Center for Rheumatology

Osteoporosis causes fractures which further increase the disease burden of rheumatoid arthritis (RA), however, osteoporosis treatment rates remain low. While several studies have reported that biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) can prevent or improve osteoporosis in RA, our large-scale, real-world study showed that 1 year-b/tsDMARDs use did not arrest osteoporosis progression. This study aimed to examine longer-term changes in bone mineral density (BMD). BMD was observed for up to 5 years in patients receiving b/tsDMARDs for active RA. The primary endpoint was change in BMD (T-score), and the secondary endpoint was change in T-score-related factors. In total, 797 patients (anti-osteoporosis (-), n = 645; anti-osteoporosis (+), n = 152) were included, with a median 3.1-year follow-up (2,489 patient-years). Clinical disease activity index (CDAI) improved in both groups (26.0/24.4 → 6.6/6.8). T-scores decreased significantly in the femoral neck and radius in the anti-osteoporosis (-) group but not in the anti-osteoporosis (+) group [anti-osteoporosis (-): mean change -0.11/-0.33, both p < 0.001; anti-osteoporosis (+):-0.01/-0.10, p = 0.830/0.071]. Overall, 460 patients (58%) experienced a decrease in T-score. A high baseline T-score correlated with a subsequent decrease, while longer osteoporosis treatment duration correlated with an increase. Unexpectedly, the duration of b/tsDMARD use and mean CDAI during observation were not associated with BMD maintenance. Even when RA activity was controlled with b/tsDMARDs, BMD still decreased. This study emphasizes the importance of considering osteoporosis as an independent aspect of RA, beyond inflammation control.

Rheumatoid arthritis (RA) and osteoarthritis (OA) are prevalent chronic joint diseases characterized by persistent inflammation, progressive cartilage degeneration, and impaired tissue repair mechanisms. While inflammatory pathways have been extensively studied, increasing attention has been directed toward the failure of inflammation resolution as a key contributor to chronic joint pathology. Specialized pro-resolving mediators (SPMs), including Maresin-1 (MaR1), play an active role in terminating inflammation and promoting tissue homeostasis. However, the relationship between MaR1 and cartilage-specific biomarkers such as Cartilage Oligomeric Matrix Protein (COMP) and Wnt1-inducible signaling pathway protein-1 (WISP-1) has not been sufficiently elucidated. This study investigated circulating MaR1 levels in RA and OA and examined their associations with serum COMP and WISP-1 as well as clinical inflammatory parameters. This cross-sectional, biomarker-based study included a total of 150 participants, comprising 50 patients with RA, 50 patients with OA, and 50 sex-matched healthy controls. Serum levels of MaR1, COMP, and WISP-1 were measured using enzyme-linked immunosorbent assay (ELISA). Demographic characteristics and inflammatory parameters, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and rheumatoid factor (RF), were recorded. Intergroup comparisons were performed using one-way analysis of variance (ANOVA) followed by appropriate post-hoc tests. Serum MaR1 levels were significantly reduced in both RA (44.1 ± 2.2 ng/L) and OA (42.2 ± 3.2 ng/L) compared with controls (78.5 ± 7.5 ng/L; p < 0.001). COMP levels were significantly lower in the RA group than in the OA and control groups (p < 0.05 and p < 0.001, respectively). Similarly, WISP-1 concentrations were decreased in both RA and OA compared with healthy controls (p < 0.05). The marked reduction in MaR1 levels in RA and OA is consistent with altered inflammation-resolution biology. Concurrent decreases in COMP and WISP-1 may reflect changes in cartilage remodeling dynamics. Overall, MaR1 appears to be a candidate biomarker associated with inflammation-resolution pathways in arthritic diseases.

Etrasimod is an oral selective sphingosine-1 phosphate receptor modulator, and its anti-inflammatory mechanism of action in inflammatory bowel diseases is not completely understood. It targets pro-inflammatory immune cells expressing sphingosine-1-phosphate receptors during their migration from the lymphatic system to the circulation and intestinal mucosa. Reductions in certain lymphocyte subsets in the peripheral blood have been reported, but its effects in lymph nodes remain unknown. This study investigated changes in leukocyte subpopulations in peripheral lymph nodes and blood in Crohn's disease patients treated with etrasimod. Moderate-to-severe Crohn's disease patients participated in this randomized, double-blind study, within the phase 2 CULTIVATE clinical trial. At baseline and after 14 weeks of etrasimod treatment, peripheral blood and inguinal lymph node biopsies were obtained. Isolated peripheral blood mononuclear cells and lymph node leukocyte populations were analyzed at single cell level using mass cytometry at both timepoints. The immunophenotyping revealed 15 innate and adaptive major immune cell populations, as well as 14 subpopulations of CD4+ and CD8+ T-cells. In peripheral lymph nodes, etrasimod resulted in significant accumulation of naïve, central memory, and effector memory CD4+ T-cells (+10.7%, +4.2%, and +2.3%, respectively; all p = 0.03), as well as naïve CD8+ T-cells (+4.2%; p = 0.03). Conversely, these subsets were reduced in peripheral blood (-6.2%, -6.0%, -2.0%, and -2.2%, respectively; all p = 0.03). Naïve and memory B-cells decreased in the circulation (-1.7%, p = 0.057; -0.6%, p = 0.03, respectively) but were unchanged in the lymph nodes. Innate immune cell populations remained mostly unaffected in both compartments. Our data indicate that etrasimod's pharmacodynamic effect is related primarily with the attenuation of the T-cell mediated inflammation with minor changes in B-cells. However, additional follow-up studies are needed for the validation of these observations in the context of Crohn's disease.

Childhood-onset Sjögren's disease is a rare and under-investigated rheumatic condition. The natural course of childhood-onset Sjögren's disease in adulthood in not known. This study aimed to evaluate long-term disease trajectories and complications of childhood-onset Sjögren's disease and explore management strategies. This combined retrospective and prospective analysis of a childhood-onset Sjögren's disease cohort with long-term follow-up into adulthood was done in individuals aged 13-36 years with childhood-onset Sjögren's disease recruited from a single tertiary adolescent and young adult rheumatology service at University College London Hospital, UK. Participants were either approached consecutively during routine clinical appointments, or their data were collected retrospectively from the time of diagnosis to the time of transition to the service, and prospectively thereafter. We mapped the cohort onto clinical phenotypes defined by the Florida Scoring System at disease onset and stratified them based on the Newcastle Sjögren's Stratification Tool at last assessment. Disease activity, symptom severity, and damage trajectories were assessed using European Alliance of Associations for Rheumatology (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI), EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), and Sjögren's Syndrome Disease Damage Index (SSDDI), respectively. People with related lived experience were involved in the study design and implementation. Between March 1, 2020, and June 30, 2024, we identified 30 children and young people diagnosed with childhood-onset Sjögren's disease based on expert opinion. Mean age at onset was 12·7 years (SD 3·3). 28 (93%) of 30 individuals were female and two (7%) were male. The most common disease manifestations at onset were fatigue (22 [73%] of 30 individuals), arthralgia (21 [70%]), dryness (17 [57%]), glandular swelling (15 [50%]), and skin rashes (ten [30%]). Diagnostic delay of more than 3 years from symptoms onset increased the prevalence of reported dryness (nine [100%] of nine vs eight [38%] of 21; p=0·0014). Children and young people with childhood-onset Sjögren's disease had two distinct disease activity and symptom trajectories (high ESSDAI: mean 3·9 [SD 2·2] vs low ESSDAI: mean 0·8 [1·1]; p<0·0001 and high ESSPRI: mean 5·6 [2·7] vs low ESSPRI: mean 3·1 [1·0]; p=0·036), which could not be predicted by sex or age at onset, symptom duration, or duration of follow-up. Damage accrual did not differ based on activity and symptom trajectory (p=0·080 and p=1·0, respectively). At last review, the median ESSDAI score was 2·0 (IQR 2·0-8·0) and the ESSPRI score was 5·3 (3·0-7·0). Four (13%) of 30 patients developed lymphoma and 17 (57%) accumulated damage (SSDDI score ≥1). This preliminary evaluation of long-term outcomes of childhood-onset Sjögren's disease in adulthood showed distinct patterns of disease and symptom trajectories and that a high proportion of children and young people develop damage in early adulthood. These findings highlight the need for improved research quality and evidence-based management strategies for better outcomes in this population. None.

Background: Sleep impairment is common in rheumatoid arthritis (RA) but has not been extensively studied with wearables and self-observation following treatment. This study investigates the impact of upadacitinib (UPA) on subjective (self-reported) and objective (actigraphy-based) sleep quality in RA patients. Methods: SLEERA is a sub-study of UPHOLD, an international observational cohort study (NCT04497597) that assessed sleep quality in RA patients after UPA treatment. Subjective sleep quality was measured using Pittsburgh Sleep Quality Index (PSQI) at baseline and post-treatment months 3, 6, 12 and 24. Objective sleep quality was assessed by actigraphy at baseline and post-treatment month 3. Results: Among 39 patients, 76% had impaired subjective sleep quality at baseline (total PSQI: 7.84). Actigraphy sleep efficiency was 85.1%, 85.6% and 82.1% in patients with good (PSQI ≤ 5), moderate (PSQI &gt; 5 and ≤ 8) and poor (PSQI &gt; 8) sleep quality. After 3 months of UPA treatment, the total PSQI significantly improved (-2.42, p &lt; 0.001), while actigraphy outcomes remained unchanged across the whole cohort. Of 19 patients with impaired sleep quality at baseline, 8 achieved good sleep quality, accompanied by improvements in actigraphy-based sleep efficiency (+ 1.5%), total wake time (-7.3 min) and movement index (-0.7%). Shifts from objectively impaired to good sleep efficiency were only observed in patients achieving remission or normative values of pain and fatigue. Conclusions: Sleep impairment in RA patients can improve with treatment. Actigraphy showed improvements, particularly in patients with high subjective sleep impairment who achieve remission. Trial registration: NCT04497597.

Background: Patients with inflammatory rheumatic diseases (IRD) are susceptible to influenza infections and their complications. However, they may avoid vaccination for fear of exacerbating their IRD. This study evaluates the 2023/24 influenza vaccine in IRD patients, aiming to provide recommendations for this group in the upcoming season. Methods: In this prospective, longitudinal study, we assessed the self-reported impact of influenza vaccination on patients with IRD. Participants were recruited nationwide between October and December 2023 and completed an online questionnaire after vaccination as well as at three and six months of follow-up. Results: Among 633 patients, 87.5% were female, with a median age of 50.4 (18-84) years. Post-vaccination, 50% experienced injection site pain; 41% reported no side effects. IRD flares occurred in 5%, with 1% requiring changes to immunomodulation. Among 428 patients with follow-up, influenza infections were reported in 38 patients (8.9%), including 10 (2.3%) with reinfections. No severe cases requiring hospitalization were reported. Spondyloarthritis patients had higher susceptibility to influenza (p = 0.002), accounting for 55.3% of infections. IRD flare-ups in the 12 months before vaccination predicted infections (p = 0.002). Conclusions: The 2023/24 vaccine was well tolerated by IRD patients, with no impact on the course of the disease in 95% of cases. Only 9% of patients reported influenza infections, none of which were severe. In light of these findings, physicians are advised to recommend vaccination to eligible IRD patients prior to or in the respective season.

The purpose of this review is to discuss antineutrophil cytoplasmic antibody (ANCA) vasculitis (microscopic polyangiitis and granulomatosis with polyangiitis) and how we have arrived at our current guidelines and treatment methods. The goal is to offer a greater understanding of major clinical trials in the field, and how they have enabled treatment options which have led to reduced morbidity and improved survival for patients. Our understanding and treatment of ANCA vasculitis has changed tremendously over the past 40 years, from a condition with a high mortality without significant treatment options, to a treatable condition. We have moved from the use of more toxic therapies such as Cyclophosphamide towards more common use of rituximab for both induction and maintenance regimens. More recently, the focus has been on attempting to reduce steroid burden and toxicity. The approval of avacopan (a C5a inhibitor) enables a more rapid steroid taper regimen along with usual induction therapy with rituximab or cyclophosphamide. Readers will have the chance to learn about new targets being evaluated for the treatment of ANCA vasculitis. ANCA Vasculitis is complex with varying presentations. Through collaboration among multiple specialists, including nephrologists, rheumatologists, pulmonologists, ENT specialists, and neurologists, we are able to achieve a diagnosis and offer organ and life-saving treatments for our patients.

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.