Assessing changes in relapse rates in multiple sclerosis

Abstract

Multiple Sclerosis (MS) annualized relapse rates (ARRs) in trials may be declining due to changes in diagnostic criteria, MS etiology, study criteria, and selection biases. This review examines if there is a trend in the ARR for relapsing—remitting MS patients (RRMS) over time and if so, why. A comprehensive literature search was performed using PubMed, Web of Science^®, and the Cochrane Library using electronic searches, screen scraping for abstracts, and hand searching of references for randomized trials conducted between 1960 and 2008. Out of 72 randomized trials, 56 (77.8%) defined relapse. This study uses 32 placebo relapsing—remitting studies out of the 37 (66.1%) with RRMS. The mean ARR for the treatment arms was 0.68 and the one for the placebo groups was 1.002. The year of publication was negatively associated with the ARR (p = 0.0001). The annual reduction amounts to 0.36 relapses over a 10-year period. Age and duration of symptoms were negatively associated with the ARR. Year of publication was significantly negatively associated with ARR after controlling for covariates. ARRs have fallen with relapse definition, entrance criteria remain important, but time exceeds all these variables and reflects two likely sources, selection of patients for trials by clinicians and rescue of patients truncating the number of multiple relapses. The impact of truncating the number of relapses on the falling rates is important, not only on the ARRs, but also on the impact of informative censoring in drop-outs.

Keywords

multiple sclerosis relapsing—remitting annualized relapse rate symptoms duration exacerbation Expanded Disability Status Scale

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References

Amato MP and Portaccio E. Clinical outcome measures in multiple sclerosis. J Neurol Sci 2007; 259: 118-122.

Greenstein JI Problems in Clinical Trial Design in Multiple Sclerosis. Int J MS Care [serial-online]. 2002; 4(3).

Kappos L. , Antel J. , Comi G. , Montalban X. , O’Connor P. , Polman CH , et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 2006; 355: 1124-1140.

Poser CM , Paty DW , Scheinberg L. , McDonald WI , Davis FA , Ebers GC , et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13: 227-231.

Rice GP , Incorvaia B. , Munari L. , Ebers G. , Polman C. , D’Amico R. , et al. Interferon in relapsing-remitting multiple sclerosis. Cochrane Database Syst Rev 2001; 4: CD002002.

Koch-Henriksen N. , Sørensen PS , Christensen T. , Frederiksen J. , Ravnborg M. , Jensen K. , et al. A randomized study of two interferon-beta treatments in relapsing-remitting multiple sclerosis . Neurology 2006; 66: 1056-1060.

Johnson KP , Brooks BR , Cohen JA , Ford CC , Goldstein J. , Lisak RP , et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. Neurology 1995; 45: 1268-1276.

Jacobs LD , Cookfair DL , Rudick RA , Herndon RM , Richert JR , Salazar AM , et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 1996; 39: 285-294.

Jacobs LD , Cookfair DL , Rudick RA , Herndon RM , Richert JR , Salazar AM , et al. A phase III trial of intramuscular recombinant interferon beta as treatment for exacerbating-remitting multiple sclerosis: design and conduct of study and baseline characteristics of patients. Multiple Sclerosis Collaborative Research Group (MSCRG). Mult Scler 1995; 1: 118-135.

10.

Brod SA , Lindsey JW , Vriesendorp FS , Ahn C. , Henninger E. , Narayana PA , et al. Ingested IFN-alpha: results of a pilot study in relapsing-remitting MS. Neurology 2001; 57: 845-852.

11.

Anon. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Neurology 1999; 53: 457-465.

12.

Rudick RA , Stuart WH , Calabresi PA , Confavreux C. , Galetta SL , Radue EW , et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis . N Engl J Med 2006; 354: 911-923.

13.

Anon. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet 1998; 352: 1498-1504.

14.

Anon. Evidence of interferon beta-1a dose response in relapsing-remitting MS: The OWIMS Study. The Once Weekly Interferon for MS (OWIMS) Study Group. Neurology 1999; 53: 679-686.

15.

Andersen O. , Lycke J. , Tollesson PO , Svenningsson A. , Runmarker B. , Linde AS , et al. Linomide reduces the rate of active lesions in relapsing-remitting multiple sclerosis. Neurology 1996; 47: 895-900.

16.

Bech E. , Lycke J. , Gadeberg P. , Hansen HJ , Malmeström C. , Andersen O. , et al. A randomized, double-blind, placebo-controlled MRI study of anti-herpes virus therapy in MS. Neurology 2002; 58: 31-36.

17.

Fazekas F. , Deisenhammer F. , Strasser-Fuchs S. , Nahler G. and Mamoli B. Randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Lancet 1997; 349: 589-593.

18.

Freedman MS , Francis GS , Sanders EA , Rice GP , O’Connor P. , Comi G. , et al. Randomized study of once-weekly interferon beta-1a therapy in relapsing multiple sclerosis: three-year data from the OWIMS study. Mult Scler 2005; 11: 41-45.

19.

Haas J. and Hommes OR A dose comparison study of IVIG in postpartum relapsing-remitting multiple sclerosis. Mult Scler 2007; 13: 900-908.

20.

Jacobs LD , O’Malley J. , Freeman A. and Ekes R. Intrathecal interferon reduces exacerbation of multiple sclerosis. Science 1981; 214: 1026-1028.

21.

Knobler RL , Panitch HS , Braheny SL , Sipe JC , Rice GP , Huddlestone JR , et al. Systematic alpha-interferon therapy of multiple sclerosis. Neurology 1984; 34: 1273-1279.

22.

Lewan ska M. , Siger-Zajdel M. and Selmaj K. No difference in efficacy of two different doses of intravenous immunoglobulins in MS: clinical and MRI assessment. Eur J Neurol 2002; 9: 565-572.

23.

Lycke J. , Svennerholm B. , Hjelmquist E. , Frise n L, Badr G. , Andersson M. , et al. Acyclovir treatment of relapsing- remitting multiple sclerosis. A randomized, placebo-controlled, double-blind study. J Neurol 1996; 243: 214-224.

24.

Myhr KM , Riise T. , Green Lilleås FE , Beiske TG , Celius EG , Edland A. , et al. Interferon-alpha2a reduces MRI disease activity in relapsing-remitting multiple sclerosis. Norwegian Study Group on Interferon-alpha in Multiple Sclerosis. Neurology 1999; 52: 1049-1056.

25.

Oger J. , Francis G. and Chang P. PRISMS Study Group. Prospective assessment of changing from placebo to IFN beta-1a in relapsing MS: the PRISMS study . J Neurol Sci 2005; 237: 45-52.

26.

Polman CH , O’Connor PW , Havrdova E. , Hutchinson M. , Kappos L. , Miller DH , et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354: 899-910.

27.

PRISMS Study Group , The University of British Columbia MS/MRI Analysis Group. PRISMS-4: Long-term efficacy of interferon-beta-1a in relapsing MS. Neurology 2001; 56: 1628-1636.

28.

Filippi M. , Wolinsky JS , Comi G. and CORAL Study Group. Effects of oral glatiramer acetate on clinical and MRI-monitored disease activity in patients with relapsing multiple sclerosis: a multicentre, double-blind, randomised, placebo-controlled study. Lancet Neurol 2006; 5: 213-220.

29.

Hauser SL , Waubant E. , Arnold DL , Vollmer T. , Antel J. , Fox RJ , et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008; 358: 676-688.

30.

Comi G. , Pulizzi A. , Rovaris M. , Abramsky O. , Arbizu T. , Boiko A. , et al. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 2008; 371: 2085-2092.

31.

Fazekas F. , Lublin FD , Li D. , Freedman MS , Kartung HP , Rieckmann P. , et al. Intravenous immunoglobulin in relapsing-remitting multiple sclerosis: a dose-finding trial. Neurology 2008; 71: 265-271.

32.

Fazekas F. , Deisenhammer F. , Strasser-Fuchs S. , Nahler G. and Mamoli B. Treatment effects of monthly intravenous immunoglobulin on patients with relapsing-remitting multiple sclerosis: further analyses of the Austrian Immunoglobulin in MS study. Mult Scler 1997; 3: 137-141.

33.

Comi G. , Filippi M. and Wolinsky JS European/ Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging-measured disease activity and burden in patients with relapsing multiple sclerosis. European/Canadian Glatiramer Acetate Study Group. Ann Neurol 2001; 49: 290-297.

34.

Johnson KP , Brooks BR , Cohen JA , Ford CC , Goldstein J. , Lisak RP , et al. Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Copolymer 1 Multiple Sclerosis Study Group. Neurology 1998; 50: 701-708.

35.

Achiron A. , Gabbay U. , Gilad R. , Hassin-Baer S. , Barak Y. , Gornish M. , et al. Intravenous immunoglobulin treatment in multiple sclerosis. Effect on relapses. Neurology 1998; 50: 398-402.

36.

Goodkin DE , Bailly R. , Teetzen ML , Hertsgaard D. and Beatty WW The efficacy of azathioprine in relapsing-remitting multiple sclerosis. Neurology 1991; 41: 20-25.

37.

Millefiorini E. , Gasperini C. , Pozzilli C. , D’Andrea F. , Bastianello S. , Trojano M. , et al. Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome. J Neurol 1997; 244: 153-159.

38.

Miller DH , Khan OA , Sheremata WA , Blumhardt LD , Rice GP , Libonati MA , et al. A controlled trial of natalizumab for relapsing multiple sclerosis . N Engl J Med 2003; 348: 15-23.

39.

Giovannoni G. , Comi G. , Cook S. , Rammohan K. , Rieckmann P. , Soelberg Sørensen P. , et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med 2010; 362: 416-426.