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Research Article| Volume 71, 104523, March 2023

Effectiveness of ocrelizumab on clinical and MRI outcome measures in multiple sclerosis across black and white cohorts: A single-center retrospective study

Open AccessPublished:January 15, 2023DOI:https://doi.org/10.1016/j.msard.2023.104523
Effectiveness of ocrelizumab on clinical and MRI outcome measures in multiple sclerosis across black and white cohorts: A single-center retrospective study
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      Abstract

      Objective

      To examine differences in the therapeutic response to ocrelizumab in multiple sclerosis (MS) patients who self-identified as either White or Black, assessed longitudinally by expanded disability status scale (EDSS) progression and MRI brain volume loss.

      Methods

      MS subjects treated with ocrelizumab were retrospectively identified. Clinical data were available for 229 subjects (White 146; Black 83) and MRI data from for 48 subjects (White 31; Black 17). Outcome measures were changes in the EDSS and brain volume over time. EDSS were analyzed as raw scores, ambulatory (EDSS <5.0) vs. ambulatory with assistance (5.5 ≤ EDSS ≤ 6.5) status, and EDSS severity (< 3.0, 3.0–5.0, and > 5.5 ≤ 6.5). General linear mixed model was used for statistical analysis. FreeSurfer was used for volumetric analysis.

      Results

      The Black cohort had overrepresentation of females (78% vs. 62%, p = 0.013), lower age (median, 45 (IQR 39–51) vs. 49 (38–58), p = 0.08), lower Vitamin D levels (33 (21–45) vs. 40 (29–52), p = 0.002), and higher EDSS (4 (2–6) vs. 2.5 (1–6), p = 0.019). There was no progression of EDSS scores over the 2-year observation period. The covariates with significant influence on the baseline EDSS scores were older age, race, longer disease duration, prior MS treatment, and lower vitamin D levels. No differences were observed between the racial groups over time in the cortical, thalamic, caudate, putamen, and brainstem gray matter volumes nor in the cortical thickness or total lesion volume.

      Conclusion

      In this real-world clinical and radiological study, ocrelizumab treatment was highly effective in stabilizing clinical and MRI measures of disease progression in Blacks and Whites, despite higher baseline disability in the Black cohort.

      Keywords

      Abbreviations:

      BMI (body mass index), CNS (central nervous system), DMT (disease modifying therapy), EDSS (expanded disability status scale), IQR (interquartile range), MS (multiple sclerosis)

      1. Introduction

      Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS). The disease manifestation and its severity are due to a complex interplay between genetic predisposition and environmental triggers (
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      ). It has a strong bias towards the female sex and a predilection for certain races. Although MS has historically been regarded as a disease with a White preponderance, it may be underreported in other racial groups, particularly Blacks (
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      ). In support, recent epidemiological data suggest that MS may be equally prevalent in Black individuals residing in the Northern hemisphere and is particularly overrepresented in Black females (
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      ). Furthermore, MS disease course is notably more severe in Blacks compared to Whites, with well described differences including multifocal symptoms and signs at disease onset, more frequent involvement of the spinal cord and optic nerves, and higher risk of developing ambulatory disability and wheelchair dependency over time (
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      ). The age of symptom onset and diagnosis of MS is also earlier in Blacks (
      • Weinstock-Guttman B.
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      New York state multiple sclerosis consortium. multiple sclerosis characteristics in African American patients in the New York State multiple sclerosis consortium.
      Mult. Scler. 2003; 9 (JunPMID: 12814178): 293-298https://doi.org/10.1191/1352458503ms909oa
      ). The more rapid accrual of disability in Black MS patients is believed to be due to a higher rate of and incomplete recovery from relapses (
      • Weinstock-Guttman B.
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      • Smiroldo J.
      New York state multiple sclerosis consortium. multiple sclerosis characteristics in African American patients in the New York State multiple sclerosis consortium.
      Mult. Scler. 2003; 9 (JunPMID: 12814178): 293-298https://doi.org/10.1191/1352458503ms909oa
      ).
      Imaging markers of disease progression also reflect a more aggressive disease course in Black patients. Blacks with MS have a more pronounced cortical volume loss, higher T2 and T1 lesion volume, and a lower magnetization transfer ratio (MTR) in both lesions and normal appearing gray and white matter (
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      Differential impact of multiple sclerosis on cortical and deep gray matter structures in African Americans and Caucasian Americans.
      J. Neuroimaging. 2017; 27 (MayEpub 2016 Sep 16. PMID: 27634620): 333-338https://doi.org/10.1111/jon.12393
      ;
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      • Bergsland N.
      • Munschauer F.E.
      • Zivadinov R.
      Increased tissue damage and lesion volumes in African Americans with multiple sclerosis.
      Neurology. 2010; 74 (Feb 16Epub 2010 Jan 20. PMID: 20089944): 538-544https://doi.org/10.1212/WNL.0b013e3181cff6fb
      ). Additionally, the rate of atrophy in the gray and white matter and the thalamus is twice as high in Blacks than in Whites (
      • Caldito N.G.
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      • Reich D.S.
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      Brain and retinal atrophy in African-Americans versus Caucasian-Americans with multiple sclerosis: a longitudinal study.
      Brain. 2018; 141 (Nov 1PMID: 30312381; PMCID: PMC6202573): 3115-3129https://doi.org/10.1093/brain/awy245
      ). Finally, retinal nerve fiber layer and ganglion cell inner plexiform layer atrophy rates are greater in Blacks than Whites (
      • Caldito N.G.
      • Saidha S.
      • Sotirchos E.S.
      • Dewey B.E.
      • Cowley N.J.
      • Glaister J.
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      • Ogbuokiri E.
      • Fioravante N.
      • Feldman S.
      • Kwakyi O.
      • Risher H.
      • Kimbrough D.
      • Frohman T.C.
      • Frohman E.
      • Balcer L.
      • Crainiceanu C.
      • Van Zijl P.C.M.
      • Mowry E.M.
      • Reich D.S.
      • Oh J.
      • Pham D.L.
      • Prince J.
      • Calabresi P.A.
      Brain and retinal atrophy in African-Americans versus Caucasian-Americans with multiple sclerosis: a longitudinal study.
      Brain. 2018; 141 (Nov 1PMID: 30312381; PMCID: PMC6202573): 3115-3129https://doi.org/10.1093/brain/awy245
      ). These observations are consistent with the theory that Blacks have a more inflammatory and neurodegenerative disease course than White patients.
      Despite a more aggressive disease course, Black patients are underrepresented in most MS clinical trials, making up less than 5% of participants, including the Phase III trials of ocrelizumab in MS (
      • Mateen F.J.
      Is it time for quotas to achieve racial and ethnic representation in multiple sclerosis trials?.
      Front. Neurol. 2021; 12 (May 13PMID: 34054715; PMCID: PMC8155278)680912https://doi.org/10.3389/fneur.2021.680912
      ;
      • Cree B.A.C.
      • Pradhan A.
      • Pei J.
      • Williams M.J.
      OPERA I and OPERA II clinical investigators
      Efficacy and safety of ocrelizumab vs interferon beta-1a in participants of African descent with relapsing multiple sclerosis in the phase III OPERA I and OPERA II studies.
      Mult. Scler. Relat. Disord. 2021; 52 (JulEpub 2021 May 7. PMID: 34147885)103010https://doi.org/10.1016/j.msard.2021.103010
      ). Given the heterogeneity of MS across age, race, sex, and clinical and radiographic phenotype, it is imperative that clinical trials have adequate representation of minorities in order to determine the effectiveness of various disease modifying treatments (DMTs) in diverse cohorts. Treatments for MS are expanding at a rapid pace and knowledge from these trials is essential to guide which treatments are most effective in particular individuals. These considerations are particularly imperative given the potential for poor outcomes in Black patients, where possible delays in the diagnosis and initiation of high efficacy treatment could lead to greater accrual of disability in this cohort.
      Prompted by the paucity of literature on the effectiveness of ocrelizumab in patients of African descent, the current study was undertaken to examine the therapeutic response of this agent in a real-world, outpatient, clinical setting with a large cohort of Black patients. The null hypothesis tested was that there is no difference in the therapeutic response to ocrelizumab in either the Black or White patient cohorts, assessed longitudinally by expanded disability status scale (EDSS) progression for clinical outcomes and regional brain atrophy for radiographic outcomes.

      2. Methods

      2.1 Study design and patient population

      This is a retrospective, observational study, for which the data were derived from archival medical and radiological records (University of Chicago MS Database). Only patients with Relapsing Remitting MS (RRMS) were included, who had been receiving ocrelizumab from August 2017 to May 2021. All patients examined had been continuously taking ocrelizumab infusions as outlined in the medication guideline (package insert). All data were anonymized prior to access for analysis. The study was approved by the Institutional Review Board of the University of Chicago Medical Center under protocol number IRB20-2007, and since this was a retrospective review of data, consent was waived. This study conformed to the ethical standards of the 1964 Declaration of Helsinki.

      2.2 Clinical assessment

      The primary clinical endpoint of the study was EDSS progression. Clinical assessments, including the EDSS, were derived from comprehensive neurological exams conducted at each patient visit. Clinical data was examined at three time points: baseline at therapy initiation and at years 1 and 2 of treatment. Well established prognostic factors were analyzed as covariates, including age, sex, body mass index (BMI), smoking status, prior treatment, disease duration, and Vitamin D level. For internal validity, EDSS as a clinical outcome measure was examined as raw scores, by binary outcome (ambulatory (EDSS<5.0) vs. ambulatory with assistance (5.5 ≤ EDSS ≤ 6.5), and trivariate disease severity category (Mild Disease=EDSS < 3.0, Moderate Disease=EDSS 3.0–5.0, and Severe Disease=EDSS > 5.0).

      2.3 MRI acquisition and processing

      MR scans were obtained from 6 different clinical scanners at the University of Chicago Hospital, all 3.0 Tesla magnetic strength in this real-world dataset. All MR scans included a high-resolution 3D T1-weighted images for atrophy assessment and either a 3D or 2D FLAIR images for lesion assessment. For the anatomical images, the scanner information and acquisition parameters are listed in the Supplementary Table.
      All volumetric analyses were performed using a FreeSurfer cross-sectional image processing pipeline (
      • Greve D.N.
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      • Cordero D.
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      A deep learning toolbox for automatic segmentation of subcortical limbic structures from MRI images.
      Neuroimage. 2021; 244 (Dec 1Epub 2021 Sep 25. PMID: 34571161; PMCID: PMC8643077)118610https://doi.org/10.1016/j.neuroimage.2021.118610
      ;
      • Iglesias J.E.
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      • Bocchetta M.
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      • Greve D.N.
      • van der Kouwe A.
      • Fischl B.
      • Caballero-Gaudes C.
      • PM Paz-Alonso
      A probabilistic atlas of the human thalamic nuclei combining ex vivo MRI and histology.
      Neuroimage. 2018; 183 (Alzheimer's Disease Neuroimaging Initiative) (DecEpub 2018 Aug 17. PMID: 30121337; PMCID: PMC6215335): 314-326https://doi.org/10.1016/j.neuroimage.2018.08.012
      ). From the large number of outputs from the FreeSurfer pipeline, only cortical gray matter volume and thickness, thalamus, caudate, putamen, and brainstem were examined because of their larger structure size and less variable segmentation results, and their importance in correlation with clinical measures of disability (
      • Iscan Z.
      • Jin T.B.
      • Kendrick A.
      • Szeglin B.
      • Lu H.
      • Trivedi M.
      • Fava M.
      • McGrath P.J.
      • Weissman M.
      • Kurian B.T.
      • Adams P.
      • Weyandt S.
      • Toups M.
      • Carmody T.
      • McInnis M.
      • Cusin C.
      • Cooper C.
      • Oquendo M.A.
      • Parsey R.V.
      • DeLorenzo C.
      Test-retest reliability of freesurfer measurements within and between sites: effects of visual approval process.
      Hum. Brain Mapp. 2015; 36 (SepEpub 2015 May 28. PMID: 26033168; PMCID: PMC4545736): 3472-3485https://doi.org/10.1002/hbm.22856
      ;
      • Eshaghi A.
      • Prados F.
      • Brownlee W.J.
      • Altmann D.R.
      • Tur C.
      • Cardoso M.J.
      • De Angelis F.
      • van de Pavert S.H.
      • Cawley N.
      • De Stefano N.
      • Stromillo M.L.
      • Battaglini M.
      • Ruggieri S.
      • Gasperini C.
      • Filippi M.
      • Rocca M.A.
      • Rovira A.
      • Sastre-Garriga J.
      • Vrenken H.
      • Leurs C.E.
      • Killestein J.
      • Pirpamer L.
      • Enzinger C.
      • Ourselin S.
      • Wheeler-Kingshott C.A.M.G.
      • Chard D.
      • Thompson A.J.
      • Alexander D.C.
      • Barkhof F.
      • Ciccarelli O.
      Deep gray matter volume loss drives disability worsening in multiple sclerosis.
      Ann. Neurol. 2018; 83 (FebEpub 2018 Feb 6. PMID: 29331092; PMCID: PMC5838522): 210-222https://doi.org/10.1002/ana.25145
      ). More importantly, most of these structures have been shown to have a relatively high rate of atrophy in MS longitudinally despite age and sex adjustment (
      • Azevedo C.J.
      • Cen S.Y.
      • Jaberzadeh A.
      • Zheng L.
      • Hauser S.L.
      • Pelletier D.
      Contribution of normal aging to brain atrophy in MS.
      Neurol. Neuroimmunol. Neuroinflamm. 2019; 6 (Sep 25PMID: 32330116; PMCID: PMC6807662): e616https://doi.org/10.1212/NXI.0000000000000616
      ). Paired volumes from FreeSurfer output were summed and normalized as percent of intracranial volume, as previously described (
      • Azevedo C.J.
      • Cen S.Y.
      • Jaberzadeh A.
      • Zheng L.
      • Hauser S.L.
      • Pelletier D.
      Contribution of normal aging to brain atrophy in MS.
      Neurol. Neuroimmunol. Neuroinflamm. 2019; 6 (Sep 25PMID: 32330116; PMCID: PMC6807662): e616https://doi.org/10.1212/NXI.0000000000000616
      ). For FreeSurfer volumetric analysis, white matter lesion hypointensities were not filled-in to make them isointense. FreeSurfer program segments white matter hypointensities separately and filling in these lesions does not influence the gray or white matter segmented volumes in MS (
      • Guo C.
      • Ferreira D.
      • Fink K.
      • Westman E.
      • Granberg T.
      Repeatability and reproducibility of freesurfer, FSL-SIENAX and SPM brain volumetric measurements and the effect of lesion filling in multiple sclerosis.
      Eur. Radiol. 2019; 29 (MarEpub 2018 Sep 21. PMID: 30242503; PMCID: PMC6510869): 1355-1364https://doi.org/10.1007/s00330-018-5710-x
      ). Automated lesion detection was performed using the FreeSurfer Samseg pipeline as previously described, https://surfer.nmr.mgh.harvard.edu/fswiki/Samseg (
      • Cerri S.
      • Puonti O.
      • Meier D.S.
      • Wuerfel J.
      • Mühlau M.
      • Siebner H.R.
      • Van Leemput K.
      A contrast-adaptive method for simultaneous whole-brain and lesion segmentation in multiple sclerosis.
      Neuroimage. 2021; 225 (Jan 15Epub 2020 Oct 22. PMID: 33099007; PMCID: PMC7856304)117471https://doi.org/10.1016/j.neuroimage.2020.117471
      ), with some manual editing if needed.
      Since different types of MRI scanners were used in this study, the imaging data was adjusted for scanner variation. This was performed using ComBat (combating batch effects when combining batches), to remove inter-scanner technical variability while maintaining biological variability (
      • Fortin J.P.
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      • Tunç B.
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      • Gur R.C.
      • Gur R.E.
      • Schultz R.T.
      • Verma R.
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      Harmonization of multi-site diffusion tensor imaging data.
      Neuroimage. 2017; 161 (Nov 1Epub 2017 Aug 18. PMID: 28826946; PMCID: PMC5736019): 149-170https://doi.org/10.1016/j.neuroimage.2017.08.047
      ;
      • Fortin J.P.
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      • Aselcioglu I.
      • Cook P.A.
      • Adams P.
      • Cooper C.
      • Fava M.
      • McGrath P.J.
      • McInnis M.
      • Phillips M.L.
      • Trivedi M.H.
      • Weissman M.M.
      • Shinohara R.T.
      Harmonization of cortical thickness measurements across scanners and sites.
      Neuroimage. 2018; 167 (Feb 15Epub 2017 Nov 17. PMID: 29155184; PMCID: PMC5845848): 104-120https://doi.org/10.1016/j.neuroimage.2017.11.024
      ;
      • Johnson W.E.
      • Li C.
      • Rabinovic A.
      Adjusting batch effects in microarray expression data using empirical bayes methods.
      Biostatistics. 2007; 8 (JanEpub 2006 Apr 21. PMID: 16632515): 118-127https://doi.org/10.1093/biostatistics/kxj037
      ). The imaging data were harmonized across scanners prior to performing downstream statistical analysis for outcome measures. Matlab version of ComBat software (https://github.com/Jfortin1/ComBatHarmonization) was used, with age, sex, race, disease duration, baseline EDSS, time between MRI scans, BMI, vitamin D levels, prior DMT, and smoking status as biological covariates in the design matrix.

      2.4 Statistical analysis

      Baseline characteristics between groups were compared using t-tests for continuous variables and chi-squared analysis for categorical variables. Collinearity among covariates was assessed by examining correlation coefficients prior to further analysis, with cutoff for inclusion being < 0.7. The primary clinical outcome was progression of EDSS score from baseline, to year 1, and year 2. The MRI end points were regional brain volumes at baseline and on average year 2. Linear mixed-effect regression models, including ordinal or logistic, were used to gauge disease progression over time and to assess the influence of various covariates, particularly race, on clinical and MRI outcome measures. A paired t-test was performed on the two-time point MRI dataset for brain atrophy assessment. All statistical analyses were conducted using Stata V16 (StataCorp, College Station, TX).

      3. Results

      3.1 Demographics

      Within the MS database, 229 subjects were eligible for clinical data analysis. Of these, 83 subjects self-identified as Black and 146 as White. Demographic and baseline disease characteristics of these cohorts are shown in Table 1. The Black cohort consisted of 36% of the total subjects for clinical outcome measures. There was an overrepresentation of female subjects in the Black cohort, 78% vs. 62%. There was a trend for the Black cohort to be younger (p = 0.08). A greater proportion of Black subjects were deficient in Vitamin D and had a higher EDSS at baseline. Tobacco use was variable, while a higher percentage of Blacks reported no history of using cigarettes, there was a slightly higher percentage of current smokers (p = 0.045). The remaining covariates such as age, BMI, prior DMT treatment, disease duration, and ambulatory status at baseline were not different between the two groups. Collinearity was assessed between age and variables that were prone to increase with age such as disease duration, BMI, and prior treatment, all of which had correlation coefficients < 0.7.
      Table 1Demographics and baseline disease characteristics of the subjects.
      Black n = 83White n = 146P-Value
      Female, n(%)65(78)91(62.33)0.013
      Age, Median(IQR)45.42(39.51–51.40)49.03(38.79–58.66)0.08
      BMI, median(IQR)29.49(25.67–36.31)27.51(24–33.52)0.12
        Normal <25, n(%)16(19.28)45(31.47)
        Overweight 25–30, n(%)27(32.53)44(30.80)
        Obese 30, n(%)40(48.19)54(37.76)
      Vitamin D ng/mL, Median (IQR)33(21–45)40(29.3–52)0.002
        Insufficient (<30), n(%)41(82.0)87(94.57)
        Sufficient (30), n(%)6(11.76)4(4.35)
      Tobacco Use0.045
        Never Smoked, n(%)58(70.73)91(62.76)
        Former Smoker, n(%)12(14.63)41(28.28)
        Current Smoker, n(%)12(14.63)13(8.97)
      Received Prior Treatment, n(%)71(85.54)116(79.45)0.25
      Disease Duration, Median (IQR)11(6–16)12(5–20)0.26
      EDSS, Median(IQR)4(2–6)2.5(1–6)0.019
      EDSS Ambulatory, n(%)48(57.83)94(64.38)0.33
      From the clinical dataset of patients, 48 patients were available for examining longitudinal MRI measures of disease progression, such as regional brain atrophy and T2 lesion volume, 35% of whom were Black. Since the MRI data was obtained from clinical scanners, the attrition in the MRI vs. the clinical sample size was due to maintaining high image quality and examining only 3D T1-weighted images, which are necessary for volumetric and cortical thickness analysis. Demographic and baseline disease characteristics of these 48 subjects are shown in Table 2. The Black and White cohorts were well matched.
      Table 2Demographics and baseline disease characteristics of the subjects with MRI analysis.
      Black n = 17White n = 31P-Value
      Female, n(%)17(35)31(65)0.46
      Age (y), Median(IQR)39.5(31–51)38.5(32–46)0.86
      BMI, median(IQR)30.59(25.52–33.17)28.37(24.49–33.42)0.37
      Tobacco use, former n (%)6(35)9(29)0.18
      Disease Duration (y), Median (IQR)12.5(7–16)11(5–15)0.32
      EDSS, Median(IQR)2(1–4.5)1.5(0–3.5)0.612
      Time between MRI, Baseline to Follow Up, Median (IQR)26(15.06–28.43)21.55(12.63–30.67)0.95

      3.2 Clinical measures

      Linear-mixed model output analyzing EDSS progression in relation to treatment duration (time), race, age, sex, disease duration, prior DMT use, smoking, vitamin D levels, and BMI is shown in Table 3. The median (IQR) EDSS for the entire sample at baseline, year 1, and year 2 were: 2.5 (1.5–6.0), 2.5 (1.5–6.0), 3 (2.0–6.0). Despite the higher baseline EDSS scores observed in Blacks, an older age, longer disease duration, prior use of DMT, and low vitamin D levels, EDSS scores remained stable over time in the entire sample in the adjusted model. Ocrelizumab treatment effect on EDSS stability over time was consistent, regardless of whether EDSS scores were analyzed as raw data, grouped into disease severity category, or binary ambulatory status.
      Table 3Effects of treatment duration, baseline demographic, and disease characteristics on EDSS.
      EDSSVariableRegression Coefficient

      (95% CI)      		p-Value
      Raw ScoresTime−0.038 (−0.098- 0.020)0.197
      Race0.745 (0.078–1.413)0.029
      Age0.070 (0.040–0.100)0.000
      Sex−0.140(−0.850–0.568)0.697
      Disease Duration0.053 (0.011–0.096)0.013
      Smoking0.274 (−0.214–0.763)0.272
      Prior DMT0.831 (−0.037–1.700)0.061
      Vitamin D0.002 (−0.011–0.015)0.771
      BMI0.007 (−0.033–0.047)0.730
      Severity Category
      Severity category (Mild Disease=EDSS < 3.0, Moderate Disease=EDSS 3.0–5.0, and Severe Disease=EDSS > 5.0); # Ambulatory EDSS <5.0, ambulatory with assistance 5.5 ≤ EDSS ≤ 6.5.
      		Odds Ratio (95% CI)
      Time0.93 (0.703–1.237)0.631
      Race2.37 (1.446–3.903)0.001
      Age1.08 (1.052–1.106)0.000
      Sex0.84 (0.485–1.463)0.544
      Disease Duration1.06 (1.025–1.092)0.000
      Smoking1.27 (0.875–1.851)0.206
      Prior DMT4.84 (2.110–11.145)0.000
      Vitamin D1.0 (0.997–1.018)0.128
      BMI1.01 (0.980–1.042)0.475
      Ambulatory Status #Time1.0 (0.749–1.333)1.000
      Race2.88 (1.702–4.878)0.000
      Age1.06 (1.029–1.084)0.000
      Sex1.44 (0.812–2.571)0.210
      Disease Duration1.07 (1.037–1.109)0.000
      Smoking1.19 (0.812–1.765)0.361
      Prior DMT3.09 (1.276–7.511)0.012
      Vitamin D1.02 (1.00–1.026)0.009
      BMI1.02 (0.994–1.058)0.104
      low asterisk Severity category (Mild Disease=EDSS < 3.0, Moderate Disease=EDSS 3.0–5.0, and Severe Disease=EDSS > 5.0); # Ambulatory EDSS <5.0, ambulatory with assistance 5.5 ≤ EDSS ≤ 6.5.

      3.3 MRI measures

      Cortical and subcortical gray matter and T2 lesion volume changes in MS patients treated with ocrelizumab are shown in Table 4. Paired t-tests did not show significant change in the volume of these structures over a median of 23.36 months (IQR 13.43, 28.95). Linear mixed-effect model was used to gauge the effects of race, age, sex, disease duration, prior DMT use, smoking, vitamin D levels, and BMI on MRI metrics (Table not shown). Race had no effect on any of the MRI volumetric or cortical thickness measures at baseline and over time. In certain brain regions, some of the covariates showed statistically significant effects or trends: lower cortical volume was associated with older age (p = 0.002) and longer disease duration (p = 0.063); lower cortical thickness with older age (p = 0.062); lower thalamic volume with higher EDSS (p = 0.027); lower caudate volume with female sex (p = 0.041) and higher EDSS (p = 0.008); lower putamen volume with longer disease duration (p = 0.018); lower brainstem volume with higher EDSS (p = 0.013). T2 lesion volume remained stable over time.
      Table 4Brain parenchymal and lesion volume changes in RRMS patients treated with ocrelizumab.
      Region
      Mean (SD); Gray matter values represent percent of total intracranial volume, except cortical thickness and lesion volume; # paired t-test.
      		BaselineFollow Upp-value #
      Cortical Volume33.98 (1.97)33.98 (1.99)1.00
      Cortical Thickness (mm)2.40 (0.10)2.40 (0.10)0.78
      Thalamus0.83 (0.09)0.81 (0.08)0.06
      Caudate Nucleus0.44 (0.07)0.43 (0.07)0.69
      Putamen0.67 (0.07)0.67 (0.08)0.94
      Brainstem1.33 (0.11)1.32 (0.11)0.17
      Lesion Volume (ml)11.47 (8.88)10.79 (9.05)0.13
      low asterisk Mean (SD); Gray matter values represent percent of total intracranial volume, except cortical thickness and lesion volume; # paired t-test.

      4. Discussion

      Despite the scarcity of research on racial differences in MS disease manifestation, course, and therapeutic response, there is accumulating evidence that the incidence of MS in the Black population may be just as high as those of Whites, and this cohort may suffer from a disproportionately high burden of disease. Black patients may have a more progressive disease course, which is less amenable to treatment. Imaging characteristics show a more pronounced brain volume loss and inflammatory disease activity in Black patients. Furthermore, immune mechanisms may be more robust in this population. IgG index and synthesis rate are higher in Black patients (
      • Rinker 2nd, J.R.
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      • Naismith R.T.
      • Cross A.H
      Higher IgG index found in African Americans versus caucasians with multiple sclerosis.
      Neurology. 2007; 69 (Jul 3PMID: 17606883): 68-72https://doi.org/10.1212/01.wnl.0000265057.79843.d9
      ) and they have lower GM volume, which is inversely correlated with CSF IgG index (
      • Seraji-Bozorgzad N.
      • Khan O.
      • Cree B.A.C.
      • Bao F.
      • Caon C.
      • Zak I.
      • Razmjou S.
      • Tselis A.
      • Millis S.
      • Bernitsas E
      Cerebral Gray Matter Atrophy Is Associated with the CSF IgG index in African American with Multiple Sclerosis.
      J Neuroimaging. 2017; 27 (SepEpub 2017 Mar 29. PMID: 28371088): 476-480https://doi.org/10.1111/jon.12435
      ). These findings suggest a prominent role of humoral immunity reflecting a more severe CNS injury in Black patients. These immunological differences may influence which disease modifying treatments have greater success in that cohort based on their mechanism of action.
      The intent of this study was to corroborate previous and ongoing studies analyzing the unique features of MS in a more diverse MS cohort, particularly noting any differences in the therapeutic response in such patients. In this study, we examined the demographic and disease characteristics of a large cohort of MS patients, 36% of whom were Black. This cohort had a higher EDSS score at baseline, despite shorter disease duration. The Black cohort was younger, had lower vitamin D, and higher BMI. The characteristics of the patient cohorts described in this study are generally in keeping with prior published data, validating the results herein and implying generalizability. Although socioeconomic factors such as accessibility of care and distrust of physicians have been proposed as potential explanations for delayed care and worse disease, the shorter disease duration and lower proportion of patients on prior treatment would argue against treatment delays or problematic access as contributing factors to a higher baseline EDSS score in this cohort. The alternative hypothesis is that there is likely to be a more aggressive pathological and genetic mechanisms contributing to disease manifestation in Black patients.
      Variations in the inflammatory pathways and allelic frequencies could ultimately influence the severity of disease expression in different MS cohorts. Racial differences in other diseases have been well noted. The incidence of systemic lupus erythematosus (SLE), sarcoidosis, infectious diseases (tuberculosis, HIV), septicemia, cardiovascular disease, and cancer is higher in Black subjects (
      • Richardus J.H.
      • Kunst A.E.
      Black-white differences in infectious disease mortality in the United States.
      Am. J. Public Health. 2001 Aug; 91 (PMID: 11499113; PMCID: PMC1446755): 1251-1253https://doi.org/10.2105/ajph.91.8.1251
      ;
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      • Thun M.J.
      Cancer statistics, 2008.
      CA Cancer J. Clin. 2008; 58 (Mar-AprEpub 2008 Feb 20. PMID: 18287387): 71-96https://doi.org/10.3322/CA.2007.0010
      ;
      • Albert M.A.
      Inflammatory biomarkers, race/ethnicity and cardiovascular disease.
      Nutr. Rev. 2007; 65 (DecPMID: 18240555): S234-S238https://doi.org/10.1111/j.1753-4887.2007.tb00369.x
      ;
      • Sève P.
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      • Durupt F.
      • Jamilloux Y.
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      • Isaac S.
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      • Calender A.
      • Androdias G.
      • Valeyre D.
      • El Jammal T
      Sarcoidosis: a clinical overview from symptoms to diagnosis.
      Cells. 2021; 10 (Mar 31PMID: 33807303; PMCID: PMC8066110): 766https://doi.org/10.3390/cells10040766
      ). Blacks have an increase in the frequency of alleles associated with a high production of pro-inflammatory cytokines of T helper type I (TH1) relative to anti-inflammatory cytokines of T helper type II (TH2) (
      • Van Dyke A.L.
      • Cote M.L.
      • Wenzlaff A.S.
      • Land S.
      • Schwartz A.G.
      Cytokine SNPs: comparison of allele frequencies by race and implications for future studies.
      Cytokine. 2009; 46 (MayEpub 2009 Apr 7. Erratum in: Cytokine. 2010 Feb;49(2):235. PMID: 19356949; PMCID: PMC2742911): 236-244https://doi.org/10.1016/j.cyto.2009.02.003
      ). For example, pro-inflammatory cytokine alleles IL1A (889T), IL1B (3957C, 511A), IL6 (174 G), IL18 (137 G), TNF-alpha (308A), Interferon-gamma (874) are found in greater frequency in the Black population (
      • Van Dyke A.L.
      • Cote M.L.
      • Wenzlaff A.S.
      • Land S.
      • Schwartz A.G.
      Cytokine SNPs: comparison of allele frequencies by race and implications for future studies.
      Cytokine. 2009; 46 (MayEpub 2009 Apr 7. Erratum in: Cytokine. 2010 Feb;49(2):235. PMID: 19356949; PMCID: PMC2742911): 236-244https://doi.org/10.1016/j.cyto.2009.02.003
      ;
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      • DiMercurio B.S.
      • Wesley R.A.
      • Harlan D.M.
      • Kirk A.D.
      • Blair P.J.
      Cytokine polymorphic analyses indicate ethnic differences in the allelic distribution of interleukin-2 and interleukin-6.
      Transplantation. 2001; 72 (Aug 27PMID: 11544437): 720-726https://doi.org/10.1097/00007890-200108270-00027
      ;
      • Hoffmann S.C.
      • Stanley E.M.
      • Cox E.D.
      • DiMercurio B.S.
      • Koziol D.E.
      • Harlan D.M.
      • Kirk A.D.
      • Blair P.J.
      Ethnicity greatly influences cytokine gene polymorphism distribution.
      Am. J. Transplant. 2002; 2 (JulPMID: 12118901): 560-567https://doi.org/10.1034/j.1600-6143.2002.20611.x
      ;
      • Hassan M.I.
      • Aschner Y.
      • Manning C.H.
      • Xu J.
      • Aschner J.L.
      Racial differences in selected cytokine allelic and genotypic frequencies among healthy, pregnant women in North Carolina.
      Cytokine. 2003; 21 (Jan 7PMID: 12668154): 10-16https://doi.org/10.1016/s1043-4666(02)00489-1
      ;
      • Ness R.B.
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      • Harger G.
      • Ferrell R.
      Differential distribution of allelic variants in cytokine genes among African Americans and white Americans.
      Am. J. Epidemiol. 2004; 160 (Dec 1PMID: 15561982): 1033-1038https://doi.org/10.1093/aje/kwh325
      ). Conversely, anti-inflammatory cytokines are found in lower frequency in Black subjects: IL10 (592A, 819T, 1082A) (
      • Rady P.L.
      • Matalon R.
      • Grady J.
      • Smith E.M.
      • Hudnall S.D.
      • Kellner L.H.
      • Nitowsky H.
      • Tyring S.K.
      • Hughes T.K.
      Comprehensive analysis of genetic polymorphisms in the interleukin-10 promoter: implications for immune regulation in specific ethnic populations.
      Genet. Test. 2004; 8 (SummerPMID: 15345120): 194-203https://doi.org/10.1089/gte.2004.8.194
      ). In the most general terms, there appears to be a predisposition to heightened inflammatory response to multiple disease states in Blacks, which could reasonably be extended to encompass MS disease as well.
      The main goal of this study was to examine the effect of race on the therapeutic response of a high efficacy, anti-B cell therapy in Blacks compared to White patients, given the worse baseline disease characteristics of the former cohort. The hypothesis was that a treatment that suppresses inflammatory, humoral response from B cells could stabilize disease despite the pre-existing baseline differences. Race as a covariate in the model did not have any effect on EDSS scores over time nor on any of the MRI surrogate markers of disease progression. EDSS and brain volume changed insignificantly over the course of the observation period, with no appreciable difference between Blacks and Whites. Given the worse disease trajectory for Black MS patients described in prior studies, the results of our study show that an anti-B cell therapy is an effective treatment for this cohort of patients, which underscores the importance of starting this agent early in the disease process. Our study corroborates and extends the results of phase III ocrelizumab clinical trials, OPERA I in II, both of which enrolled about 4.3% Black patients (n = 71). Both our study enrolling a large cohort of Black patients (n = 83) and the OPERA studies demonstrate that ocrelizumab stabilizes clinical and MRI MS disease activity and progression over time in a more diverse cohort of patients.
      This study does have several limitations: retrospective design, cohort differences, short two-year follow up, and use of EDSS as the main clinical outcome measure, given that this metric, though standard, is not sensitive to subtle disease changes. Nonetheless, as a measure of the internal validity of our results, the variables that are expected to have a significant effect on EDSS did influence the EDSS scores, such as age, disease duration, and prior treatment history (suggesting more DMT resistant disease). To overcome some insensitivity of the assessment tool, EDSS was examined in 3 different ways: raw scores, ordinal severity score, and binary, all of which yielded essentially that same outcome, strengthening the validity of our analysis. Prospective studies are needed, and ongoing, to extend these findings and elucidate immunological and/or genetic mechanisms associated with disparity in disease manifestation and therapeutic response.

      Funding source

      The study was supported by /Genentech.

      CRediT authorship contribution statement

      Amanda Frisosky Abuaf: Formal analysis, Data curation, Conceptualization, Visualization, Funding acquisition, Data curation, Writing – original draft, Writing – review & editing, Formal analysis, Supervision. Adil Javed: Formal analysis, Data curation, Conceptualization, Visualization, Funding acquisition, Data curation, Writing – review & editing, Formal analysis, Supervision. Samuel R. Bunting: Writing – review & editing, Formal analysis. Timothy J. Carroll: Writing – review & editing. Anthony T. Reder: Writing – review & editing. Veronica P. Cipriani: Formal analysis, Data curation, Conceptualization, Visualization, Writing – review & editing, Supervision.

      Declaration of Competing Interest

      AJ has received honorarium and consultations fees from Biogen, Serono, Roche/Genentech, BMS, and TG therapeutics.
      ATR has received unrestricted grant support from Roche/Genentech.
      VPC has received compensation for consulting and/or speaking engagements from EMD Serono, Sanofi and Roche/Genentech.
      AFA: has received fellowship funding from Roche/Genentech
      SRB and TJC have nothing to disclose.

      Acknowledgments

      This work was completed in part with resources provided by the University of Chicago's Research Computing Center. The authors thank the patients who contributed to this study.

      Appendix. Supplementary materials

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      Publication history

      Published online: January 15, 2023
      Accepted: January 15, 2023
      Received in revised form: December 14, 2022
      Received: November 14, 2022

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      DOI: https://doi.org/10.1016/j.msard.2023.104523

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