A broad range of antiphospholipid IgM are elevated across different multiple sclerosis clinical phenotypes

Demyelination releases structural components that trigger immune responses and autoantibodies, indicating central nervous system damage and potential for further injury. Elevated antiphospholipid antibodies (aPL) are reported in multiple sclerosis (MS), but comparisons of their reactivities beyond those included in current antiphospholipid syndrome (APS) criteria across MS types are limited. This exploratory cross-sectional study evaluated serum from 35 healthy controls (HC), 20 clinically isolated syndrome (CIS) and 83 clinically confirmed MS participants (33 relapsing remitting [RRMS], 30 secondary progressive [SPMS], 20 primary progressive [PPMS]). IgM levels to phosphatidyl-choline (PC), -ethanolamine (PE), -inositol (PI), -serine (PS), -sphingomyelin (SM), and APS criteria aPL, cardiolipin (CL) and β2-glycoprotein I (βGP), were measured by enzyme-linked immunosorbent assay to assess their biomarker potential. Independent of age and sex, elevated aPL levels to all phospholipids were associated with a higher likelihood of being CIS over HC (p < 0.005). Independent of age, sex, disease duration (DD), Kurtzke Expanded Disability Status Scale (EDSS), and disease modifying therapy (DMT) use, elevated aPL to PI, PS, SM, CL, and βGP were associated with SPMS over RRMS (p < 0.05). Demographic associations showed increased aPL with: older age in CIS (PI, PS, CL; p < 0.05); longer DD in SPMS alone (PE, PI, SM; p < 0.05) and when pooled with RRMS (PC, PE, SM; p < 0.03); and higher EDSS in PPMS (PE, PI, SM; p < 0.05). DMT use tended to be associated with lower aPL titers in the RRMS group or in pooled group comparisons, although this only reached significance for aPL to PE (p < 0.05). Positivity to an individual phospholipid was more common in CIS (25-40 %) and SPMS (16.7-33.3 %) than other groups (0-20 %). Broad positivity (≥3 aPL) was greater in CIS (40.0 %) than HC (2.9 %; p = 0.001) or MS (19.3 %), and greater in SPMS (33.3 %) than RRMS (12.1 %). Higher aPL responses in a participant were more likely in CIS or MS over HC (β = 0.794, 0.454; p < 0.005), and SPMS over RRMS or PPMS (β = 0.346, 0.429; p < 0.03). aPL reactivities vary across MS participants and, though levels tend to be impacted by DMT usage, the higher levels in specific groups warrant longitudinal exploration to determine potential relevance to MS pathophysiology.