Journal of neurology, neurosurgery, and psychiatry · 2025
Объединение индексов массы тела и клиническая реакция пациентов, получающих атумумаб, на лечение множественных склерозов.
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Winter Pia, Axhausen Franziska, Wolff Stephanie, Willison Alice Grizzle, Räuber Saskia, Konen Franz Felix, Schreiber Stefanie, Schwenkenbecher Philipp, Hagler Ramona, Ruck Tobias, Huttner Hagen B, Kleinschnitz Christoph, Pawlitzki Mark, Skripuletz Thomas, Pul Refik, Meuth Sven G, Pfeuffer Steffen
Аннотация
СПРАВОЧНАЯ ИНФОРМАЦИЯ: Воздействие веса тела на темпы развития инвалидности среди пациентов, получающих atumumumab, еще не было оценено. МЕТОДЫ: Среди пациентов из многоцентральной потенциальной группы базовые демографические показатели сравнивались с квартилями индекса массы тела, а также с долей клинических рецидивов, поражения МРТ и ухудшения инвалидности в ходе последующей деятельности. Результаты: было охвачено 536 пациентов из четырех центров. Базовые демографические показатели равномерно распределяются среди пациентов. Доля рецидивов и новых/расширяющихся повреждений MRI была сопоставима между слоями BMI. Подтвержденное ухудшение состояния здоровья было значительно более значительным среди пациентов с 4-м квартилем BMI (BMI ≥29,2 кг/м2; скорректированный HR: 3,33 (95% CI: 1,72-6.42; p<0,001). Ухудшение ситуации, связанное с возвращением пациентов из различных слоев БМИ, существенно не отличалось (HR: 1,19 (95% CI: 0,40-3,52; p=0,750). Тем не менее прогресс, не зависящий от рецидивной активности, был более вероятным для пациентов с 4-м квартилем BMI (HR: 2,00 (95% CI: 1,47-2,70; p<0,001). Масса тела (4-й вес тела: ≥ 84,5 кг) не была связана с ухудшением состояния здоровья (скорректированный HR: 1,91 (95% CI: 0,97-3,76; p=0,060). Уровень сыворотки Офатумумаба был ниже у пациентов с более высоким уровнем BMI. ВЫВОДЫ: Результаты воспламенительных заболеваний не отличались друг от друга, однако в самом высоком количестве квартилей БМИ темпы развития инвалидности были более частыми (BMI >29,2 кг/м2). Это связано с более низким уровнем сыворотки атумумаба. Поскольку вес тела сам по себе не был прогнозируемым, мы полагаем, что состав жира в организме имеет решающее значение для эффективности атумумаба.
Оригинал публикации
Association of body mass index and clinical response in patients receiving ofatumumab for treatment of multiple sclerosis.
BACKGROUND: The impact of body weight on disability progression rates among patients receiving ofatumumab was not evaluated yet.
METHODS: Among patients from a multicentre prospective cohort, baseline demographics were compared among body mass index (BMI) quartiles as well as proportions of clinical relapses, MRI lesions and disability worsening during follow-up.
RESULTS: 536 patients from four centres were included. Baseline demographics were evenly distributed among patients. Proportions of relapses and new/enlarging MRI lesions were comparable among BMI strata.Confirmed disability worsening was significantly more abundant among patients from the 4th BMI quartile (BMI ≥29.2 kg/m2; adjusted HR: 3.33 (95% CI: 1.72 to 6.42; p<0.001). Relapse-associated worsening was not substantially different among relapsing patients from different BMI strata (HR: 1.19 (95% CI: 0.40 to 3.52; p=0.750)). Yet, progression independent from relapse activity was more likely in patients from 4th BMI quartile (HR: 2.00 (95% CI: 1.47 to 2.70; p<0.001)).Body weight (4th body weight quartile: ≥84.5 kg) was not associated with disability worsening (adjusted HR: 1.91 (95% CI: 0.97 to 3.76; p=0.060). Ofatumumab serum levels were lower in patients with higher BMI as well.
CONCLUSIONS: Inflammatory disease outcomes did not differ but disability progression was more frequent in the highest BMI quartile (BMI >29.2 kg/m2). This was associated with lower ofatumumab serum levels. Since body weight itself was not predictive, we assume that body fat composition is critical for ofatumumab effectiveness.
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Introduction
Among therapeutic options for active relapsing multiple sclerosis (RMS), B cell depletion using anti-CD20 antibodies has drawn increasing attention. Ocrelizumab was the first substance approved for treatment of RMS following superiority over beta-interferon in the OPERA studies. 1
Post hoc analyses of OPERA however provided further insights. Most patients experience disability progression independent from relapse activity (PIRA) despite their relapsing course of the disease. 2 Furthermore, low ocrelizumab serum levels were associated with disability worsening (CDW) but not with inflammatory disease activity. Antibody levels strongly correlated to body mass index (BMI) of patients. 3
Among further anti-CD20 antibodies, ofatumumab (OFA) is administered subcutaneously once a month. It was effective in the ASCLEPIOS studies. 4 Post hoc analyses of these studies indicated that its impact on PIRA is independent from body weight. 5 Since data on BMI were not presented yet, we analysed data from our multicentre cohort to determine the association of BMI and CDW among OFA patients.
Methods
Patients
Among four German tertiary centres (Duesseldorf, Essen, Giessen, Hannover), patients subjected to OFA for treatment of RMS according to most recent guidelines are subsequently included in local prospective cohorts with standardised assessment of baseline and follow-up parameters. For the current study, patients first subjected to OFA from 1 September 2021 to 31 December 2023 were included. Patients were followed every 3 months including laboratory testing, clinical examination and evaluation of recent injections. MRI scans were obtained at baseline and semiannually. Patients with a known history of manifest cardiovascular disease (apart from arterial hypertension responsive to monotherapy) and psychiatric disorders requiring specific medication as well as patients with known comorbid autoimmunity were excluded.
Outcome measures
Confirmed relapses required an increase of at least one function system score of the expanded disability status scale (EDSS). 6 CDW was considered relevant in accordance with the ASCLEPIOS study: +1.5 points (baseline=0.0), +1.0 point (baseline=1.0–5.0) and +0.5 points (baseline ≥5.5) and required confirmation 6 months later. MRI scans were judged by a qualified neuro-radiologist in a standardised manner to account for the development of new or enlarging T2-hyperintense MRI lesion (T2L) compared with the previous scan. PIRA was assessed as previously described. 2 OFA serum levels were determined via ELISA (KBI1516; Krishgen Biosystems, California, USA) from stored patient blood samples collected 5 days following last administration (assumed date of peak concentration according to previous studies 7 ). Serum neurofilament light chain levels were measured using a commercial assay and the ADVIA Centaur device (both Siemens Healthineers).
Statistical analysis
Baseline demographics were assessed using descriptive statistics and were compared using a χ 2 test for categorical variables and a Kruskal-Wallis test for continuous variables. Kaplan-Meier plots were generated for the respective endpoints and compared using the log-rank test. Cox proportional hazard models were used including ‘sex’, ‘age’, ‘disease duration’, ‘relapse rate at baseline’, ‘EDSS at baseline’, ‘MRI lesion load at baseline’ and ‘OFA line-of-use’ and ‘BMI/BW quartile’ as covariates with p values being determined using a likelihood-ratio test. A p value below 0.05 was considered significant. All analyses were performed using R (R Core Team, 2024, V.4.4.2).
Standard protocol approvals, registrations and patient consents
The local cohorts were reviewed and approved by the respective local authorities and all patients gave informed consent.
Data availability statement
Anonymised study data will be shared upon reasonable request from qualified investigators.
Results
Baseline demographics
536 patients were analysed in this cohort (70.9% female patients; mean age at baseline: 36 years). Patients had a mean disease course of 44.8 months and 39.2% of patients received OFA as first-line treatment. Baseline disability was low (mean EDSS score at baseline: 2.0; mean number of T2L at baseline: 19.1). Mean follow-up of our cohort was 21.6 months and the overall cohort is representative of 11 576 patient-months.
89 patients experienced a clinical relapse and 106 patients developed new or enlarging T2L. 87 patients experienced CDW during follow-up: 39 patients experienced relapse-associated worsening (RAW) and 48 patients experienced PIRA.
We stratified the patient cohorts according to BMI quartiles at baseline with Q1: <22.2 kg/m 2 ; Q2: 22.2–25.7 kg/m 2 ; Q3: 25.7–29.2 kg/m 2 ; and Q4: ≥29.2 kg/m 2 similar to respective analyses in previous studies. 3
Table 1 shows baseline parameters among BMI strata. Baseline demographics were evenly distributed among groups apart from a slightly higher baseline age among higher BMI strata.
Table 1 Baseline demographics of OFA patients stratified by BMI quartile BMI quartiles P 1 (<22.2) 2 (22.2–25.7) 3 (25.7–29.2) 4 (≥29.2) Number of patients 135 136 133 132 n/a Study centre Duesseldorf Essen Giessen Hannover 32 (23.7) 24 (17.8) 70 (51.9) 9 (6.7) 32 (23.5) 36 (26.5) 57 (41.9) 11 (8.1) 33 (24.8) 22 (16.5) 68 (51.1) 10 (7.5) 37 (28.0) 34 (25.8) 59 (44.7) 2 (1.5) 0.080 Age at baseline, years 34.3±11.2 35.9±9.3 36.9±8.6 36.7±9.1 0.021 Female patients, n (%) 101 (74.8) 94 (69.1) 97 (72.9) 88 (66.7) 0.472 MS duration since debut, months 44.9±47.3 45.5±36.5 44.1±30.86 44.6±35.9 0.670 Annualised relapse rate at baseline 1.0±0.6 1.0±0.7 1.1±0.7 1.0±0.6 0.511 EDSS score at baseline 2.0±1.0 2.0±1.0 2.1±0.9 2.0±1.1 0.349 Cranial T2 lesion load at baseline 18.9±8.0 17.7±6.3 21.0±9.9 18.8±7.9 0.082 Patients with CEL at baseline, N (%) 18 (13.3) 29 (21.3) 31 (23.3) 28 (21.2) 0.161 Number or previous DMT 1.0±1.1 1.2±1.2 1.1±1.0 1.0±1.0 0.463 Ofatumumab line-of-use First line Second line Third line 55 (40.7) 42 (31.1) 38 (28.1) 52 (38.2) 34 (25.0) 50 (36.8) 48 (36.1) 37 (27.8) 48 (36.1) 55 (41.7) 38 (28.8) 39 (29.5) 0.679 Follow-up duration, months 21.2±6.1 21.3±6.1 21.9±6.8 22.0±6.3 0.628 CD19 + B cells/µL at baseline 230±102 215±78 245±94 241±119 0.067 OFA serum levels (ng/L) 1281.8±206.8 975.2±196.3 806.7±93.6 654.3±112.9 <0.001 Time to clinical relapse, months, mean (IQR) 22.1 (21.3–22.9) 21.2 (20.1–22.3) 21.8 (20.9–22.7) 21.4 (20.4–22.5) 0.888 Time to new/enlarging T2-hyperintense MRI lesion, months, mean (IQR) 22.0 (21.1–22.8) 21.6 (20.6–22.5) 21.6 (20.7–22.5) 21.4 (20.4–22.3) 0.880 Time to CDW, months, mean (IQR) 22.9 (22.3–23.6) 22.7 (22.0–23.4) 22.2 (21.4–23.0) 21.0 (20.1–22.0) <0.001 Time to PIRA, months, mean (IQR) 23.4 (22.9–23.9) 23.4 (22.8–23.9) 23.3 (22.7–23.9) 22.5 (21.8–23.3) 0.057 Continuous variable are displayed as mean±standard deviation; categorical variables are shown as absolute numbers (fractions). OFA serum levels were obtained in a subset of patients from each BMI stratum (I: 12 patients; II: 11 patients; III: 9 patients; IV: 8 patients). P values were determined using a χ2 test for categorical variables or Kruskal-Wallis test for continuous variables. Kaplan-Meier estimates are shown as mean±95% CI. P values were calculated using the log rank-test. CEL, contrast-enhancing MRI lesion; DMT, disease-modifying treatment; EDSS, expanded disability status scale.
Baseline demographics of OFA patients stratified by BMI quartile
Continuous variable are displayed as mean±standard deviation; categorical variables are shown as absolute numbers (fractions). OFA serum levels were obtained in a subset of patients from each BMI stratum (I: 12 patients; II: 11 patients; III: 9 patients; IV: 8 patients). P values were determined using a χ2 test for categorical variables or Kruskal-Wallis test for continuous variables. Kaplan-Meier estimates are shown as mean±95% CI. P values were calculated using the log rank-test.
CEL, contrast-enhancing MRI lesion; DMT, disease-modifying treatment; EDSS, expanded disability status scale.
Kaplan-Meier plots indicated no substantial differences among BMI strata in terms of inflammatory disease outcomes such as relapses or new or enlarging T2L ( figure 1A ; see table 1 for estimates), whereas CDW was more abundant in patients from BMI stratum 4 ( figure 1B ). Multivariate regression models again showed no association of BMI strata and inflammatory outcomes whereas CDW was confirmed to be more abundant among 4th BMI quartile (adjusted HR (aHR): 3.33 (95% CI: 1.72 to 6.42; p<0.001)) with none of the further covariates selected. PIRA was the main driver of CDW among 4th quartile (27 patients with PIRA vs 11 patients with RAW). Multivariate analysis showed an aHR of 2.00 (95% CI: 1.47 to 2.70; p<0.001) among the 4th BMI quartile (ref: 1st quartile). The association of CDW and BMI was independent from baseline disability (EDSS ≤2.0: 3.32 (95% CI: 1.48 to 7.44; p=0.004; EDSS >2.0: 3.45 (95% CI: 1.08 to 11.02; p=0.037).
Kaplan-Meier analyses and multivariate Cox regression analysis of OFA patients stratified by BMI quartile. A Proportion of patients over time without a clinical relapse (left plot) or new/enlarging T2-hyperintense MRI lesions. Numbers at risk are given below the plots. Significance levels were determined using a log-rank test and are given as univariate p values. B Proportion of patients over time without 6 months confirmed worsening of disability (CDW). C Forest plot of multivariate Cox regression models using ‘time first relapse’ (left plot) or ‘time to first new/enlarging T2L’ as dependent variables. Models included ‘sex’, ‘age’, ‘disease duration’, ‘relapse rate at baseline’, ‘EDSS at baseline’, ‘MRI lesion load at baseline’ and ‘OFA line-of-use’ besides the BMI quartiles. None of the further variables was selected in any of the models. Forest plots indicate adjusted HR ± 95% CI and p values determined using a likelihood-ratio test. D Forest plot of multivariate Cox regression models using ‘time first confirmed disability progression’ as dependent variable. E B cell counts in the peripheral blood among patients from different BMI quartiles. CD19 + B cells were obtained during clinical routine using flow cytometry. Large red dots indicate measurements from patients with confirmed worsening of disability. F Ofatumumab serum levels assessed via ELISA among a representative subgroup of patients from Giessen. Fitted line including 95% CIs was calculated using a cubic model. Box-whisker plots indicate serum neurofilament light chain levels from the respective patients (boxes: median±IQR; whiskers: 5%–95% of values). BMI, body mass index; CDW, confirmed disability worsening; NfL, neurofilament light chain; OFA, ofatumumab; T2L, T2-hyperintense MRI lesion.
To compare our findings to the results from subgroup analyses performed in ASCLEPIOS, we tested whether body weight (BW) was predictive as well. BW quartiles among our cohort were Q1: <62.0 kg; Q2: 62.0–73.7 kg; Q3: 73.7–84.5 kg; and Q4: ≥84.5 kg. Notably, Cox regression did not select any of the BW strata compared with 1st quartile as covariate linked to CDW (aHR for 4th quartile: 1.91 (95% CI: 0.97 to 3.76; p=0.060). Similar results were obtained for analysis of PIRA among BW strata.
We next evaluated whether increased BMI was associated with insufficient B cell depletion. Whereas we observed a time-dependent decrease of peripheral B cells, there were no significant differences among BMI strata. However, we found that patients with newly diagnosed CDW displayed elevated B cell levels independent of BMI strata ( figure 1E ). We assessed serum levels of OFA in a representative subgroup of patients during steady state and found that a higher BMI was indeed associated with lower OFA serum levels. Additionally, serum neurofilament levels were elevated in patients from 3rd/4th BMI strata compared with 1st stratum ( figure 1F ).
Discussion
We demonstrate that the effects of OFA on inflammatory disease outcomes in RMS are independent from BMI, whereas its effect on CDW and PIRA decreases in patients with higher BMI. Notably, the dependency on BMI but not BW might explain why subgroup analyses of ASCLEPIOS 5 did not identify this phenomenon. Additionally, simulation of pharmacokinetics of OFA again relied on BW but not BMI and included only inflammatory endpoints. 8
Data on ocrelizumab showed that inhibition of inflammatory activity and disability progression are dose-dependent, with the latter being only successful at higher serum levels. 3 The exact underlying mechanisms remain unresolved, although trials with higher doses of ocrelizumab are currently conducted ( NCT04544436 ; NCT04548999 ). Of note, recent analyses indicated that higher peripheral B cell levels are associated with CDW following ocrelizumab treatment 9 and this was here confirmed for OFA-treated patients as well.
Unlike BW alone, BMI indicates obesity and increased subcutaneous fat tissue. 10 Retention of large molecules such as antibodies within the fat tissue might result in lower peak concentrations within the lymphoid tissues required for inhibition of processes that maintain disability progression. 11 Moreover, OFA appears to rapidly distribute within lymphoid tissues. 12 However, dose-dependent changes in OFA serum levels were observed in previous studies. Administration of up to 100 mg OFA results in fourfold higher serum levels compared with standard dose. 7 Our results indicated higher serum levels in patients with low BMI who administer OFA in their steady state, thus supporting the previous hypothesis of dose-dependent effects of B cell-depleting therapies on CDW.
However, one could hypothesise that a higher BMI itself is associated with a higher risk of CDW. Previous data on this issue remain conflicting. Lutfullin et al showed accelerated disability progression in obese patients, 13 whereas Escobar et al observed more relapses in obese patients but no impact on CDW. 14 Interestingly, all these effects were restricted to formally obese patients. The hazard for CDW however already increased in patients with a BMI below 30 kg/m 2 in our study, and conversely, OFA serum levels were already substantially lower in non-obese patients. Furthermore, we observed that patients from higher BMI strata showed elevated serum neurofilament. Generally, higher BMI was associated with lower neurofilament serum levels. 15 Thus, our findings indicate that low OFA serum levels result in suboptimal disease control.
Our observational study indeed has some limitations. Unlike secondary analyses from OPERA and ASCLEPIOS studies, our analysis lacks a comparator group. Furthermore, our patients differ in some aspects from those included in the ASCLEPIOS study as they were about 3 years younger and had only half of disease duration compared with trial patients and lower baseline disability. Baseline relapse rate and distribution of previous treatments as well as sex distribution on the other hand resembled demographics from ASCLEPIOS. 4 Generally, our prospectively collected cohort remains well characterised and provides a substantial amount of cumulative follow-up, especially given the rather recent approval of OFA.
Taken together, our study underlines the association of BMI as a potential surrogate for OFA serum levels and treatment response. Further studies are warranted in order to evaluate whether dose escalation studies are warranted for OFA.
Footnotes
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Patient consent for publication: Not applicable.
Ethics approval: This study involves human participants and was approved by Institutional review board of the Medical Faculty of the Justus-Liebig-University Gießen (53/23). Participants gave informed consent to participate in the study before taking part.
Provenance and peer review: Not commissioned; externally peer reviewed.
References
Associated Data
Data Availability Statement
Anonymised study data will be shared upon reasonable request from qualified investigators.
Among therapeutic options for active relapsing multiple sclerosis (RMS), B cell depletion using anti-CD20 antibodies has drawn increasing attention. Ocrelizumab was the first substance approved for treatment of RMS following superiority over beta-interferon in the OPERA studies. 1
Post hoc analyses of OPERA however provided further insights. Most patients experience disability progression independent from relapse activity (PIRA) despite their relapsing course of the disease. 2 Furthermore, low ocrelizumab serum levels were associated with disability worsening (CDW) but not with inflammatory disease activity. Antibody levels strongly correlated to body mass index (BMI) of patients. 3
Among further anti-CD20 antibodies, ofatumumab (OFA) is administered subcutaneously once a month. It was effective in the ASCLEPIOS studies. 4 Post hoc analyses of these studies indicated that its impact on PIRA is independent from body weight. 5 Since data on BMI were not presented yet, we analysed data from our multicentre cohort to determine the association of BMI and CDW among OFA patients.
Methods
Patients
Among four German tertiary centres (Duesseldorf, Essen, Giessen, Hannover), patients subjected to OFA for treatment of RMS according to most recent guidelines are subsequently included in local prospective cohorts with standardised assessment of baseline and follow-up parameters. For the current study, patients first subjected to OFA from 1 September 2021 to 31 December 2023 were included. Patients were followed every 3 months including laboratory testing, clinical examination and evaluation of recent injections. MRI scans were obtained at baseline and semiannually. Patients with a known history of manifest cardiovascular disease (apart from arterial hypertension responsive to monotherapy) and psychiatric disorders requiring specific medication as well as patients with known comorbid autoimmunity were excluded.
Outcome measures
Confirmed relapses required an increase of at least one function system score of the expanded disability status scale (EDSS). 6 CDW was considered relevant in accordance with the ASCLEPIOS study: +1.5 points (baseline=0.0), +1.0 point (baseline=1.0–5.0) and +0.5 points (baseline ≥5.5) and required confirmation 6 months later. MRI scans were judged by a qualified neuro-radiologist in a standardised manner to account for the development of new or enlarging T2-hyperintense MRI lesion (T2L) compared with the previous scan. PIRA was assessed as previously described. 2 OFA serum levels were determined via ELISA (KBI1516; Krishgen Biosystems, California, USA) from stored patient blood samples collected 5 days following last administration (assumed date of peak concentration according to previous studies 7 ). Serum neurofilament light chain levels were measured using a commercial assay and the ADVIA Centaur device (both Siemens Healthineers).
Statistical analysis
Baseline demographics were assessed using descriptive statistics and were compared using a χ 2 test for categorical variables and a Kruskal-Wallis test for continuous variables. Kaplan-Meier plots were generated for the respective endpoints and compared using the log-rank test. Cox proportional hazard models were used including ‘sex’, ‘age’, ‘disease duration’, ‘relapse rate at baseline’, ‘EDSS at baseline’, ‘MRI lesion load at baseline’ and ‘OFA line-of-use’ and ‘BMI/BW quartile’ as covariates with p values being determined using a likelihood-ratio test. A p value below 0.05 was considered significant. All analyses were performed using R (R Core Team, 2024, V.4.4.2).
Standard protocol approvals, registrations and patient consents
The local cohorts were reviewed and approved by the respective local authorities and all patients gave informed consent.
Data availability statement
Anonymised study data will be shared upon reasonable request from qualified investigators.
Results
Baseline demographics
536 patients were analysed in this cohort (70.9% female patients; mean age at baseline: 36 years). Patients had a mean disease course of 44.8 months and 39.2% of patients received OFA as first-line treatment. Baseline disability was low (mean EDSS score at baseline: 2.0; mean number of T2L at baseline: 19.1). Mean follow-up of our cohort was 21.6 months and the overall cohort is representative of 11 576 patient-months.
89 patients experienced a clinical relapse and 106 patients developed new or enlarging T2L. 87 patients experienced CDW during follow-up: 39 patients experienced relapse-associated worsening (RAW) and 48 patients experienced PIRA.
We stratified the patient cohorts according to BMI quartiles at baseline with Q1: <22.2 kg/m 2 ; Q2: 22.2–25.7 kg/m 2 ; Q3: 25.7–29.2 kg/m 2 ; and Q4: ≥29.2 kg/m 2 similar to respective analyses in previous studies. 3
Table 1 shows baseline parameters among BMI strata. Baseline demographics were evenly distributed among groups apart from a slightly higher baseline age among higher BMI strata.
Table 1 Baseline demographics of OFA patients stratified by BMI quartile BMI quartiles P 1 (<22.2) 2 (22.2–25.7) 3 (25.7–29.2) 4 (≥29.2) Number of patients 135 136 133 132 n/a Study centre Duesseldorf Essen Giessen Hannover 32 (23.7) 24 (17.8) 70 (51.9) 9 (6.7) 32 (23.5) 36 (26.5) 57 (41.9) 11 (8.1) 33 (24.8) 22 (16.5) 68 (51.1) 10 (7.5) 37 (28.0) 34 (25.8) 59 (44.7) 2 (1.5) 0.080 Age at baseline, years 34.3±11.2 35.9±9.3 36.9±8.6 36.7±9.1 0.021 Female patients, n (%) 101 (74.8) 94 (69.1) 97 (72.9) 88 (66.7) 0.472 MS duration since debut, months 44.9±47.3 45.5±36.5 44.1±30.86 44.6±35.9 0.670 Annualised relapse rate at baseline 1.0±0.6 1.0±0.7 1.1±0.7 1.0±0.6 0.511 EDSS score at baseline 2.0±1.0 2.0±1.0 2.1±0.9 2.0±1.1 0.349 Cranial T2 lesion load at baseline 18.9±8.0 17.7±6.3 21.0±9.9 18.8±7.9 0.082 Patients with CEL at baseline, N (%) 18 (13.3) 29 (21.3) 31 (23.3) 28 (21.2) 0.161 Number or previous DMT 1.0±1.1 1.2±1.2 1.1±1.0 1.0±1.0 0.463 Ofatumumab line-of-use First line Second line Third line 55 (40.7) 42 (31.1) 38 (28.1) 52 (38.2) 34 (25.0) 50 (36.8) 48 (36.1) 37 (27.8) 48 (36.1) 55 (41.7) 38 (28.8) 39 (29.5) 0.679 Follow-up duration, months 21.2±6.1 21.3±6.1 21.9±6.8 22.0±6.3 0.628 CD19 + B cells/µL at baseline 230±102 215±78 245±94 241±119 0.067 OFA serum levels (ng/L) 1281.8±206.8 975.2±196.3 806.7±93.6 654.3±112.9 <0.001 Time to clinical relapse, months, mean (IQR) 22.1 (21.3–22.9) 21.2 (20.1–22.3) 21.8 (20.9–22.7) 21.4 (20.4–22.5) 0.888 Time to new/enlarging T2-hyperintense MRI lesion, months, mean (IQR) 22.0 (21.1–22.8) 21.6 (20.6–22.5) 21.6 (20.7–22.5) 21.4 (20.4–22.3) 0.880 Time to CDW, months, mean (IQR) 22.9 (22.3–23.6) 22.7 (22.0–23.4) 22.2 (21.4–23.0) 21.0 (20.1–22.0) <0.001 Time to PIRA, months, mean (IQR) 23.4 (22.9–23.9) 23.4 (22.8–23.9) 23.3 (22.7–23.9) 22.5 (21.8–23.3) 0.057 Continuous variable are displayed as mean±standard deviation; categorical variables are shown as absolute numbers (fractions). OFA serum levels were obtained in a subset of patients from each BMI stratum (I: 12 patients; II: 11 patients; III: 9 patients; IV: 8 patients). P values were determined using a χ2 test for categorical variables or Kruskal-Wallis test for continuous variables. Kaplan-Meier estimates are shown as mean±95% CI. P values were calculated using the log rank-test. CEL, contrast-enhancing MRI lesion; DMT, disease-modifying treatment; EDSS, expanded disability status scale.
Baseline demographics of OFA patients stratified by BMI quartile
Continuous variable are displayed as mean±standard deviation; categorical variables are shown as absolute numbers (fractions). OFA serum levels were obtained in a subset of patients from each BMI stratum (I: 12 patients; II: 11 patients; III: 9 patients; IV: 8 patients). P values were determined using a χ2 test for categorical variables or Kruskal-Wallis test for continuous variables. Kaplan-Meier estimates are shown as mean±95% CI. P values were calculated using the log rank-test.
CEL, contrast-enhancing MRI lesion; DMT, disease-modifying treatment; EDSS, expanded disability status scale.
Kaplan-Meier plots indicated no substantial differences among BMI strata in terms of inflammatory disease outcomes such as relapses or new or enlarging T2L ( figure 1A ; see table 1 for estimates), whereas CDW was more abundant in patients from BMI stratum 4 ( figure 1B ). Multivariate regression models again showed no association of BMI strata and inflammatory outcomes whereas CDW was confirmed to be more abundant among 4th BMI quartile (adjusted HR (aHR): 3.33 (95% CI: 1.72 to 6.42; p<0.001)) with none of the further covariates selected. PIRA was the main driver of CDW among 4th quartile (27 patients with PIRA vs 11 patients with RAW). Multivariate analysis showed an aHR of 2.00 (95% CI: 1.47 to 2.70; p<0.001) among the 4th BMI quartile (ref: 1st quartile). The association of CDW and BMI was independent from baseline disability (EDSS ≤2.0: 3.32 (95% CI: 1.48 to 7.44; p=0.004; EDSS >2.0: 3.45 (95% CI: 1.08 to 11.02; p=0.037).
Kaplan-Meier analyses and multivariate Cox regression analysis of OFA patients stratified by BMI quartile. A Proportion of patients over time without a clinical relapse (left plot) or new/enlarging T2-hyperintense MRI lesions. Numbers at risk are given below the plots. Significance levels were determined using a log-rank test and are given as univariate p values. B Proportion of patients over time without 6 months confirmed worsening of disability (CDW). C Forest plot of multivariate Cox regression models using ‘time first relapse’ (left plot) or ‘time to first new/enlarging T2L’ as dependent variables. Models included ‘sex’, ‘age’, ‘disease duration’, ‘relapse rate at baseline’, ‘EDSS at baseline’, ‘MRI lesion load at baseline’ and ‘OFA line-of-use’ besides the BMI quartiles. None of the further variables was selected in any of the models. Forest plots indicate adjusted HR ± 95% CI and p values determined using a likelihood-ratio test. D Forest plot of multivariate Cox regression models using ‘time first confirmed disability progression’ as dependent variable. E B cell counts in the peripheral blood among patients from different BMI quartiles. CD19 + B cells were obtained during clinical routine using flow cytometry. Large red dots indicate measurements from patients with confirmed worsening of disability. F Ofatumumab serum levels assessed via ELISA among a representative subgroup of patients from Giessen. Fitted line including 95% CIs was calculated using a cubic model. Box-whisker plots indicate serum neurofilament light chain levels from the respective patients (boxes: median±IQR; whiskers: 5%–95% of values). BMI, body mass index; CDW, confirmed disability worsening; NfL, neurofilament light chain; OFA, ofatumumab; T2L, T2-hyperintense MRI lesion.
To compare our findings to the results from subgroup analyses performed in ASCLEPIOS, we tested whether body weight (BW) was predictive as well. BW quartiles among our cohort were Q1: <62.0 kg; Q2: 62.0–73.7 kg; Q3: 73.7–84.5 kg; and Q4: ≥84.5 kg. Notably, Cox regression did not select any of the BW strata compared with 1st quartile as covariate linked to CDW (aHR for 4th quartile: 1.91 (95% CI: 0.97 to 3.76; p=0.060). Similar results were obtained for analysis of PIRA among BW strata.
We next evaluated whether increased BMI was associated with insufficient B cell depletion. Whereas we observed a time-dependent decrease of peripheral B cells, there were no significant differences among BMI strata. However, we found that patients with newly diagnosed CDW displayed elevated B cell levels independent of BMI strata ( figure 1E ). We assessed serum levels of OFA in a representative subgroup of patients during steady state and found that a higher BMI was indeed associated with lower OFA serum levels. Additionally, serum neurofilament levels were elevated in patients from 3rd/4th BMI strata compared with 1st stratum ( figure 1F ).
Discussion
We demonstrate that the effects of OFA on inflammatory disease outcomes in RMS are independent from BMI, whereas its effect on CDW and PIRA decreases in patients with higher BMI. Notably, the dependency on BMI but not BW might explain why subgroup analyses of ASCLEPIOS 5 did not identify this phenomenon. Additionally, simulation of pharmacokinetics of OFA again relied on BW but not BMI and included only inflammatory endpoints. 8
Data on ocrelizumab showed that inhibition of inflammatory activity and disability progression are dose-dependent, with the latter being only successful at higher serum levels. 3 The exact underlying mechanisms remain unresolved, although trials with higher doses of ocrelizumab are currently conducted ( NCT04544436 ; NCT04548999 ). Of note, recent analyses indicated that higher peripheral B cell levels are associated with CDW following ocrelizumab treatment 9 and this was here confirmed for OFA-treated patients as well.
Unlike BW alone, BMI indicates obesity and increased subcutaneous fat tissue. 10 Retention of large molecules such as antibodies within the fat tissue might result in lower peak concentrations within the lymphoid tissues required for inhibition of processes that maintain disability progression. 11 Moreover, OFA appears to rapidly distribute within lymphoid tissues. 12 However, dose-dependent changes in OFA serum levels were observed in previous studies. Administration of up to 100 mg OFA results in fourfold higher serum levels compared with standard dose. 7 Our results indicated higher serum levels in patients with low BMI who administer OFA in their steady state, thus supporting the previous hypothesis of dose-dependent effects of B cell-depleting therapies on CDW.
However, one could hypothesise that a higher BMI itself is associated with a higher risk of CDW. Previous data on this issue remain conflicting. Lutfullin et al showed accelerated disability progression in obese patients, 13 whereas Escobar et al observed more relapses in obese patients but no impact on CDW. 14 Interestingly, all these effects were restricted to formally obese patients. The hazard for CDW however already increased in patients with a BMI below 30 kg/m 2 in our study, and conversely, OFA serum levels were already substantially lower in non-obese patients. Furthermore, we observed that patients from higher BMI strata showed elevated serum neurofilament. Generally, higher BMI was associated with lower neurofilament serum levels. 15 Thus, our findings indicate that low OFA serum levels result in suboptimal disease control.
Our observational study indeed has some limitations. Unlike secondary analyses from OPERA and ASCLEPIOS studies, our analysis lacks a comparator group. Furthermore, our patients differ in some aspects from those included in the ASCLEPIOS study as they were about 3 years younger and had only half of disease duration compared with trial patients and lower baseline disability. Baseline relapse rate and distribution of previous treatments as well as sex distribution on the other hand resembled demographics from ASCLEPIOS. 4 Generally, our prospectively collected cohort remains well characterised and provides a substantial amount of cumulative follow-up, especially given the rather recent approval of OFA.
Taken together, our study underlines the association of BMI as a potential surrogate for OFA serum levels and treatment response. Further studies are warranted in order to evaluate whether dose escalation studies are warranted for OFA.
Footnotes
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Patient consent for publication: Not applicable.
Ethics approval: This study involves human participants and was approved by Institutional review board of the Medical Faculty of the Justus-Liebig-University Gießen (53/23). Participants gave informed consent to participate in the study before taking part.
Provenance and peer review: Not commissioned; externally peer reviewed.
References
Associated Data
Data Availability Statement
Anonymised study data will be shared upon reasonable request from qualified investigators.