Rational development and application of biomarkers in the field of autoimmunity: A conceptual framework guiding clinicians and researchers.

Clear guidance is needed in the development and implementation of laboratory biomarkers in medicine. So far, no standardized phased approach is established that would pilot researchers and clinicians in this process. This leads to often incompletely validated biomarkers, which can bear the consequence of wrong applications, misinterpretation and inadequate management in the clinical context. In this conceptual article, we describe a stepwise approach to develop and comprehensively validate laboratory biomarkers. We will delineate basic steps including technical performance, pre-analytical issues, and biological variation, as well as advanced aspects of biomarker utility comprising interpretability, diagnostic and prognostic accuracy, and health-care outcomes. These aspects will be illustrated by using well-known examples from the field of immunology. The application of this conceptual framework will guide researchers in conducting meaningful projects to develop and evaluate biomarkers for the use in clinical practice. Furthermore, clinicians will be able to adequately interpret pre-clinical and clinical diagnostic literature and rationally apply biomarkers in clinical practice. Improvement in the implementation and application of biomarkers might relevantly change the management and outcomes of our patients for the better

Belimumab treatment in autoimmune hepatitis and primary biliary cholangitis - a case series.

BACKGROUND The majority of patients with autoimmune hepatitis (AIH) achieve complete remission with established treatment regiments. In patients with intolerance or insufficient response to these drugs, the remaining options are limited and novel treatment approaches necessary. In primary biliary cholangitis (PBC), ursodeoxycholic acid (UDCA) and fibrates have improved prognosis dramatically, but there remains a proportion of patients with refractory disease.In patients with refractory AIH and/or PBC, we used a novel treatment strategy with the anti-B cell activating factor, belimumab. The first three patients had concomitant Sjögren's disease. The connecting element between all three diseases is B cell activation, including elevated levels of the B cell activating factor (BAFF). Furthermore, belimumab has been shown to be beneficial in Sjögren's disease. AIMS AND METHODS To retrospectively investigate treatment response in six patients with AIH or PBC with or without concomitant Sjögren's disease treated with the anti-BAFF therapy belimumab at the University Hospital in Bern, Switzerland. RESULTS In all three patients with AIH, belimumab improved disease control and helped by-pass or reduce problematic side effects from corticosteroids and calcineurin inhibitors. In PBC patients (n = 3), there was no clear improvement of liver function tests, despite reduction or normalization of IgM. All patients with concomitant Sjögren's disease (n = 3) had an improvement of sicca symptoms and two out of three patients experienced an initially marked reduction in fatigue, which lessened over time. CONCLUSIONS Belimumab may be a promising treatment option for patients with AIH and further investigations are needed. In PBC however, response was not convincing. The effects on sicca symptoms and fatigue were encouraging

Mycophenolate mofetil as second line treatment in autoimmune hepatitis – A retrospective single center analysis

Background: Most patients with autoimmune hepatitis respond to standard treatment with steroids and azathioprine. While the disease is usually fatal if untreated, patients who respond well to therapy have an excellent prognosis. Nevertheless, second-line treatment is necessary in approximately 20% of patients, due to either intolerance or insufficient response to first line treatment.While data for mycophenolate mofetil (MMF) in patients intolerant to azathioprine is encouraging, MMF seems of less benefit in patients with insufficient response to first line treatment, but analyzed data on this issue is limited. Aim: To evaluate the efficacy and safety of MMF as a second-line therapy in patients with AIH. Methods: Retrospective analysis of a monocentric database of AIH patients who received medical care from 2000 to 2022. Clinical, immunological and biochemical parameters were assessed at different time points including last follow-up. Results: Overall, 144 patients with AIH were identified. Fifty out of 144 (35%) AIH patients received MMF. Forty (80%) received MMF due to first line treatment intolerance, while ten (20%) due to insufficient response to first line treatment.Remission with MMF monotherapy was 81.5% in the intolerance group versus 30% in the insufficient response group. Patients switched to MMF because of an insufficient response, more often needed additional prednisolone doses higher than 5 mg/day, a switch to third-line treatment or combination regiments, to achieve disease control. Conclusions: Patients treated with MMF because of intolerance to first line treatment show a good disease control under MMF in the majority of cases. Efficacy is considerably lower in the patients switched to MMF because of an insufficient response to first line treatment

Hepatic safety and efficacy of immunomodulatory drugs used in patients with autoimmune hepatitis.

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

Histological and serological features of acute liver injury after SARS-CoV-2 vaccination

Codoni G, Kirchner T, Engel B, Villamil AM, Efe C, Stättermayer AF, Weltzsch JP, Sebode M, Bernsmeier C, Lleo A, Gevers TJ, Kupčinskas L, Castiella A, Pinazo J, De Martin E, Bobis I, Sandahl TD, Pedica F, Invernizzi F, Del Poggio P, Bruns T, Kolev M, Semmo N, Bessone F, Giguet B, Poggi G, Ueno M, Jang H, Elpek GÖ, Soylu NK, Cerny A, Wedemeyer H, Vergani D, Mieli-Vergani G, Lucena MI, Andrade RJ, Zen Y, Taubert R, Beretta-Piccoli BT, Histological and serological features of acute liver injury after SARS-CoV-2 vaccination, JHEP Reports (2022), doi: https://doi.org/10.1016/j.jhepr.2022.100605.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 patients with acute hepatitis arising after SARS-CoV-2 vaccination, focusing on histological and serological features

Retrospective Analysis of Drowning Incidents at a University Hospital in Switzerland

Background: The annual rate of accidental fatal drowning in Switzerland is about 50 deaths/year (0.6/100 000). We report on the fatal and non-fatal drowning incidents among adults that were treated at the University Hospital inBern, Switzerland, between 2000 and 2014. Methods: Retrospective analysis of the electronic database of the emergency centre for adults of the university hospital in Bern. Between 2000 and 2014 all fatal and non-fatal drowning incidents were analysed using specific medical keywords. Results: 126 patients were included. Ninety-one (72%) were male, 94 (76%) aged between 16-44 years, 107 (89%) of the incidents occurred in rivers. In 83 (68%) cases the activity during the incident was swimming. Twentytwo (18%) were non-accidental drowning incidents, 14 (11%) of all the drowning patients needed reanimation and 6 (4.8%) died within 24 h. Conclusion: Our analysis shows that it is important to have a closer look at the efforts and effectiveness of prevention done against drowning of young men in high-risk aquatic settings. Further there is a need to report drowning incidents according to international standards in order to draw conclusions for prognostic factors and therapy in the future

Belimumab treatment in autoimmune hepatitis and primary biliary cholangitis – a case series

Background: The majority of patients with autoimmune hepatitis (AIH) achieve complete remission with established treatment regiments. In patients with intolerance or insufficient response to these drugs, the remaining options are limited and novel treatment approaches necessary. In primary biliary cholangitis (PBC), ursodeoxycholic acid (UDCA) and fibrates have improved prognosis dramatically, but there remains a proportion of patients with refractory disease.In patients with refractory AIH and/or PBC, we used a novel treatment strategy with the anti-B cell activating factor, belimumab. The first three patients had concomitant Sjögren's disease. The connecting element between all three diseases is B cell activation, including elevated levels of the B cell activating factor (BAFF). Furthermore, belimumab has been shown to be beneficial in Sjögren's disease. Aims and methods: To retrospectively investigate treatment response in six patients with AIH or PBC with or without concomitant Sjögren's disease treated with the anti-BAFF therapy belimumab at the University Hospital in Bern, Switzerland. Results: In all three patients with AIH, belimumab improved disease control and helped by-pass or reduce problematic side effects from corticosteroids and calcineurin inhibitors. In PBC patients (n = 3), there was no clear improvement of liver function tests, despite reduction or normalization of IgM. All patients with concomitant Sjögren's disease (n = 3) had an improvement of sicca symptoms and two out of three patients experienced an initially marked reduction in fatigue, which lessened over time. Conclusions: Belimumab may be a promising treatment option for patients with AIH and further investigations are needed. In PBC however, response was not convincing. The effects on sicca symptoms and fatigue were encouraging

Belimumab in Autoimmune Liver Diseases with associated Sjögren’s Syndrome

Background: B cell-activating factor (BAFF) levels are elevated in autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC). About 20% of patients with PBC and 5% with AIH have a Sjögren’s syndrome (SjS). PBC and SjS have many features in common. Belimumab (anti-BAFF) shows positive effects in SjS. Methods: Retrospective analysis on treatment response to belimumab in three female patients with AIH and/or PBC with SjS. Patient 1: 52y, with AIH (F2), PBC and SjS. Indication: active AIH with intolerance to standard treatment; belimumab since 01/20. Patient 2: 72y, with PBC (F3) and SjS. Indication: refractory PBC; belimumab since 11/20. Patient 3: 54y, with PBC (F2, ductopenia), SjS and erosive rheumatoid arthritis. Indication: refractory PBC; belimumab since 11/20. Results: Patient 1: AIH in remission under belimumab monotherapy. Patient 2: PBC in remission 6 months after treatment start. Patient 3: Cholestasis stable. Slight decrease of mildly elevated transaminases and almost normalization of IgM. The effects on SjS were overall encouraging in all patients. Conclusions: These preliminary findings indicate belimumab as a promising treatment option in AIH and PBC, with so far no safety concerns. Our study shows how the occurrence of different autoimmune diseases can guide us to further personalize treatment and highlights the strengths of a tight collaboration between hepatology and rheumatolog