Evaluation of biological therapies in autoimmune hepatitis: A case-based systematic review

Table 1 Biologics for the treatment of autoimmune hepatitis

Ref.	Country	Age	Patient-comorbidity	Type of AIH	Previous intervention	Intervention	Comparison	Study design	Outcomes measured	Result
Kolev et al[22]	Switzerland	37-65 (6 pt)	There were 3 patients with AIH and 3 with PBC. Pt 1: AIH, Sjögren’s disease; Pt 2: AIH, PBC, Coeliac, Asthma; Pt 3: AIH, Autoimmune thyroiditis	3 patients with type 1 AIH	Pt 1: Prednisolone, AZA, rituximab, MMF, UDCA; Pt 2: Prednisolone, AZA, UDCA, MMF, CyA; Pt 3: Prednisolone, AZA, MMF, budesonide, CyA	Belimumab 200 mg SC weekly	No comparison	Case series	Improvement of Fibroscan and normalization of AST and ALT	3/3 patients respond positively to Belimumab
Arvaniti et al[23]	Greece	27 and 58	Pt 1: AIH, SLE, Hypergammaglobulinemia; Pt 2: Acute severe hepatitis	Refractory AIH	Pt 1: Prednisolone, AZA; Pt 2: Prednisolone, AZA and MMF	Belimumab: 10 mg/kg initially every 28 days	No comparison	Case series	Improvement of Fibroscan, Histology and normalization of AST and ALT	Both patients (2/2) achieved and maintained complete response to Belimumab
Burak et al[24]	Canada	36-68 (6 pt)	Pt 1: T2DM, HTN; Pt 2: Osteoporosis; Pt 3: Asthma; Pt 4: None reported; Pt 5: CAD; Pt 6: CKD	Refractory AIH	Pt 1: Prednisone; Pt 2: Prednisone; Pt 3: Prednisone; Pt 4: AZA + MMF; Pt 5: Prednisone; Pt 6: Prednisone + AZA + MMF	Rituximab 1000 mg given each two weeks day 1 and 15 over 72 weeks	No comparison	Case series	Improvement of liver histology and of AST and ALT levels and reduction of steroids dose	All 6 patients had significant improvement histology: 4/6 improved inflammation grades in all and 2/6 patients improved fibrosis stages
Carey et al[25]	Arizona- United States	44	Several autoimmune disorders including Evan syndrome	Refractory AIH	Prednisolone and AZA	Rituximab for 375 mg/m2 once a week /four weeks	No comparison	Case report	Normalization of haemoglobin, platelets, AST and ALT	Complete response
Al-Busafi et al[26]	Canada	68	Hypertension, osteoporosis and a Waldenström macroglobulinemia	Refractory AIH	Prednisone	Rituximab given as high-dose-rituximab four weekly 375 mg/m2 rituximab	No comparison	Case report	Histological, AST and ALT improvement	Partial responde, demanding the use of prednisone and AZA
Barth et al[27]	United States	27	B cell lymphoma	AIH intolerance to steroid	Prednisone	Rituximab 375 mg/m² weekly for 8 weeks and extra four weeks upon relapse	No comparison	Case report	Improvement in AST and ALT	Complete remission, with a relapse which responded to an increase of rituximab frequency
Riveiro-Barciela et al[28]	Barcelona	19-73 (32 pts)	10 patients with cirrhosis, 4 patients with overlap with PBC or PSC	Refractory AIH	Corticosteroids and immunosuppressive medications	Rituximab 1 g/2 weeks in (9%) patients, periodical doses in 32 (91%), fixed/6 months in 16 (46%) and 16 (46%) in periods	No comparison	Case series	Improvement in AST and ALT	Biochemical response in 31.89% patients, discontinuation of ≥ 1 immunosuppressive drugs in 47%, significant reduction in corticosteroid dose in most patients; safe even in cirrhotic patients
Santos et al[29]	United States	52	Asthma, DM, ITP	Refractory AIH	Methylprednisolone, prednisone, IV immune globulin (IVIG), anti-D immune globulin, danazol	Rituximab administration: 375 mg/m2 IV weekly for 4 weeks	No comparison	case report	Normalization of AST and ALT	Complete laboratorial remission
Zarrabi et al[30]	United States	22	PBC overlap, recurrent metastatic osteosarcoma	Refractory AIH	Steroids, tacrolimus and MMF	Basiliximab six doses of 20 milligrams/dose, then weekly for four weeks	No comparison	Case report	Normalization of AST and ALT	Complete and sustained response

AIH: Autoimmune hepatitis; Pt: Patient; PBC: Primary biliary cholangitis; AZA: Azathioprine; MMF: Mycophenolate mofetil; UDCA: Ursodeoxycholic acid; CyA: Cyclosporine A; SLE: Systemic lupus erythematosus; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; HTN: Hypertension; T2DM: Type 2 Diabetes mellitus; IV: Intravenous; SC: Subcutaneous; ITP: Immune thrombocytopenia; CKD: Chronic kidney disease; CAD: Computer-aided detection.

Table 2 Anti-TNFα induced autoimmune hepatitis

Ref.	Country	Age	Comorbidities	AIH type	Previous intervention	Intervention	Comparison	Type of the study	Outcome	Result
Jenkins et al[31]	United States	31	UC	AIH induced by infliximab	Mesalamine, prednisone, adalimumab, Clostridioides difficile colitis	Suspension of Infliximab and use of Vedolizumab	None	Case report	AST and ALT improvement -AIH; Clinical and endoscopic improvement - UC	UC was controlled with the use of Vedolizumab AST and ALT normalized after infliximab was withdrawn
Wong et al[32]	Canada	69	AIH, HTN, diverticular disease	AIH induced by infliximab	Prednisolone	Infliximab	No comparison	Case report	Elevated AST and ALT, with elevated INR and positive ASMA and ANA. Liver biopsy showed multiacinar hepatocyte necrosis and interface hepatitis	Infliximab led to deterioration in liver markers compared to baseline instead of improvement
Mancini et al[33]	Italy	33	Psoriasis	AIH induced by infliximab	Methotrexate	Infliximab and prednisone	No comparison	Case report	Elevated AST and ALT levels, positive ANA and anti-dsDNA	Infliximab induced AIH
Adar et al[34]	Israel	36	Psoriasis and psoriatic arthritis, hypothyroidism, Crohn’s disease	AIH induced by adalimumab	AZA, methotrexate and prednisolone	Adalimumab	No comparison	Case report	Elevated AST and ALT and IgG levels, positive ANA and anti-DNA. Liver biopsy showed fibrosis, inflammatory cell infiltrate, interface hepatitis, and hepatic rosettes	Adalimumab induced AIH, which was discontinued due to adverse effects
Karanfilian et al[35]	United States	37	Crohn’s disease, psoriasis	AIH induced by infliximab	Prednisone	Infliximab	No comparison	Case report	Elevated AST and ALT, positive ANA and weakly positive smooth muscle antibody Liver biopsy showed active hepatitis with moderate interface activity, cholestasis, and infiltrate of eosinophils and plasma cells	Severe drug-induced autoimmune hepatitis secondary to infliximab and discontinuation of infliximab led to improvement in liver function tests
Rodrigues et al[36]	Portugal	22-69 year (8 pts)	Ulcerative colitis, Ankylosing spondylitis, Psoriatic arthritis, Rheumatoid arthritis; Crohn’s disease, Palmoplantar pustular psoriasis	AIH induced by infliximab	Prednisone administered all AIH patients	Infliximab administered in 7 cases. Adalimumab administered in 1 case	No comparison	Case series	Infliximab: Six patients developed AIH and one patient developed DILI and cirrhosis	Normalisation of the liver function testes after discontinuation of anti-TNF
Yilmaz et al[37]	United States	39	Ankylosing spondylitis	AIH induced by infliximab	Methotrexate, sulfasalazine, hydroxychloroquine	Infliximab	No comparison	Case report	ALT and AST elevated with positive ANA. Liver biopsy showed an acute autoimmune hepatitis with a lymph plasmatic infiltration	Normal liver function tests two months after discontinuation of the anti-TNF drug
Dang et al[38]	Australia	47	Chronic plaque psoriasis	AIH induced by infliximab	Methotrexate	Infliximab	No comparison	Case report	Elevated AST, ALT and IgG levels. Liver biopsy indicated acute AIH	Infliximab discontinued and liver condition improved
van Casteren-Messidoro et al[39]	Netherlands	46 and 30	Case 1: Crohn's disease, erythema nodosum; Case 2: UC	AIH induced by infliximab	Prednisone and AZA	Case 1: Infliximab; Case 2: Pregnant, infliximab and azathioprine	No comparison	Case series	Case 1: After the fourth infliximab dose, positive ANA and IgG; liver biopsy indicated acute AIH; Case 2: Elevated AST and ALT; liver biopsy showed hepatitis	In both cases liver enzymes improved after infliximab was withdrawn
Cravo et al[40]	Portugal	38	Crohn’s disease	AIH induced by infliximab	Azathioprine and prednisolone	Infliximab and Adalimumab	Infliximab vs Adalimumab	Case report	AIH induced by Infliximab and switched to adalimumab. Elevated AST and ALT and IgG with positive ANA, anti-dsDNA, and antihistone antibodies. Liver Biopsy showed chronic hepatitis and mild periportal fibrosis	Infliximab discontinued and with adalimumab liver function normalized
Grasland et al[41]	France	35	Hypertension, obesity	AIH induced by adalimumab	Methotrexate, prednisone, NSAIDs, paracetamol and etanercept	Adalimumab	Adalimumab vs Abatacept	Case report	AIH induced by Adalimumab - AST and ALT elevated	Adalimumab was discontinued and liver function improved Abatacept was restarted and liver enzymes normalized
Petríková et al[42]	Slovakia	33	Sjögren syndrome, rheumatoid arthritis	AIH induced by adalimumab	Etanercept, certolizumab and anakinra	Adalimumab	No comparison	Case report	Increased AST, ALT, IgG and positive ASMA and AMA. Liver biopsy showed chronic hepatitis suggestive of AIH	Adalimumab induced autoimmune hepatitis and liver enzymes improved with withdrawal of adalimumab

AIH: Autoimmune hepatitis; Pt: Patient; UC: Ulcerative colitis; HTN: Hypertension; DILI: Drug-induced liver injury; AZA: Azathioprine; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; ANA: Antinuclear antibodies; ASMAs: Anti-smooth muscle antibodies; INR: International normalised ratio; IgG: Immunoglobulin G; NSAID: Non-steroidal anti-inflammatory drug; AMA: Anti-mitochondrial antibodies; TNF: Tumor necrosis factor.