Erica Slaughter, MS

By applying a validated algorithm to multiple sets of administrative health data (AHC), researchers have shown that there has been a steady rise in the prevalence of 

 in the US over the past 5 years to nearly 1 million people.

This number is nearly double that of previously reported estimates from prior studies, which had estimated that this population in the US numbered approximately 

403,630 individual cases (95% CI 387,445-419,833)

. Establishing an accurate estimate of MS prevalence in the US is essential for evaluating changes in disease frequency in relation to changing population demographics.

“We must understand the reasons behind the growing MS prevalence estimates in the US,” Mitchell Wallin, MD, MPH, Director for The Multiple Sclerosis Centers of Excellence (MSCoE) East at the US Department of Veterans Affairs (VA), told 

®. “For example, how are the demographic changes in the US influencing the incidence and mortality experience of MS?”

Wallin said more neurologists and health care providers experienced in MS will be needed to care for the rising rate of older patients with MS.

“Using large population-based MS cohorts and datasets that are well characterized is critical to a better understanding of the disease,” he said.

In a new study, researchers describe how this novel algorithm-based approach responds to the need for estimating the true prevalence of MS in the US, using analyses of AHCs from government and private health claims databases as the most reliable and cost-effective method. Previously, the primary method used to estimate national MS prevalence has been probability health surveys that relied on patient or family member reports of physician-diagnosed MS.

The data are less reliable due to the risk of the inclusion of false-positive MS cases or provisional cases that would not meet formal case definition criteria, and insufficient numbers of people with MS to enable precise estimation of MS prevalence, much less prevalence within demographic or regional subgroups. What’s more, the national survey no longer includes questions about MS.

While AHC databases present a tremendous resource for analyzing neurologic disease incidence using the international disease coding (ICD) system, there are potential limitations when used for epidemiological purposes. The algorithm developed is optimal in terms of sensitivity, specificity, and simplicity, requiring ≥3 MS-related hospitalizations, outpatient visits, or prescription release encounters for an MS disease-modifying therapy within a 1-year period that was approved by the US Food and Drug Administration (FDA) for MS by 2010. Depending on the dataset, the sensitivity of the MS algorithm was 86% to 92% and the specificity was 66% to 83%, when tested among individuals with at least 1 MS claim.

“The planned US Neurological Disease Surveillance System, if properly launched and funded, could be very helpful in this regard and should be supported,” continued Wallin. “Additionally, we must understand how the aging process itself impacts with morbidity and mortality of MS.”

Though the MS Prevalence Workgroup intends to analyze how race impacts MS prevalence to the extent possible in national healthcare datasets, more work must be done to confirm new variables, because of known risk factors for MS onset and progression, Wallin concluded.

The prevalence of MS in the United States

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Articles

The prevalence of multiple sclerosis in the United States has steadily grown over the past 5 years to nearly 1 million people.

Study Shows Steady Rise of Multiple Sclerosis Prevalence in United States

Nonmyeloablative hematopoietic stem cell transplantation (HSCT) was associated with prolonged time to disease progression when compared to disease-modifying therapies (DMT) for patients with relapsing-remitting 

 (RRMS), according to results published in 

Journal of the American Medical Association (JAMA).

In a randomized controlled trial, participants who met inclusion criteria for the trial (N=110) were randomized into the HSCT group (n=55) and continuation of DMT group (n=55). There were no significant differences between the HSCT and DMT groups in terms of sex, age, baseline expanded disability status scale (EDSS) scores, number of gadolinium-enhancing lesions, T2-weighted lesion volume on MRI before randomization, number of prior DMTs, or type of prior DMT or immune treatments.

Participants in the DMT group received a DMT of higher efficacy or a different class than the therapy taken at the time of randomization (based on decision of their treating neurologist). For patients in the HSCT group, DMT use was discontinued, followed by variable washout periods before admission for HSCT.

Peripheral blood stem cells were collected 10 days after intravenous cyclophosphamide (2 g/m

) and 5 to 10 μg/kg per day of subcutaneous filgrastim beginning 5 days after cyclophosphamide. The immune ablative regimen was intravenous cyclophosphamide, 50 mg/kg per day on days −5 to day −2 before stem cell infusion (day 0) and rabbit antithymocyte globulin, .5 mg/kg on day −5, 1 mg/kg on day −4, and 1.5 mg/kg on days −3, −2, and −1. Blood products were irradiated, cytomegalovirus safe, and leukocyte depleted. Filgrastim (5-10 μg/kg per day) was started on day +4 and continued until engraftment.

The primary endpoint, defined as an increase in disease progression (EDSS score increase of ≥1) of at least 1 point on 2 evaluations 6 months apart after at least 1 year of treatment, occurred in 3 patients in the HSCT group and 34 patients in the DMT group, with a median follow-up of 2 years. The proportion of patients in the HSCT group with disease progression was 1.92% (95% confidence interval [CI], .27%-12.9%) at 1 year and 2 years, 5.19% (95% CI, 1.26%- 20.1%) at 3 years, and 9.71% (95% CI, 3%-28.8%) at 4 and 5 years.

The proportion of patients in the DMT group with disease progression was 24.5% (95% CI, 14.7%-39.1%) at 1 year, 54.5% (95% CI, 40.7%-69.4%) at 2 years, 62.5% (95% CI,48.3%- 76.7%) at 3 years, 71.2% (95% CI, 56.8%-84.2%) at 4 years, and 75.3% (95% CI, 60.4%-87.8%) at 5 years.

Mean EDSS score decreased (improved) in the HSCT group, from a pre-HSCT score of 3.38 to 2.36 at 1 year (mean change, −1.02 points), while the mean EDSS score increased (worsened) in the DMT group, from 3.31 to 3.98 at 1 year (mean change, +.67 points). The difference between the HSCT group and DMT group in the change in EDSS scores from baseline to 1 year was −1.7 (95% CI, −2.03 to −1.29; 

Notably, there was significant improvement in EDSS scores, NRS scores, and T2-weighted lesion volume percentages in the 31 patients who crossed over from the DMT group to receive HCST, suggesting that current definitions of progression for RRMS may not accurately assess irreversible disease progression for all patients.

Investigators noted this study was limited by its small sample size and the limited ability to collect follow-up data for patients receiving DMT and to assess longer-term secondary outcomes due to a study design that allowed patients in the DMT group in whom that treatment failed to cross over to receive HSCT.

HSCT is designed to eliminate autoreactive lymphocytes and “reboot” the immune system in a non-inflammatory environment. In an observational study of long-term disability outcomes of patients with relapsing and progressive forms of MS, researchers found that nearly half of these patients were free of neurological progression 5 years after receiving autologous HSCT

. Better outcomes were associated with younger age, relapsing form of MS, fewer prior immunotherapies, and lower EDSS score at baseline.

“We think what happens in HSCT is that the immune response is exposed to myelin in the absence of the danger signal,” Richard K. Burt, MD, principle investigator and chief, division of immunotherapy at Northwestern University's Feinberg School of Medicine in Chicago, Illinois, said in an interview with the National MS Society. “What we’re doing is stopping inflammation you need to treat when the disease in its inflammatory stage.”

Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis

 Journal of the American Medical Association (JAMA).

[1] Muraro PA, Pasquini M, Atkins HL, et al. Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. 

. 2017;74(4):459-469. doi:10.1001/jamaneurol.2016.5867

Nonmyeloablative hematopoietic stem cell transplant found to prolong time to multiple sclerosis disease progression compared with disease-modifying therapies.

Stem Cell Transplantation Shows Greater Benefits for Relapsing-Remitting MS

Efficacy of ocrelizumab, a humanized anti-CD20 monoclonal antibody, was found to be superior to or comparable with 14 other disease-modifying therapies (DMTs) currently approved by the European Medicines Agency (EMA) for relapsing 

 (RMS) in 7 network meta analyses (NMAs). Ocrelizumab also demonstrated a similar safety profile to each of the DMTs in the analysis.  

A systematic literature review was conducted in MEDLINE, Embase, the Cochrane Library, trial registers, relevant conferences websites, and health technology assessment agency websites by researchers at York Health Economics Consortium and Quantics Biostatistics. A total of 33 randomized controlled trials (RCTs) met the eligibility criteria of a trial duration of at least 12 weeks and evaluation of suitable interventions for a subject base in which at least 75% of patients had RMS. Key efficacy outcome variables of interest were the 12-week confirmed disability progression (12-week CDP) and annualized relapse rate (ARR).

The key safety outcomes of interest were severe adverse events (SAEs) and discontinuation of treatment due to an adverse events (AEs). Outcomes were analyzed using standard Bayesian approaches, as described in the NICE Decision Support Unit Technical Support Document (DSU TSD) 2. Two sensitivity analyses were conducted to evaluate the assumptions of the base-case NMA for each outcome.

Heterogeneity and inconsistency assessments were also conducted for base-case NMAs. Surface under the cumulative ranking curve (SUCRA) values were used to demonstrate the efficacy and safety profile of each treatment for the 2 key efficacy outcomes (12-week CDP and ARR) and 2 key safety outcomes (SAEs and discontinuation due to AEs).

Investigators found that ocrelizumab was more effective in reducing the risk of 12-week CDP compared with 10 other treatments, including placebo, with no evidence to suggest that any other treatment was more effective than ocrelizumab. Analysis of the second key efficacy outcome showed that ocrelizumab was also found to be more effective in reducing ARR than 12 other treatments. There were no differences in SAEs or discontinuation due to AEs between ocrelizumab and other DMTs studied.

Ocrelizumab demonstrated a consistently high probability of ranking the most effective or tolerable treatment across all 4 outcomes when probabilities of the 2 key efficacy outcomes were plotted with the 2 key safety outcomes.

Limitations of using NMAs included the lack of RCTs that were statistically powered to analyze safety, and that SAEs and AEs were only recorded during trial periods. Short-term (12 week) results obtained from the RCTs may not be relevant for long-term outcomes.

The researchers concluded that “in the absence of head-to-head trials against other DMTs for the treatment of patients with RMS, this NMA provides important evidence on the relative efficacy and safety of ocrelizumab compared with other approved treatments for RMS. This evidence suggests that ocrelizumab has an efficacy superior to or comparable with all other current approved DMTs across all endpoints analyzed as well as a similar safety profile, indicating that it offers a complete and valuable package for the treatment of patients with RMS.”

Systematic review and network meta-analysis comparing ocrelizumab with other treatments for relapsing multiple sclerosis

Multiple Sclerosis and Related Disorders. 

Ocrelizumab found more effective in reducing the risk of 12-week confirmed disability progression compared with 10 other treatments for relapsing multiple sclerosis.