Animedix

Multiple Sclerosis (G35)

Advances in the mechanistic understanding of multiple sclerosis (MS) have shifted the field from a purely T-cell–centric autoimmune paradigm to a multidimensional model integrating adaptive and innate immunity, compartmentalized CNS inflammation, mitochondrial dysfunction, and neurodegeneration. Pathobiology now implicates autoreactive Th1/Th17 cells, clonally expanded B cells within meningeal follicles, microglial activation, complement-mediated synaptic pruning, and blood–brain barrier (BBB) dysregulation, alongside axonal metabolic failure and ion channel redistribution in demyelinated fibers. These insights have expanded druggable nodes beyond broad immunosuppression to include selective immune trafficking (α4-integrin blockade with natalizumab), S1P receptor modulation (fingolimod, ozanimod, ponesimod), anti-CD20 B-cell depletion (ocrelizumab, ofatumumab, ublituximab), and IL-2 receptor targeting (daclizumab, withdrawn). Emerging strategies focus on Bruton’s tyrosine kinase (BTK) inhibitors to modulate both B cells and microglia, complement pathway inhibitors, remyelination-promoting agents targeting LINGO-1 and oligodendrocyte precursor differentiation, and neuroprotective interventions addressing mitochondrial bioenergetics and sodium channel dysregulation. The therapeutic landscape is therefore evolving toward compartment-penetrant, state-dependent immune modulation combined with regenerative and neuroprotective strategies—an integrated precision-medicine framework aimed not only at reducing relapse activity but at altering long-term disability trajectories in progressive disease.

Causes

The etiology of multiple sclerosis (MS) reflects a complex interplay between genetic susceptibility and environmental exposures that converge on immune dysregulation. Genome-wide association studies have identified over 200 risk loci, with the strongest signal in the HLA region—particularly HLA-DRB1*15:01—highlighting aberrant antigen presentation as a central predisposition. Additional variants implicate IL-2/IL-7 signaling, co-stimulatory pathways, and innate immune regulation. Environmental factors act as disease modifiers or triggers, including prior infection with Epstein–Barr virus (EBV)—now considered a near-obligate antecedent—vitamin D deficiency, cigarette smoking, adolescent obesity, and higher latitude–associated UV exposure gradients. These influences appear to alter immune tolerance thresholds, B-cell maturation, and CNS immune surveillance. Increasing evidence also supports a prodromal phase characterized by subtle neuroimmune perturbations years before clinical onset, suggesting that MS arises from a temporally staged breakdown of peripheral tolerance and CNS compartmentalization rather than a single inciting event.

Pathophysiology

The pathophysiology of multiple sclerosis is characterized by immune-mediated demyelination, axonal injury, and progressive neurodegeneration within the central nervous system (CNS). Autoreactive CD4⁺ Th1 and Th17 cells, along with CD8⁺ cytotoxic T cells, cross a dysregulated blood–brain barrier and initiate inflammatory cascades through cytokines such as IFN-γ, IL-17, and GM-CSF. B cells contribute via antigen presentation, proinflammatory cytokine secretion, and intrathecal antibody production, leading to oligoclonal band formation. Activated microglia and infiltrating macrophages amplify injury through reactive oxygen species, nitric oxide, and complement-mediated synaptic stripping. Demyelination exposes voltage-gated sodium channels redistributed along denuded axons, initially preserving conduction but increasing metabolic demand and mitochondrial stress. Over time, energy failure, calcium influx, and oxidative damage drive irreversible axonal transection and neuronal loss. In progressive disease, inflammation becomes compartmentalized behind a relatively intact blood–brain barrier, with meningeal B-cell aggregates and chronic microglial activation sustaining smoldering lesions independent of overt peripheral immune cell influx. This integrated immune–neurodegenerative cascade underlies both acute relapses and gradual disability accumulation.

Clinical features

The clinical features of multiple sclerosis reflect the spatial and temporal dissemination of demyelinating lesions within the central nervous system. Presentations commonly include optic neuritis (subacute unilateral vision loss with pain on eye movement), sensory disturbances (paresthesias, numbness), limb weakness, diplopia from internuclear ophthalmoplegia, ataxia, and bladder dysfunction. Symptoms typically evolve over hours to days and may partially or completely remit in relapsing forms. Heat sensitivity (Uhthoff phenomenon), fatigue, and cognitive slowing are frequent and often underrecognized contributors to disability. With disease progression—particularly in secondary or primary progressive phenotypes—patients develop gradual gait impairment, spasticity, cerebellar dysfunction, and cognitive decline independent of overt relapses. The heterogeneity of lesion localization—optic nerves, brainstem, cerebellum, spinal cord, and periventricular white matter—accounts for the broad clinical spectrum and fluctuating course characteristic of the disease.

Diagnosis

The diagnosis of multiple sclerosis is based on demonstrating dissemination of central nervous system lesions in both space and time, while excluding alternative etiologies. Current criteria—most recently revised in the McDonald Criteria—integrate clinical findings, MRI features, and cerebrospinal fluid (CSF) analysis. Brain and spinal cord MRI typically reveal T2-hyperintense lesions in characteristic locations (periventricular, juxtacortical/cortical, infratentorial, and spinal cord), with gadolinium enhancement indicating active inflammation. Dissemination in time can be established by simultaneous presence of enhancing and non-enhancing lesions or by new lesions on follow-up imaging; CSF-specific oligoclonal IgG bands may substitute for temporal dissemination in appropriate clinical contexts. Evoked potentials can provide supportive evidence of subclinical demyelination. A rigorous diagnostic process also requires exclusion of mimics such as neuromyelitis optica spectrum disorder, MOG-antibody–associated disease, vascular, infectious, or metabolic causes. Increasingly, advanced imaging metrics (e.g., cortical lesion detection, central vein sign, quantitative volumetrics) and serum neurofilament light chain are being incorporated to refine early diagnosis and prognostication.

Mechanism of action videos

Biological pathways

  • Ubiquitin mediated proteolysis
  • Toll-like receptor signaling pathway
  • Th17 cell differentiation
  • Th1 and Th2 cell differentiation
  • Calcium signaling pathway
  • TNF signaling pathway
  • Rheumatoid arthritis
  • Regulation of actin cytoskeleton
  • Proteasome
  • PI3K-Akt signaling pathway
  • Phase 1 - inactivation of fast Na+ channels
  • Necroptosis
  • Natural killer cell mediated cytotoxicity
  • NF-kappa B signaling pathway
  • Multiple sclerosis mechanism and therapies
  • MAPK signaling pathway
  • Phase 3 - rapid repolarisation
  • JAK-STAT signaling pathway
  • Inflammatory bowel disease
  • Glucagon signaling pathway
  • Cell adhesion molecule (CAM) interaction
  • Apoptosis
  • Antigen processing and presentation
  • Alanine, aspartate and glutamate metabolism
  • Voltage gated Potassium channels
  • Potassium Channels
  • Neuronal System
  • Nuclear Receptor transcription pathway
  • Cardiac conduction
  • Glucagon-like Peptide-1 (GLP1) regulates insulin secretion
  • Potential therapeutics for SARS
  • Muscle contraction
  • RUNX3 Regulates Immune Response and Cell Migration
  • Regulation of insulin secretion
  • RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)
  • Integration of energy metabolism
  • Generic Transcription Pathway
  • Regulation of IFNA/IFNB signaling

Clinical trials

  • A Phase Ib Study of Nivolumab in Patients With Autoimmune Disorders and Advanced Malignancies (AIM-NIVO)
  • A Phase 2, Multi-Center Study Consisting of a Randomized, Double-Blind, Placebo-Controlled Period, Followed by an Open-Label Extension Period, to Assess the Efficacy, Safety, and Tolerability of Tibulizumab in Adults With Systemic Sclerosis
  • A Randomized, Double-blind, Placebo-controlled Phase III Study to Evaluate the Efficacy and Safety of Remibrutinib in Patients With Secondary Progressive Multiple Sclerosis
  • Treatment With Full-spectrum Cannabis Extract of Refractory Epilepsy Associated With Tuberous Sclerosis Complex (TSC)
  • A Phase 1b, Open-label, Multi-cohort Study of AZD0120, an Autologous CD19/BCMA Targeting Chimeric Antigen Receptor T-cell, in Adults With Autoimmune Diseases
  • A Phase 1, Multicenter, Single-arm, Dose-escalation Study of CC-97540 (BMS-986353), CD19-Targeted NEX-T Chimeric Antigen Receptor (CAR) T Cells, Evaluating Safety and Tolerability in Participants With Autoimmune Neurological Diseases: Relapsing Forms of Multiple Sclerosis (RMS), Progressive Forms of Multiple Sclerosis (PMS), or Refractory Myasthenia Gravis (MG).
  • A Multiple Ascending Dose Phase 1 Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intrathecally Administered LY4256984 in Participants With Sporadic Amyotrophic Lateral Sclerosis
  • An Open-label, Single-arm Study to Evaluate Pharmacokinetics, Pharmacodynamic Effects, Safety and Tolerability of Fenebrutinib in Children and Adolescents With Relapsing Multiple Sclerosis
  • A Randomized, Phase 3, Open-label Study to Investigate Pharmacokinetics, Safety, and Efficacy of Subcutaneous Compared to Intravenous Frexalimab in Adult Participants With Multiple Sclerosis
  • Targeting Residual Activity By Precision, Biomarker-Guided Combination Therapies of Multiple Sclerosis (TRAP-MS)
  • A Phase 1, Open-label, Multiple Ascending Dose Basket Study to Evaluate the Safety and Activity of DR-0201 in Patients With Select Autoimmune Rheumatic Diseases
  • A Phase 3, Multicenter, Double-blind, Active-controlled Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Oral Ozanimod Compared to Oral Fingolimod in Children and Adolescents With Relapsing Remitting Multiple Sclerosis
  • A Phase II, Multi-part, Randomized, Open-label, Assessor-blinded, Active-controlled, Multicenter Study to Evaluate the Efficacy and Safety of Rapcabtagene Autoleucel Versus Rituximab Treatment in Participants With Severe Refractory Diffuse Cutaneous Systemic Sclerosis
  • A Randomized, Double-blind, Parallel-group Study to Compare Pharmacokinetics, Pharmacodynamics, Clinical Effects, and Safety Between ABP 692 and Ocrevus® (Ocrelizumab) in Subjects With Relapsing-remitting Multiple Sclerosis
  • An Open-label, Multi-center Long-term Safety Roll-over Study in Patients With Tuberous Sclerosis Complex (TSC) and Refractory Seizures Who Are Judged by the Investigator to Benefit From Continued Treatment With Everolimus After Completion of Study CRAD001M2304.
  • A Randomized, Double-blind, Parallel-group Study to Compare the Pharmacokinetics, Efficacy, Pharmacodynamics, Safety, and Immunogenicity of CYB704 (Proposed Ocrelizumab Biosimilar) and Ocrevus® in Participants With Relapsing Multiple Sclerosis (RMS) [STRIVE-MS].
  • An Open-Label, Prospective, Single-arm, Multi-center Study to Assess Disease Activity and Biomarkers of Neuronal Damage in Minority Patients With Relapsing Multiple Sclerosis Receiving Treatment With Ocrelizumab
  • Effects and Mechanisms of Ocrevus on Ambulatory Functions in People With Relapsing Multiple Sclerosis
  • A Phase II, Randomized, Open-label, Parallel Group, Multicenter Study to Assess Bioequivalence of Two Subcutaneous Formulations of Ocrelizumab in Patients With Multiple Sclerosis
  • A Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy of Fenebrutinib in Relapsing Multiple Sclerosis
  • Evaluating Safety, Efficacy and Pharmacokinetics of a Modified Regimen of Ublituximab (ENHANCE )
  • A Phase 1, Open-label Study to Evaluate the Safety and Clinical Activity of Azercabtagene Zapreleucel in Participants With B-cell Mediated Autoimmune Disorders
  • An Open-Label, Single-Arm 4-Year Study to Evaluate Effectiveness and Safety of Ocrelizumab Treatment in Patients With Progressive Multiple Sclerosis
  • Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multi-Center, 24-Week Study With Additional 24-Week Blinded Active Extension to Evaluate the Safety and Efficacy of COYA 302 for the Treatment of Amyotrophic Lateral Sclerosis (ALS)
  • A Randomized, Double-blind, Double-dummy, Parallel-group Study, Comparing the Efficacy and Safety of Remibrutinib Versus Teriflunomide in Participants With Relapsing Multiple Sclerosis, Followed by Extended Treatment With Open-label Remibrutinib
  • A Clinical Study Evaluating the Safety and Preliminary Efficacy of Universal Allogeneic CAR T-cell Therapy Targeting CD19 and BCMA in Patients With B Cell Mediated Autoimmune Disease
  • A Phase 3, Non-Inferiority, Randomized, Open-Label, Parallel Group, Multicenter Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Safety, Radiological and Clinical Effects of Subcutaneous Ublituximab Versus Intravenous Ublituximab in Patients With Multiple Sclerosis
  • A Multi-center, Double-blind, Placebo-controlled, Phase II Study Evaluating the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of RO7268489, a Monoacylglycerol Lipase Inhibitor, as Add-on Therapy to Ocrelizumab, in Participants With Progressive Forms of Multiple Sclerosis
  • A Randomized, Double-blind, Double-dummy, Parallel-group Study, Comparing the Efficacy and Safety of Remibrutinib Versus Teriflunomide in Participants With Relapsing Multiple Sclerosis, Followed by Extended Treatment With Open-label Remibrutinib
  • Phase IV, Prospective Single Arm Study of Safety and Efficacy of Votubia (Everolimus) in Taiwanese Adults With Tuberous Sclerosis Complex Who Have Renal Angiomyolipoma
  • An Open Label Extension Study of Ublituximab in Subjects With Relapsing Multiple Sclerosis
  • A Multicenter, Single-Arm, Open-Label, Extension, Rollover Study To Evaluate The Long-Term Safety And Efficacy Of Ocrelizumab In Patients With Multiple Sclerosis
  • Molecular Imaging of Norepinephrine Transporter (NET) Using [C-11]Methylreboxetine PET in Multiple Sclerosis
  • A Phase IIB Randomized, Double-Blind, Placebo-Controlled, Multi-Dose Study to Evaluate the Effects of PHENOGENE-1A (Cromolyn) as an Adjuvant Treatment in Subjects With Mild to Moderate Amyotrophic Lateral Sclerosis (ALS)
  • A Phase 1b, Open-label, Multi-center, Randomized Study Evaluating the Safety and Tolerability of AZD0120, an Autologous CD19/BCMA Targeting Chimeric Antigen Receptor T-cells, in Adults With Refractory Relapsing or Progressive Multiple Sclerosis
  • A Multiple-center, Non-randomized, Open-label, Adaptive, Single-ascending Dose (Part 1 and Part 2) and Multiple-ascending Dose (Part 3) Parallel, Phase IB Study to Investigate the Safety, Tolerability, Immunogenicity, Pharmacokinetics, and Pharmacodynamics of RO7121932 Following Intravenous (Parts 1) and Subcutaneous Administration (Parts 2 and 3) in Participants With Multiple Sclerosis
  • A Prospective Randomized Trial of Non-inferiority Comparing RItuximab Versus Ocrelizumab in Relapsing-remitting Multiple Sclerosis
  • A Phase III Multicenter, Randomized, Double-blind, Double-dummy Study to Evaluate Safety and Efficacy of Ocrelizumab in Comparison With Fingolimod in Children and Adolescents With Relapsing-Remitting Multiple Sclerosis
  • A Randomized, Open Label, Multi-center, Active-comparator Study to Assess Efficacy, Safety & Tolerability of Ofatumumab 20mg sc Monthly Versus Continued Current Therapy in Relapsing-remitting Multiple Sclerosis After Elevation of Serum Neurofilament Light Levels (SOSTOS)
  • Microglial Activation PET Brain Imaging in Multiple Sclerosis, Alzheimer's Disease, and Other Neurological and Neuropsychiatric Diseases

Therapeutic area: Immunology