The prediagnostic period of Behçet's disease: a nationwide population-based study

The diagnosis of Behçet's disease (BD) is often delayed because its characteristic manifestations may emerge sequentially over time. Whether BD is preceded by a clinically active prediagnostic phase remains unclear. We aimed to characterize the clinical and laboratory features during the five-year period preceding the formal diagnosis of BD.

We conducted a nationwide retrospective matched case-control study using the electronic health records of Leumit Health Services. Patients with BD fulfilling the International Criteria for Behçet's Disease or International Study Group classification criteria were identified by manual chart review and matched 1:5 with controls by sex, age, socioeconomic category and year of first observation. Clinical diagnoses, diagnostic investigations and laboratory measurements and medication dispensing recorded during the five years preceding diagnosis were compared between groups. Early and late laboratory measurements within the prediagnostic period were analyzed to assess temporal trends. Manifestations documented over the entire available record were analyzed separately.

The study included 218 patients who subsequently developed BD and 1,090 matched controls. During the five years preceding diagnosis, future patients with BD more frequently exhibited oral aphthosis (36.2% vs 3.0%; OR 18.2), panuveitis (4.6% vs 0.1%; OR 52.4), inflammatory polyarthritis (7.3% vs 0.6%; OR 14.3), and venous thromboembolism (4.6% vs 0.2%; OR 26.2) (all P<0.001). Over the entire available record, oral aphthosis was documented in 61.0% of patients with BD and 11.8% of controls. Autoimmune serology was frequently requested but remained largely negative. Laboratory analyses demonstrated a biphasic trajectory. Absolute monocyte count and the neutrophil-to-lymphocyte ratio were lower than in controls at the early assessment (0.40 vs 0.44 ×10⁹/L, P = 0.009, and 1.45 vs 1.49, P = 0.023) but significantly higher near diagnosis (0.64 vs 0.58 ×10⁹/L, P = 0.025, and 2.44 vs 2.09, P = 0.003). This transition was accompanied by rising CRP, ESR, platelet count and globulin levels, persistently lower mean corpuscular volume and consistently higher IgA at both assessments (247 vs 189 mg/dL, P = 0.009, and 256 vs 189 mg/dL, P = 0.012), whereas IgG and IgM remained comparable between groups.

BD seems to be preceded by a clinically and biologically active prediagnostic phase characterized by a distinct inflammatory multisystem footprint.