Infusion- and injection-related reactions (IRRs) are the most common adverse events (AEs) observed with administration of anti-CD20 mAbs in people with MS. Signs and symptoms associated with IRRs generally occur within the first 24 h following administration and predominantly after the first administration [
41].
Immediate IRRs are common for rituximab and tend to reduce in frequency with subsequent infusions [
106]. Data from phase I and II trials of rituximab in MS, as well as real-world evidence data for off-label rituximab use by Zecca et al., reported an incidence of IRRs ranging from 50.5% (160/317) to 78.3% (54/69), with the majority of these AEs being mild to moderate in severity (Table
2) [
52‐
54,
107]. Other reports suggest that severe IRRs develop in approximately 10% of patients treated with rituximab [
106]. Severe IRRs typically occur 30–120 min after rituximab infusion and can be fatal [
25]. During the Hermes trial, 92.6% (50/54) of participants experienced mild or moderate (grade 1 or 2) IRRs, with 7.6% (4/54) of participants experiencing severe IRRs (grade 3) [
52]. Likewise, grade 3 IRRs were reported in 5.8% (17/292) of patients treated with rituximab during the OLYMPUS trial [
53].
During the phase III ORATORIO and phase III OPERA trials, IRRs were reported by 39.9% (194/486) and 34.3% (283/825) of patients treated with ocrelizumab, respectively (Table
2) [
55,
56]. Within these trials, incidences were compared with the IRR incidences in placebo only (25.5% [61/239]) or placebo-infused interferon beta-1a-treated (9.7% [80/826]) cohorts, respectively (Table
2) [
55,
56]. Two patients treated with ocrelizumab in the ORATORIO trial withdrew from the study owing to serious IRRs, while one patient treated with ocrelizumab withdrew from the OPERA trial following a serious IRR of bronchospasm [
55,
56]. Subsequent trials have not revealed substantially differing IRR safety profiles, including those evaluating faster ocrelizumab administration compared with the conventional infusion duration (3.5 h), and real-world evidence data have further corroborated the IRR incidence data from the pivotal ORATORIO and OPERA trials [
108‐
114].
In the ASCLEPIOS phase III trials, injection-related systemic reactions (IRSRs) (defined as systemic reactions happening ≥ 24 h after any injection) were observed in 20.2% (191/946) of patients who received subcutaneous ofatumumab, versus 15.0% (140/936) of those who received placebo injections as part of their oral teriflunomide regimen (Table
2) [
57]. Of the 191 IRSRs in patients treated with ofatumumab, two were considered serious, with one patient leaving the study after the first injection as a result. Injection-site reactions (ISRs) were reported in 10.9% (103/946) of patients treated with ofatumumab—one of these AEs was serious—versus 5.6% (52/936) of patients treated with teriflunomide (Table
2) [
57]. Similarly, the phase II MIRROR study of subcutaneous ofatumumab reported IRRs as the most common AEs in patients treated with ofatumumab (52.4% [86/164] vs. 14.9% [10/67] with placebo injections; Table
2); however, patients were treated with higher doses (30 and 60 mg) of ofatumumab in this trial. Three of these IRRs in patients treated with ofatumumab were considered serious, including one report of cytokine-release syndrome, with all three patients remaining in the trial [
92]. Although still being the most commonly reported AE (IRSR, 28.5% [81/284]; ISR, 10.2% [29/284]), there were no serious IRRs in the phase II APLIOS bioequivalence study of subcutaneous ofatumumab 20 mg (Table
2). One patient was reported to have a grade 3 severe reaction after their first pre-filled syringe injection into the abdomen; however, this patient completed the study [
94]. The incidence of severe IRRs in < 1.0% of participants during the APLIOS (1/292) and ASCLEPIOS (2/946) studies is lower than the incidence reported in clinical trials of rituximab [
52,
53] and ublituximab [
74]. The incidence of IRRs in the phase II APOLITOS study was also consistent with the safety profile observed in the other completed studies (week 48 IRR analysis, 25.0% [10/40]) (Table
2) [
90,
91]. Interestingly, subcutaneous administration of low-dose ofatumumab resulted in a reduced incidence of IRRs (23.2% [435/1873]) when compared with high-dose ofatumumab administered intravenously (78.9% [30/38]) [
93,
115]. Furthermore, interim data from ongoing studies of subcutaneous ofatumumab 20 mg, including the long-term phase IIIb ALITHIOS study [
116,
117], have shown consistent IRR profiles, in line with the pivotal studies outlined above.
In the phase III ULTIMATE trials of ublituximab, 47.7% (260/545) of patients reported IRRs with ublituximab, compared with 12.2% (67/548) of teriflunomide-stratified patients who received placebo infusions (Table
2). Grade 3 or higher IRRs were reported in 2.8% of participants. Two patients in this trial experienced grade 4 IRRs, and six patients withdrew from the study owing to serious IRRs [
35]. Similar incidences were observed in the phase II study by Fox et al
., with 50% (24/48) of patients treated with ublituximab experiencing IRRs, all of which were low grade, and no IRRs with placebo [
36]. Preliminary clinical results for BCD-132 showed that 25.0% (6/24) of patients with MS treated with BCD-132 reported IRRs. Further studies are currently ongoing in larger and adequately powered cohorts to fully elucidate the risk of IRRs (Table
2) [
40,
118].
Overall, the IRR data from these trials indicate a reduced incidence of IRRs with low-dose subcutaneous injection of ofatumumab compared with the intravenously infused mAbs [
116]. It is thought that ofatumumab’s fully human molecular structure and the ability to administer the antibody at lower doses due to its direct targeting of lymph nodes via subcutaneous injection are major factors in ofatumumab’s reduced IRR incidence [
41]. Although ofatumumab does induce IRRs, premedication has not been shown to significantly reduce this incidence, and it is therefore not required for administration [
32,
97]. Conversely, premedication is required before each infusion of ocrelizumab, rituximab and ublituximab [
41].
Infections and hypogammaglobulinemia
The immune interference of anti-CD20 mAb therapies can diminish patients’ immune responses and increase susceptibility to infection [
119], which may increase the already elevated risk of infection associated with MS [
120].
Interestingly, similar rates of infection were reported for the placebo and rituximab groups in the phase II HERMES study of rituximab in patients with MS [
52]. Moreover, previous phase II trials of ocrelizumab in patients with RRMS found no difference in the incidence of infection between the placebo and ocrelizumab groups [
121]. Because both studies collected safety data at < 52 weeks, this may indicate that the risk of infection associated with anti-CD20 mAbs increases during long-term treatment. Consistent with this, the 96-week OLYMPUS trial of rituximab found that 4.5% of patients treated with rituximab experienced serious infections, compared with < 1.0% of patients receiving the placebo [
53].
Long-term use of anti-CD20 mAb therapies is thought to reduce serum Ig levels [
41], which is consistent with an increasing risk of infection over time. A longer-term assessment of patients treated with ocrelizumab over 6 years found that reductions in serum Ig levels were associated with an elevated risk of serious infection. Moreover, this association is stronger in relation to the levels of IgG, rather than IgM or IgA [
122], suggesting that serum IgG levels may be an indicator of infection risk in patients treated with anti-CD20 mAb therapies. Consistent with this hypothesis, patients receiving ofatumumab for 3.5 years displayed stable levels of serum IgG, which corresponded with low incidence of serious infection. This is despite 23.1% of patients experiencing IgM levels below the LLN at least once during the trial [
116].
During the HERMES clinical trial of rituximab, infections were reported in 69.6% (48/69) of patients treated with rituximab, with upper respiratory tract infections and urinary tract infections being among the more common infections reported, affecting 18.8% (13/69) and 14.5% (10/69) of patients, respectively [
52]. Furthermore, rituximab is frequently used off-label in Sweden as a treatment for MS, and several studies of patients with MS report that infections were the most common AEs associated with rituximab [
123‐
125].
Across the OPERA I and II trials of ocrelizumab, infections were reported in 56.9% (232/408) and 60.2% (251/417) of patients, respectively [
56]. Pooled data from both trials highlighted that upper respiratory tract infections and urinary tract infections were common, affecting 15.2% (125/825) and 11.6% (96/825) of participants treated with ocrelizumab [
56]. Direct comparison between the ocrelizumab and interferon beta-1a treatment groups in these trials shows that upper respiratory tract infections were more prevalent in the ocrelizumab group (15.2% vs. 10.5%). In contrast, urinary tract infections were less common in the ocrelizumab group compared with the interferon beta-1a group (11.6% vs. 12.1%) [
56].
Infections were reported in 51.6% (488/946) of patients receiving ofatumumab during the ASCLEPIOS I and II trials, which is a relatively low incidence compared with clinical trials of rituximab in patients with MS [
57]. Consistent with findings for other anti-CD20 mAbs, upper respiratory tract infections and urinary tract infections were common types of infection reported among patients treated with ofatumumab, albeit at a reduced incidence, affecting 10.3% of patients [
57]. The ULTIMATE I and II trials of ublituximab in patients with MS reported a similar incidence of infection, affecting 55.8% (304/545) of patients. Respiratory tract infections and urinary tract infections were reported in 7.7% and 4.0% of patients, respectively [
35].
Opportunistic infections
Cases of opportunistic infections such as hepatitis B reactivation and progressive multifocal leukoencephalopathy (PML), caused by the John Cunningham virus, have been reported in patients receiving anti-CD20 mAb therapies [
126‐
128]. In line with published findings when looking at severe COVID-19 outcomes [
129], an analysis of patients with MS receiving varied treatments found that rituximab was associated with the highest rate of serious infection [
123]. This study reported two cases of PML in patients with MS, one of whom was receiving rituximab. In both cases, the patient had recently started a new treatment regimen, having switched from natalizumab therapy. It was concluded that the cases of PML resulted from natalizumab treatment, which has previously been linked to PML [
123].
The increased risk of infection associated with MS, the age of the patient and the immune suppression resulting from ocrelizumab treatment were all deemed to have contributed to a previously reported occurrence of PML [
128]. However, a further nine cases of PML were reported in patients with MS during the post-marketing setting for ocrelizumab. Most of these cases were linked to prior treatment with natalizumab and fingolimod, with the exception of one patient who had not received prior treatment with disease-modifying therapies. This represented the first occurrence of PML directly associated with ocrelizumab treatment [
130,
131]. A documented case of hepatitis B reactivation also occurred in a patient with MS receiving ocrelizumab [
126]. Despite the absence of detectable hepatitis B viral DNA at the start of ocrelizumab treatment, reactivation of the infection was confirmed 6 weeks later [
126]. The risk of infection reactivation should be considered in treatment decisions and can be mitigated through an effective program of screening and preventative treatment [
132,
133].
COVID-19
Given the links between anti-CD20 mAb therapy and an increased risk of infection, there was speculation over the susceptibility of patients with MS to severe COVID-19 infection [
41]. A retrospective analysis of patients with MS in Italy reported an association between COVID-19 infections and rituximab and ocrelizumab, respectively. Moreover, these anti-CD20 mAb therapies were linked to more severe COVID-19 infections and increased frequency of hospitalization compared with other therapies [
134]. Further retrospective analyses found that rituximab and ocrelizumab were associated with a higher risk of COVID-19 infection compared with alternative drug classes. However, this study did not find that these anti-CD20 mAb therapies meant patients were more prone to COVID-19-related hospitalization compared with alternative therapies [
135]. A systematic review of severe COVID-19 outcomes found disparities in patients with MS receiving either rituximab or ocrelizumab [
129]. A comparison of a range of MS treatments found a pooled estimate of death of 1.8%, while the estimate for patients receiving rituximab or ocrelizumab was 4.5% and 1.6%, respectively [
129]. However, these findings did not consider the length of time patients had been treated with anti-CD20 mAb therapies [
129,
134]. Retrospective analysis of North American patients with MS and COVID-19 found that rituximab was associated with a significant increase in the risk of hospitalization. Ocrelizumab treatment was also associated with an increase in the risk of hospitalization, although this association was less pronounced compared with rituximab [
136].
The ALITHIOS trial of ofatumumab found that 8.2% (139/1703) of patients reported COVID-19 infections, of which 94.2% (131/139) were considered mild or moderate and 7.2% (10/139) were considered serious [
137]. When compared with the general population, these findings suggest that ofatumumab did not increase the susceptibility of patients to severe COVID-19 infections [
137]. This may be influenced by the stability of IgG serum levels associated with ofatumumab treatment [
116], but further data and analyses are needed before this can be concluded.
The effects of anti-CD20 mAb therapies on COVID-19 vaccine response in patients with MS have also been a point of concern [
41]. Given the relatively recent development of COVID-19 vaccines, there are limited findings related to the effect of anti-CD20 mAb therapies on vaccine response. Analysis of anti-CD20 mAb therapies found varied seroconversion following COVID-19 vaccination. Patients who received rituximab and ocrelizumab demonstrated seropositivity of 11% (1/9) and 43% (19/44), respectively [
138]. Diminished humoral responses to a range of vaccines (not including the COVID-19 vaccine) were reported in patients with MS receiving ocrelizumab [
139]. A retrospective study of patients treated with ocrelizumab reported a positive serological response in 37.5% of patients following COVID-19 vaccination. However, these findings were based on a small sample size, and the techniques used to collect serological data were inconsistent [
140].
Seropositivity was demonstrated in 75% (3/4) of patients treated with ofatumumab [
138]. However, the small sample size limits the conclusions that can be made from these data. Additional findings from patients with MS treated with ofatumumab have reported reduced humoral immune responses following COVID-19 vaccination, without significantly disrupting T-cell responses [
141]. Likewise, Faissner et al. reported that patients with MS treated with ofatumumab for 3 months had significant depletion of B cells and an impaired humoral response following COVID-19 vaccination. Despite this, T-cell response remained strong and underpinned preserved cellular immunity [
84].
Malignancies
The immune suppression associated with anti-CD20 mAb therapies may increase the risk of malignancies developing in patients with MS [
42]. A retrospective analysis of patients with MS in Sweden reported that rituximab did not increase the risk of invasive cancers, when compared to the general population [
142]. Further, no incidences of neoplasm were reported in the ULTIMATE I trial of ublituximab; however, the incidence was 0.7% (2/272) during the ULTIMATE II trial [
35]. The rates of neoplasm reported during the ASCLEPIOS I and II trials in patients with MS receiving ofatumumab were 0.5% (5/946) [
57]. During the OPERA I and II trials, neoplasms were reported in 0.5% (4/825) of patients in the ocrelizumab group, with a further five cases of neoplasm detected during the open-label extension phase [
56]. Of the nine cases of neoplasm reported, 44.4% (4/9) were a form of breast cancer [
56]. However, subsequent analysis of safety data across multiple clinical trials and real-world sources found that the standardized incidence ratio for breast cancer for people treated with ocrelizumab did not indicate an elevated risk when compared with a typical population of patients with MS. Furthermore, analysis of real-world data found that the incidence rate of breast cancer was not elevated in patients treated with ocrelizumab compared to the US general population [
130]. Cumulatively, these findings suggest that the associated risk of malignancies appears to be low across anti-CD20 mAb therapies.
Pregnancy
Prescribing information for anti-CD20 mAb therapies advises against receiving this treatment during pregnancy, and that effective forms of contraception should be used when undergoing treatment [
25,
31,
32,
37].
A retrospective analysis of pregnancies that featured rituximab use within 6 months of conception reported B-cell depletion in 39% of newborn babies. However, B-cell levels were restored within 6 months post-birth [
143]. An additional study reported two cases of rituximab treatment at 13 and 21 weeks’ gestation, respectively, and observed no clinical or developmental adverse outcomes [
144]. In patients with MS treated with ocrelizumab before pregnancy, congenital abnormalities were reported in 1.6% of live births, which is consistent with the 2.1% rate seen in the UK general population [
145]. Moreover, a case study of a patient with MS treated with ocrelizumab at 19 weeks’ gestation reported normal neonatal lymphocyte levels at birth, followed by normal developmental milestones being met at 3 months of age [
146]. Analyzing data from the ASCLEPIOS I and II, ALITHIOS, MIRROR and post-marketing trials of ofatumumab, no birth defects or congenital abnormalities were reported in 23 pregnant patients, and further observations and analysis of patients with MS exposed to ofatumumab during pregnancy are being planned [
147]. Owing to limited data surrounding the effects of anti-CD20 mAb therapies in pregnant people, it is difficult to draw firm conclusions regarding safety. Observations from larger cohorts of pregnancies exposed to anti-CD20 mAb therapies are required.
Colitis
Rituximab has previously been linked to gastrointestinal injury, such as diarrhea and bowel perforation. Moreover, there are multiple reports of colitis in patients treated with rituximab who had otherwise healthy bowels prior to starting treatment [
148‐
150].
One case study of a 62-year-old patient with marginal zone B-cell lymphoma reports the development of severe abdominal pain and colon distension, which required partial removal of the colon to alleviate symptoms [
149]. After a recurrence of lymphoma, the patient received further rituximab treatment, which was followed by repeated abdominal pain and a diagnosis of severe colitis. The patient’s symptoms deteriorated before requiring eventual proctectomy treatment [
149]. An analysis of patients treated with rituximab who experienced diarrhea found that 4.6% (21/460) had confirmed colitis. Interestingly, there were no reports of colitis in the 47.6% (10/21) of these patients who had undergone a colonoscopy prior to starting rituximab treatment, suggesting an association between rituximab and the development of colitis [
148].
Likewise, a case of treatment-emergent colitis was reported in a patient with MS treated with ocrelizumab who had no prior history of inflammatory bowel disease [
151]. In this instance, colitis developed following only two rounds of ocrelizumab treatment and resulted in the patient undergoing a total colectomy [
151]. Diarrhea has also been reported as an AE in clinical trials for ofatumumab and ublituximab [
36,
57,
116]; however, it is unclear if these instances were due to colitis.
The risk of colitis may be underestimated because it is a rare and unrecognized event. Emphasis should be placed on studying the link between colitis and anti-CD20 mAb therapies, with the aim of reducing the risk of colitis and the necessity for significant colitis-related clinical interventions.