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Ocrelizumab Wearing-Off Phenomenon Is Associated With Reduced Immunomodulatory Response and Increased Neuroaxonal Damage in Patients With MS
abstract
This abstract is available on the publisher's site.
Access this abstract nowOBJECTIVE
The wearing-off phenomenon is common in people with multiple sclerosis (MS) treated with ocrelizumab. We aim to evaluate the presence and severity of wearing-off to ocrelizumab in relation to demographic and MS clinical variables, immune profiling, and a marker of neuroaxonal damage (plasma neurofilament light chain (pNfl)).
METHODS
This cross-sectional study included MS patients treated with ocrelizumab from at least 1 year. Wearing-off questionnaire and blood samples were collected between 21 and 23 weeks after the previous ocrelizumab infusion. Lymphocyte subpopulations were evaluated on peripheral blood using flow cytometry. PNfl was evaluated using fully automated chemiluminescent enzyme immunoassay.
RESULTS
We included 106 people with MS (age 49.5 ± 11.6 years; females 42.3%; wearing-off 57.6%). On regression models, wearing-off was associated with higher pNfl, CD8, CD3, and CD3CD27 lymphocytes. Most frequent wearing-off symptoms were cognitive, sensory, and balance problems; wearing-off started < 1 week (9.4%), 1-4 weeks (10.7%) or > 4 weeks (10.7%) before infusion; 44.8% of the complaints were moderate to severe. Severity of wearing-off was associated with higher pNfl and CD8 lymphocytes.
CONCLUSIONS
Wearing-off is common in people with MS treated with ocrelizumab, and is associated with reduced immunomodulation (higher T lymphocytes) and increased neuroaxonal damage, suggesting reduced treatment response.
Additional Info
Disclosure statements are available on the authors' profiles:
The ocrelizumab wearing-off phenomenon is associated with reduced immunomodulatory response and increased neuroaxonal damage in multiple sclerosis
J Neurol 2024 May 23;[EPub Ahead of Print], I Monteiro, V Nicolella, M Fiorenza, F Novarella, A Carotenuto, R Lanzillo, L Mauriello, G Scalia, G Castaldo, D Terracciano, V Brescia Morra, M MocciaFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The wearing-off phenomenon is common among patients with MS treated with monoclonal antibodies. Such patients experience perceived symptomatic benefit after a dose, but the benefit wears off in advance of the next dose being due. Initially reported in patients receiving natalizumab, subsequent studies have examined it in patients receiving other disease-modifying therapies (DMTs), including ocrelizumab, ofatumumab, and rituximab therapy.1 In patients treated with ocrelizumab, the majority report experiencing wearing off, typically beginning 1 to 4 weeks before their next infusion is due.1,2 Despite being common, previous efforts to characterize the basis of wearing-off have proven challenging. In a cohort of ocrelizumab-treated patients, participants’ self-reported symptoms across a broad number of domains were stable or even slightly improved throughout the treatment cycle, even though more than half responded affirmatively when asked directly whether they had experienced wearing-off, suggesting a possible component of acquiescence bias.3 Additionally, depression has been associated with decreased treatment satisfaction and higher odds of the wearing-off phenomenon, suggesting a possible contribution based on an individual’s mental health that may prejudice their perception of the treatment effect.1 In some studies, a higher BMI, but not higher B-cell counts or extended infusion intervals, increased the odds of the wearing-off phenomenon, whereas other studies failed to find a BMI-based association.1,2
Recently, in the Journal of Neurology, Monteiro and colleagues reported on the wearing-off phenomenon in 106 patients with MS treated with ocrelizumab. They performed a cross-sectional investigation to evaluate for a potential underlying physiologic correlate to the wearing-off effect. Specifically, they examined associations between participants who reported the wearing-off phenomenon, their symptoms, their immune profiles, and a plasma marker of neuroaxonal damage (plasma neurofilament light chain [pNFL]). Participant questionnaires and serum samples were collected between 4 and 5 months after the last ocrelizumab infusion. The proportion of patients reporting the wearing-off phenomenon and the timing of the symptoms were similar to those reported in previous studies, suggesting good external validity. In regression models controlling for vascular comorbidities, disease severity, disease course, and DMT characteristics, the severity of wearing-off was associated with higher counts of CD8 and CD3CD27 lymphocytes and increased levels of pNFL. Similar to previous studies, this study also found no association between CD19/CD20 lymphocyte counts and wearing-off.
The existence of the wearing-off phenomenon has been a challenging-to-define construct and has proven controversial, with some evidence suggesting that it is primarily a placebo effect or that it may be exaggerated by depression.1,3 Interestingly, the wearing-off effect in natalizumab-treated patients has been associated with lower receptor occupancy, providing a potential physiologic explanation with that monoclonal antibody.4 The findings of Monteiro et al are intriguing as, for the first time, they provide a potential biological basis for the same phenomenon in ocrelizumab-treated patients. It is also worth noting that the results suggest that T-cell modulation, rather than B-cell depletion, may be the underlying culprit, emphasizing the importance of investigating secondary effects of MS DMTs when studying the wearing-off effect. Further interrogation of the association of CD8, CD3CD27, and pNFL levels with the wearing-off effect is needed, including longitudinal sampling and pre-DMT baselines of these biomarkers to further evaluate the reliability of the relationships over time. Exploring how traditional measures of disease activity, such as relapses and new MRI lesions, are related to the identified biomarkers as well as specific parsing of wearing-off symptoms (mobility/sensory/cognitive/fatigue/other) with underlying immune profiles and axonal integrity may also be of interest.
Given the high prevalence of the wearing-off phenomenon with monoclonal antibody treatment, there is no question about its relevance to MS patient care. Advancements in clinicians' understanding of any biological basis will be critical to determining appropriate strategies to mitigate the symptoms, whether it be by switching to alternative immunotherapy or through innovative symptom-management techniques.
References
Ocrelizumab is a monoclonal antibody targeting CD20 utilized in the treatment of both relapsing–remitting and primary progressive MS.1,2 Patients with MS on monoclonal antibody therapy may encounter a "wearing-off" effect as their treatment cycle nears its end, characterized by a temporary resurgence of MS-related symptoms like fatigue, cognitive difficulties, balance issues, motor impairments, or sensory disturbances.3 These symptoms typically subside soon after the subsequent infusion. The wearing-off phenomenon is frequently described by patients using natalizumab (50%–70%), and more recent studies show that wearing-off symptoms are reported by patients using ocrelizumab as well (54%–61%).3-5 One study reported that more than half of patients with MS on ocrelizumab experience the wearing-off phenomenon, with a higher BMI being the only predictor.4 In that study, wearing-off symptoms did not reflect suboptimal control of MS disease activity. Another longitudinal study showed that, on average, MS symptom scores remained stable or even improved slightly towards the end of each ocrelizumab cycle, and the authors concluded that the perceived wearing-off effect of ocrelizumab is likely due to natural symptom fluctuations and attribution bias rather than a physiological response to ocrelizumab treatment.5 However, the exact cause of the wearing-off phenomenon remains unknown.
Exploring the wearing-off phenomenon is vital for pinpointing risk factors associated with less-effective ocrelizumab treatment and comprehending patient satisfaction. Additionally, as the trend toward extended interval dosing (EID) for monoclonal antibodies grows, it becomes increasingly relevant to investigate the etiology of the wearing-off phenomenon.6
In a recent study published in the Journal of Neurology, Monteiro and colleagues report the wearing-off phenomenon in patients with MS treated with ocrelizumab, focusing on its possible associations with demographic and clinical factors, immune profiles, and neuroaxonal damage (indicated by plasma neurofilament light chain [pNfl] levels). The study involved 106 patients treated for at least 1 year, and data were collected via a questionnaire and blood samples taken 21 to 23 weeks after the last infusion. Among the participants, 58% reported wearing-off symptoms, such as cognitive, sensory, and balance issues. Higher pNfl and CD8 lymphocyte levels were associated with more severe wearing-off symptoms. The authors conclude that the wearing-off phenomenon is common among patients with MS treated with ocrelizumab and is linked to increased neuroaxonal damage and elevated T-lymphocyte counts, indicating a potentially reduced treatment response.
The findings presented by Monteiro and colleagues contradict those from previous studies on ocrelizumab wearing-off, where NfL levels, B-cell count, and EID were not linked to wearing-off symptoms.4,5 Monteiro and colleagues did examine additional lymphocyte subsets, a factor not explored in prior research. However, all studies to date face the challenge of distinguishing wearing-off symptoms from other MS-related neurological symptoms. Kister and colleagues attempted to minimize attribution bias by analyzing MS-related symptoms throughout an entire treatment cycle, finding no objective evidence of wearing-off symptoms.5 Nonetheless, as Monteiro et al highlight, reporting MS-related symptoms leading up to the next treatment cycle may indicate increased neuroaxonal damage.7 Whether this specifically denotes ocrelizumab losing efficacy at the end of the cycle (true "wearing-off") or reveals an association between experiencing more MS-related symptoms or disease progression and neuroaxonal damage in general remains unclear. Physicians should address potential wearing-off symptoms and patient concerns over an extended period during ocrelizumab treatment, particularly when considering EID.
References