Czaja, Albert J.

Abstract Smooth muscle antibodies (SMA) with anti-microfilament actin (MF-SMA) specificity are regarded as highly specific markers of type 1 autoimmune hepatitis (AIH-1) but their recognition relying on immunofluorescence of vessel, glomeruli, and tubules (SMA-VGT pattern) in rodent kidney tissue, is restricted by operator-dependent interpretation. A gold standard method for their identification is not available. We assessed and compared the diagnostic accuracy for AIH-1 of an embryonal aorta vascular smooth muscle (VSM) cell line-based assay with those of the rodent tissue-based assay for the detection of MF-SMA pattern in AIH-1 patients and controls. Sera from 138 AIH-1 patients and 295 controls (105 primary biliary cholangitis, 40 primary sclerosing cholangitis, 50 chronic viral hepatitis, 20 alcohol-related liver disease, 40 steatotic liver disease, and 40 healthy controls) were assayed for MF-SMA and SMA-VGT using VSM-based and rodent tissue-based assays, respectively. MF-SMA and SMA-VGT were found in 96 (70%) and 87 (63%) AIH-1 patients, and 2 controls (P < 0.0001). Compared with SMA-VGT, MF-SMA showed similar specificity (99%), higher sensitivity (70% vs 63%, P = ns) and likelihood ratio for a positive test (70 vs 65). Nine (7%) AIH-1 patients were MF-SMA positive despite being SMA-VGT negative. Overall agreement between SMA-VGT and MF-SMA was 87% (kappa coefficient 0.870, [0.789–0.952]). MF-SMA were associated with higher serum γ-globulin [26 (12–55) vs 20 g/l (13–34), P < 0.005] and immunoglobulin G (IgG) levels [3155 (1296–7344) vs 2050 mg/dl (1377–3357), P < 0.002]. The easily recognizable IFL MF-SMA pattern on VSM cells strongly correlated with SMA-VGT and has an equally high specificity for AIH-1. Confirmation of these results in other laboratories would support the clinical application of the VSM cell-based assay for reliable detection of AIH-specific SMA.

SummaryBackgroundThe B cell activation system, consisting of B cell activating factor and a proliferation‐inducing ligand, may have pathogenic effects in autoimmune hepatitis.AimsTo describe the biological actions of the B cell activation system, indicate its possible role in autoimmune diseases, and evaluate its prospects as a therapeutic target in autoimmune hepatitisMethodsEnglish abstracts were identified in PubMed by multiple search terms. Full length articles were selected for review, and secondary and tertiary bibliographies were developed.ResultsThe B cell activating factor is crucial for the maturation and survival of B cells, and it can co‐stimulate T cell activation, proliferation, and survival. It can also modulate the immune response by inducing interleukin 10 production by regulatory B cells. A proliferation‐inducing ligand modulates and diversifies the antibody response by inducing class‐switch recombination in B cells. It can also increase the proliferation, survival, and antigen activation of T cells. These immune stimulatory actions can be modulated by inducing proliferation of regulatory T cells. The B cell activation system has been implicated in diverse autoimmune diseases, and therapeutic blockade is a management strategy now being evaluated in autoimmune hepatitis.ConclusionsThe B cell activation system has profound effects on B and T cell function in autoimmune diseases. Blockade therapy is being actively evaluated in autoimmune hepatitis. Clarification of the critical pathogenic components of the B cell activation system will improve the targeting, efficacy, and safety of blockade therapy in this disease.

SummaryBackgroundThiopurines in combination with glucocorticoids are used as first‐line, second‐line and maintenance therapies in autoimmune hepatitis and opportunities exist to improve and expand their use.AimsTo describe the metabolic pathways and key factors implicated in the efficacy and toxicity of the thiopurine drugs and to indicate the opportunities to improve outcomes by monitoring and manipulating metabolic pathways, individualising dosage and strengthening the response.MethodsEnglish abstracts were identified in PubMed by multiple search terms. Full‐length articles were selected for review, and secondary and tertiary bibliographies were developed.ResultsThiopurine methyltransferase activity and 6‐tioguanine (6‐thioguanine) nucleotide levels influence drug efficacy and safety, and they can be manipulated to improve treatment response and prevent myelosuppression. Methylated thiopurine metabolites are associated with hepatotoxicity, drug intolerance and nonresponse and their production can be reduced or bypassed. Universal pre‐treatment assessment of thiopurine methyltransferase activity and individualisation of dosage to manipulate metabolite thresholds could improve outcomes. Early detection of thiopurine resistance by metabolite testing, accurate estimations of drug onset and strength by surrogate markers and adjunctive use of allopurinol could improve the management of refractory disease. Dose‐restricted tioguanine (thioguanine) could expand treatment options by reducing methylated metabolites, increasing the bioavailability of 6‐tioguanine nucleotides and ameliorating thiopurine intolerance or resistance.ConclusionsThe efficacy and safety of thiopurines in autoimmune hepatitis can be improved by investigational efforts that establish monitoring strategies that allow individualisation of dosage and prediction of outcome, increase bioavailability of the active metabolites and demonstrate superiority to alternative agents.

Linked ContentThis article is linked to Czaja and Gkamprela et al papers. To view these articles, visit https://doi.org/10.1111/apt.15173 and https://doi.org/10.1111/apt.15266.