Differentiating central nervous system demyelinating disorders: The role of clinical, laboratory, imaging characteristics and peripheral blood type I interferon activity

Abstract

Objective: While multiple sclerosis (MS) is considered the cornerstone of autoimmune demyelinating CNS disorders, systemic autoimmune diseases (SADs) are important MS mimickers. We sought to explore whether distinct clinical, laboratory, and imaging characteristics along with quantitation of peripheral blood type I interferon (IFN) activity could aid in differentiating between them.Methods: A total of 193 consecutive patients with imaging features suggesting the presence of CNS demyelinating disease with or without relevant clinical manifestations underwent full clinical, laboratory, and imaging evaluation, including testing for specific antibodies against 15 cellular antigens. Expression analysis of type I IFN-inducible genes (MX-1, IFIT-1, and IFI44) was performed by real-time PCR, and a type I IFN score, reflecting type I IFN peripheral activity, was calculated. After joint neurological/rheumatological evaluation and 1 year of follow-up, patients were classified into MS spectrum and CNS autoimmune disorders.Results: While 66.3% (n = 128) of the patients were diagnosed with MS spectrum disorders (predominantly relapsing–remitting MS), 24.9% (n = 48) were included in the CNS autoimmune group, and out of those, one-fourth met the criteria for SAD (6.7% of the cohort, n = 13); the rest (18.1% of the cohort, n = 35), despite showing evidence of systemic autoimmunity, did not fulfill SAD criteria and comprised the “demyelinating disease with autoimmune features” (DAF) subgroup. Compared to the MS spectrum, CNS autoimmune patients were older, more frequently females, with increased rates of hypertension/hyperlipidemia, family history of autoimmunity, cortical dysfunction, anti-nuclear antibody titers ≥1/320, anticardiolipin IgM positivity, and atypical for MS magnetic resonance imaging lesions. Conversely, lower rates of infratentorial and callosal MRI lesions, CSF T2 oligoclonal bands, and IgG-index positivity were observed in CNS autoimmune patients. Patients fulfilling SAD criteria, but not the DAF group, had significantly higher peripheral blood type I IFN scores at baseline compared to MS spectrum [median (IQR)]: 50.18 (152.50) vs. −0.64 (6.75), p-value: 0.0001.Conclusion: Our study suggests that underlying systemic autoimmunity is not uncommon in patients evaluated for possible CNS demyelination. Distinct clinical, imaging and laboratory characteristics can aid in early differentiation between MS and CNS-involving systemic autoimmunity allowing for optimal therapeutic strategies. Activated type I IFN pathway could represent a key mediator among MS-like-presenting SADs and therefore a potential therapeutic target.

Editorial: Demyelinating neurological syndromes: The role of autoimmunity

“…These patients were older, more frequently females, with increased rates of hypertension/hyperlipidemia, family history of autoimmunity, cortical dysfunction, anti-nuclear antibody titers ≥1/320, anticardiolipin IgM positivity, and atypical for MS magnetic resonance imaging lesions. Of note patients fulfilling criteria for systemic autoimmune disease had significantly higher peripheral blood type I interferon IFN scores at baseline compared to patients with MS spectrum disorders (1). In conclusion, it is increasingly recognized that immune pathway activation has a chief role in clinical and pathogenetic features of patients presenting with several neurological features.…”

Neuromyelitis optica spectrum disorders (NMOSD) and systemic lupus erythematosus (SLE): Dangerous duo

“…It is crucial that rheumatologists and physicians in general be able to timely and accurately diagnose patients with ARDs, particularly SLE, presenting with CNS manifestations and to distinguish between SLE-related CNS manifestations and NMO with coexisting SLE (Table 1). [17][18][19] The correct diagnosis is essential so as to intervene promptly with immunosuppression as the ultimate goal is to prevent further damage, relapses, and damage accrual (as debility accrues with each attack) which leads to severe disability with significant morbidity and mortality.…”

“…In the differential diagnosis and work-up of such patients, the following should be considered: differentiating spinal cord syndromes in SLE patients, including lupus myelitis, NMO, and multiple sclerosis (MS), which can be challenging (Table 1). [17][18][19] Gadolinium-enhanced magnetic resonance imaging (MRI) excludes compression, and detects T2-hyperintense lesions. Cerebrospinal fluid (CSF) analysis detects inflammation/rules out infection.…”

The role of type I IFN in autoimmune and autoinflammatory diseases with CNS involvement

“…A subset of these patients was shown to meet classification criteria for a systemic autoimmune disease (e.g., Sjogren's syndrome, SLE). These patients displayed higher expression of type I IFN-stimulated genes in peripheral blood, compared to the patients who received a final diagnosis of MS or cerebral small vessel disease and so this distinct group may be of potential therapeutic benefit from type I IFN blockade ( 81 ).…”

“…The model is characterized by a strong IFN signature, autoantibody production, glomerulonephritis, arthritis, and anemia. Among the neuropsychiatric manifestations in this model are learning and memory deficits as well as decreased locomotion ( 80 , 81 ). The spontaneous NZB/NZW F1 mouse NPSLE model is characterized by splenomegaly, glomerulonephritis, haemolytic anemia, and lymphadenopathy, while learning and memory deficits are among its neuropsychiatric manifestations.…”