title: Selection of first-line therapy in multiple sclerosis using risk-benefit decision analysis.
abstract: OBJECTIVE
  To integrate long-term measures of disease-modifying drug efficacy and risk to guide selection of first-line treatment of multiple sclerosis.
  
  
  METHODS
  We created a Markov decision model to evaluate disability worsening and progressive multifocal leukoencephalopathy (PML) risk in patients receiving natalizumab (NTZ), fingolimod (FGL), or glatiramer acetate (GA) over 30 years. Leveraging publicly available data, we integrated treatment utility, disability worsening, and risk of PML into quality-adjusted life-years (QALYs). We performed sensitivity analyses varying PML risk, mortality and morbidity, and relative risk of disease worsening across clinically relevant ranges.
  
  
  RESULTS
  Over the entire reported range of NTZ-associated PML risk, NTZ as first-line therapy is predicted to provide a greater net benefit (15.06 QALYs) than FGL (13.99 QALYs) or GA (12.71 QALYs) treatment over 30 years, after accounting for loss of QALYs due to PML or death (resulting from all causes). NTZ treatment is associated with delayed worsening to an Expanded Disability Status Scale score ≥6.0 vs FGL or GA (22.7, 17.0, and 12.4 years, respectively). Compared to untreated patients, NTZ-treated patients have a greater relative risk of death in the early years of treatment that varies according to PML risk profile.
  
  
  CONCLUSIONS
  NTZ as a first-line treatment is associated with the highest net benefit across full ranges of PML risk, mortality, and morbidity compared to FGL or GA. Integrated modeling of long-term treatment risks and benefits informs stratified clinical decision-making and can support patient counseling on selection of first-line treatment options.
authors.affiliation: From the Ann Romney Center for Neurologic Diseases (D.B., B.C.H., P.L.D.J., Z.X.), Department of Neurology, and Program in Translational Neuropsychiatric Genomics (D.B., P.L.D.J., Z.X.), Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston; Program for Medical and Population Genetics (D.B., L.B.C., P.L.D.J., Z.X.), Broad Institute, Cambridge; Harvard Medical School (D.B., M.T.B., M.B.W., L.B.C., P.L.D.J., Z.X.); Department of Neurology (M.T.B., M.B.W.) and Biostatistics Center (B.C.H.), Massachusetts General Hospital; Harvard T.H. Chan School of Public Health (L.B.C.), Boston, MA; and Department of Neurology (Z.X.), University of Pittsburgh, PA.
authors.forename: David
authors.initials: D
authors.lastname: Bargiela
authors.affiliation: From the Ann Romney Center for Neurologic Diseases (D.B., B.C.H., P.L.D.J., Z.X.), Department of Neurology, and Program in Translational Neuropsychiatric Genomics (D.B., P.L.D.J., Z.X.), Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston; Program for Medical and Population Genetics (D.B., L.B.C., P.L.D.J., Z.X.), Broad Institute, Cambridge; Harvard Medical School (D.B., M.T.B., M.B.W., L.B.C., P.L.D.J., Z.X.); Department of Neurology (M.T.B., M.B.W.) and Biostatistics Center (B.C.H.), Massachusetts General Hospital; Harvard T.H. Chan School of Public Health (L.B.C.), Boston, MA; and Department of Neurology (Z.X.), University of Pittsburgh, PA.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Bianchi
authors.affiliation: From the Ann Romney Center for Neurologic Diseases (D.B., B.C.H., P.L.D.J., Z.X.), Department of Neurology, and Program in Translational Neuropsychiatric Genomics (D.B., P.L.D.J., Z.X.), Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston; Program for Medical and Population Genetics (D.B., L.B.C., P.L.D.J., Z.X.), Broad Institute, Cambridge; Harvard Medical School (D.B., M.T.B., M.B.W., L.B.C., P.L.D.J., Z.X.); Department of Neurology (M.T.B., M.B.W.) and Biostatistics Center (B.C.H.), Massachusetts General Hospital; Harvard T.H. Chan School of Public Health (L.B.C.), Boston, MA; and Department of Neurology (Z.X.), University of Pittsburgh, PA.
authors.forename: M Brandon
authors.initials: MB
authors.lastname: Westover
authors.affiliation: From the Ann Romney Center for Neurologic Diseases (D.B., B.C.H., P.L.D.J., Z.X.), Department of Neurology, and Program in Translational Neuropsychiatric Genomics (D.B., P.L.D.J., Z.X.), Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston; Program for Medical and Population Genetics (D.B., L.B.C., P.L.D.J., Z.X.), Broad Institute, Cambridge; Harvard Medical School (D.B., M.T.B., M.B.W., L.B.C., P.L.D.J., Z.X.); Department of Neurology (M.T.B., M.B.W.) and Biostatistics Center (B.C.H.), Massachusetts General Hospital; Harvard T.H. Chan School of Public Health (L.B.C.), Boston, MA; and Department of Neurology (Z.X.), University of Pittsburgh, PA.
authors.forename: Lori B
authors.initials: LB
authors.lastname: Chibnik
authors.affiliation: From the Ann Romney Center for Neurologic Diseases (D.B., B.C.H., P.L.D.J., Z.X.), Department of Neurology, and Program in Translational Neuropsychiatric Genomics (D.B., P.L.D.J., Z.X.), Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston; Program for Medical and Population Genetics (D.B., L.B.C., P.L.D.J., Z.X.), Broad Institute, Cambridge; Harvard Medical School (D.B., M.T.B., M.B.W., L.B.C., P.L.D.J., Z.X.); Department of Neurology (M.T.B., M.B.W.) and Biostatistics Center (B.C.H.), Massachusetts General Hospital; Harvard T.H. Chan School of Public Health (L.B.C.), Boston, MA; and Department of Neurology (Z.X.), University of Pittsburgh, PA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Healy
authors.affiliation: From the Ann Romney Center for Neurologic Diseases (D.B., B.C.H., P.L.D.J., Z.X.), Department of Neurology, and Program in Translational Neuropsychiatric Genomics (D.B., P.L.D.J., Z.X.), Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston; Program for Medical and Population Genetics (D.B., L.B.C., P.L.D.J., Z.X.), Broad Institute, Cambridge; Harvard Medical School (D.B., M.T.B., M.B.W., L.B.C., P.L.D.J., Z.X.); Department of Neurology (M.T.B., M.B.W.) and Biostatistics Center (B.C.H.), Massachusetts General Hospital; Harvard T.H. Chan School of Public Health (L.B.C.), Boston, MA; and Department of Neurology (Z.X.), University of Pittsburgh, PA.
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.affiliation: From the Ann Romney Center for Neurologic Diseases (D.B., B.C.H., P.L.D.J., Z.X.), Department of Neurology, and Program in Translational Neuropsychiatric Genomics (D.B., P.L.D.J., Z.X.), Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston; Program for Medical and Population Genetics (D.B., L.B.C., P.L.D.J., Z.X.), Broad Institute, Cambridge; Harvard Medical School (D.B., M.T.B., M.B.W., L.B.C., P.L.D.J., Z.X.); Department of Neurology (M.T.B., M.B.W.) and Biostatistics Center (B.C.H.), Massachusetts General Hospital; Harvard T.H. Chan School of Public Health (L.B.C.), Boston, MA; and Department of Neurology (Z.X.), University of Pittsburgh, PA. zxia1@pitt.edu.
authors.forename: Zongqi
authors.initials: Z
authors.lastname: Xia
mesh_terms: D000328:Adult; D000066491:Clinical Decision-Making / Q000379:methods*; D003661:Decision Support Techniques; D004185:Disability Evaluation; D018450:Disease Progression; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000009:adverse effects / Q000627:therapeutic use*; D000068717:Glatiramer Acetate / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007155:Immunologic Factors / Q000009:adverse effects / Q000627:therapeutic use*; D007968:Leukoencephalopathy, Progressive Multifocal / Q000453:epidemiology / Q000209:etiology; D008297:Male; D008390:Markov Chains; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000453:epidemiology; D000069442:Natalizumab / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D012306:Risk; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D007155:Immunologic Factors; D000069442:Natalizumab; D000068717:Glatiramer Acetate; D000068876:Fingolimod Hydrochloride