OBJECTIVE:Immune checkpoint inhibitors (ICIs) induce a broad range of immune-related adverse events (irAEs), including rheumatic manifestations. Evidence from dedicated rheumatology cohorts on the clinical spectrum, severity, treatment, and outcomes of rheumatic irAEs (rh-irAEs) remains limited. We aimed to describe clinical phenotypes, treatment, and outcomes of rh-irAEs in a national registry. METHODS:The German ERIN Registry (Registry for the Documentation of Rheumatic Immunotherapy-Related Adverse Events) is a multicenter observational registry of adults receiving ICIs. Rh-irAEs were classified using a rheumatology-oriented phenotype-based framework. Variables included demographics, oncological characteristics, treatments, and outcomes. Severity was graded by Common Terminology Criteria for Adverse Events version 5.0. Univariate analyses identified predictors of second-line systemic therapy. RESULTS:As of January 1, 2026, 60 patients (56.7% men; median age 66 years) were included. Predominant malignancy was melanoma (40.0%). The leading phenotype was rheumatoid arthritis-like polyarthritis (41.7%), followed by polymyalgia rheumatica-like (18.3%) and peripheral spondyloarthritis-like syndrome (11.7%). Axial spondyloarthritis (axSpA)-like syndrome occurred in younger patients. Rh-irAEs were moderate or severe in 90%; 23.3% required hospitalization and 38.3% led to permanent ICI discontinuation. Systemic glucocorticoids (GCs) were used in 85.0%; 58.3% were GC-refractory and 53.3% required second-line immunomodulatory therapy. Complete remission was achieved in 33.3% and partial remission in 51.7%. Oncological progression occurred in 15.0% overall and in 28.1% of patients requiring second-line therapy. Male sex was the strongest predictor of second-line systemic therapy. CONCLUSION:Rh-irAEs in a rheumatologists-referred population were more severe than previously described, with frequent ICI discontinuation and escalation beyond GCs. Male sex was associated with treatment escalation. An underrecognized axSpA-like phenotype occurred in younger patients, warranting further study.

To give further insights into the safety of SARS-CoV-2 vaccinations in patients with inflammatory rheumatic diseases (IRDs) compared to healthy individuals and to highlight changes over the course of repeated vaccinations. In this single-centre study, SARS-CoV-2 vaccinated IRD patients were recruited from the hospital of the University of Munich. Healthcare workers served as the control group. Adverse events following each vaccination were assessed using questionnaires. Descriptive statistics and non-parametric tests were used to illustrate the differences between IRD patients and the control group. Between January 1, 2021, and Septemper 30, 2022, 235 IRD patients (60.4

Inflammatory back pain is a characteristic of spondyloarthritis. It is not, however, an exclusive symptom of inflammatory rheumatic diseases as it can also be associated with non -inflammatory entities. Infrequently, the etiology can be found in neoplastic conditions such as malignant lymphoma. Even in the presence of comorbidities indicatory of underlying rheumatic disease, like psoriasis vulgaris, the clinician should not be led astray. It is essential to pay attention to contradictory findings, as treatment crucially differs depending on diagnosis. Herein, we report on a psoriasis patient who presented with characteristic inflammatory back pain and deceptive imaging results. While the patient was initially thought to suffer from an inflammatory rheumatic disease with axial involvement, it was the accompanying atypical circumstances, particularly her age, that instantly challenged the diagnosis of axial psoriatic arthritis. She was eventually diagnosed with stage IV follicular lymphoma that manifested with rare and exclusively extranodal lesions and spondyloarthritis-like morphology. This case effectively demonstrates the importance of a thorough diagnostic workup and how certain clinical factors, such as the patient's age, should be considered when confronted with inflammatory back pain.

Systemic sclerosis, a severe inflammatory autoimmune disease, shares a common thread with cancer through the underlying mechanism of inflammation. This inflammatory milieu not only drives the immune dysregulation characteristic of autoimmune diseases but also plays a pivotal role in the pathogenesis of cancer. Among the cellular components involved, B cells have emerged as key players in hematologic tumor and autoimmune disease, contributing to immune dysregulation and persistent tissue fibrosis in systemic sclerosis, as well as tumor progression and immune evasion in cancer. Consequently, novel therapeutic strategies targeting B cells hold promise in both conditions. Recent exploration of CD19 CAR T cells in severe systemic sclerosis patients has shown great potential, but also introduced possible risks and drawbacks associated with viral vectors, prolonged CAR T cell persistence, lengthy production timelines, high costs, and the necessity of conditioning patients with organotoxic and fertility-damaging chemotherapy. Given these challenges, alternative CD19-depleting approaches are of high interest for managing severe systemic autoimmune diseases. Here, we present the pioneering use of blinatumomab, a bispecific anti-CD3/anti-CD19 T cell engager in a patient with progressive, severe systemic sclerosis, offering a promising alternative for such challenging cases.

Key Clinical Message In women of childbearing age, severe proteinuria in systemic lupus erythematosus raises concern for renal involvement and pregnancy complications. While persisting renal loss of protein is known to culminate in extensive interventions, intermittent proteinuria in inactive disease requires an adjusted approach. Contextual awareness of this urinary finding is thus essential.

Background Interleukin (IL)-17A is essential for intestinal mucosal integrity, contributing to the prevention of detrimental immunity such as infectious colitis and inflammatory bowel disease (IBD). Indeed, neutralization of IL-17A has been abandoned as a therapeutic principle in IBD because of increased disease activity. However, it is controversial whether IL-17A inhibitors increase the risk of developing colitis in patients who do not have underlying IBD. Here, we present two cases of different forms of colitis that occurred during treatment with two IL-17A inhibitors, secukinumab and ixekizumab. Case presentations We report the case of a 35-year-old female with SAPHO (synovitis–acne–pustulosis–hyperostosis–osteitis) syndrome who was admitted due to severe colitis with bloody diarrhea, fever, abdominal pain and weight loss after receiving secukinumab for 3 months as well as the case of a 41-year-old male with psoriatic arthritis who presented himself to the outpatient clinic with bloody stools, abdominal pain and nausea 5 months after changing his therapy from secukinumab to ixekizumab. In both patients, treatment with IL-17A-inhibitors was stopped and tumor necrosis factor inhibitors were started. Both patients recovered, are clinically stable and show no more signs of active colitis. Conclusion The role of IL-17A inhibitors in the pathogenesis of infectious colitis and new-onset IBD is not fully understood and requires further research. Patients receiving IL-17A-inhibitor therapy should be carefully screened and notified of the possible side effects.

Methotrexate is associated with bone lesions that are rare and, although presenting with a typical localisation to the lower extremities and appearing with a characteristic radiologic morphology, largely unknown and often misdiagnosed as osteoporotic insufficiency fractures. The correct and early diagnosis, however, is key for treatment and prevention of further osteopathology. Here, we present a patient with rheumatoid arthritis who developed multiple painful insufficiency fractures in the left foot (processus anterior calcanei, tuber calcanei) and in the right lower leg and foot (anterior and dorsal calcaneus and at the cuboid and distal tibia) during therapy with methotrexate, which were all misdiagnosed as osteoporotic. The fractures occurred between 8 months and 35 months after starting methotrexate. Discontinuation of methotrexate resulted in rapid pain relief and no further fractures have occurred. This case powerfully demonstrates the importance of raising awareness of methotrexate osteopathy in order to take appropriate therapeutic measures, including and perniciously discontinuing methotrexate.

SARS-CoV-2 has been recognised as a potential trigger of inflammatory arthritis in individuals with inflammatory rheumatic diseases as well as in previously unaffected individuals. However, new-onset arthritis after COVID-19 is a heterogeneous phenomenon that complicates differential diagnosis. For example, acute arthritis with features of viral arthritis has been reported after COVID-19, as has crystal-induced arthritis. Arthritides mimicking reactive arthritis (ReA) have also been described, but these patients often do not fulfil the typical features of ReA: several reports describe cases of patients older than 45 years at the onset of arthritis, and the characteristic genetic feature of ReA, HLA-B27, is rarely found. Because viral infections are much less likely to cause ReA than bacterial infections, and respiratory infections are rarely the cause of ReA, it is currently unknown whether SARS-CoV-2 can cause true ReA. Here, we report the case of a 30-year-old patient who presented with acute pain, swelling and redness in the left metatarsophalangeal (MTP) joint and ankle 7 days after resolution of a SARS-CoV-2 infection. Diagnostics revealed arthritis of the MTP2, synovitis of the upper ankle with significant joint effusion and peritendinitis of the flexor tendons. Based on the clinical manifestations and diagnostic test results, ReA appeared to be the most likely cause. A screening for typical ReA-associated infections was negative. The patient was treated with NSAIDs and intra-articular and systemic glucocorticoids. At a follow-up visit after discontinuation of glucocorticoids, the patient was symptom-free. Overall, we observed a ReA with typical clinical, genetic and patient characteristics after SARS-CoV-2 infection, and we conclude that a direct association with COVID-19 is highly plausible.

Since the start of the SARS-CoV-2 vaccination campaign, our knowledge of the effects of vaccines in people with inflammatory rheumatic diseases has remained incomplete. In particular, the effects of immunomodulatory therapies on vaccine success are poorly understood. Three notable papers from the past year have helped to fill these knowledge gaps.

Dyrk1a triplication in Down9s syndrome and its overexpression in Alzheimer9s disease suggest a role for increased DYRK1A activity in the abnormal metabolism of APP. Transport defects are early phenotypes in the progression of Alzheimer9s disease, which lead to APP processing impairments. However, whether DYRK1A regulates the intracellular transport and delivery of APP in human neurons remains unknown. From a proteomic dataset of human cerebral organoids treated with harmine, a DYRK1A inhibitor, we found expression changes in protein clusters associated with the control of microtubule-based transport and in close interaction with the APP vesicle. Live imaging of APP axonal transport in human-derived neurons treated with harmine or overexpressing a dominant negative DYRK1A revealed a reduction in APP vesicle density and enhanced the stochastic behavior of retrograde vesicle transport. Moreover, harmine increased the fraction of slow segmental velocities and changed speed transitions supporting a DYRK1A-mediated effect in the exchange of active motor configuration. Contrarily, the overexpression of DYRK1A in human polarized neurons increased the axonal density of APP vesicles and enhanced the processivity of retrograde APP. In addition, increased DYRK1A activity induced faster retrograde segmental velocities together with significant changes in slow to fast anterograde and retrograde speed transitions, suggesting the facilitation of the active motor configuration. Our results highlight DYRK1A as a modulator of the axonal transport machinery driving APP intracellular distribution in neurons, and stress DYRK1A inhibition as a putative therapeutic intervention to restore APP axonal transport in Down9s syndrome and Alzheimer9s disease. SIGNIFICANCE STATEMENT Axonal transport defects are early events in the progression of neurodegenerative diseases, such as Alzheimer9s disease. However, the molecular mechanisms underlying transport defects remain elusive. Dyrk1a kinase is triplicated in Down9s syndrome and overexpressed in Alzheimer9s disease, suggesting that DYRK1A dysfunction affects molecular pathways leading to early-onset neurodegeneration. Here, we show by live imaging of human-derived neurons that DYRK1A activity differentially regulates the intracellular trafficking of APP. Further, single-particle analysis revealed DYRK1A as a modulator of axonal transport and the configuration of active motors within the APP vesicle. Our work highlights DYRK1A as a regulator of APP axonal transport and metabolism, supporting DYRK1A inhibition as a therapeutic strategy to restore intracellular dynamics in Alzheimer9s disease.

Vaccination against SARS-CoV-2 has become available and will hopefully end the current pandemic. Understandably, patients with inflammatory rheumatic diseases (iRMDs) and their physicians are feverishly preoccupied with questions about vaccination and the vaccines against SARS-CoV-2. However, as it will take months before all patients with iRMDs will have access to the vaccines, measures that are taken now in order to increase potential safety and efficacy of the vaccines may impose a risk for the patients with regard to reactivation of their underlying iRMD. The ad hoc commission 'Covid-19' and the board of directors of the German Society for Rheumatology have addressed this topic and have developed considerations, which are intended to answer urgent questions, to take away concerns and fears and to make initial recommendations for patients with iRMDs.

It is currently unknown whether immunosuppressive and/or immunomodulating agents such as biological disease-modifying antirheumatic drugs (bDMARDs) affect the rate and the outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections of patients with inflammatory rheumatic diseases (IRDs). While several national authorities have defined patients under immunosuppressive therapy as at risk for severe COVID-19,1 accumulating data from individual cases and also from case series, such as a series from Italy published in the Annals of the Rheumatic Diseases by Monti et al 2 and a report about patients with immune-mediated inflammatory diseases from New York,3 suggest that baseline use of bDMARDs is not associated with worse COVID-19 outcome. Although the idea of a potentially protective effect of bDMRADs in COVID-19 is intriguing, we feel that extrapolation of these initial data is dangerous and potentially harmful. In particular, some caution may have to be applied when employing rituximab (RTX), a B-cell depleting bDMARD, in patients with immune-mediated disease. This notion may be illustrated by the following observations: We recently lost two patients with rheumatoid arthritis (RA) treated with RTX to lethal COVID-19. The first patient, a 71-year-old man with rheumatoid factor positive, …

Immune dysregulation diseases are characterized by heterogeneous clinical manifestations and may have severe disease courses. The identification of the genetic causes of these diseases therefore has critical clinical implications. We performed whole-exome sequencing of patients with immune dysregulation disorders and identified two patients with previously undescribed mutations in LRRC32, which encodes glycoprotein A repetitions predominant (GARP). These patients were characterized by markedly reduced numbers and frequencies of regulatory T cells (Tregs). Tregs with mutated LRRC32 exhibited strongly diminished cell-surface GARP expression and reduced suppressor function. In a model of conditional Garp deficiency in mice, we confirmed increased susceptibility to inflammatory diseases once GARP expression on Tregs was decreased. Garp deficiency led to an unstable Treg phenotype due to diminished Foxp3 protein acetylation and stability. Our study reinforces the understanding of the immunological mechanisms of immune dysregulation and expands the knowledge on the immunological function of GARP as an important regulator of Treg stability.