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Unlabelled: Chronic recurrent multifocal osteomyelitis is a rare chronic inflammatory musculoskeletal process observed in children and young adults. Recently, the acronym SAPHO syndrome (for synovitis, acne, pustulosis, hyperostosis, osteitis) was coined to emphasise the association between osteo-articular inflammations and different skin abnormalities which are aseptic and filled with neutrophils. In adults, chronic recurrent multifocal osteomyelitis is now a classical manifestation of SAPHO syndrome. Chronic skin disorders were seen in eight of ten children on follow-up at the University Children's Hospitals in Bern and Zurich and in 61 of 260 paediatric cases reported in the literature. The different skin lesions were palmoplantar pustulosis (n = 40), non-palmoplantar pustulosis (n = 6), psoriasis vulgaris (n = 16) or severe acne (n = 4). More rarely Sweet syndrome (n = 2) or pyoderma gangrenosum (n = 1) were reported.Conclusion: The synovitis, acne, pustulosis, hyperostosis, osteitis syndrome is pertinent even in paediatrics since skin involvement is frequent. [ABSTRACT FROM AUTHOR]

Many diseases are linked with uveitis, but few studies have specifically looked at the noninfectious triggers of childhood uveitis in Central Europe. The charts of 70 paediatric patients with non-infectious uveitis admitted to the Department of Pediatrics, University of Bern, Switzerland, between 1983 and 1998 were therefore reviewed. In the patients the age at presentation with uveitis ranged between 0.3 and 16 y, median 8.5 y. Based on the localization, uveitis anterior was diagnosed in most cases (n = 40; 57%), followed by panuveitis (n = 20; 29%) and uveitis posterior (n = 10; 14%). Uveitis was chronic in 54 (77%) and acute in 16 (23%), bilateral in 38 (54%) and unilateral in 32 (46%) cases. An associated condition was noted in 32 (46%) cases: juvenile idiopathic arthritis in 24 cases, sarcoidosis and juvenile spondyloarthropathy in 3 cases, and Sjögren's syndrome and Behçet's disease in 1 case each. In the remaining 38 (54%) patients, no associated condition was diagnosed. It is concluded that in Swiss children, uveitis can be due to a wide spectrum of non-infectious diseases, juvenile idiopathic arthritis being the leading cause. In the majority of the children, no associated condition was recognized. [ABSTRACT FROM AUTHOR]

Sulphonamides and trimethoprim, although generally well-tolerated, have been temporally associated with aseptic meningitis. To address its presentation and outcome, a literature search was performed. We retained articles reporting patients with features of acute aseptic meningitis following intake of trimethoprim, sulfamethoxazole or sulfisoxazole. A cerebrospinal fluid investigation in ≥1 episode was a prerequisite for inclusion. Sixty articles reporting on 74 patients experiencing a total of 155 episodes were retained. Forty-five (61%) patients had one or more recurrences. Median age at first episode was 43 (interquartile range [IQR] 23-61) years. Symptoms presented within 48 (IQR 6-168) hours of intake at the first episode and within 1.3 (IQR 1-5) hours at recurrences (p < .0001). Cerebrospinal fluid analysis revealed a predominantly neutrophilic (82%, IQR 65%-94%) pleocytosis (180, IQR 38-507 10 6  cells/L), without low glucose or high proteins. Recovery took place within 2 (IQR 1-3) days after stopping the suspected agent. All but one patient completely recovered., (© 2024 British Pharmacological Society.)

Background and Aims: In autoimmune hepatitis, achieving complete biochemical remission (CBR) with current weight-based thiopurine dosing is challenging. We investigated whether patients could be stratified regarding CBR according to a target range of thiopurine metabolites. Moreover, we explored the effects of azathioprine dosage increases and co-therapy of allopurinol with low-dose thiopurines on metabolite profiles and treatment response., Approach and Results: The relation between metabolites and treatment response was assessed in 337 individuals from 4 European centers. In a global, cross-sectional analysis, active metabolites 6-thioguanine nucleotides (6TGN) were similar in those with and without CBR. However, analyzing patients with sequential measurements over 4 years (N = 146) revealed higher average 6TGN levels in those with stable CBR (260 pmol/0.2 mL) compared to those failing to maintain CBR (181 pmol/0.2 mL; p = 0.0014) or never achieving CBR (153 pmol/0.2 mL; p < 0.0001), with an optimal 6TGN cutoff of ≥223 pmol/0.2 mL (sensitivity: 76% and specificity: 78%). Only 42% exhibited 6TGN ≥223 pmol/0.2 mL following weight-based dosing, as doses weakly correlated with 6TGN but with 6-methylmercaptopurine (6MMP), a metabolite associated with toxicity. Azathioprine dose increases led to preferential 6MMP formation (+127% vs. 6TGN +34%; p < 0.0001). Conversely, adding allopurinol to thiopurines in difficult-to-treat patients (N = 36) raised 6TGN (168→321 pmol/0.2 mL; p < 0.0001) and lowered 6MMP (2125→184 pmol/0.2 mL; p < 0.0001), resulting in improved transaminases in all patients and long-term CBR in 75%., Conclusions: Maintaining CBR in autoimmune hepatitis was associated with 6TGN ≥223 pmol/0.2 mL. For patients who fail to achieve CBR and therapeutic 6TGN levels despite thiopurine dose increase due to preferential 6MMP formation, comedication of allopurinol alongside low-dose thiopurines represents an efficient alternative., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Introduction and Aims: mRNA vaccines against Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) infection have been associated with immune-related adverse reactions. We aimed at investigating whether SARS-CoV-2 vaccines may worsen autoimmune reactions in patients with autoimmune liver diseases., Methods: We centrally tested a large panel of liver- and non-liver-related autoantibodies in patients with primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and in healthcare workers (HW) before and after SARS-CoV-2 mRNA vaccines., Results: 49 PBC, 35 AIH, 9 PSC and 38 HW were included. The proportion of subjects with at least one autoantibody positivization after vaccination was 11 % for HW, 37 % for AIH, 35 % for PBC and 56 % for PSC patients, patients having a significantly higher frequency of positivization as compared to HW. The proportion of seropositive subjects before vaccination who had at least one autoantibody negativization was 25 % for HW, 57 % for AIH, 40 % for PBC and 50 % for PSC, AIH patients having a significantly higher frequency of negativization as compared to HW. In the AIH group, the number of autoantibody negativizations was higher than the number of positivizations. The BNT162b2 vaccine was associated with a higher risk of developing new autoantibodies as compared to the mRNA-1273 vaccine. No new-onset autoimmune disease was observed after one year. One AIH patient had a relapse after vaccination., Conclusion: mRNA SARS-CoV-2 vaccines do not induce short-term worsening of autoimmunity in patients with autoimmune liver diseases., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: A limited number of drugs are used as standard or alternative therapies in autoimmune hepatitis (AIH). No specific recommendations are available for patients failing to respond to these therapies. We analyzed the efficacy and safety of infliximab in patients with AIH., Approach and Results: We performed a retrospective study of 42 patients with AIH who received infliximab at 21 liver centers in 12 countries. Patients were categorized according to the reason for infliximab therapy. Patients in group 1 (n=20) had failed standard, second-line (mycophenolate mofetil and 6-mercaptopurine) or third-line (tacrolimus or cyclosporine) therapy. In group 2 (n=22), infliximab was given for treatment of concomitant extrahepatic autoimmune diseases. Patients received a median of 17 (range: 3-104) infliximab infusions. Complete biochemical response (CR) was achieved or maintained in 33 (78%) patients during infliximab therapy. In group 1, infliximab induced CR in 11 of 20 (55%) patients. In group 2, 16 patients with CR prior to infliximab maintained remission, and the remaining 6 patients with active AIH (5 on standard and 1 on both second-line and third-line therapy) showed CR following infliximab therapy. Infliximab led to CR in 75% (6/8) of nonresponders to second-line and in 46% (6/13) of failing third-line therapy. Overall, 65% (17/26) of the patients with active AIH achieved CR on infliximab. Infliximab was discontinued in 3 patients of group 1. One patient had a severe allergic reaction and 2 developed anti-infliximab autoantibodies., Conclusions: Our study suggests that infliximab may be an effective and safe rescue therapy in AIH., (Copyright © 2024 American Association for the Study of Liver Diseases.)

An acute aseptic meningitis has been occasionally observed on intravenous polyclonal human immunoglobulin therapy. Since case reports cannot be employed to draw inferences about the relationships between immunoglobulin therapy and meningitis, we conducted a systematic review and meta-analysis of the literature. Eligible were cases, case series, and pharmacovigilance studies. We found 71 individually documented cases (36 individuals ≤ 18 years of age) of meningitis. Ninety percent of cases presented ≤ 3 days after initiating immunoglobulin therapy and recovered within ≤ 7 days (with a shorter disease duration in children: ≤ 3 days in 29 (94%) cases). In 22 (31%) instances, the authors noted a link between the onset of meningitis and a rapid intravenous infusion of immunoglobulins. Cerebrospinal fluid analysis revealed a predominantly neutrophilic (N = 46, 66%) pleocytosis. Recurrences after re-exposure were observed in eight (N = 11%) patients. Eight case series addressed the prevalence of meningitis in 4089 patients treated with immunoglobulins. A pooled prevalence of 0.6% was noted. Finally, pharmacovigilance data revealed that meningitis temporally associated with intravenous immunoglobulin therapy occurred with at least five different products. In conclusion, intravenous immunoglobulin may cause an acute aseptic meningitis. The clinical features remit rapidly after discontinuing the medication., (© 2024. The Author(s).)

The term Hoigné's syndrome denotes a mimicker of anaphylaxis, which occurs immediately after the parenteral administration of a drug and is likely caused by non-thrombotic pulmonary and systemic drug micro-embolization. It has so far been documented uniquely in case reports and small case series. Because this condition has never been systematically evaluated, we performed a structured literature review (pre-registered as CRD42023392962). The search was carried out in Excerpta Medica, National Library of Medicine, and Google Scholar. Cases with features consistent with anaphylaxis, urticaria, angioedema, asthma, syncope, anxiety, or panic attack triggered by needle phobia, and local anesthetic systemic toxicity were excluded. For the final analysis, we retained reports published between 1951 and 2021, which presented 247 patients with Hoigné's syndrome: 37 children and 211 adults with a male: female ratio of 2.1 : 1.0. The patients presented within 1 min after parenteral administration of a drug (intramuscular penicillin in 90 % of the cases) with chest discomfort, shortness of breath, fear of death, psychomotor agitation, and auditory or visual hallucinations and impairment. Recovery occurred within 30 min. The diagnosis of Hoigné's syndrome was also established in five patients 66-91 years of age with pre-existing cardiovascular or pulmonary diseases, who suddenly died after the administration of penicillin despite not exhibiting the aforementioned symptoms. It was therefore speculated that pulmonary drug micro-embolization induced a lethal cardiovascular compromise in these individuals. Histologic investigations supporting this hypothesis were performed in only one case. The diagnosis of Hoigné's pulmonary drug micro-embolization was established also in five patients with pre-existing cardiovascular or pulmonary diseases, who suddenly died after the administration of penicillin despite not exhibiting the afore mentioned symptoms. Histologic investigations supporting this hypothesis were performed in only one case. In conclusion, Hoigné's syndrome is an uncommon non-immune-mediated reaction. This report seeks to promote broader awareness and knowledge regarding this alarming mimicker of anaphylaxis. Diagnosis relies solely on clinical evaluation., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of many malignancies in recent years. However, immune-related adverse events (irAE) are a frequent concern in clinical practice. The safety profile of ICI for the treatment of malignancies in patients diagnosed with autoimmune and cholestatic liver disease (AILD) remains unclear. Due to this uncertainty, these patients were excluded from ICI clinical trials and ICI are withheld from this patient group. In this retrospective multicenter study, we assessed the safety of ICI in patients with AILD., Methods: We contacted tertiary referral hospitals for the identification of AILD patients under ICI treatment in Europe via the European Reference Network on Hepatological Diseases (ERN RARE-LIVER). Fourteen centers contributed data on AILD patients with malignancies being treated with ICI, another three centers did not treat these patients with ICI due to fear of irAEs., Results: In this study, 22 AILD patients under ICI treatment could be identified. Among these patients, 12 had primary biliary cholangitis (PBC), five had primary sclerosing cholangitis (PSC), four had autoimmune hepatitis (AIH), and one patient had an AIH-PSC variant syndrome. Eleven patients had hepatobiliary cancers and the other 11 patients presented with non-hepatic tumors. The applied ICIs were atezolizumab (n=7), durvalumab (n=5), pembrolizumab (n=4), nivolumab (n=4), spartalizumab (n=1), and in one case combined immunotherapy with nivolumab plus ipilimumab. Among eight patients who presented with grade 1 or 2 irAEs, three demonstrated liver irAEs. Cases with grades ≥ 3 irAEs were not reported. No significant changes in liver tests were observed during the first year after the start of ICI., Discussion: This European multicenter study demonstrates that PD-1/PD-L1 inhibitors appear to be safe in patients with AILD. Further studies on the safety of more potent dual immune checkpoint therapy are needed. We conclude that immunotherapy should not categorically be withheld from patients with AILD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kocheise, Piseddu, Vonderlin, Tjwa, Buescher, Meunier, Goeggelmann, Fianchi, Dumortier, Riveiro Barciela, Gevers, Terziroli Beretta-Piccoli, Londoño, Frankova, Roesner, Joerg, Schmidt, Glaser, Sutter, Fründt, Lohse, Huber, von Felden, Sebode and Schulze.)

Background and Aims: There is little data on the hepatic efficacy and safety of immunomodulatory drugs used in patients with autoimmune hepatitis (AIH), despite their established use in dermatology, rheumatology and inflammatory bowel diseases (IBD). Our aim was to collect real-life data on the experience of expert centres in treating AIH patients with these drugs, considered unconventional for AIH management., Methods: Online survey among hepatology centres being part of the European Reference Network on Hepatological Diseases (ERN RARE-LIVER)., Results: 25 AIH patients have been reported. Ten were female, median age at diagnosis was 28 years; median follow-up was 17 months. All had initially received AIH-standard treatment. AIH-unconventional treatment was initiated for concomitant autoimmune diseases in 15 cases: nine for IBD (five vedolizumab and four ustekinumab), and one each for following diseases: autoinflammatory syndrome (tocilizumab), chronic urticaria (omalizumab), rheumatoid arthritis (abatacept), psoriasis (guselkumab), psoriatric arthritis (secukinumab, followed by ustekinumab) and alopecia (ruxolitinib). Three patients were treated with immunomodulatory drugs for side effects of previous treatments, including two patients with IBD treated with vedolizumab and ustekinumab, respectively, and one treated with belimumab. At the end of follow-up, 13 patients were in complete biochemical response, the patient on omalizumab had a relapse, and four patients with concomitant IBD had insufficient response. Seven patients were treated for lack of biochemical remission, of whom six with belimumab, all initially reaching complete biochemical response, but five relapsing during follow-up; and one with secukinumab, having concomitant rheumatoid arthritis and ankylosing spondylitis, reaching complete biochemical response. Only the patient on abatacept received unconventional treatment as monotherapy. Side effects were reported in two patients on belimumab: one recurrent soft tissue infections, one fatigue and arthralgia., Conclusion: Among 25 AIH patients who were treated with immunomodulatory drugs for different reasons, the majority had a fovorable course, relapse was frequent in difficult-to-treat patients who received belimumab, and four with concomitant IBD had insufficient response., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: Liver injury after COVID-19 vaccination is very rare and shows clinical and histomorphological similarities with autoimmune hepatitis (AIH). Little is known about the pathophysiology of COVID-19 vaccine-induced liver injury (VILI) and its relationship to AIH. Therefore, we compared VILI with AIH., Methods: Formalin-fixed and paraffin-embedded liver biopsy samples from patients with VILI (n = 6) and from patients with an initial diagnosis of AIH (n = 9) were included. Both cohorts were compared by histomorphological evaluation, whole-transcriptome and spatial transcriptome sequencing, multiplex immunofluorescence, and immune repertoire sequencing., Results: Histomorphology was similar in both cohorts but showed more pronounced centrilobular necrosis in VILI. Gene expression profiling showed that mitochondrial metabolism and oxidative stress-related pathways were more and interferon response pathways were less enriched in VILI. Multiplex analysis revealed that inflammation in VILI was dominated by CD8 + effector T cells, similar to drug-induced autoimmune-like hepatitis. In contrast, AIH showed a dominance of CD4 + effector T cells and CD79a + B and plasma cells. T-cell receptor (TCR) and B-cell receptor sequencing showed that T and B cell clones were more dominant in VILI than in AIH. In addition, many T cell clones detected in the liver were also found in the blood. Interestingly, analysis of TCR beta chain and Ig heavy chain variable-joining gene usage further showed that TRBV6-1, TRBV5-1, TRBV7-6, and IgHV1-24 genes are used differently in VILI than in AIH., Conclusions: Our analyses support that SARS-CoV-2 VILI is related to AIH but also shows distinct differences from AIH in histomorphology, pathway activation, cellular immune infiltrates, and TCR usage. Therefore, VILI may be a separate entity, which is distinct from AIH and more closely related to drug-induced autoimmune-like hepatitis., Impact and Implications: Little is known about the pathophysiology of COVID-19 vaccine-induced liver injury (VILI). Our analysis shows that COVID-19 VILI shares some similarities with autoimmune hepatitis, but also has distinct differences such as increased activation of metabolic pathways, a more prominent CD8+ T cell infiltrate, and an oligoclonal T and B cell response. Our findings suggest that VILI is a distinct disease entity. Therefore, there is a good chance that many patients with COVID-19 VILI will recover completely and will not develop long-term autoimmune hepatitis., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Drug-induced liver injury (DILI) can mimic almost all other liver disorders. A phenotype increasingly ascribed to drugs is autoimmune-like hepatitis (ALH). This article summarises the major topics discussed at a joint International Conference held between the Drug-Induced Liver Injury consortium and the International Autoimmune Hepatitis Group. DI-ALH is a liver injury with laboratory and/or histological features that may be indistinguishable from those of autoimmune hepatitis (AIH). Previous studies have revealed that patients with DI-ALH and those with idiopathic AIH have very similar clinical, biochemical, immunological and histological features. Differentiating DI-ALH from AIH is important as patients with DI-ALH rarely require long-term immunosuppression and the condition often resolves spontaneously after withdrawal of the implicated drug, whereas patients with AIH mostly require long-term immunosuppression. Therefore, revision of the diagnosis on long-term follow-up may be necessary in some cases. More than 40 different drugs including nitrofurantoin, methyldopa, hydralazine, minocycline, infliximab, herbal and dietary supplements (such as Khat and Tinospora cordifolia) have been implicated in DI-ALH. Understanding of DI-ALH is limited by the lack of specific markers of the disease that could allow for a precise diagnosis, while there is similarly no single feature which is diagnostic of AIH. We propose a management algorithm for patients with liver injury and an autoimmune phenotype. There is an urgent need to prospectively evaluate patients with DI-ALH systematically to enable definitive characterisation of this condition., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Aims: The Swiss Autoimmune Hepatitis Cohort Study is a nationwide registry, initiated in 2017, that collects retrospective and prospective clinical data and biological samples from patients of all ages with autoimmune hepatitis treated at Swiss hepatology centres. Here, we report the analysis of the first 5 years of registry data., Results: A total of 291 patients with autoimmune hepatitis have been enrolled, 30 of whom were diagnosed before 18 years of age and composed the paediatric cohort. Paediatric cohort: median age at diagnosis 12.5 years (range 1-17, interquartile range (IQR) 8-15), 16 (53%) girls, 6 (32%) with type 2 autoimmune hepatitis, 8 (27%) with autoimmune sclerosing cholangitis, 1 with primary biliary cholangitis variant syndrome, 4 (15%) with inflammatory bowel disease and 10 (41%) with advanced liver fibrosis at diagnosis. Adult cohort: median age at diagnosis 54 years (range 42-64, IQR 18-81), 185 (71%) women, 51 (20%) with primary biliary cholangitis variant syndrome, 22 (8%) with primary sclerosing cholangitis variant syndrome, 9 (4%) with inflammatory bowel disease and 66 (32%) with advanced liver fibrosis at diagnosis. The median follow-up time for the entire cohort was 5.2 years (IQR 3-9.3 years). Treatment in children: 29 (97%) children were initially treated with corticosteroids, 28 of whom received combination treatment with azathioprine. Budesonide was used in four children, all in combination with azathioprine. Mycophenolate mofetil was used in five children, all of whom had previously received corticosteroids and thiopurine. Treatment in adults (data available for 228 patients): 219 (96%) were treated with corticosteroids, mostly in combination with azathioprine. Predniso(lo)ne was the corticosteroid used in three-quarters of patients; the other patients received budesonide. A total of 78 (33%) patients received mycophenolate mofetil, 62 of whom had previously been treated with azathioprine. Complete biochemical response was achieved in 13 of 19 (68%) children and 137 of 182 (75%) adults with available follow-up data. All children were alive at the last follow-up, and none had undergone liver transplantation. Five (2%) adults underwent liver transplantation, two of whom had a fulminant presentation. Four (2%) adults with autoimmune hepatitis died (two from liver-associated causes)., Conclusion: Patients with autoimmune hepatitis in Switzerland had clinical features similar to those in other cohorts. The proportion of patients diagnosed with primary biliary cholangitis variant syndrome was higher than expected. Autoimmune hepatitis was managed according to guidelines, except for the use of budesonide in a small proportion of paediatric patients. The outcomes were excellent, but the findings must be confirmed over a longer follow-up period.

Finkelstein-Seidlmayer vasculitis, also called acute hemorrhagic edema of young children or infantile immunoglobulin A vasculitis, is habitually a benign skin-limited small vessel leukocytoclastic vasculitis that mainly affects infants 24 months or less of age. Since this disease is commonly triggered by an infection, an immune-mediated origin has been postulated. To better appreciate the possible underlying immune mechanism of this vasculitis, we addressed circulating autoimmune markers and vascular immune deposits in patients contained in the Acute Hemorrhagic Edema BIbliographic Database, which incorporates all original reports on Finkelstein-Seidlmayer vasculitis. A test for at least one circulating autoimmune marker or a vascular immune deposit was performed in 243 cases. Subunits of complement system C4 resulted pathologically reduced in 4.7% and C3 in 1.4%, rheumatoid factor was detected in 6.1%, and antinuclear antibodies in 1.9% of cases. Antineutrophil cytoplasmic antibodies were never demonstrated. Immunofluorescence studies were performed on 125 skin biopsy specimens and resulted positive for complement subunits in 46%, fibrinogen in 45%, immunoglobulin A in 25%, immunoglobulin M in 24%, immunoglobulin G in 13%, and immunoglobulin E in 4.2% of cases. Infants testing positive for vascular immunoglobulin A deposits did not present a higher prevalence of systemic involvement or recurrences, nor a longer disease duration. In conclusion, we detected a very low prevalence of circulating autoimmune marker positivity in Finkelstein-Seidlmayer patients. Available immunofluorescence data support the notion that immune factors play a relevant role in this vasculitis. Furthermore, vascular immunoglobulin A deposits seem not to play a crucial role in this disease., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: A few case reports of autoimmune hepatitis-like liver injury have been reported after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. We evaluated clinical features, treatment response and outcomes of liver injury following SARS-CoV-2 vaccination in a large case series., Approach and Results: We collected data from cases in 18 countries. The type of liver injury was assessed with the R-value. The study population was categorized according to features of immune-mediated hepatitis (positive autoantibodies and elevated immunoglobulin G levels) and corticosteroid therapy for the liver injury. We identified 87 patients (63%, female), median age 48 (range: 18-79) years at presentation. Liver injury was diagnosed a median 15 (range: 3-65) days after vaccination. Fifty-one cases (59%) were attributed to the Pfizer-BioNTech (BNT162b2) vaccine, 20 (23%) cases to the Oxford-AstraZeneca (ChAdOX1 nCoV-19) vaccine and 16 (18%) cases to the Moderna (mRNA-1273) vaccine. The liver injury was predominantly hepatocellular (84%) and 57% of patients showed features of immune-mediated hepatitis. Corticosteroids were given to 46 (53%) patients, more often for grade 3-4 liver injury than for grade 1-2 liver injury (88.9% vs. 43.5%, p = 0.001) and more often for patients with than without immune-mediated hepatitis (71.1% vs. 38.2%, p = 0.003). All patients showed resolution of liver injury except for one man (1.1%) who developed liver failure and underwent liver transplantation. Steroid therapy was withdrawn during the observation period in 12 (26%) patients after complete biochemical resolution. None had a relapse during follow-up., Conclusions: SARS-CoV-2 vaccination can be associated with liver injury. Corticosteroid therapy may be beneficial in those with immune-mediated features or severe hepatitis. Outcome was generally favorable, but vaccine-associated liver injury led to fulminant liver failure in one patient., (© 2022 American Association for the Study of Liver Diseases.)

Finkelstein-Seidlmayer vasculitis, also referred to as acute hemorrhagic edema of young children, is a rare small-vessel leukocytoclastic vasculitis. This condition is skin-limited, mainly affects infants up to 2 years of age and spontaneously remits. It has been suggested that an infection or a vaccine precede (by ≤ 14 days) this vasculitis. To better understand the interplay between infections or vaccines and Finkelstein-Seidlmayer vasculitis, we utilized the data contained in the Acute Hemorrhagic Edema BIbliographic Database AHEBID. The database, initiated in 2019, is being regularly updated, encompasses the entire original literature on Finkelstein-Seidlmayer vasculitis published after the original description and is attainable on request. The possible existence of an infectious or a vaccine precursor was addressed in 447 cases. Most cases were preceded by an infection (N = 384; 86%), by a vaccination (N = 20; 4.4%), or both an infection and a vaccination (N = 17; 3.8%). No precursor was reported in the remaining cases (N = 26; 5.8%). Two distinct infections preceded the onset of the vasculitis in 11 of the 381 cases with infection-associated Finkelstein-Seidlmayer vasculitis. The following infectious precursors were reported: upper respiratory tract infection (N = 292); acute gastroenteritis (N = 40); a benign febrile infection (N = 36); lower respiratory tract infection (N = 22); further infections (N = 8). The temporal relationship between the infectious precursor and the onset of the skin eruption was detailed in 336 cases: 54 cases developed before resolution and 282 after resolution of the infection. In conclusion, most cases of Finkelstein-Seidlmayer vasculitis are preceded by an infection. In a minority of cases, this skin vasculitis develops before resolution of the infection. In most cases, however, this vasculitis develops after resolution of the infection. More rarely, this vasculitis is preceded by a vaccination., (© 2022. The Author(s).)

Background & Aims: Liver injury with autoimmune features after vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is increasingly reported. We investigated a large international cohort of individuals with acute hepatitis arising after SARS-CoV-2 vaccination, focusing on histological and serological features., Methods: Individuals without known pre-existing liver diseases and transaminase levels ≥5x the upper limit of normal within 3 months after any anti-SARS-CoV-2 vaccine, and available liver biopsy were included. Fifty-nine patients were recruited; 35 females; median age 54 years. They were exposed to various combinations of mRNA, vectorial, inactivated and protein-based vaccines., Results: Liver histology showed predominantly lobular hepatitis in 45 (76%), predominantly portal hepatitis in 10 (17%), and other patterns in four (7%) cases; seven had fibrosis Ishak stage ≥3, associated with more severe interface hepatitis. Autoimmune serology, centrally tested in 31 cases, showed anti-antinuclear antibody in 23 (74%), anti-smooth muscle antibody in 19 (61%), anti-gastric parietal cells in eight (26%), anti-liver kidney microsomal antibody in four (13%), and anti-mitochondrial antibody in four (13%) cases. Ninety-one percent were treated with steroids ± azathioprine. Serum transaminase levels improved in all cases and were normal in 24/58 (41%) after 3 months, and in 30/46 (65%) after 6 months. One patient required liver transplantation. Of 15 patients re-exposed to SARS-CoV-2 vaccines, three relapsed., Conclusion: Acute liver injury arising after SARS-CoV-2 vaccination is frequently associated with lobular hepatitis and positive autoantibodies. Whether there is a causal relationship between liver damage and SARS-CoV-2 vaccines remains to be established. A close follow-up is warranted to assess the long-term outcomes of this condition., Impact and Implications: Cases of liver injury after vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) have been published. We investigated a large international cohort of individuals with acute hepatitis after SARS-CoV-2 vaccination, focusing on liver biopsy findings and autoantibodies: liver biopsy frequently shows inflammation of the lobule, which is typical of recent injury, and autoantibodies are frequently positive. Whether there is a causal relationship between liver damage and SARS-CoV-2 vaccines remains to be established. Close follow-up is warranted to assess the long-term outcome of this condition., Competing Interests: The authors do not have any conflict of interest pertaining to this study. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Author(s).)

Circulating autoantibodies are a key diagnostic tool in autoimmune hepatitis (AIH), being positive in 95% of the cases if tested according to dedicated guidelines issued by the International Autoimmune Hepatitis Group. They also allow the distinction between type 1 AIH, characterized by positive anti-nuclear and/or anti-smooth muscle antibody, and type 2 AIH, characterized by positive anti-liver kidney microsomal type 1 and/or anti-liver cytosol type 1 antibody. Anti-soluble liver antigen is the only AIH-specific autoantibody, and is found in 20-30% of both type 1 and type 2 AIH. Anti-neutrophil cytoplasmic antibody is frequently positive in type 1 AIH, being associated also with inflammatory bowel disease and with primary/autoimmune sclerosing cholangitis. The reference method for autoantibody testing remains indirect immunofluorescence on triple tissue (rodent liver, kidney and stomach), allowing both the detection of the majority of liver-relevant reactivities, including those autoantibodies whose molecular target antigens are unknown. Of note, the current knowledge of the clinical significance of autoantibodies relies on studies based on this technique. However, immunofluorescence requires trained laboratory personnel, is observer-dependent, and lacks standardization, leading to ongoing attempts at replacing this method with automated assays, the sensitivity, and specificity of which, however, require further studies before they can be used as a reliable alternative to immunofluorescence; currently, they may be used as complementary to immunofluorescence., (© 2021. The Author(s).)

Genetic susceptibility to autoimmune liver diseases is conferred mainly by polymorphisms of genes encoding for the human leukocyte antigens (HLA). The strongest predisposition to autoimmune hepatitis type 1 (AIH-1) is linked to the allele DRB1*03:01 , possession of which is associated with earlier disease onset and more severe course. In populations where this allele is very rare, such as in Asia, and in DRB1*03 -negative patients, risk of AIH-1 is conferred by DRB1*04 , which is associated with later disease onset and milder phenotype. AIH type 2 (AIH-2) is associated with DRB1*07 . The pediatric condition referred to as autoimmune sclerosing cholangitis (ASC), is associated with the DRB1*13 in populations of Northern European ancestry. DRB1*1501 is protective from AIH-1, AIH-2 and ASC in Northern European populations. Possession of the DRB1*08 allele is associated with an increased risk of primary biliary cholangitis (PBC) across different populations. DRB1*03:01 and B*08:01 confer susceptibility to primary sclerosing cholangitis (PSC), as well as DRB1*13 and DRB1*15 in Europe. The hepatic blood supply is largely derived from the splanchnic circulation, suggesting a pathophysiological role of the gut microbiome. AIH appears to be associated with dysbiosis, increased gut permeability, and translocation of intestinal microbial products into the circulation; molecular mimicry between microbial and host antigens may trigger an autoaggressive response in genetically-predisposed individuals. In PBC an altered enteric microbiome may affect intestinal motility, immunological function and bile secretion. Patients with PSC have a gut microbial profile different from health as well as from patients with inflammatory bowel disease without PSC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Terziroli Beretta-Piccoli, Mieli-Vergani and Vergani.)

A diet rich in saturated fat and carbohydrates causes low-grade chronic inflammation in several organs, including the liver, ultimately driving nonalcoholic steatohepatitis. In this setting, environment-driven lipotoxicity and glucotoxicity induce liver damage, which promotes dendritic cell activation and generates a major histocompatibility complex class II (MHC-II) immunopeptidome enriched with peptides derived from proteins involved in cellular metabolism, oxidative phosphorylation, and the stress responses. Here, we demonstrated that lipotoxicity and glucotoxicity, as driven by a high-fat and high-fructose (HFHF) diet, promoted MHC-II presentation of nested T and B cell epitopes from protein disulfide isomerase family A member 3 (PDIA3), which is involved in immunogenic cell death. Increased MHC-II presentation of PDIA3 peptides was associated with antigen-specific proliferation of hepatic CD4 + immune infiltrates and isotype switch of anti-PDIA3 antibodies from IgM to IgG3, indicative of cellular and humoral PDIA3 autoreactivity. Passive transfer of PDIA3-specific T cells or PDIA3-specific antibodies also exacerbated hepatocyte death, as determined by increased hepatic transaminases detected in the sera of mice subjected to an HFHF but not control diet. Increased humoral responses to PDIA3 were also observed in patients with chronic inflammatory liver conditions, including autoimmune hepatitis, primary biliary cholangitis, and type 2 diabetes. Together, our data indicated that metabolic insults caused by an HFHF diet elicited liver damage and promoted pathogenic immune autoreactivity driven by T and B cell PDIA3 epitopes.

Autoimmune hepatitis (AIH) is a T-cell mediated, inflammatory liver disease affecting all ages and characterized by female preponderance, elevated serum transaminase and immunoglobulin G levels, positive circulating autoantibodies, and presence of interface hepatitis at liver histology. AIH type 1, affecting both adults and children, is defined by positive anti-nuclear and/or anti-smooth muscle antibodies, while type 2 AIH, affecting mostly children, is defined by positive anti-liver-kidney microsomal type 1 and/or anti-liver cytosol type 1 antibody. While the autoantigens of type 2 AIH are well defined, being the cytochrome P4502D6 (CYP2D6) and the formiminotransferase cyclodeaminase (FTCD), in type 1 AIH they remain to be identified. AIH-1 predisposition is conferred by possession of the MHC class II HLA DRB1*03 at all ages, while DRB1*04 predisposes to late onset disease; AIH-2 is associated with possession of DRB1*07 and DRB1*03. The majority of patients responds well to standard immunosuppressive treatment, based on steroid and azathioprine; second- and third-line drugs should be considered in case of intolerance or insufficient response. This review offers a comprehensive overview of pathophysiological and clinical aspects of AIH., (© 2021. The Author(s).)

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease affecting all ages, characterised by elevated transaminase and immunoglobulin G levels, positive autoantibodies, interface hepatitis on histology and good response to immunosuppressive treatment. If untreated, it has a poor prognosis. The aim of this review is to analyse AIH therapeutic interventions with reference to our knowledge of the pathogenesis of AIH. Standard treatment, based on steroids and azathioprine, leads to disease remission in 80-90% of patients. Alternative first-line treatment with budesonide is effective in adults, but less so in the juvenile form of AIH; first-line treatment with ciclosporin does not provide convincing advantages compared to standard treatment. Second-line treatments are needed for patients not responding or intolerant to first-line standard management. Mycophenolate mofetil is the most widely used second-line drug, and has good efficacy particularly for patients intolerant to azathioprine, but is teratogenic. Only few and heterogeneous data on calcineurin inhibitors and m-TOR inhibitors are available. Biologicals, including anti-tumour necrosis factor- α and anti-CD20 monoclonal antibodies, have given ambivalent results and may have severe side-effects. Clinical trials with new therapeutic options aiming at targeting B lymphocytes and proinflammatory cytokines, or expanding regulatory T cells to restore tolerance are ongoing., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021. Published by Elsevier Ltd.)

Autoimmune phenomena and clinically apparent autoimmune diseases, including autoimmune hepatitis, are increasingly been reported not only after natural infection with the SARS-CoV-2 virus, but also after vaccination against it. We report the case of a 63-year old man without a history of autoimmunity or SARS-CoV-2 natural infection who experienced acute severe autoimmune-like hepatitis seven days after the first dose of the mRNA-1273 SARS-CoV-2 vaccine. Liver histology showed inflammatory portal infiltrate with interface hepatitis, lobular and centrilobular inflammation with centrilobular necrosis, in absence of fibrosis and steatosis. Serum immunoglobulin G was slightly elevated. Autoimmune liver serology showed an indirect immunofluorescence pattern on triple rodent tissue compatible with anti-mitochondrial antibody (AMA), but, unexpectedly, this pattern was not mirrored by positivity for primary biliary cholangitis (PBC)-specific molecular tests, indicating that this antibody is different from classical AMA. Anti-nuclear antibody (ANA) was also positive with a rim-like indirect immunofluorescence pattern on liver and HEp2 cell substrates, similar to PBC-specific ANA; however, anti-gp210 and a large panel of molecular-based assays for nuclear antigens were negative, suggesting a unique ANA in our patient. He carries the HLA DRB1*11:01 allele, which is protective against PBC. Response to prednisone treatment was satisfactory. The clinical significance of these novel specificities needs to be further evaluated in this emerging condition., (Copyright © 2021 Elsevier Ltd. All rights reserved.)