how to address multiple sclerosis
Most patients with multiple sclerosis (MS) experience sensory, motor, and cognitive impairments. However, there is currently no cure for MS. The approved disease-modifying therapies (DMTs) for relapsing-remitting MS show effective short-term results, but they offer limited benefits for progressive subtypes and have fewer treatment options. In contrast, autologous hematopoietic stem cell transplantation (AHSCT) can completely suppress MS disease activity in 70-80% of patients for 4-5 years, outperforming other MS treatments. AHSCT has also shown promising results in aggressive MS and in patients unresponsive to DMTs. It is more frequently used than allogeneic hematopoietic stem cell transplantation (SCT) for treating aggressive MS due to the risk of graft-versus-host disease associated with allogeneic SCT, which increases morbidity and mortality rates.
Preclinical studies using animal models have shown that mesenchymal stem cells (MSCs) can alleviate MS symptoms and slow disease progression. Recent human clinical trials have demonstrated that MSCs improve MS symptoms and have immunoregulatory and anti-inflammatory effects without the need for intense immunosuppression.
To evaluate the effect of SCT on MS, we included nine randomized controlled trials (RCTs) in our meta-analysis with a total of 422 patients. Our results showed that SCT significantly improved the expanded disability status scale (EDSS) at 2 months and reduced MRI-T2 weighted lesion volumes. However, improvements in EDSS for other clinical outcomes were not significant. In terms of SCT safety, there were no significant differences in adverse events, except for site reactions, and SCT patients experienced a significantly lower incidence of total infections.
The primary outcome of our meta-analysis was EDSS, a standardized and validated tool for measuring disability progression. We pooled EDSS changes from baseline to the last follow-up reported by the studies. Because follow-up period variation could confound disability outcomes, we conducted a subgroup analysis based on the follow-up period. Our subgroup results confirmed the effect of SCT on delaying disability progression at 2 months and at 6 months (after sensitivity analysis), consistent with a previous meta-analysis on AHSCT. Although EDSS change was not significant at 6 and 12 months, sensitivity analysis showed a significant change in effect size. EDSS at 6 months significantly favored SCT after excluding one study, and EDSS at 12 months significantly changed after excluding another study that included only secondary progressive multiple sclerosis (SPMS) patients with longer disease duration and deteriorating disability. Previous literature found that SCT is more effective for relapsing-remitting multiple sclerosis (RRMS) than for progressive MS, linked to lower baseline EDSS and early disease stage. However, our subgroup analysis based on baseline EDSS scores showed nonsignificant effects on disability progression. Other subgroup analyses regarding stem cell source and dose supported previous findings of nonsignificant effects on disease progression.
We assessed SCT’s effect on patients’ walking ability using the T25-FW test, which is reliable for short- and long-term assessments. The analysis showed nonsignificant improvement overall and in patients who received MSCs without immunosuppression. However, significant improvement was seen in patients who received AHSCT preceded by immunosuppression. The T25-FW scores analysis aligns with the EDSS analysis, as both endpoints are influenced by lower extremity disability. Regarding radiological outcomes, the reduction in MRI lesion volumes indicates suppression of brain inflammation and prevention of further disease progression. This reduction is consistent with EDSS improvement, as a positive correlation between MRI lesion volume and disability has been established.
Overall improvement in upper extremity function was nonsignificant, and none of the trials showed significant changes in the 9-HPT, except one that included only RRMS patients with low baseline EDSS. The 9-HPT’s sensitivity issues might have affected this outcome. Nonsignificant adverse events in the studies included headache and gastrointestinal disturbances. MS patients typically have a high incidence of infections, particularly respiratory infections. Surprisingly, SCT patients in this meta-analysis experienced a significantly lower incidence of total infections, likely due to the antimicrobial properties of stem cells. No deaths were reported during the follow-up period, aligning with a previous meta-analysis. Treatment-related mortality of AHSCT in MS has decreased significantly in recent years.
Studies with immune ablative regimens before AHSCT showed significant improvements in EDSS, T25-FW, 9HPT, and lesion volume. Immunoablation followed by SCT is used to induce sustained remission in several autoimmune diseases. Future trials should assess the long-term effects of immunoablation before SCT.
Our meta-analysis provides an up-to-date evaluation of SCT efficacy and safety based on RCTs, following PRISMA guidelines and the Cochrane Handbook for Systematic Reviews of Interventions. We included cross-over trials up to the cross-over point to avoid carry-over effects. We analyzed all potential efficacy and safety outcomes to offer a comprehensive view of SCT’s role in MS.
However, our meta-analysis faced limitations, including the inability to provide a quantitative comparison between SCT and approved DMTs due to insufficient studies, short follow-up periods, and heterogeneity among the studies. Variations in patient characteristics and procedural parameters contributed to this heterogeneity. Future RCTs should compare SCT with approved DMTs, investigate different sources and routes of stem cell transplantation, and assess the long-term effects on disease progression and safety.
In conclusion, SCT improves disability and reduces brain lesion volume in MS patients at 2 months. SCT is tolerable and safe, with no mortality reported during follow-up. Further RCTs of longer duration, without cross-over, and focused on specific MS subtypes and immunosuppression before transplantation are needed to support evidence-based management. Including treatment-naïve patients will ensure a pure assessment of SCT safety and efficacy.
We continue to see more advances in regenerative medicine as treatments. Please watch this space as the innovations move forward.
Our Editorial Note: Above is our brief summary of an article from Nature. You may need a subscription to view the article in its entirety. Here is a link to the article that was published May 31, 2024:
https://www.nature.com/articles/s41598-024-62726-4
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