Results:
The total number of AEs from all drugs in this study was 29,662. Amongst these, 25,014 were from the newly approved humanized monoclonal antibodies (daclizumab, ocrelizumab and ofatumumab) [Table 1 and Supplemental Tables 1-3]. These include 4,010 due to daclizumab, 17,018 due to ocrelizumab, and 3,986 were due to ofatumumab.
Amongst these reported AEs for daclizumab, ocrelizumab and ofatumumab, there were a total of 432 adverse events related to AF, CAD and heart failure. [Table 1]. A little over 50% of these cardiac related AEs were due to coronary artery disease. Ocrelizumab reported on the highest number of related CAD, but in relation to its total reported AEs had the lowest prevalence of 0.8% for CAD in comparison to daclizumab (1.5%) and ofatumumab (1.2%) [Table 2]. Heart failure was reported around 102 reported while 99 cases reported for atrial fibrillation associated with these three drugs [Table 1]. Ocrelizumab again had the highest reported cases for heart failure with a total of 48 reported AEs. For atrial fibrillation, the highest reported cases and the most prevalent occurred with ofatumumab, which had a total of 43 reported AEs.
Tables 2 and Supplemental Tables 1-3. further characterize the cardiac related AEs that were associated with ocrelizumab, daclizumab, and ofatumumab. Ofatumumab and daclizumab showed male predominance (66% and 61%.4 respectively). Mortality rate was comparable among all the three medications. More than 90% of the cases were serious.
Next, we conducted disproportionality signal analysis for daclizumab, ocrelizumab and ofatumumab versus all other drugs in FAERS for CAD, cardiac failure and atrial fibrillation [Table 3]. Daclizumab reported the highest ROR for cardiac failure (2.7 with 95% CI: 1.9-3.9) with ofatumumab comes next (1.8, 95% CI:1.5-3.2). CAD showed the same pattern; daclizumab (ROR:3.3 with 95% CI: 2.5-4.4), ofatumumab (ROR: 3.1 with 95% CI: 2.3-4.1), and then ocrelizumab (ROR: 1.9 with 95% CI: 1.6-2.3). Interestingly, atrial fibrillation was only significantly elevated with ofatumumab is (ROR:3.2 with 95% CI: 2.2-4.1), however, ocrelizumab showed significantly low ROR (ROR: 0.6, 95% CI: 0.5-0.9).
Among the S1P receptor modulators (ponesimod, ozanimod, siponimod and fingolimod), there were a total of 4,648 reported AEs. [Supplemental Table 4]. Fingolimod showed the highest number of adverse events followed by siponimod. There was a total of 31 cardiac related events including atrial fibrillation, heart failure and coronary artery disease associated with siponimod while fingolimod had 927 cardiac related events. Siponimod and fingolimod showed a significant increase in bradycardia with ROR of 5.6 and 7.7, respectively [Table 4]. In addition, siponimod and fingolimod also showed a significant association with AV block with ROR of 7.6 and 11.7, respectively which was not observed for any of the other S1P receptor modulators.
Discussion :
The reported adverse events of the novel multiple sclerosis agents span multiple systems. While the cardiac related adverse events of CD20/CD25 inhibitors ranges from 3.45-5.8%, few major cardiac conditions were remarkably high. Specifically, our results showed that the risk of atrial fibrillation, cardiac failure and coronary artery disease were significantly elevated in patients taking daclizumab, ocrelizumab, ofatumumab for multiple sclerosis. Interestingly, coronary artery disease showed the highest ROR compared to the other major adverse events. However, when compared to other CD20 inhibitors (ibritumomab, rituximab, obinutuzumab), daclizumab, ocrelizumab, ofatumumab were associated with significantly lower ROR regarding atrial fibrillation, cardiac failure and coronary artery disease.
Over the last two decades, the role of immune cell depletion via CD20/CD25 inhibitors received considerable attention in the field of neuroimmunology. Rituximab probably was the first CD20 inhibitors used for multiple sclerosis, however, its cardiovascular complications are well studied. Almost 10 years later, two major clinical trials (OPERA I and OPERA II) investigated ocrelizumab in relapsing remitting multiple sclerosis and elegantly revealed the therapeutic potential of ocrelizumab. Subsequent clinical trials placed ofatumumab in therapeutic array for multiple sclerosis. Unfortunately, Daclizumab approval for multiple sclerosis vanished quickly after serious adverse forced the company to withdraw the drug from the market.
While clinical studies demonstrated the cardiotoxicity of rituximab (e.g. atrial fibrillation)[11, 12], much less is known about the new immunomodulators associated cardiotoxicity. Clinical trials of ocrelizumab for multiple sclerosis showed no serious adverse events[9, 10, 13]. However, trials for rheumatoid arthritis were actually terminated after the STAGE study showed one patient died due to myocardial infarction after receiving 500 mg (higher dose when compared to multiple sclerosis dose)[14, 15]. Early clinical trials on daclizumab reported rare cases of allergic myonecrosis of the myocardium and pleural effusions[16]. Two cases of congestive heart failure have been reported in patients taking daclizumab for adult T-cell leukemia[5]. One case of atrial fibrillation has been linked to Ofatumumab in a trial comparing ofatumumab versus Ibrutinib[17]. Even rarer (<1%), pericarditis, heart failure and myocardial infarction cases were reported to be associated with ofatumumab use[18].
Fingolimod, the first SPR modulator introduced into the market, is well known for its cardiovascular side effects, mainly bradycardia and AV block. The FREEDOMS and TRANSFORMS trials reported respectively 14 (3%) and 9 (2.1%) cases of bradycardia in patients on the 1.25 mg dose[19, 20], which were corroborated in our study with a significantly higher ROR compared to other SPR1 modulator. These side effects are thought to be mediated by the activation of S1P1 and S1P3 receptors in cardiomyocytes[21]. Interestingly, siponimod, a newer SPR1 modulator that binds more selectively to S1P1 and S1P5, was expected to have lower risk of bradycardia and AV block, however, our study shows that siponimod also has a significantly high ROR for bradycardia and AV block compared to the other SPR agents. Ponesimod and ozanimod did not show high incidence of bradycardia or AV block suggesting that these agents might be more specific.
Despite of the novelty of our findings, certain limitations to this study are appreciated. For example, patient’s comorbidities and other risk factors are unknown. Additionally, cardiovascular history and baseline cardiac functioning are not taken into account when performing these studies. Besides patient’s risk stratification, the molecular mechanisms underlying immunomodulators-associated cardiotoxicity remain unknown.
The importance of this study comes from the wide use of these medications for multiple sclerosis management. While significant studies addressed few cardiac adverse events of the novel MS therapy as mentioned earlier, comprehensive cardiotoxicity studies are wanting. The present study corroborates with the findings that novel MS therapy does indeed have cardiotoxicity risk. As the use of these new agents increases for MS treatment, the need for cardiovascular risk stratification is much needed now than ever. Since the risk of cardiac failure, coronary artery disease, atrial fibrillation, and bradycardia is enhanced in patients using CD20/CD25 inhibitors and S1P modulators, we suggest clinician to obtain baseline electrocardiography and echocardiogram when initiating these medications. Additionally, patients should be educated about the cardiac risk when taking these medications. Physician are recommended to monitor the sign and symptoms of cardiac failure and coronary artery disease during the treatment period.
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