Articles on HepB Vaccine Safety

Thomas Keske TKeske at
Thu Jan 13 06:01:52 EST 2000

Hepatitis B Immunization Linked to Autoimmune Rheumatic Diseases

Two abstracts being presented at the 62nd Annual Meeting of the
American College of Rheumatology (held November 8-12, 1998, in San
Diego, California) link the development of autoimmune rheumatic
diseases to immunization with hepatitis B vaccine. A recently
published paper from Canada also links the development of rheumatic
diseases to immunization with hepatitis B vaccine. In all cases
immunization starting after 2 months of life was associated with
autoimmunity while immunization starting at birth has not been
linked to the development of autoimmunity.

The development of rheumatoid arthritis after recombinant hepatitis
B vaccination.

Pope JE, Stevens A, Howson W, Bell DA Department of Medicine, the
University of Western Ontario, London, Canada.

J Rheumatol 1998 Sep;25(9):1687-93

OBJECTIVE: Hepatitis B vaccination has been associated with reactive
arthritis and rarely rheumatoid arthritis (RA). We defined the
clinical, serologic, and immunogenetic background of patients
developing RA, soon after recombinant hepatitis B vaccination.
METHODS: The clinical, serologic, and HLA antigens of a cluster of
firefighters who developed arthritis after prophylactic recombinant
hepatitis B vaccination (5 subjects), as well as a second group of
sporadic cases of arthritis (6 patients) after hepatitis B
vaccination are described.  RESULTS: Ten of 11 patients fulfilled
revised American College of Rheumatology criteria for RA. All cases
had persistent arthritis for more than 6 months; at 48 months
followup 2 cases no longer had inflammatory arthritis. Nine patients
required disease modifying antirheumatic drugs. Five subjects were
HLA-DR4 positive.  HLA class II genes expressing the RA shared
motif were identified in 9/11 patients genotyped for HLA-DRbeta1
and DQbeta1 alleles (0401, 0101, or 0404). All the firefighters
shared the HLA-DRbeta1 allele 0301 and the DQbeta1 allele 0201,
with which it is in linkage disequilibrium.  CONCLUSION: These
polymorphic residues in the binding site of the MHC class II
molecules of the affected patients appear capable of binding some
peptide sequences of the recombinant vaccine peptides they received
and may be responsible for hepatitis B vaccine triggering
development of RA in these cases.  Recombinant hepatitis B vaccine
may trigger the development of RA in MHC class II genetically
susceptible individuals.

Abstract: 1185

November 10, 1998

Poster Session D: Miscellaneous Rheumatic Diseases

12:30-2:00 pm, Hall B1/C


S. Laoussadi, V. Sayag-Boukris, C.-J. Menkes, André Kahan

Department of Rheumatology A, Cochin Hospital, Paris V University,
Paris, France

HBV vaccination may induce hypersensitivity and autoimmune
reactions in susceptible individuals and healthy

Subjects. Seven patients (4 F, 3 M; mean age 35 ± 10 yrs), developed
severe rheumatic disorders after the first (4) or the third (3)
injection of HBV vaccine.  Before HBV vaccination, one was a
healthy subject and 6 were previously suffering from: eosinophilic
fasciitis (1), systemic lupus (1), HLA B27 positive axial
ankylosing spondylitis (2), sickle cell disease (1) and idiopathic
cutaneous urticaria (1). The underlying disease was in remission
induced by treatment (4 cases), including NSAIDs (2),
corticosteroids (CS; 1), sulfasalazine (SZ; 2) and
hydroxychloroquine (HC; 1) and in 3 cases there was no treatment.
Fourteen days (mean) after vaccine injection, they developed
rheumatic disorders including: 3 severe symetric polyarthritis
fulfilling ARA RA criteria, associated in one case with vasculitis
and 2 monoclonal IgM cryoglobulins. Two cases of oligoarthritis
(one associated with palatine and laryngeal oedema, ocular sicca
syndrome, hypereosinophilia, positive ANA, and C4 defect), 1 case of
Sjögren syndrome, 1 severe systemic flare of lupus with arthritis,
pleural effusion, vasculitis and a grade IIIa glomerulonephritis.

In all patients these disorders were controlled using prednisone
therapy (0.3 to 1 mg/kg/day; 7) combined, according to the
underlying rheumatic disease with HC (2), SZ (2), cyclophosphamide
(1), azathioprine (1), methotrexate (1) and IV Ig (1). Six patients
met a remission after 2 months to one year treatment, but they are
still under treatment. In one patient, with eosinophilic fasciitis,
a total recovery was observed after 7 years and he has stopped any
treatment for 2 years.

Hepatitis B virus vaccination may induce severe reactions requiring
the use of a long term treatment (mean period of time of 32.5 ± 24.
8 months) in healthy subjects and in patients who suffer from
autoimmune diseases and from ankylosing spondylitis or reactive
arthritis, even if a complete remission has been already obtained.

Abstract: 1186

November 10, 1998

Poster Session D: Miscellaneous Rheumatic Diseases

12:30-2:00 pm, Hall B1/C


J.F. Maillefert1, J. Sibilia2, E. Toussirot3, E. Vignon4, R. Juvin5,
C.  Piroth1, D.  Wendling3, J.L. Kuntz2,

C. Tavernier1, P. Gaudin5

Departments of Rheumatology; 1Dijon; 2Strasbourg; 3Besançon; 4Lyon;
5Grenoble, France

Aim: to obtain an overview of rheumatic disorders occurring after
hepatitis B vaccination.

Methods: a questionnaire was sent to rheumatology departments in
nine french hospitals. Criteria for entry were rheumatic complaints
of one-week duration or more, occurrence during the 2 months
following hepatitis B vaccination, no previously diagnosed
rheumatic disease, exclusion of bacterial or viral reactive

Results: 21 patients (18 women, 3 men; mean age = 30.7 years +/- 12.
6 SD) were included. All received recombinant hepatitis B vaccine.
The time interval between the vaccination and occurrence of
complaints was one week or less for 10 patients, between one week
and one month for 8 patients, between one and two months for 3
patients. In 9 patients, the next vaccinal dose was inoculated
despite the complaints. The symptomatology worsened in 7 cases, and
was not modified in one case (effects unknown for the last patient).
The observed disorders were as follows: rheumatoid arthritis for 6
patients, systemic lupus erythematosus for 2, reactive arthritis
for 5, polyarthralgia-myalgia-fatigue for 3, suspected or biopsy-
proved vasculitis for 3, miscellaneous for 2.

Conclusion: hepatitis B vaccination might be followed by various
rheumatic conditions, and might trigger the onset of underlying
inflammatory and/or auto-immune rheumatic diseases. However, a
causal relation between hepatitis B vaccination and the observed
rheumatic manifestations cannot be easily established. Further
epidemiological works are needed to establish whether hepatitis B
vaccination is associated or not with an incidence of rheumatic
disorders higher than normal.

Additional Human Data

Several papers have been published linking immunization to lupus and
other rheumatoid diseases. A study of lupus patients receiving
polio vaccines showed 5% had a flare following immunization
(Schattner et al., 1992). Several papers have reported patients
with lupus developing deterioration in kidney function following
immunization (Ristow et al., 1978); (Louie et al., 1978).  Lupus has
been reported to occur following immunization with the Hepatitis B
(Tudela et al., 1992), and pneumococcal (Ries & Shemonsky, 1981)
vaccines.  Immunization with the influenza vaccine has been
associated with a rise in anti-double stranded DNA antibodies, an
marker for lupus (Huang et al., 1992).  Rheumatoid arthritis has
been observed to occur following immunization with Hepatitis B
vaccine (Vautier & Carty, 1994). Rheumatoid factor, autoantibodies
that bind other antibodies, have been reported to develop following
vaccination (Aho et al., 1962); (Aho et al., 1967); (Palit et al.,
1977); (Welch et al., 1982).

Animal Data

1. The graph below shows that immunization starting at birth with
low doses of the DTP and anthrax vaccines can prevent or slow the
onset of lupus in mice.

[Lupus Mice 01a.wmf (19006 bytes)]


Pregnant MRL/MpJ-lpr mice (Jackson Laboratory, Bar Harbor, Maine)
gave birth to pups which were injected with PBS or a combination of
the anthrax vaccine and the acellular DTP vaccine. A series of nine
intraperitoneal injections of the vaccines, diluted in PBS, were
given to newborn mice using the following protocol: day 1 (.1 ml, 1:
100), day 3 (.1 ml, 1:100), day 10 (.15 ml, 1:100 ml), week 4 and
every 2 weeks through week 14 (.2 ml, 1:50). Weaning was done at
approximately 21 days and only the female mice were used in the
experiment. One group of 18 control mice received a similar
injection schedule of PBS starting on day 1 and a second group of
20 control mice received a similar schedule (i.e., every 2 weeks
through week 14) but starting at 4 weeks of age.

Urine was screened for the presence of protein, a common clinical
test for glomerulonephritis. A few drops of mouse urine were placed
on a urine protein dipstick (Albustix, Miles Inc, Elkhart, IN).  At
13 weeks 6/38 (15.8%)of PBS control mice had a urine with a protein
over 300mg/dl while 0/28 of the vaccinated mice had a urine with a
protein over 300mg/dl. At 14 weeks 8/38 (21%) of PBS control mice
had a urine with protein of over 300mg/dl while 0/27 of the
vaccinated mice had developed urines with similar protein levels.
At 15 weeks 10/38 (26.3%)of PBS control mice had a urine with
protein of over 300mg/dl while 2/26 (7.7%) of the vaccinated mice
had developed urines with similar protein levels.

= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = =  = = =


    Dr Charles Shepherd (Letter to BMJ, Sept 9, 1996)

Antigenic challenges by infection and vaccination have both been
implicated as precipitating factors in the development of chronic
fatigue syndrome(CFS).1 Although it has recently been suggested that
infection with hepatitis B virus may be more likely to result in CFS
than other types of infection 2, there are contradictory reports
about the possible role of hepatitis B vaccination.

I wish to report some preliminary findings on a cohort of 91 CFS
patients where the outset or a significant degree of relapse appears
to have been associated with vaccination. Of particular interest is
the fact that 50% (54/91) of these cases involve vaccination against
hepatitis B.

The hepatitis B vaccination subgroup were all immunised between 1987
and 1996. Onset of chronic debilitating fatigue and various other
symptoms commonly associated with CFS coincided with or occurred
shortly after one or more doses of hepatitis B vaccine.  Seven of
this subgroup also reported arthralgia - a finding which is
consistent with an earlier report linking this vaccine with reactive

The vast majority of this subgroup (41/54) are health care workers
particularly nurses. The remainder were also immunised for
occupational purposes or foreign travel. Overall, the prognosis has
been poor with very few reporting complete recovery. Several have had
to terminate their employment and apply for early retirement.

Of concern is the fact that (a) several health workers reported that
they were persuaded to continue with their vaccination course despite
the fact that they did not appear to be fully recovered from an
adverse reaction (eg general malaise) following the first or second
dose, (b) very few of these adverse reactions have been reported to
the Committee on Safety of Medicines and (c) the manufacturers
acknowledge that individual adverse reactions can include fatigue,
myalgia, arthralgia, headache, insomnia and lymphadenopathy but
refuse to accept that any causal link has been established with a
combination of the above (ie CFS).

If viral infections are capable of precipitating CFS then it seems
feasible that vaccines - which act by mimicking the effect of
infection on the immune system - could also be involved. One possible
explanation for the apparent bias towards hepatitis B vaccine is that
it is a highly immunogenic compound (containing thiomersal and a
preservative) which has already been linked to a variety of
immunological hypersensitivity reactions. 5

Effective protection against hepatitis B is a necessary precaution
which should undoubtedly be encouraged amongst high risk occupational
groups.  However, CFS may be an important adverse reaction in
susceptible individuals.


1. Lloyd A R, Wakefield D, Boughton C, Dwyer J, What is myalgic
encephalomyelitis? Lancet 1988: 1: 1286-1287 2. Berelowitz GJ,
Burgess A P, Thanabalsingham T, Murray-Lyon I M, Wright D J M. Post-
hepatitis syndrome revisited. Journal of Viral Hepatitis 1995; 2: 133-
138 3. Delage G, Salit I, Pennie R, Alary M, Duval B. Report of the
Working group on the possible relationship between hepatitis B
vaccination and chronic fatigue syndrome. Canadian Medical
Association Journal 1993; 149: 314-316 4. Hassan W, Oldham R.  Reiter'
s syndrome and reactive arthritis in health care workers after
vaccination. British Medical Journal 1994; 309: 94

5 Mayboom R H B, Fucik H, Edwards I R. Thrombocytopenia reported in
association with hepatitis B and A vaccines.  Lancet 1995; 345: 1638

Myalgic Encephalomyelitis Association, 4 Corringham Road, Stanford le
Hope, Essex SS17 OAH. Tel: 01375 642466


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