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Objectives: To analyze the prevalence, incidence, survival and contribution on mortality of major central nervous system (CNS) involvement in systemic lupus erythematosus (SLE). Methods: Patients fulfilling the SLE 1997 ACR classification criteria from the multicentre, retrospective RELESSER-TRANS (Spanish Society of Rheumatology Lupus Register) were included. Prevalence, incidence and survival rates of major CNS neuropsychiatric (NP)-SLE as a group and the individual NP manifestations cere-brovascular disease (CVD), seizure, psychosis, organic brain syndrome and transverse myelitis were calculated. Furthermore, the contribution of these manifestations on mortality was analysed in Cox regression models adjusted for confounders. Results: A total of 3591 SLE patients were included. Of them, 412 (11.5%) developed a total of 522 major CNS NP-SLE manifestations. 61 patients (12%) with major CNS NP-SLE died. The annual mortality rate for patients with and without ever major CNS NP-SLE was 10.8% vs 3.8%, respectively. Individually, CVD (14%) and organic brain syndrome (15.5%) showed the highest mortality rates. The 10% mortality rate for patients with and without ever major CNS NP-SLE was reached after 12.3 vs 22.8 years, respectively. CVD (9.8 years) and organic brain syndrome (7.1 years) reached the 10% mortality rate earlier than other major CNS NP-SLE manifestations. Major CNS NP-SLE (HR 1.85, 1.29-2.67) and more specifically CVD (HR 2.17, 1.41-3.33) and organic brain syndrome (HR 2.11, 1.19-3.74) accounted as independent prognostic factors for poor survival. Conclusion: The presentation of major CNS NP-SLE during the disease course contributes to a higher mortality, which may differ depending on the individual NP manifestation. CVD and organic brain syndrome are associated with the highest mortality rates.

Objective: Semaphorin 3B (Sema3B) decreases the migratory and invasive capacities of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) and suppresses expression of matrix metalloproteinases. We undertook this study to examine the role of Sema3B in a mouse model of arthritis and its expression in RA patients. Methods: Clinical responses, histologic features, and FLS function were examined in wild-type (WT) and Sema3B−/− mice in a K/BxN serum transfer model of arthritis. Protein and messenger RNA expression of Sema3B in mouse joints and murine FLS, as well as in serum and synovial tissue from patients with arthralgia and patients with RA, was determined using enzyme-linked immunosorbent assay, immunoblotting, quantitative polymerase chain reaction, and RNA sequencing. FLS migration was determined using a wound closure assay. Results: The clinical severity of serum-induced arthritis was significantly higher in Sema3B−/− mice compared to WT mice. This was associated with increased expression of inflammatory mediators and increased migratory capacity of murine FLS. Administration of recombinant mouse Sema3B reduced the clinical severity of serum-induced arthritis and the expression of inflammatory mediators. Sema3B expression was significantly lower in the synovial tissue and serum of patients with established RA compared to patients with arthralgia. Serum Sema3B levels were elevated in patients with arthralgia that later progressed to RA, but not in those who did not develop RA; however, these levels drastically decreased 1 and 2 years after RA development. Conclusion: Sema3B expression plays a protective role in a mouse model of arthritis. In RA patients, expression levels of Sema3B in the serum depend on the disease stage, suggesting different regulatory roles in disease onset and progression.