Correspondence
Vaccinations and Multiple Sclerosis
N Engl J Med 2001; 344:1793-1796June 7, 2001
- Article
To the Editor:
Ascherio et al. (Feb. 1 issue)1 report that they found no association between hepatitis B vaccination and the onset of multiple sclerosis. Vaccination was confirmed only in the respondents who said they had been vaccinated. Exclusions involved only the women with multiple sclerosis or the controls who had potentially been vaccinated, not those stating they had not been vaccinated. Similar rates of exclusion are cited for the women with multiple sclerosis and the controls, but with the wrong denominator, which should have referred to the positive cases and controls. Rather than exclude 35 percent of the women with multiple sclerosis, the study excluded 68 percent of the women with multiple sclerosis who had possible vaccine exposure, as compared with only 50 percent of the controls with possible exposure. With the new figures, the odds ratio decreases from 1.9 (95 percent confidence interval, 1.1 to 3.3) to 0.7 (95 percent confidence interval, 0.3 to 1.7).
In addition, only women with possible or confirmed multiple sclerosis, and not those with demyelinating disease or episodes, were included. Women with a single demyelinating episode after hepatitis B vaccination were excluded from the study, a factor that may in part explain the “negative” results. Ascherio et al. wrongly contrast their results to those of two as yet unpublished studies of acute demyelinating episodes performed at the request of the French authorities. In the French multicenter study that we conducted, a two-month cutoff date for exposure was chosen on the basis of expert neurologic advice. Of the 773 patients with demyelinating disease after hepatitis B vaccination in France, 83 percent had been exposed within two months. There were 236 patients with demyelinating disease and 355 controls, all of whom were interviewed with the use of a 30-minute structured questionnaire. The odds ratios were 1.8 (95 percent confidence interval, 0.7 to 4.6) for all the patients, 1.4 (95 percent confidence interval, 0.4 to 4.5) for those who had a vaccination certificate, and 2.0 (95 percent confidence interval, 0.8 to 7.9) and 1.5 (95 percent confidence interval, 0.5 to 6.2) for the patients with definite or probable multiple sclerosis who did or did not have a vaccination certificate, respectively.
The results presented by Ascherio et al. are not contradictory. At worst the authors found the same increased risk; at best, a small but epidemiologically important increase in risk cannot be ruled out.
1 ReferencesBernard Bégaud, M.D., Ph.D.
Université Victor Segalen, 33076 Bordeaux, FranceAnnick Alpérovitch, M.D., Ph.D.
INSERM, 75651 Paris, France1
Ascherio A ,Zhang SM ,Hernan MA , et al. Hepatitis B vaccination and the risk of multiple sclerosis. N Engl J Med 2001;344:327-332
Full Text | Web of Science | Medline
To the Editor:
We are worried about the discrepancies in the risks among the various subgroups in the study by Ascherio et al. The authors restricted their analysis to women with an onset of multiple sclerosis after 1986, for whom all the relative risks were less than 1. However, they did not analyze the subgroup of women with an onset of multiple sclerosis before 1986, for whom we calculate that all the point estimates of the relative risk are greater than 2 for each window of exposure to the vaccine and for each control group. Moreover, there is a significant association between hepatitis B vaccination and the onset of multiple sclerosis when the subgroup of women with multiple sclerosis who were vaccinated at any time before onset (i.e., before the index date) is compared with the corresponding subgroup of healthy controls (relative risk, 12; 95 percent confidence interval, 1.3 to 110).
Ascherio et al. also restricted their window of exposure to a period of two years or less, whereas most authors consider that the appropriate window is three months or less (as in the study by Confavreux et al. [Feb. 1 issue]1 and the studies cited in their references 1 to 39). To present point estimates for both time windows would have been more informative.
1 ReferencesThomas Hanslik, M.D.
Cecile Viboud, M.P.H.
Antoine Flahault, M.D., Ph.D.
INSERM Unité 444, 75571 Paris CEDEX 12, France1
Confavreux C ,Suissa S ,Saddier P ,Bourdes V ,Vukusic S . Vaccinations and the risk of relapse in multiple sclerosis. N Engl J Med 2001;344:319-326
Full Text | Web of Science | Medline
To the Editor:
The benefit of modern immunization programs is well known and unquestioned. The study by Ascherio et al. rules out a possible link between hepatitis B vaccine and multiple sclerosis. Although we agree that the hepatitis B vaccine is not in itself the cause of multiple sclerosis, the studies conducted in Europe did not rule out such an association.1,2 These discrepancies could be due to the fact that Ascherio et al. considered only patients with a diagnosis of multiple sclerosis and have excluded those with the central demyelinating events that can be either a first attack of multiple sclerosis or a limited form of acute disseminated encephalomyelitis.
The authors chose a long risk period (two years), which may have had a diluting effect. In addition, the number of vaccinated women in the study (32) was low. If we consider the women with multiple sclerosis who had been vaccinated during the two years before the onset of their disease, the number drops to nine.
Vaccines with a new antigen in the adult population, such as the hepatitis B vaccine, may have side effects that are not observed in children or newborn infants, because of differences in immunologic status. Although the widespread use of hepatitis B vaccination in France may explain the observed association, a deleterious effect of the vaccine cannot be ruled out in a specific group. Consequently, we have to look at the risk–benefit ratio of a specific vaccine in each individual or subgroup.
2 ReferencesOlivier Gout, M.D.
Fondation A. de Rothschild, 75019 Paris, France1
Sturkenboom MC ,Wolfson C ,Roullet E ,Heinzlef O ,Abenhaim L . Demyelination, multiple sclerosis, and hepatitis B vaccination: a population-based study in the U.K. Neurology 2000;54:Suppl 3:A166-A166 abstract.
Web of Science2
Touze E ,Gout O ,Verdier-Taillefer MH ,Lyon-Caen O ,Alperovitch A . Premier épisode de démyélinisation du système nerveux central et vaccination contre l'hépatite B. Rev Neurol (Paris) 2000;156:242-246
Web of Science | Medline
To the Editor:
The study by Ascherio et al. examines whether there is an association between hepatitis B vaccination and multiple sclerosis. To eliminate recall bias, the authors tried to validate the date of vaccination, but this effort introduced serious selection bias because of the exclusion of substantial numbers of women who had received the hepatitis B vaccine. Lack of a response from employers to confirm vaccination resulted in the loss of 106 of the exposed women with multiple sclerosis (67.9 percent), 466 of the exposed healthy controls (53.2 percent), and 96 exposed controls with breast cancer (56.5 percent). The authors express the loss as a percentage of the whole population, instead of a percentage of the vaccinated population. Since the rate of exclusion was higher among the exposed women with multiple sclerosis than among the exposed controls, any comparison of exposure odds between the women with multiple sclerosis and the controls in the final population favored the vaccine. This may partly explain why the relative risk was 0.7 in the selected population and 1.9 in the overall population. The significantly elevated risk of 1.9 was easily discarded as being caused by recall bias, but the authors never directly quantified the effects of recall bias. The well-meant attempts to reduce recall bias introduced serious selection bias that favored the vaccine.
Miriam C.J.M. Sturkenboom, Pharm.D., Ph.D.
Erasmus University Medical Center, 3000 DR Rotterdam, the NetherlandsAnnie Fourrier, Pharm.D., M.P.H.
Université Victor Segalen, 33076 Bordeaux CEDEX, FranceTo the Editor:
We endorse the conclusion by Confavreux et al. that vaccination does not increase the short-term risk of relapse in multiple sclerosis. Nonetheless, we would like to recommend some caution in clinical practice. As stated by the authors, their study excluded patients with very frequent relapses. There is circumstantial evidence that patients with sustained disease activity may be at increased risk of exacerbations after vaccination,1 suggesting that in such conditions the proinflammatory stimuli associated with any given vaccination find a decreased threshold for the recruitment of pathogenic immune effectors. A simple precaution may be to defer vaccination in patients with clinical or paraclinical evidence of strong disease activity. Examination of a recent contrast-enhanced, magnetic resonance image may be advisable before a patient with multiple sclerosis is vaccinated.
In view of preliminary evidence that vaccination with bacille Calmette–Guérin2 is safe and of potential benefit in multiple sclerosis, it is interesting that in the study by Confavreux et al., patients with at least one confirmed vaccination between 1992 and 1997 seemed to do significantly better — in terms of both disability and the number of relapses — than nonvaccinated controls. This difference does not seem to be related to other base-line characteristics of the patients studied.
2 ReferencesCarla Buttinelli, M.D.
Marco Salvetti, M.D.
Giovanni Ristori, Ph.D.
University La Sapienza, 00185 Rome, Italy1
Salvetti M ,Pisani A ,Bastianello S ,Millefiorini E ,Buttinelli C ,Pozzilli C . Clinical and MRI assessment of disease activity in patients with multiple sclerosis after influenza vaccination. J Neurol 1995;242:143-146
CrossRef | Web of Science | Medline2
Ristori G ,Buzzi MG ,Sabatini U , et al. Use of Bacille Calmette-Guèrin (BCG) in multiple sclerosis. Neurology 1999;53:1588-1589
Web of Science | Medline
To the Editor:
I am a patient with multiple sclerosis. I did not have symptoms of multiple sclerosis until I had the hepatitis B vaccine series. About a month after I took my first shot, I started slurring my words. That turned out to be my first symptom of multiple sclerosis. I do not know, and neither do my neurologists, whether the hepatitis B vaccination series had anything to do with my multiple sclerosis. I grew up in northern Europe, so I may have been at risk, but I don't think we'll ever know whether I was or not.
Even after all that I've been through, I still believe in the good that vaccination does.
Larry Hostetler
152 Tyson Ln., Allenhurst, GA 31301Author/Editor Response
The authors reply:
To the Editor: Drs. Bégaud and Alpérovitch and Drs. Sturkenboom and Fourrier overstate the magnitude of selection bias in our study, and they ignore efforts to remove that bias. The presumed source of selection bias arises from our focus on women for whom we could confirm the dates of immunization. When women with missing vaccination records were included in the analyses and classified as exposed or not exposed according to their self-reported dates of vaccination, the estimated relative risk was 1.0 (for vaccination at any time or for vaccination within two years before the index date), not 1.9, as suggested by the correspondents. The relative risk of 1.9 (95 percent confidence interval, 1.1 to 3.3) refers to analyses based on the self-reported dates of vaccination for all the women, even when a valid certificate of vaccination was available. The comparison of these relative risks (1.0 and 1.9) provides a direct estimate of the effects of recall bias, since the same women were included in both analyses. An analysis based on recalled dates would create the false impression of a doubling of risk in women in whom an analysis based on documented dates finds no risk at all. Concern about recall bias led us to seek validated records, and we believe that the results justify that decision.
Our study was restricted to cases of probable or definite multiple sclerosis; therefore, we did not address the possible relation of the vaccine to single demyelinating episodes. However, according to the results reported by Drs. Bégaud and Alpérovitch, in the French multicenter study the odds ratio was higher for definite or probable multiple sclerosis than for all cases combined. Therefore the basis for their suggestion that the exclusion of other demyelinating conditions would contribute to our null findings is unclear. The two-month cutoff for exposure chosen by the French investigators could be an appropriate estimate of the time between the hypothetical triggering stimulus and the beginning of demyelination. However, demyelination often precedes the clinical onset of multiple sclerosis by several months.1 It therefore seems likely that any excess in the risk of multiple sclerosis caused by the vaccine would gradually increase over time, with a peak at about the (unknown) median time between the beginning of myelin loss and the onset of recognizable signs or symptoms. Our study did not have the power to address possible effects restricted to a two-month window after exposure.
Dr. Hanslik and colleagues are concerned about the association between vaccination and an onset of multiple sclerosis before 1987. Since only five women were vaccinated during that period (as can be inferred from Table 2 and Table 3 in our article), it is not possible to obtain a stable estimate of the relative risk, and there was no significant association between vaccination and the risk of multiple sclerosis in any subgroup. Dr. Gout, in addition to sharing some of the concerns of the other correspondents, suggests that the risk–benefit ratio for the vaccination should be assessed in each age group. All the women in our study were vaccinated as adults, and adults constitute the group considered at higher risk according to the French studies.
1 ReferencesAlberto Ascherio, M.D., Dr.P.H.
Shumin M. Zhang, M.D., Sc.D.
Alexander M. Walker, M.D., Dr.P.H.
Harvard School of Public Health, Boston, MA 021151
Brex PA ,O'Riordan JI ,Miszkiel KA , et al. Multisequence MRI in clinically isolated syndromes and the early development of MS. Neurology 1999;53:1184-1190
Web of Science | Medline
Author/Editor Response
Dr. Buttinelli and colleagues refer to a patient with three relapses in the year before influenza vaccination and a progressive worsening of disability after vaccination.1 They are concerned that our study population includes only patients with multiple sclerosis who had a relapse after a relapse-free period of at least 12 months. This choice was dictated by the case–crossover design of our study. This 12-month span allowed sufficient time to estimate exposure during the control period and was meant to ensure a constant probability of exposure to a vaccine during the control and risk periods. Nevertheless, in studying the natural history of relapsing–remitting multiple sclerosis, we previously showed that the probability of a new relapse was highest immediately after a relapse and then fell exponentially: 72 percent of the patients had not yet had their second relapse 12 months after the first relapse, and 50 percent had not yet had their second relapse at 2 years.2
The natural occurrence of relapses in any given patient can vary substantially, but relapses tend to decrease in frequency over time. Even those who usually have a high frequency of relapse can have a relapse-free period of 12 months or more and thus be afforded the chance of vaccination. In the already mentioned series of six patients with multiple sclerosis who had received an influenza vaccine, there was no increase in the number of relapses after vaccination in the five patients with up to two relapses in the year before vaccination.1 Still, there is currently no objective statistical evidence that vaccination is safe in patients with relapses at shorter intervals than 12 months. The suggestion by Dr. Buttinelli and colleagues that contrast-enhanced magnetic resonance imaging be performed before a patient with multiple sclerosis is vaccinated is interesting but not yet evidence-based.
Finally, we agree that at the time of the index relapse in our study, the patients with a confirmed vaccination were younger, had had fewer previous relapses, and had lower Kurtzke disability scores than the patients with no validated vaccination. These differences suggest that the patients with less active and less advanced disease were more likely to have been vaccinated than the others. The data we provided showed the absence of a short-term effect of vaccination on the risk of relapse. We did not assess the long-term effect of vaccination. Our data do not allow us to conclude that there is a beneficial effect of vaccination on the activity of the disease.
2 ReferencesChristian Confavreux, M.D.
Hôpital Neurologique, 69394 Lyons, FranceSamy Suissa, Ph.D.
McGill Pharmacoepidemiology Research Unit, Montreal, QC H3A 1A1, CanadaPatricia Saddier, M.D., Ph.D.
Aventis Pasteur, 69007 Lyons, France1
Salvetti M ,Pisani A ,Bastianello S ,Millefiorini E ,Buttinelli C ,Pozzilli C . Clinical and MRI assessment of disease activity in patients with multiple sclerosis after influenza vaccination. J Neurol 1995;242:143-146
CrossRef | Web of Science | Medline2
Confavreux C ,Aimard G ,Devic M . Course and prognosis of multiple sclerosis assessed by the computerized data processing of 349 patients. Brain 1980;103:281-300
CrossRef | Web of Science | Medline
- Citing Articles (2)
Citing Articles
1
M.N. Hocine, C.P. Farrington, E. Touzé, H.J. Whitaker, A. Fourrier, T. Moreau, P. Tubert-Bitter. (2007) Hepatitis B vaccination and first central nervous system demyelinating events: Reanalysis of a case–control study using the self-controlled case series method. Vaccine 25:31, 5938-5943
CrossRef2
Marc Girard. (2005) Autoimmune hazards of hepatitis B vaccine. Autoimmunity Reviews 4:2, 96-100
CrossRef
