Dr Yvonne NaegelinYvonne Naegelin, MD
Patients with secondary progressive multiple sclerosis (SPMS) treated with rituximab saw significant reductions in their Expanded Disability Status Scale (EDSS) scores over the course of 10 years in a retrospective cohort study.1

In addition to the mean difference of –0.52 EDSS points (95% CI, –0.79 to –0.26; P <.001) compared to matched controls not treated with the rituximab, those treated with the monoclonal CD20 antibody experienced a delayed in confirmed disability progression (hazard ratio [HR], 0.49; 95% CI, 0.26 to 0.93; P = .03). The mean follow-up was 3.5 years (standard deviation [SD], 2.6).

Coauthor Yvonne Naegelin, MD, from the department of neurology at University Hospital Basel, and colleagues wrote that “these findings suggest that rituximab administration may be associated with a beneficial therapeutic effect in patients with SPMS,” and that as a result, “a prospective randomized clinical trial is needed to show efficacy in this patient group with a higher level of evidence.”

In total, the analysis compared 54 patients with SPMS treated with rituximab to 59 patients with SPMS who were never treated with the therapy. The authors used yearly standardized clinical assessments, including a full Neurostatus-EDSS examination. As well, they utilized routine magnetic resonance imaging (MRI) findings for new T2 lesions and gadolinium-enhancing lesions, although only 33 patients had baseline MRIs, thus those findings were not used for the matching process.

The analysis of the primary end point also showed that rituximab treatment significantly reduced progression of disability (estimate, −0.45; 95% CI, −0.71 to −0.20; P <.001) and confirmed disability progression in the total cohort (HR, 0.48; 95% CI, 0.26 to 0.91; P = .02).

Patients with confirmed progression were observed to have higher cumulative doses of rituximab as well as more treatment cycles, though for a longer period of time.

“The treatment intensity (defined as the total amount of rituximab administered in milligrams divided by the duration of treatment in months) remained similar compared with patients without confirmed progression,” Naegelin and colleagues wrote. “In summary, no associations between confirmed progression and individual patient baseline characteristics could be identified.”

As for safety, 54% of patients (n = 29) treated with rituximab were still being treated without complications at the analysis’s cutoff point. In 9% of cases (n = 5), a complication was reported. A single patient had leukocytoclastic vasculitis in both legs, which was confirmed by biopsy, after the first infusion, 1 patient had a segmental herpes zoster infection, and 3 had ≥1 pneumonia events or urinary tract infections. During the follow-up period, 2 patients died. One from a spontaneous intracerebral hemorrhage 3 years post-halting of rituximab treatment (it was stopped due to disease stabilization), and 1 from pneumonia 4 years after rituximab treatment had been stopped.

According to the analysis, about 75% of the rituximab-untreated patients and 50% of the rituximab-treated patients, respectively, developed a clinically significant confirmed disability progression over the 10-year assessment period. Naegelin et al. noted that “this is in line with other cohorts in which the rates of progression during a 3- and a 10-year follow-up were 15% and 75%, respectively,” according to studies conducted by Bove et al.2, Healy et al.3, and Cree et al.4.

Previously, in the EXPAND trial, siponimod, a sphingosine-1-phosphate receptor modulator, was assessed in a cohort of patients with SPMS with similar baseline characteristics to this analysis by Naegelin et al. That trial revealed a significant reduction in disability progression compared to placebo. After 2 years, 20% of those treated with siponimod had a 6-month confirmed disability progression compared to 28% with placebo. After 3 years, those percentages jumped to 23% and 30%, respectively.

“This is comparable to a [confirmed disability progression] in 25% of matched controls and in 12.5% of rituximab-treated patients at year 2 and in 37.5% of matched controls and in 25% of rituximab-treated patients at year 3 in our cohort,” Naegelin and colleagues wrote.

As the authors acknowledge, identifying patient characteristics which suggest a higher probability of treatment response is crucial, although this analysis showed no significant differences in any of the tested categories. However, the authors noted these results “should be interpreted with caution” as the lack of baseline MRI findings was notable.

The authors did admit that the higher proportion of patients in the control group which had not been treated with a disease-modifying therapy in the year before baseline measurements—49% and 48% in the total and matched groups, respectively, compared with 39% and 41% of the rituximab-treated patients—was a limitation of the analysis. This “could indicate a bias toward a less aggressive disease course in the control group that may contribute to underestimating the effects associated with [the] administration of rituximab,” they wrote, though they suggested that propensity score-based matching was utilized to mitigate confounding effects.

“Furthermore, it was reassuring that the significant association observed in the propensity score-matched comparison was also significant in the total group analysis,” they wrote. They concluded that “therapeutic options for patients with secondary progressive multiple sclerosis are limited; however, these findings suggest that B-cell–depleting therapy may be beneficial.”
REFERENCES
1. Naegelin Y, Naegelin P, von Felton S, et al. Association of rituximab treatment with disability progression among patients with secondary progressive multiple sclerosis. JAMA Neurol. Published online January 7, 2019. doi:10.1001/jamaneurol.2018.4239. Accessed January 7, 2019.
2. Bove  R, Chitnis  T, Cree  BA,  et al.  SUMMIT (Serially Unified Multicenter Multiple Sclerosis Investigation): creating a repository of deeply phenotyped contemporary multiple sclerosis cohorts. Mult Scler. 2018;24(11):1485-1498. doi:10.1177/1352458517726657
3. Healy  BC, Engler  D, Gholipour  T, Weiner  H, Bakshi  R, Chitnis  T.  Accounting for disease modifying therapy in models of clinical progression in multiple sclerosis.  J Neurol Sci. 2011;303(1-2):109-113. doi:10.1016/j.jns.2010.12.024PubMedGoogle ScholarCrossref
4. Cree  BA, Gourraud  PA, Oksenberg  JR,  et al.  Long-term evolution of multiple sclerosis disability in the treatment era.  Ann Neurol. 2016;80(4):499-510. doi:10.1002/ana.24747