Recent Multiple Sclerosis Studies: Interventions, Safety, and Efficacy

Anti-CD20 Therapies and Their Outcomes

Ocrelizumab Studies

A post-hoc analysis of pooled data from 13 clinical trials involving 6,155 patients evaluated the safety profile of ocrelizumab in multiple sclerosis patients. Over a median treatment period of 3.7 years (maximum 13.9 years), 6.8% of patients experienced 583 serious infections. Incidence rates remained stable at 1.50 per 100 patient years in relapsing MS and 3.70 per 100 patient years in progressive MS. The most common serious infections affected the lower respiratory tract, urinary tract, abdominal/gastrointestinal, and skin. Approximately 90% of serious infections resolved, and treatment continued in >80% of cases.

Risk factors for infections included the presence of comorbidities (rate ratio=1.66 for 1 comorbidity, 2.73 for ≥2), recent relapse activity (2.06), and EDSS score ≥6.0 (2.02) in RMS patients. In primary progressive MS, EDSS score ≥6.0 showed the greatest risk (rate ratio 4.31).

Ocrelizumab was the first proven therapy to reduce disability progression in primary progressive MS, with its trial being the first to reach the primary disability endpoint. Over >9 years of continuous ocrelizumab treatment, the rate of infections remained low and stable over time. During the double-blind period of ocrelizumab trials, safety profiles in both ocrelizumab and interferon groups were similar, with no new safety signals observed during the open-label extension.

Anti-CD20 Therapies Real-World Study

A retrospective cohort study of 160 MS patients treated with anti-CD20 drugs since 2016 provided real-world data on these therapies. The study included 83 patients on ocrelizumab, 48 on rituximab, and 29 on ofatumumab with a mean follow-up of 30.5±21.3 months. Serious adverse events occurred in 9 patients, including SARS-CoV-2 infection (one death), urinary tract infection, febrile neutropenia, severe diarrhea, and acute hepatitis.

Serious infections in the ocrelizumab group were consistent with literature, but higher rates were observed in the rituximab group. The study found a positive correlation between serious infectious complications and lower IgG levels. Longer exposure to anti-CD20 therapy was associated with increased risk of IgG deficiency and higher incidence of serious infections. Lymphopenia was detected in 25 patients but not directly linked to serious infections.

Ofatumumab Studies

Ofatumumab, a fully human anti-CD20 monoclonal antibody, became available for treatment of MS in 2021. It is administered subcutaneously at low doses on a monthly basis due to its high affinity to the target structure. Long-term data for ofatumumab show stable IgG levels over up to four years and high efficacy with respect to relapse rate, progression, and cognition. According to current study data, the effect of ofatumumab compared to teriflunomide is greater the earlier therapy is initiated. Four-year study data for ofatumumab showed no abnormalities in the rate of severe infections or malignancies.

Treatment Discontinuation Patterns

Patients starting B cell depleting therapies (BCDT) like ocrelizumab/rituximab were less likely to discontinue treatment than all other disease-modifying therapies (DMT) combined (HR=0.26, 95% CI=0.18-0.36, p<.01). BCDT discontinuation was lower compared to oral DMT (HR=0.28, 95% CI=0.20-0.39, p<.01) and natalizumab (HR=0.35, 95% CI=0.21-0.58, p<.01).

Other Therapeutic Approaches

When combined with beta interferon, atorvastatin resulted to be safe and well tolerated, with no serious adverse effects reported. Daratumumab was associated with adverse drug events (ADEs), including pneumonia and diarrhea, with conflicting evidence regarding hematological ADEs association.

After natalizumab discontinuation, 1 patient developed progressive multifocal leukoencephalopathy during the observation period, with complete recovery. Therapy discontinuation after 24 doses in natalizumab-responding patients should be considered only if the risk of progressive multifocal leukoencephalopathy is high and outweighs the benefits of continuing the drug.

Global Multiple Sclerosis Epidemiology: Recent Estimates and Trends

Global Incidence and Prevalence

Recent epidemiological studies have revealed significant changes in the global burden of Multiple Sclerosis (MS). According to current estimates, the median estimated incidence of MS globally stands at 5.2 per 100,000 person-years, with a range varying from 0.5 to 20.6. The median estimated prevalence is 112.0 per 100,000 person-years, ranging from 5.2 to 335. The average disease duration has been calculated at 20.2 years, with a range of 7.6 to 36.2 years.

In recent years, an increasing number of epidemiological studies have demonstrated significantly higher MS prevalence and incidence rates. Over the past few decades, the global prevalence and incidence patterns of MS have changed dramatically, suggesting the need for a novel classification system based on global MS disease burden.

Regional Variations in MS Epidemiology

The geographic distribution of MS was traditionally divided into three zones based on frequency, as established by Kurtzke in the early 1970s. More recent approaches have grouped MS studies by continent: the Americas, Europe, Asia, Australia/New Zealand, and Africa. A systematic review identified 101 studies meeting inclusion criteria, with 58 reporting incidence estimates.

European Data

In the UK, based on 642 incident cases from 1993-2000, incidence rates of MS adjusted to the world population were 7.2 (95% CI 6.5, 7.8) per 100,000 in women and 3.1 (95% CI 2.6, 3.5) per 100,000 in men. The estimated lifetime risk from birth of receiving an MS diagnosis in the UK was 5.3 per 1,000 in women and 2.3 per 1,000 in men.

In Germany, within a 10-year follow-up period, the incidence of MS was 22.6 cases per 100,000 person-years among patients with infectious mononucleosis but only 11.9 cases per 100,000 person-years among individuals without infectious mononucleosis.

Middle East and North Africa

Recent studies indicate a rising prevalence of MS in the Middle East and Persian Gulf region. In Egypt, a retrospective study of 1,581 patients between 2001 and 2015 found the mean age of disease onset was 26.6±7.8 years, with a female-to-male ratio of 2.11:1. Observations in the Middle East show a heavy MRI lesion load at the onset of disease in a relatively younger native population. In an Emirati cohort, the average age of onset was about 26 years with female dominance of about 2:1.

Asian Data

A population-based survey in Guangzhou, China (August 8, 2021 to December 31, 2021) calculated the prevalence of multiple sclerosis in 18,676,605 residents. A total of 143 patients were diagnosed with MS, resulting in a crude prevalence of 0.77 per 100,000 (95% confidence interval (CI): 0.65-0.90). The prevalence was higher in females (1.14/100,000) than in males (0.44/100,000). The age-adjusted prevalence was 0.92 per 100,000 (95% CI: 0.77-1.10). The prevalence peaked at the age of 25-29 years (2.86/100,000) for both males and females (1.44/100,000 and 4.42/100,000, respectively). This was the first study to report the prevalence of MS in Guangzhou, China, according to the 2017 McDonald criteria, showing that the prevalence of MS in Guangzhou is lower than that in other cities in China.

Research Challenges and Recommendations

Heterogeneity was high among all studies, even when stratified by country. Only half of the studies reported standardized rates, making comparisons difficult. There are gaps in epidemiological knowledge of MS in many regions and inconsistencies in methodologies among published studies.

Future studies of MS prevalence and incidence need to include uniform case definitions, employ comparable methods of ascertainment, report standardized results and be performed on a national level. Other factors such as sex distribution, ethnic make-up and population lifestyle habits should also be considered.

Environmental factors may better explain increasing incidence and prevalence in previously low-prevalence areas like Iran. The gene-environment interaction plays an important role in Multiple Sclerosis development.