Tissue-specific dysregulation of S100A8 in synovium and cartilage reveals limitations of NSAID therapy in inflammatory arthritis.

Association between symptomatic knee osteoarthritis and health-related quality of life in individuals with type 2 diabetes: A cross-sectional study.

Whipple's disease (WD) is a rare systemic infection caused by Tropheryma whipplei, often misdiagnosed as seronegative rheumatoid arthritis (RA) due to overlapping clinical features. Delayed diagnosis may lead to multisystem complications, particularly in patients treated with immunosuppressive or biologic therapies. We describe two cases of WD initially misdiagnosed as refractory seronegative rheumatoid arthritis. Both patients were middle-aged men with persistently elevated inflammatory markers and poor responses to multiple biologic treatments. One developed constrictive pericarditis-the first reported to be successfully treated with anakinra-while the other presented with immune reconstitution inflammatory syndrome (IRIS)-related myositis, representing the first reported IRIS myositis in WD. A literature review of 215 cases of WD misdiagnosed as RA or RA-like arthritis (including the two current cases) revealed that 77% were male, and most were seronegative. Among 139 patients with serologic data, 13.6% were RF-positive; of 132 with ACPA results, only 3.7% were positive. Erosive disease was reported in 33%. The median diagnostic delay was 7years (range: 3-35years). Gastrointestinal and constitutional symptoms were the most frequent triggers for reevaluation. Non-invasive PCR testing (saliva, stool) has emerged as a sensitive and practical diagnostic approach, particularly in localized or rheumatology-predominant presentations. WD remains underrecognized in rheumatology practice. Early consideration in patients with refractory seronegative arthritis-especially middle-aged men with persistent inflammation-may prevent unnecessary immunosuppression and life-threatening complications. Based on accumulated evidence, we propose a pragmatic, tiered diagnostic algorithm to guide screening and confirmation of WD in rheumatologic settings, emphasizing the integration of noninvasive PCR-based testing to improve diagnostic yield and reduce delays. Key Points • Whipple's disease should be considered in inflammatory arthritis that is refractory to treatment and often seronegative with elevated CRP despite multiple immunosuppressive therapies. • Structured screening strategies may be warranted in rheumatology settings for patients meeting "high-risk criteria". Further studies are needed to assess the utility and cost-effectiveness of such approaches. • Saliva and stool PCR testing demonstrate high negative predictive value in the literature and are proposed as suitable non-invasive tools for initial screening. • Immune reconstitution inflammatory syndrome (IRIS) is a potentially serious complication following antimicrobial therapy for Whipple's disease, especially in patients previously treated with immunosuppressive agents. Early recognition is critical for appropriate management.

Rheumatoid arthritis can affect extra-articular organs such as the liver, and the problem of drug-induced liver injury caused by traditional antirheumatic drugs for improving the condition cannot be ignored. This study aims to investigate the therapeutic effects of resveratrol (Res) on hepatic inflammation and oxidative stress in mice with collagen-induced arthritis (CIA) and to elucidate the relationship between the regulatory mechanisms of the nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) signaling pathway. In this study, we used chicken type II collagen in combination with complete Freund's adjuvant to induce arthritis in a mouse model, and Res was administered by tube feeding to detect the serum biochemical liver function and inflammation levels, oxidative stress, and apoptosis in the livers of mice. An in vitro cellular model of liver inflammation and oxidative stress was established by treating mouse primary hepatocytes (MPHs) with tumor necrosis factor-α (TNF-α) and H2O2. The intrinsic mechanism of Res in attenuating hepatic inflammation and oxidative stress in CIA mice was explored by treating MPHs with an Nrf2 inhibitor and Keap1 overexpression plasmid. Res significantly reduced the levels of inflammation and oxidative stress in liver tissues of CIA mice as well as in MPHs treated with TNF-α and H2O2 and activated the Nrf2/Keap1 signaling pathway. Inflammation and oxidative stress levels in MPHs were exacerbated by the use of Nrf2 inhibitors and Keap1 overexpression, which promoted apoptosis. This study demonstrated the intrinsic mechanism of Res of attenuating hepatic inflammation and oxidative stress in CIA mice through the Nrf2/Keap1 pathway, which provides a new idea for finding hepatoprotective treatments for rheumatoid arthritis.

Inhibition of joint inflammation in rheumatoid arthritis by Wuwei Ganlu Medicinal Bath Granules via blocking toll-like receptor 4/nuclear factor-kappa B and NOD-like Receptor Pyrin Domain-Containing 3 signaling.

Healthcare professionals’ perspectives on digital biomarkers for monitoring inflammatory arthritis: insights from a qualitative study rooted in design thinking

Calcium Pyrophosphate Dihydrate (CPPD) deposition disease, also known as pseudogout, is a crystal-induced arthropathy that primarily affects larger, weight-bearing joints such as the knees, hips, and shoulders. CPPD can present with a wide spectrum of clinical manifestations, ranging from asymptomatic chondrocalcinosis to acute inflammatory arthritis. CPPD in the spine is rare and can lead to calcification of the ligamentum flavum, potentially causing spinal cord compression, myelopathy, and significant neurological impairment. The absence of chondrocalcinosis on imaging does not rule out the diagnosis of spinal CPPD. On microscopy, CPPD is characterised by rhomboid-shaped, positively birefringent crystals, in contrast to the needle-shaped, negatively birefringent crystals observed in gout. The present case report of a 78-year-old female highlights a rare and isolated clinical presentation of CPPD causing lumbar spine myelopathy, which was discovered incidentally on histopathology after spinal decompression and discectomy surgery. Although imaging modalities may raise suspicion for CPPD by revealing chondrocalcinosis, they often lack the specificity to differentiate it from other degenerative or inflammatory conditions. Histopathological analysis and polarised microscopic examination remain the cornerstones in diagnosing CPPD, even in atypical clinical presentations or ambiguous imaging findings. This underscores the importance of including pseudogout in the differential diagnosis of lumbar myelopathy, particularly in elderly patients, to provide early, targeted treatment and prevent severe irreversible neurological deficits.

<p><strong>Background: </strong>Felty's syndrome is a rare condition affecting 1–3% of patients with rheumatoid arthritis. It typically arises after a prolonged course of RA. Although rheumatic fever and RA may share overlapping features, they are distinct entities; their co-occurrence in a patient is rare and considered coincidental.</p> <p><strong>Case presentation:</strong> A 27-year-old woman with childhood rheumatic fever and mitral stenosis presented with low-grade fever and inflammatory arthritis. Three years earlier, she had developed pancytopenia and hepatosplenomegaly, and she was recently diagnosed with seropositive rheumatoid arthritis. Her earlier cytopenias and organomegaly were retrospectively attributed to Felty’s syndrome, likely preceding RA onset. Treatment with corticosteroids and hydroxychloroquine led to significant improvement, and methotrexate was added for maintenance and relapse prevention.</p> <p><strong>Conclusion:</strong> Careful medical history and clinical examination, as well as thorough other investigations, should be performed to exclude other causes of neutropenia.</p> <p> </p>

Background and Objectives: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis characterized by marked clinical heterogeneity and variable disease trajectories, underscoring the need for robust biomarkers of inflammatory burden. Serum calprotectin, a neutrophil- and monocyte-derived protein, has been proposed as a surrogate marker of active inflammation in inflammatory arthritis due to its close association with innate immune activation. In this study, we compare serum calprotectin levels among patients with PsA, axial spondyloarthritis (AxSpA), and healthy controls and evaluate their association with disease activity. Materials and Methods: This single-center, cross-sectional study included 123 patients with PsA, 119 patients with AxSpA, and 77 healthy controls. Serum calprotectin levels were measured by enzyme-linked immunosorbent assay, and their associations with disease activity were evaluated using correlation, multivariable regression, and receiver operating characteristic analyses. Results: Serum calprotectin levels were significantly higher in PsA and AxSpA patients compared with healthy controls (p < 0.001 for both) and were higher in PsA than in AxSpA (p = 0.022). In PsA, serum calprotectin levels showed significant correlations with ASDAS-CRP, DAS28-CRP, and DLQI, but not with CRP or ESR. In contrast, in AxSpA, calprotectin showed only a weak association with CRP and was not related to disease activity indices. In multivariable analysis, serum calprotectin was independently associated with ASDAS-CRP in PsA (B = 0.704, p = 0.003), but not in AxSpA. Receiver operating characteristic analysis demonstrated that serum calprotectin discriminated high disease activity in PsA with an area under the curve of 0.669 (95% CI: 0.563-0.775; p = 0.003). Conclusions: Serum calprotectin levels are elevated in patients with PsA and are associated with disease activity, supporting its potential role as a biomarker in this condition. In contrast, serum calprotectin does not appear to reflect disease activity in AxSpA, suggesting disease-specific differences in its clinical utility.

Air pollution (AP), intensified by industrialization and urbanization, is a key environmental factor linked to rheumatoid arthritis (RA). However, its molecular and immunological impact on RA remains unclear. This study integrates epidemiological data, bioinformatics, single-cell transcriptomics, and animal models to investigate how AP contributes to the development of RA. Global epidemiological analysis shows rising RA prevalence in over 95% of countries. Mendelian randomization analysis indicated a positive correlation between PM10 exposure and the risk of RA. Machine learning identifies Formin Binding Protein 1 (FNBP1) as a key air pollution-related gene (APRG), with decreasing expression in RA patients and strong correlation with disease activity. PM10 exposure may impair natural killer (NK) cell differentiation and cytotoxicity by suppressing FNBP1 expression, ultimately weakening immune surveillance and exacerbating inflammatory responses. Furthermore, by integrating single-cell sequencing, animal models, and human-derived cell experiments, we demonstrated that PM10 exposure aggravates inflammation and joint damage in a collagen-induced arthritis (CIA) model. Mechanistically, PM10 likely impairs the cytotoxic function of CD56dim NK cells through the modulation of FNBP1. Taken together, our research results have unveiled a completely novel mechanistic hypothesis regarding the onset and development of RA, the "PM10-FNBP1-NK cells" axis.

Anatomic Shoulder Replacement has Superior Functional Outcomes with Equivalent Survivorship Compared with Reverse Shoulder Replacement in Patients with Inflammatory Arthritis - New Zealand Registry Results.

Background Gout is an acute inflammatory arthritis triggered by monosodium urate (MSU) crystal deposition and activation of innate immune responses. In addition to inflammasome signaling, emerging evidence suggests that metabolic reprogramming of arachidonic acid (AA) pathways amplifies inflammatory responses during gout flares. However, the contribution of upstream fatty acid desaturation processes that regulate endogenous AA availability remains poorly defined. 1,2,3,4,6-Penta-O-galloyl-β-D-glucose (PGG) is a naturally occurring polyphenol with reported anti-inflammatory activity, but its effects on MSU-induced fatty acid metabolism and gouty inflammation have not been well established. Methods Publicly available bulk and single-cell transcriptomic datasets from human and mouse gout studies were analyzed to assess dysregulation of AA-associated pathways. MSU-induced inflammatory responses were examined in mouse bone marrow-derived macrophages and in a murine MSU-induced gout model. Macrophages were treated with PGG prior to MSU stimulation, and inflammatory cytokine production, phagocytosis, and expression of fatty acid desaturases were assessed. Lipidomic analysis of macrophages and plasma was performed using gas chromatography-mass spectrometry (GC-MS) to quantify arachidonic acid and related fatty acids. In vivo disease severity, cytokine expression, and anti-inflammatory markers were evaluated following PGG treatment. Results Analysis of public datasets revealed consistent dysregulation of arachidonic acid-associated inflammatory pathways during gout flares. In macrophages, MSU stimulation increased expression of fatty acid desaturases FADS1 and FADS2 and promoted accumulation of arachidonic acid, concomitant with robust production of pro-inflammatory cytokines. PGG treatment significantly suppressed MSU-induced FADS1, FADS2 and arachidonic acid levels, and attenuated pro-inflammatory cytokine production. PGG also markedly impaired macrophage phagocytosis of MSU crystals. In vivo, PGG treatment significantly reduced clinical disease severity in an MSU-induced gout model, suppressed fatty acid desaturation and arachidonic acid accumulation in plasma, decreased pro-inflammatory cytokine expression, and enhanced anti-inflammatory markers. Conclusion These findings identify fatty acid desaturation as an important metabolic contributor to gouty inflammation and demonstrate that PGG suppresses MSU-induced inflammation by limiting endogenous arachidonic acid availability, reducing inflammatory amplification, and impairing MSU crystal phagocytosis. Targeting upstream fatty acid metabolism represents a potential therapeutic strategy for modulating acute gout flares beyond conventional anti-inflammatory approaches.

"Rice body" describes the gross appearance of hyperplastic synovial villi that develop into rice-like fibrinous loose bodies. Rice bodies have historically been associated with tuberculosis and inflammatory arthritis, but no retrospective studies have correlated their magnetic resonance imaging (MRI) appearances to histology or to the underlying diagnoses. We sought to correlate the appearance on MRI of rice body-like particles with histology and describe the associated diagnoses. We conducted a retrospective cross-sectional study of MRI reports in our institutional imaging database in which a radiologist described "rice bodies." The search was performed by a keyword search for "rice," ultimately yielding a total of 100 patients between June 1992 and July 2022. Patients were excluded if their MRI was not available for retrospective review or if there was insufficient follow-up to establish a clear underlying diagnosis. Cases were included if the MRI finding of rice bodies was confirmed by retrospective review of the images and there was clinical follow-up or surgery with histology establishing the underlying diagnosis. Of the 52 patients who met inclusion criteria and were enrolled in our retrospective study, 37% (19/52) had prior surgery, 73% (14/19) being arthroplasty. Diagnoses associated with rice body-like particles on MRI were inflammatory arthritis (52%; 27/52), infection (25%; 13/52), synovial chondromatosis (8%; 4/52), osteoarthritis (6%; 3/52), bursitis (6%; 3/52), and adverse local tissue reaction (4%; 2/52). Among 13 infections, only 1 was mycobacterial while 46% (6/13) were staphylococcal and 31% (4/13) were culture-negative. In the presence of arthroplasty, rice body-like particles were associated with infection in 71% (10/14), followed by adverse local tissue reaction (14%; 2/14), 46% (24/52) underwent surgery after MRI, and 45% (10/22) had rice bodies confirmed on histology. Our retrospective findings suggest that rice body-like synovial particles on MRI are not specific to tuberculosis and inflammatory arthritis. Other diagnoses may also be considered, particularly nonmycobacterial infection when there is an arthroplasty. Level IV: retrospective cross-sectional study.

In clinically suspect arthralgia(CSA) ultrasound(US) can be used to detect subclinical joint-inflammation, which is a known predictor for progression to clinically apparent inflammatory arthritis(IA). Most US-protocols include both hands, while a more efficient, unilateral US approach is also sufficient, has never been investigated. Therefore, we described US-findings for one and both hands in CSA-patients and investigated if a US-protocol that includes one hand is as predictive as a protocol with two hands. CSA-patients of two cohorts underwent bilateral US. Subclinical synovitis and tenosynovitis (Gray Scale ≥2 and/or Power Doppler ≥1) in one and both hands were described per hand and joint. Additionally, we analyzed the association between inflammatory arthritis (IA)-development and US-positivity. In total, 320 patients were studied. In cohort 1, 23% patients had bilateral US-detected subclinical (teno)synovitis, 20% only in the dominant hand and 10% only in non-dominant hand. In cohort 2, 10% had bilateral involvement, 12% in the dominant hand only and 8% in the nondominant hand only. US of the dominant hand predicted IA-development almost equal compared to US of both hands, with hazard ratios of 2.8(95%CI 1.3-6.0) for both hands and 2.6(95%CI 1.3-5.3) for the dominant hand in cohort 1. In cohort 2, HRs were comparable. US-detected subclinical (teno)synovitis in CSA-patients is partly bilateral and partly unilateral. Predictive values for IA-development are comparable. To reduce scanning time in clinical practice one could consider scanning the one hand instead of both hands in patients with CSA.

As part of a research program examining rheumatology referrals in British Columbia, the Patient SAID study evaluated the 'SAID tool', which contains validated patient-completed questionnaires for identifying and prioritizing individuals with inflammatory arthritis, supporting its utility and feasibility. This article reports the perspectives of participating patients and rheumatologists regarding the SAID tool. A multi-methods design was used to collect and analyze patient survey and rheumatologist interview data, with an emphasis on implementation relevance. Ninety-two patients who completed the questionnaires in the SAID study also provided feedback on their experience. Semi-structured interviews were conducted with three rheumatologists. Quantitative and qualitative data were analyzed using Excel and NVivo to identify usability, relevance, and barriers or enablers to implementing the tool in primary-to-specialist referral. Most patients (85%) found the SAID tool easy to log into and complete (78%). Across diagnostic groups, most (76%) believed it could help their GP assess symptoms, but emphasized the need for more nuanced response options and space for elaboration. Rheumatologists viewed the tool as brief, useful, and potentially valuable for triage, especially if integrated at the referral stage. Key barriers included time constraints, false negatives, and lack of integration with electronic medical records. All supported optional implementation led by motivated patients, provided it complemented, not complicated, existing workflows. With targeted modifications and appropriate implementation mechanisms, the SAID tool has the potential to improve the quality of referrals, support triage decision-making, and address current gaps in access to rheumatology care within evolving digital health systems.

There is no consensus on the ideal surgical intervention for trapeziometacarpal joint arthritis. Although trapeziectomy has been the preferred procedure for several decades, trapeziometacarpal joint replacement has been gaining favour over several years owing to improvements in implant design. Dual mobility implants have been introduced to reduce the risk of dislocation associated with earlier single mobility versions. The aim of this study was to report the medium-term clinical outcomes of trapeziometacarpal joint replacement using the MAÏA® dual mobility implant, from a single tertiary referral centre. This study included 106 patients with trapeziometacarpal joint osteoarthritis who received MAÏA® dual mobility implants between 2017 and 2023. Patients were selected based on clinical and radiological criteria, with exclusions for inflammatory arthritis and STT joint involvement. Outcomes were assessed pre- and postoperatively using validated clinical scores, grip strength and radiographs at set intervals. Patients were followed for an average of 53 months (IQR 20 to 58 months). The Brief Michigan score improved from 42 to 83, the pain score improved from 7 to 1, pinch strength improved from 2 to 4 kg and power grip improved from 14 to 22 kg. Two cups were revised owing to symptomatic loosening, while an additional two cups exhibited loosening but were not revised as both patients were asymptomatic. There were two intraoperative trapezium fractures. Survivorship of implants with maximum final follow-up of 6 years was 97% (IQR 20 to 58 months). The MAÏA® dual mobility implant shows good improvement in pain, strength, mobility, and patient reported outcomes over the medium term, with no dislocations. Therapeutic IV.

The mucosal origins hypothesis of rheumatoid arthritis (RA) posits that inhalant exposures, such as cigarette smoke and crystalline silica (c-silica), trigger immune responses in the lungs that contribute to joint disease onset. However, the relationship between inhalants, lung inflammation, and inflammatory arthritis remains poorly understood. This study compared the development of inflammatory arthritis in two genetically susceptible mouse strains, the BXD2/TyJ (BXD2) and chimeric HLA-DR4-IE transgenic (DR4-Tg), following delivery of c-silica to the lungs via oropharyngeal aspiration. In BXD2 mice, c-silica exposure was associated with rapid arthritis development, marked by synovial cell hyperplasia, pannus formation, and severe erosion of cartilage and bone. These features were preceded by pulmonary inflammation characterized by lymphoid-like cell clusters lining vessels and bronchi which cell-specific immunofluorescent microscopy identified as organized lymphoid structures consistent with inducible bronchus-associated lymphoid tissue (iBALT). Inflammatory arthritis was also preceded by autoantibodies associated with RA and other systemic autoimmune diseases including anti-citrullinated protein autoantibodies (ACPA) and rheumatoid factor (RF) in bronchoalveolar lavage fluid (BALF). However, the most predominant autoantibodies in BALF were against extractable nuclear antigens (ENA). Anti-ENA were also prominent in serum and microarray autoantigen analysis confirmed the response as targeting components of Sm and RNP small nuclear ribonucleoproteins (snRNPs). In contrast, DR4-Tg mice had no signs of arthritis, milder lung inflammation lacking iBALT, and negligible autoantibody responses. Genetic predisposition beyond HLA-DR4 alone is required for the immunological manifestations that lead to c-silica mediated inflammatory arthritis. These findings provide novel insights into the relationship between mucosal exposure and RA pathogenesis.

Background: The body maintains homeostasis by inflammation, and arthritis is related to autoimmunity or inflammation. Angiogenesis contributes to synovitis through angiogenic factors and proteolytic enzymes, while different inflammatory arthritis conditions, such as osteoarthritis and rheumatoid arthritis, share similar cytokine networks and immune cell populations. Notably, progressive joint damage can occur despite effective systemic immunosuppression, suggesting that local stromal-immune interactions within the joint microenvironment may sustain inflammation and tissue destruction. Methods: We conducted an exploratory single-cell RNA-sequencing analysis using publicly available datasets from the NCBI GEO database, including synovial tissue and synovial fluid samples. Cell-cell communication and transcriptional regulatory networks were inferred using CellChat and SCENIC. Results: Computational analyses suggested that, in RA, macrophage-associated signaling shifts from TNF-related pathways toward SPP1-associated patterns, coinciding with transcriptional features of MMP3+ fibroblast-like synoviocytes (FLS). FLS-FLS interactions were associated with FGF-related signaling across disease contexts. ANGPTL-related signaling patterns differed among arthritis subtypes, with ANGPTL4 more prominent in OA and PsA and ANGPTL2 more frequently in RA-related transcriptional programs. Conclusions: These findings provide an exploratory framework for stromal-immune interactions and ANGPTL-associated signaling across inflammatory arthritis. The therapies for PsA may focus on systemic immune modulation and preservation of joint structural integrity. For OA and RA, the highlight may target ANGPTL4 and ANGPTL2 in the early and late stages of disease progression. Given the reliance on computational inference, the results warrant further experimental validation.

Rheumatoid Arthritis (RA), a systemic autoimmune disorder of unknown etiology, disproportionately affects females at a 3:1 ratio compared to males. While biological sex differences in the immune system exist, sex-related differences in inflammatory and immune mediators of RA disease severity are undefined. Our objective was to characterize sex-related differences in immune responses in a murine collagen-induced arthritis (CIA) model and in human RA patients. In CIA compared to saline control mice, inflammatory disease severity was assessed using standardized clinical scores. Anti-collagen antibodies, neutrophil elastase, calprotectin/ S100A8/A9 heterodimer, CRAMP, MMP3, and MMP9 were quantified by ELISA in the sera and joint tissues. Cytokine/chemokine levels in sera and joints were assessed using a Luminex based-44-Plex Discovery Assay® Array. Immunophenotyping of mouse splenic T cells analysis was performed by flow cytometry. Proteomic profiling of serum samples from an established RA cohort (72 female and 19 male that were at least 84% ACPA+) was performed using an aptamer-based SomaScan platform. We identified distinct sex-related differences in disease severity and pro-inflammatory profiles in the sera and joint tissues of CIA mice, with inflammatory responses that were male-skewed in the sera and female-skewed in the joints. Furthermore, we demonstrated heightened neutrophil activation markers and CD4+ T cell-mediated inflammatory responses in female CIA mice. Similar sex-related differences in neutrophil activation and leucocyte migration were identified in RA patients. Our study demonstrates novel sex differences in pro-inflammatory mediators and activities of neutrophils and CD4+ T cells associated with disease severity in CIA mice, and in human RA patients. These findings provide new insights into sex-related differences in immunological pathways associated with inflammatory arthritis, which may contribute to the sex disparity in RA pathogenesis.

Post hoc analyses of clinical trials have characterized dupilumab's adverse effects, yet the real-world impact in chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma is not well described. This study aims to characterize the risks of lymphoma, cardiovascular events, eosinophilia, joint pain, inflammatory arthritis, and sleep apnea in dupilumab-treated CRSwNP and/or asthma patients compared to those not taking dupilumab, and to other biologics. This retrospective cohort study used TriNetX, a de-identified database containing over 100 million patient records. Demographics and adverse effects associated with immunotherapy use were collected. We identified 21,249 dupilumab-treated CRSwNP and/or asthma patients. After matching for demographics, comorbid conditions, and medication use, dupilumab was associated with a lower risk of acute myocardial infarction (RR 0.538, 95% CI 0.435-0.665), pulmonary embolism (RR 0.639, 95% CI 0.500-0.817), cerebral infarction (RR 0.716, 95% CI 0.580-0.884), venous thrombosis (RR 0.625, 95% CI 0.511-0.763), cardiovascular disease (RR 0.733, 95% CI 0.678-0.791), and sleep apnea (RR 0.891, 95% CI 0.818-0.970), with a higher risk of eosinophilia (RR 3.157, 95% CI 2.606-3.826), versus no biologic. Dupilumab was associated with a similar risk of lymphoma and musculoskeletal outcomes. Compared to omalizumab and mepolizumab, dupilumab showed a more favorable musculoskeletal and cardiovascular profile, while it demonstrated a largely similar profile to tezepelumab. Despite eosinophilia, dupilumab was associated with decreased risk of major cardiovascular, thromboembolic, and sleep apnea outcomes in CRSwNP and asthma. These findings suggest dupilumab may confer protection against adverse outcomes beyond respiratory symptom control.