Neurology -- Correspondence for Waubant et al., 61 (2) 184-189

Correspondence published:

Reply to Villoslada: Emmanuelle L Waubant, Sandra Vukusic and Christian Confavreux (18 November 2003)

Clinical characteristics of responders to interferon therapy for relapsing MS: Pablo Villoslada, Jorge R Oksenberg, Jordi Rio, and Xavier Montalban (13 October 2003)

Reply to Villoslada 18 November 2003

Emmanuelle L Waubant,
UCSF MS Center
350 Parnassus St, suite 908, San Francisco, CA 94117,
Sandra Vukusic and Christian Confavreux
Send Correspondence to journal:
Re: Reply to Villoslada

waubant{at}itsa.ucsf.edu Emmanuelle L Waubant, et al.

We thank Villoslada et al. for their letter on “Clinical characteristics of responders to interferon beta therapy in MS”. [1] Although methodologically different, their analysis has the merit to reproduce two of the results reported in our publication in a cohort of patients with relapsing MS on various interferon beta (IFNB) therapies. [2] Villoslada et al. confirmed that responders to IFNB were older and had longer disease duration than non-responders at onset of interferon therapy. Contrary to our report, Villoslada et al. did not find a difference in relapse rate the year or two years previous to initiating IFNB. This could be explained by the differences in the respective cohorts and definitions of response to IFNB. They selected their cohort differently than we did. They kept only patients who had received IFNB for two full years. They rejected patients with early treatment discontinuation and possibly introduced a selection bias towards those responding to IFNB therapy. Their patients may also have had slightly higher EDSS at the time IFNB was initiated. Those points could explain the higher proportion of responders in their cohort, despite more stringent definitions.
Villoslada et al.’s definition of treatment response differs from ours. Their definition B for response to IFNB is more stringent as it requires a 30% decrease or more of relapse rate to meet criteria of response to IFNB. Their definition A is more stringent than definition B for response to therapy. Definition A does not take into account previous disease activity, but has the merit to divide the cohort in three groups (responders, in between, and non- responders) and allow comparison of extreme phenotypes. This method reduces the sample size, which may decrease the ability to detect differences between groups.
Dr Roullet et al. have also reported significant changes in their results according to various definitions of response to IFNB; however, when using a definition comparable to ours, they found that relapse rate before IFNB initiation predicted response to therapy. [3] It is intriguing that these studies suggest that older patients with longer disease duration and possibly less devastating disease may benefit more from IFNB. The underlying reason is unclear. These studies also show how widely the definition for treatment response may vary, which ultimately could reflect on the criteria we use to decide when to alter therapy in a given patient in our daily practice. It may be helpful in the future to develop a consensus on how best to define treatment response, as it has direct implications for patient management.
References
1. Villoslada P et al. Clinical characteristics of responders to interferon beta therapy in MS. Neurology (in press)
2. Waubant E, Vukusic S, Gignoux L, Durand- Dubief F, Achiti I, Blanc S, Renoux C, and Confavreux C. Clinical characteristics of responders to interferon therapy for relapsing MS. Neurology 2003; 61: 184-189
3. Roullet E, Pez D, Le Canuet P, Ouallet JC, Giannesini C, Trifan IF, Heinzlef O. Application of different criteria for clinical response to beta-interferon in relapsing-remitting MS. Neurology 2003(suppl1):A168

Clinical characteristics of responders to interferon therapy for relapsing MS 13 October 2003

Pablo Villoslada,
University of Navarra
Pio XII 36. 31008 Pamplona, Spain,
Jorge R Oksenberg, Jordi Rio, and Xavier Montalban
Send Correspondence to journal:
Re: Clinical characteristics of responders to interferon therapy for relapsing MS

pvilloslada{at}unav.es Pablo Villoslada, et al.

Waubant et al. assessed the clinical characteristics of multiple sclerosis (MS) patients associated with a favorable response to interferon beta (IFNB) therapy based on a retrospective analysis of 200 relapsing-remitting and 62 secondary-progressive affecteds with at least 6 months of treatment. [1]
We assessed 202 MS patients starting IFNB treatment between January 1995 and December 1998. They were ascertained according to rigorous recruitment criteria at the Neuroimmunology Unit, Hospital Vall d'Hebron, Barcelona, Spain. Patients were followed prospectively for two years from initiation of therapy and clinical data, including EDSS scores, were recorded every three months. [2-4] Using primary and secondary end-points, patients were categorized as follows:
Criteria A) Responders were defined as having 0 relapses and no increase in the EDSS after 2 years follow-up period; Non-responders were defined as having suffered two or more relapses or having an increase of 1 point in the EDSS score, or both;
Criteria B) Responders were defined as having decrease in the relapse rate (RR) > 30% in the 2 year follow-up compared with the 2 year before IFNB onset, Non-responders were defined as having a decrease in RR <30%, the same RR or an increase in the RR in the same period.
Criteria A classification was more stringent to avoid misclassifying patients that would compromise statistics in genetic studies. [2-3] The second criteria classification was more realistic based on the results of the IFNB clinical trials and is also close to the definition of responders from Waubant et al.
As expected, we found significant differences in the number of relapses, relapse rate, EDSS status and EDSS increase after the 2 year follow-up between responders and non-responders by using any of the two criteria. In agreement with Waubant et al, we found that responder MS patients defined by criteria B (the closest to the one used in their work), were older (p=0.013) and tended to have a longer duration of their disease (p=0.087). This may be because responders represent a subset of MS patients with milder disease.
Interestingly, we found no significant differences when applying a more stringent criteria such as criteria A, suggesting that the evolution in the natural history of the disease outweighs the effect of IFNB, introducing an important confounding factor for analysis of trials data.
Table
References
1. Waubant E, Vukusic S, Gignoux L, Dubief FD, Achiti I, Blanc S et al. Clinical characteristics of responders to interferon therapy for relapsing MS. Neurology 2003; 61:184-189.
2. Villoslada P, Barcellos L, Rio J, Begovich A, Tintore M, Sastre-Garriga J et al. The HLA locus and multiple sclerosis in Spain. Role in disease susceptibility, clinical course and response to interferon-beta. J Neuroimmunol 2002; 130:194-201.
3. Sriram U, Barcellos LF, Villoslada P, Rio J, Baranzini SE, Caillier S et al. Pharmacogenomic analysis of interferon receptor polymorphisms in multiple sclerosis. Genes Immun 2003; 4:147-152.
4. Rio J, Nos C, Tintore M, Borras C, Galan I, Comabella M et al. Assessment of different treatment failure criteria in a cohort of relapsing-remitting multiple sclerosis patients treated with interferon beta: implications for clinical trials. Ann Neurol 2002; 52:400-406.