Cellular and Humoral Immunity to SARS-CoV-2 Infection in Multiple Sclerosis Patients on Ocrelizumab and Other Disease-Modifying Therapies: A Multi-Ethnic Observational Study.

OBJECTIVE: The objective of this study was to determine the impact of multiple sclerosis (MS) disease-modifying therapies (DMTs) on the development of cellular and humoral immunity to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection. METHODS: Patients with MS aged 18 to 60 years were evaluated for anti-nucleocapsid and anti-Spike receptor-binding domain (RBD) antibody with electro-chemiluminescence immunoassay; antibody responses to Spike protein, RBD, N-terminal domain with multiepitope bead-based immunoassays (MBI); live virus immunofluorescence-based microneutralization assay; T-cell responses to SARS-CoV-2 Spike using TruCulture enzyme-linked immunosorbent assay (ELISA); and IL-2 and IFNγ ELISpot assays. Assay results were compared by DMT class. Spearman correlation and multivariate analyses were performed to examine associations between immunologic responses and infection severity. RESULTS: Between January 6, 2021, and July 21, 2021, 389 patients with MS were recruited (mean age 40.3 years; 74% women; 62% non-White). Most common DMTs were ocrelizumab (OCR)-40%; natalizumab -17%, Sphingosine 1-phosphate receptor (S1P) modulators -12%; and 15% untreated. One hundred seventy-seven patients (46%) had laboratory evidence of SARS-CoV-2 infection; 130 had symptomatic infection, and 47 were asymptomatic. Antibody responses were markedly attenuated in OCR compared with other groups (p ≤0.0001). T-cell responses (IFNγ) were decreased in S1P (p = 0.03), increased in natalizumab (p <0.001), and similar in other DMTs, including OCR. Cellular and humoral responses were moderately correlated in both OCR (r = 0.45, p = 0.0002) and non-OCR (r = 0.64, p <0.0001). Immune responses did not differ by race/ethnicity. Coronavirus disease 2019 (COVID-19) clinical course was mostly non-severe and similar across DMTs; 7% (9/130) were hospitalized. INTERPRETATION: DMTs had differential effects on humoral and cellular immune responses to SARS-CoV-2 infection. Immune responses did not correlate with COVID-19 clinical severity in this relatively young and nondisabled group of patients with MS. ANN NEUROL 2022;91:782-795.

Relapse rates in patients with multiple sclerosis treated with fingolimod: Subgroup analyses of pooled data from three phase 3 trials.

BACKGROUND: Fingolimod is a once-daily, orally administered therapy for relapsing forms of MS. It has been shown to reduce relapse rates significantly in all phase II and phase III clinical trials when compared with placebo and intramuscular interferon ß-1a (IFNß-1a IM). METHODS: This study compared annualized relapse rates (ARRs) associated with fingolimod, placebo and IFNß-1a IM, in patient subgroups from the pooled FREEDOMS, FREEDOMS II, and TRANSFORMS populations. This provided a large data set in which the efficacy of fingolimod could be assessed across a range of patient subgroups, including clinically relevant subgroups not previously analysed. RESULTS: Compared with placebo, fingolimod was associated with significantly lower ARRs across all patient subgroups with relative reductions in ARRs ranging from 35% (patients who had previously received treatment for their MS for up to 1 year; P<0.05) to 69% (patients with symptoms for less than 3 years before study entry; P<0.001). Other relative reductions in ARR compared with placebo included 64% in patients aged 40 years or younger and 63% in those naïve to treatment (P<0.001 for both). Compared with IFNß-1a IM, the greatest benefits to ARR were seen in patients aged 40 years or younger (55% relative ARR reduction, P<0.001) and in a small subgroup of patients who had previously received IFNß and glatiramer acetate (55% relative ARR reduction; P<0.05). Reductions in ARR compared with IFNß-1a IM were not statistically significant in men (33%, P=0.081), in patients aged over 40 years (23%, P=0.230) and in those who had received treatment prior to the study for 1 year or less (35%, P=0.108). Fingolimod was associated with significantly lower ARRs compared with placebo and with IFNß-1a IM irrespective of treatment status (treatment-naïve and previously treated for MS), and regardless of type of previous therapy. CONCLUSIONS: Fingolimod provided consistent efficacy benefits over placebo and IFNß-1a IM across a range of subgroups of patients with relapsing MS. The magnitude of the beneficial effect of fingolimod over IFNß-1a IM may depend on age, sex, and duration of previous treatment. These findings suggest that most benefit will be gained by patients who start fingolimod early in the disease course, but the findings also suggest that fingolimod treatment will benefit patients later in the disease course when they have already accrued disability.

Fingolimod: a review of its mode of action in the context of its efficacy and safety profile in relapsing forms of multiple sclerosis.

Fingolimod is an orally administered, first-in-class therapy for the treatment of relapsing forms of multiple sclerosis. Data from pivotal clinical trials show that fingolimod has a robust, significant effect on annualized relapse rates and MRI outcomes. Fingolimod has a novel, well-characterized mechanism of action. It acts through a specific set of receptors, sphingosine 1-phosphate receptors, present on the surface of a wide range of human cells and tissues, including neural cells, neurons and lymphocytes. Here we review the current literature to describe the mechanism of action of fingolimod in the context of its well-established clinical efficacy and safety profile. Understanding of the mechanisms behind any non-therapeutic effects of fingolimod facilitates their prediction and management in the clinical setting.

Progressive multiple sclerosis: characteristics and management.

Progressive multiple sclerosis (MS) consists of 3 phenotypic subtypes: secondary progressive MS, primary progressive MS, and progressive relapsing MS. There has been a paucity of approved treatments for these subtypes possibly driven by irreversible neurodegeneration within the central nervous system and not amenable to drugs that target inflammation. This article reviews magnetic resonance imaging and clinical data that show that progression may occur early in the course of MS and specific subsets of progressive patients may respond to disease modifying drugs.

A one-year prospective, randomized, placebo-controlled, quadruple-blinded, phase II safety pilot trial of combination therapy with interferon beta-1a and mycophenolate mofetil in early relapsing-remitting multiple sclerosis (TIME MS).

BACKGROUND: Mycophenolate mofetil (MMF) is an oral DNA base synthesis inhibitor with immunomodulatory effects on B cells, T cells, and macrophages. OBJECTIVE: To conduct a safety and tolerability pilot study of interferon beta-1a (IFN-b1a) in combination with either placebo or oral MMF in multiple sclerosis (MS). METHODS: Twenty-four treatment-naïve R-RMS patients participated in a one-year prospective, placebo-controlled, blinded, safety pilot clinical trial. Every patient injected weekly intramuscular interferon beta-1a. The cohort was then randomized (1 : 1) to either active oral MMF or identical-appearing placebo tablets. Clinical evaluations were assessed every 3 months, along with brain MRI scans performed at baseline and repeated every 60 days for one year. Comprehensive laboratory assessments were monitored for safety, along with adverse events. RESULTS: In this small pilot investigation, no differences were identified between the two treatment groups with respect to patient-reported adverse events, MRI metrics, or laboratory abnormalities. Notwithstanding these observations, and the limited number of patients treated, trends appeared to favor the combination therapy regimen. CONCLUSIONS: The combination treatment regimen of interferon beta-1a and MMF appeared to be well tolerated in this pilot study. Despite the small sample size, therapeutic trends were observed in favor of combination therapy. An adequately powered controlled trial of MMF in MS appears warranted.

Primary progressive multiple sclerosis.

Primary progressive multiple sclerosis (MS), comprising 10% to 15% of all cases of MS, is characterized by an insidious progression from the onset of disease, making it clinically distinct from the commonest form, relapsing remitting MS. Making the diagnosis can be challenging, and misdiagnosis and delay in diagnosis are common. Although no effective treatments are currently known, insights into the pathogenesis of this phenotype aid in understanding the processes that drive progression in all forms of MS.

Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial.

OBJECTIVE: Rituximab, a monoclonal antibody selectively depleting CD20+ B cells, has demonstrated efficacy in reducing disease activity in relapsing-remitting multiple sclerosis (MS). We evaluated rituximab in adults with primary progressive MS (PPMS) through 96 weeks and safety through 122 weeks. METHODS: Using 2:1 randomization, 439 PPMS patients received two 1,000 mg intravenous rituximab or placebo infusions every 24 weeks, through 96 weeks (4 courses). The primary endpoint was time to confirmed disease progression (CDP), a prespecified increase in Expanded Disability Status Scale sustained for 12 weeks. Secondary endpoints were change from baseline to week 96 in T2 lesion volume and total brain volume on magnetic resonance imaging scans. RESULTS: Differences in time to CDP between rituximab and placebo did not reach significance (96-week rates: 38.5% placebo, 30.2% rituximab; p = 0.14). From baseline to week 96, rituximab patients had less (p < 0.001) increase in T2 lesion volume; brain volume change was similar (p = 0.62) to placebo. Subgroup analysis showed time to CDP was delayed in rituximab-treated patients aged <51 years (hazard ratio [HR] = 0.52; p = 0.010), those with gadolinium-enhancing lesions (HR = 0.41; p = 0.007), and those aged <51 years with gadolinium-enhancing lesions (HR = 0.33; p = 0.009) compared with placebo. Adverse events were comparable between groups; 16.1% of rituximab and 13.6% of placebo patients reported serious events. Serious infections occurred in 4.5% of rituximab and <1.0% of placebo patients. Infusion-related events, predominantly mild to moderate, were more common with rituximab during the first course, and decreased to rates comparable to placebo on successive courses. INTERPRETATION: Although time to CDP between groups was not significant, overall subgroup analyses suggest selective B-cell depletion may affect disease progression in younger patients, particularly those with inflammatory lesions.

B cells as a target of immune modulation.

B cells have recently been identified as an integral component of the immune system; they play a part in autoimmunity through antigen presentation, antibody secretion, and complement activation. Animal models of multiple sclerosis (MS) suggest that myelin destruction is partly mediated through B cell activation (and plasmablasts). MS patients with evidence of B cell involvement, as compared to those without, tend to have a worse prognosis. Finally, the significant decrease in new gadolinium-enhancing lesions, new T2 lesions, and relapses in MS patients treated with rituximab (a monoclonal antibody against CD20 on B cells) leads us to the conclusion that B cells play an important role in MS and that immune modulation of these cells may ameliorate the disease. This article will explore the role of B cells in MS and the rationale for the development of B cell-targeted therapeutics. MS is an immune-mediated disease that affects over 2 million people worldwide and is the number one cause of disability in young patients. Most therapeutic targets have focused on T cells; however, recently, the focus has shifted to the role of B cells in the pathogenesis of MS and the potential of B cells as a therapeutic target.

B-cell-targeted treatment for multiple sclerosis: mechanism of action and clinical data.

Strategies for treating autoimmune disorders are increasingly employing targeted therapies rather than non-specific, multitargeted treatments. Accumulating evidence on the involvement of B lymphocytes in the pathophysiology of autoimmune demyelinating disease has led to a renewed interest in B cells as potential therapeutic targets. In particular, antigen presentation between B cells and T cells, increased trafficking of B cells across the blood-brain barrier, and autoantibodies produced by plasma cells may contribute to the pathophysiology of autoimmune disorders such as multiple sclerosis. Several B-cell-targeted, depletion therapies are currently in development, including rituximab, epratuzumab, diphtheria toxin-single chain Fv (DC2219), belimumab, atacicept, abatacept, and abetimus sodium. Of these agents, only rituximab and abatacept have been evaluated in multiple sclerosis patients. Preliminary results of a phase II trial of rituximab in multiple sclerosis suggest that rituximab is well tolerated and significantly reduces the number of gadolinium enhancing lesions over 24 weeks of treatment. Results of an exploratory analysis suggest the potential promise of abatacept 10 mg/kg for multiple sclerosis. It is expected that future clinical trials will establish a role for B-cell-targeted therapies in the treatment of multiple sclerosis and other autoimmune neurological diseases. This article describes the mechanism of action behind B-cell-targeted depletion therapies in development and reviews available clinical data.

Genetic analysis of the exon 1 position 49 CD152 dimorphism in multiple sclerosis.

Several studies have examined whether a dimorphism in the CD152 costimulatory molecule may influence the development of multiple sclerosis (MS). A sample of 108 patients with a diagnosis of relapsing remitting (RRMS), 28 with secondary progressive (SPMS), 23 with primary progressive (PPMS) and 63 people with no prior history of neurological conditions were selected from the MS clinic at the University of Texas Southwestern Medical Center at Dallas. Peripheral blood was separated with gradient extraction for leukocytes and genomic DNA extracted for CD152 A/G dimorphism analysis. A 163 bp PCR product in exon 1 including the position 49 A/G dimorphism was examined via single strand conformation polymophism (SSCP). Patient haplotype frequencies were compared between cases and controls and Pearson Chi-Square test performed to demonstrate statistical differences between MS groups and controls. Our results, similar to several recent studies, suggest that there is no statistical association with the risk of developing MS and no increased frequency in A or G at position 49 of exon 1 of CD152. Demonstration of prolonged proliferation in patient samples containing the GG genotypes and altered CD152 surface expression was also not demonstrated suggesting that the CD152 exon 1 position 49 A/G dimorphism does not contribute significantly to the development of MS in this patient population.

Urodynamic distinctions between idiopathic detrusor overactivity and detrusor overactivity secondary to multiple sclerosis.

OBJECTIVES: To evaluate the urodynamic characteristics of neurogenic detrusor overactivity (NDO) secondary to multiple sclerosis (MS) compared with idiopathic DO (IDO) to determine whether urodynamic distinctions could differentiate the different etiologies of DO. METHODS: The urodynamic characteristics of DO in women with MS (n = 54) were compared with the overactive contractions found in women with lower urinary tract symptoms and IDO (n = 42). Among other parameters, the amplitude of the first overactive contraction, maximal detrusor contraction, and threshold volume for the first overactive contraction were evaluated to assess the DO severity. A sensitivity analysis using cutoff values determined from those urodynamic parameters that differed between the patient groups is presented. RESULTS: The amplitude of the first overactive contraction was statistically greater in the patients with MS and NDO compared with patients with IDO (28.3 cm H2O versus 20.5 cm H2O, P = 0.003), as was the maximal detrusor contraction (46.4 cm H2O versus 30.8 cm H2O, P = 0.002). The threshold volume for DO was greater among patients with NDO (186.8 mL versus 150.5 mL, P = 0.037), likely secondary to the elevated postvoid residual urine volume noted among patients with MS (P = 0.049). Using a cutoff value of 30 cm H2O for amplitude of the first overactive contraction achieved a positive predictive value of 88% for identifying MS in our data set. CONCLUSIONS: The urodynamic characteristics of NDO differed significantly from those of IDO. Additional investigation is required to determine whether these differences are due to neurogenic influences directly on the detrusor muscle through aberrant innervation or by other mechanisms, such as enhanced outlet resistance during voiding.

Therapeutic considerations for disease progression in multiple sclerosis: evidence, experience, and future expectations.

In the management of patients with multiple sclerosis (MS), providers are all faced with the highly formidable challenge of ascertaining whether, and to what degree, disease-modifying therapy is effective in the individual patient. While much has been learned in randomized, controlled clinical trials, we cannot simply extrapolate the outcomes of these initiatives and apply them to the care of a single patient. In the future, the application of pharmacogenetic techniques, proteomics, and microarray analysis will yield novel profiling information on individual patients that will substantially refine the specific therapeutic questions of relevance: (1) What is the best treatment for an individual patient? (2) Which patients require intensive therapeutic combination regimens to optimize control of the disease process? (3) What are the appropriate drug dosing targets for an individual patient? and (4) Which patients will be predisposed to the development of drug-related adverse events? Such data may provide a novel variable of drug responsiveness that will mandate its inclusion into the process of covariate analyses for clinical trials.

Incidence of upper tract abnormalities in patients with neurovesical dysfunction secondary to multiple sclerosis: analysis of risk factors at initial urologic evaluation.

OBJECTIVES: To determine the incidence of upper tract abnormalities on renal ultrasonography in patients with multiple sclerosis (MS) referred for urologic evaluation, as well as to identify any risk factors present on the basis of the historical information and urodynamic findings. METHODS: Data were derived from all patients with MS referred to the neurourology clinic during a 4-year period. The database was specifically queried for patients found to have upper tract abnormalities on screening renal ultrasonography. Demographic parameters, as well as laboratory values (creatinine) and urodynamic results, were evaluated for risk factors associated with abnormal upper tract findings. RESULTS: Of the 113 patients referred and evaluated, 66 completed both urodynamic testing and renal ultrasonography. Eleven (16.7%) had abnormal ultrasound findings, with focal caliectasis the most common finding. No demographic parameter (age, sex, time since MS diagnosis, MS pattern) was associated with a greater likelihood of abnormal renal ultrasonography on univariate analysis. Neither serum creatinine nor any urodynamic finding (including the presence of dyssynergia or the threshold and amplitude of detrusor overactivity) was associated with abnormal renal ultrasound findings. CONCLUSIONS: No patients in our series had any indication of obstructive uropathy more severe than mild hydronephrosis. Of the 16.7% of patients with any abnormal findings, most were noted to have minor caliectasis, likely to be of little clinical significance. Although no factors identifying patients at risk of renal abnormalities at presentation were found, ongoing evaluation of patients with baseline findings will serve to identify those at risk of progression.

Effect of rituximab on the peripheral blood and cerebrospinal fluid B cells in patients with primary progressive multiple sclerosis.

BACKGROUND: Rituximab, an anti-CD20 monoclonal antibody that depletes CD20(+) B cells, has demonstrated efficacy in peripheral neurological diseases. Whether this efficacy can be translated to neurological diseases of the central nervous system with possible autoimmune B-cell involvement remains unknown. OBJECTIVE: To determine the effect of rituximab on cerebrospinal fluid B cells in patients with multiple sclerosis. DESIGN: Four patients with primary progressive multiple sclerosis were treated with rituximab. Cerebrospinal fluid and peripheral blood B-cell subsets were identified by flow cytometry from each patient before and after rituximab treatment. RESULTS: The B cells in cerebrospinal fluid were not as effectively depleted as their peripheral blood counterparts. Rituximab treatment temporarily suppressed the activation state of B cells in cerebrospinal fluid. The residual B cells underwent expansion after rituximab treatment. CONCLUSION: The effect(s) of rituximab on the cerebrospinal fluid B-cell compartment is limited in comparison with the effect(s) on the B cells in the periphery, but this finding will need to be confirmed in a larger group of MS patients.

Mycophenolate mofetil in multiple sclerosis.

OBJECTIVE: To describe experience with the use of mycophenolate mofetil (MMF) in the treatment of multiple sclerosis (MS). BACKGROUND: MMF is a potent immunosuppressant that is a selective inhibitor of inosine 5'-monophosphate dehydrogenase type II, the enzyme responsible for the de novo synthesis of the purine nucleotide guanine within activated T and B lymphocytes and macrophages. METHODS: A retrospective review of experience in treating 79 MS patients with MMF (61 with secondary progressive, 14 with relapsing-remitting, and 4 with primary progressive MS) in the authors' MS center. RESULTS: In most cases, MMF was added as adjunctive therapy in patients already being treated with either interferon-beta (n = 44) or glatiramer acetate (n = 20). Fifteen patients not able to use interferon or glatiramer acetate were treated with MMF monotherapy. Seventy percent of the patients continued MMF therapy. Eight patients discontinued therapy because of side effects, 7 patients continued to exhibit evidence of disease progression, 4 were denied insurance coverage, 2 were lost to follow-up, and 1 patient had an elevation of hepatic transaminases that resolved on discontinuation of MMF. One patient discontinued MMF therapy secondary to cytomegalovirus diarrhea. CONCLUSION: MMF was well tolerated by the majority of patients treated. While these clinical observations were uncontrolled, the clinical course of MS was either unchanged or subjectively improved in many of the treated patients. A randomized controlled trial of MMF in MS, either as monotherapy or in conjunction with interferon or glatiramer acetate, appears warranted.

Levetiracetam for phasic spasticity in multiple sclerosis.

BACKGROUND: Spasticity is a common and debilitating symptom of multiple sclerosis (MS). Current treatments are effective, but may be difficult to tolerate for many patients. OBJECTIVE: To determine if levetiracetam, a second-generation antiepileptic drug, may be useful for the treatment of spasticity in MS. METHODS: A retrospective medical record review of patients attending the Multiple Sclerosis Program at the University of Texas, Southwestern Medical Center at Dallas was performed. A series of 12 patients who had been treated with levetiracetam for spasticity was identified. Most of the patients were female (10/11), and the mean age was 41.0 years. The main outcome measure was a change in Penn spasm score or modified Ashworth score. Both scores are measured on a scale of 0 to 4. RESULTS: The Penn Spasm score (a measure of phasic spasticity) was decreased for all patients following treatment with levetiracetam. The mean +/- SD Penn Spasm score was 2.7 +/- 0.65 at baseline and decreased to 0.9 +/- 0.29 at follow-up. There was no change in modified Ashworth scores (a measure of tonic spasticity). Five patients reported adverse events; 1 patient discontinued treatment owing to an adverse event (edema). Three patients incidentally reported improvements in neuropathic pain. CONCLUSIONS: Levetiracetam was effective for reducing phasic spasticity but not tonic spasticity in this 12-patient case series. The drug was well tolerated and therefore shows promise as a treatment for phasic spasticity. Large, well-controlled trials are needed to confirm these findings.

Disease-modifying therapy in multiple sclerosis: strategies for optimizing management.

BACKGROUND: The objective for this article is to highlight several challenges faced by patients and providers in the utilization of disease-modifying agent (DMA) therapy in multiple sclerosis (MS) and to offer practical management strategies that can effectively mitigate or even prevent limiting adverse reactions and enhance treatment compliance. REVIEW SUMMARY: Our discussion will be limited to the use of interferon beta1a (Avonex, Rebif), interferon beta1b (Betaseron), and glatiramer acetate (Copoxane) as these are the primary agents used in the United States for primary disease-modifying therapy in relapsing forms of MS. Some of the recommendations contained herein are derived from evidence-based studies, while others are contingent upon our collective clinical experiences. At the University of Texas Southwestern Medical Center at Dallas and Texas Neurology in Dallas we actively follow approximately 5000 MS patients. The majority of our patients with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) are treated with one of the currently available DMAs. Our experience with these patients, and the challenges they face in continuing long-term treatment, constitutes the basis of our proposed treatment strategies. As part of this effort we formulated an assessment and intervention instrument that can be used in the clinic and by telephone to enhance compliance and minimize adverse events. CONCLUSION: A comprehensive treatment approach to the utilization of disease-modifying therapy in MS can serve to optimize the management of our patients and effectively meet the challenges that arise during the course of treatment.

Bladder, Bowel, and Sexual Dysfunction in Multiple Sclerosis.

The majority of patients with multiple sclerosis (MS) experience genitourinary and bowel dysfunction over the course of their illness. Lower extremity pyramidal signs are excellent predictors of concurrent bladder dysfunction. Constipation is the most common bowel dysfunction, which results from a range of causes including pelvic floor spasticity, decreased gastro-colic reflex, inadequate hydration, medications, immobility, poor physical conditioning, and weak abdominal muscles. Despite the advent of new therapeutic modalities, the physician and patient commonly overlook sexual dysfunction. A detailed history of the patient is crucial to determine the cause of the dysfunction. Fatigue, pain, mood disorders, spasticity, bowel, and bladder dysfunction can all interfere with normal sexual functioning, and these subjects should be explored in detail in order to plan for proper treatment. Integrated treatment plans, often in conjunction with an urologist, can lead to amelioration of symptoms.