Comparison of recent updates in genetics, immunology, biomarkers, and neuroimaging of primary‐progressive and relapsing‐remitting multiple sclerosis and the role of ocrelizumab in the management of their refractory cases

Abstract Background Primary‐progressive multiple sclerosis (PPMS) and relapsing‐remitting multiple sclerosis (RRMS) are two frequent multiple sclerosis (MS) subtypes that involve 10%–15% of patients. PPMS progresses slowly and is diagnosed later in life. Both subtypes are influenced by genetic and environmental factors such as smoking, obesity, and vitamin D insufficiency. Although there is no cure, ocrelizumab can reduce symptoms and delay disease development. RRMS is an autoimmune disease that causes inflammation, demyelination, and disability. Early detection, therapy, and lifestyle changes are critical. This study delves into genetics, immunology, biomarkers, neuroimaging, and the usefulness of ocrelizumab in the treatment of refractory patients of PPMS. Method In search of published literature providing up‐to‐date information on PPMS and RRMS, this review conducted numerous searches in databases such as PubMed, Google Scholar, MEDLINE, and Scopus. We looked into genetics, immunology, biomarkers, current breakthroughs in neuroimaging, and the role of ocrelizumab in refractory cases. Results Our comprehensive analysis found considerable advances in genetics, immunology, biomarkers, neuroimaging, and the efficacy of ocrelizumab in the treatment of refractory patients. Conclusion Early detection, timely intervention, and the adoption of lifestyle modifications play pivotal roles in enhancing treatment outcomes. Notably, ocrelizumab has demonstrated potential in symptom control and mitigating the rate of disease advancement, further underscoring its clinical significance in the management of MS.


| INTRODUCTION
The chronic inflammatory disease of the central nervous system (CNS) known as multiple sclerosis (MS) causes a progressive loss of sensory, motor, cognitive, and visual abilities. [1][2][3][4][5] It is most prevalent in young females. 3,4 Immune-mediated inflammation, demyelination, and axonal destruction are the pathological outcomes of MS. 5,6 A wide variety of comorbidities can affect patients diagnosed with this disorder, and a thorough awareness of these comorbidities is essential to provide complete patient treatment. 2 Venous drainage problems, endothelial cell abnormalities, and arterial cerebral hypoperfusion are only a few of the vascular features of MS that have been studied, and the venous part of the illness is still the least investigated. 4 While MS has multiple subtypes, relapsing-remitting multiple sclerosis (RRMS) is the most common subtype of MS, [5][6][7][8] characterized by periods of partial or total recovery following instances of abrupt neurological symptoms.
Ocrelizumab, a monoclonal antibody, has been granted approval for the treatment of both RRMS and primary-progressive multiple sclerosis (PPMS) through its targeted depletion of CD20-positive B cells. The findings indicate that Ocrelizumab exhibits efficacy in mitigating not only the annual rate of relapse, but also the T2-lesions, and progression in patients with RRMS. The drug was found to be effective in two Phase III clinical trials (OPERA I and OPERA II), reducing the annual rate of relapse by 46% and 47% compared to interferon beta-1a, respectively.

| METHODOLOGY
A thorough literature search was carried out utilizing electronic databases such as PubMed, MEDLINE, Scopus, and Web of Science.
The search phrases included "MS subtypes," "genetic and environmental variables linked with MS onset and progression," "diseasemodifying therapy," and specific areas of research interest. Relevant keywords such as "MS" AND "Recent Updates" AND/OR "PPMS" AND/OR "RRMS," and "Ocrelizumab" were used, and searches were conducted.
Studies were considered if they matched the following requirements: (1) produced studies in peer-reviewed journals, (2) focused on current advances in PPMS and RRMS genetics, immunology, biomarkers, and neuroimaging, and (3) evaluated the usefulness of ocrelizumab in the therapy of refractory patients. Inclusion criteria were clinical trials, observational studies, reviews, and meta-analyses.
The review did not include conference abstracts, case reports, or editorials. Only articles written in English were considered. The underlying mechanisms of PPMS are not yet fully understood, but research suggests that it may be influenced by a confluence of genetic and environmental determinants. Recent studies have identified specific genetic variants that may contribute to the development of PPMS, including variants in genes involved in immune regulation and myelin repair. 11 Environmental factors such as smoking, obesity, and vitamin D deficiency have also been implicated in the development and progression of PPMS. 12,13 The clinical course of PPMS can vary widely among individuals, with some experiencing a more rapid progression of disability while others have a slower progression. 14 Common symptoms of PPMS include progressive weakness, difficulty with balance and coordination, vision problems, and bladder and bowel dysfunction. 9 Although there is currently no treatment for PPMS, there are a number of DMTs that can help decrease the disease's development and control symptoms.
These include interferon beta-1b, glatiramer acetate, and ocrelizumab, which was approved by the FDA in 2017 for treating PPMS. 15 Several ongoing clinical trials also investigate new treatments for PPMS, including therapies targeting specific immune cells and pathways. 16

| Genetics
Research into the genetics of PPMS has identified several genetic variants that may play a role in disease development as well as its progression. Recent studies have identified specific genes involved in immune regulation and myelin repair as potential targets for PPMS treatment. 17 One of the key genetic factors associated with PPMS is the human leukocyte antigen (HLA) system, which plays a role in immune regulation. Several HLA variants have been identified as risk factors for PPMS, including HLA-DRB115 and HLA-DRB1501:01. 18,19 These variants have also been implicated in the development of RRMS, the most common subtype of MS.
In addition to HLA variants, other genetic factors have been associated with PPMS. In the context of PPMS, a comprehensive genome-wide association study (GWAS) was conducted to investigate the genetic underpinnings of the disease. The study revealed the presence of multiple genetic variants that are significantly associated with PPMS. Notably, the genes IL12A and CD58 were found to harbor variants that are particularly relevant to the disease. These findings provide valuable insights into the genetic basis of PPMS and may inform the development of targeted therapies for this debilitating condition. 20 Although CD58 is extensively expressed in both immune and nonimmune cells, it has been hypothesized that changes in immune function play a part in how the disease MS develops. This is similar to the prominent inflammatory lesions that accompany Brain demyelination. Furthermore, once the illness has begun, increased CD58 expression may guard against the onset of MS as well as moderate acute bouts of inflammatory demyelination.
Recent studies have also identified genetic variants associated with myelin repair as potential targets for PPMS treatment. A study published in 2022 identified a genetic variant in the gene encoding the protein chitinase 3-like 1 (CHI3L1) as a potential therapeutic target for PPMS. 21 In MS, nonlymphocytic inflammation that is of low grade in addition to active neurodegeneration may be linked to CHI3L1 and therefore linked to progressive disease.
In one study, an investigation was conducted to explore the correlations between alleles of the CRYAB gene, which encodes for abcrystallin, in a cohort of 490 individuals diagnosed with MS. The cohort included 94 individuals diagnosed with PPMS and 182 healthy controls. 22 A disease course that is primarily progressive in nature was linked to the CRYAB-650*C. Not only that but the CRYAB gene was also associated with an onset in the elderly, a lower volume in T2-lesion, as well as a greater loss of brain volume CRYAB650*C allele impact on the volume of brain was found in both PPMS as well as RR/secondary progressive multiple sclerosis (SPMS) patients.

| Pathogenesis
The prevalent lesions observed in PPMS are characterized by a gradual increase in size and comprise of T cells, microglia, and macrophage-mediated demyelination. 23 Since the very first events in MS are the participation of several CD+ subtypes, CD8+ cells are the major lymphocytes observed in lesions, which correspond with the degree of damage to the axons. 24 In PPMS, sCD27, an intrathecal inflammatory marker released mostly by T cells, is increased. 25 Patients with PPMS had high TFH and Th17 activation in their serum, which was associated with the pace of progression.
The Intrathecal production of IgG, B-cells detection within the lesions of MS, infiltration of meninges, perivascular space, and parenchyma, and B-cell-based treatments success in PPMS are all evidence for the involvement of B cells in PPMS. 26

B lymphocytes
have been observed to be distributed throughout the meninges.
However, it has been noted that the formation of tertiary lymphoid follicles occurs only in instances of severe illness with active progression. 27 The quantity of B-and plasma cells and the level of axonal damage are correlated with PPMS lesions. B cells cause disease by a variety of mechanisms, including the presentation of antigens, release of cytokine, and the production of autoantibodies. 28 The persistence of long-lasting antibody-generating plasma cells, despite the use of highly efficient monoclonal anti-CD-20 antibodies, supports their role beyond just the production of autoantibodies. In addition to their role in autoantibody production, these cells are capable of inducing a pro-inflammatory reaction in myeloid cells through the secretion of granulocyte-macrophage colony-stimulating factor and the augmentation of Th1-and Th17-differentiating cytokines, namely IL-6 and IL-12. 29 B-regulatory cells' complex role in MS is demonstrated by their secretion of IL-10, IL-35, and TGF-β. Breg can stop the formation of Th1 and Th17 cells, balance the Th1/Th2 axis, and reduce macrophages. 28 The preponderance of phagocytic cells, such as macrophages, is a notable characteristic of the slowly progressing lesions observed in PPMS. The cells in question are derived from monocytes present in the bloodstream and subsequently migrate into the brain in response to blood stimulation. 30 Through reactive oxygen species, nitric oxide, and glutamate, the pro-inflammatory M1 plays a crucial part in both demyelination and axonal injury. 30 Macrophages that infiltrate the CNS are capable of inducing the development of experimental autoimmune encephalomyelitis in a gradual manner. This is achieved through the sustained release of tumor-necrosis factor (TNF) by these cells. 31 PPMS patients had higher sCD14 levels than healthy controls, although they were equivalent to RRMS patients who were experiencing relapses rather than remission. Regardless of the foregoing, the involvement of macrophages is deemed necessary for the process of remyelination, as they facilitate the removal of damaged tissue in lesions. 30 sCD14 levels in PPMS patients were greater than in healthy controls, but they were comparable to those in RRMS patients who were going through relapses as opposed to remission and triggered just a Th1 cell response in vitro, rather than Th1 and Th2 as in RRMS, implying a role for dendritic cells in the illness transition into the progressive phase. 32 The potential similarities between secondaryprogressive and PPMS warrant further investigation into the possible involvement of dendritic cells in the pathogenesis of PPMS.
A main mechanism causing degeneration of neurons and loss of axons in MS is microglial activation which has drawn more attention recently. Microglia were shown to be diffusely active in PPMS lesions as well as normally appearing white and gray matter. 33  One of the hallmark clinical features of PPMS is the progressive accumulation of disability. Patients with PPMS experience a gradual decline in neurological function, with symptoms such as muscle weakness, spasticity, and gait disturbance. 29 Unlike in RRMS, these symptoms worsen steadily over time without distinct relapses or remissions. PPMS patients may also experience urinary dysfunction, sexual dysfunction, cognitive impairment, and fatigue, which can significantly impact their quality of life. 34 PPMS typically affects patients who are older at the time of onset, with an average age of onset of around 40-50 years old. 35 Men and women are affected equally. PPMS also appears to be more common in patients of African descent.

| Characteristic differentiating biomarkers
Biomarkers have been proposed as potential tools for early diagnosis, disease monitoring, and predicting treatment response in PPMS patients.
One of the most promising biomarkers for PPMS is the neurofilament light chain (NfL), which is a protein found in neurons and released into the CSF and blood following neuroaxonal damage.
In a recent study, the utility of NfL was investigated as a biomarker for PPMS. NfL levels were shown to be considerably greater in PPMS patients when compared to healthy controls since elevated NfL levels in the blood and CSF has been linked to disease activity and the development of impairment in PPMS patients. 36 For example, a recent study published in JAMA Neurology found that higher baseline levels of NfL in the CSF were associated with greater cognitive decline and lesion accumulation over a 2-year period in patients with PPMS. 37 According to a study, people with PPMS who had higher blood levels of NfL had a higher chance of becoming disabled and experiencing brain atrophy during a 5-year period. 36 According to these results, NfL may be a helpful biomarker for tracking the development of the illness and the effectiveness of treatment in PPMS patients.
Another potential biomarker for PPMS is a glial fibrillary acidic protein (GFAP). In a recent investigation, it was discovered that CSF GFAP concentrations exhibited a marked increase in individuals diagnosed with PPMS in comparison to those who were deemed healthy controls. Furthermore, heightened GFAP levels were linked to heightened disability and hastened disease progression. 38 The results of this study indicate that GFAP has the potential to serve as a  In addition to these diffuse changes, neuroimaging studies have also identified specific regions of the brain that are affected in PPMS.
For example, studies using functional MRI (fMRI) have shown that patients with PPMS have decreased activation in the motor cortex during a hand movement task, suggesting that there is damage to the motor pathways in these patients. 46 Other studies have shown that the thalamus, a key relay center in the brain, is also affected in PPMS, with decreased volume and functional connectivity in this region. 47,48

| RRMS
Approximately 85% of all cases of MS fall within the most prevalent subtype, RRMS. 49 Relapses or exacerbations of acute neurological symptoms, also known as RRMS hallmarks, are followed by intervals of partial or total recovery, also known as remissions. In comparison to PPMS, the average age at which RRMS onset occurs is 30 years older ( Table 2). 50 For example, the Epstein-Barr virus has been implicated as a potential trigger for RRMS, as individuals with higher levels of EBV antibodies are at an increased risk of RRMS development. 55 Vitamin D deficiency has also been associated with an increased risk of developing RRMS, possibly due to its role in regulating immune function. 56

| Characteristic clinical features
The clinical presentation of RRMS can vary greatly between individuals, but there are some common features that are seen in most patients.
The most common initial symptom of RRMS is optic neuritis. 34 Other T A B L E 2 Features of relapsing-remitting and primary-progressive multiple sclerosis. common initial symptoms include sensory disturbances, such as tingling or numbness in the limbs, and motor symptoms, such as weakness or spasticity. 34 During a relapse, the symptoms may worsen or new symptoms may appear. These symptoms can affect body parts and can include weakness, numbness, tingling, visual disturbances, problems with balance and coordination, and cognitive difficulties. 60  Ocrelizumab's anti-CD20 antibody action allows it to avoid targeting plasma cells with negative CD20 on their surface while depleting circulating immature and mature B cells (Figure 3). The effector mechanisms of the anti-CD20 antibody include complementdependent cytotoxicity and antibody-dependent cellular cytotoxicity. 67 Ocrelizumab demonstrated to result in a complete reduction in CD19+ count in B cells. 68  all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.

CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
All the data used in this study are present within the study itself. No new data were created or analyzed in this study.

TRANSPARENCY STATEMENT
The lead author Omniat Amir affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and if relevant, registered) have been explained.