Higher infection risk, less disability worsening with rituximab in MS
Researchers: Infection risk should be considered toward long-term outcomes
Rituximab, which is sometimes used off-label for multiple sclerosis (MS), doubles the risk of hospital-treated infections, but may prevent worsening disability better than some approved disease-modifying therapies (DMTs), a Swedish study finds.
Hospital-treated infections were significantly associated with a higher risk of relapse-independent disability worsening among relapsing-remitting MS (RRMS) patients treated with glatiramer acetate, which is sold as Copaxone, among others, or interferon beta-based therapies, but not with rituximab.
Still, the risk of disability worsening after a hospital-treated infection was greater for people with progressive forms of MS than for those with RRMS.
“Our findings suggest that severe infections may impact both … immune and neurodegenerative processes, thereby increasing the risk of worsening of MS disability,” the researchers wrote, adding that “infection risk should be considered to improve long term outcomes.”
The study, “Hospital-Treated Infections and Risk of Disability Worsening in Multiple Sclerosis,” was published in the Annals of Neurology.
Disability from MS tends to worsen over time, even as relapses, or periods when symptoms appear or suddenly get worse, become less frequent.
It’s been suggested that whole-body infections, which promote changes in immune system activity, contribute to risk of disability worsening in MS. The link between infections and long-term MS-related disability isn’t fully understood, however.
“The question if and to what degree infections contribute to disability progression in MS has become more pertinent with increasing use of highly effective disease-modifying therapies that impair the immune system’s physiological defenses against infection,” the researchers wrote.
Infections, disability worsening with rituximab
Rituximab, which is sold as Rituxan and has generics available, works by killing B-cells, a type of immune cell implicated in MS. Ocrevus (ocrelizumab), another B-cell-depleting antibody, is a highly effective DMT approved for all forms of MS.
B-cell-depleting therapies, as well as some other highly effective DMTs, “have been associated with an increased risk of hospital-treated infections, compared with first-generation DMTs, such as interferons and glatiramer acetate,” the researchers wrote. Interferon beta-based therapies include Avonex (interferon beta-1a), Rebif (interferon beta-1a), Betaseron (interferon beta-1b), and Extavia, a generic for Betaseron.
Here, the researchers looked at the link between hospital-treated infections and disability worsening in patients treated with either rituximab, interferons, or glatiramer acetate. Drawing on 2000-2021 data from the Swedish MS Registry, the study included 8,759 treatment episodes with rituximab and 7,561 treatment episodes with interferons or glatiramer acetate (IFN/GA).
Hospital-treated infections included events recorded in both inpatient and specialized outpatient visits. Disability progression was measured using the Expanded Disability Status Scale (EDSS), where a higher score indicates more severe disability.
People with progressive forms of MS, those starting a DMT at age 40 or older, and men were significantly more likely to have infections that required hospital care, regardless of the DMTs used.
Patients on rituximab had double the risk of inpatient-treated infections and a 26% higher risk of outpatient-treated infections than those on IFN/GA. Inpatient-treated infections in MS were linked to an average 0.19 point EDSS score increase.
“The association between infections and EDSS was greater for inpatient- compared to outpatient-treated infections, suggesting a relationship between severity of [body-wide] inflammation and the risk of disability worsening,” wrote the researchers. They said further analyses showed the link between inpatient-treated infections and EDSS increase “was mainly driven by progressive MS and treatment episodes with IFN/GA.”
Differences in progressive MS, RRMS
The fact that the risk of disability worsening was significantly higher among those with progressive MS than those with RRMS suggested the body-wide immune activation “acting on underlying neurodegenerative processes [was] more prominent in those with a progressive disease course,” the researchers wrote.
Moreover, in people with RRMS, there were fewer events of disability worsening under treatment episodes with rituximab than with IFN/GA (10.1% vs. 18.9%). Also, fewer hospital-treated infections were linked to disability progression with rituximab (9.4% vs. 26.7%).
Further analyses adjusted for both relapses and MRI scan activity, which was more commonly seen with IFN/GA, showed inpatient-treated infections were significantly associated with a twofold higher risk of disability worsening in RRMS patients treated with IFN/GA. No such link was seen among those treated with rituximab.
This suggests while rituximab increases the risk of infections, it may better protect against relapse-independent disability worsening, perhaps because it’s more effective at controlling the disease, as shown by less disease activity on MRI scans.
“We corroborate earlier findings of an increased risk of infections with rituximab, compared with traditional self-injected platform therapies, and further demonstrate an association between infections and worsening of disability status,” the researchers wrote.
Accounting for infection risk when choosing MS treatments could help improve patients’ long-term outcomes, giving doctors valuable information to make better decisions that balance benefits and risks.
“These observations are important for evaluating the benefit-risk balance of MS DMTs and highlight the importance of risk mitigation and de-escalation strategies to optimize long-term outcomes in MS,” the researchers wrote.
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