A173: Cerebrospinal Fluid Cytokines Correlate With Innate Immune Cells in Neonatal Onset Multisystem Inflammatory Disease (NOMID) Patients in Clinical Remission Treated With Anakinra

Background/Purpose: Neonatal onset multisystem inflammatory disease (NOMID) is a rare autoinflammatory disease caused by NLRP3 mutations that lead to constitutive NLRP3 inflammasome activation and IL-1β release. Patients present with neutrophilic urticaria, chronic aseptic meningitis, and papilledema. IL-1β inhibitors improve the inflammatory manifestations, normalize acute phase reactants, decrease CSF WBC and protein, and proinflammatory cytokine levels. We found that cytokine levels decrease with anakinra treatment, but do not normalize during clinical remission. The higher IL-6 and IP-10 levels in CSF than in the blood suggest local production in the brain/CSF. Our objective is to examine whether CSF cytokines, particularly IL-6 and IP-10, correlate with CSF subpopulations of immune cells and CSF characteristics. Methods: Immunophenotyping and cytokine data were available on 2 baseline and 16 anakinra treated patients, 9/16, fulfilled clinical remission criteria (ESR ≤25 mm/hr, CRP ≤0.5 mg/dl, CSF WBC ≤5 cells/μl and protein ≤40 mg/dl) and control patients (n = 7). Cytokines levels (IL-1β, IL-6, IL-10, IP-10, IL-12 (p70) and (p40), IFN-γ, TNF-α, and IL-18) were correlated to CSF WBC, protein, albumin quotient (AQ), and opening pressure at baseline, post-treatment, and clinical remission. Correlation was assessed with Pearson and Spearman tests. Results: At baseline, monocytes, granulocyte, and T cells were higher in NOMID patients versus controls. Post-treatment monocytes and granulocyte counts decreased but remained higher even in clinical remission, relative to control. Only IL-6 and IP-10 correlated with monocytes (r = .66, p = .051; r = .86, p = .002) respectively. A correlation of IP-10 but not IL-6 with granulocytes was weaker than with monocytes (r = .66, p = .058). IL-6, IP-10, and IL-18 correlated with CSF protein, AQ, and WBC (except IL-18). At baseline, IL-6 and IL-18 significantly correlated with CSF protein (r = .68, p = .027; r = .80, p = .0065) and AQ (r = .82, p = .011; r = .78, p = .029) respectively. At post-treatment, IL-18 significantly correlated and IL-6 trend towards significance with CSF protein (r = .53, p = .022; r = .40, p = .096) and AQ (r = .83, p = .0002; r = .47, p = .087) respectively. Conclusion: 1) Inflammatory cells significantly decrease in NOMID patients, especially monocytes which remain elevated even in patients in clinical remission, suggesting residual inflammation. 2) The correlation of monocytes with IL-6 and IP-10 suggests their contribution to IL-6 and IP-10 production, which may contribute to the recruitment of other inflammatory cells including granulocytes. 3) IL-6, IP-10, and IL-18 may be a marker for blood brain barrier dysfunction in NOMID and their use in long term monitoring should be explored. 4) These results are consistent with the notion that NOMID is caused by dysfunction in innate immune cells, particularly monocytes.