Neurology -- Correspondence for Kappos et al., 67 (7) 1242-1249

Correspondence published:

Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patien: Marcus W. Koch, Jop P. Mostert, Joeke J. de Vries, Jacques De Keyser (31 October 2006)

Reply from the Authors: Ludwig Kappos, Chris H. Polman, Mark S. Freedman, Gilles Edan, Hans- Peter Hartung, David H. Miller, Xavier Montalban, Frederik Barkhof, Lars Bauer, Christoph Pohl, Ruppert Sandbrink for the BENEFIT Study Group (31 October 2006)

Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patien 31 October 2006

Marcus W. Koch,
University Medical Centre Groningen
Hanzeplein 1, 9713GZ Groningen, The Netherlands,
Jop P. Mostert, Joeke J. de Vries, Jacques De Keyser
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Re: Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patien

m.w.koch{at}neuro.umcg.nl Marcus W. Koch, et al.

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The BENEFIT trial on patients with a first clinical event suggestive of MS (clinically isolated syndrome; CIS) showed a significantly lower rate of conversion to clinically definite MS (CDMS) in patients treated with interferon beta-1b versus patients receiving placebo. The authors conclude that treatment with interferon beta-1b should be considered as a therapeutic option in patients presenting with a first clinical event suggestive of MS.[1]
A crucial inclusion criterion of the study was the presence of at least two T2 lesions on a brain MRI-scan. However, we believe that the uncommonly high number of baseline T2 lesions on brain MRI of the patients included in this study may represent an important source of bias concerning the applicability of this study to everyday practice.
It is well established that CIS patients with a higher T2 lesion load on baseline brain MRI are more likely to progress to CDMS. Previous studies on MR imaging in CIS reported median T2 lesion numbers of less than ten. In the optic neuritis treatment trial, including 351 patients, Beck et al report a median lesion number of 0.[2] O�Riordan et al found a median lesion number between two and three in their study on 81 patients with different types of CIS.[3] For patients with two or more lesions, the median lesion number in these two studies was six(RW Beck, personal communication) and in the range of 4 to 10 lesions. [3]
The patients included in the BENEFIT trial had median lesion numbers of 17 (placebo) and 18 (interferon) on baseline MRI, and are therefore much more likely to progress to clinically definite MS than patients seen in everyday practice. Interestingly, the median lesion number in the two previous trials on interferon treatment in CIS, were also much higher than could be expected: 13 in the CHAMPS [4] and 26 (interferon)/22 (placebo) in the ETOMS trial. [5]
We believe that the patients included in the CIS interferon trials represent only a subgroup of patients with CIS characterized by a high number of T2 lesions, indicative of a more aggressive disease course. Therefore, the results of these studies cannot be extrapolated to all patients with CIS.
References
1. Kappos L, Polman CH, Freedman MS, et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology 2006; 67: 1242-1249.
2. Beck RW, Trobe JD, Moke PS, et al. High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis: experience of the optic neuritis treatment trial. Arch Ophthalmol 2003;121:944-949.
3. O'Riordan JI, Thompson AJ, Kingsley DP, et al. The prognostic value of brain MRI in clinically isolated syndromes of the CNS. A 10-year follow-up. Brain 1998; 121:495-503.
4. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 2000; 343:898-904.
5. Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 2001; 357:1576-1582.
Disclosure: The authors report no conflicts of interest.

Reply from the Authors 31 October 2006

Ludwig Kappos,
Neurology and Department of Research, University Hospital Basel
Petersgraben 4, CH-4031 Basel, Switzerland,
Chris H. Polman, Mark S. Freedman, Gilles Edan, Hans- Peter Hartung, David H. Miller, Xavier Montalban, Frederik Barkhof, Lars Bauer, Christoph Pohl, Ruppert Sandbrink for the BENEFIT Study Group
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Re: Reply from the Authors

lkappos{at}uhbs.ch Ludwig Kappos, et al.

Koch et al address the issue of applicability of the findings of the BEtaferon� in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) study to everyday practice. They suggest that patients in our study had unusually high baseline numbers of T2 lesions, and that this put them at heightened risk of conversion to MS compared with natural course studies or the North American optic neuritis treatment trial (ONTT). [6]
They further state that the median T2 lesion number of 17 at baseline, as observed in BENEFIT patients, is considerably higher than in both the ONTT (which evaluated the effects of corticosteroids in ON) and the London natural history study of clinically isolated syndrome (CIS) patients. [7] Koch et al conclude that BENEFIT patients had unusually aggressive disease and that the results of the BENEFIT study can not be extrapolated to all CIS patients.
As stated in our paper, the BENEFIT study included CIS patients with at least two clinically silent T2 lesions on the baseline MRI scan. Therefore, findings of this study can only apply to patients with MRI findings suggestive of MS.
Comparing lesion numbers found in BENEFIT with those found in the ONTT or in the London study is problematic for several reasons: 49% and 33%, respectively, of patients in the ONTT and London studies showed no abnormalities suggestive of MS in baseline brain MRIs. [6,7] The difference in the inclusion criteria between these studies and those of the BENEFIT study contributes to the difference in lesion numbers. The ONTT recruited only patients presenting with ON, who in some regional studies have fewer MRI lesions than other CIS patients. [8,9] Lesion counts may also be influenced by differences in scanner field strength and slice thickness as well as variability in assessments performed by central evaluation centers. [10]
A more recent study using equipment better comparable to the standards in the BENEFIT study has reported 60% of patients with more than 10 lesions. [11] More importantly, as reported in our article, the BENEFIT study also found robust treatment effects of interferon beta-1b in CIS patients with less subclinical disease dissemination (i.e. participants with less than 9 T2-lesions).
Considering these issues, we are convinced that the results of the BENEFIT study are applicable in guiding a physician�s decision on interferon-beta 1b-treatment in CIS patients who have MRI evidence of subclinical disease dissemination (at least two clinically silent lesions on brain MRI).

References
6. Beck RW, Arrington J, Murtagh FR et al. Brain magnetic resonance imaging in acute optic neuritis. Experience of the Optic Neuritis Study Group. Arch Neurol. 1993;50:841-846.
7. O'Riordan JI, Thompson AJ, Kingsley DP et al. The prognostic value of brain MRI in clinically isolated syndromes of the CNS. A 10-year follow- up. Brain 2001;124:1052�1053.
8. Tintore M, Rovira A, Rio J et al. Is optic neuritis more benign than other first attacks in multiple sclerosis? Ann Neurol. 2005;57:210�5.
9. Swanton JK, Fernando K, Dalton CM et al. Is the frequency of abnormalities on magnetic resonance imaging in isolated optic neuritis related to the prevalence of multiple sclerosis? A global comparison. J Neurol Neurosurg Psychiatry 2006 Sep;77:1070�1072
10. Schach S, Scholz M, Wolinsky JS, Kappos L. Pooled historical MRI data as a basis for research in multiple sclerosis � a statistical evaluation. Multiple Sclerosis 2006;12:1�8.
11. Tintore M, Rovira A, Rio J et al. Baseline MRI predicts future attacks and disability in clinically isolated syndromes. Neurology. 2006;67:968�972.
Disclosures: L. Kappos has received compensation for acting as principal investigator, member, or chair of planning and steering committees or advisory boards in clinical trials in multiple sclerosis and for lecturing at medical conferences sponsored by pharmaceutical companies. Payments for all mentioned activities have been exclusively used for funding of research at L.K.�s department. Research and the clinical operations (nursing and patient care services) of the Multiple Sclerosis Clinic and Research Centre at the University Hospital Basel, led by L.K., have also been supported by non-restricted grants from one or more pharmaceutical companies. The sponsoring pharmaceutical companies include Biogen Idec, GlaxoSmithKline, Novartis, Sanofi Aventis, Schering, Serono (all > US $10,000 per year); furthermore, Abbott, Bayer, Bayhill, Berlex, Boehringer Ingelheim, Bristol Myers, Centocor, Eisai, Elan, Genzyme, Neurocrine, Roche, Teva, UCB, Wyeth, and others. C Polman has received consulting fees from Biogen Idec, Schering, Teva, Serono, Novartis, Antisense and GlaxoSmithKline; lecture fees from Biogen Idec, Schering AG and Teva; and grant support from Biogen Idec, Novartis, Serono, Schering, Wyeth, and GlaxoSmithKline. M Freedman has received stipends from Transition Therapeutics and BioMS (both > $10,000 per year); honoraria from Bayer, Serono, Schering, Berlex, Teva, Pfizer; and a research grant from Serono. G Edan has received honoraria/consulting fees from Schering, Biogen Idec, Wyeth, Novartis, UCB Pharma, LFB; lecture fees from Schering, Biogen Idec; and grant support from Serono. H-P Hartung has received fees for speaking at scientific symposia and honoraria for consulting ad hoc from Bayer, Biogen Idec, Schering, Teva and Serono. D Miller has received honoraria/consulting fees from Biogen Idec, Wyeth, Novartis, UCB Pharma, and Bristol Meyers Squibb; lecture fees from Biogen Idec and Serono; and grant support from Biogen Idec, GlaxoSmithKline, and Schering. X Montalban has received honoraria/consulting fees from Biogen Idec, Wyeth, Novartis, and Bristol Myers Squibb; lecture fees from Biogen Idec, Serono and Schering; and grant support from Biogen Idec, Serono and Schering. F. Barkhof has served as a consultant to various pharmaceutical companies, including Aventis, Schering, and Serono. As the director of the Image Analysis Centre, he has been remunerated for time spent conducting the blind MRI analyses. L. Bauer, C. Pohl, and R. Sandbrink are salaried employees of Schering. P. Jakobs was a salaried employee of Schering and owns shares in Schering.