Institute of Rheumatology

BackgroundBrepocitinib is a first-in-class, oral, selective TYK2–JAK1 inhibitor that blocks cytokine signaling, which has been implicated in dermatomyositis.MethodsIn this phase 3, double-blind, randomized, placebo-controlled trial, adults with dermatomyositis were assigned in a 1:1:1 ratio to receive once-daily oral brepocitinib at a dose of 30 mg, brepocitinib at a dose of 15 mg, or placebo for 52 weeks. Standard therapies were continued, and glucocorticoids were tapered. The primary end point was the Total Improvement Score, a validated composite myositis index (with scores ranging from 0 to 100 and higher scores indicating greater improvement) at week 52. Key secondary end points, including skin disease activity, glucocorticoid tapering, and physical function, were tested in a multiplicity-controlled sequence.ResultsA total of 241 patients underwent randomization: 81 to receive brepocitinib 30 mg, 81 to receive brepocitinib 15 mg, and 79 to receive placebo. At week 52, the mean Total Improvement Score was 46.5, 37.5, and 31.2, respectively (difference with brepocitinib 30 mg vs. placebo, 15.3; 95% confidence interval [CI], 6.7 to 24.0; P<0.001; difference with brepocitinib 15 mg vs. placebo, 6.3; 95% CI, −2.4 to 14.9). Brepocitinib 30 mg was superior to placebo across all nine key secondary end points, including skin disease activity, systemic glucocorticoid tapering, and functional disability, with improvements observed as early as week 4. Serious infections were more frequent in the brepocitinib 30-mg group than in the placebo group (10% vs. 1%). No deaths occurred during the trial.ConclusionsIn adults with dermatomyositis that was resistant to previous therapy, the use of brepocitinib at a dose of 30 mg (but not at a dose of 15 mg) resulted in significant benefits with respect to a composite myositis index, skin disease severity, glucocorticoid tapering, and functional disability. (Funded by Priovant Therapeutics; ClinicalTrials.gov number, NCT05437263.)

poorest sleep quality (p = 0.001).Depression scores correlated with age (p = 0.03) and pain (p = 0.001), while stress correlated with difficulty falling asleep (p = 0.019) and poor sleep quality (p = 0.004).Professional activity showed no significant association with stress levels or sleep quality.No significant associations were found between stress, depression, or sleep quality and professional activity, inflammatory markers (ESR, CRP), ANA, anti-dsDNA, antiphospholipid antibodies, SSA, SSB, C3, C4, IL-6, or TNF.However, SLEDAI scores correlated with IL-6 levels (p = 0.002).No notable associations were observed between medication and sleep, stress, or depression.Conclusions Sleep disturbances are frequent in SLE patients, mainly associated with nighttime pain, stress, and depression.Comprehensive management should address SLE manifestations and mental health, as early intervention on these factors may improve patients' well-being and quality of life.

Abstract Background Acute severe ulcerative colitis (ASUC) remains a medical emergency with limited therapeutic progress over the past two decades. Up to half of patients fail to respond to intravenous corticosteroids, and about 15% require colectomy during the acute episode. The systemic immune response in ASUC has not previously been characterised in detail. We performed longitudinal, multi-omic profiling of peripheral blood in ASUC to define immune signatures associated with steroid responsiveness and therapeutic resistance. Methods Peripheral blood from 24 patients with ASUC defined by Truelove &amp; Witts’ criteria, active UC controls matched for endoscopic activity (n = 4), and infectious Campylobacter spp. colitis (n = 3) was analysed using multi-omics including full cohort single-cell RNA-seq/CITE-seq, bulk RNA-seq, and ALAMAR NULISA proteomics, alongside ex vivo functional assays (Fig 1). In ASUC all patients received standard Oxford management. Longitudinal sampling captured pre-steroid (day 1) and early post-steroid (day 3) states, enabling both cross-sectional and temporal analyses. Differential cell-type abundance and pathway enrichment analyses were performed to identify inflammatory programs linked to ASUC and to steroid responsiveness. Results Principal component analysis identified myeloid cells as the principal source of variance in ASUC, with this compartment exhibiting marked transcriptional reprogramming between pre- and post-steroid states and relative to controls (adjusted p = 3.0 × 10−7) (Fig 2a-c). Among up-regulated pathways, IL-6/JAK/STAT3 signalling was the most enriched in ASUC myeloid cells compared to active UC controls (adjusted FDR q-value &amp;lt;0.01), and persisted after corticosteroid therapy, whereas other inflammatory pathways were suppressed (Fig 2d). Ex vivo stimulation of primary monocytes confirmed that IL6-JAK1 signalling was relatively resistant to hydrocortisone but suppressed by JAK1 inhibition, whereas TNF inhibition remained steroid-sensitive. In 3 patients who required colectomy within 3 months due to treatment non-response, this myeloid JAK-1 responsive signature increased between day 1 and day 3, suggesting progressive steroid-resistant activation. Conclusion Longitudinal multi-omic profiling identifies a myeloid-driven inflammatory program in ASUC that is incompletely suppressed by corticosteroids, but responsive to JAK1 inhibition. These findings support early or adjunctive use of upadacitinib alongside corticosteroids in ASUC and provide a mechanistic rationale for JAK-1 targeted therapy in ASUC.

Artesunate (ART), a drug renowned for its anti-inflammatoryandantiproliferative properties, shows promise in psoriasis treatmentby potentially modulating autoimmune responses. This study evaluatedthe efficacy of ART in an imiquimod (IMQ)-induced mouse psoriaticmodel via topical application and intraperitoneal injection, alongsidein vitro investigations using a HaCaT cell-based model. Our resultsdemonstrated that topical ART application significantly alleviatedpsoriatic inflammation and hyperkeratinization and reduced Th17 andIL-17A+ γδ T-cell infiltration, proving superiorto intraperitoneal administration. Notably, ART markedly suppressedthe expression of the pathogenic keratins Krt16 and Krt17, which arecrucial in psoriasis pathogenesis. In vitro, ART not only enhancedthe anti-inflammatory effect of dexamethasone (DEX) by reducing pro-inflammatorycytokines (IL-1β, IL-6, IL-8) but also effectively counteractedthe rebound elevation of CCL-20 exacerbated by DEX in the M4-stimulatedmodel. Importantly, the topical application of ART presents a promisingtherapeutic strategy, particularly due to its potential to mitigateadverse effects associated with glucocorticoid therapies, such asthose linked to CCL-20 rebound. Mechanistically, ART exerted thesetherapeutic effects primarily by inhibiting the phosphorylation ofNF-κB p65 and STAT3 in keratinocytes. The findings underscorethat ART ameliorates psoriasis-related inflammation and proliferationthrough modulating the NF-κB and STAT3 signaling pathways. Theinflammatory response centered on IL-17A and the abnormal keratinizationstate are the most critical pathological processes in psoriasis, withthe aberrantly expressed CCL-20 and Keratin17 (Krt17) via NF-κBand STAT3 pathways in keratinocytes serving as key molecular targetswithin these processes. In complementary and alternative medicine(CAM), ART combined with DEX is an ideal choice for anti-inflammatorytreatment. In conclusion, the observed synergy between artesunateand glucocorticoids further highlights its potential in combinationtherapies.

Abstract Extracellular particles (EP) released by cells are heterogenous, with extracellular vesicles (EV) believed to be the major component. To investigate different EV subpopulations, we conducted a panel screen of 15 fluorescent EV markers in 4 adherent cell lines. Nanoflow cytometry identifies TSPAN14 as the best EV marker in 3 of 4 cell lines. Surprisingly, less than 50% of EPs are labelled by the top 2 EV markers in half the cell lines. The EV marker negative EPs are detergent resistant, non-lipophilic, dense and have Thrombospondin shells by dSTORM; and were thus named Thrombospondin Encapsulated Dense particles (ThrEDs). ThrEDs are ubiquitous, contain extracellular matrix regulators and are released following cell stress. ThrEDs accelerate scratch-wound closure and downregulate the fibrotic phenotype in Dupuytren’s disease patient myofibroblasts. The TSP-1 C-terminus is exposed on the surface of ThrEDs, opening engineering applications.

BackgroundSacroiliac joint (SIJ) MRI is commonly used in diagnosing spondyloarthritis (SpA). Current Assessment of SpondyloArthritis International Society (ASAS) recommendations on reporting SIJ MRIs in patients with known or suspected axial SpA recommend always stating whether bone marrow oedema (BME), erosions and fat lesions are present/absent and whether the MRI is compatible with axial SpA.PurposeTo investigate if routine care radiologists already report what has now been recommended and to assess the agreement between local radiologists and central SpA experts.Materials and methodsThis study includes retrospective interpretation of images acquired in routine care. Patients diagnosed with SpA enrolled in a clinical registry in one of five European countries involved in the EuroSpA Collaboration, with an available SIJ MRI and an associated local MRI report, were included. MRIs were read centrally by two readers, who registered global features (eg, MRI indicative of SpA), and various inflammatory and structural lesions as present/absent. Similar information was extracted from local reports. Findings were analysed with descriptive statistics.ResultsOverall, 913 patients (40 years±13, 492 men) were included. In 24%, the local MRI reports stated whether the MRI was overall indicative of SpA or not. Presence/absence of BME, erosions and fat lesions was mentioned in 88%, 48% and 29% of local reports, respectively. Inflammatory lesions were more often reported as present by local than central readers (46% vs 36%), and structural lesions less often (33% vs 50%).ConclusionThis study demonstrated a large gap between the clinical practice of reporting SIJ MRIs and recent reporting recommendations.

Abstract The autoimmune disease systemic lupus erythematosus (SLE) is associated with genetic variants in the X-linked gene CXORF21, which encodes the protein TASL. TASL acts as an adaptor in the IRF5 pathway and is necessary for the phosphorylation of IRF5 in response to TLR7 or TLR9 stimulation. Here, we investigate the role of TASL in the humoral immune response, and in the development of lupus in the B6.MRLlpr murine model of SLE. We find that while TASL is dispensable for their development, it is required for the full activation of B cells via endolysosomal TLR stimulation, and consequent interferon signalling and inflammatory cytokine expression. Additionally, TASL is crucial for the emergence of age-associated B cells (ABCs), a B cell population derived from the extrafollicular response that increases with age and is expanded in autoimmune disease, and the production of IgG2c antibodies. We also find that deletion of TASL prevents the onset of autoimmunity in the genetically-determined B6.MRLlpr model of lupus.

BackgroundTo investigate a patient-level single imputation approach for patient reported outcomes (PROs) that express similar contents or associated PROs, where a PRO whose value is missing at a particular timepoint is substituted by another PRO whose value is available at the same timepoint.MethodsWe performed a simulation study on registry-based spondyloarthritis data to explore the potential interchangeability between the patient pain (PPA) and fatigue (PFA) assessment scores and relevant Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) individual questions, and between PPA, PFA and patient global assessment (PGA). Performance was assessed per imputation method in terms of relative bias and coverage. Sample size, level of missingness and missing data pattern were included as parameters in the simulations.ResultsAll applied scenarios to interchange PPA with BASDAI question 2 (axial pain), BASDAI question 3 (peripheral joint pain/swelling) or their average failed. Interchangeability between PFA and BASDAI question 1 (fatigue/tiredness) was acceptable for partially (up to 50%) missing data. When interchanging patient assessment scores (PPA, PFA and PGA), we observed inconsistent results in terms of performance. The performance of the applied methods depended on the sample size and the level of missingness, but not heavily on the underlying missing data pattern.ConclusionsInterchanging PFA and the BASDAI fatigue question was justified for partially missing data, while interchangeability between PPA, PFA and PGA, and between PPA and the BASDAI pain questions was not advised. Our findings suggest that registering patient assessment scores and BASDAI questions is recommended.

IntroductionPlasma concentrations of cell-free DNA (cfDNA) serve as markers of overtraining or muscle injury. We examined whether nuclear (n) or mitochondrial (mt) cfDNA has potential as a marker of muscle burden or damage.Material and methodsTen healthy, physically active volunteers (6 females, aged 27.1 ±6.8 years) performed a downhill running test. Samples for cfnDNA and cell-free mitochondrial DNA (cfmtDNA) analysis were collected before, 30 min, 1 h, and 14 days after the downhill run. CfnDNA and cfmtDNA (two markers for each) were analyzed using qPCR.ResultsThere was an extreme (~40-fold) increase in cfnDNA at the 30-min time-point against the baseline (p < 0.00001 for both markers), followed by a quick drop to baseline levels after 1 h after the end of the downhill run for all subjects. In contrast, plasma levels of cfmtDNA did not increase significantly (p = 0.27 and 0.12). It reflects the fact that in 6 subjects, the pattern was similar as for cfnDNA, but in 4 subjects a decrease of cfmtDNA concentration was observed at the 30-min time-point. These differences correlate with age, body mass index, and sex of the participants. Plasma cfnDNA significantly (p < 0.01 for all) correlated with concentrations of muscle damage markers such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LD), and chemokines MIP-1α and IP-10 (positive). No homogeneous correlation between cfmtDNA and biomarkers was detected.ConclusionsOur study confirmed the extreme release and clearance of cfnDNA in physically active subjects after strenuous exercise. In contrast, the trajectory of cfmtDNA concentrations seems to have much higher inter-individual variability than cfnDNA concentrations.