Serofast Syphilis Is Associated with Phospholipid-Dependent Coagulation Abnormalities and B-Cell Activation Following Treatment

A substantial proportion of patients treated for early syphilis fail to achieve the expected ≥4-fold decline in non-treponemal titers despite appropriate therapy. This serofast state remains a common clinical dilemma, and repeated antibiotic therapy is often ineffective. We hypothesized that persistent seroreactivity may reflect infection-associated immune dysregulation rather than ongoing infection. In this prospective study, 36 adults with early syphilis were treated with benzathine penicillin. At 6 months, 11 patients with inadequate serological response underwent cerebrospinal fluid evaluation; 3 with neurosyphilis were excluded. The remaining 33 patients were classified as serofast (n = 8) or serologically cured (n = 25). Eleven healthy individuals served as controls. Serofast patients demonstrated prolonged phospholipid-dependent coagulation assays compared with serologically cured individuals (all qBH < 0.01; δ = 0.75–0.83). They also exhibited higher BAFF levels and B-cell counts at baseline and follow-up. Posttreatment VDRL titers strongly correlated with BAFF levels, B-cell counts, and coagulation parameters. After exclusion of neurosyphilis, persistent non-treponemal seroreactivity was associated with coordinated B-cell activation and phospholipid-dependent coagulation abnormalities, suggesting an infection-triggered immune phenotype rather than ongoing Treponema pallidum infection.