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

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,

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

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.