
==== Front
J Neurol
J Neurol
Journal of Neurology
0340-5354
1432-1459
Springer Berlin Heidelberg Berlin/Heidelberg

39039273
12581
10.1007/s00415-024-12581-0
Original Communication
Quality of life and tolerability of B-cell directed therapy of multiple sclerosis with ofatumumab in a patient-centered real-world observational study
Karl Anna-Sophia 1
http://orcid.org/0000-0001-5989-2195
Klimas Rafael rafael.klimas@rub.de

1
Katsimpoura Melina 1
Sgodzai Melissa 1
Theile-Ochel Simon 1
Poser Philip Lennart 1
Gisevius Barbara 1
Faissner Simon 1
Salmen Anke 1
Nastos Ilias 2
Gold Ralf 1
Motte Jeremias 1
1 grid.5570.7 0000 0004 0490 981X Clinic for Neurology, St. Josef Hospital, Ruhr University Bochum, Gudrunstraße 56, 44791 Bochum, Germany
2 Specialist Practice for Neurology, Bochum, Germany
22 7 2024
22 7 2024
2024
271 9 60806088
27 5 2024
10 7 2024
12 7 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Introduction

Ofatumumab (Kesimpta®) is a subcutaneous CD20-targeting antibody approved in Germany in 2021 for the treatment of relapsing multiple sclerosis (RMS). After careful instruction, patients can administer the treatment themselves. We previously reported data of 101 patients (Klimas et al. in Nervenarzt 94:923–933, 2023). The objective of this longitudinal study is to explore the tolerability and acceptability of ofatumumab from a patient perspective over a follow up period of 6 months.

Methods

In this prospective observational real-world study, we report follow up data of 81 patients. We evaluated sociodemographic data, disease duration, duration and side effects of ofatumumab use, expanded disability status scale (EDSS), Beck Depression Inventory II (BDI-II), Short-Form 36 (SF-36), Fatigue Scale of Motor and Cognitive Functions (FSMC), and modified Multiple Sclerosis Functional Composite Test (MSFC). In addition, we asked for subjective treatment outcomes, such as impact on quality of life, walking distance, concentration, mood, medication adherence, fatigue and the subjective course of MS on a numerical rating scale (1 = very negative; 5 = very positive). Furthermore, treatment discontinuations were recorded.

Results

The average duration of ofatumumab treatment was 10 months. In comparison to previous published data of our cohort, patients reported a significant increase in headache (10% up to 26%, p = 0.004) and limb pain (5% up to 26%, p < 0.001) as persistent side effects after the injections. More patients reported a very positive effect (p < 0.0001) on quality of life. 4 confirmed relapses occurred but no EDSS worsening, and no treatment discontinuations were documented during the observation period.

Discussion

As previously described, our prospective study indicates that patients have a good tolerability of ofatumumab, precisely because of the mild and few side effects at the first administration. However, the longer the observation period, the more headaches and limb pain occurred after the injections. Despite this, patients’ subjective quality of life improved. There were no discontinuations during the follow-up period, with the limitation of a high loss to follow-up.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00415-024-12581-0.

Keywords

Ofatumumab
B-cell depletion
Multiple sclerosis
Anti-CD20 monoclonal antibody
Katholisches Klinikum Bochum gGmbh (9607)Open Access funding enabled and organized by Projekt DEAL.

issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2024
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pmcIntroduction

Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by inflammation, demyelination, and neurodegeneration within the central nervous system. The disease can present in various forms, with relapsing–remitting MS (RRMS) being the most common, followed by secondary progressive MS (SPMS) which can exhibit active relapsing symptoms contributing to disability accumulation. Early initiation of disease-modifying therapies (DMTs) has been shown to reduce the risk of disability progression, underscoring the importance of effective and well-tolerated treatment options [1–4].

B-cell depleting therapies, particularly monoclonal antibodies (MoAbs) targeting the CD20 antigen on B cells, have emerged as a pivotal advancement in the treatment landscape for MS [5–7]. Ofatumumab (Kesimpta®), a fully human anti-CD20 antibody, was approved in Germany in 2021 for the treatment of RMS. Unlike its predecessor ocrelizumab, ofatumumab is administered subcutaneously, allowing patients the convenience of self-administration after appropriate training. Clinical trials, notably the ASCLEPIOS I and II, demonstrated the superior efficacy of ofatumumab compared to teriflunomide, highlighting its potential in delaying disability progression, reducing relapse rates, and diminishing central nervous system inflammation [8–11].

Despite these promising clinical trial results, real-world data on the tolerability and impact of ofatumumab on patient-reported outcomes in everyday clinical practice remain limited. Our initial study demonstrated that ofatumumab administered subcutaneously was highly accepted and well-tolerated [12]. Here, our study aims to bridge the gap between real-word data and clinical trials by providing observational data from a patient-centered perspective over a 6-month follow-up period. This study evaluates the tolerability, safety, and subjective treatment outcomes of ofatumumab in a real-world setting, focusing on quality of life, functional status, and side effect profile.

Our specific research questions include:How do reported side effects evolve over the course of treatment?

How does ofatumumab influence quality of life and functional outcomes during the observation period?

Are patient-reported outcomes and Multiple Sclerosis Functional Composite Test (MSFC) scores stable or improved during the treatment period?

Do patients report relapses under therapy with ofatumumab?

This prospective observational study aims to provide comprehensive insights into the real-world application of ofatumumab, supporting its role as a viable treatment option for patients with relapsing MS.

Methods

Patients and study design

Adult patients (male/female) who have initiated treatment with ofatumumab as indicated during routine clinical treatment decision-making qualified for the study and have been asked to participate after treatment initiation at the Department of Neurology, St. Josef University Hospital Bochum, and in a large MS specialist practice in the Ruhr region (Dr. med. Nastos) between September 2021 and November 2023. No additional in-/exclusion criteria were set. After enrollment, clinical data and scores were collected at baseline [12], and a follow-up appointment was scheduled for 6 months later (Follow-up 6 months (FU1)) (Fig. 1).Fig. 1 Study design. 118 patients were enrolled in the study after medical adjustment. 17 patients did not want participate in the study, leaving 101 patients in the study. At baseline, patients were required to complete a questionnaire and provide their disease and current medical history. Furthermore, a physical examination and MSFC were conducted. Following baseline assessments, 20 of the 101 patients either withdraw from the study for the personal reasons or could not be contacted. Subsequently, a second appointment was scheduled after a period of 6 months. 81 patients have already completed this appointment

Standard protocol approval, registrations, and patient consent

The ethics committee of the Medical Faculty of Ruhr-University Bochum, Germany approved our study (reg.-no. 20-6827). Written informed consent was obtained from all patients. All procedures performed in studies involving human participants were in accordance with the ethical standard of the institutional and/or national research committee and with the 1975 Helsinki Declaration and its later amendment or comparable ethical standards.

Outcome analyses

The systematic data collection included the following elements for each of the two time points:Sociodemographic data:age and sex

Disease-specific data:disease duration

EDSS

relapses during treatment

Ofatumumab treatment data:duration of treatment with ofatumumab

treatment discontinuations

side effects

Patient reported outcomes (PROs):Beck depression inventory II (BDI-II)

Short form 36 (SF-36)

Fatigue Scale for Motor and Cognitive Functions (FSMC)

Functional tests:modified Multiple Sclerosis Functional Composite Test (MSFC)

Times 25-Foot Walk Test (T25FT)

9 Hole Peg Test (NHPT)

At FU1, questionnaires and documentation collected during the study visit were used to collect data. At the first visit, we assessed early side effects (within 48 h after the first injection) and late side effects (during one week after the first injection) as described previously. We here assessed persistent side effects from baseline to FU1, regardless of the time of injection. Additionally, we recorded participants’ subjective experiences of handling the self-administration, as well as treatment impact on quality of life, walking distance, concentration, mood, medication adherence, fatigue and the subjective course of MS on a numerical rating scale (1 = very negative/hard/inaccurate, 2 = negative/hard/inaccurate, 3 = neutral, 4 = positive/ease/accurate, 5 = very positive/easy/accurate, 0 = “I don’t know”). In case of treatment discontinuation, reasons were explored. For unanswered FSMC and BDI questions, the mean of other responses is imputed. The SF-36 questionnaire results are condensed into a physical and mental sum scale, ranging from 0 (very low quality of life) to 100 (very high quality of life), and benchmarked against a German norm population [13]. A modified MSFC was applied, omitting the PASAT due to low patient tolerance.

Statistics

Statistical analysis was performed using SPSS (Statistical Package for the Social Sciences, version 27), GraphPad Prism (GraphPad Software, www.graph pad.com, version 9.5.0) and SankeyMATIC. Parametric data are presented as mean with standard deviation (SD), and nonparametric data as median with interquartile range (IQR) if not stated otherwise. Nominal and dichotomous variables are presented as counts and percentages. Clinical characteristics were compared between groups using Wilcoxon matched-pairs signed rank test for numerical non-normally distributed paired values, chi-squared test (χ2-test) for nominal variables and McNemar test (χ2-test) for dichotomous variables. The statistically significant threshold was set at p-value < 0.05. For multiple testing, the p-value was corrected according to Bonferroni. The primary outcome is defined as improvement in the application questions. Secondary outcomes are stability of EDSS, PROs and MSFC.

Results

Patient characteristics

Between September 2021 and November 2023, 101 patients newly treated with ofatumumab were recruited. Follow-up questionnaires and study visits were performed on 81 patients at FU1. 20 of the 101 patients (20%) either withdrew from the study for personal reasons or could not be contacted. At follow-up time point 67 patients (83%) were female, and the mean age was 45 years (SD: 10, range 23–70). The median length of time since initial diagnosis was 7.5 years (IQR: 10.5, range 0–35). On average, patients were treated with ofatumumab for 10 months (IQR: 5.25, range 4–19, n = 76, Table 1). The pre-treatments and EDSS scores at baseline of the patients enrolled in the study can be found in the preliminary work [12]. The median FU1 EDSS score remained stable at 2 (IQR: 1.5, range 1.0–6.5, n = 76) after 6 months observational period (Table 1).Table 1 Patients characteristics at FU1

Patients, n	81	
Female patients, n (%)	67 (83)	
 Age of patients (years), mean (SD), n	45 (10), 81	
 Disease duration since diagnosis, years median (IQR), n	7.5 (10.5), 10	
Disease duration since manifestation, years median (IQR), n	9 (11), 79	
Month since first ofatumumab injection, median (IQR), n	10 (5.25), 76	
EDSS, median (IQR), n	2.0 (1.5), 76	

Four confirmed relapses and no treatment discontinuation in the 6-month observational period

5 patients (6%) reported a relapse event during the observation period. One was associated with respiratory infection, leading to a confirmed relapse event in 4 patients (5%). At the time of the relapse, the mean disease duration was 94 ± 63 months, Ofatumumab was taken by the patients for an average of 13 ± 2 months, and the mean EDSS was 3.0. Each relapse had up to 6 different symptoms. Gait disturbance and gait unsteadiness were the most common relapse symptoms, accounting for 3/4 of cases. This was followed by sensory disturbance affecting more than one part of the body (2/4 of cases), paralysis or weakness of more than one part of the body, e.g., hemiplegia (2/4 of cases) and sexual disorders (2/4 of cases). Each relapse was treated with intravenous corticosteroids and recovered fully. During the 6-month observation period, none of the 81 patients discontinued treatment. Details are displayed in supplementary Fig. 1.

Increasing severity of side effects with predominantly headache and limb pain

To enable a longitudinal comparison of side effects, we analyzed the 81 patients intraindividually. We used the McNemar test to compare early (within 48 h after the first injection) and late (within 1 week after the first injection) side effects at baseline with FU1 (Table 2). When comparing the early side effects reported at baseline to those reported after 6 months, a significantly higher number of individuals reported the absence of those side effects (p < 0.001). Additionally, side effects such as chills and fever (p < 0.001), headache (p = 0.004), and limb pain (p < 0.001) were reported significantly less frequently. However, it is important to note that certain side effects, such as headache (p = 0.004) and limb pain (p = < 0.001), increased significantly when compared to the late side effects. In conclusion, it can be stated that the incidence of long-lasting side effects has increased, while that of short-lasting side effects has decreased.Table 2 Side effects of longitudinal cases

	A: early side effects	B: late side effects	C: FU1 side effects	A vs. C	B vs. C	
Total n	81	81	81			
No side effects, n (% of cases)	21 (26)	54 (67)	43 (53)	< 0.001	0.043	
Chills/fever, n (% of cases)	36 (44)	0 (0)	4 (5)	< 0.001	–	
Headache, n (% of cases)	37 (46)	8 (10)	21 (26)	0.004	0.004	
Pain in the limbs, n (% of cases)	41 (51)	4 (5)	21 (26)	< 0.001	< 0.001	
Respiratory difficulties, n (% of cases)	2 (3)	1 (1)	7 (9)	0.125	–	
Skin rash, n (% of cases)	1 (1)	1 (1)	1 (1)	1	1	
Urinary tract infection, n (% of cases)	1 (1)	0 (0)	6 (7)	0.125	–	
Local inflammation at the injection site, n (% of cases)	0 (0)	0 (0)	1 (1)	–	–	
Other, n (% of cases)	17 (21)	6 (7)	14 (17)	0.648		
Early (within 48 h after the first injection), late (during 1 week after the first injection) and side effects at follow-up after 6 months (FU1). McNemar test between baseline early side effects and FU1 and baseline late side effects and FU1

The severity of side effects at FU6 was perceived by 19% of the participants (n = 15) as “very mild”, 14% (n = 11) “mild”, 11% (n = 9) “neutral”, 2% (n = 2) “severe”, 7% (n = 6) “very severe” and 47% (n = 38) did not know how to answer. The results of the post-hoc test, which was conducted using the Bonferroni correction, indicated that the observed significance was since a greater proportion of patients selected the answers “very severe” and “I don’t know” than expected (p < 0.0001, Fig. 2).Fig. 2 Application questions. Impact of ofatumumab on various patient-Reported outcomes over time. Figure illustrates the changes in the patient-reported outcomes over the course of ofatumumab treatment during a 6 month observation period. Parameters accessed include quality of life, walking distance, concentration, mood, medication adherence, and fatigue from a patients subjective perspective. Statistically significant differences were determined using the chi-squared test. Drug-handling: p = 0.099. Quality of life: p = 0.002. Walking distance p < 0.001. Concentration: p < 0.001. Mood: p = 0.010. Fatigue: p < 0.001. Disease course: p < 0.001. Compliance: p = 0.085. Ofatumumab side effects: p < 0.001. The symbols within the bars indicate significance after post-hoc testing with Bonferroni correction

High patient acceptance and positive impact on quality of life

We previously reported the baseline data in a separate paper [12]. The FU1 data can be found in Fig. 2.

88% (n = 71) of the patients reported finding the medication handling “very easy” at follow-up, 10% (n = 8) “easy”, 1% (n = 1) “very hard” and one patient (1%, n = 1) selected the “I don’t know” option. There was no statistical difference between baseline and FU1 (p = 0.099).

The influence of ofatumumab on quality of life was rated as “very positive” by 44% (n = 36) and “positive” by 19% (n = 15) of participants. 11% of participants (n = 9) selected “neutral” and 26% (n = 21) were unsure how to respond. Here, a significant difference in response options (p = 0.002) was observed. Following Bonferroni correction, more patients reported a “very positive” effect (p = 0.0001), and significantly fewer patients selected the “I don’t know” option (p = 0.001) than expected.

19% (n = 15) of participants rated the impact of ofatumumab on their walking distance as “very positive,” with another 7% (n = 6) rating it as “positive”. No changes (“neutral”) in walking distance were reported by 17% of the participants (n = 14) while 57% (n = 46) were unsure about the effect of ofatumumab. A significant difference is evident here (p < 0.001). Following Bonferroni correction, less patients reported a “very positive” effect (p = 0.0001), and significantly more patients selected “neutral” as their answer option (p = 0.0004).

The effect of ofatumumab on concentration is widely regarded as "neutral” (16% (n = 13).

9% (n = 7) experienced a very positive effect, 12% (n = 10) experienced a positive effect, 4% (n = 3) experienced a negative effect and 59% (n = 48) did not know. A statistically significant difference was found between the baseline and FU1 (p < 0.001). The Bonferroni correction indicates that a significantly higher number of patients selected “negative” compared to what was expected.

At FU1, 12% (n = 10) reported a “very positive” impact on their mood, 12% (n = 10) a positive, 20% (n = 16) neutral, and 2% (n = 2) negative. 53% (n = 43) chose “I don’t know.” The statistical significance of the results is apparent (p = 0.010) as significantly more patients selected “neutral” than expected.

Fatigue during therapy with ofatumumab was rated as “neutral” by 31% (n = 25). 2% (n = 2) reported “more fatigue” and 7% (n = 6) “much more fatigue”. “Much less fatigue” was reported by 6% (n = 5) and “less fatigue” by 5% (n = 4). 48% (n = 39) did not know. However, due to the small sample size the Bonferroni post-hoc test is unable to determine between which pairwise comparisons this significant difference exists.

85% (n = 69) of patients adhered “very accurate” to monthly self-injection. 14% (n = 1^) adhered “accurate” to monthly intervals. 1% (n = 1) chose the option “I don’t know”. There was no statistical difference (p = 0.085).

After 6 months, a significant difference (p < 0.001) was observed in the influence on subjective MS disease progression. 25% (n = 20) of patients reported a “very positive” influence, 26% (n = 21) a “positive” influence, 5% (n = 4) a “neutral” influence of ofatumumab on disease progression. However, one patient (1% (n = 1) reported a “negative” influence and 43% (n = 35) chose the option “I don’t know”. A significantly higher percentage of patients selected the response “I don’t know” (p < 0.0001) and a slightly higher percentage selected the response “neutral” (p < 0.0001).

No significant changes in multiple sclerosis impact scale (MSIS-29)

The study utilized the MSIS-29 to analyze the effect of MS on physical (physical impact score) and psychological (psychological impact score) factors. The scores were plotted on a scale ranging from 0 (‘no effect of the disease’) to 100 (‘maximum effect of the disease’).

At FU1, the median physical score remained at 23.75 (IQR: 30, range 0–80, n = 81). In the psychological assessment, a median score 36.11 (IQR: 38.89, range 0–94.45, n = 81) was achieved at the FU1. No significant difference was observed between Baseline and FU1 for either score (Supp. Figure 2).

No significant changes in fatigue scale for motor and cognitive functions (FSMC)

The level of fatigue symptoms was evaluated using FSMC, distinguishing between global, motor, and cognitive fatigue. The cohort’s median score for global fatigue at FU1 was 63 (IQR: 32, range 20–100, n = 81), representing severe global fatigue (Supp. Figure 3A). With a median of 31 points at FU1 (IQR: 19, range 10–50, n = 81), indicating moderate cognitive fatigue (Supp. Figure 3B). The cohort’s median score for motor fatigue remained at 32 points (IQR: 16, range 10–50, n = 81). This indicated severe motor fatigue (Supp. Figure 3C). Compared to our previous reported data [12] there were no significant chances in neither one of the scores.

BDI-II remained stable, indicating no worsening of depressive symptoms

The frequency of depressive symptoms in our study cohort was assessed using the BDI-II. At FU1, the median score remained at 12 points (IQR: 16, range 0–33, n = 80). Median scores indicate a minimal level of depression. 38% (n = 31) did not suffer from depressive symptoms. 15% (n = 12) reported minimal depressive symptoms, 17% (n = 14) mild symptoms and 18% (n = 15) moderate symptoms. Severe depression was reported by 10% (n = 8) of the patients. No significant difference in BDI-II was detected during the observation period (Supp. Figure 4).

Short-Form (SF-36) Health Survey shows no alterations

The quality of life was evaluated using the SF-36 questionnaire. Our findings indicate that our cohort exhibited lower disease-related quality of life compared to the German norm population in both the physical (mean: 41.46 ± 11.88, min: 17.91, max: 62.40, n = 80) and mental (mean: 44.37 ± 11.63, min: 18.66, max: 62.68, n = 80) sum scales at FU1 (Tab. 3). However, no significant changes were observed in the physical sum scale after 6 months. Furthermore, no alterations were observed in the remaining scales.Table 3 Short Form (36) Healthy Survey of longitudinal cases after 6 months (FU1)

	N	Minimum	Maximum	Mean	SD	Two-tailed p value	
Physical sumscale	80	17.91	62.40	41.46	11.88	0.830	
Mental sumscale	80	18.66	62.68	44.37	11.63	0.193	
Physical functioning	81	0.00	100.00	69.25	29.78	0.282	
Physical role function	81	0.00	100.00	54.63	42.41	0.461	
Physical pain	81	0.00	100.00	61.21	30.93	0.309	
General health perception	80	0.00	100.00	47.83	22.52	0.266	
Vitality	81	0.00	100.00	39.32	24.34	0.206	
Social role functioning	81	0.00	100.00	68.06	30.29	0.371	
Emotional role functioning	81	0.00	100.00	63.79	44.78	0.140	
Mental health	81	12.00	100.00	66.32	20.44		

Modified multiple sclerosis functional composite (MSFC)

A modified MSFC was applied, omitting the PASAT due to low patient tolerance.

No significant changes in Timed 25-Foot Walk Test (T25FT)

At baseline, patients took an average of 5.14 ± 1.55 s (min: 3.3, max: 11.45, n = 63) to cover the distance. At the FU1, the patients required an average of 5.26 ± 1.97 s (min: 3.2, max: 15.1, n = 63). No significant differences were observed between the two time points.

9-Hole Peg Test (NHPT) with no significant differences

At baseline, patients achieved a mean time of 20.81 ± 3.81 s (min: 14.9, max: 34.65, n = 63) using their dominant hand and 21.31 ± 3.31 s (min: 15.7, max: 30.7, n = 63) using their non-dominant hand. No significant differences were found compared to FU1, where patients completed the test using a mean time of 20.28 ± 4.25 s (min: 12.4, max: 32.75, n = 63) with their dominant hand and a mean time of 21.07 ± 3.75 s (min: 13.5, max: 29.1, n = 63) with their non-dominant hand.

Discussion

Following a 6-month observation period, it can be demonstrated that ofatumumab has a good tolerability profile in patients due to its simple administration and mild side effect profile. In addition, clinical course assessment using PROs, EDSS and functional tests shows that most patients had a stable disease course under ofatumumab. Yet, during the observation period, 4 out of 81 (5%) patients experienced a relapse, from which all patients recovered after the administration of intravenous corticosteroids. None of the patients required plasmapheresis. The number of relapses is consistent with pivotal studies. In ASCLEPIOS I, 90 out of 454 (19%) treatment-naive patients suffered relapses in a 30-month observation period. Similarly, in ASCLEPIOS II, 95 out of 469 (20%) treatment-naive patients suffered relapses in a 30-month observation period [11]. However, it must be emphasized that comparing these studies is difficult, as they were conducted under strictly standardized conditions. Due to the small number of cases, an analysis of relapse events and risk factors was here not conducted [14]. Nevertheless, none of the 81 patients discontinued therapy, highlighting the high level of acceptance of the drug among both patients and treating physicians.

After a median of 10 months under treatment with ofatumumab, patients report a very positive subjective perception of their disease and a subjective improvement in their quality of life. Ofatumumab seems to have a high rate of side effects after the first injection, but these are subjectively mild and late side effects are rarely reported. We assume that side effects are particularly high after the first injection due to a rapid cytokine release. The same mechanism leads to the necessity of administration of methylprednisolone and antihistamines prior to infusion of ocrelizumab [15]. Of note, the side effect profile of the longitudinally observed patients changed surprisingly during the observation period. Headaches and aching limbs increased significantly compared to the late side effects at baseline and were mostly of minor intensity. We suspect that patients received a recurrent increase in inflammatory cytokine profile through ofatumumab, which may trigger the adverse effects. Experiments and further studies are needed to proof this hypothesis. Another explanation is that multiple injections of ofatumumab may induce an increased psychological sensitivity to new side effects, which may then be perceived as more severe. A number of studies have been conducted which examine the relationship between anxiety and self-injection [16]. However, further research is required to determine how and to what extent anxiety can manifest itself, and whether this can have an impact on attention to side effects.

As demonstrated in our previous study [12], our cohort is mildly affected with a median EDSS of 2. This EDSS stability is also evident in terms of fatigue. Our patients report high global fatigue (median: 63) and psychological burden in the MSIS-29 (median: 36.11), but do not accelerate disease progression. In addition, Timed 25-Foot Walk Test as well as 9-hole peg test and BDI show disease stability in our cohort.

While DMT is not expected to improve the course of the disease, our patients report some positive effects. As expected, our cohort had a lower disease-related quality of life compared to the normal German population in the SF-36 at BL. In the follow up evaluation, no significant alterations were observed in the SF-36. The subjective assessment of quality of life, however, revealed a “very positive” effect of ofatumumab. The discrepancy between these findings could be since the SF-36 does not assess disease-specific quality of life. Moreover, the scientific analysis of subjective experience reports is particularly challenging and therefore must be interpreted with caution. Subjective evaluations of walking distance (p < 0.001), concentration (p < 0.001), mood (p = 0.010), fatigue (p < 0.001) and disease course (p < 0.001) depicted significant improvements between baseline and follow-up. We suggest that these, positive effects are mainly due to the form of administration and the knowledge that a highly effective substance is being received. Although some patients have previously undergone highly effective therapy, the positive perception may be influenced by the ease of use and the patients’ sense of self-determination and self-efficacy.

A study conducted in Canada demonstrated that ofatumumab is significantly more cost-effective than other DMTs approved for RRMS in Canada [17]. The simple and accessible route of administration of ofatumumab enables a high degree of autonomy and independence from hospitalization and long stays in infusion clinics compared to other immunotherapies. Additionally, the subcutaneous administration method enhances patient convenience and adherence, thereby facilitating earlier initiation of treatment [18].

Our study has some limitations. Patients were not included in the study right from the start when they initiated ofatumumab. Therefore, not all patients took the drug for the same duration, making it challenging to compare its benefits and drawbacks and making PROs more difficult to interpret. The subjective questionnaires were not validated and therefore should be interpreted with caution. Furthermore, we employed a modified shorter version of the MSFC, in which neither the PASAT nor its alternative, the SDMT, were utilized. There were 20 dropouts from baseline to follow-up. This means that relapse rates and adherence to treatment can only be assessed to a limited extent. The proportion of patients who were recorded in our structured and exploratory study, especially at follow-up, could be further increased. It is possible that a center effect exists within this cohort.

Conclusion

Patients reacted positively to the drug, with both good tolerance and acceptance rates. However, after a median of 10 months on ofatumumab, especially late side effects are significantly more common than at baseline, when patients were on ofatumumab for a median of 4 months. Headache and limb pain have increased significantly. Nevertheless, there have been no instances of treatment discontinuation due to side effects or relapse symptoms. In our opinion, the question of long-term tolerability has not yet been conclusively resolved. Further observations are needed to demonstrate the long-term therapeutic effects of administering ofatumumab for more than one year and the mechanisms underlying adverse effects.

Supplementary Information

Below is the link to the electronic supplementary material.Supplementary file1 (PNG 1772 KB)

Supplementary file2 (PNG 2726 KB)

Supplementary file3 (PNG 3944 KB)

Supplementary file4 (PNG 2439 KB)

Funding

Open Access funding enabled and organized by Projekt DEAL.

Data availability

The data collected for this study can be requested upon reasonable request.

Declarations

Conflicts of interest

Anna-Sophia Karl: none. Rafael Klimas: received travel support from Takeda, Grifols, Ruhr-University Bochum and research support by Ruhr-University Bochum, and LFB Group France; none related to this manuscript. Melina Katsimpoura: none. Philip Lennart Poser: none. Simon Theile-Ochel: none. Melissa Sgodzai: none. Barbara Gisevius: none. Simon Faissner: has received speaker’s and/or scientific board honoraria and/or congress travel support from Academy2, AstraZeneca, Biogen, BMS, Celgene, Genesis Pharma, Hexal, Janssen, Merck, Neuraxpharm, Novartis and Roche and grant support from Ruhr-University Bochum, German Research Foundation (DFG), DMSG, DMSG North-Rhine-Westfalia, Stiftung für therapeutische Forschung, Lead Discovery Center GmbH and Novartis; none related to this manuscript. Anke Salmen: received speaker honoraria for activities with Bristol Myers Squibb, CSL Behring, Novartis, and Roche, and research support by the Baasch Medicus Foundation, the Medical Faculty of the University of Bern, the Swiss MS Society and the regional association of North Rhine-Westphalia of the German MS Society (DMSG Landesverband NRW). Ralf Gold: serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, and Novartis; has received speaker honoraria from Biogen Idec, Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma, and Novartis; serves as editor for Therapeutic Advances in Neurological Diseases and on the editorial boards of Experimental Neurology and the Journal of Neuroimmunology; and receives research support from Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, Genzyme, Merck Serono, and Novartis, none related to this manuscript. Jeremias Motte: received speaker honoraria for activities with Alnylam, Biogen Idec, travel grants from Biogen Idec, Novartis AG, Teva, and Eisai GmbH; and his research is supported by Biogen Idec, Novartis AG, Kyverna Therapeutics Inc., GBS/CIDP Foundation International, Klaus TschiraFoundation, Hertie Foundation and Ruhr-University, Bochum, regional association of North Rhine-Westphalia of the German MS Society (DMSG Landesverband NRW); none related to this manuscript.

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki of 1975 and approved by the local ethics committee of the Ruhr University Bochum (20-6827).

Anna-Sophia Karl, Rafael Klimas, Ralf Gold and Jeremias Motte contributed equally.
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References

1. Lublin FD Häring DA Ganjgahi H Ocampo A Hatami F Čuklina J Aarden P Dahlke F Arnold DL Wiendl H Chitnis T Nichols TE How patients with multiple sclerosis acquire disability Brain 2022 145 3147 3161 10.1093/brain/awac016 35104840
Lublin FD, Häring DA, Ganjgahi H, Ocampo A, Hatami F, Čuklina J, Aarden P, Dahlke F, Arnold DL, Wiendl H, Chitnis T, Nichols TE et al (2022) How patients with multiple sclerosis acquire disability. Brain 145:3147–316135104840 10.1093/brain/awac016
2. Kavaliunas A Manouchehrinia A Stawiarz L Ramanujam R Agholme J Hedström AK Beiki O Glaser A Hillert J Importance of early treatment initiation in the clinical course of multiple sclerosis Mult Scler 2017 23 1233 1240 10.1177/1352458516675039 27754943
Kavaliunas A, Manouchehrinia A, Stawiarz L, Ramanujam R, Agholme J, Hedström AK, Beiki O, Glaser A, Hillert J (2017) Importance of early treatment initiation in the clinical course of multiple sclerosis. Mult Scler 23:1233–124027754943 10.1177/1352458516675039
3. Chalmer TA Baggesen LM Nørgaard M Koch-Henriksen N Magyari M Sorensen PS Early versus later treatment start in multiple sclerosis: a register-based cohort study Eur J Neurol 2018 25 1262 e110 10.1111/ene.13692 29847005
Chalmer TA, Baggesen LM, Nørgaard M, Koch-Henriksen N, Magyari M, Sorensen PS (2018) Early versus later treatment start in multiple sclerosis: a register-based cohort study. Eur J Neurol 25:1262-e11029847005 10.1111/ene.13692
4. He A Merkel B Brown JWL Zhovits Ryerson L Kister I Malpas CB Sharmin S Horakova D Kubala Havrdova E Spelman T Izquierdo G Eichau S Timing of high-efficacy therapy for multiple sclerosis: a retrospective observational cohort study Lancet Neurol 2020 19 307 316 10.1016/S1474-4422(20)30067-3 32199096
He A, Merkel B, Brown JWL, Zhovits Ryerson L, Kister I, Malpas CB, Sharmin S, Horakova D, Kubala Havrdova E, Spelman T, Izquierdo G, Eichau S et al (2020) Timing of high-efficacy therapy for multiple sclerosis: a retrospective observational cohort study. Lancet Neurol 19:307–31632199096 10.1016/S1474-4422(20)30067-3
5. Delgado SR Faissner S Linker RA Rammohan K Key characteristics of anti-CD20 monoclonal antibodies and clinical implications for multiple sclerosis treatment J Neurol 2024 271 1515 1535 10.1007/s00415-023-12007-3 37906325
Delgado SR, Faissner S, Linker RA, Rammohan K (2024) Key characteristics of anti-CD20 monoclonal antibodies and clinical implications for multiple sclerosis treatment. J Neurol 271:1515–153537906325 10.1007/s00415-023-12007-3
6. Montalban X Hauser SL Kappos L Arnold DL Bar-Or A Comi G de Seze J Giovannoni G Hartung H-P Hemmer B Lublin F Rammohan KW Ocrelizumab versus placebo in primary progressive multiple sclerosis N Engl J Med 2017 376 209 220 10.1056/NEJMoa1606468 28002688
Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, de Seze J, Giovannoni G, Hartung H-P, Hemmer B, Lublin F, Rammohan KW et al (2017) Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 376:209–22028002688 10.1056/NEJMoa1606468
7. Hauser SL Waubant E Arnold DL Vollmer T Antel J Fox RJ Bar-Or A Panzara M Sarkar N Agarwal S Langer-Gould A Smith CH B-cell depletion with rituximab in relapsing-remitting multiple sclerosis N Engl J Med 2008 358 676 688 10.1056/NEJMoa0706383 18272891
Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, Bar-Or A, Panzara M, Sarkar N, Agarwal S, Langer-Gould A, Smith CH (2008) B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 358:676–68818272891 10.1056/NEJMoa0706383
8. Faissner S Plemel JR Gold R Yong VW Progressive multiple sclerosis: from pathophysiology to therapeutic strategies Nat Rev Drug Discov 2019 18 905 922 10.1038/s41573-019-0035-2 31399729
Faissner S, Plemel JR, Gold R, Yong VW (2019) Progressive multiple sclerosis: from pathophysiology to therapeutic strategies. Nat Rev Drug Discov 18:905–92231399729 10.1038/s41573-019-0035-2
9. Bar-Or A Wiendl H Montalban X Alvarez E Davydovskaya M Delgado SR Evdoshenko EP Giedraitiene N Gross-Paju K Haldre S Herrman CE Izquierdo G Rapid and sustained B-cell depletion with subcutaneous ofatumumab in relapsing multiple sclerosis: APLIOS, a randomized phase-2 study Mult Scler 2022 28 910 924 10.1177/13524585211044479 34605319
Bar-Or A, Wiendl H, Montalban X, Alvarez E, Davydovskaya M, Delgado SR, Evdoshenko EP, Giedraitiene N, Gross-Paju K, Haldre S, Herrman CE, Izquierdo G et al (2022) Rapid and sustained B-cell depletion with subcutaneous ofatumumab in relapsing multiple sclerosis: APLIOS, a randomized phase-2 study. Mult Scler 28:910–92434605319 10.1177/13524585211044479
10. Spelman T Magyari M Piehl F Svenningsson A Rasmussen PV Kant M Sellebjerg F Joensen H Hillert J Lycke J Treatment escalation vs immediate initiation of highly effective treatment for patients with relapsing-remitting multiple sclerosis: data from 2 different national strategies JAMA Neurol 2021 78 1197 1204 10.1001/jamaneurol.2021.2738 34398221
Spelman T, Magyari M, Piehl F, Svenningsson A, Rasmussen PV, Kant M, Sellebjerg F, Joensen H, Hillert J, Lycke J (2021) Treatment escalation vs immediate initiation of highly effective treatment for patients with relapsing-remitting multiple sclerosis: data from 2 different national strategies. JAMA Neurol 78:1197–120434398221 10.1001/jamaneurol.2021.2738
11. Hauser SL Bar-Or A Cohen JA Comi G Correale J Coyle PK Cross AH de Seze J Leppert D Montalban X Selmaj K Wiendl H Ofatumumab versus teriflunomide in multiple sclerosis N Engl J Med 2020 383 546 557 10.1056/NEJMoa1917246 32757523
Hauser SL, Bar-Or A, Cohen JA, Comi G, Correale J, Coyle PK, Cross AH, de Seze J, Leppert D, Montalban X, Selmaj K, Wiendl H et al (2020) Ofatumumab versus teriflunomide in multiple sclerosis. N Engl J Med 383:546–55732757523 10.1056/NEJMoa1917246
12. Klimas R Karl A-S Poser PL Sgodzai M Theile-Ochel S Gisevius B Faissner S Nastos I Gold R Motte J Over one year of B-cell targeted therapy with Ofatumumab s.c.: first results of a prospective, patient-centered real-world observational study Nervenarzt 2023 94 923 933 10.1007/s00115-023-01470-y 37042954
Klimas R, Karl A-S, Poser PL, Sgodzai M, Theile-Ochel S, Gisevius B, Faissner S, Nastos I, Gold R, Motte J (2023) Over one year of B-cell targeted therapy with Ofatumumab s.c.: first results of a prospective, patient-centered real-world observational study. Nervenarzt 94:923–93337042954 10.1007/s00115-023-01470-y
13. Ellert U Kurth B-M Methodische Betrachtungen zu den Summenscores des SF-36 anhand der erwachsenen bundesdeutschen Bevölkerung Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2004 47 1027 1032 10.1007/s00103-004-0933-1 15549195
Ellert U, Kurth B-M (2004) Methodische Betrachtungen zu den Summenscores des SF-36 anhand der erwachsenen bundesdeutschen Bevölkerung. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 47:1027–103215549195 10.1007/s00103-004-0933-1
14. Moons KGM de Groot JAH Bouwmeester W Vergouwe Y Mallett S Altman DG Reitsma JB Collins GS Critical appraisal and data extraction for systematic reviews of prediction modelling studies: the CHARMS checklist PLoS Med 2014 11 e1001744 10.1371/journal.pmed.1001744 25314315
Moons KGM, de Groot JAH, Bouwmeester W, Vergouwe Y, Mallett S, Altman DG, Reitsma JB, Collins GS (2014) Critical appraisal and data extraction for systematic reviews of prediction modelling studies: the CHARMS checklist. PLoS Med 11:e100174425314315 10.1371/journal.pmed.1001744
15. Hauser SL Bar-Or A Comi G Giovannoni G Hartung H-P Hemmer B Lublin F Montalban X Rammohan KW Selmaj K Traboulsee A Wolinsky JS Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis N Engl J Med 2017 376 221 234 10.1056/NEJMoa1601277 28002679
Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung H-P, Hemmer B, Lublin F, Montalban X, Rammohan KW, Selmaj K, Traboulsee A, Wolinsky JS et al (2017) Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 376:221–23428002679 10.1056/NEJMoa1601277
16. Mohr DC Boudewyn AC Likosky W Levine E Goodkin DE Injectable medication for the treatment of multiple sclerosis: the influence of self-efficacy expectations and injection anxiety on adherence and ability to self-inject Ann Behav Med 2001 23 125 132 10.1207/S15324796ABM2302_7 11394554
Mohr DC, Boudewyn AC, Likosky W, Levine E, Goodkin DE (2001) Injectable medication for the treatment of multiple sclerosis: the influence of self-efficacy expectations and injection anxiety on adherence and ability to self-inject. Ann Behav Med 23:125–13211394554 10.1207/S15324796ABM2302_7
17. Bhan V Clift F Baharnoori M Thomas K Patel BP Blanchette F Adlard N Vudumula U Gudala K Dutta N Grima D Mouallif S Cost-consequence analysis of ofatumumab for the treatment of relapsing-remitting multiple sclerosis in Canada J Comp Eff Res 2023 12 e220175 10.57264/cer-2022-0175 37606897
Bhan V, Clift F, Baharnoori M, Thomas K, Patel BP, Blanchette F, Adlard N, Vudumula U, Gudala K, Dutta N, Grima D, Mouallif S et al (2023) Cost-consequence analysis of ofatumumab for the treatment of relapsing-remitting multiple sclerosis in Canada. J Comp Eff Res 12:e22017537606897 10.57264/cer-2022-0175
18. Gold R Schmidt S Deisenhammer F Motte J Richter N Taipale K Salmen HC Bohland C Schirduan K Real-world evidence and patient preference for subcutaneous versus intravenous natalizumab in the treatment of relapsing-remitting multiple sclerosis - initial results from the observational SISTER study Ther Adv Neurol Disord 2024 17 17562864241241382 10.1177/17562864241241382 38616781
Gold R, Schmidt S, Deisenhammer F, Motte J, Richter N, Taipale K, Salmen HC, Bohland C, Schirduan K (2024) Real-world evidence and patient preference for subcutaneous versus intravenous natalizumab in the treatment of relapsing-remitting multiple sclerosis - initial results from the observational SISTER study. Ther Adv Neurol Disord 17:1756286424124138238616781 10.1177/17562864241241382
