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- ACR, American College of Rheumatology
- CRP, C reactive protein
- ESR, erythrocyte sedimentation rate
- HBsAg, hepatitis B surface antigen
- RA, rheumatoid arthritis
Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis of unknown cause. Various genetic and environmental factors have been associated with an increased risk for the development of disease.1 Several reports describing the appearance of RA after vaccination with tetanus, rubella,2 and hepatitis B3–5 suggest a causal relationship. These reports raise the questions whether vaccines may induce RA and how safe are vaccines in people already diagnosed with the disease.
Hepatitis B vaccine was initially recommended for adults or children at high risk of hepatitis B virus infection.6 It has also been suggested that immunosuppressed patients with RA who are treated with potentially hepatotoxic drug such as methotrexate should be vaccinated in order to neutralise another potentially source of hepatic injury.7 However, the safety and efficacy of the hepatitis B vaccine in patients with RA are not known.
This study was undertaken to evaluate the humoral immune response of patients with RA to hepatitis B recombinant vaccine and to investigate the short term adverse effects and /or exacerbation of the autoimmune disease.
PATIENTS AND METHODS
Forty four consecutive patients fulfilling the American College of Rheumatology (ACR) criteria for rheumatoid arthritis8 who gave their informed consent participated in this study, which was approved by the ethics committee for research in human beings. Subjects screening positive for hepatitis B surface antigen (HBsAg), anti-hepatitis B surface, or anti-hepatitis B core antibodies or with liver enzymes—aspartate aminotransferase and alanine aminotransferase—above the normal ranges were not enrolled. Exclusion criteria included pregnancy and a history of past vaccination allergy.
The patients, who were unaware of the study hypothesis, were allocated into one of two groups—it had been proposed that all of them would be vaccinated—those who accepted comprised the study group while the patients who declined were included in the control group. In all cases, the reason for refusing vaccination was a personal reluctance to undergo vaccination rather than an objective contraindication to it. The study group comprised 22 patients with RA who were vaccinated with three doses (each 20 μg, 1 ml) of recombinant hepatitis B vaccine (ENGERIX ) intramuscularly in the deltoid region. The second and third doses were given one and six months after the first dose. The control group comprised the 22 other patients with RA who did not receive the vaccine.
A complete history and physical examination was carried out on day 0. The medical records were reviewed. Use of concomitant drugs was recorded.
Clinical assessment before, and two and seven months after immunisation included duration of morning stiffness (minutes), evaluation of daytime pain with a 10 cm visual analogue scale—where 10 represents extremely high pain and 0 no pain—and the number of tender and swollen joints.
Laboratory assessment of disease activity
Routine laboratory tests performed before vaccination, two and seven months after immunisation included complete blood cell count, serum chemistry panel, urine analysis, Westergren erythrocyte sedimentation rate (ESR), and C reactive protein (CRP).
Humoral response to the vaccine
Antibodies to HBsAg were determined by a commercial enzyme linked immunosorbent assay (ELISA) routine test kit. Patients were regarded as responders if antibody titres after vaccination were greater than 10 IU/l.
Statistical analysis was carried out with the SPSS software, version 10. Repeated measurement analysis of variance was performed to compare measures of disease activity across three time periods and between groups.
Descriptive statistics, Fisher's exact test, Student's t test, and Mann-Whitney tests when needed were used to compare patients and controls.
Table 1 shows the demographic and clinical characteristics of the patients and controls. Both groups had comparable proportions of women and were of similar mean age. Disease duration was longer in the study group. Sixteen of 22 patients were positive for rheumatoid factor in each group.
Table 2 summarises the drugs used by the patients—the greatest proportion of patients were treated with methotrexate.
None of the patients reported any adverse effect after vaccination.
Vaccination was not associated with a significant worsening in any clinical or laboratory measure of disease. The different measurements of disease activity of the patients and controls over the study period were not statistically different. The combined p value (time×group) for each measurement was 0.76 for daytime pain, 0.1 for morning stiffness, 0.24 and 0.3 for tender and swollen joints respectively, 0.08 for CRP, and 0.12 for ESR (table 3).
Use of drugs
No significant change in the use of drugs over the seven months of follow up was noticed—the distribution and doses of drugs in the study and control groups were similar at vaccination and after seven months (table 2).
Antigen-specific response to vaccination against hepatitis B
Fifteen of 22 (68%) patients responded to vaccination with an antibody level of more than 10 IU/l after six months—the mean (SD) antibody level of the responders after six months was 302 (54) IU/l. Humoral response to hepatitis B vaccination is expected to be more than 85% in young healthy adults.9
Factors influencing the antibody response to hepatitis B vaccine
Lack of humoral response was significantly associated with older age (mean (SD) age 59 (10.5) in non-responders v 46.3 (17.5) in responders) and increased daytime pain at vaccination (4.8 (4.8) in non-responders v 2.2 (2.1) in responders). The humoral response was not associated with the number of tender and swollen joints at vaccination, ESR, CRP or the use and doses of drugs such as prednisone, methotrexate, azathioprine, hydroxychloroquine, intramuscular gold, and non-steroidal anti-inflammatory drugs.
Concerns about the safety and efficacy of immunising subjects with connective tissue diseases have persisted for over 50 years.10 Indeed, descriptions of RA have been reported after tetanus toxoid administration, influenza, and recombinant hepatitis B vaccine.3–5,11
Immunisation with a recombinant hepatitis B vaccine has been found to be extremely efficient.12 The side effects are usually minor, including headache, injection site pain, tiredness, fever arthalgia, usually resolving within 24–48 hours.12 However, together with the universal use of the vaccine, serious adverse effects have been reported, including central retinal vein occlusion, uveitis, nephrotic syndrome, central nervous system demyelinisation, and others.12 Several rheumatological manifestations have been reported after hepatitis B vaccination. Maillefert et al reported a series of 22 subjects who developed rheumatic disorders after hepatitis B immunisation, including RA, exacerbation of a previously non-diagnosed systemic lupus erythematosus, post-vaccinal arthritis, polyarthralgia-myalgia, and vasculitis.13 At least 20 cases of patients satisfying the 1987 ACR criteria for the diagnosis of RA have been described.3–5,13
However, these sporadic reports of connective tissue disease induction should not preclude routine immunisation of patients with RA. By analogy, although a cluster of juvenile RA was seen in children born in 1963 during an epidemic of influenza A,11 influenza vaccination of patients with RA14 has been well tolerated.
In our study we have shown that immunisation with a recombinant hepatitis B vaccine did not induce major side effects and was not accompanied by an exacerbation of the disease. We compared different clinical and laboratory features of disease activity in a cohort of patients who were vaccinated with hepatitis vaccine with a similar group who did not receive the vaccine. The course of the disease seven months after vaccination was similar in both groups.
Overall, the study group had significant increases in mean antibody response seven months after vaccination. However, 7/22 (32%) patients did not show a significant response to the hepatitis B vaccine, though response is expected in more than 85% of young healthy adults.12 However, the expected response to hepatitis B vaccination in older healthy patients is not well known. The lack of antibody response was correlated with older age and high daytime pain, suggesting that immunisation should preferably be given when disease activity is low. The use of immunosuppressive drugs has been found to impair antibody response to hepatitis vaccine. Impaired response to hepatitis B vaccine has been demonstrated in children receiving anticancer chemotherapy15 and in patients with systemic lupus erythematosus treated with oral corticosteroids.16 In our study, treatment with low dose corticosteroids, methotrexate, azathioprine, sulfasalazine, and antimalarial drugs did not affect the antibody response.
We are aware of the limitations of this study. If hepatitis B vaccination induces only a low percentage of flares, the small number of patients included in this study might have missed it. The design of the study might have failed to demonstrate a flare or an adverse effect between the visits. Likewise, a possible selection bias inherent in the study design cannot be excluded. However, this is the first study that aimed at determining the response of patients with RA to hepatitis vaccine, and these preliminary results on the safety of the hepatitis B vaccine in patients with RA are encouraging.
In conclusion, vaccination against hepatitis in this small cohort of patients with RA was safe and was immunogenic in most of them. A subgroup of patients still remains exposed to infection with hepatitis B despite immunisation. Further studies are needed to determine the long term, large scale clinical efficacy of the vaccination as well as the factors underlying the depressed response of some patients.
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