OBJECTIVES:Avacopan, an oral C5a receptor antagonist, is approved for treatment of severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in combination with rituximab or cyclophosphamide. This study evaluated its real-world efficacy, safety and glucocorticoid-sparing effects. METHODS:This retrospective single-centre study included 35 patients with new-onset or relapsing AAV treated with avacopan plus standard induction therapy (rituximab, cyclophosphamide or both). Outcomes were compared with 70 matched controls receiving standard therapy. Primary endpoints were remission (Birmingham Vasculitis Activity Score (BVAS)=0, prednisolone ≤5 mg/day) at 6 and 12 months. Secondary endpoints included relapse, renal function, glucocorticoid exposure and adverse events. RESULTS:Baseline characteristics were generally comparable, although median estimated glomerular filtration rate (eGFR) was lower in the avacopan group (24 vs 49 mL/min). Induction therapy included rituximab (28%), cyclophosphamide (11%) or combination therapy (61%), reflecting severe disease. Remission rates were similar at 6 months (69% vs 68%) but tended to be higher with avacopan at 12 months (86% vs 68%; p=0.11). Relapses occurred less frequently with avacopan (16% vs 51%, p=0.003), including after treatment discontinuation. Avacopan was associated with accelerated glucocorticoid tapering (≤5 mg/day; 102 vs 164 days, p<0.001), lower cumulative doses (3266 vs 4288 mg, p=0.008) and greater renal function improvement (ΔeGFR+18 vs +7 mL/min after 1 year). Nine patients (26%) discontinued avacopan due to adverse events. CONCLUSION:In a real-world practice, avacopan was effective with an acceptable safety profile, enabling steroid sparing, improved renal recovery and reduced relapse rates, including in patients receiving combined induction therapy. Benefits persisted beyond 12 months, but prospective confirmation of these presumed long-term benefits is needed.

Common variable immunodeficiency (CVID) is frequently complicated by autoimmune and inflammatory manifestations associated with profound immune dysregulation (CVIDc), including expansion of T-bethighCD21low B cells (CD21low B cells). Elevated serum IL-10 levels have repeatedly been reported in CVIDc, yet their relationship to CD21low B-cell differentiation remains unclear. In this study, we determined a significant correlation between increased serum IL-10 levels and frequency of circulating CD21low B cells, particularly marked in CVIDc patients. Transcriptomic and protein analyses identified multiple cellular sources of IL-10 in CVID, including monocytes, T cells, and a subset of CD21low B cells in peripheral blood and inflamed tissues. CD21low B cells expressed elevated levels of IL-10 receptor subunits and displayed intact IL-10–induced STAT3 signaling, indicating preserved responsiveness to IL-10. Functionally, IL-10 alone neither induced CD21low B-cell differentiation nor inhibited IFN-γ–driven polarization. However, in vitro differentiation assays showed that IL-10 can substitute for IL-21 during CD40L/T cell–dependent differentiation of CD21low-like B cells and promote their survival in vitro. These findings suggest that IL-10 may support the expansion and persistence of CD21low B cells at inflammatory sites. Collectively, our data identify IL-10 as a component of the inflammatory environment associated with CD21low B-cell expansion and suggest that IL-10 can functionally replace IL-21 during their differentiation and promote their survival in CVID-associated immune dysregulation.

Objective Axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) are overlapping yet distinct conditions within the SpA spectrum. As divergent immunophenotypes may influence disease course and therapeutic response, we compared immune cell subsets, cytokine profiles, and inflammatory mediators. Methods Peripheral blood mononuclear cells (PBMCs) from 179 patients (88 axSpA, 91 PsA) and 49 healthy donors were profiled using spectral flow cytometry, comprising 230 million acquired events and 55 million quality‐controlled cells. Immune subsets, activation‐ and differentiation‐associated markers, and cytokines were analyzed to define disease‐specific profiles. Results axSpA and PsA exhibited distinct immunophenotypic profiles. axSpA was characterized by expansion of double‐negative and γδ T cells, increased plasmablasts and CD21 low B cells, and higher expression of activation‐associated markers (CD80, CD86, CD95), consistent with dysregulated innate‐like immune activation. PsA showed increased dendritic cells and a higher frequency of IgM + IgD − memory B cells. Both diseases exhibited Th1 enrichment; however, axSpA showed additional Th17 skewing and increased expression of activation‐ and checkpoint‐associated markers (HLA‐DR, CD38, PD‐1), whereas PsA displayed more central memory CD4 + T cells and lower PD‐1 expression. Cytokine profiling revealed elevated inflammasome‐related and innate cytokines in axSpA, whereas PsA showed increased soluble interleukin‐2 (IL‐2) receptor, IL‐17A, soluble tumor necrosis factor receptor type I, and vascular‐associated inflammatory mediators. Regularized regression identified a stable immune signature distinguishing axSpA from PsA (cross‐validated area under the receiver operating characteristic curve 0.94). Conclusion axSpA and PsA share overlapping yet distinguishable immunophenotypic signatures. axSpA shows enrichment of innate‐associated and broadly activated immune features, whereas PsA is characterized by adaptive and memory‐associated immune responses. These findings may support biomarker‐guided stratification within the SpA spectrum. image

Abstract CD20 is a four-helix transmembrane protein specifically expressed in B-cells that serves as a prominent target of therapeutic anti-CD20 antibodies. It is localized in a membrane nanocluster harboring the B-cell antigen receptor of IgD class (IgD-BCR), where it functions to maintain the resting state of naïve B-lymphocytes. How CD20 exerts this resting B-cell gatekeeper function is not yet known. Using Ramos and human peripheral blood B-cells, we show here that the serine/threonine kinase PKCδ constitutively phosphorylates serine residues in the two cytosolic tails of CD20. Phosphorylated CD20 becomes a binding target for 14-3-3 adaptor proteins, which link it to the RhoA GDP/GTP exchange factor GEF-H1 and the microtubule network, supporting the function of the IgD-BCR nanocluster. Binding of anti-CD20 antibodies results in microtubule dissociation and replacement of the GEF-H1/CD20 complex with a RhoA-GTP/ROCK1/CD20 complex, which promotes actomyosin contractility. Our study suggests that CD20 not only maintains the resting state of B-lymphocytes by anchoring the microtubule network and controlling the stability of the IgD-BCR nanocluster, but also mediates the microtubule/actin switch in active B-lymphocytes. These findings could have important implications for anti-CD20 antibody treatment and the optimization of therapeutic protocols.

The early and accurate detection and diagnosis of diseases play a crucial role in impeding disease progression and guiding appropriate treatment selection. Complex diseases such as autoimmune diseases (ADs), often present nonspecific symptoms that can overlap also with other conditions, leading to misdiagnosis. Medical software, known as clinical decision support systems (CDSS), is used by clinicians to categorize patients based on specific criteria. However, existing CDSS implementations, generally developed within individual hospitals, are often limited to specific data types, and reflect questionnaires that do not take advantage of machine learning (ML) methods for detection and prediction of complex patterns. To address this gap, we developed Personalis as a proof-of-concept medical software. Personalis integrates various modalities of medical datasets and applies ML models to target hospital datasets and disease-target specific prediction tasks within a unified software environment. The platform has been run with real-world data to investigate the potential of this proof-of-concept medical software in providing early clinical support for the personalized prediction of specific autoimmune diseases in individual patients. These intermediate results have been implemented to redesign the front-end to enhance user-experience, and serve the conveyed clinical needs and expectations. Personalis is a proof-of-concept medical software that demonstrated the feasibility of integrating various data modalities and machine learning methods to support clinicians in the diagnosis, treatment or management of individual patients with autoimmune diseases. By leveraging ML methods, Personalis provided prediction with a certain accuracy of a specific autoimmune disease for an individual patient, highlighting factors that contributed to the prediction results. Explainable machine learning made the models’ decisions understandable to humans, and the resulting factors were further used to provide additional clinical insights beyond the disease prediction accuracy metric. The platform was designed considering user-experience and human factors to enable actionable clinical practical adoption. Its results may provide hints on the prognosis assessment by selecting a specific patient record. Personalis provides a proof-of-concept medical software for integrating heterogeneous clinical data with configurable ML-based prediction and interpretation workflows for autoimmune diseases. It offers a mechanistic overview of the parameters that mostly influence the prediction of the machine learning models, therefore providing interpretable results and mechanistic insights essential to model transparency. The potential of the medical software Personalis is be extended to several diseases, and support in cases of challenging differential diagnoses.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a prototypic autoimmune disease, with a subset of AAV patients manifesting anti-myeloperoxidase (MPO) IgG. Patients with AAV respond positively to B cell-targeting and complement-targeting therapies, but disease flares are not uncommon. Here, by comparing samples from healthy individuals and MPO+ AVV patients, we show that B cell autoreactivity against MPO in the circulation of patients is dominated by CD27+IgM+ B cells whereas MPO-specific IgG+ cells are infrequent. Additionally, while naive anti-MPO-IgM B cells are present in both patients and controls and produce anti-MPO IgM upon stimulation, anti-MPO-IgM memory B cells and serum anti-MPO IgM are features of patients. Our results thus hint that defective elimination of B cell reactivity to MPO in the human repertoire, the presence of activated IgM+ anti-MPO B cells in disease, and a dominant role for anti-MPO IgM in complement activation, may all contribute to MPO+ AAV etiology and thereby serve as potential target for therapy.

Objective To identify candidate Systemic Lupus Erythematosus (SLE) domains from the literature for consideration towards the development of the SLE Core Outcome Set. Methods This was a comprehensive scoping literature review of SLE clinical trials and systematic reviews published since 2010. Studies were identified from 5 databases and were screened for eligibility. Candidate domains were extracted from the included studies. Candidate domains were winnowed and binned by the Outcome Measures in Rheumatology (OMERACT) SLE Advisory Group. Results Of the 4063 studies identified, 507 met inclusion criteria and proceeded to data extraction. Multiple domains and items were extracted, which winnowing and binning reduced to 25 candidate domains. Conclusion The 25 candidate domains cover the important aspects of SLE and the 4 core areas of disease impact according to OMERACT framework. The 25 candidate domains constitute a feasible and manageable number of domains to proceed with to the core domain consensus stage that covers the wide range of impact of SLE. The candidate domains will be supplemented by ongoing qualitative research with patients living with SLE to identify additional domains before proceeding to the consensus stage.

Background Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic necrotising vasculitis characterised by tissue and blood hypereosinophilia. Cardiac involvement has previously been identified as the most significant predictor of mortality.Objective To identify and characterise previously untreated patients with EGPA and their cardiac manifestations at disease onset.Methods A retrospective monocentre study was conducted on 103 patients. Upon patient presentation, detailed multidisciplinary physical evaluations and laboratory diagnostics were performed. Cardiac events were defined as EGPA-related abnormalities in ECG, echocardiography, cardiac MRI, invasive coronary angiography or cardiac histopathology.Results Cardiac manifestations were diagnosed in 36 of 103 patients with EGPA (35%). Patients with EGPA with cardiac involvement (EGPA-CI) exhibited typical symptoms of EGPA concomitant with elevated cardiac biomarkers. Pericarditis (77%), cardiomyopathy with cardiac failure (55%) and definite myocarditis (36%) were the most common diagnoses, which in some cases resulted in cardiogenic shock (14%) or cardiac arrest (6%). Vasospastic coronary arteries causing myocardial infarctions were identified as a life-threatening cardiac manifestation in 8% of patients with EGPA-CI. Overall, patients with EGPA-CI presented with significantly higher disease activity and worse prognosis, with elevated median eosinophilic count and C-reactive protein levels.Conclusions Cardiac involvement is a common initial manifestation of EGPA and is associated with elevated systemic disease activity. In addition to pericarditis and myocarditis, coronary vasospasms were identified as a rare and severe manifestation of EGPA that may mimic myocardial infarction. Consequently, at the early stage of disease, patients may present with advanced cardiac impairment, emphasising the necessity of prompt diagnostic and therapeutic intervention to positively affect prognosis.

CD20 is a B cell-specific four-helix transmembrane protein and a prominent target of therapeutic anti-CD20 antibodies. We have recently described that CD20 is localized within a membrane nanocluster harboring the IgD class B cell antigen receptor (IgD-BCR) where it functions as a gatekeeper for the resting state of naïve human B lymphocytes. How CD20 exerts its gatekeeper function is not yet known. Using Ramos and human peripheral blood B cells, we show here that the serine/threonine kinase PKCδ, constitutively phosphorylates serine residues at the cytosolic tails of CD20. The phosphorylated CD20 becomes a target for 14-3-3 adaptor proteins that link CD20 to the RhoA GDP/GTP exchange factor GEF-H1 and the microtubule (MT) network controlling the stability of the IgD-BCR nanocluster. Binding of anti-CD20 antibodies results in MT disassembly and the replacement of the GEF-H1/CD20 complex by a RhoA-GTP/ROCK1/CD20 complex which drives actomyosin contractility. Our study suggests that CD20 not only maintains the resting state, but also orchestrates the MT/actin switch in active B lymphocytes. This could have implications for treatment with anti-CD20 antibodies and may help to optimize therapeutic protocols. ![Figure][1] ### Competing Interest Statement The authors have declared no competing interest. R01 Human Vaccine institute, A031503 Roche (Switzerland), https://ror.org/00by1q217, ZVK-2023101202 Deutsche Forschungsgemeinschaft, 31778431, FOR2743, 450392965 Nanoscale Microscopy and Molecular Physiology of the Brain Cluster of Excellence 171 – DFG Research Center 103, https://ror.org/02wkzzr31, 541758684 DFG TRR130, C01 University of Freiburg, 2023/A2-Fol, 2021/B3-Fol DKTK [1]: pending:yes

Background: B cells are central in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides (AAV). The efficacy of remission induction and maintenance by B cell depleting therapy strongly underlines the importance of B cells in the disease and the use of rituximab (RTX) has successfully been implemented in the treatment of AAV. However, B cell depletion after application of RTX is markedly prolonged in AAV compared to other autoimmune diseases, suggesting an impairment of the B cell compartment. Objectives: Our study aimed to understand the base of the defect in B cell reconstitution after RTX treatment in AAV, and to dissect B cell function and development in AAV. Methods: We recruited 91 AAV patients and performed deep phenotyping of the peripheral B cell compartment by spectral flow cytometry. In a subgroup of patients, we analyzed the bone marrow using flow- as well as mass cytometry. In vitro modeling assays of B lymphopoiesis have been applied to study dynamic of development of AAV B cell precursors. BAFFR involvement into peripheral B cell survival and maturation have been studied by investigating serum BAFF concentration by ELISA, BAFFR expression of isolated B cells was determined by qPCR and Western Blot, and by in vitro survival assays. Results: AAV patients show B-lymphocytopenia. Low transitional B cell numbers in treatment-naive patients indicate an impaired central B cell development. In RTX-treated AAV patients the median time of B cell depletion, defined as less than 5 cells/µL, was 17 months (IQR 9-36). We studied phenotype and development of bone marrow B cells and found a defect in early B cell development in both treatment-naive and RTX-treated AAV patients. Only in a subgroup of RTX-treated patients, transitional B cells were increased, indicative of beginning or ongoing B cell repopulation. The increased amount of transitional B cells did not lead to replenishment of the later stages of peripheral B cell maturation, suggesting a maturation stop in peripheral B cell reconstitution in these patients. We found low BAFFR expression in AAV peripheral B cells, caused by enhanced shedding of BAFFR, that resulted in a reduced B cell survival in response to BAFF. Conclusion: Our data suggest that prolonged depletion of B cells in AAV patients after RTX therapy indicate a B cell defect that is unmasked by treatment. Impaired central B lymphopoiesis associated with disturbed peripheral B cell maturation because of enhanced BAFFR processing and shedding, resulting in reduced immature B cell survival, contribute to a delayed recovery of the peripheral B cell pool after RTX treatment in AAV. Our data point to a severe defect in B cell maturation and development in patients with AAV that may influence the therapeutic use of B cell depleting agents in this disease. In addition, our results emphasize the need for close immune monitoring after B cell depletion in AAV. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: None declared.

Defective FAS (CD95/Apo-1/TNFRSF6) signaling causes autoimmune lymphoproliferative syndrome (ALPS). Hypergammaglobulinemia is a common feature in ALPS with FAS mutations (ALPS-FAS), but paradoxically, fewer conventional memory cells differentiate from FAS-expressing germinal center (GC) B cells. Resistance to FAS-induced apoptosis does not explain this phenotype. We tested the hypothesis that defective non-apoptotic FAS signaling may contribute to impaired B cell differentiation in ALPS. We analyzed secondary lymphoid organs of patients with ALPS-FAS and found low numbers of memory B cells, fewer GC B cells, and an expanded extrafollicular (EF) B cell response. Enhanced mTOR activity has been shown to favor EF versus GC fate decision, and we found enhanced PI3K/mTOR and BCR signaling in ALPS-FAS splenic B cells. Modeling initial T-dependent B cell activation with CD40L in vitro, we showed that FAS competent cells with transient FAS ligation showed specifically decreased mTOR axis activation without apoptosis. Mechanistically, transient FAS engagement with involvement of caspase-8 induced nuclear exclusion of PTEN, leading to mTOR inhibition. In addition, FASL-dependent PTEN nuclear exclusion and mTOR modulation were defective in patients with ALPS-FAS. In the early phase of activation, FAS stimulation promoted expression of genes related to GC initiation at the expense of processes related to the EF response. Hence, our data suggest that non-apoptotic FAS signaling acts as molecular switch between EF versus GC fate decisions via regulation of the mTOR axis and transcription. The defect of this modulatory circuit may explain the observed hypergammaglobulinemia and low memory B cell numbers in ALPS.

SARS-CoV‑2 („severe acute respiratory syndrome coronavirus type 2“) spielt auch weiterhin eine große Rolle als schwere und potenziell tödliche Atemwegsinfektion insbesondere bei vulnerablen Patient:innengruppen. Angesichts der dünnen Datenlagen zum Einfluss von Therapien auf Impfantworten war es zu Beginn der Corona-Pandemie eine große Herausforderung, die Verträglichkeit und Wirksamkeit bei Patient:innen mit entzündlich rheumatischen Erkrankungen unter Immunmodulation/Immunsuppression vorherzusagen. Inzwischen haben zahlreiche Studien die Fragen nach Ansprechen und Verträglichkeit zumindest für die COVID-19(Coronavirus-Erkrankung 2019)-Impfung adressiert. Bereits in den ersten Monaten der Impfkampagne konnte eine kleine Studie an einer monozentrischen Kohorte zeigen, dass bis auf Patient:innen unter B‑Zell-Depletion alle eingeschlossenen Patient:innen in der Lage waren, nach den ersten 2 Impfungen eine Serokonversion zu zeigen. Dabei kam es weder zu einem vermehrten Auftreten von Schüben der Grunderkrankungen noch zu neuen Autoimmunphänomenen. Diverse Studien haben diese Daten seitdem bestätigt.

Objective In systemic lupus erythematosus (SLE), the non-classical monocyte compartment is expanded, but its phenotype and association with clinical disease manifestations have not been explored. Method Monocyte subsets from 39 SLE patients, 32 healthy age-matched controls, and 16 patients from a disease control (autoimmune connective tissue disease other than SLE) were determined based on CD14 and CD16 surface expression. Cell surface expression of the receptors for macrophage colony-stimulating factor (M-CSF) (CD115) and granulocyte-macrophage colony-stimulating factor (GM-CSF) (CD116), as well as 6-Sulpho LacNAc (slan), were analysed by flow cytometry. The association of monocyte populations with disease manifestations, disease activity markers, and current medication of each patient was analysed by chart review. Results Non-classical monocytes displayed a cell-type specific signature of high M-CSF receptor CD115 and low GM-CSF receptor CD116 expression that separated them from the other two monocyte subsets. In healthy individuals, the M-CSF receptor on non-classical monocytes was an age-dependent surface marker, with lower expression in young adults. However, SLE monocytes were characterized by a marked expansion of M-CSF receptor/CD115+ non-classical monocytes in patients of all ages. The expanded population of M-CSF receptor/CD115+ non-classical monocytes was associated with lupus nephritis but not with disease activity, and coexpressed slan. Conclusion The non-classical monocyte subset in SLE is characterized by an expansion of M-CSF receptor/CD115+ cells that are associated with lupus nephritis and coexpress slan.

The Advances in Targeted Therapies meets annually, convening experts in the field of rheumatology to both provide scientific updates and identify existing scientific gaps within the field. To review the major unmet scientific needs in rheumatology. The 23rd annual Advances in Targeted Therapies meeting convened with more than 100 international basic scientists and clinical researchers in rheumatology, immunology, infectious diseases, epidemiology, molecular biology and other specialties relating to all aspects of immune-mediated inflammatory diseases. We held breakout sessions in five rheumatological disease-specific groups including: rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (axSpa), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and vasculitis, and osteoarthritis (OA). In each group, experts were asked to identify and prioritise current unmet needs in clinical and translational research. An overarching theme across all disease states is the continued need for clinical trial design innovation with regard to therapeutics, endpoint and disease endotypes. Within RA, unmet needs comprise molecular classification of disease pathogenesis and activity, pre-/early RA strategies, more refined pain profiling and innovative trials designs to deliver on precision medicine. Continued scientific questions within PsA include evaluating the genetic, immunophenotypic, clinical signatures that predict development of PsA in patients with psoriasis, and the evaluation of combination therapies for difficult-to-treat disease. For axSpA, there continues to be the need to understand the role of interleukin-23 (IL-23) in pathogenesis and the genetic relationship of the IL-23-receptor polymorphism with other related systemic inflammatory diseases (eg, inflammatory bowel disease). A major unmet need in the OA field remains the need to develop the ability to reliably phenotype and stratify patients for inclusion in clinical trials. SLE experts identified a number of unmet needs within clinical trial design including the need for allowing endpoints that reflect pharmacodynamic/functional outcomes (eg, inhibition of type I interferon pathway activation; changes in urine biomarkers). Lastly, within SSc and vasculitis, there is a lack of biomarkers that predict response or disease progression, and that allow patients to be stratified for therapies. There remains a strong need to innovate clinical trial design, to identify systemic and tissue-level biomarkers that predict progression or response to therapy, endotype disease, and to continue developing therapies and therapeutic strategies for those with treatment-refractory disease. This document, based on expert consensus, should provide a roadmap for prioritising scientific endeavour in the field of rheumatology.

In systemic lupus erythematosus, loss of immune tolerance, autoantibody production and immune complex deposition are required but not sufficient for organ damage1. How inflammatory signals are initiated and amplified in the setting of autoimmunity remains elusive. Here we set out to dissect layers and hierarchies of autoimmune kidney inflammation to identify tissue-specific cellular hubs that amplify autoinflammatory responses. Using high-resolution single-cell profiling of kidney immune and parenchymal cells, in combination with antibody blockade and genetic deficiency, we show that tissue-resident NKp46+ innate lymphoid cells (ILCs) are crucial signal amplifiers of disease-associated macrophage expansion and epithelial cell injury in lupus nephritis, downstream of autoantibody production. NKp46 signalling in a distinct subset of group 1 ILCs (ILC1s) instructed an unconventional immune-regulatory transcriptional program, which included the expression of the myeloid cell growth factor CSF2. CSF2 production by NKp46+ ILCs promoted the population expansion of monocyte-derived macrophages. Blockade of the NKp46 receptor (using the antibody clone mNCR1.15; ref. 2) or genetic deficiency of NKp46 abrogated epithelial cell injury. The same cellular and molecular patterns were operative in human lupus nephritis. Our data provide support for the idea that NKp46+ ILC1s promote parenchymal cell injury by granting monocyte-derived macrophages access to epithelial cell niches. NKp46 activation in ILC1s therefore constitutes a previously unrecognized, crucial tissue rheostat that amplifies organ damage in autoimmune hosts, with broad implications for inflammatory pathologies and therapies. NKp46+ innate lymphoid cells are identified as pivotal signal amplifiers of autoinflammatory responses in lupus nephritis.

Background Individuals with anti-citrullinated protein antibodies (ACPAs) and subclinical inflammatory changes in joints are at high risk of developing rheumatoid arthritis. Treatment strategies to intercept this pre-stage clinical disease remain to be developed. We aimed to assess whether 6-month treatment with abatacept improves inflammation in preclinical rheumatoid arthritis. Methods The abatacept reversing subclinical inflammation as measured by MRI in ACPA positive arthralgia (ARIAA) study is a randomised, international, multicentre, double-blind, placebo-controlled trial done in 14 hospitals and community centres across Europe (11 in Germany, two in Spain, and one in the Czech Republic). Adults (aged >= 18 years) with ACPA positivity, joint pain (but no swelling), and signs of osteitis, synovitis, or tenosynovitis in hand MRI were randomly assigned (1:1) to weekly subcutaneous abatacept 125 mg or placebo for 6 months followed by a double-blind, drug-free, observation phase for 12 months. The primary outcome was the proportion of participants with any reduction in inflammatory MRI lesions at 6 months. The primary efficacy analysis was done in the modified intention-to-treat population, which included participants who were randomly assigned and received study medication. Safety analyses were conducted in participants who received the study medication and had at least one post-baseline observation. The study was registered with the EUDRA-CT (2014-000555-93). Findings Between Nov 6, 2014, and June 15, 2021, 139 participants were screened. Of 100 participants, 50 were randomly assigned to abatacept 125 mg and 50 to placebo. Two participants (one from each group) were excluded due to administration failure or refusing treatment; thus, 98 were included in the modified intention-to-treat population. 70 (71%) of 98 participants were female and 28 (29%) of 98 were male. At 6 months, 28 (57%) of 49 participants in the abatacept group and 15 (31%) of 49 participants in the placebo group showed improvement in MRI subclinical inflammation (absolute difference 265%, 95% CI 59-456; p=0014). Four (8%) of 49 participants in the abatacept group and 17 (35%) of 49 participants in the placebo group developed rheumatoid arthritis (hazard ratio [HR] 014 [004-047]; p=00016). Improvement of MRI inflammation (25 [51%] of 49 participants in the abatacept group, 12 [24%] of 49 in the placebo group; p=0012) and progression to rheumatoid arthritis (17 [35%] of 49, 28 [57%] of 49; HR 014 [004-047]; p=0018) remained significantly different between the two groups after 18 months, 12 months after the end of the intervention. There were 12 serious adverse events in 11 participants (four [8%] of 48 in the abatacept group and 7 [14%] of 49 in the placebo group). No deaths occurred during the study. Interpretation 6-month treatment with abatacept decreases MRI inflammation, clinical symptoms, and risk of rheumatoid arthritis development in participants at high risk. The effects of the intervention persist through a 1-year drug-free observation phase. Funding Innovative Medicine Initiative. Copyright (c) 2024 Elsevier Ltd. All rights reserved.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to play a major role as a severe and potentially fatal airway infection, especially in vulnerable patient groups. In view of the thin data situation on the influence of treatment and response to vaccination, at the beginning of the corona pandemic it was a major challenge to predict the tolerability and effectiveness in patients with inflammatory rheumatic diseases under immunomodulation or immunosuppression. In the meantime, numerous studies have addressed the questions of response and tolerability, at least for the COVID-19 vaccination. Even in the first months of the vaccination campaign, a small study on a single center cohort could show that apart from patients with B‑cell depletion, all included patients showed a seroconversion after the first two vaccinations. This resulted in neither an increased occurrence of exacerbations of the underlying disease nor new autoimmune phenomena. Various studies have since then confirmed these data.

ObjectivesTo investigate, whether inflammatory rheumatic diseases (IRD) inpatients are at higher risk to develop a severe course of SARS-CoV-2 infections compared to the general population, data from the German COVID-19 registry for IRD patients and data from the Lean European Survey on SARS-CoV-2 (LEOSS) infected patients covering inpatients from the general population with SARS-CoV-2 infections were compared.Methods4310 (LEOSS registry) and 1139 cases (IRD registry) were collected in general. Data were matched for age and gender. From both registries, 732 matched inpatients (LEOSS registry: n = 366 and IRD registry: n = 366) were included for analyses in total.ResultsRegarding the COVID-19 associated lethality, no significant difference between both registries was observed. Age > 65°years, chronic obstructive pulmonary disease, diabetes mellitus, rheumatoid arthritis, spondyloarthritis and the use of rituximab were associated with more severe courses of COVID-19. Female gender and the use of tumor necrosis factor-alpha inhibitors (TNF-I) were associated with a better outcome of COVID-19.ConclusionInflammatory rheumatic diseases (IRD) patients have the same risk factors for severe COVID-19 regarding comorbidities compared to the general population without any immune-mediated disease or immunomodulation. The use of rituximab was associated with an increased risk for severe COVID-19. On the other hand, the use of TNF-I was associated with less severe COVID-19 compared to the general population, which might indicate a protective effect of TNF-I against severe COVID-19 disease.