deferred until six or more months after treatment initiation to avoid confounding by inflammation[1,11].

Treatment withdrawal and relapse

The AASLD 2019 guidelines recommend considering withdrawal in patients who have normalized serum aminotransferase and IgG levels for at least two years (LoE: Guideline)[1]. In AIH-SLE overlap, treatment withdrawal is particularly challenging because immunosuppression is typically required for SLE management regardless of hepatic disease status.

Biologic therapies

Rituximab (anti-CD20) has been used in refractory AIH: A 2025 systematic review (27 studies, 80 patients) found complete remission in 55% and partial remission in 11%, with infectious complications in six patients (LoE: Systematic review)[36]. Belimumab [anti-B-cell activating factor (BAFF)] is Food and Drug Administration-approved for active SLE and lupus nephritis and has been used in small cohorts with refractory AIH with laboratory improvement; its anti-BAFF mechanism targets a critical pathogenic pathway shared by both diseases (LoE: Case series/expert review)[13]. Anifrolumab (anti-interferon-α/β receptor 1) is Food and Drug Administration-approved for moderate-to-severe SLE; by blocking the type I interferon receptor it targets the dominant pathogenic pathway in SLE but not the primary pathogenic mechanism in AIH (LoE: Expert opinion)[9,14]. Low-dose recombinant IL-2 represents a mechanistically rational approach for the overlap population given the documented severity of Treg impairment[15].

Special considerations for hydroxychloroquine

Hydroxychloroquine is recommended for all SLE patients without contraindications per European League Against Rheumatism 2023 guidelines (grade A)[9]. In AIH-SLE overlap, hydroxychloroquine should be continued for its SLE benefits (reduced flares, organ damage accrual, thrombosis risk), with awareness that it is an unlikely but possible contributor to liver enzyme abnormalities (LiverTox likelihood score D; rare toxic hepatitis)[16].

SPECIAL POPULATIONS

Pregnancy

Serum aminotransferase levels tend to improve during pregnancy, but flares occur at any time; the highest risk period is postpartum (13%-55%, median 27%) (LoE: Systematic review/meta-analysis)[5,17,18]. Key management principles include: (1) Preconception counselling to optimize disease control; (2) Continuation of immunosuppression at the lowest effective dose; (3) Mandatory switch from MMF to azathioprine at least three months before conception (MMF is absolutely contraindicated, category X); (4) Continuation of hydroxychloroquine throughout pregnancy; and (5) Preemptive increase in immunosuppression postpartum with liver enzyme monitoring every two to four weeks for the first six months. For AIH-SLE overlap, SLE itself carries increased risks of pre-eclampsia, preterm birth, and fetal loss, particularly in patients with active disease, lupus nephritis, or antiphospholipid antibodies[9].

Acute severe AIH and acute liver failure

The AASLD 2019 guidelines recommend corticosteroids for acute AIH and acute severe AIH with coagulopathy (international normalized ratio > 1.5)[1]. For AIH presenting as acute liver failure (international normalized ratio ≥ 2 with hepatic encephalopathy within 26 weeks of onset), liver transplantation is generally advised[8]. In AIH-SLE overlap, the differential includes lupus flare with hepatic involvement, macrophage activation syndrome (affecting 0.9%-4.6% of SLE patients), drug-induced liver injury, and thrombotic microangiopathy. Urgent liver biopsy and early transplant evaluation should be initiated in parallel with empiric corticosteroid therapy (LoE: Expert opinion).

Liver transplantation

Outcomes of liver transplantation for AIH are generally good, with five-year patient survival rates of 80%-90%[1,19]. AIH recurs in 20% of patients after five years and 31% after ten years based on a large international multicenter cohort (n = 736); recurrent AIH was significantly associated with graft loss (hazard ratio: 10.79; 95%CI: 5.37-21.66) and death (hazard ratio: 2.53; 95%CI: 1.48-4.33) (LoE: Retrospective multicenter cohort)[37]. For AIH-SLE overlap patients requiring liver transplantation, ongoing SLE management adds complexity; no specific guidelines exist for post-transplant management of this overlap (LoE: Expert opinion/case reports).

EMERGING BIOMARKERS AND NOVEL DIAGNOSTICS

Polyreactive IgG

Quantification of polyreactive IgG (pIgG) had 25%-14% higher specificity for AIH diagnosis than conventional ANA and SMA, respectively, with 12%-20% higher overall accuracy (LoE: Multicenter retrospective and prospective validation, n = 1568 from ten centers in eight countries)[22]. pIgG was present in up to 88% of patients with seronegative AIH and in up to 71% of AIH patients with normal IgG levels[22]. In SLE-AIH overlap, pIgG could potentially improve diagnostic discrimination in SLE patients with unexplained liver enzyme abnormalities, though this application has not been specifically studied.

Anti-mitochondrial ribosomal protein S27 antibody

A 2026 study using a high-content human protein microarray (> 16000 proteins) identified anti-mitochondrial ribosomal protein S27 (anti-MRPS27) as a novel AIH-associated autoantibody (LoE: Case-control)[24]. At a cutoff of 35.4 arbitrary units, anti-MRPS27 yielded sensitivity 61.8%, specificity 87.1%, with titers unchanged after corticosteroid induction, suggesting an intrinsic autoimmune signature rather than disease activity marker[24].

Clinical proteomics

Jensen et al[38] conducted the first parallel characterization of the liver and plasma proteome in newly diagnosed, untreated AIH patients, enabling classification of AIH from metabolic dysfunction-associated steatotic liver disease and healthy controls with an area under the receiver operating characteristic curve of 0.91 (SD: 0.09), validated in the United Kingdom Biobank (LoE: Case-control with external validation).

LONG-TERM OUTCOMES AND PROGNOSIS

Survival

The overall ten- and twenty-year survival rates of treated AIH in a non-transplant center are 91% and 70%, respectively, with a standardized mortality ratio of 1.63 (95%CI: 1.25-2.02) (LoE: Retrospective cohort)[39]. A 2025 systematic review with meta-analysis identified cirrhosis at diagnosis (hazard ratio: 3.21; 95%CI: 2.38-4.34) and insufficient response to therapy (hazard ratio: 4.35; 95%CI: 2.5-7.58) as the prognostic factors with the highest impact on reduced survival (LoE: Systematic review/meta-analysis)[4].

Fibrosis regression

Patients with F3/F4 fibrosis who remained in biochemical remission showed considerable decrease in fibrosis stage on histological follow-up; complete biochemical remission was the only independent predictor for histological fibrosis regression (relative risk: 3.66; 95%CI: 1.54-10.2; P = 0.001) (LoE: Prospective cohort)[31].

Hepatocellular carcinoma

Hepatocellular carcinoma occurs in AIH patients with cirrhosis at lower rates than in viral hepatitis (1.1% in a 20-year German cohort of 535 patients) (LoE: Retrospective cohort)[40]. The European Association for the Study of the Liver 2025 and AASLD 2019 guidelines recommend hepatocellular carcinoma surveillance in AIH patients with cirrhosis, following standard protocols (LoE: Guideline)[9].

GAPS IN EVIDENCE AND FUTURE DIRECTIONS

Lack of validated diagnostic criteria

No validated diagnostic criteria exist specifically for AIH-SLE overlap syndrome. Development of overlap-specific diagnostic algorithms - incorporating anti-SMA, anti-SLA/LP, complement levels, anti-ribosomal P, pIgG, and histological features (interface hepatitis, C1q deposition) - represents a critical unmet need (LoE: Expert opinion).

Absence of prospective cohort data

All existing data on AIH-SLE overlap derive from retrospective case series, cross-sectional studies, and case reports. No prospective cohort has been established to systematically characterize the natural history, treatment response, relapse rates, fibrosis progression, and long-term outcomes of this overlap population. The IAIHG Consortium has proposed a prospective registry for new AIH diagnoses, which could incorporate systematic screening for concurrent SLE and other autoimmune diseases (LoE: Expert consensus)[10].

Unanswered questions regarding biologic therapy safety

The hepatic safety of SLE-directed biologics (belimumab, anifrolumab, voclosporin) in patients with concurrent AIH is unknown. Key unanswered questions include: Does belimumab (anti-BAFF) provide dual benefit in AIH-SLE overlap, or does it risk mobilization of memory B cells that could exacerbate hepatic autoimmunity? Does anifrolumab (anti-interferon-α/β receptor 1) worsen AIH by impairing innate antiviral immunity in the liver, or is it neutral given that AIH is not primarily interferon-driven? Do Janus kinase inhibitors (tofacitinib, baricitinib) - which have shown efficacy in animal models of immune-mediated liver injury - represent a viable therapeutic option for refractory AIH-SLE overlap?

Research priorities

Based on the evidence gaps identified in this review, the following research priorities are proposed: Development and validation of overlap-specific diagnostic criteria for AIH-SLE, incorporating multimarker panels and histological features (interface hepatitis, C1q immunofluorescence). Establishment of prospective multicenter registries that systematically capture AIH-SLE overlap cases with standardized phenotyping, treatment protocols, and long-term follow-up. Prospective evaluation of emerging biomarkers (pIgG, anti-MRPS27, plasma proteomics) for their ability to distinguish AIH from lupus hepatitis in SLE patients. Clinical trials of dual-purpose agents (MMF, belimumab, voclosporin, Janus kinase inhibitors) in AIH-SLE overlap, with hepatic and systemic endpoints. Investigation of adoptive regulatory T-cell therapy and low-dose IL-2 in the overlap population, given the documented severity of regulatory T-cell impairment. Evaluation of the gut-liver axis as a therapeutic target, including microbiome-modulating interventions, in both AIH and SLE.

CONCLUSION

AIH-SLE overlap syndrome represents a diagnostically challenging and therapeutically complex entity at the intersection of hepatology and rheumatology. Despite shared genetic susceptibility (HLA-DRB1*03:01, CTLA-4, STAT4), immunological mechanisms (Treg/Th17 imbalance, B-cell hyperactivation), and serological markers (ANA, hypergammaglobulinemia), AIH and lupus hepatitis are fundamentally distinct in their effector mechanisms: AIH is cell-mediated and organ-directed, while lupus hepatitis is humoral and immune complex-mediated with complement consumption. This mechanistic distinction has direct diagnostic implications: Serum complement levels, anti-SMA/anti-SLA/LP, anti-ribosomal P, and liver biopsy with C1q immunofluorescence are the key discriminators.

Management of AIH-SLE overlap follows standard AIH treatment principles, with MMF representing an attractive dual-purpose agent given its established efficacy in both diseases. Novel biologics (belimumab, anifrolumab, voclosporin) and emerging therapeutic modalities (Janus kinase inhibitors, adoptive Treg therapy, low-dose IL-2) offer theoretical promise but lack clinical data in the overlap population.

Clinicians managing patients with both AIH and SLE should adopt a multidisciplinary approach involving hepatology and rheumatology, with liver biopsy as the cornerstone of diagnostic evaluation, and should maintain a low threshold for suspecting AIH in any SLE patient with persistent, unexplained liver enzyme abnormalities - particularly when transaminase elevation exceeds 5 × ULN, anti-SMA or anti-SLA/LP is positive, or fibrosis is detected on non-invasive assessment.

ACKNOWLEDGEMENTS

The authors thank the clinical and research teams at Marshall University Joan C. Edwards School of Medicine for their continued support.