Axial spondyloarthritis (axial-SpA) is a multifactorial disease characterized by inflammation in sacroiliac joints and spine, bone reabsorption, and aberrant bone deposition, which may lead to ankylosis. Disease pathogenesis depends on genetic, immunological, mechanical, and bioenvironmental factors. HLA-B27 represents the most important genetic factor, although the disease may also develop in its absence. This MHC class I molecule has been deeply studied from a molecular point of view. Different theories, including the arthritogenic peptide, the unfolded protein response, and HLA-B27 homodimers formation, have been proposed to explain its role. From an immunological point of view, a complex interplay between the innate and adaptive immune system is involved in disease onset. Unlike other systemic autoimmune diseases, the innate immune system in axial-SpA has a crucial role marked by abnormal activity of innate immune cells, including γδ T cells, type 3 innate lymphoid cells, neutrophils, and mucosal-associated invariant T cells, at tissue-specific sites prone to the disease. On the other hand, a T cell adaptive response would seem involved in axial-SpA pathogenesis as emphasized by several studies focusing on TCR low clonal heterogeneity and clonal expansions as well as an interindividual sharing of CD4/8 T cell receptors. As a result of this immune dysregulation, several proinflammatory molecules are produced following the activation of tangled intracellular pathways involved in pathomechanisms of axial-SpA. This review aims to expand the current understanding of axial-SpA pathogenesis, pointing out novel molecular mechanisms leading to disease development and to further investigate potential therapeutic targets.

Juvenile idiopathic arthritis (JIA) associated uveitis (JIA-U) is the most common extra-articular manifestation of JIA, affecting 10–15% of patients, especially in oligoarticular JIA where its course may be faint. Therefore, JIA-U is one of the most challenging pediatric uveitis, associated with major ocular morbidity and possibly leading to irreversible structural ocular damage and to vision-threatening complications. Adequate management is crucial for avoiding visual impairment complications. Since the introduction of biologic disease modifying anti-rheumatic drugs (bDMARDS), the visual prognosis of JIA-U has dramatically improved over the decades. Tumor necrosis factor-α (TNF-α) blockers are the most used bDMARDs in treating JIA-U with large evidence of efficacy. However, inadequate response to these agents, either due to intolerance or inefficacy, may be observed, requiring a swap to other classes of immunosuppressive agents, including anti-IL-6, anti-CD20, and, more recently, JAK inhibitors. Tocilizumab is a humanized monoclonal antibody to the interelukin-6 receptor preventing IL-6 from binding to its soluble and membrane-bound receptors. A growing body of literature provides promising results about the efficacy of intravenous and subcutaneous tocilizumab in the treatment of JIA-U. A narrative review of the literature on this topic will improve our knowledge on the potential use of tocilizumab in JIA-U.

Background/Objectives: Pulmonary arterial hypertension (PAH) is a complication of systemic sclerosis (SSc), and several screening algorithms have been proposed for the early detection of PAH in SSc. This study aimed to evaluate the predicting values of the DETECT algorithm for SSc-PAH screening in patients with SSc undergoing right heart catheterization (RHC) based on 2015 ESC/ERS echocardiographic criteria in a real-life setting. Methods: Patients fulfilling the 2013 ACR/EULAR classification criteria for SSc and with available data for PAH screening with the DETECT algorithm and the 2015 ESC/ERS echocardiographic criteria were retrospectively enrolled from January to June 2017 and then followed for 5 years. Baseline and annual clinical, laboratory, and instrumental data were collected. Results: A total of 33 out of 131 (25%) patients were selected based upon the ESC/ERS echocardiographic criteria, but 30 (23%) underwent RHC, while 51 (39%) patients with SSc were positive based on the DETECT algorithm. PAH diagnosis was confirmed in 28/30 cases (93.3%). The DETECT algorithm showed lower specificity and positive predictive value (PPV) (p < 0.0001) but higher sensitivity and negative predictive value (NPV) (p < 0.0001) than ESC/ERS criteria. Notably, patients with SSc with a negative DETECT screening at baseline had a low probability of developing PAH during a 5-year follow-up (OR 0.15, 95% CI 0.10–0.60—p < 0.0001). Conclusions: The DETECT algorithm has proven to be an easy, fast, and inexpensive tool for screening PAH in patients with SSc. Overall, a low probability of PAH using DETECT is highly predictive of a good prognosis.

Background: Anti‐neutrophil cytoplasmic antibodies (ANCA), a hallmark of systemic vasculitis (SV), have been reported in patients with idiopathic interstitial pneumonia (IIP). However, the clinical significance of ANCA in IIP remains unclear.Methods: We retrospectively studied 101 IP patients diagnosed by pneumologists as idiopathic interstitial pneumonia (IIP,64) and IP with autoimmune features (IPAF,37). ANCA, anti‐myeloperoxidase and anti‐proteinase‐3 were tested by immunofluorescence and ELISA. Chest HRCT patterns, pulmonary function tests (PFTs) and the evolution to SV during a 12‐month follow‐up were assessed. Multivariable regression analysis was performed to assess the association of baseline covariates with SV. The proximity of patients with close characteristics was investigated by cluster analysis.Results: Twenty‐one patients (20.8%) were ANCA+, similarly distributed between IPAF and IIP. ANCA+ patients were more likely to have NSIP (p = .02) and bronchiectasis (p = .02) on HRCT, less impaired 6MWD (p = .02), higher CRP (p = .02) and more arthralgias (p < .001) than ANCA− patients. During follow‐up, 9 (43%) p‐ANCA+ patients, but no ANCA− patients, developed SV (p = .001). p‐ANCA+ IP had 26.3 OR (95% CI 3.20–36.8) to evolve to SV within 12 months (p < .0001). Cluster analysis identified one group of 25 patients with significantly higher baseline NSIP (88%), p‐ANCA+ (48%), arthralgias (32%), and SV (24%) at 12 months. Nevertheless, 12 p‐ANCA+ IP patients never developed SV.Conclusions: ANCA+ IP patients had a high risk of developing SV and need close monitoring and prompt immunotherapy. ANCA+ IP patients not evolving to SV had a diagnosis of IIP or IPAF. These patients need longer observational studies to investigate if they represent a distinct ILD entity.

Background: Granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (EGPA) are distinct forms of antineutrophil cytoplasm antibody (ANCA)‐associated vasculitis (AAV). Increasing evidence suggests overlapping features, particularly in proteinase 3 (PR3)‐ANCA‐positive EGPA and GPA with eosinophilia. This study aimed to characterize overlapping EGPA/GPA forms and assess their clinical and therapeutic implications. Methods: We conducted a European, multicenter, observational study, including 135 patients with overlapping EGPA/GPA features. Definitions were based on ACR/EULAR classification criteria and other clinical and biological findings. Clinical, biological, and histological characteristics were analyzed using unsupervised hierarchical clustering approach. Comparisons were made with established EGPA and GPA control cohorts. Results: Three clusters emerged: Cluster 1, a hybrid phenotype (pulmonary nodules, PR3‐ANCA positivity, high relapse rate); Cluster 2, a systemic inflammatory phenotype (constitutional symptoms, PR3‐ANCA positivity, moderate renal involvement); and Cluster 3, a severe vasculitis form (severe renal disease, alveolar hemorrhage). Including typical EGPA and GPA control cohorts revealed two main clusters a posteriori: an EGPA cluster and a GPA cluster. Cluster 1 overlapped with both EGPA and GPA clusters, whereas Clusters 2 and 3 predominantly aligned with GPA. Kaplan–Meier analysis revealed that Cluster 1 and the typical EGPA cohort had the best overall survival, whereas Cluster 3 had the poorest survival. Relapse‐free survival was highest in typical EGPA and poorest in Cluster 3 and typical GPA. Conclusion: This study delineates the heterogeneity of EGPA/GPA overlap and underscores the need for personalized treatment approaches. Future prospective studies should explore targeted therapies, including rituximab and IL‐5 blockade, in these overlapping AAV subtypes.

Objectives: Digital ulcers (DUs) affect ∼50% of SSc patients, causing significant pain and functional impairment. Current management involves both systemic and local therapies. However, the burden in terms of pain and quality of life due to refractory DUs still remains heavy. While selexipag is approved for SSc-associated pulmonary arterial hypertension, its potential in treating DUs is unexplored. We aimed to evaluate the long-term efficacy of selexipag compared with iloprost in treating DUs. Methods: In this multicentre case-control study, we retrospectively evaluated 96 SSc patients with refractory DUs (32 treated with selexipag, 64 with iloprost), matched for gender, disease subset and age. DU number, ischaemic pain and RP severity were assessed at baseline, 6, 12 and 24 months. Pain and RP were evaluated using the Likert Pain Scale (LPS) and Raynaud Condition Score (RCS), respectively. Additionally, DUs recurrence and new onset were recorded. Healing rates were estimated using Kaplan–Meier analysis. Results: Selexipag showed higher efficacy with 87% of DUs healing rate vs 28% for iloprost at 96 weeks (P < 0.001). DUs number, RCS and LPS showed significant improvement in selexipag-treated patients compared with iloprost (P < 0.001 for all) throughout 24 months. Selexipag-treated patients achieved faster healing (75% by week 40) and maintained significantly lower relapse rates (5% vs 45% at 24 months, P < 0.001). New DUs formation remained consistently lower in the selexipag group compared with the iloprost group (5% vs 40% at 24 months, P < 0.001). Conclusions: This observational study suggests that selexipag may be strongly effective in treating DUs refractory to conventional drugs.