Rheumatic disorders developed after hepatitis B vaccination

J. F. Maillefert, J. Sibilia1, E. Toussirot2, E. Vignon3, J. P. Eschard4, B. Lorcerie5, R. Juvin6, N. Parchin-Geneste7, C. Piroth, D. Wendling2, J. L. Kuntz1, C. Tavernier and P. Gaudin6

Department of Rheumatology, Dijon University Hospital,
1 Department of Rheumatology, Strasbourg University Hospital,
2 Department of Rheumatology, Besançon University Hospital,
3 Department of Rheumatology, Centre Hospitalier Lyon-Sud,
4 Department of Rheumatology, Reims University Hospital,
5 Department of Internal Medicine, Dijon University Hospital,
6 Department of Rheumatology, Grenoble University Hospital and
7 Center of Pharmacovigilance, Dijon University Hospital, France

Correspondence to: J. F. Maillefert, Department of Rheumatology, Hôpital Général, 3 rue du Fb Raines, 21000 Dijon, France.


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Objective. 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 1 week's duration or more, occurrence during the 2 months following hepatitis B vaccination, no previously diagnosed rheumatic disease and no other explanation for the complaints.

Results. Twenty-two patients were included. The observed disorders were as follows: rheumatoid arthritis for six patients; exacerbation of a previously non-diagnosed systemic lupus erythematosus for two; post-vaccinal arthritis for five; polyarthralgia–myalgia for four; suspected or biopsy-proved vasculitis for three; miscellaneous for two.

Conclusions. Hepatitis B vaccine might be followed by various rheumatic conditions and might trigger the onset of underlying inflammatory or autoimmune rheumatic diseases. However, a causal relationship between hepatitis B vaccination and the observed rheumatic manifestations cannot be easily established. Further epidemiological studies are needed to establish whether hepatitis B vaccination is associated or not with an incidence of rheumatic disorders higher than normal.

KEY WORDS: Hepatitis B vaccine, Adverse effects, Arthritis, Polyarthritis, Rheumatoid arthritis, Lupus erythematosus, Vasculitis.


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Hepatitis B vaccine was initially recommended for adults or children at high risk of hepatitis B virus (HBV) infection [1]. However, since vaccination programmes had not been effective in reducing the incidence of HBV infection, immunization strategies including universal immunization of infants were developed [24]. Both plasma-derived and recombinant hepatitis B vaccines are safe to administer to adults and children. The side-effects are usually minor, including headache, injection site pain, tiredness, fever, arthralgia [511]. These reactions usually resolve within 24–48 h. Serious adverse effects are rare [511]. However, medical and public interest in the safety of hepatitis B vaccination was recently heightened by medical journals and media reports of adverse effects. Some authors have described cases of various diseases occurring after hepatitis B vaccination, such as occlusion of the central retinal vein [12], uveitis [13], lichen ruber planus [14], erythema multiforme [15], nephrotic syndrome [16], acute cerebellar ataxia [17], central nervous system demyelinization [18] and transverse myelitis [19]. A few cases of rheumatological manifestations have been reported [2032]. However, it is difficult to know whether there is a coincidental or a causal relationship between immunization and the observed manifestations. This paper reports our experience of a larger series of 22 patients. The aim of our work was not to assess whether hepatitis B immunization is associated or not with an incidence of rheumatic disorders higher than normal, but to obtain an overview of articular problems that might occur after such a vaccination. Some aspects of a single case have previously been published as a case report [33]. This observation has, however, been included in the series.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
In 1997, a questionnaire about rheumatic complaints following hepatitis B vaccination was sent to the rheumatology departments of the hospitals in Besançon, Bourg en Bresse, Chalon sur Saone, Dijon, Grenoble, Pierre Bénite, Reims, Saint Etienne and Strasbourg (France). Criteria for entry were any rheumatic complaints of 1 week duration or more, occurrence of the complaints during the 2 months following hepatitis B vaccination, no previously diagnosed rheumatic disease and no other explanation for the occurrence of complaints. The participating hospitals were given no indication as to the time period of interest. The clinical and laboratory data from all patients were collected and analysed retrospectively.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Twenty-two patients were included. There were three males and 19 females, mean age 31.5±12.4 (S.D.) yr (range 15–53 yr). All patients received recombinant hepatitis B vaccine between 1992 and 1997. Two were given several vaccines (hepatitis A and hepatitis B for one patient; hepatitis B, rubeola and typhoid for the other). Among the 22 cases, eight developed symptoms after the first vaccine dose, five after the second dose, three after the third dose (1 month between two injections) and six after a booster injection. The last six patients had not complained of adverse events after the previous injections. For 10 patients, the next hepatitis B vaccine inoculation was performed despite the complaints. The complaints worsened in eight cases and were not modified in one (the effects of the new injection are unknown for the last patient). The time interval between the vaccination and the occurrence of complaints was <=1 week for nine patients, between 1 week and 1 month for 10 patients, and 2 months for three patients. Owing to the retrospective analysis, the laboratory investigations for differential diagnosis were performed according to the complaints, and were not the same for all patients. In particular, extensive serological tests were not performed in all cases. A summary of cases is given in Table 1Go.


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TABLE 1.  Summary of cases
 
Rheumatoid arthritis (RA)
Six women developed an inflammatory polyarthritis satisfying the 1987 ARA criteria for the diagnosis of RA. They had received immunization 1, 2, 3, 10, 18 and 20 days, respectively, prior to symptom onset. All received another injection. The symptoms worsened in four cases, and were not modified in one (the effects of the next injection were unknown for the last patient). The follow-up is now 6, 5, 3, and 2 yr, and 20 and 6 months, respectively. The affection is still persisting. During the follow-up, all patients were treated with at least one disease-modifying anti-rheumatic drug (DMARD), including methotrexate for four. Joint erosions occurred in three out of the five patients followed up for >1 yr.

Systemic lupus erythematosus (SLE)
Two women developed exacerbation of SLE. The first patient presented with an arthritis of the right ankle occurring 1 week after immunization. The blood cell count showed moderate neutropenia (1800) and lymphopenia (1300). The tests for antinuclear antibodies (ANA) on Hep-2 cells (1:640) and for anti-SSA antibodies were positive. She had no anti-double-stranded (ds) DNA. The second patient presented with thrombocytopenic purpura occurring 1 month after the third injection of the vaccine series. The tests for ANA (1:1280), anti-dsDNA, anticardiolipin and anti-SSA antibodies were positive. In both patients, the affection was probably present prior to the vaccination: the first had a 4 yr history of photosensitivity; the second had a 2 yr history of migratory polyarthralgia.

`Post-vaccinal' arthritis
Five women developed `post-vaccinal' arthritis. The distribution of arthritis was heterogeneous: symmetrical polyarthritis in the first patient, right and left metacarpophalangeal joints in the second patient, monoarthritis of the knee in the third patient, and asymmetrical migratory oligoarthritis predominating in the lower limb in the last two patients. In three cases, a further vaccine injection was performed, resulting in all cases in worsening of the complaints. The patients were all treated with non-steroidal anti-inflammatory drugs (NSAIDs). For two of them, the complaints regressed completely. In a third patient, the complaints regressed under NSAIDs, but she still complained of moderate arthralgia after 3 months of therapy. For the two other patients, classical NSAIDs proved ineffective and were discontinued. For the first, treatment with prednisone (1 mg/kg/day) resulted in a dramatic improvement. During the next 6 months, the dose of prednisone was progressively diminished. At this time, the treatment was discontinued. No recurrent attack occurred during the follow-up (3 yr). For the last patient, treatment with phenylbutazone resulted in some improvement, but the arthritis persisted for 5 months. At the present time, 15 months after initiation of phenylbutazone, she complains of arthralgia, but the arthritis has regressed. Consequently, a characteristic outcome in all these patients was that the arthritis regressed, although some were left with arthralgia.

Arthralgia, myalgia
Four patients suffered from polyarthralgia and myalgia, and three of them from fatigue. The complaints persisted for 2 months in the first patient and 1 yr in the second one, and then disappeared. In the third patient, the complaints have persisted for 3 months, but are now improving. In the last patient, the complaints persisted for 13 months. The patient was then lost to follow-up.

Suspected or proven vasculitis
One patient developed a biopsy-proven vasculitis, and two others developed manifestations suggesting vasculitis, but no biopsy was performed for confirmation. The clinical manifestations were: polyarthritis, pain in the cervical column, myalgia, skin rash with vesicle (leucocytoclastic vasculitis on skin biopsy), low-grade fever (38°C) for one patient; polyarthritis, abdominal pain, urticaria, low-grade fever (37.8°C) for another patient; pain in the cervical column and mental nerve neuropathy, followed by low-back pain, arthralgia and paraesthesiae of the lower limbs for the last patient. The complaints regressed rapidly under NSAIDs (two patients) or spontaneously (one patient).

Miscellaneous
A 43-yr-old man developed fever (38°C), erythema nodosum and oligoarthritis of the inferior limbs. He was treated with NSAIDs. The complaints regressed within 1 month.

A 53-yr-old man complained of migratory inflammatory polyarthralgia, talalgia, and sensation of dry eyes and mouth. He was referred to an ophthalmologist, who demonstrated sicca syndrome (Rose Bengal test), and was successfully treated with NSAIDs. Four months later, he was well, with persistence of moderate arthralgia. In particular, the sensation of dry eyes and mouth had regressed. Unfortunately, he was not referred to an ophthalmologist at this time, and was then lost to follow-up.


    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Rheumatic disorders described after hepatitis B immunization
Some observations suggest that hepatitis B vaccine might be followed by various rheumatic conditions. These conditions can be put together in two groups: transient conditions, such as vasculitis, post-vaccinal arthritis, erythema nodosum; and onset or relapse of rheumatic (RA, lupus erythematosus, spondyloarthropathies, etc.) or non-rheumatic (multiple sclerosis, etc.) chronic diseases.

At least 20 cases of patients satisfying the 1987 ARA criteria for the diagnosis of RA have been described (including ours) [24, 26, 28, 30, 31]. The patients were five men and 15 women, aged from 20 to 58 yr. The onset of symptoms occurred within 1–30 days following the vaccination. Despite the arthritis, nine patients received a new injection of vaccine. The arthritis worsened in six and was unchanged in one. The effects of the new injection are unknown in the two others. The tests for rheumatoid factor (RF) were positive in 10 out of 13 patients. HLA testing showed the presence of DR1 and/or DR4 antigen in 14 out of 16 patients. During the evolution, at least 12 patients needed DMARDs, and joint erosions or periarticular osteoporosis occurred in 10 (data not known for some patients). These data suggest that there is apparently no difference between cases of RA following hepatitis B vaccination and other RA. This is in accordance with results from Harrison et al. [34], who suggested that patients who develop inflammatory polyarthritis, especially RA, after various immunizations (tetanus toxoid, influenza vaccine and miscellaneous) are clinically indistinguishable from other patients with inflammatory polyarthritis.

A few cases of onset or reactivation of SLE after vaccination against hepatitis B have been described [25, 35, 36]. The onset of symptoms occurred within 5 days–1 month after the immunization. Two patients had a lupus nephritis (associated in one with fever and arthralgia), one patient had pericarditis, one had thrombocytopenic purpura. For all patients, the tests for ANA were positive. The evolution was favourable in all after therapy using corticosteroids and, in one, on cyclophosphamide.

Several cases of reactive arthritis following hepatitis B vaccination have been reported [20, 22, 26, 32]. Some reports of Reiter's syndrome [23] and psoriatic arthropathy [27] can probably or possibly be added to these cases. The symptoms were often controlled with NSAIDs, but sulphasalazine was sometimes needed. The complaints frequently regressed after a few months.

We observed four patients with myalgia and polyarthralgia, and, in three of them, fatigue following hepatitis B vaccination. These manifestations can be connected to the chronic fatigue syndrome. A few years ago, an independent working group agreed that there was no evidence of a cause–effect relationship between hepatitis B vaccine and chronic fatigue syndrome [37]. However, the number of patients followed up may have been too small to detect a slight increase in the relative risk.

Various other conditions following hepatitis B vaccination have been described. They include erythema nodosum and polyarthritis [21], erythema nodosum with arthralgia and Takayasu's arteritis [38], vasculitis [3941], polyarthritis associated with hypercalcaemia and lytic bone lesions [29]. In most cases, the complaints were treated with NSAIDs or steroids, persisted for a few days, weeks or months, then regressed without recurrence. In our series, we observed one case of erythema nodosum with oligoarthritis and one case of vasculitis confirmed by skin biopsy. Two other patients developed manifestations suggesting vasculitis, but biopsies were not performed to confirm it. In all cases, the manifestations regressed spontaneously, or under NSAIDs or steroids, and did not recur.

Several pathogenetic models can be put forward to explain rheumatic disorders following hepatitis B vaccination. Transient conditions might be due to deposition within the synovium of circulating immune complexes containing viral antigen and anti-HBs antibodies, such as observed in some hepatitis B infections, or they might be due to hypersensitivity to some components of the vaccine, such as thimesoral [42, 43] or yeast proteins [44]. Onset of chronic inflammatory or autoimmune diseases might be due to molecular mimicry or to post-immunization conditions indistinguishable from individualized diseases. The diversity of the observed diseases is not in favour of these hypotheses. A more attractive hypothesis is that hepatitis B immunization might trigger the onset or the relapse of the diseases in individuals with underlying genetic and immunological susceptibility [34].

Coincidental or causal relationship?
However, it is difficult to know whether there is a coincidental or a causal relationship between immunization and the observed rheumatic manifestations. Our work was an observational retrospective study, and was not performed to respond to this question. Since the investigations performed for differential diagnosis were not the same for all patients, we cannot exclude some misdiagnosis. Particularly in some patients (those who underwent hepatitis B and other immunizations before the occurrence of complaints, those with a time interval of >1 month between the vaccination and the occurrence of complaints), the imputation may be considered as more doubtful. Moreover, our large series could be due to a recent French national campaign to encourage adolescents and young adults to receive hepatitis B vaccine. Following this campaign, a great number of subjects (including middle-aged subjects) received the vaccine and, at this time, >20 million French people have been vaccinated (but it is difficult to know exactly the total number of people immunized between 1992 and 1997). A number of these subjects would have developed rheumatic disorders if not vaccinated. Our national reporting system did not show any increase in the incidence of autoimmune disorders following hepatitis B immunization. This result is in favour of a coincidental relationship.

However, several arguments are in favour of a causal relationship. For a majority of patients, the temporal association was suggestive. The manifestations worsened in most of the patients who were given a further injection. In some patients, the complaints regressed after a few weeks or months, and did not recur during the follow-up. In most patients, the explorations and the follow-up did not show any other plausible cause for the complaints. Moreover, since patients with rheumatic disorders were not systematically questioned about prior immunization in the past years, and since the national reporting system of drug adverse effects is based not on obligatory but on voluntary notifications, the negative results from this reporting system do not exclude a link between immunization and some rheumatic disorders.

Large-scale immunization programmes have not established any association between vaccination and the occurrence of serious adverse effects [6, 7, 11]. However, systematic surveillance for adverse reactions in these populations was sometimes performed with questionnaires. Moreover, the number of subjects may not have been sufficient to detect a slight increase in the incidence of rheumatic disorders. Unfortunately, our work does not allow us to know the frequency of rheumatic disorders in people undergoing hepatitis B vaccination, and to know whether this frequency is different or not from that in other people. Because of the retrospective design, patients presenting in our departments were not systematically questioned about prior immunization. Consequently, we do not know what percentage of patients seen in our departments during the period covered by the study developed symptoms following immunization. Moreover, we do not know how many patients developing musculoskeletal symptoms following hepatitis B immunization were treated by office-based rheumatologists or general practitioners during the time period covered by the study.

Consequently, at this time, there is a discrepancy between the negative results of epidemiological studies and the description of suggestive cases, including ours. Further epidemiological studies including a sufficient number of subjects to detect a slight increase in the relative risk are needed to establish whether hepatitis B vaccination is associated or not with an incidence of rheumatic disorders higher than normal.

On the other hand, the presumed risk for adverse events must be weighed against the expected risk for HBV-related liver disease [6]. Since the relative risk of occurrence of rheumatic complaints following hepatitis B vaccination is not or is slightly increased compared to the general population, the morbidity and mortality that can be prevented by immunization against hepatitis B outweigh by far the risk of possible adverse events [42]. Consequently, in our opinion, the possible rheumatic adverse effects do not put into question universal immunization. However, questions are raised about hepatitis B vaccine recommendation in some patients, especially those with chronic inflammatory or autoimmune diseases, and those with previously suspected adverse effects related to hepatitis B immunization. Studies are needed to respond to these questions.

In conclusion, hepatitis B vaccine might be followed by various rheumatic conditions and might trigger the onset of underlying inflammatory or autoimmune rheumatic diseases. However, a causal relationship between hepatitis B vaccination and the observed rheumatic manifestations cannot be easily established. Further epidemiological studies are needed to establish whether hepatitis B vaccination is associated or not with an incidence of rheumatic disorders higher than normal.


    Acknowledgments
 
The authors thank Dr Alexandre, Dr Bocquet and Dr Richard for responding to the questionnaire.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1.  Immunization Practices Advisory Committee. Inactivated hepatitis B virus vaccine. MMWR Morb Mortal Wkly Rep 1982;31:317–28.[Medline]
  2.  American Academy of Pediatrics, Committee on Infectious Diseases. Universal hepatitis B immunization. Pediatrics 1992;89:795–800.[ISI][Medline]
  3.  Centers for Disease Control. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Morb Mortal Wkly Rep 1991;40(RR-1 3):1–25.[Medline]
  4.  National Advisory Committees on Immunization. Statement on universal immunization against hepatitis B. CCDR Can Commun Dis Rep 1991;17:165.
  5.  Greeberg DP. Pediatric experience with recombinant hepatitis B vaccines and relevant safety and immunogenicity studies. Pediatr Infect Dis J 1993;12:438–45.[ISI][Medline]
  6.  Anonymous. Update: vaccine side effects, adverse reactions, contraindications, and precautions. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 1996;45:1–35.[Medline]
  7.  McMahon BJ, Helminiak C, Wainwright RB, Bulkow L, Trimble BA, Wainwright K. Frequency of adverse reactions to hepatitis B vaccine in 43,618 persons. Am J Med 1992;92:254–6.[ISI][Medline]
  8.  Centers for Disease Control. Update on hepatitis B prevention: recommendations of the Immunization Practices Advisory Committee. MMWR Morb Mortal Wkly Rep 1987;36:353–66.[Medline]
  9.  West DJ. Clinical experience with hepatitis B vaccines. Am J Infect Control 1989;17:172–80.[ISI][Medline]
  10. Dentico P, Buongiorno R, Volpe A, Zavoianni A, Pastore G, Schiraldi O. Long-term immunogenicity, safety and efficacy of a recombinant hepatitis B vaccine in healthy adults. Eur J Epidemiol 1992;8:650–5.[ISI][Medline]
  11. Dobson S, Scheifele D, Bell A. Assessment of a universal, school-based hepatitis B vaccination program. J Am Med Assoc 1995;274:1209–13.[Abstract]
  12. Devin F, Roques G, Disdier P, Rodor F, Weiller PJ. Occlusion of central retinal vein after hepatitis B vaccination. Lancet 1996;347:1626.
  13. Fried M, Conen D, Conzelmann M, Steinemann E. Uveitis after hepatitis B vaccination. Lancet 1987;ii:631–2.
  14. Trevisan G, Stinco G. Lichen ruber planus following HBV vaccination. Acta Dermatol Venereol (Stockh) 1993;73:73.
  15. Di Lernia V, Lo Scocco G, Bisighini G. Erythema multiforme following hepatitis B vaccine. Pediatr Dermatol 1994;11:363–4.[Medline]
  16. Macario F, Freitas L, Correia J, Campos M, Marques A. Nephrotic syndrome after recombinant hepatitis B vaccine. Clin Nephrol 1995;43:349.[ISI][Medline]
  17. Deisenhammer F, Pohl P, Bösch S, Schmidauer C. Acute cerebellar ataxia after immunization with recombinant hepatitis B vaccine. Acta Neurol Scand 1994;89:462–3.[ISI][Medline]
  18. Kaplanski G, Retornaz F, Durand JM, Soubeyrand J. Central nervous system demyelinisation after vaccination against hepatitis B and HLA haplotype. J Neurol Neurosurg Psych 1995;58:758–9.[ISI][Medline]
  19. Trevisani F, Castelli Gattinara G, Caraceni P, Bernardi M, Albertoni F, D'Alessandro F et al. Transverse myelitis following hepatitis B vaccination. J Hepatol 1993; 19:317–8.[ISI][Medline]
  20. Hachulla E, Houvenagel E, Mingui A, Vincent G, Laine A. Reactive arthritis after hepatitis B vaccination. J Rheumatol 1990;17:1250–1.
  21. Rogerson SJ, Nye FJ. Hepatitis B vaccine associated with erythema nodosum and polyarthritis. Br Med J 1990;301:345.[ISI][Medline]
  22. Biasi D, De Sandre G, Bambara LM, Carletto A, Caramaschi P, Zanoni G et al. A new case of reactive arthritis after hepatitis B vaccination. Clin Exp Rheumatol 1993;11:215–20.[ISI][Medline]
  23. Hassan W, Oldham R. Reiter's syndrome and reactive arthritis in health care workers after vaccination. Br Med J 1994;309:94.[Free Full Text]
  24. Vautier G, Carty JE. Acute seropositive rheumatoid arthritis occurring after hepatitis B vaccination. Br J Rheumatol 1994;33:991.
  25. Mamoux V, Dumont C. Lupus erythémateux disséminé et vaccination contre l'hépatite B. Arch Pediatr 1994;1:307–8.[ISI][Medline]
  26. Gross K, Combe C, Krüger K, Schattenkirchner M. Arthritis after hepatitis B vaccination. Report of three cases. Scand J Rheumatol 1995;24:50–2.[ISI][Medline]
  27. Aherne P, Collins M. Psoriatric arthropathy. Ir Med J 1995;88:72.[ISI][Medline]
  28. Pope JE, Stevens A, Howson W, Bell DA. Rheumatoid arthritis linked to hepatitis B vaccination. J Rheumatol 1998;25:1687–93.[ISI][Medline]
  29. Cathébras P, Cartry O, Lafage-Proust MH, Lauwers A, Acquart S, Thomas T et al. Arthritis, hypercalcemia, and lytic bone lesions after hepatitis B vaccination. J Rheumatol 1996;23:558–60.[ISI][Medline]
  30. Soubrier M, Dubost JJ, Bielsa C, Ristori JM, Bussière JL. Polyarthrite érosive déclenchée par une vaccination contre l'hépatite B. Presse Med 1997;26:75.
  31. Treves R, Lacoste L, Bontoux D, Pitrou E, Bertin P, Bonnet C. Polyarthrite nodulaire érosive déclenchée par une vaccination contre l'hépatite B. Presse Med 1997;26:670.
  32. Bracci M, Zoppini A. Polyarthritis associated with hepatitis B vaccination. Br J Rheumatol 1997;36:300–1.[ISI][Medline]
  33. Maillefert JF, Farge P, Gazet-Maillefert MP, Tavernier C. Mental nerve neuropathy as a result of hepatitis B vaccination. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83:663–4.[ISI][Medline]
  34. Harrison BJ, Thomson W, Pepper L, Ollier WER, Chakravarty K, Barrett EM et al. Patients who develop inflammatory polyarthritis (IP) after immunization are clinically indistinguishable from other patients with IP. Br J Rheumatol 1997;36:366–9.[ISI][Medline]
  35. Tudela P, Marti S, Bonal J. Systemic lupus erythematosus and vaccination against hepatitis B. Nephron 1992;62:236.[ISI][Medline]
  36. Delbrel X, Fach J, Neau D, Le Bras M, Longy Boursier M. Poussée lupique après vaccination contre l'hépatite B. Presse Med 1998;27:260.
  37. CCDR. Report of the working group on the possible relationship between hepatitis B vaccination and the chronic fatigue syndrome. Can Med Assoc J 1993;149:314–9.[Medline]
  38. Castresana-Isla CJ, Herrera-Martinez G, Vega-Molina J. Erythema nodosum and Takayasu arteritis after immunization with plasma derived hepatitis B vaccine. J Rheumatol 1993;20:1417–8.[ISI][Medline]
  39. Allen MB, Cockwell P, Page RL. Pulmonary and cutaneous vasculitis following hepatitis B vaccination. Thorax 1993;48:580–1.[ISI][Medline]
  40. Journe F, Deschamps F, Germain ML. Vascularite et vaccination contre l'hépatite B. Arch Mal Prof 1995;56:48.
  41. Le Hello C, Cohen P, Bousser MG, Letellier P, Guillevin L. Suspected hepatitis B vaccination related vasculitis. J Rheumatol 1999;26:191–4.[ISI][Medline]
  42. Anonymous. Adverse events following the administration of hepatitis B vaccines. CCDR Can Commun Dis Rep 1992;18–7:49–56.
  43. Rietschel RL, Adams RM. Reactions to thimesoral in hepatitis B vaccines. Dermatol Clin 1990;8:161–4.[ISI][Medline]
  44. Brightman CAJ, Scadding GK, Dumbreck LA, Latchman Y, Brostoff J. Yeast-derived hepatitis B vaccine and yeast sensitivity. Lancet 1989;i:903.
Submitted 5 October 1998; revised version accepted 28 April 1999.