ABSTRACT Introduction Juvenile spondyloarthropathies (JSpA) are a group of chronic inflammatory diseases that differ in their clinical features and course from adult spondyloarthropathies and other subtypes of juvenile idiopathic arthritis (JIA). Therefore, defining disease inactivity in JSpA requires specific criteria. This Delphi study aimed to establish a national consensus on its core clinical, laboratory, and radiological domains. Methods A total of 27 pediatric rheumatologists participated in the Delphi survey, conducted in two rounds. Participants were asked multiple‐choice and Likert‐type questions regarding their preferences for using domains including anamnesis, laboratory findings, imaging methods, and predefined disease activity scores for assessing inactivity. At the end of each round, the study coordinators determined the “strong consensus” items based on a power analysis of these parameters. Results The absence of “pain or tenderness in the peripheral joints, lower back and entheseal regions” in anamnesis domain and “tenderness in the peripheral joints, entheseal areas, and hip examination”; “swelling in the peripheral joints; tenderness on sacroiliac compression testing”; and “no reduction in hip RoM examination” in physical examination domain received the highest scores and were accepted as strong consensus. Furthermore, normalization of MRI findings of SIJ and hip/peripheral joint and “physician global score = 0” reached the specified thresholds, resulting in strong consensus following the second round. Conclusions This Delphi study highlights the need for a multidimensional approach that integrates clinical, radiological, and physician assessments to define disease inactivity in patients with JSpA. The resulting consensus provides a more specific assessment on inactivity defining JSpA patients and reflects a national consensus.
Understanding the cellular and molecular mechanisms of T cell activation has enabled the identification of immune checkpoints, such as PD‐1 and CTLA‐4, and the development immune checkpoint inhibitors (ICI) which have revolutionized cancer therapy. However, ICI cancer treatment is commonly associated with autoimmune side effects, including inflammatory arthritis (ICI‐IA). ICI‐IA occurs in ~6% of ICI‐treated patients and often resembles rheumatoid arthritis phenotypically, although it is generally seronegative. Imaging often demonstrates joint inflammation in patients with ICI‐associated joint pain, even in the absence of joint swelling. The ICI‐IA synovium is characterized by clonal expansion of actively proliferating CD38 hi CD127 ‐ CD8 + T cells and expansion of IL‐1β hi macrophages, communicating along CXCL10‐CXCR3 and CCR1‐CCL3/5 axes. Activation of naïve CD4 + T cells and impaired Tregs play a synergistic and amplifying role especially in the setting of combination ICI (anti‐CTLA‐4 plus anti‐PD‐1). ICI‐IA has the potential to teach us about mechanisms underlying the biology and evolution of other forms of inflammatory arthritis. In this review, we summarize our current understanding of ICI‐IA and propose promising avenues for future research. image
Radiographic axial spondyloarthritis (r-axSpA), non-radiographic axial spondyloarthritis (nr-axSpA), and psoriatic arthritis (PsA) represent distinct yet overlapping entities within the spondyloarthritis (SpA) spectrum. Enthesitis has emerged as a unifying hallmark of these diseases, linking mechanical stress, immune dysregulation, and structural remodeling. Understanding similarities and differences in entheseal pathology among these entities may elucidate shared and divergent mechanisms driving disease pathogenesis and progression. Mechanical stress at entheses activates mechanosensitive pathways leading to inflammatory changes and eventually new bone formation. In both research and clinical practice, enthesitis is assessed though the use of clinical indices and imaging modalities, particularly ultrasound and Magnetic Resonance Imaging (MRI), while modern modalities emerge on. Despite shared inflammatory mechanisms, variations in cytokine profiles, soft tissue and underlying bone involvement drive disease-specific patterns of damage and repair in axial and peripheral sites. Combining standardized multimodal imaging with molecular biomarkers holds promise for refining classification, improving early diagnosis, and guiding targeted therapeutic strategies across the SpA spectrum. In this review we explore enthesitis from various standpoints, including pathophysiology, clinical and imaging approaches under the prism of the similarities and differences between PsA and AxSpA.
Patients with normal BMD were more likely to respond well to first-line treatment. Osteoporosis and axial involvement are predictive factors for therapy switching in refractory disease. Although vitamin D deficiency is common in our cohort, its effect on relapse was not found. Monitoring of osteoporosis may be critical in the selection of second-line treatment.
Background While ankylosing spondylitis (AS) and psoriatic arthritis (PsA) share similar immune dysregulation, their relative risks for inflammatory bowel disease (IBD), including definitive subtypes (Crohn’s disease [CD] and ulcerative colitis [UC]) and possible subtypes (indeterminate colitis [IC] and microscopic colitis [MC]), remain unquantified. We aimed to establish comparative IBD risk gradients among AS, psoriasis (PSO), and PsA cohorts. Methods The study utilized a long-term retrospective cohort design by analyzing an electronic health record database. Propensity score matching (PSM) was used to adjust multiple confounders. Cox proportional hazards models and log rank test were employed to evaluate the risk of IBD development. Results The study included 26,610 patients with AS and 322,317 with PSO (2005–2023). After PSM, 26,569 matched pairs were analyzed. Compared to PSO, AS was associated with a significantly higher risk of definite IBD [hazard ratio (HR) = 2.96, 95% CI: 2.64–3.33], CD (HR = 3.38, 95% CI: 2.90–3.94), UC (HR = 2.43, 95% CI: 2.07–2.85), and IC (HR = 2.45, 95% CI: 1.33–4.51), but not MC. Subgroup analyses confirmed a consistently higher IBD risk in AS across all ages, sexes, races, BMI categories, and comorbidity profiles. Compared to the general population, AS conferred the highest independent risk for definite IBD (HR = 4.22, 95% CI: 3.60–4.94), followed by PsA (HR = 1.52) and PSO (HR = 1.37). AS also showed a 2.60-fold higher definite IBD risk than PsA (95% CI: 2.32–2.92). Conclusions AS is the phenotype most strongly associated with IBD among the studied spectrum. Compared to PSO, AS confers a significantly higher risk of CD, UC, and IC, and it carries a greater burden of definite IBD than PsA or the general population.
Spondyloarthritides (SpA) and inflammatory bowel disease (IBD) are immune-mediated diseases with overlap in clinical and immunological features. However, temporal correlation of SpA and IBD in individual patients and risk factors are not well characterized. We conducted a nationwide population-based study between January 1, 1998 and July 31, 2022 to determine SpA prevalence preceding and its incidence following IBD diagnosis. Using cross-linked register data, we identified individuals with IBD diagnosis and matched them to individuals without IBD. Using logistic regression, we determined the odds of SpA preceding IBD diagnosis and using Cox regression, the hazard of new-onset SpA following IBD diagnosis. Of 102,648 individuals included in the study, 17,108 (16.7%) individuals were diagnosed with IBD. The aOR of SpA in the 8-year period preceding IBD, Crohn's disease (CD), or ulcerative colitis (UC) diagnosis, compared to matched individuals, was 1.95 (95% CI 1.78, 2.14), 2.84 (95% CI 2.43, 3.32), and 1.61 (95% CI 1.43, 1.81), respectively. The aHR of SpA following IBD, CD, and UC diagnosis, compared to matched individuals, was 2.51 (95% CI 2.34, 2.70), 3.17 (95% CI 2.81, 3.59), and 2.24 (95% CI 2.05, 2.45), respectively. SpA prevalence demonstrated temporal variability, with increase during the few years around IBD diagnosis. Associations were stronger for axial SpA, and among women and young adults preceding IBD diagnosis. In a population-based cohort, we report that SpA diagnosis is associated with IBD preceding and following its diagnosis. We demonstrate temporal variability and highlight clinical variables associated with SpA in IBD.
Peripheral manifestations (peripheral arthritis/enthesitis/dactylitis) are frequent in axial spondyloarthritis (axSpA) yet, understudied. We (i) evaluated the assessment/reporting of peripheral manifestations in trials of biological or targeted synthetic DMARDs (b/tsDMARDs) for axSpA and peripheral SpA (pSpA), and (ii) synthesized the efficacy of b/tsDMARDs on these manifestations. Systematic literature review (SLR) of controlled trials evaluating b/tsDMARDs in axSpA/pSpA (excluding psoriatic arthritis). Records were identified through previous SLRs informing ASAS-EULAR recommendations and updated searches. Outcomes included (i) frequency of assessment/reporting of peripheral arthritis/enthesitis/dactylitis and (ii) treatment efficacy of b/tsDMARDs on these peripheral manifestations [standardized mean differences (SMDs) or relative risk]. We included 100 axSpA and four pSpA trials. In axSpA, peripheral arthritis was assessed in 54%, enthesitis in 64% and dactylitis in only 10% of studies. When assessed, results were reported in 69%, 72% and 10% of studies, respectively, and often in all patients (instead of those affected at baseline). Most frequently used instruments were 44-joint count for peripheral arthritis (48%), Maastricht Ankylosing Spondylitis Enthesitis Score for enthesitis (88%) and digit count for dactylitis (40%). Composite indices like DAS were not used. SMDs (range 0.26 to -1.18) indicated mainly small-to-moderate b/tsDMARD effects, typically higher in patients with baseline peripheral involvement. In pSpA, peripheral manifestations were always assessed/reported, with generally moderate effects (SMD range -0.10 to -1.22). Peripheral manifestations are inconsistently assessed and reported in axSpA trials. While b/tsDMARDs have small-to-moderate effects on peripheral manifestations, these may be underestimated due to not being assessed in the population affected at baseline.
Ferroptosis, an iron-dependent cell death pathway driven by lipid peroxidation (LPO), is implicated in the pathogenesis of autoimmune diseases (AIDs). However, comprehensive clinical evidence establishing the association between specific LPO biomarkers and AIDs is lacking. To systematically evaluate the clinical evidence for elevated LPO in major AIDs through a meta-analysis, focusing on key biomarkers including malondialdehyde (MDA) and 8-isoprostaglandin F2α (8-isoPGF2α). We searched four databases for studies reporting serum, plasma, or urinary LPO levels in patients with AIDs and healthy controls. Standardized mean differences (SMDs) were pooled using a random-effects model. Across 175 studies (8227 patients; 6866 controls), serum/plasma MDA levels were significantly elevated in all ten investigated AIDs: Rheumatoid arthritis (RA) (SMD = 2.82), systemic sclerosis (SSc) (SMD = 2.08), graves' disease (GD) (SMD = 1.92), Behçet's disease (BD) (SMD = 1.90), Crohn's disease (CD) (SMD = 1.71), multiple sclerosis (MS) (SMD = 1.52), psoriasis (PsO) (SMD = 1.44), ulcerative colitis (UC) (SMD = 1.32), systemic lupus erythematosus (SLE) (SMD = 1.20) and type 1 diabetes (T1DM) (SMD = 1.12). Disease-specific elevations were found for serum/plasma 8-isoPGF2α and 4-hydroxynonenal in RA, urinary 8-isoPGF2α in SSc and T1DM, and serum/plasma oxidized low-density lipoprotein in T1DM. MDA was higher in active or severe subgroups, with significant between-subgroup differences in GD and PsO. This meta-analysis provides robust, large-scale clinical evidence that elevated lipid peroxidation is a common feature across diverse AIDs. These findings solidify the clinical relevance of ferroptosis, positioning LPO products as promising biomarkers and underscoring the therapeutic potential of targeting ferroptosis in autoimmune conditions.
Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease most commonly affecting children and young people. CNO can cause bone pain, hyperostosis and fractures, thereby significantly impacting on patients' wellbeing. The molecular pathophysiology of CNO is characterized by NLRP3 inflammasome activation and a pronounced imbalance between pro- and anti-inflammatory cytokines. In the absence of clinical trials, treatment of CNO remains empiric and is based on personal experience and published case series. This project systematically reviewed the available literature in pediatric CNO following 'Preferred Reporting Items for Systematic Reviews and Meta-Analyses' (PRISMA) guidance accessing Medline, Embase, NCBI PubMed, Cochrane Library Clinical Trials, ClinicalTrials.gov, and WHO ICTRP. Nonsteroidal anti-inflammatory drugs are usually used as first-line treatment. They facilitate pain control and induce early remission in some patients but also associate with later flares. Conventional disease modifying antirheumatic drugs (DMARDs) have been used with mixed success and may be helpful in patients with associated arthritis, skin inflammation, and/or inflammatory bowel disease. Biologic DMARDs, namely TNF inhibitors, are effective for the treatment of bone and associated skin and/or bowel disease. Bisphosphonates induce rapid remission in most patients but may associate with higher relapse rates when compared to TNF inhibitors. The longstanding absence of diagnostic and, until recently, classification criteria as well as defined study endpoints, the small sample size and variable therapeutic approaches challenge interpretation of studies and comparisons between treatments. Prospective randomised controlled trials are urgently needed to improve the evidence base, resulting in approval of treatments for CNO.