Clinical Review & Education
JAMA Clinical Evidence Synopsis
Association of Immunotherapies With Outcomes in Relapsing-Remitting Multiple Sclerosis Irene Tramacere, PhD; Cinzia Del Giovane, PhD; Graziella Filippini, MD
CLINICAL QUESTION What immunotherapies for multiple sclerosis are associated with the greatest benefit and highest risk of discontinuation due to adverse events in patients with relapsing-remitting multiple sclerosis? BOTTOM LINE Alemtuzumab, natalizumab, and fingolimod were associated with the greatest benefit with regard to relapse prevention. Their association with prevention of disability worsening was unclear. Fingolimod was associated with a high risk of treatment discontinuation due to adverse events.
This JAMA Clinical Evidence Synopsis summarizes a Cochrane review1 thatassessedtheassociationsofimmunotherapieswithbenefitandwith treatment discontinuation due to adverse events in patients with relapsing-remittingmultiplesclerosis(RRMS).Thereviewusednetwork meta-analysis to rank competing immunotherapies from trials that addressedthesamequestionbutuseddifferenttreatments.Fortreatment AcomparedwithB,directevidenceisprovidedbystudiesdirectlycomparing A and B, whereas indirect evidence in a network meta-analysis for the A vs B comparison is obtained from studies that compare A with C and B with C.2,3
Summary of Findings Comparedwithplacebo,mosttreatmentswereassociatedwithalower proportion of participants who experienced new clinical relapses during 24-month follow-up. Moderate- to high-quality evidence (Grading of Recommendations Assessment, Development and Evaluation
Evidence Profile No. of randomized clinical trials: 39 Study years: Conducted, 1983-2013; published, 1987-2014; date of last literature search: September 30, 2014 No. of patients: 25 113 Men: 31% Women: 69%
[GRADE])4 indicated that alemtuzumab, natalizumab, and fingolimod wereassociatedwiththegreatestbenefitintermsofpreventingrelapses (Figure).Specifically,assumingthat57per100patientstakingaplacebo experience relapses over 2 years, 26 per 100 patients taking alemtuzumab (3 trials vs subcutaneous interferon beta-1a; N = 1582 participants), 32 per 100 patients taking natalizumab (1 trial vs placebo; N = 942participants),and41per100patientstakingfingolimod(2trials vs placebo; N = 2355 participants) experience relapses over 2 years.1 Disabilityworseningwasdefinedasasustained(3-to6-monthduration) increase in score on the Expanded Disability Status Scale (EDSS) by at least 1 point during a period when patients had no relapses. The EDSSquantifiesdisabilitybasedonassessmentofneurologicalfunction and ability to walk. Scores range from 0 (no neurological abnormality) to 10 (death from multiple sclerosis). Moderate-quality evidence (GRADE) suggested that natalizumab was associated with benefit in terms of preventing disability worsening (Figure). Thus, assuming 40 per 100 patients taking a placebo experience disability worsening over 2 years, 16 per 100 patients taking natalizumab (1 trial vs placebo; N = 942 patients) experience disability worsening.1 Fingolimod was associated with a significantly greater risk of treatment discontinuation due to adverse events compared with placebo (risk ratio, 1.69; 95% CI, 1.32-2.17). The other immunotherapies (except alemtuzumab) were associated with a nonsignificantly higher proportion of patients who withdrew due to adverse events.
Discussion
Race/ethnicity: Not reported Age, mean (range): 36 years (13-65 years) Settings: Hospitals Countries: Africa, North and South America, Asia, Australia, and Europe Comparisons: Beta-interferons, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, pegylated interferon beta-1a, daclizumab, laquinimod, azathioprine, and immunoglobulins vs placebo or another active agent Primary outcomes: Benefit (participants without new clinical relapses or disability worsening) and acceptability (participants who did not withdraw from treatment due to adverse events) Secondary outcome: Safety (participants with at least 1 serious adverse event)
Moderate- to high-quality evidence suggests that alemtuzumab, natalizumab, and fingolimod are associated with greatest efficacy for preventing relapses in patients with RRMS; natalizumab may be associated with a lower risk of disability worsening. Only fingolimod was associated with an increased risk of withdrawal for adverse events. Limitations
First,mostofthetreatmentswereevaluatedinasmallnumberofshortdurationtrials,sobenefitandtreatmentdiscontinuationsduetoadverse events are uncertain beyond 2 years. Second, data on specific adverse eventswerenotcollectedinthisreview.Third,70%oftheincludedstudies were sponsored by pharmaceutical companies and this may have introduced bias. Fourth, the outcome measures used in the trials have both clinical and methodological limitations.1,5
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(Reprinted) JAMA January 26, 2016 Volume 315, Number 4
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Clinical Review & Education JAMA Clinical Evidence Synopsis
Figure. Assessment of Associations of Immunotherapies With Benefit in Patients With Relapsing-Remitting MS GRADE Relapses over 24 mo Alemtuzumab Moderate Mitoxantrone Very low Natalizumab High Fingolimod Moderate Immunoglobulins Moderate Azathioprine Very low Glatiramer acetate Moderate Interferon beta-1b Very low Interferon beta-1a (Rebif) Low Interferon beta Very low Teriflunomide Very low Laquinimod Very low Dimethyl fumarate Moderate Interferon beta-1a (Avonex) Low Disability worsening over 24 mo Mitoxantrone Low Alemtuzumab Low Natalizumab Moderate Azathioprine Very low Glatiramer acetate Very low Immunoglobulins Very low Interferon beta-1b Very low Dimethyl fumarate Low Interferon beta Very low Interferon beta-1a (Rebif) Very low Fingolimod Very low Laquinimod Low Teriflunomide Low Interferon beta-1a (Avonex) Very low
Probability, % a Risk Ratio (95% CI) 97 92 88 71 66 57 48 42 39 33 32 31 30 22
0.46 (0.38-0.55) 0.47 (0.27-0.81) 0.56 (0.47-0.66) 0.72 (0.64-0.81) 0.74 (0.60-0.91) 0.77 (0.55-1.07) 0.83 (0.75-0.91) 0.85 (0.77-0.94) 0.86 (0.77-0.95) 0.89 (0.56-1.42) 0.88 (0.75-1.03) 0.88 (0.79-0.99) 0.89 (0.81-0.98) 0.91 (0.82-1.02)
96 94 74 64 58 56 51 50 40 36 34 34 34 21
0.20 (0.05-0.84) 0.35 (0.26-0.48) 0.64 (0.49-0.85) 0.64 (0.30-1.37) 0.77 (0.64-0.92) 0.70 (0.39-1.27) 0.79 (0.65-0.97) 0.80 (0.67-0.94) 0.83 (0.34-2.07) 0.86 (0.69-1.06) 0.86 (0.73-1.03) 0.87 (0.72-1.04) 0.87 (0.69-1.10) 0.93 (0.77-1.13)
GRADE indicates Grading of Recommendations Assessment, Development and Evaluation; MS, multiple sclerosis. a
0.1
1.0
2.0
Risk Ratio (95% CI)
Comparison of Findings With Current Practice Guidelines
Our findings are consistent with the guideline from the Association of British Neurologists,6 which identified alemtuzumab and natalizumab as having the greatest ability to prevent relapses. However, because of safety concerns, the guidelines recommended these agents as second-line treatments, or for patients with rapidly evolving RRMS. Beta-interferons, glatiramer acetate, teriflunomide, ARTICLE INFORMATION Author Affiliations: Neuroepidemiology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (Tramacere); Italian Cochrane Centre, Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy (Del Giovane); Scientific Direction, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (Filippini). Corresponding Author: Graziella Filippini, MD, Scientific Direction, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Mangiagalli 3, 20133 Milan, Italy ([email protected]). Section Editor: Mary McGrae McDermott, MD, Senior Editor. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for
410
For example, for relapses over 24 months, the probability (surface under the cumulative ranking curve) for alemtuzumab was 97%, which is better than all the other treatments assessed and implies that it is highly likely to be associated with the best outcome of the treatments assessed. In contrast, intramuscular interferon beta-1a (Avonex) had a probability of 22% for relapses over 24 months, which was the lowest value obtained and implies that it is associated with the worst outcomes.
dimethyl fumarate, and fingolimod are recommended as first-line therapy.6 Areas in Need of Future Study
Long-term follow-up and large-scale patient databases are necessary to provide long-term estimates of the benefits and risks of immunotherapies.
Disclosure of Potential Conflicts of Interest and none were reported. Additional Contributions: We thank Don Ward, BSc, a freelance science editor. Mr Ward was paid for his services by the senior author. Submissions: We encourage authors to submit papers for consideration as a JAMA Clinical Evidence Synopsis. Please contact Dr McDermott at [email protected]. REFERENCES 1. Tramacere I, Del Giovane C, Salanti G, D’Amico R, Filippini G. Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis. Cochrane Database Syst Rev. 2015;9:CD011381.
2. Salanti G. Indirect and mixed-treatment comparison, network, or multiple-treatments meta-analysis. Res Synth Methods. 2012;3(2):80-97. 3. Mills EJ, Ioannidis JP, Thorlund K, et al. How to use an article reporting a multiple treatment comparison meta-analysis. JAMA. 2012;308(12): 1246-1253. 4. Salanti G, Del Giovane C, Chaimani A, et al. Evaluating the quality of evidence from a network meta-analysis. PLoS One. 2014;9(7):e99682. 5. Ebers GC, Heigenhauser L, Daumer M, et al. Disability as an outcome in MS clinical trials. Neurology. 2008;71(9):624-631. 6. Scolding N, Barnes D, Cader S, et al. Association of British Neurologists: revised (2015) guidelines for prescribing disease-modifying treatments in multiple sclerosis. Pract Neurol. 2015;15(4):273-279.
JAMA January 26, 2016 Volume 315, Number 4 (Reprinted)
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a GAZI UNIVERSITESI User on 01/27/2016
jama.com
JAMA Clinical Evidence Synopsis
Association of Immunotherapies With Outcomes in Relapsing-Remitting Multiple Sclerosis Irene Tramacere, PhD; Cinzia Del Giovane, PhD; Graziella Filippini, MD
CLINICAL QUESTION What immunotherapies for multiple sclerosis are associated with the greatest benefit and highest risk of discontinuation due to adverse events in patients with relapsing-remitting multiple sclerosis? BOTTOM LINE Alemtuzumab, natalizumab, and fingolimod were associated with the greatest benefit with regard to relapse prevention. Their association with prevention of disability worsening was unclear. Fingolimod was associated with a high risk of treatment discontinuation due to adverse events.
This JAMA Clinical Evidence Synopsis summarizes a Cochrane review1 thatassessedtheassociationsofimmunotherapieswithbenefitandwith treatment discontinuation due to adverse events in patients with relapsing-remittingmultiplesclerosis(RRMS).Thereviewusednetwork meta-analysis to rank competing immunotherapies from trials that addressedthesamequestionbutuseddifferenttreatments.Fortreatment AcomparedwithB,directevidenceisprovidedbystudiesdirectlycomparing A and B, whereas indirect evidence in a network meta-analysis for the A vs B comparison is obtained from studies that compare A with C and B with C.2,3
Summary of Findings Comparedwithplacebo,mosttreatmentswereassociatedwithalower proportion of participants who experienced new clinical relapses during 24-month follow-up. Moderate- to high-quality evidence (Grading of Recommendations Assessment, Development and Evaluation
Evidence Profile No. of randomized clinical trials: 39 Study years: Conducted, 1983-2013; published, 1987-2014; date of last literature search: September 30, 2014 No. of patients: 25 113 Men: 31% Women: 69%
[GRADE])4 indicated that alemtuzumab, natalizumab, and fingolimod wereassociatedwiththegreatestbenefitintermsofpreventingrelapses (Figure).Specifically,assumingthat57per100patientstakingaplacebo experience relapses over 2 years, 26 per 100 patients taking alemtuzumab (3 trials vs subcutaneous interferon beta-1a; N = 1582 participants), 32 per 100 patients taking natalizumab (1 trial vs placebo; N = 942participants),and41per100patientstakingfingolimod(2trials vs placebo; N = 2355 participants) experience relapses over 2 years.1 Disabilityworseningwasdefinedasasustained(3-to6-monthduration) increase in score on the Expanded Disability Status Scale (EDSS) by at least 1 point during a period when patients had no relapses. The EDSSquantifiesdisabilitybasedonassessmentofneurologicalfunction and ability to walk. Scores range from 0 (no neurological abnormality) to 10 (death from multiple sclerosis). Moderate-quality evidence (GRADE) suggested that natalizumab was associated with benefit in terms of preventing disability worsening (Figure). Thus, assuming 40 per 100 patients taking a placebo experience disability worsening over 2 years, 16 per 100 patients taking natalizumab (1 trial vs placebo; N = 942 patients) experience disability worsening.1 Fingolimod was associated with a significantly greater risk of treatment discontinuation due to adverse events compared with placebo (risk ratio, 1.69; 95% CI, 1.32-2.17). The other immunotherapies (except alemtuzumab) were associated with a nonsignificantly higher proportion of patients who withdrew due to adverse events.
Discussion
Race/ethnicity: Not reported Age, mean (range): 36 years (13-65 years) Settings: Hospitals Countries: Africa, North and South America, Asia, Australia, and Europe Comparisons: Beta-interferons, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, pegylated interferon beta-1a, daclizumab, laquinimod, azathioprine, and immunoglobulins vs placebo or another active agent Primary outcomes: Benefit (participants without new clinical relapses or disability worsening) and acceptability (participants who did not withdraw from treatment due to adverse events) Secondary outcome: Safety (participants with at least 1 serious adverse event)
Moderate- to high-quality evidence suggests that alemtuzumab, natalizumab, and fingolimod are associated with greatest efficacy for preventing relapses in patients with RRMS; natalizumab may be associated with a lower risk of disability worsening. Only fingolimod was associated with an increased risk of withdrawal for adverse events. Limitations
First,mostofthetreatmentswereevaluatedinasmallnumberofshortdurationtrials,sobenefitandtreatmentdiscontinuationsduetoadverse events are uncertain beyond 2 years. Second, data on specific adverse eventswerenotcollectedinthisreview.Third,70%oftheincludedstudies were sponsored by pharmaceutical companies and this may have introduced bias. Fourth, the outcome measures used in the trials have both clinical and methodological limitations.1,5
jama.com
(Reprinted) JAMA January 26, 2016 Volume 315, Number 4
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a GAZI UNIVERSITESI User on 01/27/2016
409
Clinical Review & Education JAMA Clinical Evidence Synopsis
Figure. Assessment of Associations of Immunotherapies With Benefit in Patients With Relapsing-Remitting MS GRADE Relapses over 24 mo Alemtuzumab Moderate Mitoxantrone Very low Natalizumab High Fingolimod Moderate Immunoglobulins Moderate Azathioprine Very low Glatiramer acetate Moderate Interferon beta-1b Very low Interferon beta-1a (Rebif) Low Interferon beta Very low Teriflunomide Very low Laquinimod Very low Dimethyl fumarate Moderate Interferon beta-1a (Avonex) Low Disability worsening over 24 mo Mitoxantrone Low Alemtuzumab Low Natalizumab Moderate Azathioprine Very low Glatiramer acetate Very low Immunoglobulins Very low Interferon beta-1b Very low Dimethyl fumarate Low Interferon beta Very low Interferon beta-1a (Rebif) Very low Fingolimod Very low Laquinimod Low Teriflunomide Low Interferon beta-1a (Avonex) Very low
Probability, % a Risk Ratio (95% CI) 97 92 88 71 66 57 48 42 39 33 32 31 30 22
0.46 (0.38-0.55) 0.47 (0.27-0.81) 0.56 (0.47-0.66) 0.72 (0.64-0.81) 0.74 (0.60-0.91) 0.77 (0.55-1.07) 0.83 (0.75-0.91) 0.85 (0.77-0.94) 0.86 (0.77-0.95) 0.89 (0.56-1.42) 0.88 (0.75-1.03) 0.88 (0.79-0.99) 0.89 (0.81-0.98) 0.91 (0.82-1.02)
96 94 74 64 58 56 51 50 40 36 34 34 34 21
0.20 (0.05-0.84) 0.35 (0.26-0.48) 0.64 (0.49-0.85) 0.64 (0.30-1.37) 0.77 (0.64-0.92) 0.70 (0.39-1.27) 0.79 (0.65-0.97) 0.80 (0.67-0.94) 0.83 (0.34-2.07) 0.86 (0.69-1.06) 0.86 (0.73-1.03) 0.87 (0.72-1.04) 0.87 (0.69-1.10) 0.93 (0.77-1.13)
GRADE indicates Grading of Recommendations Assessment, Development and Evaluation; MS, multiple sclerosis. a
0.1
1.0
2.0
Risk Ratio (95% CI)
Comparison of Findings With Current Practice Guidelines
Our findings are consistent with the guideline from the Association of British Neurologists,6 which identified alemtuzumab and natalizumab as having the greatest ability to prevent relapses. However, because of safety concerns, the guidelines recommended these agents as second-line treatments, or for patients with rapidly evolving RRMS. Beta-interferons, glatiramer acetate, teriflunomide, ARTICLE INFORMATION Author Affiliations: Neuroepidemiology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (Tramacere); Italian Cochrane Centre, Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy (Del Giovane); Scientific Direction, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (Filippini). Corresponding Author: Graziella Filippini, MD, Scientific Direction, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Mangiagalli 3, 20133 Milan, Italy ([email protected]). Section Editor: Mary McGrae McDermott, MD, Senior Editor. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for
410
For example, for relapses over 24 months, the probability (surface under the cumulative ranking curve) for alemtuzumab was 97%, which is better than all the other treatments assessed and implies that it is highly likely to be associated with the best outcome of the treatments assessed. In contrast, intramuscular interferon beta-1a (Avonex) had a probability of 22% for relapses over 24 months, which was the lowest value obtained and implies that it is associated with the worst outcomes.
dimethyl fumarate, and fingolimod are recommended as first-line therapy.6 Areas in Need of Future Study
Long-term follow-up and large-scale patient databases are necessary to provide long-term estimates of the benefits and risks of immunotherapies.
Disclosure of Potential Conflicts of Interest and none were reported. Additional Contributions: We thank Don Ward, BSc, a freelance science editor. Mr Ward was paid for his services by the senior author. Submissions: We encourage authors to submit papers for consideration as a JAMA Clinical Evidence Synopsis. Please contact Dr McDermott at [email protected]. REFERENCES 1. Tramacere I, Del Giovane C, Salanti G, D’Amico R, Filippini G. Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis. Cochrane Database Syst Rev. 2015;9:CD011381.
2. Salanti G. Indirect and mixed-treatment comparison, network, or multiple-treatments meta-analysis. Res Synth Methods. 2012;3(2):80-97. 3. Mills EJ, Ioannidis JP, Thorlund K, et al. How to use an article reporting a multiple treatment comparison meta-analysis. JAMA. 2012;308(12): 1246-1253. 4. Salanti G, Del Giovane C, Chaimani A, et al. Evaluating the quality of evidence from a network meta-analysis. PLoS One. 2014;9(7):e99682. 5. Ebers GC, Heigenhauser L, Daumer M, et al. Disability as an outcome in MS clinical trials. Neurology. 2008;71(9):624-631. 6. Scolding N, Barnes D, Cader S, et al. Association of British Neurologists: revised (2015) guidelines for prescribing disease-modifying treatments in multiple sclerosis. Pract Neurol. 2015;15(4):273-279.
JAMA January 26, 2016 Volume 315, Number 4 (Reprinted)
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a GAZI UNIVERSITESI User on 01/27/2016
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![[Immunotherapies for multiple sclerosis : review and update].](/assets/img/hold.png)
