Objective Refractory autoimmune diseases remain a significant challenge in clinical practice and new therapeutic options are needed. This systematic review evaluates the existing reported data on the CD38-targeting antibody daratumumab as a new therapeutic approach in autoantibody-mediated autoimmune diseases. Methods A protocolised systematic literature review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed. Two databases (Medline and Embase) were searched for suitable studies. Usage of daratumumab in non-oncological or non-transplantation associated diseases with autoimmune pathophysiology was analysed including patient characteristics, therapeutic regimen, adverse events and patient outcome. Results 38 publications reporting the clinical course of 83 patients met the inclusion criteria. Daratumumab usage was reported in therapy-refractory cases (median of 5 different previous therapies) in 24 different autoimmune diseases. The median number of applications of daratumumab was 4, mainly via intravenous applications (87%). Concomitant treatment included glucocorticoids in 64% of patients, intravenous immunoglobulins (33%) and rituximab (17%). Remission or improvement of disease was reported in 81% of patients. Autoantibody depletion or reduction was stated in 52% of patients. Death occurred in three patients (3%). Adverse events were reported in 45% of patients including application-associated reaction (20%), infection (19%) and hypogammaglobulinaemia (33%). Conclusion Targeting CD38 via daratumumab is a new promising therapeutic option in therapy refractory autoimmune diseases. Efficacy as well as optimal therapeutic regimen and management or prevention of adverse events require further investigation. Therefore, systematic clinical trials of this therapeutic approach are needed.

Dermatomyositis is a rare, type I interferon-driven autoimmune disease, which can affect muscle, skin and internal organs (especially the pulmonary system). In 2021, we have noted an increase in new-onset dermatomyositis compared to the years before the SARS-CoV-2 pandemic in our center. We present four cases of new-onset NXP2 and/or MDA5 positive dermatomyositis shortly after SARS-CoV-2 infection or vaccination. Three cases occurred within days after vaccination with Comirnaty and one case after SARS-CoV-2 infection. All patients required intensive immunosuppressive treatment. MDA5 antibodies could be detected in three patients and NXP2 antibodies were found in two patients (one patient was positive for both antibodies). In this case-based systematic review, we further analyze and discuss the literature on SARS-CoV-2 and associated dermatomyositis. In the literature, sixteen reports (with a total of seventeen patients) of new-onset dermatomyositis in association with a SARS-CoV-2 infection or vaccination were identified. Ten cases occurred after infection and seven after vaccination. All vaccination-associated cases were seen in mRNA vaccines. The reported antibodies included for instance MDA5, NXP2, Mi-2 and TIF1γ. The reviewed literature and our cases suggest that SARS-CoV-2 infection and vaccination may be considered as a potential trigger of interferon-pathway. Consequently, this might serve as a stimulus for the production of dermatomyositis-specific autoantibodies like MDA5 and NXP2 which are closely related to viral defense or viral RNA interaction supporting the concept of infection and vaccination associated dermatomyositis.

Myositis with anti-Ku-autoantibodies is a rare inflammatory myopathy associated with various connective tissue diseases. Histopathological studies have identified inflammatory and necrotizing aspects, but a precise morphological analysis and pathomechanistic disease model are lacking. We therefore aimed to carry out an in-depth morpho-molecular analysis to uncover possible pathomechanisms. Muscle biopsy specimens from 26 patients with anti-Ku-antibodies and unequivocal myositis were analyzed by immunohistochemistry, immunofluorescence, transcriptomics, and proteomics and compared to biopsy specimens of non-disease controls, immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). Clinical findings and laboratory parameters were evaluated retrospectively and correlated with morphological and molecular features. Patients were mainly female (92%) with a median age of 56.5 years. Isolated myositis and overlap with systemic sclerosis were reported in 31%, respectively. Isolated myositis presented with higher creatine kinase levels and cardiac involvement (83%), whereas systemic sclerosis-overlap patients often had interstitial lung disease (57%). Histopathology showed a wide spectrum from mild to pronounced myositis with diffuse sarcolemmal MHC-class I (100%) and -II (69%) immunoreactivity, myofiber necrosis (88%), endomysial inflammation (85%), thickened capillaries (84%), and vacuoles (60%). Conspicuous sarcoplasmic protein aggregates were p62, BAG3, myotilin, or immunoproteasomal beta5i-positive. Proteomic and transcriptomic analysis identified prominent up-regulation of autophagy, proteasome, and hnRNP-related cell stress. To conclude, Ku + myositis is morphologically characterized by myofiber necrosis, MHC-class I and II positivity, variable endomysial inflammation, and distinct protein aggregation varying from IBM and IMNM, and it can be placed in the spectrum of scleromyositis and overlap myositis. It features characteristic sarcoplasmic protein aggregation on an acquired basis being functionally associated with altered chaperone, proteasome, and autophagy function indicating that Ku + myositis exhibit aspects of an acquired inflammatory protein-aggregate myopathy.

Objectives: To explore efficacy and safety of CD19-directed Chimeric Antigen Receptor (CAR) T cell therapy in a patient with Jo1-Antisynthetase-syndrome refractory to multiple immunosuppressants, including anti-CD38 therapy, and review published cases on CAR T cell therapy in idiopathic inflammatory myopathies (IIM). Methods: Following lymphodepletion, the patient received a single infusion of autologous CD19-directed CAR T cells. Clinical, serologic, and safety outcomes were monitored over 6 months. A literature review analysed prior cases for patient characteristics, outcomes, and adverse events. Results: CAR T cell therapy was well tolerated, with only low-grade cytokine release syndrome (CRS) and no neurotoxicity. Clinical assessments demonstrated significant and rapid improvement in muscle strength, arthritis, and pulmonary function, alongside normalization of muscle enzymes and inflammatory markers. Autoantibody levels remained unchanged. Transient skin alterations resolved with low-dose glucocorticoids. CAR T cells persisted for 3 months, followed by B cell reconstitution without disease relapse. The patient remains in remission on low-dose prednisolone at 6 months. Eight previously published cases of CAR T cell therapy in IIM consistently report significant improvement, with most patients stable off immunosuppressive therapy. Hypogammaglobulinemia was frequent, but no high-grade CRS, immune-effector-cell associated neurotoxicity syndrome (ICANS) or serious infections were reported. Conclusion: CD19-directed CAR T cell therapy shows promise in refractory IIM, offering sustained clinical improvement and a favourable safety profile. The nine reported cases collectively highlight the potential of CAR T cell therapy even in patients with insufficient response to B cell/plasma-cell depleting therapies. Larger studies are needed to evaluate long-term efficacy, safety, and underlying mechanisms of CAR T cell therapy in refractory IIM.

Background: The plasticity of T helper-17 (Th17) and regulatory T (Treg) cells may be a clue to pathogenesis of Juvenile Idiopathic Arthritis (JIA). It is still unclear, whether targeted suppression of Interleukin (IL)-17 is able to influence regulatory function of Treg to control pro-inflammatory effectors in JIA. This study aimed to assess the effect of a Th17-stimulating cytokine environment and of IL-17A-inhibition on phenotype plasticity and suppressive function of Treg derived from JIA patients. Methods: Th17 and Treg characteristics of CD4⁺ helper T cells were investigated in blood samples of JIA patients with oligo- and polyarticular pattern and healthy controls (HC). Isolated CD4⁺CD25⁺CD127⁻ cells defined as Treg were cultivated with Th17-inducing cytokine environment as well as with IL-17A-inhibitors and analyzed for plasticity of phenotype by flow cytometry. Furthermore, inhibitory function of Treg on autologous effectors after cultivation with these stimuli was determined by suppression assays. Results: Our findings demonstrated significantly elevated proportions of Th17 and Th17-like Treg in JIA compared to HC. After incubation with Th17-inducing stimuli, increased FoxP3 expression in separated Treg in JIA and an impaired suppressive capacity in JIA and HC were found. Blockade of IL-17A resulted in adjustment of FoxP3-expression in JIA to proportions found in controls and in regular suppressive function. Conclusions: Our results demonstrate an induction of FoxP3 expressing Treg by Th17-inducing cytokines with concomitant mitigated suppressive function. In contrast, specific IL-17A blockade maintains suppressive Treg function and adjusted FoxP3-expression in JIA to levels found in controls. These findings may help to provide experimental evidence for the successful clinical use of IL-17A inhibition in JIA patients.

Background: The development and potential of artificial intelligence (AI) is remarkable. Its application in all medical disciplines, including rheumatology, is attracting attention. To what extent AI is already used in clinical routine in rheumatology is unknown. In addition, the perceived barriers, potentials, and expectations regarding AI by rheumatologists have not yet been studied.Objectives: To examine the current usage and perceived barriers and facilitators of AI, including large language models (LLMs), among rheumatologists.Design: National, observational, non-interventional, and cross-sectional web-based study.Methods: A web-based survey was developed by the Working Group Young Rheumatology (AGJR) of the German Society for Rheumatology. The survey was distributed at the Congress of the German Society for Rheumatology and via social media, QR code, and email from August 30 until November 4, 2023.Results: Responses from 172 rheumatologists (55% female; mean age 43 years) were analyzed. The majority stated that they did not previously use AI (73%) in their daily practice. Eighty-eight percent of rheumatologists rated their AI knowledge as low to intermediate and 84% would welcome dedicated training on LLMs. The majority of rheumatologists anticipated AI implementation to improve patient care (60%) and reduce daily workload (62%). Especially for diagnosis (73%), writing medical reports (70%), and data analysis (70%), rheumatologists reported a potential positive benefit of AI. Main AI concerns addressed the responsibility for medical decisions (64%) and data security (58%).Conclusion: Overall, the results indicate that rheumatologists currently have little AI knowledge and make very little use of AI in clinical routine. However, the majority of rheumatologists anticipate positive AI effects and would welcome increased AI implementation and dedicated training programs.