Background

Natalizumab (NTZ) is an effective therapy for patients with relapsing MS (RMS). However, it is associated with a risk of progressive multifocal leukoencephalopathy (PML) in patients infected with John Cunningham virus (JCV). Ocrelizumab (OCR) has demonstrated efficacy, yet its safety in patients previously treated with NTZ is unclear.

Objectives

To present interim data from OCTAVE, a prospective, observational study to evaluate the efficacy and safety of OCR in RMS patients previously treated with NTZ.

Methods

Clinically and radiologically stable RMS patients, aged 18-65 treated with a stable dose of NTZ for ≥ 12 months, were started on OCR 4-6 weeks after last dose of NTZ and followed for 12 months. Relapse assessment, Expanded Disability Status Scale (EDSS), and MRI were performed prior to starting OCR and at months 3, 6, 9 (no MRI), and 12.

Results

Thirty-seven patients, 75.7% female with mean age of 43.8 (± 10.97) and a median of 33.5 [IQR = 63.2] NTZ infusions prior to starting OCR have been enrolled between August 9^th, 2017 and February 3^rd, 2020. 23 patients have completed the study duration of 12 months. Thirty-one subjects switched to OCR due to potential PML risk. One patient had a clinical relapse reported at month 12 although no MRI correlate. However, EDSS at baseline was 4.0 and at month 12 the score was 5.5. At month 3, one patient had one enhancing lesion, and one patient had 3 enhancing lesions. At months 6 and 12, there were no enhancing or new/enlarging T2 lesions. There were no significant changes in the EDSS, physical MSIS-29, and psychological MSIS-29 from baseline to months 6 and 12, though there was an increasing trend for EDSS. Median EDSS [IQR] was 3.00 [2.0] at baseline and median EDSS [IQR] was 4.00 [2.50] at month 12. Infusion reactions were seen in 40.5% of patients with the first dose (includes both 300mg infusions) and 13.5 % with the second dose (600mg infusion). Eight serious adverse events (SAEs) have been reported with three possibly related to OCR, breast cancer, urinary tract infection, and acute cystitis. No cases of PML have been reported.

Conclusions

The transition from NTZ to OCR resulted in limited disease activity. In 2 patients, MRI activity was present at 3 months, but no MRI changes were seen at months 6 and 12. One patient was reported to have a clinical relapse at month 12; however, there were no MRI changes. The trend in increasing EDSS is concerning.

Background

The North American Registry for Care and Research in Multiple Sclerosis (NARCRMS) registry is a physician-based registry/longitudinal database for patients with multiple sclerosis (MS). NARCRMS may elucidate the patient characteristics of underserved populations such as Blacks/African Americans (AA) and Hispanics/Latinos.

Objectives

To describe the socio-demographic and clinical characteristics of patients presenting with relapsing-remitting MS (RRMS) within the NARCRMS registry by race and ethnicity.

Methods

The NARCRMS registry contains data of MS patients aged 18-50 years across 24 sites from the US and Canada. This exploratory analysis describes characteristics of patients who enrolled between December 2016 and May 2020 (N=722), including age, gender, education, income level and occupation, Expanded Disability Status Scale (EDSS) categories, and disease-modifying therapy (DMT) categories/DMT use. Patient characteristics were summarized by frequencies and proportions for categorical variables and by means, standard deviations (SDs) and medians for continuous variables.

Results

The mean age (SD) of patients in this study was 40.1 (10.4) years; 71% were female. Majority (85%, n=587/695) were White; Black/AA patients comprised 11% (n=74/695). Educational attainment was comparable between races ― 22-24% with a high school degree, and 47-49% with an undergraduate degree. However, more Black/AA than White patients were unemployed (8%, n=6/72 vs 3%, n=15/565) or had an annual income <$15K (16%, n=12/73 vs 6%, n=35/573). Overall, 72% of patients had mild MS (EDSS scores 0‒2.5). However, twice as many Blacks/AAs had substantial disability (EDSS score ≥4.0) vs Whites (20%, n=15/74 vs 9.7%, n=57/587, respectively). Over half of all patients (57%, n=370/646) were treated with DMTs, with 50% (n=198) using injectables and 37% (n=147) using oral DMTs. Hispanics comprised 24% (n=152/646) of the patients, including Black/AA-Hispanic (3%, n=19/646) and White-Hispanic (21%, n=133/646). Hispanic patients were less likely than non-Hispanics to use DMTs, 43% (n=65/152) vs 62% (n=305/494). Of the subgroups, Black/AA-Hispanics were least likely to use DMTs (26%, n=5/19).

Conclusions

Blacks/AAs present with more severe disability than White patients. More Hispanics than non-Hispanics are not treated with DMTs. Real-world data show disparities in socio-demographic and clinical characteristics of patients with MS.

Supported by: Biogen

Background

The thalamus is a key gray matter structure, and a sensitive marker of neurodegeneration in multiple sclerosis (MS). Previous reports have indicated that thalamic volumetry on clinical-quality T2-FLAIR images alone is fast and reliable, using artificial intelligence (AI).

Objectives

To investigate the feasibility of thalamic atrophy measurement using AI in patients with MS, in a large multi-center, clinical routine study.

Methods

DeepGRAI (Deep Gray Rating via Artificial Intelligence) is a multi-center (31 USA sites), longitudinal, observational, real-word, registry study that will enroll 1,000 relapsing-remitting MS patients. Brain MRI exams previously acquired at baseline and at follow-up on 1.5T or 3T scanners with no prior standardization are used, in order to resemble real-world situation. Thalamic volume measurement is performed at baseline and follow-up on T2-FLAIR by DeepGRAI tool and on 3D T1-weighted image (WI) and 2D T1-WI by using FIRST software.

Results

In this pre-planned interim analysis, 515 RRMS patients were followed for an average of 2.7 years. There were 487 (94.6%) T2-FLAIR, 342 (66.4%) 2D T1-WI and 176 (34.2%) 3D T1-WI longitudinal pair of MRI exams available for analyses. Estimation of thalamic volume by DeepGRAI on T2-FLAIR correlated significantly with FIRST on 3D-T1-WI (r=0.733 and r=0.816, p<0.001) and with FIRST on 2D-T1-WI (r=0.555 and r=0.704, p<0.001) at baseline and at follow-up. The correlation between thalamic volume estimated by FIRST on 3D T1-WI and 2D T1-WI was r=0.642 and r=0.679, p<0.001, respectively. The thalamic volume % change over the follow-up was similar between DeepGRAI (-0.75) and 3D T1-WI (-0.82), but somewhat higher for 2D T1-WI (-0.92). Similar relationship was found between the Expanded Disability Status Scale (EDSS) and thalamic volume by DeepGRAI on T2-FLAIR and by FIRST on 3D T1-WI at baseline (r=-0.214, p=0.01 and r=-0.287, p=0.001) and at follow-up (r=-0.298, p=0.001 and r=-0.291, p=0.001).

Conclusions

DeepGRAI provides feasible thalamic volume measurement on multi-center clinical-quality T2-FLAIR images. The relationship between thalamic atrophy and physical disability is similar using DeepGRAI T2-FLAIR and standard high-resolution research approaches. This indicates potential for real-world thalamic volume monitoring, as well as quantification on legacy datasets without research-quality MRI.

Background

Fatigue is a very common and disabling symptom of multiple sclerosis (MS) that is challenging to characterize appropriately for both research and clinical practice. The emergence of the NIH PROMIS item banks provides new possibilities for the development of outcome measures that are brief and optimally targeted. Substantial evidence has accumulated regarding the use of the PROMIS SF 1.0 – Fatigue (MS) 8b short form to discriminate levels of fatigue among individuals who have MS. The short form was developed with input from MS patients and clinicians.

Objectives

To establish minimal important difference (MID) estimates and interpretation tools for the PROMIS Fatigue (MS) 8b in MS populations.

Methods

Two observational studies were performed in MS populations, a cross-sectional study at two tertiary MS centers in the US (n=296) [US sample] and a longitudinal study in the UK MS Register cohort (n=384) [UK sample]. The analysis sample included patients with relapsing- or progressive MS, and those with Patient-Reported Web EDSS <7. Minimal important difference (MID) of PROMIS Fatigue (MS) 8b T-score was analyzed based on score changes over a 52-week follow-up using an anchor-based approach [UK sample]. An interpretative guide for PROMIS scores was also developed [US sample].

Results

At baseline, study participants had a mean age of 44.5 – 49.9 years, and mean PROMIS Fatigue (MS) 8b T-score of 57.4 – 59.9. Three anchors met criteria and were used in the MID analysis [ i.e. PROMIS GHS fatigue question, GHS PHC global question, and the Fatigue Severity Scale]. The standard error of measurement [SD * √ (1 – reliability)] of baseline T-scores was 2.8. A score change of 3.4 – 4.0 points is proposed as MID criteria for minimal improvement or worsening in fatigue. A heatmap facilitating interpretation of scores based on fatigue concerns on individual items was developed. For example, a T-score of 60 represents a fatigue level characterized by (often) getting tired easily, (sometimes) being too tired to think clearly, and (some-) interference with physical functioning, in the last 7 days.

Conclusions

This research extends the evidence underpinning the applicability of the PROMIS Fatigue (MS) 8b in routine clinical practice and clinical research. The score interpretation guide may aid the integration of PROMIS scores into clinical decision-making as well as facilitate clinician-patient communication. MID estimates will be useful in evaluating fatigue over time.

Background

There is need to respond to the challenges of developing a robust measurement technique for self-reporting of the level of physical functioning by patients with multiple sclerosis (MS) to help with identifying strategies for improving such outcome. The emergence of the NIH PROMIS item banks has opened new possibilities for developing instruments that are brief, optimally targeted and, potentially, have high precision. This holds promise for addressing unmet measurement needs in MS populations e.g. subtle physical disability changes.

Objectives

To describe the development, validity and applicability of a multiple sclerosis (MS)-specific PROMIS short form for use in relapsing and progressive MS types, the PROMIS SF v2.1 – Physical Function (MS) 15a.

Methods

A mixed-methods sequential design was followed in this research. Step (1) Concept elicitation (CE) interviews were carried out with MS patients (n=14). Step (2) results from the interviews were mapped to the PROMIS physical function item bank, to identify items relevant for MS patients. Subsequently, neurologists (n=6) rated the relevance of the item pool. Step (3) cognitive debriefing (CD) interviews were performed with MS patients to confirm the comprehensiveness, relevance and language clarity of the draft short form (n=48). Step (4) Further item reduction and psychometric evaluation was performed in two observational studies [cross-sectional study at two MS tertiary centers, n=296 (US); 96-week longitudinal study in UK MS Register cohort, n=558 (UK)].

Results

The initial item shortlist (48 items) from the NIH PROMIS item bank was revised in sequential steps, considering 1) optimization of coverage of the underlying concept, 2) results from CD interviews and 3) results from psychometric item-level analysis. Fifteen items were retained in the final short form.

Cronbach’s alpha (> 0.9) and ICC of test-retest scores (5 to 27 days) (> 0.9) indicated the short form’s strong reliability. Convergence validity was demonstrated by moderate-to-strong correlations with related PRO measures as well the EDSS (rho = ± 0.5 to 0.9). The short form discriminated between groups of patients according to levels of physical health and other criteria. A score banding system referencing responses on the individual items as anchors, was generated, to facilitate meaningful score interpretation.

Conclusions

The PROMIS PF (MS) 15a is a reliable and valid short form for assessing physical function with self-report in people living with MS. The inclusion of input from MS patients and neurologists during its qualitative phase of development, ensured comprehensiveness and relevance for both relapsing and progressive MS types.