BACKGROUND: Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators, immunosuppressants and biological agents. Although each one of these therapies reduces relapse frequency and slows disability accumulation compared to no treatment, their relative benefit remains unclear. This is an update of a Cochrane review published in 2015.
OBJECTIVES: To compare the efficacy and safety, through network meta-analysis, of interferon beta-1b, interferon beta-1a, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, pegylated interferon beta-1a, daclizumab, laquinimod, azathioprine, immunoglobulins, cladribine, cyclophosphamide, diroximel fumarate, fludarabine, interferon beta 1-a and beta 1-b, leflunomide, methotrexate, minocycline, mycophenolate mofetil, ofatumumab, ozanimod, ponesimod, rituximab, siponimod and steroids for the treatment of people with RRMS.
SEARCH METHODS: CENTRAL, MEDLINE, Embase, and two trials registers were searched on 21 September 2021 together with reference checking, citation searching and contact with study authors to identify additional studies. A top-up search was conducted on 8 August 2022.
SELECTION CRITERIA: Randomised controlled trials (RCTs) that studied one or more of the available immunomodulators and immunosuppressants as monotherapy in comparison to placebo or to another active agent, in adults with RRMS.
DATA COLLECTION AND ANALYSIS: Two authors independently selected studies and extracted data. We considered both direct and indirect evidence and performed data synthesis by pairwise and network meta-analysis. Certainty of the evidence was assessed by the GRADE approach.
MAIN RESULTS: We included 50 studies involving 36,541 participants (68.6% female and 31.4% male). Median treatment duration was 24 months, and 25 (50%) studies were placebo-controlled. Considering the 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 68% of the studies were at high risk of other bias. The other frequent concerns were performance bias (34% judged as having high risk) and attrition bias (32% judged as having high risk). Placebo was used as the common comparator for network analysis. Relapses over 12 months: data were provided in 18 studies (9310 participants). Natalizumab results in a large reduction of people with relapses at 12 months (RR 0.52, 95% CI 0.43 to 0.63; high-certainty evidence). Fingolimod (RR 0.48, 95% CI 0.39 to 0.57; moderate-certainty evidence), daclizumab (RR 0.55, 95% CI 0.42 to 0.73; moderate-certainty evidence), and immunoglobulins (RR 0.60, 95% CI 0.47 to 0.79; moderate-certainty evidence) probably result in a large reduction of people with relapses at 12 months. Relapses over 24 months: data were reported in 28 studies (19,869 participants). Cladribine (RR 0.53, 95% CI 0.44 to 0.64; high-certainty evidence), alemtuzumab (RR 0.57, 95% CI 0.47 to 0.68; high-certainty evidence) and natalizumab (RR 0.56, 95% CI 0.48 to 0.65; high-certainty evidence) result in a large decrease of people with relapses at 24 months. Fingolimod (RR 0.54, 95% CI 0.48 to 0.60; moderate-certainty evidence), dimethyl fumarate (RR 0.62, 95% CI 0.55 to 0.70; moderate-certainty evidence), and ponesimod (RR 0.58, 95% CI 0.48 to 0.70; moderate-certainty evidence) probably result in a large decrease of people with relapses at 24 months. Glatiramer acetate (RR 0.84, 95%, CI 0.76 to 0.93; moderate-certainty evidence) and interferon beta-1a (Avonex, Rebif) (RR 0.84, 95% CI 0.78 to 0.91; moderate-certainty evidence) probably moderately decrease people with relapses at 24 months. Relapses over 36 months findings were available from five studies (3087 participants). None of the treatments assessed showed moderate- or high-certainty evidence compared to placebo. Disability worsening over 24 months was assessed in 31 studies (24,303 participants). Natalizumab probably results in a large reduction of disability worsening (RR 0.59, 95% CI 0.46 to 0.75; moderate-certainty evidence) at 24 months. Disability worsening over 36 months was assessed in three studies (2684 participants) but none of the studies used placebo as the comparator. Treatment discontinuation due to adverse events data were available from 43 studies (35,410 participants). Alemtuzumab probably results in a slight reduction of treatment discontinuation due to adverse events (OR 0.39, 95% CI 0.19 to 0.79; moderate-certainty evidence). Daclizumab (OR 2.55, 95% CI 1.40 to 4.63; moderate-certainty evidence), fingolimod (OR 1.84, 95% CI 1.31 to 2.57; moderate-certainty evidence), teriflunomide (OR 1.82, 95% CI 1.19 to 2.79; moderate-certainty evidence), interferon beta-1a (OR 1.48, 95% CI 0.99 to 2.20; moderate-certainty evidence), laquinimod (OR 1.49, 95 % CI 1.00 to 2.15; moderate-certainty evidence), natalizumab (OR 1.57, 95% CI 0.81 to 3.05), and glatiramer acetate (OR 1.48, 95% CI 1.01 to 2.14; moderate-certainty evidence) probably result in a slight increase in the number of people who discontinue treatment due to adverse events. Serious adverse events (SAEs) were reported in 35 studies (33,998 participants). There was probably a trivial reduction in SAEs amongst people with RRMS treated with interferon beta-1b as compared to placebo (OR 0.92, 95% CI 0.55 to 1.54; moderate-certainty evidence).
AUTHORS' CONCLUSIONS: We are highly confident that, compared to placebo, two-year treatment with natalizumab, cladribine, or alemtuzumab decreases relapses more than with other DMTs. We are moderately confident that a two-year treatment with natalizumab may slow disability progression. Compared to those on placebo, people with RRMS treated with most of the assessed DMTs showed a higher frequency of treatment discontinuation due to AEs: we are moderately confident that this could happen with fingolimod, teriflunomide, interferon beta-1a, laquinimod, natalizumab and daclizumab, while our certainty with other DMTs is lower. We are also moderately certain that treatment with alemtuzumab is associated with fewer discontinuations due to adverse events than placebo, and moderately certain that interferon beta-1b probably results in a slight reduction in people who experience serious adverse events, but our certainty with regard to other DMTs is lower. Insufficient evidence is available to evaluate the efficacy and safety of DMTs in a longer term than two years, and this is a relevant issue for a chronic condition like MS that develops over decades. More than half of the included studies were sponsored by pharmaceutical companies and this may have influenced their results. Further studies should focus on direct comparison between active agents, with follow-up of at least three years, and assess other patient-relevant outcomes, such as quality of life and cognitive status, with particular focus on the impact of sex/gender on treatment effects.
OBJECTIVE: To compare the efficacy and compliance of up-to-date disease modifying therapies (DMTs) in patients with remitting-relapsing MS (RRMS).
METHODS: We searched PubMed, EMBASE and Cochrane Library for eligible studies. Annualized relapse rate, discontinuation due to adverse events (AEs) were assessed as primary outcomes. Sensitivity analysis and inconsistency detection were performed to evaluated whether exclusion of high-risk studies affected the validity. Risk of bias was assessed using Cochrane's Risk-of-Bias Tool 2. Surface under the cumulative ranking curve (SUCRA) was used to estimate the rankings among different DMTs.
RESULTS: 21 studies were included for main report. Seven studies were evaluated as "high risk" and were therefore excluded. Exclusion of high-risk studies did not affect the validity of evidence. The risk of relapses for most DMTs except Betaseron 50 μg was significantly lower comparing to placebo. Incompliance in patients treated with DMTs was not significantly increased comparing to placebo. Dimethyl fumarate and ocrelizumab had superiority in improving MRI outcomes. Ocrelizumab and ofatumumab had the largest reduction of risk in disability progression at 3 months. Referring to SUCRA, ofatumumab, alemtuzumab and natalizumab showed the best efficacy and compliance.
CONCLUSION: The present study demonstrated the hierarchy of DMTs treating RRMS. Ofatumumab, alemtuzumab and natalizumab have superiority with respect to effectiveness and compliance. More studies are required to explore the long-term effect of DMTs. Our findings could provide helpful information and contribute to clinical treatment decision-making.
Aim: To compare the efficacy of ofatumumab to other disease-modifying therapies (DMTs) for relapsing multiple sclerosis (RMS). Materials & methods: A network meta-analysis was conducted to determine the relative effect of ofatumumab on annualized relapse rate and confirmed disability progression at 3 months and 6 months. Results: For each outcome, ofatumumab was as effective as other highly efficacious monoclonal antibody DMTs (i.e., alemtuzumab, natalizumab and ocrelizumab). Conclusion: Ofatumumab offers beneficial outcomes for RMS by reducing relapse and disability progression risk.
BACKGROUND: A broad range of disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) is available. However, the efficacy and safety of traditional DMTs compared with the recently developed DMTs remain unclear.
OBJECTIVE: Therefore, we have synthesised available evidence of clinical outcomes for DMTs in adults with RRMS.
METHODS: PubMed, Scopus and a manual search were performed. Bayesian network meta-analyses of randomised clinical trials assessing DMTs as monotherapies were conducted. SUCRA and GRADE were used to rank therapies and to assess quality of general evidence, respectively.
RESULTS: Thirty-three studies were included in the meta-analyses. The most effective therapies for the outcome of annualised relapse rate were alemtuzumab (96% probability), natalizumab (96%) and ocrelizumab (85%), compared with all other therapies (hazard ratio versus placebo, 0.31, 0.31 and 0.37, respectively; p < 0.05 for all comparisons) (high-quality evidence). However, no significant differences among these three therapies were found. Discontinuation due to adverse events revealed similarity across all therapies, except for alemtuzumab, which showed less discontinuation when compared with interferon-1a intramuscular (relative risk 0.37; p < 0.05).
CONCLUSION: High-quality evidence shows that alemtuzumab, natalizumab and ocrelizumab present the highest efficacy among DMTs, and other meta-analyses are required regarding adverse events frequency, to better understand the safety of therapies. Based on efficacy profile, guidelines should consider a three-category classification (i.e. high, intermediate and low efficacy).
BACKGROUND: Psychiatric comorbidity is prevalent in persons with multiple sclerosis (MS). Few studies have assessed whether second-generation disease-modifying therapies (DMT) are associated with adverse psychiatric effects.
OBJECTIVE: We aimed to systematically review the literature regarding the APEs associated with natalizumab, fingolimod, dimethyl fumarate, teriflunomide and alemtuzumab in MS. As a secondary objective, we evaluated changes in anxiety or depression scores following treatment with the aforementioned DMTs.
METHODS: We searched MEDLINE, EMBASE, International Pharmaceutical Abstracts, PsychINFO, Central Register of Controlled Trials & Cochrane database of systematic reviews for published studies, and clinicaltrials.gov and regulatory documents from the US and Canada for unpublished studies. Data sources were searched from inception to September 2017. Studies reporting adverse psychiatric effects involving any DMT of interest were included. We report the incidence proportions of the adverse psychiatric effects and, where applicable, risk differences between DMT-exposed and unexposed individuals along with the corresponding 95% confidence intervals. We calculated the standardized mean differences (SMD) of changes in anxiety and depression scores if reported as study outcomes, and pooled the data using random effects meta-analysis.
RESULTS: Of 4389 abstracts screened, 78 met the inclusion criteria, including 48 clinical trials, 28 observational studies and 2 case reports. Depression was the most commonly reported adverse psychiatric effect. Incidence proportions for all adverse psychiatric effects ranged from 0 to 24.7%. None of the DMT studied were associated with a statistically significant increased risk of any adverse psychiatric effect (range of risk difference: -7.69% [95%CI: -16.06%, 5.56%] to 6.67 [-8.56, 15.59]). Eighteen studies examined changes in depression or anxiety following fingolimod, natalizumab or dimethyl fumarate treatment; depression symptoms improved in fingolimod-treated groups (SMD [95%CI]: 1.18 [0.17, 2.19]). We did not identify studies examining changes in these outcomes following treatment with any of the other DMTs.
CONCLUSION: The DMTs reviewed were not associated with an increased risk of adverse psychiatric effect in MS, and some may reduce the incidence of depressive symptoms. This may reflect either a positive direct effect (e.g. immune modulation) or an indirect effect arising due to a positive impact on disease activity or course.
OBJECTIVE: To review evidence on starting, switching, and stopping disease-modifying therapies (DMTs) for multiple sclerosis (MS) in clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and progressive MS forms.
METHODS: Relevant, peer-reviewed research articles, systematic reviews, and abstracts were identified (MEDLINE, CENTRAL, EMBASE searched from inception to November 2016). Studies were rated using the therapeutic classification scheme. Prior published Cochrane reviews were also used.
RESULTS: Twenty Cochrane reviews and an additional 73 full-text articles were selected for data extraction through an updated systematic review (completed November 2016). For people with RRMS, many DMTs are superior to placebo (annualized relapses rates [ARRs], new disease activity [new MRI T2 lesion burden], and in-study disease progression) (see summary and full text publications). For people with RRMS who experienced a relapse on interferon-β (IFN-β) or glatiramer acetate, alemtuzumab is more effective than IFN-β-1a 44 μg subcutaneous 3 times per week in reducing the ARR. For people with primary progressive MS, ocrelizumab is probably more effective than placebo (in-study disease progression). DMTs for MS have varying adverse effects. In people with CIS, glatiramer acetate and IFN-β-1a subcutaneous 3 times per week are more effective than placebo in decreasing risk of conversion to MS. Cladribine, immunoglobulins, IFN-β-1a 30 μg intramuscular weekly, IFN-β-1b subcutaneous alternate day, and teriflunomide are probably more effective than placebo in decreasing risk of conversion to MS. Suggestions for future research include studies considering comparative effectiveness, usefulness of high-efficacy treatment vs stepped-care protocols, and research into predictive biomarkers.
OBJECTIVE: To assess the comparative efficacy and safety of cladribine tablets versus alternative disease modifying treatments (DMTs) in patients with active relapsing-remitting multiple sclerosis (RRMS), and in a subgroup with high disease activity (HRA+DAT), using systematic literature review (SLR) and network meta-analysis (NMA).
METHODS: MEDLINE, Embase, MEDLINE In-Process and CENTRAL databases were systematically searched to identify English-language publications of relevant studies of approved DMTs for RRMS. Searches were conducted from database inception to January 2017. Conference websites and trial registries were also searched. NMA considered the effects of DMTs on annualized relapse rate (ARR), confirmed disease progression (CDP), no evidence of disease activity (NEDA), and safety.
RESULTS: Of 10,825 articles retrieved and screened, 44 studies assessing 12 DMTs contributed to the NMA. In patients with active RRMS, cladribine tablets were associated with a significant 58% reduction in ARR versus placebo (p < 0.05); cladribine tablets were similar or significantly better than other DMT regimens and ranked fourth among DMTs, behind alemtuzumab, natalizumab, and ocrelizumab. For CDP for 6 months and NEDA, improvements with cladribine tablets were significantly greater than those of placebo (p < 0.05), with no comparator DMT demonstrating significantly better results. Similar findings were reported in the HRA+DAT population. Overall adverse event risk for cladribine tablets did not differ significantly from that of placebo and most alternative DMTs.
CONCLUSION: In this first NMA to consider cladribine tablets, ocrelizumab, and daclizumab for treatment of RRMS, cladribine tablets are a comparatively effective and safe alternative to other DMTs in both active RRMS and HRA+DAT populations.
OBJETIVO: Evaluar el grado en que el efecto del tratamiento sobre la atrofia cerebral es capaz de mediar, en primera instancia, el efecto del tratamiento sobre la progresión de la discapacidad en la esclerosis múltiple recurrente-remitente (EMRR).
MÉTODOS: Se recogieron todos los ensayos clínicos aleatorios publicados en EMRR que duran al menos 2 años y que incluyen como criterios de valoración progresión de la discapacidad (definida como 6 o 3 meses confirmado aumento de 1 punto en la Disability Status Scale Ampliado), resonancia magnética (MRI) activa lesiones (definida como nuevos / ampliación de lesiones T2), y atrofia cerebral (definida como el cambio en el volumen del cerebro entre meses y 24 meses 6-12). Los efectos del tratamiento se expresaron como reducciones relativas. Una regresión lineal, ponderados por el tamaño del ensayo y la duración, se utilizó para evaluar la relación entre los efectos del tratamiento sobre los marcadores de resonancia magnética y en la progresión de la discapacidad.
RESULTADOS: Trece ensayos incluidos> 13500 EMRR pacientes fueron incluidos en el meta-análisis. Los efectos del tratamiento sobre la progresión de la discapacidad se correlacionaron con los efectos del tratamiento, tanto en la atrofia cerebral (R (2) = 0,48, p = 0,001) y en las lesiones de MRI activos (R (2) = 0,61, p <0,001). Cuando se incluyeron los efectos en ambos extremos de resonancia magnética en un modelo multivariado, la correlación fue mayor (R (2) = 0,75, p <0,001), y ambas variables se mantiene como independiente relacionado con el efecto del tratamiento sobre la progresión de la discapacidad.
En conclusión, en EMRR, el efecto del tratamiento sobre la atrofia cerebral se correlaciona con el efecto sobre la progresión de la discapacidad más de 2 años. Este efecto es independiente del efecto de las lesiones de MRI activos sobre la discapacidad; las 2 medidas de resonancia magnética predicen el efecto del tratamiento sobre la discapacidad más estrechamente cuando se utiliza en combinación.
ANTECEDENTES: Diferentes estrategias terapéuticas están disponibles para el tratamiento de la esclerosis múltiple (MS), incluyendo inmunosupresores, inmunomoduladores, y anticuerpos monoclonales. Su eficacia relativa en la prevención de la recaída o la progresión de la discapacidad está claro debido al número limitado de ensayos de comparación directa. Un resumen de los resultados, incluyendo tanto las comparaciones directas e indirectas de los efectos del tratamiento, puede ayudar a aclarar la incertidumbre anteriormente.
OBJETIVOS: Estimar la eficacia relativa y la aceptabilidad de interferón beta-1b (IFNß-1b) (Betaseron), el interferón beta-1a (IFNß-1a) (Rebif y Avonex), acetato de glatiramer, natalizumab, mitoxantrona, metotrexato, ciclofosfamida, azatioprina , inmunoglobulinas intravenosas y corticosteroides a largo plazo versus placebo u otro agente activo en los participantes con EM y para proporcionar un ranking de los tratamientos en función de su eficacia y equilibrio riesgo-beneficio.
ESTRATEGIA DE BÚSQUEDA: Se realizaron búsquedas en la Base de Datos Cochrane de Revisiones Sistemáticas, Ensayos Cochrane MS Group Registro, y la Administración de Alimentos y Medicamentos (FDA) de los informes. La búsqueda más reciente se llevó a cabo en febrero de 2012.
Criterios de selección: Ensayos controlados aleatorios (ECA) que estudió uno de los 11 tratamientos para su uso en adultos con esclerosis múltiple y que informó fueron considerados nuestros resultados de eficacia fi cados pre-específicas para la inclusión.
Recopilación y análisis de datos: La identificación de resultados de búsqueda y extracción de datos se realizaron de forma independiente por dos autores. Síntesis de los datos fue realizada por dos a dos meta-análisis y meta-análisis de la red que se realizó en un marco bayesiano. El cuerpo de la evidencia de los resultados dentro de la meta-análisis por pares se evaluó de acuerdo al grado, como muy baja, baja, moderada o alta calidad.
Resultados principales: Cuarenta y cuatro ensayos fueron incluidos en esta revisión, en la que habían sido asignados al azar 17.401 participantes. Veintitrés ensayos incluyeron EM recurrente-remitente (EMRR) (9096 participantes, 52%), 18 ensayos incluyeron progresiva MS (7726, 44%), y tres ensayos incluyeron tanto EMRR y progresiva MS (579, 3%). La mayoría de los ensayos incluidos fueron estudios a corto plazo, con una mediana de 24 meses de duración. Los resultados originados en su mayoría de 33 ensayos sobre IFNß, acetato de glatiramer y natalizumab que en general contribuyeron datos de resultado para 9881 participantes (66%).
Desde el meta-análisis de pares, no había pruebas de alta calidad que el natalizumab y IFNß-1a (Rebif) fueron eficaces contra la recurrencia de recaídas en EMRR durante los primeros 24 meses de tratamiento en comparación con el placebo (odds ratio (OR) 0,32; IC del 95% intervalo (IC) 0,24-0,43; OR 0,45; IC del 95%: 0,28 a 0,71; respectivamente); que eran más eficaces que IFNß-1a (Avonex) (OR 0,28; IC del 95%: 0,22-0,36; OR 0,19; IC del 95%: 0,06 a 0,60, respectivamente). IFNß-1b (Betaseron) y mitoxantrona probablemente disminuyeron las probabilidades de los participantes con EMRR que tienen recaídas clínicas en comparación con el placebo (OR 0.55, IC 95% 0,31-0,99; OR 0.15, IC 95% 0,04 hasta 0,54, respectivamente), pero la calidad de evidencia de estos tratamientos se calificó como moderada. Desde el meta-análisis de redes, el fármaco más eficaz parecía estar natalizumab (mediana O versus placebo 0,29, 95% intervalos de credibilidad (CRI) 0,17 hasta 0,51), seguido por IFNß-1a (Rebif) (mediana O versus placebo 0.44, 95 % CrI desde 0,24 hasta 0,70), mitoxantrona (mediana O versus placebo 0,43, 95% CrI 0,20 a 0,87), el acetato de glatiramer (mediana O versus placebo 0,48, 95% CrI 0,38 a 0,75), IFNß-1b (Betaseron) (mediana O frente placebo 0,48, 95% CrI 0,29 a 0,78). Sin embargo, nuestra confianza fue moderada para la comparación directa de la mitoxantrona y IFNB-1b frente a placebo y muy bajo para la comparación directa de glatiramer vs placebo. El resultado de recaída para la EMRR en tres años de seguimiento no se informó en ninguno de los ensayos incluidos.
Progresión de la discapacidad se basa en marcadores indirectos en la mayoría de los estudios incluidos y no estaba disponible para la EMRR más allá de dos o tres años. El meta-análisis por pares sugirió, con pruebas de calidad moderada, que el natalizumab y IFNß-1a (Rebif), probablemente disminuyó las probabilidades de los participantes con tener progresión de la discapacidad EMRR a los dos años de seguimiento, con una reducción absoluta del 14% y 10 %, respectivamente, en comparación con el placebo. Natalizumab y IFNß-1b (Betaseron) fueron significativamente más efectiva (OR 0.62, IC 95%: 0,49 hasta 0,78; OR 0.35, IC 95% 0,17 a 0,70, respectivamente) que IFNß-1a (Avonex) para reducir el número de los participantes con EMRR que tuvieron progresión a los dos años de seguimiento, y la confianza en este resultado se clasificó como moderada. Desde la red metanálisis, mitoxantrona parecía ser el agente más eficaz en la disminución de las probabilidades de los participantes con EMRR con progresión a los dos años de seguimiento, pero nuestra confianza era muy bajo para la comparación directa de la mitoxantrona versus placebo. Ambos metanálisis pares y de la red reveló que ninguno de los agentes individuales incluidos en esta revisión fueron eficaces en la prevención de la progresión de la discapacidad en dos o tres años en pacientes con EM progresiva.
No hubo una relación dosis-efecto para cualquiera de los tratamientos incluidos con la excepción de la mitoxantrona.
Conclusiones de los revisores: Esta revisión debería proporcionar alguna orientación a los médicos y los pacientes. Sobre la base de pruebas de alta calidad, el natalizumab y IFNß-1a (Rebif) son superiores a todos los otros tratamientos para la prevención de recaídas clínicas en EMRR en el corto plazo (24 meses) en comparación con el placebo. Pruebas de calidad moderada apoya un efecto protector de natalizumab y IFNß-1a (Rebif) contra la progresión de la discapacidad en la EMRR en el corto plazo en comparación con el placebo. Estos tratamientos están asociados con eventos adversos graves a largo plazo y su relación beneficio-riesgo podrían ser desfavorable. IFNß-1b (Betaseron) y mitoxantrona probablemente disminuyeron las probabilidades de los participantes con EMRR que tienen recaídas, en comparación con el placebo (calidad de evidencia moderada). El balance beneficio-riesgo con azatioprina es incierto, sin embargo, este agente podría ser eficaz en la disminución de las probabilidades de los participantes con EMRR con recaídas y la progresión de la discapacidad de más de 24 a 36 meses, en comparación con el placebo. La falta de datos de eficacia convincente muestra que IFNß-1a (Avonex), inmunoglobulinas intravenosas, ciclofosfamida y esteroides a largo plazo tienen una relación beneficio-riesgo desfavorable en EMRR. Ninguno de los tratamientos incluidos son eficaces en la disminución de la progresión de la discapacidad en los pacientes con EM progresiva. Es importante considerar que los efectos clínicos de todos estos tratamientos allá de dos años son inciertos, un punto relevante para una enfermedad de 30 a 40 años de duración. Comparación cabeza a cabeza Directa (s) entre el natalizumab y IFNß-1a (Rebif) o entre la azatioprina y IFNß-1a (Rebif) debe ser la máxima prioridad en la agenda de investigación y seguimiento de las cohortes del ensayo debe ser obligatorio.
Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators, immunosuppressants and biological agents. Although each one of these therapies reduces relapse frequency and slows disability accumulation compared to no treatment, their relative benefit remains unclear. This is an update of a Cochrane review published in 2015.
OBJECTIVES:
To compare the efficacy and safety, through network meta-analysis, of interferon beta-1b, interferon beta-1a, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, pegylated interferon beta-1a, daclizumab, laquinimod, azathioprine, immunoglobulins, cladribine, cyclophosphamide, diroximel fumarate, fludarabine, interferon beta 1-a and beta 1-b, leflunomide, methotrexate, minocycline, mycophenolate mofetil, ofatumumab, ozanimod, ponesimod, rituximab, siponimod and steroids for the treatment of people with RRMS.
SEARCH METHODS:
CENTRAL, MEDLINE, Embase, and two trials registers were searched on 21 September 2021 together with reference checking, citation searching and contact with study authors to identify additional studies. A top-up search was conducted on 8 August 2022.
SELECTION CRITERIA:
Randomised controlled trials (RCTs) that studied one or more of the available immunomodulators and immunosuppressants as monotherapy in comparison to placebo or to another active agent, in adults with RRMS.
DATA COLLECTION AND ANALYSIS:
Two authors independently selected studies and extracted data. We considered both direct and indirect evidence and performed data synthesis by pairwise and network meta-analysis. Certainty of the evidence was assessed by the GRADE approach.
MAIN RESULTS:
We included 50 studies involving 36,541 participants (68.6% female and 31.4% male). Median treatment duration was 24 months, and 25 (50%) studies were placebo-controlled. Considering the 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 68% of the studies were at high risk of other bias. The other frequent concerns were performance bias (34% judged as having high risk) and attrition bias (32% judged as having high risk). Placebo was used as the common comparator for network analysis. Relapses over 12 months: data were provided in 18 studies (9310 participants). Natalizumab results in a large reduction of people with relapses at 12 months (RR 0.52, 95% CI 0.43 to 0.63; high-certainty evidence). Fingolimod (RR 0.48, 95% CI 0.39 to 0.57; moderate-certainty evidence), daclizumab (RR 0.55, 95% CI 0.42 to 0.73; moderate-certainty evidence), and immunoglobulins (RR 0.60, 95% CI 0.47 to 0.79; moderate-certainty evidence) probably result in a large reduction of people with relapses at 12 months. Relapses over 24 months: data were reported in 28 studies (19,869 participants). Cladribine (RR 0.53, 95% CI 0.44 to 0.64; high-certainty evidence), alemtuzumab (RR 0.57, 95% CI 0.47 to 0.68; high-certainty evidence) and natalizumab (RR 0.56, 95% CI 0.48 to 0.65; high-certainty evidence) result in a large decrease of people with relapses at 24 months. Fingolimod (RR 0.54, 95% CI 0.48 to 0.60; moderate-certainty evidence), dimethyl fumarate (RR 0.62, 95% CI 0.55 to 0.70; moderate-certainty evidence), and ponesimod (RR 0.58, 95% CI 0.48 to 0.70; moderate-certainty evidence) probably result in a large decrease of people with relapses at 24 months. Glatiramer acetate (RR 0.84, 95%, CI 0.76 to 0.93; moderate-certainty evidence) and interferon beta-1a (Avonex, Rebif) (RR 0.84, 95% CI 0.78 to 0.91; moderate-certainty evidence) probably moderately decrease people with relapses at 24 months. Relapses over 36 months findings were available from five studies (3087 participants). None of the treatments assessed showed moderate- or high-certainty evidence compared to placebo. Disability worsening over 24 months was assessed in 31 studies (24,303 participants). Natalizumab probably results in a large reduction of disability worsening (RR 0.59, 95% CI 0.46 to 0.75; moderate-certainty evidence) at 24 months. Disability worsening over 36 months was assessed in three studies (2684 participants) but none of the studies used placebo as the comparator. Treatment discontinuation due to adverse events data were available from 43 studies (35,410 participants). Alemtuzumab probably results in a slight reduction of treatment discontinuation due to adverse events (OR 0.39, 95% CI 0.19 to 0.79; moderate-certainty evidence). Daclizumab (OR 2.55, 95% CI 1.40 to 4.63; moderate-certainty evidence), fingolimod (OR 1.84, 95% CI 1.31 to 2.57; moderate-certainty evidence), teriflunomide (OR 1.82, 95% CI 1.19 to 2.79; moderate-certainty evidence), interferon beta-1a (OR 1.48, 95% CI 0.99 to 2.20; moderate-certainty evidence), laquinimod (OR 1.49, 95 % CI 1.00 to 2.15; moderate-certainty evidence), natalizumab (OR 1.57, 95% CI 0.81 to 3.05), and glatiramer acetate (OR 1.48, 95% CI 1.01 to 2.14; moderate-certainty evidence) probably result in a slight increase in the number of people who discontinue treatment due to adverse events. Serious adverse events (SAEs) were reported in 35 studies (33,998 participants). There was probably a trivial reduction in SAEs amongst people with RRMS treated with interferon beta-1b as compared to placebo (OR 0.92, 95% CI 0.55 to 1.54; moderate-certainty evidence).
AUTHORS' CONCLUSIONS:
We are highly confident that, compared to placebo, two-year treatment with natalizumab, cladribine, or alemtuzumab decreases relapses more than with other DMTs. We are moderately confident that a two-year treatment with natalizumab may slow disability progression. Compared to those on placebo, people with RRMS treated with most of the assessed DMTs showed a higher frequency of treatment discontinuation due to AEs: we are moderately confident that this could happen with fingolimod, teriflunomide, interferon beta-1a, laquinimod, natalizumab and daclizumab, while our certainty with other DMTs is lower. We are also moderately certain that treatment with alemtuzumab is associated with fewer discontinuations due to adverse events than placebo, and moderately certain that interferon beta-1b probably results in a slight reduction in people who experience serious adverse events, but our certainty with regard to other DMTs is lower. Insufficient evidence is available to evaluate the efficacy and safety of DMTs in a longer term than two years, and this is a relevant issue for a chronic condition like MS that develops over decades. More than half of the included studies were sponsored by pharmaceutical companies and this may have influenced their results. Further studies should focus on direct comparison between active agents, with follow-up of at least three years, and assess other patient-relevant outcomes, such as quality of life and cognitive status, with particular focus on the impact of sex/gender on treatment effects.
