This incongruence was also evident in the included DMT. Six of the 16 Conclusions: Translating DMT efficacy studies into evidence-based clinical practice requires greater methodological consistency in meta-analyses, more data on the relative effects of DMT through head-to-head clinical trials, and better reporting of adverse events. As with other pharmacological treatments, systematic reviews and meta-analyses of DMT efficacy are essential for the development of effective, evidence-based clinical guidelines 1.
However, meta-analyses on this subject often do not reach the same conclusions, which impedes translation of findings into clinical practice. In this study, we compared meta-analyses of DMT efficacy on MS disability progression to assess differences in their results and methodologies, and identify knowledge gaps in areas that are critical for accurate risk-benefit assessment and the development of effective guidelines. MS is a complex disease of the central nervous system that results in demyelination, axonal loss and neurodegeneration, and often leads to significant accumulated disability over its typical 30—40 year course.
There is significant variation in MS disease presentation and disease course after onset. At onset, there are two main disease phenotypes: relapsing-remitting intermittent periods of markedly increased disability, followed by significant or complete remission , and primary progressive continuous increase in disability with no remission.
MS disease course is understood to have two aspects. The first is disease activity, which is active disease pathology that may or may not result in worsening disability and is assessed with relapse rate and MRI imaging. The second is disease progression, the worsening of disability separate from markers of disease activity and is assessed with objective measures of worsening, such as change in Kurtzke Expanded Disability Status Scale EDSS 3.
The pathology of MS is currently understood to be immune-mediated, incorporating several immune and neurodegenerative processes, including either primary, or secondary due to inflammation neurodegeneration. However, DMT have a series of limitations. DMT are expensive and their cost continues to rise rapidly. DMT can also have significant adverse side effects, including risk of serious infections 7 , and the long-term and relative benefits remain unclear. These issues are particularly problematic when you consider that patients often need long-term treatment. Because of their importance to the MS community, it is essential that the effect of DMT on health outcomes is well understood, including accurate risk-benefit assessment, to provide a foundation for evidence-based clinical practice.
While there are several promising potential biomarkers, such as neurofilaments and MRI metrics, to date, no effective biomarker has been identified for the accurate assessment of MS disease progression. In this overview, we are interested in the most inclusive measure of disability progression, which encompasses the experience of both RRMS and PPMS cases. Therefore, for the purposes of this review, disability progression refers to measures of accumulated disability, which is a major concern for people with MS, as the level of accrued disability is directly correlated with quality of life 8.
However, their conclusions vary substantially, making it challenging to synthesize them into concrete clinical recommendations. This suggests that an overview of reviews, or a systematic review of reviews, is necessary to compare the results. Here we present an overview of meta-analyses that evaluate the effect of DMT on disability progression measured as accumulated disability in people with MS, to better understand and contextualize the results, identify differences in methodology that might explain differences in results, and highlight areas for future research.
The objective of the overview was to summarize the evidence of DMT efficacy on disability progression in people living with MS in published meta-analyses and to evaluate meta-analysis methodology. Inclusion criteria are presented in Table 1. Exclusion criteria were: 1 study does not include a meta-analysis; 2 outcome measure not related to accumulated disability. The searches for relevant articles employed search terms for DMT and multiple sclerosis. For the search terms, please see Appendix 1 in the online supporting information. One author SC extracted information on the citation details, objective, study design, participant details, search details, inclusion criteria, interventions, and outcomes, including quality assessment instrument, from the included meta-analyses using a standard form.
The inclusion criteria we extracted from each meta-analysis included study, participant, and intervention criteria. Study criteria included publication date if there was a date range set on the search , study type design and approach , outcomes, language restriction, bias assessment criteria, and sample size. Participant criteria included diagnosis criteria, age, and phenotype.
Intervention criteria included comparison group, dosage and DMT. For meta-analyses that assessed multiple time points, we included the longest follow-up that maintained most of the included studies. We compared similar outcomes from included meta-analyses we did not gather results from the individual studies included in the meta-analyses , separating outcomes into risk, odds, and hazard ratios. Risk ratios, odds ratios, and hazard ratios are all measures of probability, but they differ considerably in their calculation and are not directly comparable.
The risk ratio is calculated as the probability of an event occurring in one group divided by the probability of it occurring in another group.
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The odds ratio is calculated as the probability of an event occurring in a group divided by the probability of the event not occurring. The hazard ratio is calculated as the ratio of two hazard functions, the hazard function for one group divided by the hazard function for another 9.
We did not have access to the data required to convert one metric to another, and so presented and assessed them separately. We prioritized results comparing an active agent to placebo and collected this data if it was available. We also collected data comparing active agents if the data were adequately summarized. We did not collect information on dose comparisons. We collected data from network meta-analyses and traditional pairwise meta-analyses. We were particularly interested in comparing meta-analyses with similar aims, and so focused our attention on the general meta-analyses rather than the specific meta-analyses.
We defined general meta-analyses as those that aimed to include all approved DMT or all DMT returned by their search terms and specific meta-analyses as those that aimed to include three or less DMT. From the general meta-analyses , we extracted a list of the included studies and risk of bias assessment results. We compared the number of randomized controlled trials RCT included in the general meta-analyses with the number of available RCT. We calculated the number of available RCT as the number of RCT included in general meta-analyses that were published by the year before the search date, or the year before the publication year of the meta-analysis, if no search date was stated.
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If the publication year of a RCT was unknown, it was assumed to be the year following the year of study completion. A RCT was also considered available if it was included in a meta-analysis published prior to the one being assessed. We could not access a list of the studies included in one meta-analysis 10 and another provided a truncated list 11 , leaving the identity of some RCT uncertain.
Where RCT were not explicitly listed, we assumed that they were already represented in the list of included RCT, making our estimates conservative i. Observational and review studies were excluded from this analysis, as they were only included in one general meta-analysis We compared risk of bias assessment among the four general meta-analyses that used the Cochrane Collective risk of bias assessment tool. We selected this tool because it has strong face and construct validity This tool includes ten items, nine that query the reporting methodology of the study, which are scored by selecting yes, no, partial or can't tell and one overall assessment question item 10 , which asks assessors to rate the overall quality on a scale from 1 to 7.
We used the enhanced version, which incorporates guidelines for its use This tool consists of 18 items, focusing on reporting in the abstract and methods sections. One author SC evaluated the included meta-analyses. Meta-analyses of RCT were initially graded as high quality evidence and meta-analyses that included non-randomized studies were initially graded as low quality evidence. All meta-analyses were then evaluated for eight factors that might lower or raise the quality of evidence assessment: limitations in study execution, inconsistency of results, indirectness of evidence, imprecision, publication bias, magnitude of effect, confounding, and a dose-response gradient.
Our initial search returned articles, including 24 meta-analyses Figure 1. We excluded two of these meta-analyses, as they did not cover the subject area of this review. One evaluated short-term suboptimal response criteria to first-line DMT 17 , and the second evaluated the effect of DMT on brain atrophy, a potential but unvalidated marker of MS disease progression Our subsequent search returned Cochrane reviews, none of which met our inclusion criteria and were unique from our initial search. Twenty-two meta-analyses were included in this overview.
The characteristics of the included meta-analyses, including reporting quality and quality of evidence scores, are presented in Tables 2 , 3. All but two 28 , 35 conducted systematic reviews of the literature.
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Network meta-analyses analyse both direct comparisons within trials and indirect comparisons between trials Seven The most commonly assessed time points were 3 months 8 studies; Four meta-analyses Table 2. Characteristics of included meta-analysis, including search strategy and study, population and intervention inclusion criteria. RCT:randomized controlled trial. All included meta-analyses sought to evaluate the efficacy of one or more DMT on health outcomes in people living with MS.
Sixteen Two meta-analyses 9. We discuss three of the included meta-analyses separately, as they evaluated particular patient subgroups rather than a general population or evaluated long-term effects. One evaluated the effect of DMT on highly active RRMS and rapidly evolving severe MS 24 , the second evaluated the effect of DMT on patients with larger treatment benefits 31 and the third evaluated the long-term effects of interferon beta and glatiramer acetate Of the 19 remaining meta-analyses, eight The other 11 Eight reported results as risk ratios Three studies One general meta-analysis was not included in our assessment of studies included in general meta-analyses because we could not access a list of its included studies However, it was included in all other analyses.
Another meta-analysis 11 was included in this assessment, although its list of included studies was truncated; only providing information on 36 of 44 studies. On review of the meta-data in forest plots, two studies displayed data showing treatment effects that were counter to expectation 10 , On review of the raw data it was clear that the results had been inadvertently inverted. These were corrected by taking the inverse of the reported odds or risk ratios.
The confidence intervals in these papers were asymmetrical even when plotted on a logarithmic scale, which is atypical. We did not see any clear cause for this asymmetry in the study methods. Item 3, which queries the reporting of inclusion criteria, had the lowest compliance, with 15 studies Item 14, which queries the reporting of quantitative data synthesis, had the lowest compliance, with 8 meta-analyses The most common cause for a downgrade in evidence quality was imprecision, with the majority of meta-analyses unable to rule out no effect Supplementary Table 4. In one meta-analysis, the average duration was only 1.
Only one meta-analysis returned by our search 32 , assessed long-term effects and only did so for two DMT, glatiramer acetate and interferon beta. This analysis of 14 studies found that glatiramer acetate and interferon beta significantly reduced the time to progression to EDSS 6. Subgroup analyses were also rare, with only two meta-analyses focusing on them. The second evaluated two studies that included a subgroup analysis of highly active RRMS or rapidly evolving severe MS A numerical, but not statistically significant, increase in three-month confirmed disability progression in patients treated with fingolimod compared to those treated with natalizumab was found Supplementary Table 8.
One meta-analysis included a subgroup analysis as a secondary analysis 35 , comparing first and second line DMT and injectable and oral DMT. The authors found no significant difference between these groups first line RR: 0. Overall, the evidence suggests that, when compared to placebo, disease modifying therapies reduce the risk of disability progression in people with RRMS 19 , 22 , 25 , 27 , 34 — 37 Figures 2 , 3 ; Supplementary Tables 5 , 6 , 7. When analyzed as a group, DMT significantly reduced the risk of disability progression compared to placebo RR: 0.
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Figure 2. Source citation and dosages if specified are given in the data label. These could not be consolidated due to overlap in included studies between meta-analyses. Figure 3. Source citation and dosages if specified are listed in the data label. All meta-analyses included studies of people with relapsing MS. Combined indicates an aggregation of DMT, including dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, natalizumab, peg-interferon beta-1a, and teriflunomide.
Similarly, the Canadian Agency for Drugs and Technologies in Health CADTH found that while all ten treatments varying DMT and dosages directly compared to placebo in their analysis numerically reduced the risk of sustained disability progression, only six interferon beta-1a 44 mcg and 30 mcg , natalizumab, fingolimod, teriflunomide 14 mg and dimethyl fumarate had a significant effect There was also substantial variability in outcomes for the same DMT.
Figures 2 , 3 demonstrate that there was variance in the relative risk or the odds of progression for natalizumab and interferon beta-1a compared to placebo, with confidence intervals that do not overlap. However, it should be noted that while the meta-analyses of interferon beta-1a included different studies one only included PRISMS, the other included other studies as well , in the cases where the analyzed studies were identified, the data on natalizumab came from the same study AFFIRM in all meta-analyses.
Based on their inclusion criteria, 13 However, limited direct comparisons were possible. In their network meta-analysis of 48 studies, Hadjigeorgiou et al. Wolfe St. Use the link below to share a full-text version of this article with your friends and colleagues.
Learn more. In analyses using tertiles, individuals in the lowest tertile of baseline TMV had an average 0.
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The macula may be a retinal region of particular interest in assessing burden of neurodegeneration, as patients with predominant macular thinning display higher levels of disability. Measures of visual function are other potential attractive biomarkers to clinicians as testing can be easily performed in routine clinical practice. Baseline clinical and demographic characteristics, including EDSS scores, were recorded. Johns Hopkins University Institutional Review Board approval was obtained for all study protocols, and written informed consent was obtained from all participants.
All OCT scans were performed without pupillary dilation by experienced technicians, as described in detail elsewhere. Optic disc and macular scans with an image quality signal strength less than 7 on a scale of 1—10 or with artifact, including motion artifact, were excluded from analyses. All testing were performed monocularly and binocularly. The results were recorded as the number of letters that was correctly identified maximum of 70 letters per chart; 14 lines with 5 letters per line.
Participants were allowed to attempt the letters on a line if they correctly identified three or more letters on the previous line. Initial analyses compared demographic and clinical characteristics including age, sex, race, disease duration, MS subtype, and optic neuritis history across tertiles of baseline TMV. The composite measure of both eyes was applied because our primary outcome measure EDSS is a global measure; additionally, this approach may reduce the impact of prior ON on analyses.
In similarly adjusted models, individuals in the lowest tertile of TMV had an average 0. They were also similar in models additionally adjusted for disease duration; individuals in the lowest tertile of TMV had on average 0. As neuroaxonal degeneration is now recognized to be the primary driver of disability in MS, 1 , 2 , 11 , 24 our findings support growing evidence that neurodegeneration within the retina in MS is a meaningful biomarker of global neurodegeneration occurring as part of the disease process.
Multiple studies have reported correlations between retinal layer measurements and disability measures in MS. We propose that people with MS with significant retinal atrophy have de facto evidence of global CNS neurodegeneration. Furthermore, microscopic evidence of neurodegeneration may help to define subsets of patients in whom there is increased tissue susceptibility to future similar pathology. MRI markers of neurodegeneration in MS also support this hypothesis, as reduced deep gray matter volumes at baseline are predictive of future EDSS progression.
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The macula is a region enriched for neuronal cell bodies so it is possible that measuring reductions in macular volume is a better indicator of irreversible pathology and therefore cumulative disability. This is consistent with our prior publication which described a subset of MS patients with predominant macular thinning on OCT who demonstrated higher disability scores compared to patients without this finding.
This suggests that retinal thinning in these subgroups of patients is a more compelling marker of poor prognosis than retinal thinning in patients with advanced disease in whom retinal layer thicknesses are already expected to be lower.
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A history of clinical ON should be carefully considered in studies of OCT measurements in people with MS, as it is associated with a substantial, significant, and persistent reduction in both macular and peripapillary OCT measurements. Predicting future disability outcomes in patients with MS remains a major challenge due to clinical heterogeneity, a long disease course and confounding from therapy effects. MRI is a cornerstone of disease evaluation in patients with MS; however, conventional measures alone such as T2 lesion load are weak predictors of future disability accumulation, 40 - 42 with lesion location likely acting as an important modifier.
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