Discussion of the various studies 20 October 2004
Since the introduction of hepatitis B immunisation, concerns have repeatedly been expressed that hepatitis B (HB) vaccination causes the onset of or worsens multiple sclerorsis (MS). Based on this hypothesis, several case-control and cohort studies n1,3,4,7-9 and one ”case cross-over study”2 have been published in the past few years, however, up to now, none of these studies described a significant risk MS or other demyelinising diseases occurring after HB vaccination. The table below shows a listing of important studies published so far:
| Author | Study design | Case numbers | Time interval HB vaccination and MS | OR or. RR (95% CI) |
|---|---|---|---|---|
| DeStefano et al., 2003 | Retrospective case-control study in adults | Pat(ient) n = 440 vs Con(trol) n= 950 | < 1 year 1-5 years > 5 years | 0,8 (0,4 - 1,8) 1,6 (0,8 - 3,0)# 0,6 (0,2 - 1,4) |
| Touze et al.., 2002 | Retrospective, multicentre, case-control study | Pat. n = 236 vs Con. n = 355 | 0 - 2 months 2 - 12 months | 1,8 (0,7 - 4,6) 0,9 (0,4 - 2,0) |
| Ascherio et al., 2001 | Retrospective case-control study in women (nurses) | Pat. n = 192 vs Con. n = 645 | general before < 2 years | 0,9 (0,5 - 1,6) 0,7 (0,3 - 1,8) |
| Zipp et al., 1999* | Cohort study in adults | 27229 (vaccinated) vs 107469 (unvaccinated) | < 6 months < 1 year < 2 years < 3 years | 1,3 (0,4 - 4,8) 1,0 (0,3 - 3,0) 1,0 (0,4 - 2,4) 0,9 (0,4 - 2,1) |
| Confavreux et al., 2001 | "Case cross-ower"study in MS patients | n = 6432 vaccinated 2 months before relapse n = 15 | 0 - 2 months | 0,67 (0,2 - 2,17) |
Against this background, the latest case-control study by MA Hernán et al.5 ("Recombinant Hepatitis B Vaccine and the Risk of Multiple Sclerosis"
in Neurology 2004) has attracted attention. In their study, the authors Hernán et al identified a slightly increased odds ratio (=> risk) of 3.1 (95 % CI 1.5-6.3) for MS after a hepatitis B vaccination. As far as tetanus and influenza vaccinations were concerned, no evidence was found for such an increased risk. The retrospective selection of the patients for this case-control study was carried out by Hernán by means of a data analysis from an English General Practice Research Database (GPRD). Medial data on more than 3 million patients from the UK are stored in this database. They were collected by selected general practicioners in England. The patient data relevant for this were extracted from the database in two steps.
In a first step, all entries within the period of January 1993 to December 2000 with a diagnosis of multiple sclerosis (conforming to the ICD Code) were selected. Then, the appropriate medical documentations in paper form were assigned to the electronic data by two independent specialists of internal medicine in an anonymised form based on the criteria of Poser et al6 in view of an MS diagnosis. The patients were subdivided into groups with confirmed MS, possible MS, and “no safe indication for MS”. From the initially 713 cases in the database, 438 patients with MS were identified by means of this selection.
In a second step, the patients were subdivided according to the time of the onset of first clinical symptoms of MS during the observation period. In 282 of the 428 patients with MS, first symptoms were identified after entry into the database. For subsequent analysis, however, only 163 patients’ records were evaluated which were entered in the databank at least 3 years before the first diagnosis of MS.
Out of these 163 patients, 11 were identified who were vaccinated against hepatitis B within three years of the first diagnosis of MS. The result of the study was an odds ratio of 3.1 (95% CI 1.6 – 6.3) compared with a control group (correlated by age and gender) who was maintained in the database over the same period of time.
It is important to note that all vaccinated MS patients in this study were older than 18 years, i.e. children were not included.
In the case-control study by Hernán et al, a significantly increased risk of MS after hepatitis B vaccinations was described for the first time in the literature, even though the authors cannot explain the physiopathological connection. No statement can thus be made regarding a causal relationship. The World Health Organisation (WHO) expressed criticism of this study, indicating various methodological problems. E.g. the small number of cases included in the study (n = 11 adults with MS after vaccination), and the variations in the results cased by only minimal differences in the recorded data, are mentioned as a weakness relating to the arguments given.
In addition, the reason for the a. m. selection leading to the inclusion of the 163 MS patient was not sufficiently described in the publication. In addition, the question arises whether the vaccination coverage of the control group really represents that of the general population.
Another point of criticism was the definition of the control group which only refers to age, gender, time of registration in the physician’s office, as well as location of the physician, not, however, other possible factors that may lead to an indication for vaccination. It is known that during the observation period of the study, the vaccination against hepatitis B in the United Kingdom was targeted to high risk individuals: Health care and laboratory workers, dialysis patients, those with liver damage, travellers to endemic regions, prostitutes. Thus, it cannot be ruled out that the results are not representative, since important risk factors may not have been taken into account in the selection of the control. In addition, an explanation is required why a significant risk could no longer be found when the time between vaccination and diagnosis was used in the evaluation instead of the period between the vaccination and the onset of the first symptoms.
A study design, which can certainly be classified as similar, performed with patient data from the USA (DeStefano F et al.,4 Pharamacoepidemiology and Drug Safety 2004;13:143-144) has recently not shown a significantly increased risk (odds ratio 0.8; 95 % CI: 0.4-1.4). However, this paper is currently available only as an abstract.
The results of the study by Hernán et al. must be seen in context with the other a. m. studies. Despite the criticism regarding the methodology of the a. m. study, its results should not be ignored, and further studies should be performed. In addition, the author himself is of the opinion that the benefit of an HB vaccination by far outweighs the risks found so far.
Ascherio A, Zhang SM, Hernán MA, et al. Hepatitis B vaccination and the risk of multiple sclerosis. N Engl J Med 2001;344:327-332.
DeStefano F, Verstraeten T, Jacksin LA, et al. Vaccinations and risk of central nervous system dermyelinating diseases in adults. Arch Neurol 2003;60:504-509.
Updated: 29.11.2005
