Relapses and disability accumulation in progressive multiple sclerosis.
OBJECTIVE
We examined the effect of relapses-before and after progression onset-on the rate of postprogression disability accrual in a progressive multiple sclerosis (MS) cohort.


METHODS
We studied patients with primary progressive MS (n = 322) and bout-onset progressive MS (BOPMS) including single-attack progressive MS (n = 112) and secondary progressive MS (n = 421). The effect of relapses on time to Expanded Disability Status Scale (EDSS) score of 6 was studied using multivariate Cox regression analysis (sex, age at progression, and immunomodulation modeled as covariates). Kaplan-Meier analysis was performed using EDSS 6 as endpoint.


RESULTS
Preprogression relapses (hazard ratio [HR]: 1.63; 95% confidence interval [CI]: 1.34-1.98), postprogression relapses (HR: 1.37; 95% CI: 1.11-1.70), female sex (HR: 1.19; 95% CI: 1.00-1.43), and progression onset after age 50 years (HR: 1.47; 95% CI: 1.21-1.78) were associated with shorter time to EDSS 6. Postprogression relapses occurred in 29.5% of secondary progressive MS, 10.7% of single-attack progressive MS, and 3.1% of primary progressive MS. Most occurred within 5 years (91.6%) after progressive disease onset and/or before age 55 (95.2%). Immunomodulation after onset of progressive disease course (HR: 0.64; 95% CI: 0.52-0.78) seemingly lengthened time to EDSS 6 (for BOPMS with ongoing relapses) when analyzed as a dichotomous variable, but not as a time-dependent variable.


CONCLUSIONS
Pre- and postprogression relapses accelerate time to severe disability in progressive MS. Continuing immunomodulation for 5 years after the onset of progressive disease or until 55 years of age may be reasonable to consider in patients with BOPMS who have ongoing relapses.
From the Mayo Clinic Center for Multiple Sclerosis and CNS Demyelinating Diseases, Department of Neurology (M.M.P.S., M.N., B.M.K., I.P., S.J.P., C.F.L., B.G.W., M.R., O.H.K.), and Division of Biomedical Statistics & Informatics (D.J.C., E.J.A.), Mayo Clinic College of Medicine, Rochester, MN; International Clinical Research Center (M.N.), St. Anne's University Hospital Brno, Czech Republic; Department of Neurology (N.A.Z.), American University of Beirut Medical Center, Lebanon; Department of Neurology (N.K.), Bakirkoy State Hospital, Istanbul; and Department of Neurology (M.T., A.S.), Cerrahpasa School of Medicine, Istanbul University, Turkey. N.A.Z., N.K., and M.T. were previous fellows of the Department of Neurology, Mayo Clinic College of Medicine.
M Mateo
MM
Paz Soldán
From the Mayo Clinic Center for Multiple Sclerosis and CNS Demyelinating Diseases, Department of Neurology (M.M.P.S., M.N., B.M.K., I.P., S.J.P., C.F.L., B.G.W., M.R., O.H.K.), and Division of Biomedical Statistics & Informatics (D.J.C., E.J.A.), Mayo Clinic College of Medicine, Rochester, MN; International Clinical Research Center (M.N.), St. Anne's University Hospital Brno, Czech Republic; Department of Neurology (N.A.Z.), American University of Beirut Medical Center, Lebanon; Department of Neurology (N.K.), Bakirkoy State Hospital, Istanbul; and Department of Neurology (M.T., A.S.), Cerrahpasa School of Medicine, Istanbul University, Turkey. N.A.Z., N.K., and M.T. were previous fellows of the Department of Neurology, Mayo Clinic College of Medicine.
Martina
M
Novotna
From the Mayo Clinic Center for Multiple Sclerosis and CNS Demyelinating Diseases, Department of Neurology (M.M.P.S., M.N., B.M.K., I.P., S.J.P., C.F.L., B.G.W., M.R., O.H.K.), and Division of Biomedical Statistics & Informatics (D.J.C., E.J.A.), Mayo Clinic College of Medicine, Rochester, MN; International Clinical Research Center (M.N.), St. Anne's University Hospital Brno, Czech Republic; Department of Neurology (N.A.Z.), American University of Beirut Medical Center, Lebanon; Department of Neurology (N.K.), Bakirkoy State Hospital, Istanbul; and Department of Neurology (M.T., A.S.), Cerrahpasa School of Medicine, Istanbul University, Turkey. N.A.Z., N.K., and M.T. were previous fellows of the Department of Neurology, Mayo Clinic College of Medicine.
Nuhad
N
Abou Zeid
From the Mayo Clinic Center for Multiple Sclerosis and CNS Demyelinating Diseases, Department of Neurology (M.M.P.S., M.N., B.M.K., I.P., S.J.P., C.F.L., B.G.W., M.R., O.H.K.), and Division of Biomedical Statistics & Informatics (D.J.C., E.J.A.), Mayo Clinic College of Medicine, Rochester, MN; International Clinical Research Center (M.N.), St. Anne's University Hospital Brno, Czech Republic; Department of Neurology (N.A.Z.), American University of Beirut Medical Center, Lebanon; Department of Neurology (N.K.), Bakirkoy State Hospital, Istanbul; and Department of Neurology (M.T., A.S.), Cerrahpasa School of Medicine, Istanbul University, Turkey. N.A.Z., N.K., and M.T. were previous fellows of the Department of Neurology, Mayo Clinic College of Medicine.
Nilufer
N
Kale
From the Mayo Clinic Center for Multiple Sclerosis and CNS Demyelinating Diseases, Department of Neurology (M.M.P.S., M.N., B.M.K., I.P., S.J.P., C.F.L., B.G.W., M.R., O.H.K.), and Division of Biomedical Statistics & Informatics (D.J.C., E.J.A.), Mayo Clinic College of Medicine, Rochester, MN; International Clinical Research Center (M.N.), St. Anne's University Hospital Brno, Czech Republic; Department of Neurology (N.A.Z.), American University of Beirut Medical Center, Lebanon; Department of Neurology (N.K.), Bakirkoy State Hospital, Istanbul; and Department of Neurology (M.T., A.S.), Cerrahpasa School of Medicine, Istanbul University, Turkey. N.A.Z., N.K., and M.T. were previous fellows of the Department of Neurology, Mayo Clinic College of Medicine.
Melih
M
Tutuncu
From the Mayo Clinic Center for Multiple Sclerosis and CNS Demyelinating Diseases, Department of Neurology (M.M.P.S., M.N., B.M.K., I.P., S.J.P., C.F.L., B.G.W., M.R., O.H.K.), and Division of Biomedical Statistics & Informatics (D.J.C., E.J.A.), Mayo Clinic College of Medicine, Rochester, MN; International Clinical Research Center (M.N.), St. Anne's University Hospital Brno, Czech Republic; Department of Neurology (N.A.Z.), American University of Beirut Medical Center, Lebanon; Department of Neurology (N.K.), Bakirkoy State Hospital, Istanbul; and Department of Neurology (M.T., A.S.), Cerrahpasa School of Medicine, Istanbul University, Turkey. N.A.Z., N.K., and M.T. were previous fellows of the Department of Neurology, Mayo Clinic College of Medicine.
Daniel J
DJ
Crusan
From the Mayo Clinic Center for Multiple Sclerosis and CNS Demyelinating Diseases, Department of Neurology (M.M.P.S., M.N., B.M.K., I.P., S.J.P., C.F.L., B.G.W., M.R., O.H.K.), and Division of Biomedical Statistics & Informatics (D.J.C., E.J.A.), Mayo Clinic College of Medicine, Rochester, MN; International Clinical Research Center (M.N.), St. Anne's University Hospital Brno, Czech Republic; Department of Neurology (N.A.Z.), American University of Beirut Medical Center, Lebanon; Department of Neurology (N.K.), Bakirkoy State Hospital, Istanbul; and Department of Neurology (M.T., A.S.), Cerrahpasa School of Medicine, Istanbul University, Turkey. N.A.Z., N.K., and M.T. were previous fellows of the Department of Neurology, Mayo Clinic College of Medicine.
Elizabeth J
EJ
Atkinson
From the Mayo Clinic Center for Multiple Sclerosis and CNS Demyelinating Diseases, Department of Neurology (M.M.P.S., M.N., B.M.K., I.P., S.J.P., C.F.L., B.G.W., M.R., O.H.K.), and Division of Biomedical Statistics & Informatics (D.J.C., E.J.A.), Mayo Clinic College of Medicine, Rochester, MN; International Clinical Research Center (M.N.), St. Anne's University Hospital Brno, Czech Republic; Department of Neurology (N.A.Z.), American University of Beirut Medical Center, Lebanon; Department of Neurology (N.K.), Bakirkoy State Hospital, Istanbul; and Department of Neurology (M.T., A.S.), Cerrahpasa School of Medicine, Istanbul University, Turkey. N.A.Z., N.K., and M.T. were previous fellows of the Department of Neurology, Mayo Clinic College of Medicine.
Aksel
A
Siva
From the Mayo Clinic Center for Multiple Sclerosis and CNS Demyelinating Diseases, Department of Neurology (M.M.P.S., M.N., B.M.K., I.P., S.J.P., C.F.L., B.G.W., M.R., O.H.K.), and Division of Biomedical Statistics & Informatics (D.J.C., E.J.A.), Mayo Clinic College of Medicine, Rochester, MN; International Clinical Research Center (M.N.), St. Anne's University Hospital Brno, Czech Republic; Department of Neurology (N.A.Z.), American University of Beirut Medical Center, Lebanon; Department of Neurology (N.K.), Bakirkoy State Hospital, Istanbul; and Department of Neurology (M.T., A.S.), Cerrahpasa School of Medicine, Istanbul University, Turkey. N.A.Z., N.K., and M.T. were previous fellows of the Department of Neurology, Mayo Clinic College of Medicine.
B Mark
BM
Keegan
From the Mayo Clinic Center for Multiple Sclerosis and CNS Demyelinating Diseases, Department of Neurology (M.M.P.S., M.N., B.M.K., I.P., S.J.P., C.F.L., B.G.W., M.R., O.H.K.), and Division of Biomedical Statistics & Informatics (D.J.C., E.J.A.), Mayo Clinic College of Medicine, Rochester, MN; International Clinical Research Center (M.N.), St. Anne's University Hospital Brno, Czech Republic; Department of Neurology (N.A.Z.), American University of Beirut Medical Center, Lebanon; Department of Neurology (N.K.), Bakirkoy State Hospital, Istanbul; and Department of Neurology (M.T., A.S.), Cerrahpasa School of Medicine, Istanbul University, Turkey. N.A.Z., N.K., and M.T. were previous fellows of the Department of Neurology, Mayo Clinic College of Medicine.
Istvan
I
Pirko
From the Mayo Clinic Center for Multiple Sclerosis and CNS Demyelinating Diseases, Department of Neurology (M.M.P.S., M.N., B.M.K., I.P., S.J.P., C.F.L., B.G.W., M.R., O.H.K.), and Division of Biomedical Statistics & Informatics (D.J.C., E.J.A.), Mayo Clinic College of Medicine, Rochester, MN; International Clinical Research Center (M.N.), St. Anne's University Hospital Brno, Czech Republic; Department of Neurology (N.A.Z.), American University of Beirut Medical Center, Lebanon; Department of Neurology (N.K.), Bakirkoy State Hospital, Istanbul; and Department of Neurology (M.T., A.S.), Cerrahpasa School of Medicine, Istanbul University, Turkey. N.A.Z., N.K., and M.T. were previous fellows of the Department of Neurology, Mayo Clinic College of Medicine.
Sean J
SJ
Pittock
From the Mayo Clinic Center for Multiple Sclerosis and CNS Demyelinating Diseases, Department of Neurology (M.M.P.S., M.N., B.M.K., I.P., S.J.P., C.F.L., B.G.W., M.R., O.H.K.), and Division of Biomedical Statistics & Informatics (D.J.C., E.J.A.), Mayo Clinic College of Medicine, Rochester, MN; International Clinical Research Center (M.N.), St. Anne's University Hospital Brno, Czech Republic; Department of Neurology (N.A.Z.), American University of Beirut Medical Center, Lebanon; Department of Neurology (N.K.), Bakirkoy State Hospital, Istanbul; and Department of Neurology (M.T., A.S.), Cerrahpasa School of Medicine, Istanbul University, Turkey. N.A.Z., N.K., and M.T. were previous fellows of the Department of Neurology, Mayo Clinic College of Medicine.
Claudia F
CF
Lucchinetti
From the Mayo Clinic Center for Multiple Sclerosis and CNS Demyelinating Diseases, Department of Neurology (M.M.P.S., M.N., B.M.K., I.P., S.J.P., C.F.L., B.G.W., M.R., O.H.K.), and Division of Biomedical Statistics & Informatics (D.J.C., E.J.A.), Mayo Clinic College of Medicine, Rochester, MN; International Clinical Research Center (M.N.), St. Anne's University Hospital Brno, Czech Republic; Department of Neurology (N.A.Z.), American University of Beirut Medical Center, Lebanon; Department of Neurology (N.K.), Bakirkoy State Hospital, Istanbul; and Department of Neurology (M.T., A.S.), Cerrahpasa School of Medicine, Istanbul University, Turkey. N.A.Z., N.K., and M.T. were previous fellows of the Department of Neurology, Mayo Clinic College of Medicine.
Brian G
BG
Weinshenker
From the Mayo Clinic Center for Multiple Sclerosis and CNS Demyelinating Diseases, Department of Neurology (M.M.P.S., M.N., B.M.K., I.P., S.J.P., C.F.L., B.G.W., M.R., O.H.K.), and Division of Biomedical Statistics & Informatics (D.J.C., E.J.A.), Mayo Clinic College of Medicine, Rochester, MN; International Clinical Research Center (M.N.), St. Anne's University Hospital Brno, Czech Republic; Department of Neurology (N.A.Z.), American University of Beirut Medical Center, Lebanon; Department of Neurology (N.K.), Bakirkoy State Hospital, Istanbul; and Department of Neurology (M.T., A.S.), Cerrahpasa School of Medicine, Istanbul University, Turkey. N.A.Z., N.K., and M.T. were previous fellows of the Department of Neurology, Mayo Clinic College of Medicine.
Moses
M
Rodriguez
From the Mayo Clinic Center for Multiple Sclerosis and CNS Demyelinating Diseases, Department of Neurology (M.M.P.S., M.N., B.M.K., I.P., S.J.P., C.F.L., B.G.W., M.R., O.H.K.), and Division of Biomedical Statistics & Informatics (D.J.C., E.J.A.), Mayo Clinic College of Medicine, Rochester, MN; International Clinical Research Center (M.N.), St. Anne's University Hospital Brno, Czech Republic; Department of Neurology (N.A.Z.), American University of Beirut Medical Center, Lebanon; Department of Neurology (N.K.), Bakirkoy State Hospital, Istanbul; and Department of Neurology (M.T., A.S.), Cerrahpasa School of Medicine, Istanbul University, Turkey. N.A.Z., N.K., and M.T. were previous fellows of the Department of Neurology, Mayo Clinic College of Medicine. kantarci.orhun@mayo.edu.
Orhun H
OH
Kantarci
D000328:Adult; D004185:Disability Evaluation; D018450:Disease Progression; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000188:drug therapy / Q000503:physiopathology*; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D012008:Recurrence; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult
D007155:Immunologic Factors