This study employs a large-scale global analysis of Ocrelizumab utilizing FAERS data to identify emerging safety trends and to supplement previously unreported adverse events. This expanded dataset provides a more comprehensive and nuanced understanding of the drug's safety profile. Our statistical analysis reveals a general increase in the number of reports from 2017 to 2023, with the exception of 2020. This trend may be attributed to the increased use of Ocrelizumab and underscores the need for ongoing attention to Ocrelizumab-related AEs. The number of female patients significantly exceeds that of male patients, with a sex ratio approaching 3:1. This disparity is likely related to the higher prevalence of MS among women14. Research has documented a rising incidence of MS among women over recent decades, potentially due to factors such as gene-environment interactions or epigenetic influences15. Additionally, the data indicate that countries with higher geographic latitudes, which are known to be high-risk areas for MS, reported higher numbers of AEs. This observation aligns with the epidemiological characteristics of MS 16. While research suggests that MS predominantly affects younger individuals, typically starting between ages 20–40 17,18, some studies have provided preliminary evidence indicating an increasing age of onset for MS in recent decades. This, combined with the general increase in life expectancy and the extended survival of MS patients19, may contribute to the higher incidence of AEs observed in the 40–60 age group for Ocrelizumab.
According to the study, the most common and significant SOC is "Infections and Infestations," which also represent the most frequent adverse reactions associated with Ocrelizumab. Notably, the most frequently observed infections include urinary tract infections, nasopharyngitis, and pneumonia, all of which are listed in the drug label. Our findings corroborate these established data. Research indicates that patients with MS are generally at a higher risk for infections20,21. Furthermore, among DMTs for MS, anti-CD20 agents appear to be among the categories with the highest risk for infections 22. Infection remains a significant adverse reaction of Ocrelizumab, which may further elevate the risk of disease complications in patients. Therefore, careful monitoring of Ocrelizumab-related infection AEs is crucial to minimize the incidence of adverse events and further improve the safety of medication.
Ocrelizumab generally has good clinical tolerability, with infusion-related reactions (IRRs) being the common adverse events. Our research also identified a high frequency of these signals. In multiple trials, over 34% of MS patients experienced IRR-related AEs12,23. Although most IRRs are mild to moderate and occur during the initial infusion, they have the potential to lead to discontinuation of Ocrelizumab. Notably, research suggests that complement-dependent cytotoxicity (CDC) plays a significant role in IRRs, with these reactions often involving the release of cytokines by immune cells, such as B lymphocytes and natural killer cells24. Symptoms of infusion reactions include Fatigue, Flushing, Throat irritation, and Oropharyngeal pain, all of which are listed in the drug label, and our study also observed these AEs. Interestingly, several studies have indicated that the frequency and severity of IRRs during shorter infusion durations are comparable to those seen with standard infusion times 25,26. Thus, shorter infusion durations may improve the overall patient experience and optimize infusion-related resources. In summary, careful monitoring of IRRs and effective management of infusion times are advisable during Ocrelizumab therapy.
DMTs can modulate the immune system, potentially increasing the risk of infections, including COVID-19. A French study identified that DMTs associated with higher infection risks were linked to a more than fourfold increase in the likelihood of contracting COVID-1927. Additionally, pooled analyses have confirmed that anti-CD20 treatments are associated with a heightened risk of severe COVID-19 compared to other DMTs. Among these, anti-CD20 agents, such as Ocrelizumab and Rituximab, appear to have a higher frequency of severe COVID-19 cases. Compared to patients using Ocrelizumab, those treated with Rituximab exhibit a heightened risk of COVID-19, potentially due to the longer duration of Rituximab therapy 28. Our study uncovered numerous signals related to COVID-19 and SARS-CoV-2, including COVID-19 pneumonia、Suspected COVID-19、Post-acute COVID-19 syndrome、SARS-CoV-2 test positive. The frequency and strength of these signals were notably high and possibly associated with the context of the coronavirus pandemic. Based on this, if symptoms resembling COVID-19 occur while using the Ocrelizumab, it is essential to promptly adjust the dosage or discontinue use to prevent more severe adverse events. Additionally, trials have indicated that Ocrelizumab is linked to a higher incidence of herpesvirus-related infections 12,29. The drug label also notes potential herpes-related adverse reactions, with severe herpesvirus infections, some of which can be life-threatening, potentially occurring at any time during treatment. Our research similarly identified numerous herpesvirus-related signals, such as herpes zoster, genital herpes simplex, ocular herpes zoster, herpes simplex of the nose, and herpes simplex encephalitis. Therefore, prompt identification and management of herpesvirus infections are crucial to enhance the safety of Ocrelizumab therapy.
Notably, our study identified several adverse events related to dental issues, such as tooth infection, tooth fracture, tooth abscess, pulpitis dental, and tooth dislocations. So far, there is no clear clinical answer to whether the use of Ocrelizumab will cause dental disease problems, and it is not described in the drug label of Ocrelizumab. Research indicates that patients with MS undergoing long-term DMT are more vulnerable to oral pathological changes compared to healthy individuals. B cells contribute to bacterial homeostasis by producing IgA antibodies, and anti-CD20 therapies lead to B cell depletion, resulting in IgA deficiency30,31. These reasons can ultimately cause chronic inflammation and dental diseases. Additionally, research has shown that MS can lead to oral diseases due to symptoms such as xerostomia and other conditions affecting facial muscles and energy levels, which make maintaining oral hygiene challenging32. These factors increase the risk of dental and gingival diseases, such as cavities, periodontitis, and infections. In addition, a systematic review showed that patients with MS were more susceptible to oral infections than normal people33. However, another study did not find a clear association between MS and most oral health conditions 34. In conclusion, regardless of whether the medication is related to dental diseases, it is recommended to conduct a dental examination and ongoing monitoring before starting treatment with this medication, which can help prevent the development of new dental diseases. Furthermore, our study identified several adverse events related to meningitis. Research has also reported that patients exposed to Ocrelizumab for a shorter duration developed meningitis 35. However, further data are needed to confirm the causal relationship between Ocrelizumab and meningitis, particularly whether hypogammaglobulinemia is associated with an increased risk of such infections. Overall, it is necessary to remain vigilant for the occurrence of meningitis and to implement preventive measures to enhance the safety of the Ocrelizumab. Progressive multifocal leukoencephalopathy (PML) has been reported in patients with MS treated with Ocrelizumab, and the drug label also mentions that this adverse reaction occurs. However, our study did not detect any signal indicating the adverse effect of PML. Instead, we detected signals related to JC polyomavirus test positivity and JC virus infection. PML is a destructive central nervous system infection caused by the JC virus, characterized by lytic infection of oligodendrocytes and demyelination in the central nervous system 36. Although PML is rare, rituximab as a chimeric anti-CD20 monoclonal antibody is associated with PML, and given the structural similarity between Ocrelizumab and rituximab, Ocrelizumab may also be at risk of PML37. While the drug label mentions PML, the cases reported are primarily linked to prior medications, with Ocrelizumab itself not being considered a primary contributing factor. There have been reports of PML cases associated with Ocrelizumab monotherapy, though age-related factors may influence these occurrences 38. In summary, screening for JC virus at the onset of treatment is essential, and meticulous monitoring of patients throughout the treatment course can mitigate the risk of potential serious adverse effects.
Ocrelizumab, as a monoclonal antibody, undergoes elimination primarily through catabolic processes. In patients with mild hepatic impairment, no significant changes in the pharmacokinetics of Ocrelizumab have been observed. Consequently, Ocrelizumab generally has minimal impact on liver function. However, it is still recommended to conduct liver function tests prior to initiating Ocrelizumab therapy. Several studies have reported that Ocrelizumab is associated with may be associated with drug-induced liver injury (DILI) events and could potentially be linked to hepatitis B virus (HBV) reactivation 39. Similarly, this study also found some signals about hepatitis, including Hepatitis B, Hepatitis B surface antibody positive, Hepatitis B antibody abnormal, and Hepatitis B core antibody positive. B-cell depletion therapy may cause reactivation of hepatitis B HBV through its immunosuppressive effects, which may induce acute hepatocellular injury and ultimately lead to acute liver failure 40. Therefore, the use of Ocrelizumab in patients with hepatitis B is considered high risk and is generally contraindicated and HBV screening (including HBsAg and HBcAg tests) is recommended before initiating treatment. Notably, our study also found unexpected signals related to Hepatitis A, such as Hepatitis A antibody positive and Hepatitis A virus test positive. Currently, there is no literature linking Ocrelizumab with Hepatitis A. It is unreasonable to draw a causal relationship between the two based solely on disproportionality analysis, as current research does not support this conclusion. Overall, regular monitoring for hepatitis is essential to enhance the safety profile of Ocrelizumab use. As the use of Ocrelizumab has expanded, skin-related diseases have also been reported. The drug label indicates that infusion-related skin reactions, such as pruritus, rash, urticaria, or erythema, are frequently observed within 24 hours, especially in the first infusion. Literature describes other skin reactions, such as psoriasis and pustular psoriasis, although their causal relationship with the treatment remains inconclusive 41,42. Notably, our study identified several novel dermatological AEs, including neurodermatitis, nail bed inflammation, and perioral dermatitis. Given that Ocrelizumab may be associated with inflammatory skin AEs, We recommend that the Ocrelizumab monitoring plan incorporate regular dermatological evaluations to mitigate the risk of skin-related adverse events. Urinary tract infections are a common adverse event associated with Ocrelizumab, and our study also identified a high frequency of urinary tract infections. Additionally, several new signals related to the bladder and urethra were detected, including Cystitis, Cystitis bacterial, Urinary incontinence ,Micturition urgency and Micturition disorder. Ocrelizumab's immunosuppressive effects may reduce patients' resistance to infections, making the bladder more susceptible to infection. Our study also uncovered adverse events related to bladder disorder, such as Bladder dysfunction, Bladder spasm, Calculus bladder, Atonic urinary bladder, voiding difficulties, and loss of bladder sensation. On one hand, the prevalence of lower urinary tract symptoms in MS patients is 73%, with urgency being the most common 43. On the other hand, there is currently no direct evidence linking Ocrelizumab to these conditions, suggesting that these conditions may be a complication of the disease itself rather than an adverse reaction to the Ocrelizumab. In summary, due to the impact of Ocrelizumab on the immune system and the elevated risk of Urinary tract infections, clinicians should be vigilant in monitoring and managing bladder and urethral-related conditions in MS patients.
Immune system is closely related to cancer. The modulation of immune system induced by DMTs are thought to contribute to the increased risk of malignancies in patients undergoing long-term treatment with these drugs44,45. With the development of more effective DMTs, there is growing concern about the potential for increased cancer risk in MS patients 46. A study has indicated that MS patients may have an elevated risk of cancer due to prior exposure to DMTs rather than the disease itself. Data from the OPERA I and II and ORATORIO trials have shown that Ocrelizumab was associated with a higher number of tumors compared to interferon beta-1a or placebo12,29. Our study also identified a substantial amount of data regarding adverse events related to breast cancer, including invasive ductal breast carcinoma, invasive breast carcinoma, HER2-positive breast cancer, and hormone receptor-positive breast cancer. This may be related to tumor susceptibility, as normal B cells provide protective mechanisms against tumor development and tumor lysis, which are disrupted by B cell depletion. Research indicates that B cell suppression can lead to worsened outcomes in breast cancer patients44. In addition, our study identified several other tumor signals, such as skin papilloma, anogenital warts, papillary thyroid cancer, and follicular thyroid cancer. Given that MS patients may be exposed to various drugs with different mechanisms throughout their illness, these drugs might alter the immune system and indirectly increase their cancer risk 37. Furthermore, prolonged exposure to DMTs and the use of multiple DMTs could contribute to an increased cancer risk 47. Although the association between these new tumor signals and adverse events related to Ocrelizumab still requires further validation, tumors being a serious adverse event warrant extra attention and caution regarding cancer risk. Additionally, for multiple sclerosis patients with concomitant cancer, careful assessment of their disease staging is necessary to minimize the risk of cancer progression.
Ocrelizumab's mechanism of action involves reducing the number of B cells to modulate the immune system. This reduction can potentially lead to decreased levels of immunoglobulins. Our analysis has found adverse event signals related to reductions in IgG, IgM, IgA, and overall immunoglobulin levels, which are also noted in the drug label. In the OPERA I and OPERA II trials, Ocrelizumab was associated with a decrease in IgG levels over 336 weeks 48. Evidence from clinical trials and observational studies indicates that IgG antibody levels, in particular, are correlated with infection rates and severity in MS patients 49. Additionally, maintaining elevated levels of IgA may be associated with a reduced risk of infection 50. Key factors influencing infection risk include the reduction in the number of B cells differentiating into plasma cells and a consequent decrease in antibody production, affecting various types of antibodies or immunoglobulins, including but not limited to IgM ,IgA, and IgG51.These findings underscore the importance of monitoring immunoglobulin levels during Ocrelizumab therapy. Understanding these critical factors can aid in identifying patients at high risk for severe infections and ensure appropriate management strategies are in place.
In the report by Schweitzer et al., a small proportion of Ocrelizumab recipients had lymphocyte counts below the lower limit of normal (LLN) (20.7%), with a minority developing severe lymphopenia52. Recent studies have shown an increased risk of infections associated with lymphopenia in MS patients receiving anti-CD20 therapies53. Our study also identified relevant AEs, such as “B-lymphocyte count decreased”, “B-lymphocyte abnormalities”,“CD19 lymphocytes decreased”. Notably, our study also found signals related to T lymphocytes and their subtypes, including T-lymphocyte count decreased, CD4 lymphocytes decreased, and CD8 lymphocytes decreased. Research indicates that Ocrelizumab causes a slight decrease in T cell counts during the initial months of treatment, with more pronounced reductions in CD4+ and CD8+ T lymphocytes compared to Rituximab54. Additionally, some experimental and clinical studies have suggested that anti-CD20 therapies impair the antiviral function of CD8+T lymphocytes 55. Although the impact of Ocrelizumab on B lymphocytes and subsequently on immunoglobulins is well-established, its direct effects on T lymphocytes and other immune cells are less pronounced. Therefore, it is advisable to pay attention to changes in the number of other lymphocytes when using the Ocrelizumab. Given that long-term use of Ocrelizumab may lead to overall immune suppression and increased infection risk, patients receiving Ocrelizumab should be closely monitored for immune function and infection symptoms to facilitate timely interventions.
MS treatments generally increase the risk of infectious diseases, and many relapses in MS patients may be triggered by infections. Therefore, vaccination against infectious diseases is crucial for maintaining health in MS patients. As a monoclonal antibody with a relatively long half-life and pharmacodynamic characteristics, Ocrelizumab, while reducing the frequency of administration, can impact vaccine efficacy56,57. The study uncovered signals related to AEs associated with the vaccine, including vaccination failure, vaccine interactions, and vaccine breakthrough infections. Despite the depletion of CD20+ B cells induced by Ocrelizumab, patients typically retain pre-existing humoral immunity against common viruses and bacteria prior to treatment. In fact, Ocrelizumab's reduction of humoral responses can diminish vaccine efficacy. Weakened humoral immunity to tetanus, seasonal influenza, and pneumococcal vaccines in patients with relapsing multiple sclerosis have all been associated with Ocrelizumab treatment 58. Nonetheless, seasonal influenza vaccination is recommended for most patients with MS with the aim of conferring potentially protective humoral immunity. In summary, it is crucial to assess or reassess the vaccination status of MS patients before initiating immunosuppressive or immunomodulatory therapies. Meanwhile, a well-structured vaccination schedule can help reduce the incidence of adverse reactions when using Ocrelizumab.
Research indicates that vitamin D has emerged as a significant factor influencing the pathogenesis of MS59. Currently, there is no literature supporting that Ocrelizumab causes vitamin deficiencies. However, We found signals related to vitamin deficiencies, such as Vitamin D deficiency, “Vitamin B12 deficiency, Vitamin B complex deficiency, Decreased vitamin D, and Decreased vitamin B. If symptoms such as fatigue, bone pain, or neurological issues occur, it is important to assess whether they are related to vitamin deficiencies to ensure comprehensive health management for the patient. A review on thyroid disorders highlights that patients with MS may also have thyroid diseases, which are among the more common comorbidities associated with MS60. Our research found signals related to thyroid nodules and subacute thyroiditis, which may be related to complications of multiple sclerosis. Long-term use of immunosuppressive drugs can affect multiple systems, including the endocrine system. Although it is not yet clear whether the thyroid issues identified in this study are adverse reactions to the drug, patients using Ocrelizumab who have symptoms or a history of thyroid problems should have regular thyroid function tests to prevent further adverse reactions.
In cases where the occurrence time was recorded, most patients experienced AEs within one month of using the Ocrelizumab, and some AEs were also observed up to two years later. Therefore, it is important to remain vigilant at specific times, particularly during the first month, when infusion-related reactions are the most common adverse events. Early detection of AEs is crucial for enhancing the overall quality and safety of pharmacotherapy, thereby ensuring the safe use of medications for patients.
Our research has some limitations. First, the database reports are inherently biased, with severe or noteworthy events more likely to be reported, potentially overlooking milder occurrences. Reports are submitted by a diverse range of personnel, leading to variability in data quality and potential inaccuracies. Second, the information in the reports may be incomplete, often lacking detailed patient backgrounds, drug usage information, or other critical medical data. Finally, the FAERS data primarily describe the occurrence of AEs without establishing causal relationships between drugs and these events. It provides only an estimate of potential signals, which are statistically significant but not causally definitive. Therefore, the causal relationship between Ocrelizumab and adverse events requires further investigation through clinical studies.