Abstract
Pediatric-onset multiple sclerosis (POMS), accounting for ~5% of all MS cases, is a chronic immune-mediated demyelinating disorder of the central nervous system. Relapse prevention remains a challenge, and B cells play a central role in the pathogenesis. Ofatumumab (OFA), a fully human anti-CD20 monoclonal antibody, is approved for adult MS. To assess the safety and efficacy of off-label OFA use in pediatric MS patients. We retrospectively analyzed clinical data from four pediatric patients with MS who received OFA. Retrospective case series. Four pediatric MS patients received OFA as disease-modifying treatment at ages ranging from 9.7 to 12.8 years for durations between 6 and 20 months. Three patients received OFA treatment for uncontrolled relapses, while one switched from rituximab. After the initial treatment phase of OFA, B-cell depletion was achieved in three patients, and this depletion was not consistently maintained throughout the maintenance phase. All patients remained relapse-free, with no new or enlarging T2 lesions or contrast-enhancing lesions observed on MRI or EDSS progression. The annual relapse rate after OFA treatment decreased compared with that before OFA treatment. One patient reported mild adverse events, including transient fever and atopic dermatitis, all of which were manageable. Ofatumumab showed favorable tolerability and potential benefit in this small pediatric MS cohort. Its subcutaneous administration offers practical advantages. While these findings suggest feasibility, the limited evidence precludes clinical recommendation at this stage. Larger prospective studies are warranted.
Plain language summary
Multiple sclerosis (MS) is a disease in which the immune system attacks the brain and spinal cord. It is rare in children, and treating it can be difficult. Ofatumumab is a medicine that works by targeting a part of the immune system and is currently approved for use in adults with MS. In this study, we looked at how four children with MS responded to this treatment. The children were between 9 and 13 years old. After starting the medicine, all four children had no further relapses, and their brain scans showed no signs of the disease getting worse. One child had mild side effects, which were easily managed. These early results suggest that ofatumumab may be a helpful treatment option for children with MS, but more research is needed to confirm this.
Introduction
Multiple sclerosis (MS) is a chronic immune-mediated disease that affects the central nervous system and leads to both inflammatory demyelination and neuronal degeneration. When MS develops before the age of 18, it is referred to as pediatric-onset MS (POMS), which accounts for an estimated 5% of all MS diagnoses. 1 Compared to adults, children with MS often present with a higher frequency of relapses, multifocal symptoms at onset, and a more pronounced inflammatory burden early in the disease course, although they typically experience better short-term recovery.1,2 Early initiation of disease-modifying treatment (DMT) is strongly advocated to prevent relapses and to limit long-term disability accumulation.
B cells are increasingly recognized as central contributors to MS pathogenesis. Their roles extend beyond antibody production to include antigen presentation to T cells, cytokine secretion, and orchestration of inflammatory responses. 3 Consequently, B-cell depletion therapies have demonstrated significant efficacy in altering disease activity in MS. 4 Recent evidence supports the efficacy of B-cell-depleting monoclonal antibodies in POMS. A systematic review of 12 rituximab (RTX) studies (n = 328) and 6 ocrelizumab studies (n = 106) demonstrated reduced relapse rates and magnetic resonance imaging (MRI) activity, with many patients achieving no evidence of disease activity, particularly in highly active cases. 5 Although used off-label, both agents are administered intravenously and are associated primarily with infusion-related reactions and infections. In adults, ocrelizumab-related AEs occur in 60.3% of patients, while SAEs remain uncommon (7%); RTX has a slightly higher SAE rate than placebo (16.4% vs 13.6%). 5 However, long-term safety data in children are limited. A recent review highlighted the efficacy of multiple DMTs in POMS and emphasized the need for robust pediatric trials. 6 Among nine ongoing studies, the phase III NEOS trial (NCT04926818) evaluating ofatumumab (OFA) in pediatric MS is expected to generate pivotal evidence supporting its clinical application in this population.
OFA is a fully human IgG1 monoclonal antibody that targets the CD20 antigen on B cells. It exerts its therapeutic effects by inducing potent B-cell depletion through both complement activation and antibody-dependent cellular cytotoxicity. 7 Unlike other anti-CD20 monoclonal antibodies, which are delivered via intravenous infusion, OFA is administered subcutaneously, enabling direct lymphatic distribution and potentially offering improved tolerability.8,9
OFA is currently approved for the treatment of relapsing MS in adults. However, its use in pediatric MS has not been systematically studied, and no published data are available in this population. In our previous clinical experience, OFA demonstrated therapeutic benefit in children with anti-NMDAR encephalitis who failed to respond to first-line immunotherapy. 10 Building upon these findings, the present study aims to evaluate the safety and efficacy of OFA in pediatric patients diagnosed with MS.
Subjects and methods
Study design
This retrospective case series was conducted at a tertiary children’s neurology center in Guangzhou to evaluate the safety and efficacy of off-label OFA use in pediatric MS patients. Expanded Disability Status Scale (EDSS) scores were extracted from medical records, based on assessments conducted by pediatric neurologists at baseline (prior to OFA initiation), during clinical relapses, and at follow-up visits approximately every 6 months. Relapse was defined as a monophasic clinical episode with patient-reported symptoms and objective findings typical of multiple sclerosis, reflecting a focal or multifocal inflammatory demyelinating event in the central nervous system, lasting at least 24 h, in the absence of fever or infection, consistent with the 2017 McDonald diagnostic criteria. 11 Asymptomatic MRI activity is defined as new or unequivocally enlarging T2-hyperintense lesions and/or new contrast-enhancing lesions, irrespective of clinical symptoms. 12
Study population
This study was designed as a retrospective case series. It included pediatric patients (age < 18 years) diagnosed with MS who received OFA treatment at a tertiary children’s neurology center in Guangzhou between January 2023 and July 2024. Patients with positive serum anti-aquaporin-4 (AQP4) or anti-myelin oligodendrocyte glycoprotein (MOG) antibodies were excluded to rule out neuromyelitis optica spectrum disorder or MOG antibody-associated disease. All patients had at least 6 months of follow-up.
Methods
Diagnostic criteria
Diagnosis of pediatric MS was established based on the revised International Pediatric Multiple Sclerosis Study Group (IPMSSG) criteria. 13 B-cell depletion was defined as a CD19+ B-cell count in peripheral blood of fewer than 10 cells/μl. 14
Treatment protocol
OFA was administered following the adult MS regimen: an initial loading phase of 20 mg subcutaneously on day 0, and at weeks 1, 2, and 4, followed by maintenance dosing every 4 weeks thereafter. 15
Antibody testing
MOG IgG and AQP4 IgG in serum were detected by the fixed cell-based assay commercial kit (Shanxi Maiyuan Biotechnology Co., Ltd, Shanxi, China). These methods had been reported in detail in our previous study. 16
Measurement of CD19+ B cell counts
Peripheral blood CD19+ B-cell counts were measured by flow cytometry using the BD Multitest IMK kit (catalog number 340503; BD Biosciences, CA, USA). The analysis was performed in the clinical laboratory of our hospital. This method has been described in detail in their previous study. 16
Follow-up procedures
Patients were monitored either through outpatient neurological consultations or via structured telephone interviews conducted by neurologists. Clinical status, laboratory findings, and MRI evaluations were documented.
Results
OFA was administered to four pediatric patients with MS, designated as Cases 1–4 for clarity of presentation.
Case 1 (female, onset at 7.1 years; initial presentation with progressive right-sided limb weakness for 3 days, followed by dysarthria, sialorrhea, and dysphagia for 1 day): Following symptom onset, the patient was admitted to our hospital. She had no significant past medical history or family history of neurological or autoimmune disorders. Her general development was age-appropriate prior to disease onset. Cerebrospinal fluid (CSF) analysis revealed normal white blood cell (WBC) and protein levels. CSF polymerase chain reaction (PCR) testing was negative for enterovirus, influenza A/B, herpes simplex virus (HSV), Epstein–Barr virus (EBV), and cytomegalovirus (CMV). Both CSF and serum oligoclonal bands (OCBs) were negative. Brain MRI revealed multiple T2-weighted hyperintense lesions involving the subcortical white matter of the left frontal, parietal, and occipital lobes, as well as the bilateral posterior limbs of the internal capsules. Some lesions demonstrated gadolinium enhancement on T1-weighted imaging. Spinal MRI showed a T2-hyperintense lesion at the T10 level without contrast enhancement. Orbital MRI and brain magnetic resonance angiography were unremarkable. Serum AQP4 and MOG antibody tests were negative. She was treated with intravenous methylprednisolone (IVMP, 15 mg/kg/day for 3 days, followed by oral prednisone) combined with intravenous immunoglobulin (IVIG, total dose 2 g/kg over 3 days). Her symptoms improved, and follow-up MRI revealed partial lesion resolution. At 5 months following disease onset, the patient experienced a relapse, manifesting as hand tremor, accompanied by new T2-hyperintense lesions in the left pons and right periventricular white matter on MRI. IVMP and IVIG were administered. At 7 months after onset, routine MRI surveillance revealed asymptomatic MRI activity, with new T2-hyperintense lesions observed in the subcortical white matter of the left frontal lobe. A diagnosis of POMS was made at that time. She was again treated with IVMP and IVIG, but DMT was not initiated due to parental refusal. At 15 months after onset, the patient experienced a relapse, manifesting as a headache, accompanied by new T2-hyperintense lesions in the right centrum semiovale and deep white matter of the right frontal lobe. She was subsequently started on mycophenolate mofetil and maintenance IVIG as DMT. However, at 18 months post-onset, routine MRI surveillance revealed asymptomatic MRI activity, with new T2-hyperintense lesions in the subcortical white matter of the right frontal and occipital lobes. RTX treatment was then initiated, after which no further relapses were observed. Eight months later, she began receiving OFA treatment at 9.7 years of age, primarily due to its subcutaneous route of administration. By the last follow-up, she had been on OFA treatment for 20 months and remained relapse-free with an annualized relapse rate (ARR) reduced from 0.8 to 0.0. MRI scans were performed at 6 months and 1 year after OFA treatment, showing no new or enlarging T2 lesions or contrast-enhancing lesions compared to pretreatment baseline scans. There was no change in the EDSS score, which remained at 1 before and after OFA treatment (Figure 1 and Table 1). After the initial treatment phase of OFA, B-cell depletion was achieved, with CD19+ B cells in peripheral blood at 2.75 cells/μl. However, during the maintenance phase, B-cell depletion was not consistently maintained (CD19+ B cells ranged from 15.00 to 112.94 cells/μl), except at the 18th month, when CD19+ B cells were 6.00 cells/μl.
Disease course and treatment regimen before and after the initiation of ofatumumab (time 0) in patients with Multiple Sclerosis.
Characteristics of the patients.
ARR, annualized relapse rate; EDSS, Expanded Disability Status Scale; IVIG, intravenous immunoglobulin; MMF, mycophenolate mofetil; MRI, magnetic resonance image; OFA, ofatumumab; RTX, rituximab.
Case 2 (male, onset at 10.4 years old; initial presentation with left eye movement limitation for 2 days): Following symptom onset, the patient was admitted to our hospital. He had no significant past medical history or family history of neurological or autoimmune disorders. His general development was age-appropriate prior to disease onset. CSF analysis revealed normal WBC and protein levels. CSF PCR testing was negative for enterovirus, influenza A/B, HSV, EBV, and CMV. CSF-specific OCBs were detected, consistent with a type 2 pattern. Brain MRI revealed T2-hyperintense lesions in the bilateral centrum semiovale and periventricular white matter adjacent to the posterior horns of the lateral ventricles, oriented perpendicular to the ventricular surface. One left-sided lesion exhibited open-ring enhancement on post-contrast T1-weighted imaging. Spinal and orbital MRI findings were unremarkable. Serum AQP4 and MOG antibodies were negative. The patient received IVMP (15 mg/kg/day for 3 days, followed by oral prednisone) combined with IVIG (total 2 g/kg over 3 days). His symptoms improved, and follow-up MRI revealed partial lesion resolution. At 8 months after onset, the patient experienced a relapse, manifesting as headache and hand tremor, accompanied by new T2-hyperintense lesions observed in the periventricular regions of the bilateral lateral ventricles, bilateral centrum semiovale, and the right cerebellar dentate nucleus. A diagnosis of POMS was made at that time. However, no DMT was initiated due to parental refusal. Two years later, routine MRI surveillance revealed asymptomatic MRI activity, with new T2-hyperintense lesions identified in the bilateral periventricular white matter. At that time, he started receiving OFA treatment at 12.8 years of age. The disease duration was 2.4 years before starting OFA treatment. The duration of OFA treatment was 16 months at the last follow-up. The patient remained relapse-free with his ARR reduced from 0.4 to 0.0. MRI scans were performed at 6 months and 1 year after OFA treatment, showing no new or enlarging T2 lesions or contrast-enhancing lesions compared to pretreatment baseline scans. There was no change in the EDSS score, which remained at 0 before and after OFA treatment (Figure 1 and Table 1). After the initial treatment phase of OFA, B-cell depletion was achieved, with CD19+ B cells in peripheral blood at 5.00 cells/μl, but during the maintenance phase, B-cell depletion was not consistently maintained with CD19+ B cells ranging from 15.00 to 27.13 cells/μl.
Case 3 (male, onset at 8.0 years, initial presentation with fever lasting 16 days, followed by headache for 10 days): The patient was referred to our hospital after initial management at a local facility. He had no significant past medical history or family history of neurological or autoimmune disorders. His general development was age-appropriate prior to disease onset. CSF analysis revealed normal WBC and protein levels. CSF PCR testing was negative for enterovirus, influenza A/B, HSV, EBV, and CMV. CSF-specific OCBs were detected, consistent with a type 2 pattern. Brain MRI revealed multiple T2-hyperintense lesions in the left basal ganglia region accompanied by focal meningeal thickening and enhancement. Spinal and orbital MRI findings were unremarkable. Serum AQP4 and MOG antibodies were negative. The patient received IVMP (20 mg/kg/day for 3 days, followed by oral prednisone) combined with IVIG (total dose 2 g/kg over 3 days). His symptoms improved, and follow-up MRI revealed partial lesion resolution. At 8 months after onset, he experienced a clinical relapse, presenting with hand tremor and unsteady movements. Brain MRI revealed new T2-hyperintense lesions involving the bilateral basal ganglia, dorsal thalami, cerebral peduncles, and both cortical and subcortical regions of the frontal and parietal lobes. Some of these lesions showed gadolinium enhancement. POMS was diagnosed at that time, and RTX was initiated as DMT. At 23 months post-onset, routine MRI surveillance revealed asymptomatic MRI activity, with new T2-hyperintense lesions in the subcortical white matter of the bilateral frontal and parietal lobes. He received IVMP treatment. At 26 months after onset, he experienced a relapse, presenting with bilateral visual impairment. Brain MRI revealed mildly increased focal enhancement of the bilateral optic nerves. Repeat testing for serum AQP4 and MOG antibodies remained negative. He was started on fingolimod as DMT, but continued to relapse despite treatment. At 48 months after onset, routine MRI surveillance revealed asymptomatic MRI activity, with new T2-hyperintense lesions in the periventricular regions of the bilateral lateral ventricles, bilateral centrum semiovale, and the right cerebellar dentate nucleus. At 51 months, routine MRI surveillance revealed asymptomatic MRI activity, with new T2-hyperintense lesions in the periventricular white matter adjacent to the body of the lateral ventricles. Then he started to receive OFA treatment at 12.4 years. The disease duration was 4.4 years before starting OFA. The OFA treatment lasted 8 months by the last follow-up, during which the patient remained relapse-free and his ARR reduced from 0.5 to 0.0. An MRI scan was performed at 6 months after OFA treatment, showing no new or enlarging T2 lesions or contrast-enhancing lesions compared to pretreatment baseline scans. There was no change in the EDSS score, which remained at 1 before and after OFA treatment (Figure 1 and Table 1). Following the initial loading phase of OFA, peripheral CD19+ B-cell counts remained detectable at 19.37 cells/μL, indicating incomplete depletion. Full B-cell clearance was observed by month six, at which point CD19+ cells had declined to 0.00 cells/μL.
Case 4 (male, onset at 11.1 years, initial presentation with right-sided limb weakness and slurred speech for 2 days): Following symptom onset, the patient was admitted to our hospital. He had no significant past medical history or family history of neurological or autoimmune disorders. His general development was age-appropriate prior to disease onset. CSF analysis revealed normal WBC and protein levels. CSF PCR testing was negative for enterovirus, influenza A/B, HSV, EBV, and CMV. Brain MRI revealed multiple T2-hyperintense lesions in the left basal ganglia, posterior limb of the internal capsule, corona radiata, and centrum semiovale. Brain magnetic resonance angiography findings were unremarkable. The patient received IVMP (20 mg/kg/day for 3 days, followed by oral prednisone) combined with IVIG (total dose 2 g/kg over 3 days). His symptoms improved, and follow-up MRI revealed partial lesion resolution. At 16 months after onset, the patient experienced a relapse, manifesting as left-sided limb weakness, accompanied by new T2-hyperintense lesions in the right frontal lobe and right basal ganglia. CSF-specific OCBs were detected, consistent with a type 2 pattern. Serum AQP4 and MOG antibodies remained negative. The patient was diagnosed with MS after his first relapse. He then started receiving OFA as DMT. His disease duration was 1.4 years before starting OFA at 12.5 years. The duration of OFA treatment was 6 months at the last follow-up, and he remained relapse-free, with the ARR reduced from 0.7 to 0.0. An MRI scan was performed at 6 months after OFA treatment, showing no new or enlarging T2 lesions or contrast-enhancing lesions compared to pretreatment baseline scans. There was no change in the EDSS score, which remained at 0 before and after OFA treatment (Figure 1 and Table 1). After the initial treatment phase of OFA, B-cell depletion was achieved, with CD19+ B cells in peripheral blood at 0.00 cells/μl. However, during the maintenance phase, B-cell depletion was not consistently maintained, with CD19+ B cells increasing to 152.00 cells/μl at the 6th month of OFA treatment.
In summary, four MS patients (one female and three males) received OFA treatment as DMT at ages ranging from 9.7 to 12.8 years for a duration of 6 to 20 months. Three patients received OFA treatment for uncontrolled disease activity—two due to asymptomatic MRI activity and one due to a clinical relapse—while one patient switched from RTX due to the convenience of subcutaneous OFA administration. After the initial treatment phase of OFA, B-cell depletion was achieved in three patients, and this depletion was not consistently maintained throughout the maintenance phase (details shown in Figure 2). All patients remained relapse-free, with no new or enlarging T2 lesions or contrast-enhancing lesions observed on MRI or in EDSS scores. Following initiation of OFA, the ARR at the last follow-up decreased compared to the pretreatment period (more details seen in Figure 1).
Peripheral blood CD19+ B-cell counts in four pediatric MS patients following ofatumumab treatment. CD19+ B-cell levels were measured at baseline and during follow-up. Blue arrows indicate the timing of ofatumumab administration, including loading and maintenance doses. The dashed horizontal line denotes the threshold for B-cell depletion (CD19+ <10 cells/µL).
During OFA treatment, one patient reported adverse events. Case 2 experienced transient fever during the first OFA injection, followed by scalp itching, hair loss, and alopecia in the third week. A fungal smear cytological examination of dandruff showed no abnormalities, and the patient was diagnosed with atopic dermatitis. After receiving oral antihistamine and topical treatment with ketoconazole and mometasone ointment, the symptoms improved. Serum IgG and IgM levels were measured at baseline and during follow-up (Figure 3). IgG levels showed mild declines but remained within the normal range. In contrast, IgM levels decreased in all patients, with three individuals falling below the lower limit of normal (0.48 g/L). No infection or life-threatening injection-related reactions were reported.
Serum IgG and IgM levels in four pediatric MS patients receiving ofatumumab treatment. (a) Serum IgG levels were measured at baseline and during follow-up. (b) Serum IgM levels were measured at baseline and during follow-up. Blue arrows indicate the timing of ofatumumab administration, including both loading and maintenance doses. Dashed horizontal lines represent the lower limits of normal (IgG: 6.7 g/L; IgM: 0.48 g/L).
Discussion
In this retrospective case series, we reported the clinical application of OFA in four POMS patients. OFA was initiated due to either uncontrolled disease activity or treatment convenience. Over a follow-up period of 6–20 months, all patients remained relapse-free, with no new MRI lesions or EDSS progression. Although CD19+ B-cell depletion was initially achieved, sustained suppression was inconsistent during maintenance. OFA was generally well tolerated, with only one patient experiencing mild, self-limited adverse events.
For MS, early initiation of DMTs after disease onset is associated with a better long-term prognosis. Pediatric MS is characterized by highly active disease and high disease burden, therefore initiation of DMT should be considered for all children with MS. DMT for MS can be categorized into moderately effective therapies (i.e., dimethyl fumarate, glatiramer acetate, interferon beta, teriflunomide) and highly effective therapies (alemtuzumab, fingolimod, mitoxantrone, cladribine, natalizumab, ocrelizumab, OFA, RTX). 17 Historically, a stepwise escalation approach was commonly employed in pediatric MS. However, retrospective cohort studies published in 2024 found the early use of highly effective therapies as initial treatment in pediatric MS was associated with a reduced risk of first relapse, optimal outcomes within the first 2 years, fewer treatment switches, and better mid-term tolerability in children. As a result, the use of highly effective therapies as first-line treatment in pediatric MS is now increasingly being considered.
Despite therapeutic advances, the approval of DMT specifically for pediatric MS remains limited. To date, fingolimod is the only agent formally approved globally for pediatric use. In the European Union, teriflunomide and dimethyl fumarate have also been approved, with limited approval of interferon-beta and glatiramer acetate for children aged 12 years and older. However, among the highly effective therapies, only fingolimod has been formally approved for use in the pediatric population. Other highly effective therapies, such as RTX, ocrelizumab, and OFA, target CD20-expressing B cells and have demonstrated substantial efficacy in MS by reducing inflammatory activity. Historically, T-cell-mediated processes were thought to be the principal drivers of MS-related pathology, though mounting evidence over the past decade has shown that B-cell-related mechanisms (including interactions between B and T cells) are important.18,19 Therapies targeting CD20 have demonstrated efficacy in reducing clinical and MRI activity.5,20,21
RTX, a chimeric anti-CD20 monoclonal antibody given via intravenous infusion, has demonstrated therapeutic benefit in MS. However, it frequently causes infusion-related side effects, for which pretreatment is often necessary. Although phase II clinical studies of RTX exist in adult MS, evidence in pediatric MS remains largely observational. 22 A 2024 multicenter retrospective analysis involving pediatric MS indicated that RTX significantly lowered the annual relapse rate and reduced the occurrence of new T2 lesions. Notably, 70% of individuals achieved a status of disease inactivity. Despite these effects, adverse reactions occurred in 67% of participants, with infusion reactions being the most frequent (48%, 29 out of 60), and nearly 10% discontinued the therapy. 21
Ocrelizumab is a humanized anti-CD20 monoclonal antibody approved for adult patients with both relapsing and primary progressive MS.23,24 While its use in pediatric MS is still under investigation, a phase III trial (NCT05123703) is ongoing. 25 The standard dosing involves two intravenous infusions of 300 mg administered 2 weeks apart, followed by maintenance doses of 600 mg every 24 weeks, enabling reduced hospital visits. Observational data in pediatric MS suggest that ocrelizumab may lower brain lesion activity, reduce relapse frequency, and improve treatment adherence compared to fingolimod. 20 Initial infusion-related reactions were reported in 45% of patients, declining to 20% with subsequent doses, and were generally well tolerated. 20 Ocrelizumab was approved in mainland China on March 31, 2025, for adults.
OFA is a humanized anti-CD20 monoclonal antibody that became available on the Chinese market in December 2021. 7 It has been approved for treating adults with relapsing MS in the USA, Europe, and other countries. 26 The ASCLEPIOS I/II phase III trials demonstrated that patients treated with OFA had a significantly lower ARR compared to teriflunomide (0.11 vs 0.22), and better outcomes in terms of EDSS progression, MRI parameters, and serum neurofilament light chain levels. 15 In contrast, ocrelizumab, another anti-CD20 monoclonal antibody, was only approved in China in March 2025. Although a phase III trial of OFA in pediatric MS (NCT04926818) is still ongoing and no published data exist to date, our study offers preliminary evidence supporting the therapeutic potential of OFA in children. 25 Four pediatric MS patients in our cohort received OFA for 6–20 months—three due to uncontrolled relapses (two as initial DMT, one after relapse under RTX and fingolimod), and one switched from RTX to OFA for improved convenience. All patients remained relapse-free, with no new lesions on MRI and stable EDSS scores.
In our study, B-cell depletion after the OFA loading phase was achieved in three patients; however, CD19+ B-cell counts during the maintenance phase were not consistently suppressed below 10 cells/μL. Notably, three patients with follow-up beyond six months exhibited a pattern of initial increase followed by delayed decline in B-cell counts (Figure 2). Similar trends have been observed in adult ofatumumab trials: although 98.2% of patients achieved B-cell depletion by Week 12, the proportion of individuals with CD19+ B < 10 cells/μL showed mild fluctuations over time within each body-weight quartile, despite uniform dosing. 14 This suggests that B-cell suppression is not uniformly sustained, even in large cohorts. In addition, Dorcet et al. reported early B-cell repopulation in 8% of adult MS patients treated with RTX, particularly among younger individuals. 27 This transient fluctuation in our cases may reflect interindividual pharmacokinetic variability, the relative immaturity of the pediatric immune system, or feedback regulation following initial depletion. Given the small sample size of our study, such variations are not unexpected. While most patients in large trials achieve stable B-cell suppression, individual cases—especially in younger populations—may exhibit dynamic reconstitution patterns. Importantly, all four patients in our cohort remained relapse-free, with stable EDSS scores and no new MRI activity observed throughout the follow-up period. Similarly, Dorcet et al. reported that early B-cell repopulation in MS does not predict relapse or clinical progression. 27 Although CD19+ B-cell counts were not consistently suppressed in our cases, the absence of clinical and radiological disease activity may reflect the multifaceted immunological mechanisms underlying MS. Previous studies suggest that the therapeutic efficacy of anti-CD20 agents may extend beyond absolute B-cell depletion and involve modulation of B-cell subset composition as well as reduction of proinflammatory CD8+ T cells, which are also implicated in MS pathogenesis. 27 Although evidence in pediatric MS is limited, our findings may imply that disease control is possible under conditions of partial depletion, warranting further investigation.
Economic considerations are particularly relevant when selecting among anti-CD20 therapies. Based on a health-economic model from the Netherlands, OFA has a comparable or slightly higher acquisition cost than ocrelizumab in the first year (€23,434 vs €22,437), but lower maintenance costs thereafter (€20,086 vs €22,437). 28 In contrast, off-label RTX shows a markedly lower annual cost (€3,802 in the first year; €2535 subsequently). 28 To standardize comparisons, we considered pediatric patients with body weight ⩾35 kg, as the dosing strategies vary: RTX is body surface area-based, ocrelizumab is weight-based, and OFA uses a fixed dose. This approach avoids underestimating treatment costs due to weight-based dose reductions and reflects full-dose use scenarios. In China, first-year drug costs are approximately ¥90,000 for OFA, ¥200,000 for ocrelizumab, and ¥54,000 for RTX. Maintenance costs are lower: ¥72,000 (OFA), ¥120,000 (ocrelizumab), and ¥36,000 (RTX). Among the three anti-CD20 therapies, RTX incurs the lowest drug cost, and ocrelizumab the highest. OFA presents an intermediate cost profile, with lower expenses during the maintenance phase. Based on a health-economic model from the Netherlands, a comprehensive health-economic model comparing anti-CD20 therapies—including drug costs, relapse rates, disability progression, and quality-adjusted life years—showed no clear difference in cost-effectiveness between OFA and ocrelizumab. 28 Moreover, administration routes affect treatment burden: OFA is self-injected subcutaneously at home, while ocrelizumab and RTX require hospital-based intravenous infusions and premedication. These differences are especially important in pediatric patients, where frequent hospital visits may disrupt schooling. However, pediatric-specific cost-effectiveness data remain limited.
The most common adverse effect of OFA treatment was injection-related systemic reactions. In the APLIOS phase II trial, such reactions were reported in 32.0% of patients, most commonly after the first injection. 14 However, in the larger phase III ASCLEPIOS I/II trials, the incidence was lower, at 20.1%. 26 In our study, one patient experienced transient fever during the first OFA injection, followed by scalp itching, hair loss, and alopecia in the third week. All these adverse events were considered as injection-related system reactions and improved with symptomatic treatment. Serum IgG and IgM levels were monitored during OFA treatment. While serum IgG levels showed a slight decline, they remained within the normal range in all patients. In contrast, serum IgM levels decreased in all four patients, with three cases dropping below the lower limit of normal (0.48 g/L). These findings are consistent with previous reports indicating that OFA may have a relatively milder impact on IgG-producing B cells in lymphoid tissues compared to intravenously delivered anti-CD20 agents such as RTX or ocrelizumab.29,30 Notably, the phase III ASCLEPIOS I/II trials excluded patients with baseline hypogammaglobulinemia and reported a limited incidence of treatment-induced IgM reduction, partly due to the protocol-mandated withdrawal of patients whose IgM levels declined by ⩾10% below the lower limit of normal.15,31 This exclusion may have underestimated the true incidence of hypogammaglobulinemia-related safety concerns in broader clinical use. In our study, despite moderate IgM suppression, no serious infections or adverse events were observed, suggesting that OFA was generally well tolerated in pediatric patients. Nonetheless, the long-term clinical implications of declining immunoglobulin levels, particularly IgM, warrant ongoing surveillance in future studies involving larger pediatric cohorts.
This study has several limitations. First, it is a small, retrospective case series without a control group, which limits the generalizability of the findings. Second, the follow-up duration was relatively short in some patients, making it difficult to assess long-term safety, sustained efficacy, and delayed adverse events. Third, the decision to initiate OFA treatment was made based on clinical judgment rather than standardized criteria, potentially introducing selection bias. Therefore, while the observed outcomes are encouraging, they should be interpreted with caution, and no definitive conclusions can be drawn regarding the efficacy, safety, or tolerability of OFA in pediatric MS at this stage.
Conclusion
OFA showed favorable tolerability and potential benefit in this small pediatric MS cohort. Its subcutaneous administration offers practical advantages. While these findings suggest feasibility, the limited evidence precludes clinical recommendation at this stage. Larger prospective studies are warranted.
