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ARTICLES: P. W. O’Connor, A. Goodman, A. J. Willmer-Hulme, M. A. Libonati, L. Metz, R. S. Murray, W. A. Sheremata, T. L. Vollmer, L. A. Stone, and the Natalizumab Multiple Sclerosis Trial Group Randomized multicenter trial of natalizumab in acute MS relapses: Clinical and MRI effects Neurology 2004; 62: 2038-2043 [Abstract] [Full text] [PDF]

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Randomized multicenter trial of natalizumab in acute MS relapses: Clinical and MRI effects

Helen Tremlett, Tony Traboulsee   (15 July 2004)

Reply to Tremlett et al

Paul W. O'Connor   (15 July 2004)

Randomized multicenter trial of natalizumab in acute MS relapses: Clinical and MRI effects 15 July 2004
Helen Tremlett, Medicine (Neurology) and MS/MRI Research Group, University of British Columbia, Vancouver, Canada Dept. Medicine, Div. Neurology (rm S159),VHHSC,2211 Wesbrook Mall, University of British Columbia, Tony Traboulsee Send Correspondence to journal: Re: Randomized multicenter trial of natalizumab in acute MS relapses: Clinical and MRI effects tremlett{at}interchange.ubc.ca Helen Tremlett, et al.	We read with interest the recent article by O'Connor et al in which the authors provide insight into the MRI natural history of acute relapses in MS. The authors conclude that ‘reassuringly, no evidence of a relapse “rebound” was seen following treatment with natalizumab, as has been suggested previously.’ However, Table 3 [1] shows a trend for those receiving natalizumab (particularly those in the 1mg/kg group) to be more likely to require a corticosteroid for an in- study relapse compared to placebo – 2 patients (3%) in the placebo group, 7 (12%) in the 1mg/kg natalizumab group and 5 (8%) in the 3mg/kg natalizumab group required corticosteroids (p=0.059). In addition, if all the in-study relapses (both the protocol-defined relapses and those classed as relapses by the blinded treating neurologist) are considered, those in the natalizumab 1mg/kg group experienced significantly more in-study relapses than those in the placebo group (p=0.023, see Table A). The 4 to 14 week MRI data might be helpful to confirm if this apparent increase in relapses is also borne out by the number/volume of gad-enhancing lesions (only week 1 and 3 data were shown). However, this data might not be useful because of the number of patients (92; 51%) who did not have a gad-enhancing lesion at baseline coupled with the high proportion of patients (60; 33%) whose MRI results were excluded as a consequence of corticosteroid treatment. The exclusion of the post-steroid MRI scans, while necessary, potentially biases the results by removal of those patients who faired badly. Would a sensitivity analysis be possible to increase confidence in the data? The most common adverse events were published in Table 4. [1] Another study has shown that natalizumab treatment (monthly over 6 months) was associated with an increased incidence of white cell count and increased risk of infection. [2] Is this data available for the current study? The authors note that binding antibodies (BABs) were measured at week 3, but the results of these measurements do not appear to be shown. Given that another study found 11% of patients developing BABs over a 6 month period, [2] it might be interesting see these results from the current study. Finally, we were intrigued by the decision to compare natalizumab to placebo and not to a corticosteroid, a treatment known to accelerate recovery from relapse. Table A: Total In-study Relapses (ISR) (protocol and non-protocol defined) Table References 1. O'Connor PW, Goodman A, Willmer-Hulme AJ, et al. Randomized multicenter trial of natalizumab in acute MS relapses: clinical and MRI effects. Neurology 2004;62(11):2038-43. 2. Miller D, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing MS. New England Journal of Medicine 2003;348:15-23.
Reply to Tremlett et al 15 July 2004
Paul W. O'Connor, University of Toronto 30 Bond St, Toronto, Ontario, Canada M5B 1W8 Send Correspondence to journal: Re: Reply to Tremlett et al oconnorp{at}smh.toronto.on.ca Paul W. O'Connor	Tremlett et al comment that our study of the effect of a single intravenous infusion of 1 mg/kg or 3 mg/kg of natalizumab on recovery from acute MS relapses suggests that the lower dose is associated with an increased risk of post-infusion relapses and steroid therapy. This post-hoc subgroup analysis is incorrect and ignores the data from Table 3 that the 1 mg/kg group was, despite randomization, the most clinically active at baseline with a significantly (p=.049) shorter time since their last previous relapse and a trend toward a higher 2 year relapse rate prior to study entry. Using logistic regression with the probability of an in-study relapse (ISR) as the outcome while controlling for time since previous relapse yields no differences in the probability of an ISR between any of the three treatment groups (p=0.11). In addition, there were no differences in ISR for protocol-defined relapses and no differences in the volume of Gadolinium-enhanced lesions between groups at 14 weeks. There is no evidence of an increase in post-infusion relapses following natalizumab administration in this study or the longer phase 2 study in which patients were infused monthly for 6 months and followed for an additional 6 months. [1] There were no significant differences for any adverse event between groups. Natalizumab administration was associated with an asymptomatic increase in lymphocyte count at week 3 which disappeared by week 14. This is not unexpected given the drug’s known mechanism of action involving demargination of lymphocytes. [2] In addition, Tremlett et al are incorrect that there was an increase in the rate of infections on natalizumab treatment in a previous study. [1] As shown in Table 4 in that publication, there were no significant differences among the groups for any of the adverse events listed. Twenty-three out of 116 patients (21%) (11 in the 1 mg/kg and 12 in the 3 mg/kg) had detectable levels of binding anti-natalizumab antibodies in the study. The binding antibody assay, dosing regimen and the timepoints at which antibodies were measured in this study are different than that of Miller et al. Therefore, the antibody incidence in our study cannot be directly compared with that of Miller et al in which the antibody rate over 6 months was 11%. Whether such antibodies are neutralizing is unclear. References 1. Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing-remitting multiple sclerosis. N Engl J Med 2003;348:15-23. 2. Kent SJ, Karlik SJ, Cannon C, et al. A monoclonal antibody to alpha-4 integrin suppresses and reverses active experimental allergic encephalomyelitis. J Neuroimmunol 1995; 58:1-10.