u/Alice-The-Chemist

AB0404 (2026)

BASELINE CLINICAL AND LABORATORY PREDICTORS OF NEW MAJOR ORGAN INVOLVEMENT IN BEHÇET’S DISEASE: RESULTS FROM AN INCEPTION COHORT

Keywords: Prognostic factors, Biomarkers, Uveitis, Descriptive Studies, Rare/orphan diseases

R. Deniz1, O. Altun1, A. Gül2, C. Bes1

1University of Health Sciences Başakşehir Çam ve Sakura City Hospital, Rheumatology, Istanbul, Türkiye

2İstanbul University Faculty of Medicine, Department of Internal Medicine Division of Rheumatology, İstanbul, Türkiye

Background: Behçet’s disease (BD) is a chronic, relapsing, multisystem inflammatory disorder characterized by a wide clinical spectrum ranging from mucocutaneous manifestations to severe, life-threatening major organ involvement (MOI), including ocular, vascular, neurological, and gastrointestinal disease. Early identification of patients at risk for progression to MOI is a major unmet need in routine clinical practice, as delayed recognition is associated with irreversible organ damage, disability, increased morbidity, and mortality. Although several clinical features have been associated with MOI in cross-sectional studies, there is limited prospective inception-cohort evidence evaluating which baseline clinical or laboratory characteristics may predict the development of new major organ involvement (NMOI) during follow-up. Understanding these predictors may support risk stratification and guide early intensified monitoring or tailored immunosuppressive strategies.

Objectives: This study aims to address this gap by investigating the prognostic value of baseline demographic, clinical, and routine laboratory parameters for predicting incident NMOI in a well-defined cohort of newly diagnosed BD patients whether a MOI is present or not at diagnosis.

Methods: This study was designed as a prospective inception cohort including patients newly diagnosed with BD according to the International Study Group (ISG) criteria. Demographic features, clinical manifestations, and routine laboratory parameters were systematically recorded at diagnosis and at scheduled follow-up visits. Major organ involvement (MOI) was defined as ocular, vascular, neurological, or gastrointestinal involvement meeting accepted clinical and radiological criteria. Patients were classified into two groups: those who developed new MOI (NMOI) during follow-up in addition to MOI at diagnosis and those who did not. Follow-up outcomes included type and timing of new MOI, relapse frequency, treatment response, and cumulative organ involvement.

Results: A total of 117 patients were included in the inception cohort, of whom 16 developed at least one new major organ involvement (NMOI) during follow-up. Sex distribution was similar between groups, whereas patients who developed NMOI were older at baseline (32 vs 39.5 years, p=0.087). Although MOI at diagnosis appeared more frequent in the group without NMOI, none of the phenotypes differed significantly. Detailed characteristics are presented in Table 1. Among the 16 NMOI cases, the distribution was as follows: 5 ocular, 9 vascular, 1 neurological, and 2 gastrointestinal events; 1 patient developed both ocular and vascular involvement.

Baseline clinical manifestations were generally comparable between the two groups, with the exception of folliculitis, which was significantly more common in patients who did not develop NMOI (64.4% vs 37.5%, p=0.040). Genital ulcers also tended to be less frequent among patients who later developed NMOI, although this difference did not reach statistical significance (66.3% vs 56.3%, p=0.302).

During follow-up, thrombotic vascular events, specifically uveitis, superficial thrombophlebitis, deep venous thrombosis, arterial, and gastrointestinal involvement, were more frequent in the NMOI group (Table 2). Presentation with MOI at diagnosis did not differ between groups; however, baseline CRP and ESR levels were tended to be higher in patients who subsequently developed NMOI (CRP 6 vs 22.7 mg/L, p=0.034; ESR 11.5 vs 25 mm/h, p=0.005). HLA-B51 positivity was not associated with NMOI development (p>0.05). By the last visit, the NMOI group had significantly higher frequencies of ocular, vascular, and gastrointestinal involvement. Cumulative follow-up duration was longer in NMOI group (24 vs 28.5 months, p=0.06). Relapse rate was similar during follow up and patients with NMOI has more active status at last visit (10.9 vs 31.1%, p=0.025).

Conclusions: In this inception cohort, some certain baseline clinical and laboratory features were associated with the development of NMOI in Behçet’s disease. While recurrent oral ulcers appeared to be a universal and phenotype-independent manifestation, folliculitis and genital ulcers were more characteristic of a stable phenotypic course and seemed to be associated with a lower likelihood of progression to NMOI.

Conversely, elevated acute phase reactants (CRP, ESR) at diagnosis emerged as potential predictors of NMOI, likely reflecting subclinical inflammatory and ischemic pathways that predispose to vascular and ocular complications. Importantly, HLA-B51 positivity did not differentiate patients who developed NMOI from those who did not, indicating limited prognostic value in this context.

These findings highlights the importance of a comprehensive baseline clinical and laboratory assessment in newly diagnosed BD patients. Identifying high-risk individuals early may allow clinicians to personalize follow-up intensity, implement more vigilant monitoring strategies, and potentially initiate timely therapeutic interventions to prevent irreversible organ damage.

Table 1. Clinical characteristics of Behçet’s disease patients with and without major organ involvement (MOI) at diagnosis

NOD2

OP0325 (2026)

ASSOCIATION OF NOD2 VARIANTS WITH CLINICAL PHENOTYPES IN AUTOINFLAMMATORY DISEASE: INSIGHTS FROM A COHORT THROUGH A VALIDATED NEXT-GENERATION SEQUENCING PANEL

Keywords: Rare/orphan diseases, Innate immunity, Epitranscriptomics, Epigenetics, And genetics

M. Schermi1, M. T. Perez-Cartier Beingolea2, S. Rizzo1, A. Fu1, S. Moz2, P. Galozzi2, R. Ramonda1, P. Sfriso1, S. Bindoli1

1University of Padova, Rheumatology Unit, Department of Medicine (DIMED), Padova, Italy

2University of Padova, Laboratory Medicine Unit, Department of Medicine (DIMED), Padova, Italy

Background: Variants in the NOD2 gene are associated with increased susceptibility to a broad spectrum of diseases, ranging from granulomatous conditions (e.g. Crohn’s disease, Blau syndrome) to autoinflammatory disorders, such as Yao syndrome. These variants may variably affect NOD2 protein function, depending on the specific mutation, resulting in altered innate immune signaling and dysregulated inflammatory responses upon microbial stimulation. In recent years, targeted next-Generation Sequencing (NGS) gene panels have become a cornerstone of molecular diagnostic, enabling confirmation or diagnostic support for genetically heterogeneous disorders, including adult-onset conditions associated with NOD2 variants.

Objectives: This study aimed to identify amongst adult patients with autoinflammatory manifestation, such as recurrent fever, skin rashes, and gastrointestinal symptoms, those who present NOD2 variants. Additionally, we sought to explore whether specific NOD2 variants correlate with distinct clinical phenotypes, potentially allowing the reclassification of adult patients from the nonspecific “undifferentiated autoinflammatory disease” (uSAID) into potential emerging subgroups of NOD2-related disorders. These conditions span a phenotypic continuum encompassing granulomatous diseases, intestinal pathologies, and autoinflammatory disorders.

Methods: Patients with clinical and biochemical features suggestive of autoinflammatory disease and referred to the outpatient clinic for between February 2023 to December 2025. NGS sequencing was performed using Custom “Fever & Autoinflammatory Disease” panel (SOPHIA Genetics) on an Illumina MiSeq platform. The panel covers the coding regions of 17 genes ( ADA2, CARD14, ELANE, IL10RB, IL10RB, IL1RN, LPIN2, MEFV, MKV, NLRP12, NLRP3, NLRP7, NOD2, PSMB8, PSTPIP1, TNFRSF11A, TNFRSF1A ). Variant calling and data analysis were performed by the Sophia-DDM-V6.5 pipeline. Variant interpretation followed the 2015 ACMG standards and guidelines.

Results: A total of 135 patients (80 females; mean age 37.08 ± 14 years) were enrolled. Of these, 115 patients (85.1%) carried at least one retained non-synonymous variant with a minor allele frequency (MAF) ≤ 0.05. Among them, 25 patients (18%) harbored at least one NOD2 variant classified as pathogenic or as a variant of uncertain significance (VUS). The identified NOD2 variants included heterozygous p.G908R (8 patients), p.R702W (7 patients), p.Leu1007Profs*2 (7 patients), p.A885P (1 patient), p.R1019L (1 patient), and p.S402F (1 patient). The clinical features associated with each variant are detailed in Figure 1 .

Eight of the 25 patients (32%) presented with recurrent fever and skin rashes, along with at least one additional symptom (such as abdominal pain, serositis, arthritis/arthralgia, or sicca manifestation), which may be compatible with a Yao syndrome–like clinical phenotype [1]. The remaining patients did not fully meet the established diagnostic criteria. Two main clinically defined patient groups were identified: one characterised by the p.G908R variant and the other by the p.R702W variant. Almost all patients in both clusters experienced recurrent fever and musculoskeletal symptoms, including arthritis, arthralgia, and myalgia. Abdominal pain was observed in 50% of patients carrying the p.G908R variant, whereas skin rashes were more prevalent among those with the p.R702W variant (71%). Additionally, 57% of patients with the p.Leu1007Profs*2 variant reported headache. About additional genetic findings, among the p.G908R carriers, 5 out of 8 patients also harbored VUS in MEFV gene (3 patients), one had a pathogenic variant in ADA2 , and one had a variant in LPIN2 . Among p.R702W carriers, one patient presented a heterozygous MEFV variant. For those with the p.Leu1007Profs*2 variant, one patient had a co-variation in NOD2 (p.R439C) and another had a pathogenic variation in ADA2 . Additionally, one patient with the p.A885P variant also harbored a VUS in ELANE . The two patients with pathogenic variations in ADA2 did not exhibit typical features of DADA2 and responded adequately to colchicine. All patients with additional VUS in MEFV showed a favourable response to colchicine. Granulomatous skin lesions developed in only one patient with the p.S402F variant, while ascertained inflammatory bowel disease was observed in a patient with the p.Leu1007Profs*2. The coexistence of additional variants in autoinflammatory genes supports a potential oligogenic or modifier-gene contribution to disease expression. Regarding treatment, patients with two VUS across the same or different genes (13 out of 25, or 52%) generally experienced a higher burden of inflammatory symptoms. Eight of these patients had a satisfactory response to colchicine, and in three cases, a combination of colchicine and IL-1 inhibitors resulted in a better clinical outcome.

Conclusions: The use of validated targeted NGS panel is essential for identifying variants that can support or refine clinical diagnosis in autoinflammatory disorders. NOD2-related diseases encompass a wide range of conditions that may not always align with established diagnostic categories such as Yao syndrome, Blau syndrome, or Crohn’s disease. Although patients carrying VUS are typically classified as having uSAID due to uncertain variant pathogenicity, the identification of patient clusters sharing the same NOD2 variants and exhibiting overlapping clinical profiles suggests the existence of previously unrecognized gene-related entities. Further investigations, including whole-exome sequencing and functional studies, are warranted to refine diagnostic frameworks and improved genotype-phenotype interpretation in individuals withNOD2 variants.

Figure 1.

Heatmap illustrating the prevalence of the main clinical features associated with each NOD2 variant detected after NGSseq