COVID-19 and Multiple Sclerosis: A Complex Relationship Possibly Aggravated by Low Vitamin D Levels

“

TL;DR

This narrative review explores the complex bidirectional relationship between COVID-19 and multiple sclerosis (MS), highlighting shared immunopathological pathways including type I IFN deficiency, Th1/Th17 hyperactivation, and NLRP3 inflammasome overactivation. The authors propose that low vitamin D levels may aggravate susceptibility and severity of both diseases, and discuss experimental animal models that could be used to investigate this interplay. Despite theoretical risks, a retrospective study found no increased short-term MS relapse risk after COVID-19, though long-term sequelae remain uncertain.

Full summary

3,981 CHARS

**Background:** COVID-19, caused by SARS-CoV-2, predominantly affects the respiratory system but can involve the central nervous system (CNS), the target tissue of the autoimmune process in multiple sclerosis (MS). This narrative review examines the interrelationship between these two diseases, focusing on shared immunological disturbances and the potential modulating role of vitamin D. The authors note that around 80% of COVID-19 patients display mild symptoms, 15% develop more severe symptoms, and 5% evolve to critical conditions including ARDS and multiorgan failure. MS affects approximately 85% of patients as the relapsing-remitting phenotype (RRMS).

**Methods:** This is a narrative review synthesizing published literature on COVID-19 immunopathogenesis, MS immunopathogenesis, the role of viral infections (particularly EBV and SARS-CoV-2) in MS, vitamin D biology in both diseases, and available experimental animal models. The authors do not describe a systematic search strategy or inclusion/exclusion criteria.

**Key Results:** The review identifies three intersecting pathways critical to the COVID-19–MS interplay: (1) type I IFN deficiency—type I IFN was adopted as the first disease-modifying therapy for MS in 1993, and dysregulated/delayed type I IFN responses are also associated with severe COVID-19 prognosis due to inborn errors, autoantibodies, or viral inhibition; (2) Th1/Th17 axis—both diseases feature IFN-γ and IL-17 production, with severe COVID-19 associated with Th17 polarization and gut microbiota dysbiosis; (3) NLRP3 inflammasome activation—NLRP3 is involved in various MS stages including initial inflammation, T cell polarization, CNS barrier breakdown, and neurodegeneration, while SARS-CoV-2 activates this platform with accentuation in more aggressive disease. A large cohort study of over 10 million US army personnel found a 32-fold increase in MS diagnosis in individuals who became EBV seropositive compared with those who remained seronegative. Regarding COVID-19 and MS, a retrospective study concluded that regardless of severity, COVID-19 was not associated with an increased risk of MS relapse shortly after infection, which the authors attribute to post-COVID-19 lymphopenia and immunomodulatory drug use. For vitamin D, a study of 20 European countries showed a significant negative correlation between vitamin D levels and COVID-19 cases. Low vitamin D at hospital admission was associated with increased IL-6 production and predicted severity of respiratory distress and mortality. However, a meta-analysis and GRADE assessment concluded low vitamin D does not play a role in disease severity and supplementation does not improve outcomes in hospitalized patients. In MS, vitamin D deficiency was formally described in 1994 and subsequently correlated with MRI load and disease severity. Supplementation studies show mixed results—one study found no difference in annual relapse rate but reduced MRI activity, while another found decreased annualized relapse rate in natalizumab-treated patients.

**Clinical Implications:** The authors emphasize that despite theoretical concerns about COVID-19 worsening MS, current evidence does not support an increased short-term relapse risk. They highlight the need for further investigation into long-term post-COVID sequelae in MS patients. The role of vitamin D supplementation remains controversial for both diseases, with no official recommendation for prophylactic or therapeutic use in COVID-19, and insufficient evidence to approve it as add-on therapy for MS. The authors recommend standardized study designs with well-defined variables for future vitamin D research. They suggest experimental animal models—including Syrian hamsters, human ACE2-transgenic mice, and C. elegans—could be explored to investigate both diseases simultaneously, particularly given that intranasal vitamin D administration downmodulated lung inflammation in a UV-inactivated SARS-CoV-2 model.