Spondyloarthritis (SpA) represents a heterogeneous group of chronic inflammatory rheumatologic diseases, including axial spondyloarthritis (axSpA), psoriatic arthritis (PsA), and SpA associated with inflammatory bowel disease (IBD). These conditions share overlapping clinical manifestations, genetic predisposition-particularly a strong association with HLA-B27-and common immunopathogenic pathways, notably the IL-23/IL-17 axis and tumor necrosis factor (TNF) signaling. Understanding SpA pathophysiology has been greatly facilitated by animal models, which have provided critical mechanistic insights and served as indispensable tools for preclinical drug testing. Among these, rodent models have been particularly informative. However, despite their contributions, no single model reproduces the full clinical spectrum of SpA, which includes axial inflammation, enthesitis, peripheral arthritis, and extra-articular manifestations such as uveitis, psoriasis, and gut involvement. This review provides a comprehensive analysis of rodent SpA models, focusing on their mechanistic underpinnings, key discoveries, and translational relevance. We first summarize the major categories of models before examining the strengths and limitations of each. We highlight how these models have advanced our understanding of the gut-joint axis, IL-23-driven entheseal inflammation, and TNF-dependent pathways, which are now major therapeutic targets. Finally, we discuss emerging strategies to enhance translational fidelity, including humanized mice, microbiome engineering, and integration of multi-omic approaches. These developments are essential to bridge the current gap between experimental findings and clinical applications in SpA.

Musculoskeletal manifestations, particularly spondyloarthritis (SpA), represent the most frequent extraintestinal manifestations of inflammatory bowel disease (IBD). The coexistence of intestinal and articular inflammation poses diagnostic and therapeutic challenges requiring coordinated multidisciplinary care. Axial SpA occurs in 6-62% of IBD patients, while peripheral arthritis affects up to one third of patients. The temporal relationship between intestinal and joint disease is variable, and musculoskeletal symptoms may often precede IBD diagnosis. Shared pathogenic mechanisms include genetic susceptibility, dysregulated immune pathways, intestinal barrier dysfunction and aberrant lymphocyte trafficking between gut and synovium. Diagnostic delay remains substantial and serologic biomarkers have limitations. Therapeutic algorithms must consider both intestinal and articular disease activity, with newer biologics and targeted therapies requiring careful selection due to differential efficacy across disease domains. Multidisciplinary care models improve diagnostic accuracy, clinical outcomes, and patient satisfaction. This narrative review summarizes and integrates current evidence on epidemiology, pathophysiology, clinical features, diagnostic strategies and management of IBD-associated axial and peripheral SpA.

Cardiovascular risk assessment and management in the paediatric population is a relatively uncharted territory. However, atherogenesis starts during childhood, making childhood and adolescence an important window of opportunity to prevent atherosclerotic cardiovascular disease (ASCVD) later in life. An emerging group at risk for early ASCVD are children with chronic conditions. This paper describes the rationale, design and methods for the Secondary Manifestations of ARTerial diseases in the Young with a chronic condition (SMART-Youth) study. This study aims to identify disease-associated and lifestyle-associated cardiovascular risk factors for preclinical atherosclerosis in children with a chronic condition. The results of this study may fuel development of tailored cardiovascular risk assessment and management strategies in children at-risk.

Tissue repair and regeneration are highly coordinated multicellular processes that rely on the active resolution of inflammation rather than merely its passive cessation. Reciprocal orchestration among stromal, innate, and adaptive immune systems is key to maintaining or restoring tissue homeostasis from pathological perturbations. Macrophages serve as a central nexus of these responses, exhibiting dynamic functional plasticity that extends beyond dichotomous M1/M2 classification. This review explores the evolving, context-dependent roles of macrophages in restoring tissue homeostasis, with a particular focus on efferocytosis and subsequent metabolic rewiring as key drivers of inflammation resolution. Furthermore, we highlight the bi-directional crosstalk between macrophages and heterogeneous fibroblast populations. While these stromal-myeloid interactions are essential for transient matrix remodeling and physiological healing, their sustained activation under inflammatory conditions drives maladaptive repair and fibrotic remodeling. We discuss how the defects and dysregulation of these cellular circuits contribute to the pathogenesis of autoimmune disorders, as exemplified by recent findings in rheumatoid arthritis (RA), systemic sclerosis (SSc), and inflammatory bowel disease (IBD). Finally, we evaluate emerging "resolution therapies" that aim to harness endogenous tissue-reparative programs of macrophages therapeutically to treat autoimmune diseases, including the application of specialized pro-resolving mediators (SPMs) and macrophage reprogramming strategies.

Background/Objectives: Children with juvenile idiopathic arthritis (JIA) frequently develop additional autoimmune conditions during follow-up, yet the clinical and diagnostic profile of this comorbid subgroup is incompletely characterised in single-centre paediatric series. We aimed to describe the prevalence, clinical pattern, and diagnostic features of autoimmune comorbidities in a seven-year cohort of children with JIA monitored at a single tertiary paediatric centre, and to document the diagnostic protocols applied for each comorbidity. Methods: We conducted a retrospective descriptive observational study of 103 consecutive children with JIA classified according to the ILAR 2001 criteria and monitored at the Paediatric Rheumatology Unit of St. Mary Children's Emergency Hospital, Iași, Romania, between 2017 and 2023, with the year 2020 excluded by design owing to the institutional reorganisation during the early COVID-19 pandemic. Autoimmune comorbidities were ascertained from medical records using ICD-10 coding and confirmed by subspecialty evaluation. The diagnostic approach for each comorbidity is reported in detail. Continuous variables are described using mean ± standard deviation, and categorical variables as frequencies (%). No inferential analysis was performed on predictor variables; the study is exploratory and hypothesis-generating. Results: Autoimmune comorbidity was identified in 21 of 103 children (20.4%; 95% confidence interval [CI] 13.1-29.5%), the JIA-AID subgroup. Patients were predominantly female (17 of 21, 81.0%) and aged over 12 years (10 of 21, 47.6%). Autoimmune thyroiditis was the most frequent comorbidity, present in 10 of 21 cases (47.6%) when the euthyroid, hypothyroid, and vitiligo-associated forms were combined, followed by inflammatory bowel disease (4 of 21, 19.0%), alopecia areata (4 of 21, 19.0%), localised scleroderma (2 of 21, 9.5%), and coeliac disease (1 of 21, 4.8%). Three patients (14.3%) had polyautoimmunity, defined as two or more autoimmune diagnoses in addition to JIA. The HLA-B27-positive enthesitis-related arthritis subtype, although small in absolute numbers, was over-represented within the JIA-AID subgroup: 5 of 7 HLA-B27-positive ERA patients (71.4%; 95% CI 29.0-96.3%) carried a coexisting autoimmune diagnosis, compared with 16 of 96 patients in the remainder of the cohort (16.7%; 95% CI 9.8-25.6%); the predominant comorbidity in this subtype was inflammatory bowel disease. Conclusions: Autoimmune comorbidity affected approximately one in five children with JIA in this single-centre cohort, with autoimmune thyroiditis and inflammatory bowel disease as the most frequent associations and a notable concentration of comorbidity within the HLA-B27-positive enthesitis-related arthritis subtype. These descriptive observations are hypothesis-generating and support the case for proactive multidisciplinary screening in selected subgroups. Prospective registry-based studies with explicit exposure classification and standardised functional outcomes will be needed to confirm the patterns reported here.

Systemic treatments for moderate-to-severe plaque psoriasis have been advanced from broad immunosuppressants up to agents more selectively targeting cytokines, cytokine receptors, or intracellular signaling. The current systemic treatments mainly consist of conventional systemic agents, biologics targeting tumor necrosis factor (TNF)-α, interleukin (IL)-12/23p40, IL-17, or IL-23p19, and targeted oral agents. This review summarizes current evidence on efficacy, long-term disease control, safety, head-to-head comparisons, and practical selection of systemic treatments for adults with moderate-to-severe plaque psoriasis. Older conventional systemic agents, such as cyclosporin, acitretin, or methotrexate, remain useful in selected settings, especially when treatment options are limited by cost or availability, when short-term disease control is needed, or when the patient prefers these treatments. However, these conventional agents require careful monitoring and generally achieve lower rates of complete skin clearance compared to high-efficacy biologics. Biologics targeting TNF-α or anti-IL-12/23p40 ustekinumab have established the biologic treatment era, and remain clinically relevant, especially for patients having psoriatic arthritis or prioritizing long-term safety. Biologics targeting IL-17 can provide rapid and complete or almost complete skin clearance; however, require attention to mucocutaneous candidiasis and inflammatory bowel diseases. Biologics targeting IL-23p19 offer durable treatment responses and longer dosing intervals. Targeted oral therapies increase options for patients who prefer non-injectable treatment; established or emerging agents include apremilast, deucravacitinib, icotrokinra, zasocitinib, envudeucitinib, and orismilast. Emerging IL-17-directed agents, including sonelokimab and izokibep, may further refine pathway targeting. Selection of treatment should be decided dependently on the completeness of skin clearance achieved, speed and duration of responses, effectiveness on high-impact sites, safety, route of administration, monitoring requirements, patients' comorbidities, and the treatment goals aimed.

Patients with chronic inflammatory disorders, including inflammatory bowel disease (IBD), carry an increased risk of cardiovascular disease. The 2022 ORAL Surveillance study reported that the pan-selective Janus kinase inhibitor (JAKi) tofacitinib was associated with increased risk of major adverse cardiovascular events (MACE) among patients with rheumatoid arthritis compared to anti-tumor necrosis factor (anti-TNF) therapy. This prompted guideline changes regarding the use of all JAKis, including upadacitinib, a JAK1-selective drug approved for use in chronic inflammatory conditions, including IBD. However, the mechanism underlying JAKi-related MACE outcomes and the significance of JAK selectivity relative to TNF inhibition remain unclear. Microvascular dysfunction (MVD) is a predictor of MACE. Flow-mediated dilation (FMD) is a measure of MVD. Using an established ex vivo model of resistance arterioles isolated from adipose tissue, we performed the first mechanistic comparison of anti-tumor necrosis factor (anti-TNF; infliximab), pan-JAK inhibitor (tofacitinib), and JAK1-selective (upadacitinib) therapies on human microvascular endothelial function. Arterioles were obtained from low-cardiovascular-risk subjects of both sexes. Isolated microvessels were incubated with drugs of interest. Flow-mediated dilation (FMD), an assessment of MVD, was measured before and after nitric oxide (NO) synthase inhibition or hydrogen peroxide (H2O2) scavenging. No therapy statistically altered FMD magnitude, yet underlying mechanisms differed. Control and infliximab-treated vessels maintained physiologic NO-mediated dilation. Tofacitinib induced a shift toward pathologic H2O2-mediated dilation. Upadacitinib impaired NO-dependent dilation without evidence of compensatory H2O2 signaling. In summary, anti-TNF therapy and selective versus non-selective JAKi differentially modulate endothelial mechanisms of vasodilation, suggesting unique microvascular phenotypes with potential implications for cardiovascular risk.

To perform cross-disease immunological comparison across the broader spondyloarthritis (SpA) spectrum and examine their association with disease activity. We analyzed 111 patients with active broader SpA spectrum (ankylosing spondylitis, inflammatory bowel disease-associated SpA, psoriatic arthritis, pustulotic arthro-osteitis, and chronic non-bacterial osteitis) and 24 age- and sex-matched healthy controls (HC). Serum IL-17A, IL-17F, TNFα, and Oncostatin M levels were higher in the broader SpA spectrum than in HC. These cytokines levels did not differ among the broader SpA spectrum. Activated Th17, activated Th1-17, classical and intermediate monocytes were increased in the broader SpA spectrum compared with HC. Although Kruskal-Wallis test showed differences among the spectrum for activated Th17, activated Th1-17, and classical monocytes, post hoc analyses did not identify a specific disease driving these differences. Intermediate monocytes positively correlated with CRP and MMP-3 levels. Circulating immune subsets remained unchanged following DMARDs treatment despite clinical improvement. Systemic immune alterations, including activation of IL-17 axis, elevated Oncostatin M, and expansion of intermediate monocytes, are broadly shared across the broader SpA spectrum. Although global differences among the spectrum were observed for some immune cell populations, post hoc analyses did not identify disease-specific enrichment.

The tumor necrosis factor (TNF) and TNF receptor (TNFR) superfamilies comprise 47 proteins that regulate immune signaling and T cell costimulation. While TNF inhibitors are established therapies for immune-mediated inflammatory diseases (IMIDs), their efficacy is limited by primary non-response and secondary loss of efficacy. Preclinical data suggest that the TNF/TNFR members exhibit redundant and synergistic signaling, motivating combination targeting strategies.