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.
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Abstract |
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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; polyarthralgiamyalgia 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.
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Introduction |
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Methods |
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Results |
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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.
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Discussion |
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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 130 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 days1 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 causeeffect 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.
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Acknowledgments |
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References |
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