Objectives The objective of this study was to evaluate and update the evidence on pharmacologic and interventional treatments for major organ involvement in Behçet syndrome (BS), in order to inform the 2025 update of the European Alliance of Associations for Rheumatology recommendations. Methods A systematic literature review was conducted using 2 distinct search strategies for pharmacologic and surgical/interventional therapies, covering major databases from October 2015 to November 2024. Controlled studies comparing active interventions with placebo or another active treatment were included. If no controlled trials were available for a specific research question, uncontrolled studies or case series with at least 10 patients with BS were included. Results Of 7128 citations, 69 studies on major organ involvement and tapering/withdrawal of immunosuppressives were included. Only 5 were randomised controlled trials (RCTs), 4 of them included patients with eye involvement, and 1 included patients with vascular or nervous system involvement. RCTs and comparative observational studies for eye involvement supported the use of monoclonal tumour necrosis factor alfa inhibitors and interferon alfa. The RCT that included patients with vascular or nervous system involvement favoured infliximab over cyclophosphamide based on complete response rates and safety. Observational data additionally supported the use of interferon alfa for venous thrombosis, whereas the role of adjunctive anticoagulation remains unclear. Noncomparative observational studies showed benefit with monoclonal tumour necrosis factor alfa inhibitors in patients with gastrointestinal involvement. Conclusions This systematic literature review provided evidence on the management of major organ involvement to inform the task force for developing the 2025 update of the European Alliance of Associations for Rheumatology recommendations for the management of BS.

ObjectivesBehçet’s disease (BD) is a systemic vasculitis with inflammatory lesions mediated by cytotoxic T cells and neutrophils. Here, we explore the critical involvement of NF-κB signaling pathway in proinflammatory CD8+ T cells differentiation and disease progress of BD patients.MethodsWe performed microarray gene expression analyses, flow cytometry, immunophenotyping, immunohistochemistry and functional assessments of CD8+ T cells from BD patients and HD.ResultsTranscriptionally, among the 6,595 up-regulated genes in CD8+ T cells of BD vs HD, we highlighted a great enrichment for pathways linked to NF-κB and TLR signaling (i.e. NFKB1, RELB, REL, TLR1, IRF4). Phenotypically, CD8+ T cells from BD had a higher expression of phosphorylated NF-κB (pNF-κB, 4.4 ± 0.9 vs. 1.8 ± 0.2 in MFI, p = 0.001), were more activated (higher CD11c, CD11b, CD25 and TNF-α, IFN-γ expression) and exhibited more expression of Perforin and Granzyme B (33% ± 9 vs. 9 ± 5, p = 0.009, 47% ± 8 vs.21% ± 6, p = 0.02, respectively) as compared to HD. Phosphodiesterase-4 (PDE4), an immune cell enzyme that activate the NF-κB pathway was up-regulated in blood and skin lesions of BD. In vitro and in vivo inhibition of PDE4 strongly inhibited CD8+ T cell activation, cytokine secretion, cytotoxicity and proliferation.ConclusionWe highlighted that activated CD8+ T cells through NF-κB signaling pathway are instrumental in BD.

BACKGROUND:Indolent systemic mastocytosis (ISM), a clonal mast cell disease primarily driven by the KIT D816V mutation, can cause long-term debilitating symptoms and poor quality of life. Most patients rely on symptom-directed best supportive care (BSC) medications, which do not treat the underlying driver of ISM. Avapritinib, an oral, potent, selective KIT D816V inhibitor, is approved in adults with ISM. OBJECTIVE:We sought to understand the long-term efficacy and safety of avapritinib in ISM. METHODS:The PIONEER trial (NCT03731260) enrolled adults with moderate to severe ISM symptoms. Patients initiated avapritinib 25 mg once daily (QD; recommended dose) plus BSC in part 1, 2, or 3; open-label part 3 is ongoing with up to 5 years of follow-up. As per investigator discretion and disease burden, a dose increase up to avapritinib 50 mg QD was permitted in part 3. RESULTS:As of February 21, 2025, 226 patients initiated avapritinib at 25 mg QD. The median (range) treatment duration was 40.0 (0.7-67.2) months. Patients receiving avapritinib experienced durable and clinically meaningful symptom improvement (mean change, -19.39 [n = 127] in the Indolent Systemic Mastocytosis Symptom Assessment Form total symptom score) through approximately 3 years. Avapritinib continued to be well tolerated for a longer term with a safety profile comparable with the previously reported placebo-controlled portion. Most treatment-related adverse events (TRAEs) were grades 1 to 2, with limited grade 3 or higher reported. Edema events were the most frequent TRAEs (mostly grade 1). Serious TRAEs occurred in 3 patients (1%), and 7 patients (3%) discontinued treatment because of TRAEs. CONCLUSIONS:Long-term follow-up (median, ∼3 years) demonstrates that avapritinib is effective and well tolerated. Avapritinib shows a favorable benefit-risk profile as a chronic ISM treatment.

Objectives We aimed to update the evidence for the management of mucocutaneous and joint involvement of Behçet’s syndrome (BS) to inform the 2025 update of European Alliance of Associations for Rheumatology (EULAR) recommendations. Methods A systematic literature review was conducted to evaluate the benefits and harms of therapeutic interventions in patients with BS. All comparative studies were included, and in the absence of controlled studies for a specific intervention, noncomparative studies were also considered. We presented here the summary of the outcomes for mucocutaneous and joint involvement, overall disease activity and health-related quality of life (HRQoL). Results Among the 7128 articles, 16 studies (7 randomised controlled trials [RCTs]) reported on mucocutaneous involvement, joint involvement, overall disease activity, or HRQoL. Apremilast was superior to placebo for oral ulcers in an RCT with low risk of bias (RoB). Few patients experienced genital ulcers, skin lesions, or arthritis during the 12 weeks. In the first head-to-head RCT with low RoB comparing adalimumab with infliximab, both drugs provided similar response rates for mucocutaneous manifestations, with a more rapid response observed with adalimumab. In other head-to-head RCTs, all with low RoB except for 1 with some concerns, the efficacy of immunosuppressive agents was confounded by concomitant glucocorticoid use for major organ involvement and by the small number of patients with active mucocutaneous manifestations. Conclusions This systematic review supported the use of apremilast and tumour necrosis factor alpha inhibitors in patients with refractory mucocutaneous involvement and provided evidence for updating the 2025 EULAR Recommendations for the management of mucocutaneous and joint involvement of BS.

Objectives This study aims to update the European Alliance of Associations for Rheumatology (EULAR) recommendations for the management of Behçet’s syndrome according to the updated EULAR standard operating procedures. Methods The task force comprised 29 members from 11 countries, including 19 rheumatologists, 2 ophthalmologists, 1 dermatologist, 1 gastroenterologist, 1 neurologist, 1 health professional, 2 patient research partners, and 2 Emerging EUlar NETwork members. Research questions were proposed by the task force through a Delphi survey and formulated into patients, interventions, comparison, and outcomes (PICO) questions for the systematic literature review. The results of the systematic literature review were discussed among the task force members. Previous recommendations and overarching principles were modified, and new recommendations were developed as needed. The updated recommendations were voted, and the levels of evidence and levels of agreement were determined. Results The updated recommendations consist of 5 overarching principles and 12 recommendations that were tabulated according to organ involvement. Among the 12 recommendations, 1 was a new recommendation, 7 recommendations were modified, and only the wording was changed in 4 recommendations. The overarching principles focus on the importance of recognising the relapsing and remitting disease course and individualising treatment according to disease activity and prognostic risk factors, and emphasise the importance of a multidisciplinary approach, patient education, and shared decision making for optimal care. For mucocutaneous and joint involvement, colchicine is recommended as the first-line treatment modality. Apremilast and immunosuppressives such as tumour necrosis factor alpha (TNFα) inhibitors are recommended for refractory patients. For patients with organ involvement, more aggressive treatment with glucocorticoids and immunosuppressives is recommended for rapid induction of remission. Early use of monoclonal antibodies against TNFα is encouraged in patients with organ or life-threatening manifestations. Conclusions These recommendations, which were updated based on new evidence and expert opinion, provide guidance for all stakeholders involved in the management of patients with Behçet’s syndrome to improve the quality of care of these patients.

BACKGROUND:Indolent systemic mastocytosis (ISM), a clonal mast cell disease driven by the KIT D816V mutation, can often cause debilitating dermatologic symptoms. OBJECTIVE:Assess improvement of ISM-related skin manifestations after treatment with avapritinib, a highly selective KIT D816V inhibitor, vs placebo in Part 2 of the PIONEER study (NCT03731260). METHODS:Patients with moderate to severe ISM received avapritinib 25 mg once daily (n = 141) or placebo (n = 71). Endpoints included skin lesion area and pigmentation at week 24, skin mast cell burden, and change in symptoms. RESULTS:Mean percent reduction in lesional surface area was -36.6% with avapritinib vs -1.8% with placebo in the most affected area; 86% vs 0% had improved skin lesion color. Mean percent change in skin mast cell burden decreased with avapritinib (-22.1%) vs placebo (10.1%). Avapritinib vs placebo significantly improved skin symptom domain score (mean change -7.2 vs -2.8; P < .0001), including the individual skin symptoms itching, flushing, and spots. Avapritinib was well tolerated. LIMITATIONS:Photography was optional, so analysis population for lesion area and color were smaller (n = 111) than the overall study population (n = 212). CONCLUSION:Avapritinib treatment improved dermatologic symptoms, decreased skin lesion size, normalized skin lesion color, and reduced skin mast cell burden in patients with ISM.

Systemic mastocytosis (SM) is a spectrum of hematologic disorders characterized by accumulation of atypical mast cells (MCs) in extracutaneous organs. SM with an associated hematologic neoplasm (SM-AHN), the most frequent subtype of advanced SM, is predominantly associated with myeloid neoplasms, consistent with shared clonal architecture. Because of its rarity and heterogeneity, robust outcome data aligned with contemporary classifications are needed to inform risk stratification. We analyzed the 10th data wave of the European Competence Network on Mastocytosis registry (34 European centers and 1 US center). SM and AHN diagnoses followed the 2022 World Health Organization classification. Baseline characteristics and overall survival (OS) were compared between patients with myeloid SM-AHN and SM without AHN (SM-no-AHN). Within SM-AHN, outcomes were analyzed by SM component (advanced: aggressive SM [ASM] or MC leukemia [MCL] vs. non-advanced: bone marrow mastocytosis, indolent SM, or smoldering SM) and AHN subtype. Among 3,925 patients with SM, 467 (11.9

Cutaneous T-cell lymphomas (CTCLs) are rare, usually refractory, and sometimes fatal diseases. Patients presenting with advanced-stage CTCL usually exhibit poor long-term survival outcomes. Only very few treatments have improved progression-free survival (PFS) in advanced CTCL, and no treatment has increased overall survival (OS). In 2023, the results of the CUTALLO trial supported the hypothesis that hematopoietic stem-cell transplantation (HSCT) was associated with significantly longer PFS as compared with standard-of-care treatment among advanced-stage patients although HSCT did not significantly affect OS. We provide herein the final OS data pertaining to the same patient population after a longer median follow-up of 38.9 months. Of the 99 patients included in the analysis, 55 (56%) were assigned to the HSCT group, whereas 44 (44%) were allocated to the non-HSCT group. The updated survival analysis reported that 16 of 55 patients (29%) in the HSCT group and 22 of 44 patients (50%) in the non-HSCT group died. The median OS was not reached in the HSCT group and 51.5 months (95% CI, 26.9 to 51.5) in the non-HSCT group (hazard ratio, 0.40 [95% CI, 0.20 to 0.80]). Compared with the standard of care for advanced CTCL, after extended follow-up, allogeneic HSCT was associated with significantly longer OS.

Background The KIT D816V mutation is a hallmark of clonal mast cell disease (cMCD) including systemic mastocytosis. cMCD diagnosis is frequently delayed because of variable symptoms until confirmatory bone marrow biopsy is performed. Screening techniques for KIT D816V variant in peripheral blood (PB) may facilitate diagnosis. Prevalence of KIT D816V in patients with anaphylaxis or mast cell activation (MCA) symptoms is unknown. Objective We sought to determine the prevalence of KIT D816V in PB of patients with anaphylaxis or systemic MCA symptoms. Methods The PROSPECTOR trial (NCT04811365) included patients with anaphylaxis or systemic MCA symptoms who had (1) moderate to severe anaphylaxis to Hymenoptera sting, (2) 20% + 2 ng/mL increase in tryptase level over the baseline level during moderate to severe anaphylaxis with cardiovascular involvement, and/or (3) involvement of both the cardiovascular system and 1 or more other organ systems with basal serum tryptase (BST) levels greater than or equal to 8 ng/mL. KIT D816V in PB, hereditary α-tryptasemia (HaT), and BST levels were centrally evaluated. Results Of the 381 enrolled patients, 179, 76, and 203 were in groups 1, 2, and/or 3, respectively. Fifteen patients (4%) had detectable KIT D816V in PB; 12 of 15 (80%) had BST levels less than 20 ng/mL. Most patients with KIT D816V (11 of 15 [73%]) had Ring-Messmer grade III/IV anaphylaxis. Fourteen additional patients with BST levels greater than 11.4 ng/mL, no HaT, and local follow-up were diagnosed with cMCD, totaling 29 of 381 patients (8%) with cMCD in the PROSPECTOR trial. The overall prevalence of HaT was 36% (138 of 381). Conclusions The PROSPECTOR trial demonstrated a meaningful KIT D816V prevalence in patients with anaphylaxis or systemic MCA symptoms; more frequent and sensitive screening for KIT D816V is needed in this patient population.

Mastocytosis is categorized into cutaneous mastocytosis (CM), mast cell sarcoma and systemic mastocytosis (SM). Within SM, indolent SM (ISM) is the more frequent subtype. Adult patients with CM but without an extracutaneous biopsy are classified as having mastocytosis in the skin (MIS), a provisional diagnosis. Mastocytosis patients may experience a wide range of symptoms that significantly impact their quality of life (QoL). In France, the estimated prevalence of mastocytosis and the burden of symptoms remain unknown. To address this, we conducted a national online survey to estimate the number of mastocytosis diagnoses and assess the burden of symptoms from the physician's perspective. Overall, 1169 of the 6239 physicians solicited completed the survey. These physicians reported managing 4121 patients of whom only 53% had ISM. By contrast, CM and MIS were reported in more patients than expected at 17% and 25% respectively. The estimated prevalence of mastocytosis in France was 8.5 per 100,000, which is lower than recent epidemiological studies and is associated with significant regional variability (p < 0.001). Among patients with ISM or MIS, 53% experienced moderate to severe symptoms-mainly affecting the skin, digestive system and general health-which impacted most QoL domains assessed. These findings highlight the need to improve awareness, access to diagnostic workup for mastocytosis (especially for patients with MIS and CM) and enhance QoL for patients.

Background: Systemic mastocytosis (SM) comprises a spectrum of subtypes characterized by neoplastic mast cell (MC) infiltration of tissues and release of MC mediators. Non-advanced SM (NonAdvSM), including indolent SM (ISM), smoldering SM (SSM), and bone marrow mastocytosis (BMM) subtypes, is the most prevalent form of SM. NonAdvSM can be associated with debilitating symptomology which can significantly impair quality of life. The gain-of-function somatic KIT c.2447 C>T (p.D816V) mutation is found in up to 95% of patients with SM. Bezuclastinib (CGT9486) is an oral, potent, and selective type 1 tyrosine kinase inhibitor with activity against KIT D816V. Results from Summit (NCT05186753) Part 1 informed the recommended phase 2 dose (100 mg QD bezuclastinib) for Part 2. We report topline results from the 24-week assessment of Summit Part 2. Methods: Summit is a multi-center, randomized, double-blind, placebo (PBO)-controlled Phase 2 trial of bezuclastinib in patients with NonAdvSM who had inadequate symptom control despite best supportive care (BSC) medications. The primary endpoint was 24-week mean change from baseline in Mastocytosis Symptom Severity Daily Diary (MS2D2) total symptom score (TSS) (range 0–110), which is a fit-for-purpose patient-reported outcome measure of NonAdvSM symptom severity. Key secondary endpoints included the proportion of patients with ≥50% reduction in serum tryptase, KIT p.D816V variant allele frequency (VAF), bone marrow (BM) MC burden, and MS2D2 TSS, ≥30% TSS reduction. Patients were randomized 2:1 to receive 100mg QD bezuclastinib + BSC or PBO + BSC. Results: As of May 22, 2025, 179 patients were enrolled in Part 2: 119 were randomized to receive bezuclastinib and 60 to placebo. Patients enrolled were representative of the NonAdvSM population with moderate to severe symptoms. Median age (range) was 51 (23-78) years; 65.9% female; mean (SD) baseline MS2D2 TSS 55.6 (19.8); 82% of patients had ISM, 11% had BMM, and 7% had smoldering SSM. At baseline, median (range) KIT p.D816V VAF in whole blood, BM MC burden, and serum tryptase was 0.25% (0-34%), 10% (1-75%), and 40 (6-692) ng/mL, respectively. Bezuclastinib demonstrated statistically significant superiority to placebo on all primary and key secondary endpoints. At Week 24, bezuclastinib led to significantly greater symptom improvement vs placebo (LS mean [95% CI] MS2D2 TSS change: –24.3 [–27.6 to –21.1] vs –15.4 [–19.6 to –11.2]; placebo-adjusted difference: –8.9 points; P=0.0002). A ≥50% reduction in serum tryptase was achieved in 87.4% of bezuclastinib-treated patients vs 0% on placebo (P<0.0001). Significantly more patients receiving bezuclastinib achieved ≥50% reductions in KIT D816V VAF, serum tryptase, BM MCs (P<0.0001), MS2D2 TSS (P=0.01), and ≥30% reduction in MS2D2 TSS (P=0.0004). Most treatment-emergent adverse events (TEAEs) were low grade (gr; 70% Gr 1) and reversible. The most common TEAEs (≥10%) in any treatment group and occurring in greater frequency in the bezuclastinib arm were hair color changes (69.5% vs 5.0%), altered taste (23.7% vs 0%), nausea (22.0% vs 13.3%), increased ALT/AST (22.0% vs 6.6%), headache (17.8% vs 11.7%), alopecia (11.9% vs 3.3%), and increased ALP (10.2% vs 3.3%). TEAEs (≥10%) that occurred more often in the placebo group were diarrhea (13% vs 18%), dizziness (10% vs 12%), fatigue (7% vs 12%), and arthralgia (6% vs 15%). ALT/AST elevations ≥Gr 3 were experienced by 5.9% of patients. The only hepatic adverse events (AEs) reported were transient lab abnormalities; none required hospitalization. Treatment-related AEs requiring dose reductions occurred in 11% of patients receiving bezuclastinib. All discontinuations (5.9%) due to treatment-related AEs were due to transaminase elevations; all fully resolved. Conclusions: At 24-weeks, bezuclastinib 100 mg QD demonstrated statistically and clinically significant improvements in symptom burden and biomarkers of disease vs placebo in patients with NonAdvSM. The treatment was generally well-tolerated and effective across a population that is representative of the real-world NonAdvSM population, including SSM. These results support the use of bezuclastinib to reduce SM burden and symptoms in pts with NonAdvSM, and a potentially disease-modifying impact.

BACKGROUND:Systemic mastocytosis (SM) is a clonal mast cell disease primarily driven by the KIT D816V mutation and often characterised by unpredictable and debilitating symptoms. The Perceptions Realities and Insights on Systemic Mastocytosis (PRISM) survey queried patient and provider perceptions of SM in Europe. METHODS:PRISM (funded by Blueprint Medicines Corporation) was composed of two independent surveys: a 119-item patient survey on diagnosis, symptom burden, quality of life (QoL) and work impact; and a 103-item healthcare provider (HCP) survey on approaches to SM diagnosis and management. RESULTS:Data were evaluated from 540 patient respondents from Italy (n = 136), France (n = 112), the UK (n = 101), Germany (n = 83), Spain (n = 64), Austria (n = 26) and Switzerland (n = 18). Patients reported a high symptom burden and reduced physical functioning and mental health due to SM, despite taking, on average, seven medications. A majority of patients reported that SM impacted their ability to work (58.9%). A total of 618 HCP responses were collected from Italy (n = 203), Germany (n = 123), the UK (n = 110), Austria (n = 63), France (n = 56), Switzerland (n = 44) and Spain (n = 19). Various HCP types reported treating patients with SM; the majority were haematologists/oncologists (n = 167) and general practitioners (n = 178). HCPs perceived that SM impacted their patients' QoL, with 54% reporting SM affected patients' lives 'quite a bit'. The most frequently reported treatment goals were improving QoL and survival. CONCLUSIONS:PRISM is the largest international and first European survey to evaluate the burden of SM from both patient and HCP perspectives. Patients and HCPs perceived a high symptom burden, reduced QoL and reduced ability to work due to SM.

Prérequis/Contexte Hereditary alpha-tryptasemia (HαT) corresponds to additional copies of the α-tryptase coding TPSAB1 gene, is reported in 5% individuals in Western countries, and was associated with basal serum tryptase (bST) levels above 8μg/L with high sensitivity. However, the specificity of this cut-off in the general population remains to be evaluated. In addition, there is very little knowledge regarding other tryptase gene copy number variations (TGCNV) such as β-duplications or tryptase gene deletions. Objectifs (i) To evaluate the prevalence of TGCNVs in a birth cohort; (ii) to determine bST levels associated with TGCNVs; (iii) to compute optimal bST cut-offs and performances to investigate for HαT. Méthodes The PARIS cohort is a French ongoing population-based prospective birth cohort. The population study included all 606 PARIS teenagers at age 15/16 years who received blood sampling, for bST measurements and TGCNV evaluation. Résultats/Discussions In our study population, 5.6% (34/606) teenagers presented TGCNV: 3% (18/606) with HαT, 2.0% (12/606) with tryptase gene deletion; 0.7% (4/606) with β-tryptase gene duplication. Participants with HαT presented with higher bST as compared with wild-type participants. Participants with β-duplications displayed intermediate bST between wild-type (P=0.0018) and HαT+ participants (P=0.033). Participants with deletion displayed lower bST as compared to wild-type (P=0.030). 8/26 (34.6%) teenagers with bST ≥8μg/L did not present TGCNV. The optimal bST thresholds for HαT was 7.2μg/L, with associated sensitivity of 94.4%, specificity of 96.0%, negative predictive value of 99.8%, but positive predictive values of 42.5%. Conclusion All TGCNVs (HαT but also β-duplication and deletions) are frequent in the general population. All appear to modulate circulating bST levels. The optimal bST cut-off to investigate for HαT was 7.2μg/L. However, a significant proportion of HαT–individuals from the general population will display bST values above this cut-off or even 8μg/L.