Background/Purpose: Systemic autoimmune diseases (SADs) may present with CNS demyelination, mimicking multiple sclerosis (MS), though driven by distinct immunopathogenic mechanisms. While ANA and aPL are commonly reported in MS, the role of specific SAD-related autoantibodies (ANA profile) in CNS demyelination remains unclear. The aims of this study were to characterize the distribution of autoantibodies in this context, investigate potential associations with clinical/ radiological/ laboratory features, compare findings with a control group of MS-spectrum patients and assess the efficacy of therapeutic strategies.

Methods: We prospectively enrolled 147 patients with CNS demyelination and ANA profile reactivity (via immunoblot) over a six-year period (CNS-autoimmune group). Patients were classified as SAD or demyelination with autoimmune features (DAF), based on whether they fulfilled criteria or not. A control group of 249 MS-spectrum patients was included. Clinical, laboratory, and imaging assessments were conducted. Univariate and multivariate analyses were performed between groups and treatment outcomes were analyzed using annualized relapse rates (ARRs).

Results: Clinical autoimmune features among CNS-autoimmune patients were generally mild, with the most common being arthralgias and sicca symptoms. Approximately 4% of unselected consecutive patients presenting with CNS demyelination and 21% of ANA profile-positive individuals were eventually diagnosed with SAD, primarily Sjögren’s disease and SLE. The remaining 79% of CNS-autoimmune patients constituted the DAF subset.Multivariate analysis identified arthritis, cerebellar signs, ANA, anti-Ro52/ Ro60 positivity and the absence of typical brain lesions as independent predictors for SAD compared to DAF diagnosis. Compared to MS-spectrum, ANA, aCL IgM and serum monoclonal band positivity, female sex and the presence of atypical brain lesions were more indicative of SAD. However, no robust model effectively discriminated between DAF and MS-spectrum groups.Among individual antibody reactivities, anti-Ro antibodies were associated with pyramidal and cerebellar manifestations, while anti-dsDNA, anti-nucleosomes, and anti-PM-Scl100 were linked to cortical clinical features. Additionally, anti-Sm, anti-RNP and anti-PMScl100 antibodies were linked to the least purely typical for MS CNS imaging. Conversely, anti-Jo1 and anti-histones were associated with gadolinium enhancement in MRI and high cerebrospinal fluid IgG index, respectively.Correlation analysis revealed notable antibody associations (e.g., anti-Ro52 with anti-aquaporin-4; AMA-M2 with aPL IgM). In follow-up, anti-CD20 mAbs were linked to zero relapses and the lowest ARR, significantly outperforming MS disease-modifying drugs, immunosuppression, and no treatment (p < 0.005).

Conclusion: Distinct autoantibody profiles in patients presenting with CNS demyelination are associated with specific clinical, radiological and laboratory features. MS-like SAD represents a clearly defined subset in contrast to DAF. Anti-CD20 therapies appear most effective in preventing neurological relapses.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/spectrum-of-autoantibodies-in-cns-demyelinating-diseases-clinical-laboratory-and-imaging-associations/