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ToolsRidley, Ben, Minozzi, Silvia, Gonzalez-Lorenzo, Marien, Del Giovane, Cinzia, Piggott, Thomas, Filippini, Graziella, Peryer, Guy, Foschi, Matteo, Tramacere, Irene, Baldin, Elisa and Nonino, Francesco (2024) Immunomodulators and immunosuppressants for progressive multiple sclerosis: A network meta-analysis (Protocol). Cochrane Database of Systematic Reviews, 2022 (11). ISSN 1361-6137
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Abstract
Background: Recent years have seen a broader range of immunomodulatory and immunosuppressive treatment options for people with progressive forms of multiple sclerosis (PMS). While consensus supports these options as reducing relapses, relative benefit and safety profiles remain unclear due to a lack of direct comparison trials. Objectives: To compare through network meta-analysis the efficacy and safety of alemtuzumab, azathioprine, cladribine, cyclophosphamide, daclizumab, dimethylfumarate, diroximel fumarate, fingolimod, fludarabine, glatiramer acetate, immunoglobulins, interferon beta 1-a and beta 1-b, interferon beta-1b (Betaferon), interferon beta-1a (Avonex, Rebif), laquinimod, leflunomide, methotrexate, minocycline, mitoxantrone, mycophenolate mofetil, natalizumab, ocrelizumab, ofatumumab, ozanimod, pegylated interferon beta-1a, ponesimod, rituximab, siponimod, corticosteroids, and teriflunomide for PMS. Search methods: We searched CENTRAL, MEDLINE and Embase up to August 2022 as well as clinicaltrials.gov and the WHO trials registry. Selection criteria: Randomised controlled trials (RCTs) that studied one or more treatments as monotherapy, compared to placebo or to another active agent, for use in adults with PMS. Data collection and analysis: Two authors independently selected studies and extracted data. We performed data synthesis by pairwise and network meta-analysis. We assessed the certainty of the body of evidence according to GRADE. Main results: We included 23 studies involving 10167 participants. Considering risk of bias, the most frequent concern was related to the role of the sponsor in the authorship of the study report or in data management and analysis, for which we judged 39% of the studies at high risk of bias. The other most frequent concerns were performance, attrition and selective reporting bias with 8.7% of the studies at high risk of bias for each domain. Relapses over 12 months was provided in one study (318 participants) comparing immunoglobulins with placebo; immunoglobulins may have little to no effect (RR 1.76, 95% confidence interval (CI) 0.76 to 1.41; very low certainty evidence). Relapses over 24 months were provided in 6 studies (1622 participants) and assessing six treatments. Using placebo as common comparator, interferon beta 1a may reduce relapse rate (RR 0.72, 95% CI 0.54 to 0.0.95; very low certainty evidence). Relapses over 36 months were provided in 4 studies (2095 participants) comparing three treatments with placebo. Interferon beta 1b probably reduces relapses rate (RR 0.82, 95% CI 0.73 to 0.93; moderate certainty evidence; azathioprine may reduce relapses rate (RR 0.54, 95% CI 0.30 to 0.99; very low certainty evidence). Disability worsening over 24 months was provided in 11 studies (5284 participants) assessing ten treatments. Using placebo as common comparator, all treatments may have little or no effect, very low certainty evidence. Disability worsening over 36 months was provided in 5 studies (2827 participants) comparing 4 treatments with placebo. All treatments may have little or no effect, very low certainty evidence. Treatment discontinuation due to adverse events (AEs) was provided in 21 studies (9981 participants) assessing 14 treatments. Using placebo as common comparator, treatment with interferon beta 1a (Avonex, Rebif) increases the number of subjects who discontinued due to AEs (OR 2.93 95% CI 1.64 to 5.26; high certainty evidence); treatment with glatiramer acetate (OR 3.98 95% CI 1.48 to 10.72; moderate certainty evidence), interferon beta 1b (Betaferon)(OR 2.98 95% CI 1.92 to 4.61; moderate certainty evidence) and fingolimod (OR 2.29 95% CI 1.46 to 3.60; moderate certainty evidence) probably increase the number of subjects who discontinued due to AEs. Serious adverse events (SAEs) were available from 15 studies (8019 participants) assessing 13 treatments. Using placebo as common comparator, treatment with immunoglobulins may increase subjects with SAEs (OR 7.13 95% CI 1.23 to 41.34; very low certainty evidence). Authors' conclusions: We are moderately confident that, compared to placebo, interferon beta-1b probably reduces the number of people with relapses after three years of treatment. However, treatments with interferon beta-1a and beta-1b are both associated with a higher proportion of withdrawals due to adverse events. Poor tolerability is associated also with the use of glatiramer acetate and fingolimod. Unfortunately, all DMTs included in our review provide little or no effect as compared to placebo on disability progression. Our confidence in most of the estimates of effect is very low, mainly because of imprecision. Serious adverse events were not significantly more frequent with DMTs than with placebo, except for immunoglobulins. Such findings are partly due to short follow up of the included RCTs, with a lack of detection of less common severe adverse events. Moreover, in many of the included studies funding by pharmaceutical companies may have influenced their results. Future research on PMS should include head-to-head rather than placebo-controlled trials with longer follow up of at least 3 years. Given the relative rarity of PMS, controlled, non-randomised studies on large samples may usefully integrate data from pivotal RCTs. Outcomes valuable for people with PMS should be consistently adopted and measured, allowing the evaluation of relative effectiveness among treatments.
| Item Type: | Article |
|---|---|
| Additional Information: | Funding Information: Contribution to the review was partly supported by the not-for-profit organisation Multiple Sclerosis International Federation to the Editorial Base of the Group hosted by IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy. |
| Uncontrolled Keywords: | pharmacology (medical) ,/dk/atira/pure/subjectarea/asjc/2700/2736 |
| Faculty \ School: | Faculty of Medicine and Health Sciences > Norwich Medical School Faculty of Medicine and Health Sciences > School of Health Sciences |
| UEA Research Groups: | Faculty of Medicine and Health Sciences > Research Centres > Institute for Volunteering Research Faculty of Medicine and Health Sciences > Research Centres > Lifespan Health |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 29 Sep 2022 09:30 |
| Last Modified: | 01 May 2025 14:30 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/88709 |
| DOI: | 10.1002/14651858.CD015443 |
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