Objective Schnitzler syndrome (SchS) is a rare autoinflammatory disease characterised by a primary pathogenic involvement of interleukin (IL)-1. Therefore, IL-1 blockers are currently considered the optimal therapeutic option for SchS patients. However, while IL-1 blockers are first-line for SchS, long-term real-world evidence is limited by the rarity of the disease. We assessed the long-term effectiveness and safety of the IL-1 inhibitors anakinra and canakinumab used in SchS, also looking for variables capable of affecting global effectiveness and drug retention over time. Methods Data analysed in this study were drawn from the international AutoInflammatory Disease Alliance (AIDA) Registry dedicated to SchS. Results 28 SchS patients corresponding to 37 treatment lines were included in the study. Complete and partial responses occurred in 73.1% and 29.9% of anakinra-treated patients, and 66.8% and 33.3% with canakinumab. The overall anakinra and canakinumab drug retention rates at 12-, 36-, and 60-month follow-up were 85.6%, 81.7% and 64.7%, respectively; the probability of discontinuing IL-1 inhibitors at 12-, 36-and 60 months due to loss of effectiveness was 9.6%, 13.7% and 24.5%, respectively. The maximum IgG M-protein levels were found to be significantly higher in patients achieving partial response compared to those benefiting from complete response (p=0.032). Lymphadenopathy independently predicted anti-IL-1 discontinuation due to loss of effectiveness (HR 7.78, 95% CI: 1.27-47.9; p=0.027). Conclusion The present study confirms the high effectiveness of IL-1 inhibitors in controlling SchS, including the complete and partial response rates and the long-term survival. Elevated IgG M-protein levels and the presence of lymphadenopathy should be considered as potential indicators for identifying patients more likely to exhibit a partial response and a possible loss of treatment efficacy.

OBJECTIVES:To assess the effectiveness of canakinumab (CAN) in controlling clinical and laboratory inflammation by achieving complete control of cardinal disease manifestations and full normalization of laboratory inflammatory markers. METHODS:Data were obtained from the international AutoInflammatory Disease Alliance (AIDA) network registry, dedicated to monogenic autoinflammatory diseases. The assessment included both retrospective and prospective real-world data. RESULTS:In total, 158 FMF patients treated with CAN were enrolled. Complete clinical-laboratory response was observed in 45.6% of patients at 3 months, 58.6% at 12 months and 55.2% at the last follow-up, after a mean treatment duration of 45 months. Partial response occurred in 16.5%, 12.5% and 16.8% at the same timepoints, respectively. Complete absence of clinical manifestations was observed in more than 80% of patients at each timepoint. Inflammatory markers normalized significantly by the 3-month assessment. The probability of achieving and maintaining complete response and full laboratory control appeared higher in patients reaching these outcomes by 3 months, although it remained substantial in other patients as well. Complete response was associated with a relapsing-remitting disease course and fewer annual attacks. Nearly all patients maintained stable organ damage scores, and therapy discontinuation due to inefficacy was rare (≤6%). CONCLUSION:CAN is effective in achieving rapid and sustained clinical and laboratory control in FMF, including stringent endpoints of complete response. Early effectiveness may favour better long-term outcomes, but delayed achievement of complete response and full laboratory control is not uncommon. This study confirms CAN as an effective, and durable therapeutic option in FMF.

Background Axial spondyloarthritis (axSpA) is a chronic inflammatory disease primarily affecting the axial skeleton. Expression studies support a role for inflammatory and immunomodulatory pathways in disease onset and progression. In this context, peroxisome proliferator-activated receptor (PPAR)-γ has been implicated in axSpA and is known to inhibit nuclear factor kappa B (NF-κB) and its related inflammatory signaling. Methods We characterized PPAR-γ deficit and related antioxidant and inflammatory response in axSpA patients, compared to healthy subjects, through the analysis of peripheral blood mononuclear cells (PBMCs). Real time PCR was employed to measure PPAR genes in PBMCs from healthy and axSpA subjects, while antioxidant, inflammatory, and apoptotic markers were assessed using a targeted RNAseq (AmpliSeq) panel. Exploratory correlations between molecular alterations and disease activity were evaluated using Matlab R2021b. Functional enrichment analysis was performed by using g:Profiler. PBMC immunophenotyping was performed through flow cytometry, while lipid-derived signaling molecules were quantified by ELISA. Results PPAR-γ expression was significantly reduced in PBMCs from axSpA patients and was paralleled by the upregulation of several genes related to oxidative stress response, inflammation and apoptosis, as well as by increased serum prostaglandin PGJ2 levels and differences in blood parameter correlation profiles compared with healthy subjects. These molecular alterations were also associated with a significant increase in CD11b-positive cells. Functional enrichment analysis within the axSpA cohort confirmed the involvement of antioxidant activity together with cytokine receptor binding, cellular response to chemical stimuli, and regulation of molecular function clusters. Exploratory correlation analyses with ASDAS-CRP revealed heterogeneous directional patterns across dysregulated genes, with IL1RN showing the clearest positive association with disease activity and IFNG displaying an inverse trend. Heterogeneous directional patterns were also observed across PPAR isoforms. Conclusions Overall, these findings support an association between reduced PPAR-γ expression, NF-κB signaling pathway activation, and Nrf2-related antioxidant response in axSpA, laying the groundwork for a better understanding of the immune molecular landscape of the disease. These results may contribute to the identification of PBMC-based molecular signatures that, after validation in larger cohorts, could support future personalized therapeutic strategies.

ObjectiveBehçet’s disease (BD) may initially manifest solely with mucocutaneous involvement. This study aimed to identify demographic and clinical factors associated with subsequent intestinal involvement in patients presenting exclusively with mucocutaneous manifestations during early disease stages.MethodsData were obtained from the International AutoInflammatory Disease Alliance Network registry dedicated to BD; a Bayesian statistical approach was employed to address the limited sample size resulting from subgroup stratifications.ResultsIn total, 328 BD patients with exclusively mucocutaneous onset were enrolled; of these, 46 (14%) developed intestinal involvement over time. The risk of ocular involvement was higher among patients with intestinal manifestations (OR: 3.02, 95% CrI: 1.24–6.08; posterior probability: 99.3%). Minor aphthous ulcers without major aphthosis were protective towards intestinal involvement (OR: 0.47, 95% CrI: 0.22–0.98; posterior probability: 97.98%). Conversely, major aphthous ulcers increased the risk (OR: 3.25, 95% CrI: 1.50–7.02; posterior probability: 99.7%), along with the combination of oral major aphthosis with: i) genital aphthosis (OR = 2.77, 95%CrI: 1.14-6.58; posterior probability: 98.45%); ii) pseudofolliculitis (OR = 3.18, 95%CrI: 1.15-8.33; posterior probability: 98.72%); iii) genital aphthosis plus pseudofolliculitis (OR = 5.22, 95%CrI: 1.71-16.35; posterior probability of 99.77%). Pseudofolliculitis plus cutaneous manifestations other than erythema nodosum were protective against intestinal involvement (OR = 0.01, 95%CrI: 0.0-0.98; posterior probability: 97.55%).ConclusionMajor aphthosis was the strongest factor associated with intestinal involvement in BD patients initially presenting with mucocutaneous symptoms only. In such patients, intestinal involvement correlated with increased risk of ocular inflammation.

Orbital inflammation is the most common presentation of VEXAS, with any orbital structure potentially affected. Non-sight-threatening and uncomplicated anterior non-granulomatous uveitis and anterior diffuse scleritis follow in frequency, along with episcleritis. Ophthalmic involvement was significantly associated with relapsing polychondritis (p = 0.014), with an increased chance of a fatal outcome (RR 5.87, p = 0.016) and independently predicts a higher mortality rate (OR 3.72, p = 0.026). Treatment of ophthalmic involvement showed full or partial response to glucocorticosteroids alone in 66.7% of cases. Ophthalmic involvement is common in VEXAS syndrome and signals a poorer prognosis in terms of mortality, highlighting the need for close monitoring.

Aim VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a recently defined adult-onset autoinflammatory disorder caused by somatic mutations in the UBA1 gene. This narrative review synthesizes current insights into its epidemiology, pathogenesis, clinical spectrum, diagnostic strategies, and emerging therapeutic approaches, emphasizing data from the French and AIDA registries. Method We conducted a comprehensive literature search of PubMed, Scopus, and Web of Science databases up to 15 June 2025, using keywords including “VEXAS”, “UBA1”, “autoinflammatory syndromes”, “myelodysplastic syndromes”, and “JAK inhibitors”. Studies reporting epidemiological data, clinical phenotypes, pathophysiological mechanisms, diagnostic pathways, or therapeutic outcomes were included. Case reports and non-English articles without abstracts were excluded. Discussion Since its identification in 2020, more than 300 VEXAS cases have been reported, primarily affecting older males. The clinical phenotypes include relapsing polychondritis, cytopenias, neutrophilic dermatoses, and frequent overlap with myelodysplastic syndromes. Diagnosis is confirmed by detecting somatic mutation in UBA1, most commonly at codon 41. Treatment responses are heterogeneous: corticosteroids are often used initially,but longer-lasting benefits are observed with JAK inhibitors, hypomethylating agents, or hematopoietic stem-cell transplantation. However, therapeutic decision-making remains empirical mainly due to the lack of controlled trials. Conclusion VEXAS syndrome exemplifies the interface between clonal hematopoiesis and systemic inflammation. Early molecular diagnosis and genotype-informed treatment strategies are critical. Collaborative, prospective studies are urgently needed to refine diagnostic algorithms and optimize therapeutic outcomes.

OBJECTIVES:To investigate cutaneous manifestations in Still's disease patients, evaluating any correlation with ethnic origin, age at disease onset, disease patterns, occurrence of macrophage activation syndrome (MAS) and systemic activity scores. METHODS:Data were retrospectively drawn from the International AutoInflammatory Disease Alliance (AIDA) Network Registry dedicated to Still's disease. RESULTS:A total of 518 patients (41.3% males) were enrolled. Salmon-coloured evanescent skin rash (n = 304, 63.9%), macules (n = 40, 7.7%), urticarial eruptions (n = 31, 5.9%), erythema (n = 27, 5.2%) and persistent pruritic papules and plaques (PPPP) (n = 25, 4.8%) accounted for the most frequent skin manifestations observed in Still's disease. Overall, atypical skin rash were described in 110 (21.2%) patients. Salmon-coloured evanescent skin rash and pruritus were more common among patients aged <16 years compared with patients aged 16-60 (P = 0.002 and P = 0.008, respectively). Pruritus was significantly more frequent among White than among Arab patients (P = 0.008) and in polycyclic vs monocyclic course (P = 0.049). Hispanics showed a significantly higher rate of atypical skin manifestations compared with Arabs (P = 0.036) and White (P = 0.036). Also, macules were more frequent among Hispanics than White (P = 0.027), while PPPP was more frequent among Hispanics than Arabs (P = 0.023) and White (P = 0.002). Salmon-coloured evanescent skin rash was significantly more frequent among patients with a systemic activity score ≥7 (P < 0.001). CONCLUSION:The present study enhances dermatologists' awareness of the diverse cutaneous lesions that may represent heterogeneous manifestations of Still's disease, shedding new light on the difference related to the age at disease onset, the patients' ethnic origin and the severity of the disease.

ObjectiveDry eye disease (DED) has been described in axial spondyloarthritis (axSpA), but patterns of tear fluid and ocular surface involvement remain incompletely characterized. This study aims to evaluate tear film instability and tear production in axSpA and explore the heterogeneity of DED manifestations.MethodsAxial spondyloarthritis patients and healthy controls underwent non-invasive tear break-up time (niTBUT), Schirmer test, and Ocular Surface Disease Index (OSDI)- 6 evaluation. Group differences were assessed using niTBUT thresholds (<10 s and <5 s).ResultsMean niTBUT was significantly lower in axSpA patients than controls (7.85 ± 5.63 vs. 10.61 ± 5.27 s; p < 0.001); niTBUT <5 s, but not <10 s, differentiated groups (p = 0.003 and p = 0.105, respectively). ROC analysis identified an optimal niTBUT cut-off of 5.15 s. Schirmer values also discriminated axSpA patients from controls, with an optimal threshold of 4.5 mm. Agreement between niTBUT and Schirmer classification was weak (Cohen κ = 0.18). OSDI-6 scores were not significantly associated with pathological niTBUT. The niTBUT values were significantly associated with patients’ age, but the diagnosis of axSpA accounted for the main determinant of niTBUT <5 s (likelihood ratio test, p = 0.026).ConclusionWithin the present cohort, a niTBUT <5 s showed greater discriminative performance than the conventional 10-s cut-off and may identify a subgroup of axSpA patients with more severe tear film instability. Aging contributes to tear film instability, but axSpA independently contributes to severe niTBUT impairment. Tear film instability and reduced tear secretion are both involved in DED affecting axSpA patients.

IntroductionRecurrent febrile episodes account for one of the most frequent symptoms observed in Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome and a key target for therapeutic intervention. Therefore, this study aims at investigating the association between recurrent febrile episodes and specific clinical manifestations, mortality and response to treatment.MethodsData were obtained from the international AutoInflammatory Disease Alliance (AIDA) Network registry and analyzed using a Bayesian statistical approach. Posterior probabilities [P(β)] were calculated to assess the likelihood that fever was associated with clinical, laboratory, genetic, and therapeutic features.ResultsIn total, 87 VEXAS patients were enrolled, 65 (74.7%) of whom suffered from recurrent fever episodes. Fever episodes showed a significant association with patients’ mortality [P(β): 99.41%], as well as with major inflammatory organ involvement, including cardiac [P(β): 99.99%], lung [P(β): 99.98%], and gastrointestinal [P(β): 97.5%] involvement. The occurrence of recurrent fever episodes was associated with a negligible probability of both complete response and treatment failure [P(β) <2.5%], instead favoring a partial response [P(β) >97.5%] to conventional disease modifying anti-rheumatic drugs, Janus Kinases inhibitors, and tocilizumab. For temperatures exceeding 40 °C, using anti-interleukin-1 agents was associated with a high probability of treatment failure [P(β): 99.3%].Conclusionsfebrile episodes are associated with more severe pattern of organ involvement and, accordingly, to death. Furthermore, febrile episodes could correlate with differential therapeutic responsiveness, thereby potentially serving as a valuable marker to guide the treatment strategies in VEXAS patients.

Sjögren's disease (SjD) is an autoimmune exocrinopathy characterized by heterogeneous extraglandular manifestations (EGM). The systemic immune-inflammation biomarkers, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII), have been proposed as indicators of the inflammatory burden, but data in SjD remain limited. This retrospective multicenter Italian study aimed to evaluate the NLR, PLR, and SII in exocrine SjD patients and across specific EGM. Consecutive patients fulfilling the 2016 ACR/EULAR classification criteria for SjD and with available full blood count data were included. Patients were classified as having exocrine or extraglandular SjD according to the presence of specific EGM. The NLR, PLR, and SII were calculated and compared across disease phenotypes and activity levels. Among 239 SjD patients (96

Abstract Thrombotic events (TEs) occur in up to 40% of patients with vacuoles, E1 enzyme, X‐linked, autoinflammatory, and somatic (VEXAS) syndrome, but data on its clinical‐genomics features and anticoagulation strategies are limited. To gain more insight into this, we conducted a two‐step study evaluating the prevalence and outcome of TE in VEXAS. First, among 1086 patients followed for TEs, 198 were men aged >40 years with unprovoked thrombosis and no known thrombophilia; 21 also had at least one VEXAS‐compatible feature and underwent UBA1 exon 3 testing. No UBA1 mutation was detected in these 21 patients. Next, we leveraged our Italian VEXAS network, and we accrued 87 molecularly confirmed Italian VEXAS cases (median age 70 years). Any history of TE was documented in 43/87 patients (49%), deep vein thrombosis being the most common (71%). Because follow‐up varied, incident thrombosis was analyzed using a time‐to‐first‐event framework from molecular VEXAS diagnosis, with death without prior TE treated as a competing event. Among 49 patients without prior/concomitant TE, five developed incident post‐diagnosis TE; the 24‐month cumulative incidence was 18.3%. Thrombophilia testing revealed a 15% co‐occurrence, including heterozygous Factor V Leiden, Factor II G20210A, and anti‐cardiolipin antibodies. Treatments comprised direct oral anticoagulants (DOACs) (51%), low molecular weight heparin (LMWH) (28%), Fondaparinux (14%), and vitamin K antagonists (AVKs) (7%). Notably, 27% experienced multiple TEs, of which 22% occurring despite anticoagulation during disease flares. Our findings provide an updated cartography of VEXAS‐related TE, suggesting early screening for thrombophilia in these patients to inform both personalized anticoagulation and disease‐control strategies.

Scleritis is a rare and severe ocular inflammatory disease that is often associated with potentially sight-threatening ocular complications. The aim of the present study was to characterize ocular complications in non-infectious scleritis and identify predictive variables for their development. Data for this registry-based study were extracted from the AutoInflammatory Disease Alliance Network for Scleritis Registry. Univariate analysis was performed to examine potential associations of demographic and clinical variables with the development of ocular complications. Uveitis and peripheral ulcerative keratitis were considered to be extensions of the inflammatory process and not to be true structural complications. Predictive factors of ocular complications were assessed using regression analysis. The impact of ocular complications on visual acuity—measured by best-corrected visual acuity (BCVA)—was also analyzed. A total of 154 patients (218 eyes) with non-infectious scleritis were enrolled. In 58 of these patients (87 eyes), 102 ocular complications were recorded, with cataract, scleral and corneal thinning, and glaucoma and/or increased ocular pressure being the most frequently recorded complications. Ocular complications were found to be significantly more frequent among patients affected by granulomatosis with polyangiitis (GPA) (p < 0.0001) and concomitant uveitis (p = 0.023). The mean severity score was significantly higher among eyes experiencing ocular complications (p < 0.0001). Regression analysis identified three variables capable of predicting the development of ocular complications: a diagnosis of GPA [odds ratio (OR) 7.747, p < 0.0001]; the presence of concomitant uveitis (OR 3.648, p = 0.019); and a high severity score (OR 1.138, p = 0.044). Mean (± standard deviation) BCVA converted to logMAR was found to be significantly higher among eyes without ocular complications (0.12 ± 0.24 vs 0.27 ± 0.49; p = 0.005). Scleritis was accompanied by irreversible ocular complications in a considerable proportion of the patients enrolled in this study. Patients with a diagnosis of GPA, concomitant uveitis, and a higher severity score are more likely to develop ocular complications, and thus warrant a tighter follow-up schedule and early treatment in order to minimize the risk of poor visual prognosis.

ObjectivesTo evaluate the therapeutic management of patients with active adult-onset Still’s disease (AOSD) in a multicentre real-world setting and to provide and compare current real-world treatment strategies with existing recent international recommendations.MethodsFrom January 2022 to December 2023, 173 consecutive patients with active AOSD attending centres participating in the Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) AOSD research study group were prospectively enrolled. Demographic, clinical, and laboratory data were collected, and therapeutic strategies prescribed by the treating physicians were systematically recorded. Factors associated with the administration of biologic disease-modifying antirheumatic drugs (bDMARDs), including IL-1 and IL-6 inhibitors, were analysed.ResultsGlucocorticoids were administered in 97.7% of patients. Conventional synthetic DMARDs were prescribed in 58.8% of cases, mainly methotrexate and cyclosporin A. Overall, 43.3% of patients received bDMARDs, predominantly IL-1 and IL-6 inhibitors. Specifically, 33.5% were treated with IL-1 inhibitors, 5.8% with IL-6 inhibitors, and 4.0% with tumour necrosis factor inhibitors. After three months of treatment, 86.7% of patients achieved clinical inactive disease as assessed by the treating physician. Comparing recorded treatment strategies with international recommendations, no compliance was found regarding the use of glucocorticoids, which are recommended to be markedly limited or avoided, and early administration of bDMARDs, which were administered within 3 months in a minority of patients.ConclusionsThis multicentre real-world study outlines current therapeutic approaches for patients with active AOSD and highlights a gap between international treatment recommendations and clinical practice, underscoring the need for further studies to optimize patient management.

Objectives To evaluate whether early canakinumab initiation may provide treatment advantages in Still’s disease (SD) patients, particularly in terms of therapy discontinuation due to long-term disease remission, glucocorticoid sparing effect, and increase in the frequency of monocyclic disease course rather than a polycyclic or chronic articular pattern. Methods SD patients treated with canakinumab were grouped according to time between disease onset and canakinumab initiation (≤3 months vs. >3 months). Patients were enrolled from the international AutoInflammatory Disease Alliance (AIDA) Network registry for SD. Results Overall, 190 patients were enrolled, 35 (19%) treated with canakinumab within three months from SD onset and 155 (82%) starting canakinumab later. Glucocorticoids use decreased more rapidly in patients receiving canakinumab within 3 months from SD onset than among patients treated later, with reductions of 50% vs 6% at month 3 (p=0.0001), and 75% vs 32% at month 6 (p=0.004). In logistic regression analysis, canakinumab initiation within 3 months from disease onset was significantly associated with treatment discontinuation due to long-term remission (OR 4.83, 95% CI 1.08-23.19; p=0.04). A monocyclic course occurred in 49% of patients starting canakinumab ≤3 months versus 8% starting later (p<0.0001). Starting canakinumab within 3 months from disease onset was significantly associated with a monocyclic disease course compared with the chronic-articular (RRR 4.43, 95% CI 1.12-17.60; p=0.034) and polycyclic courses (RRR 8.97, 95% CI 1.29-62.3; p=0.03). Conclusions Early canakinumab initiation is associated with treatment discontinuation due to long-term remission and appears linked to a greater frequency of a monocyclic disease course.

Background:A substantial overlap in demographic, clinical, and laboratory features can complicate the differential diagnosis between Schnitzler's syndrome and VEXAS syndrome. The present study was undertaken to identify clinical and laboratory parameters that should raise suspicion for VEXAS syndrome among patients previously diagnosed with, or under evaluation for, Schnitzler's syndrome. Methods:Data from male-only patients with Schnitzler's syndrome or VEXAS syndrome were obtained from international AIDA Network registries. Subjects with Schnitzler's syndrome were compared to VEXAS patients with urticarial skin manifestations resembling cutaneous features typically observed in Schnitzler's syndrome. Results:A total of 19 VEXAS patients and 18 patients with Schnitzler's syndrome were enrolled. At univariate binary logistic regression, the diagnosis of VEXAS syndrome was associated with the age at disease onset (OR = 1.08, 95% CI. 1.01-1.16, p = 0.02), hemoglobin levels (OR = 0.44, 95% CI. 0.26-0.77, p = 0.003), anemia (OR = 13.9, 95% CI. 3.4-5.7, p = 0.02), leucocytosis (OR = 0.04, 95% CI. 0.06-0.22, p < 0.001), lymphadenopathy (OR = 7.8, 95% CI. 1.41-45.4, p = 0.02), and thrombocytopenia (OR = 13.5, 95% CI. 1.47-123.7, p = 0.02). In the multivariable logistic regression analysis with the stepwise forward selection approach, the diagnosis of VEXAS syndrome was significantly associated with the age at disease onset (OR: 1.13, 95% CI: 1.02-1.30, p = 0.04) and the presence of lymphadenopathy (OR: 67.49, 95% CI: 5.36-3284.89, p = 0.007), while thrombocytopenia showed a trend toward statistical significance (OR: 12.02, 95% CI: 1.07-315.86, p = 0.06). Conclusions:Patients with lymphadenopathy, thrombocytopenia, anemia, particularly in older age and in the absence of leucocytosis, are more likely to be affected by VEXAS syndrome rather than Schnitzler's syndrome.

IntroductionThis study aimed to describe the clinical, genetic, and pathophysiologic features of four Italian patients from two unrelated families with retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache (ROSAH) syndrome, highlighting novel ocular and systemic manifestations and therapeutic considerations.MethodsWe report detailed phenotypic, ophthalmologic, and systemic findings in four genetically confirmed cases (eight eyes). Special attention was given to ocular and systemic manifestations and complications, inflammatory markers, systemic complications, and treatment responses.ResultsAll eyes exhibited bilateral optic disc and peripapillary involvement, cone-rod retinal dystrophy confirmed by full-field electroretinography and multimodal retinal imaging, low-grade uveitis and retinal vasculitis. Novel findings included keratoconus in one patient and dry eye in all patients. Acute angle-closure glaucoma was also observed in four eyes (two patients) with short axial lengths. Systemically, in addition to the previously described features of fever, splenomegaly, headache, dental anomalies, and anhidrosis, we report the first case of reactive amyloidosis in ROSAH syndrome, leading to severe renal failure and dialysis dependence. Splenectomy resolved recurrent fever in two patients. Conventional immunosuppressants were largely ineffective, whereas interleukin-6 inhibition provided systemic benefit but limited ocular improvement.ConclusionsROSAH syndrome presents with distinctive ocular features, and recognition of ocular surface, corneal and anterior segment anomalies further broadens its phenotypic spectrum. Reactive amyloidosis is a possible complication of ROSAH syndrome, as in other autoinflammatory disorders. Early diagnosis is critical to prevent irreversible ocular and extraocular organ damage, and to guide timely, targeted therapeutic interventions.

OBJECTIVES:The progression of Behçet's disease (BD) from a mucocutaneous-limited form to major organ involvement (MOI) represents a significant challenge. This study aims to identify patients without MOI at BD onset who are at increased risk of developing MOI in later stages. METHODS:Patients' data were drawn from the International AutoInflammatory Disease Alliance (AIDA) Network registry dedicated to BD. RESULTS:A total of 328 patients with exclusively mucocutaneous manifestations at BD onset were enrolled. Of these, 82 patients (25%) developed MOI over the entire follow-up period. Patients with minor oral aphthosis and no major oral aphthosis exhibited a reduced risk of developing MOI, with an odds ratio (OR) of 0.41 [95% confidence interval (95%CI): 0.22-0.79, P = 0.008]. Conversely, patients with both major and minor oral aphthosis had a significantly higher risk of developing MOI, with an OR of 12.76 (95%CI: 1.44-113, P = 0.02). Moreover, the development of MOI was associated with major oral aphthosis plus genital aphthosis (OR: 2.49, 95%CI: 1.1-5.6, P = 0.03), major oral aphthosis plus pseudofolliculitis (OR: 2.9, 95%CI: 1.15-7.4, P = 0.02) and major oral aphthosis plus both genital aphthosis and pseudofolliculitis (OR: 3.73, 95%CI: 1.22-11.4, P = 0.02). A positive family history for BD was associated with MOI (OR: 2.85, 95%CI: 1.08-7.58, P = 0.03). CONCLUSION:A positive family history and the presence of major oral aphthosis combined with minor oral aphthosis, genital aphthosis or pseudofolliculitis are associated with MOI development in patients with mucocutaneous BD at onset.

Biologic agents and small molecules have transformed the management of rheumatoid arthritis (RA), psoriatic arthritis (PsA), and spondyloarthritis (SpA). Nevertheless, some patients experience persistent, uncontrolled inflammation despite multiple targeted therapies. Evidence for dual targeted therapy (DTT) remains scarce. This study aims to describe the clinical characteristics, therapeutic rationale, and outcomes of patients with severe, multi-drug-refractory inflammatory arthritis and autoinflammatory disease treated with DTT. This clinical case series included patients with RA, PsA, FMF-associated SpA and Crohn’s disease, SpA-associated atopic dermatitis, and one patient with TRAPS and PsA treated with DTT. Disease activity was evaluated using validated indices, physician assessment, patient-reported outcomes, and inflammatory markers. Safety was evaluated through clinical and laboratory monitoring. Eight patients received nine DTT courses. Mean follow-up was 11.7 ± 4.3 months. Median ESR decreased from 42 mm/h (IQR 34) to 16.1 mm/h (IQR 9), and mean CRP declined from 1.52 ± 0.55 mg/dL to 0.35 ± 0.24 mg/dL. Disease activity improved across all assessed indices. One patient with FMF-associated SpA and Crohn’s disease required modification of DTT due to persistent intestinal activity and subsequently achieved remission. The prednisone dose decreased from 25 mg/day (IQR 12.5) to 2.5 mg/day (IQR 5). No adverse events were observed. DTT was associated with clinically meaningful improvements in refractory inflammatory arthritis and autoinflammatory disease, demonstrating a favourable safety profile and a clear steroid-sparing effect. These preliminary findings support its potential role in highly refractory settings, although larger studies are needed to define long-term safety and optimal therapeutic combinations.

Ixekizumab (IXE), an IL-17 A inhibitor, demonstrated efficacy in clinical trials in patients with psoriatic arthritis (PsA), and favorable data have emerged from real-world evidence studies on psoriasis as well. However, real-world data specific to PsA remain limited. This study aims to assess IXE effectiveness in reducing disease activity in patients with PsA and determine its drug retention rate (DRR) over 24 months. The secondary aim is to identify factors potentially affecting long-term persistence on therapy. A retrospective observational study was conducted. Consecutive adult patients meeting the CASPAR criteria for PsA and treated with IXE for ≥ 3 months were included. Patients were evaluated at regular intervals on a routine clinical basis for disease activity and quality of life assessment. 132 patients (78 females, 54 males; mean age 59.1 ± 11.9 years) were included. At baseline, the median (IQR) Disease Activity in Psoriatic Arthritis (DAPSA) was 16.2 (7.7), and the visual analogue scale (VAS) for pain was 6.5 (3.0). In patients with axial involvement, the median (IQR) Ankylosing Spondylitis Disease Activity Score – C-reactive protein (ASDAS-CRP) was 3.4 (1.3), and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 5.0 (1.5). IXE treatment was associated with statistically significant reductions in DAPSA (p < 0.001), ASDAS-CRP (p < 0.001), BASDAI (p < 0.001), VAS-pain (p < 0.001), Health Assessment Questionnaire (HAQ) (p < 0.001), erythrocyte sedimentation rate (p = 0.014), and CRP (p = 0.004) over 24 months. At 24 months, remission and low disease activity, according to DAPSA thresholds, were achieved by 46.7% and 93.3% of patients, respectively, while Very Low Disease Activity and Minimal Disease Activity criteria were met by 16.0% and 34.0%, respectively. IXE DRR was 82.1%, 76.3%, and 73.3% at 12, 18, and 24 months, respectively, with lower values in female patients (p = 0.036). No differences were observed in IXE DRR when stratifying the cohort by axial involvement (p = 0.84), prior exposure to biologics or tsDMARDs (p = 0.68), or body mass index (BMI) categories (p = 0.48). In conclusion, IXE enabled rapid and sustained disease control in patients with PsA across multiple disease domains. The high DRR supports its long-term use, regardless of prior biologic exposure or BMI. Gender differences in IXE treatment response may warrant further exploration.

ObjectivesThis study aims to explore the application of machine learning techniques in assessing macrophage activation syndrome (MAS) in Still’s disease.MethodsA multicenter, observational, prospective study was conducted, including patients with Still’s disease enrolled in the Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) AOSD Study Group and the AutoInflammatory Disease Alliance (AIDA) Network Still’s Disease Registry.ResultsA total of 737 patients (age: 35.5 ± 17.8, male sex: 44.7%) with Still’s disease were assessed; 11.4% were affected by MAS, and 3% had a poor prognosis. First, random forest imputation was applied to the original dataset. Subsequently, a machine-learning-driven assessment was developed to explore MAS occurrence. Collectively, regression models, an exploration decision tree, and a random forest were applied, suggesting the importance of ferritin, age, C-reactive protein (CRP), and systemic score. A logistic regression model accounting for data leakage concerns was then generated using these variables, and missing values were imputed using random forest imputation. This analysis supported the role of the selected variables, which were further combined across different clinical scenarios to estimate the probability of MAS. The highest risk of MAS was estimated for patients simultaneously characterized by age ≥ 45 years, ferritin ≥ 4,178.10 ng/mL, CRP ≥ 27.15 mg/L, and a systemic score ≥ 7, corresponding to a 34.7% probability of MAS, as well as for those characterized by ferritin ≥ 4,178.10 ng/mL, CRP ≥ 27.15 mg/L, and systemic score ≥ 7, corresponding to a 33.5% probability of MAS.ConclusionsA machine-learning-driven prediction of MAS was explored in Still’s disease, highlighting the importance of age of onset, hyperferritinaemia, increased CRP, and multiorgan involvement. A combination of these features may suggest a clinician-friendly algorithm for stratifying the probability of MAS during Still’s disease.