VACCINATION AND ARTHRITIS REVISITED Reported by Anabel Aron-Maor
Yehuda Shoenfeld Department of Internal Medicine B, Sheba Medical
Center Tel Hashomer and Center for Autoimmune Diseases, Sackler School of Medicine, Tel
Aviv University
published 11. September 2000
http://www.rheuma21st.com/archives/cutting_aronmaor_shoenfeld_vaccination_revisited.html
Vaccination and the possible autoimmune side effects have
been discussed recently in several articles (1-4). Not omitting for one
moment the immeasurable benefits of vaccination, the question of whether this practice may
be one of the factors implicated in the onset of autoimmune illness has arisen (3).
Based on existing case reports, there seems to be at least a temporal connection between
several vaccines and autoimmune phenomena; however, no causal relation has been proven
yet. In this cutting-edge article, we wish to focus our attention specifically on the
combination of immunization and arthritis.
The occurrence of arthritis has been described after various types of vaccines (Table 1) have been given and can be divided into isolated or reactive
arthritis (poly or monoarticular) and arthritis as part of a systemic autoimmune disease
(such as systemic lupus erythematosus [SLE] or rheumatoid arthritis [RA]). Some vaccines
have been implicated more often than others. We will review the existing reports, within
the last 10 years, on arthritis following vaccination.
Arthritis and Hepatitis B Vaccine
In the last 10 years, at least 32 cases of arthritis following immunization against
hepatitis B have been described. Some cases have been isolated inflammation of the joints
and others were part of frank RA (Table 1).
In 1990, two cases of arthritis were reported (5,6). One patient
developed erythema nodosum and polyarthritis and the other reactive arthritis shortly
after receiving an HBV vaccination. More reports were published during the following years
(7-13). Some of the patients described had high titers of rheumatoid
factor in the serum, even though they did not fulfill other criteria for frank RA (8). Others were carriers of genetic markers predisposing to autoimmune
diseases (13). A 1998 report (13) described 11
patients who developed arthritis after receiving HBV recombinant vaccine. Ten of the 11
patients reviewed fulfilled the revised ARC criteria for RA. Nine of those required
disease modifying drugs. Five subjects were HLA-DR4 positive. Nine of eleven patients
genotyped for HLA-DR and DQ expressed the RA shared motif in their HLA class II genes.
Findings raised the possibility that HBV recombinant vaccine may trigger RA in genetically
prone individuals. An additional case reported in 1996 (10) supports, to
a certain extent, the hypothesis that people genetically prone to develop autoimmune
disease will more readily develop arthritis after vaccination (of any kind). In this case,
a 44-year old man who had had myasthenia gravis 20 years earlier developed arthritis,
hypercalcemia, and lytic bone lesions shortly after administration of HBV recombinant
vaccine. It is noteworthy that a definite connection between the arthritis and the vaccine
itself has not been established (serologically) in any of the cases mentioned so far.
Additional cases of frank RA where the HBV vaccine was the trigger for the onset of the
disease, at least temporally, have been reported (9,11).
An autoimmune disease that is often connected with the HBV vaccine is systemic lupus
erythematosus (SLE). Numerous cases of SLE manifesting for the first time after
immunization against HBV have been described (14-18); some cases have
occurred in members of the same family (15). The disease developed in
patients of both sexes and all ages (15,18). In many cases,
manifestations of the disease included mono- or polyarthritis (14,16).
The possible connection between arthritis (reactive or as part of systemic autoimmune
illness) and the recombinant HBV vaccine is important and worthy of further research,
because the disease itself is a potentially lethal one, and vaccination against it has
become mass practice. We think that special emphasis should be put on possible autoimmune
side effects in infants and children, as well as prospective studies in individuals that
have been vaccinated against HBV as newborns. Are they more or less prone to develop
autoimmune side effects as their system is exposed to these foreign antigens at a very
early stage?
Arthritis and Rubella Vaccine
The rubella vaccine has been mentioned often in connection with the onset of reactive
arthritis. The wild virus itself has been reported to trigger arthritis in a large number
of patients. Similarly, arthritis has also been described in temporal proximity to the
administration of the vaccine. During the last 10 years more than 100 cases of rubella
vaccine related arthropathies have been reported (19,20). In 1991, the
Institute of Medicine released a report in JAMA examining 18 adverse effects of
diphtheria-pertussis-tetanus (DPT) vaccine and four adverse effects of rubella vaccine
strain 27/3. The report concluded that the evidence suggests a causal relation between
rubella vaccine and acute arthritis in adult women (21,22). No animal
studies were available to support (or disprove) this conclusion.
In 1997, a study published in JAMA (21) evaluated the risk of persistent
joint and neurological symptoms in rubella seronegative women, subsequently vaccinated
with rubella vaccine strain RA 27/3. The study was retrospective and included 900 to 1000
women, 15 to 59 years old. No significantly increased risk was associated with receipt of
rubella vaccine for any condition, except for carpal tunnel syndrome for vaccinated women
at least 30 years old compared to seropositive non-vaccinated women. Six of the
seronegative immunized women had onset of symptoms during the 1-year follow-up period.
Four of these had transient arthritis or arthralgias (of less than 6 weeks duration), one
had arthralgia of indeterminate chronicity, and one had carpal tunnel syndrome (20). The conclusion of this large retrospective study was that no clear-cut
evidence indicates increased chronic arthropathies (or neurological symptoms) in women
receiving rubella RA 27/3 vaccine. The data supported the continued vaccination of
rubella-susceptible women to reduce the risk of congenital rubella syndrome. Postpartum
women were less likely to develop non traumatic arthropathies following rubella
vaccination.
As with HBV vaccine, a genetic predisposition to develop autoimmune disease may play a
role in the appearance of acute reactive arthritis in proximity to the administration of
rubella vaccine. In 1998 (23), a group of scientists examined the
frequency of HLA class II (HLA-DR) in relation to the incidence of acute arthralgia or
arthritis in 283 white women who had received RA 27/3 rubella vaccine (n=146) or placebo
(n=137) postpartum. Leukocyte DNA was molecularly typed for HLA-DRB1 gene expression.
After statistical analysis of the results, which included adjustment for variables such as
age, treatment, time postpartum, the conclusion was that the risk of developing
arthropathy was 1.9 times greater after rubella vaccination than after placebo. The risk
for arthropathy was also influenced by DR interactions. Odds were 8 times greater in
individuals with both DR1 and DR4 and 7.1 times greater with both DR4 and DR6 present,
suggesting that coexpression of these specificities may predispose to postpartum
arthropathies (23).
Apart from the genetic predisposition discussed above, an additional possible risk factor
to post-vaccine arthropathy was examined. Mitchell et al (24) described
the results of a study that examined whether pre-vaccination rubella virus specific IgG
levels have any correlation with the development of acute or chronic (persistent or
recurrent) joint manifestations. Specific IgG levels were determined by whole enzyme
immunoassay (EIA), neutralization domain peptide, and neutralization bioassay in
prevaccine samples of seronegative women. Of rubella vaccinated women tested for
prevaccine antibodies, 21.7% were positive (by EIA) , 17.6% were positive by
neutralization domain peptide, and 12.7% had neutralization titers of at least 1:8.
Seropositivity tests were significanlty lower in women who developed joint symptoms after
immunization compared with those of asymptomatic women. The authors` conclusion was that
the risk for arthropathy following RA 27/3 rubella vaccination may be higher in women who
have very low prevaccine levels of rubella antibodies, particularly in assays measuring
functional (neutralizing) antibodies (24).
Arthritis and Other Vaccines
Fewer reports have appeared on arthritis following other types of vaccines.
Mumps and measles (25), influenza (26), DPT (27), and typhoid (28) are each connected with some cases
described during the last 10 years. In the first case, the mumps component of the vaccine
was deemed to be responsible for the development of acute monoarthritis (25).
In the case of influenza vaccination, the arthritic manifestations were accompanied by
neurologic symptoms and signs, namely orbital myosistis and posterior scleritis (26). Indeed, the influenza vaccine has been more often connected to
neurologic manifestations (1) than to joint involvement.
Maillefert et al describe two patients who developed monoarthritis after DPT immunization.
One patient developed monoarthritis of the knee that resolved only after synovectomy and
recurred 5 years later after a booster vaccine injection (27), and the
second patient developed monoarthritis of the ankle that persisted for 3 days and resolved
spontaneously. These cases suggest that DPT vaccine may cause arthritis, however
additional evidence is needed in order to confirm this possibility. An additional vaccine
mentioned in connection with arthritis is typhoid. Two cases, both of which were HLA-B27
negative, are reported (28). Reactive arthritis occurred in two
travelers who received oral Ty21a typhoid vaccine.
In a previous article (1), we raised the question whether administration
of polyvaccines might be more inductive of autoimmune side effects than monovaccines. A
series of patients (all of them previously healthy army personnel) have been reported (29) who developed SLE after receiving a number of vaccines among them
typhoid, tetanus toxoid, hepatitis B, influenza, and meningococcal vaccine. All patients
met the ARC criteria for SLE; all manifested mono- or polyarthritis.
Possible Mechanisms for Post-vaccination Reactive Arthritis
As we mentioned in previous reviews of this subject (1-4), possible
mechanisms to explain this phenomenon have been suggested. One of the popular explanations
is the "molecular mimicry" mechanism. Certainly in live vaccines, but also in
attenuated preparations, antigens of the infective organism remain intact and
immunologically potent. Structural similarity between these bacterial or viral antigens
and host antigens may enable the triggering of an autoimmune response. In a recent article
(30), the author suggests an immunologically based explanation for
reactive arthritis (along the lines of molecular mimicry as mentioned above) and possible
therapy. He proposes an anti-idiotypic model for the disease. Based on this hypothesis (in
support of which evidence is presented in the article) a bacterial lipopolysaccharide
(LPS) epitope is recognized by idiotypic (Id) T-cell receptors and antibody Fab immune
recognition surfaces (IRS), which have the immunologic appearance of an antigen on the
synovial surface. These Id immune effectors utilize an HLA-B27 molecule to present their
IRS on their surface, which results in an anti-idiotypic immune response that can also
target the synovial antigen. The anti-idiotypic IRS have the immunlogic appearance of LPS
and their detection in the arthritic joints falsely suggests the presence of bacterial
LPS. The synovial antigen is attacked by the anti-idiotypic response against the bacterial
LPS. Therapeutic vaccination is supported by this hypothesis (30).
Additional data supporting the molecular mimcry mechanism are found in a recent study
performed on dogs, which, to the best of our knowledge, is the only one of its kind, so
far (31). In this study, newborn puppies were immunized with a number of
mandatory vaccines (rabies and multivalent vaccine). Based on interpretation of the
results, the authors concluded that vaccination did not cause immunosuppression, but it
did induce autoantibodies and antibodies to heterologous antigens. None of the dogs
developed autoimmune illness, even though the study was discontinued at 22 weeks of age, a
time well before any clinical signs of collagen disease usually become apparent. The
authors mention similar findings in a follow-up study in dogs that were immunized with the
rabies vaccine only and with the multivalent vaccine only.
Summary
We have reviewed the existing data on the incidence of acute and
chronic arthritis following various immunizations. The vaccines most often connected with
the occurrence of reactive arthritis (either isolated or as part of systemic RA) are HBV
recombinant vaccine and rubella vaccine. Individuals genetically prone to develop
autoimmune illness (namely carriers of HLA-DR1, DR4, DR6, or HLA-B27) are more likely to
contract post-immunization arthritis. The serological immune status of rubella
seronegative women prior to vaccination also influences the likelihood of acute or chronic
arthritis after immunization with rubella vaccine. Immune mechanisms are suggested to
explain this phenomenon. A clear causal relation was not proved in any of the cases,
however a temporal one apparently exists. There are no means as yet to anticipate which
individuals will develop post-vaccination arthritis (other than the genetic tendency
detailed above). Vaccination against HBV and rubella, as well as other infectious
diseases, no doubt continues - as it should. However, we should be aware of the
possibility of autoimmune side effects (in this case specifically joint involvement) to
vaccination and perhaps abstain from less than necessary vaccination of patients at known
risk for autoimmune illness. These would include people with previously diagnosed disease,
with family members suffering from autoimmune disease, or known carriers of genetic risk
factors (as detailed above).
Table I. Vaccines associated with post-vaccination reactive
arthritis and RA .
Disease |
Vaccine |
No. of cases |
Additional symptoms |
Ref. |
Reactive arthritis |
HBV |
1 |
Erythema nodosum |
5 |
1 |
Migratory arthritis, urticaria, oedema of the glottis |
8 |
||
1 |
Hypercalcemia, lytic bone lesions |
10 |
||
4 |
Myalgia |
11 |
||
3 |
Vasculitis |
11 |
||
1 |
Adult-onset Still`s disease |
12 |
||
>10 |
Reactive arthritis alone |
6-9,11,13 |
||
Rubella |
>100 |
14,16-19 |
||
Mumps and measles |
1 |
20 |
||
Influenza |
1 |
21 |
||
DPT |
2 |
22 |
||
Typhoid |
2 |
23 |
||
Rheumatoid arthritis |
HBV |
15 |
Reviewd in 1,4 |
|
1 |
9 |
|||
6 |
11 |
|||
5 |
13 |
|||
Tetanus |
13 |
Reviewed in 1 |
||
SLE |
HBV |
7 |
Cutaneous, renal, hematological |
14-18 |
Polyvaccine: mumps, measles, tetanus, meningococcal, hepatitis A, polio |
5 |
Cutaneous, renal, hematological |
30 |
References:
1. Shoenfeld Y, Aron-Maor A. Vaccination and
autoimmunity - "Vaccinosis: A dangerous liaison? J Autoimun 2000;14:1-10.
2. Nossal GJV. Vaccination and autoimmunity. JAI
2000;14:15-22.
3. Shoenfeld Y, Aron-Maor A, Sherer Y. Vaccination as an additional player
in the mosaic of autoimmunity. Clin Exp Rheumatol 2000;18 4. Cohen AD, Shoenfeld Y.
Vaccine-induced autoimmunity, J Autoimmun 1996;9:699-703.
4. Cohen AD, Shoenfeld Y. Vaccine-induced
autoimmunity, J Autoimmun 1996;9:699-703.
5.Rogerson SJ. Nye FJ. Hepatitis B vaccine associated
with erythema nodosum and polyarthritis. BMJ 1990;301:345.
6. Haschulla E, Houvenagel E, Mingui A,
Vincent G, Laine A. Reactive arthritis after hepatitis B vaccination. J Rheumatol
1990;17:1250-1251.
7.Biasi D, De Sandre G, Bambara LM, Carletto A,
Caramaschi P, Zanoni G, Tridente G. A new case of reactive arthritis after hepatitis B
vaccination. Clin Exp Rheumatol 1993;11:215.
8. Biasi D, Carletto A, Caramaschi P, Frigo A, Pacor
ML, Bezzi D, Bambara LM. Rheumatological manifestations following hepaatitis B
vaccination. A report of 2 clinical cases (article in Italian). Recenti Prog Med
1994;85:438-440.
9. Gross K. Combe C, Kruger K,
Schattenkirschner M. Arthritis after hepatitis B vaccination. Report of three cases. Scand
J Rheumatol 1995;24:50-52.
10. Cathebras P, Cartry O, Lafage-Proust MH,
Lauwers A, Acquart S, Thomas T, Rousset H. Arthritis, hypercalcemia and lytic bone lesions
after hepatitis B vaccination. J Rheumatol 1996;23:558-560.
11. Maillefert JF, Sibilia J, Toussirot E, Vignon
E, Eschard JP, Lorcerie B, Juvin R, Parchin-Geneste N, Piroth C, wendling D, Kuntz JL,
Tavernier C, Gaudin P. Rheumatic disorders developed after hepatitis B vaccination.
Rheumatology (Oxford) 1999;38:978-983.
12. Grasland A, Le Maitre F, Pouchot J, Hazera P, Bazin C,
Vinceneux P. Adult-onset Still's disease after hepatitis A and B vaccination (article in
French). Rev Med Interne 1998;19:134-136.
13. Pope JE, Stevens A, Howson W, Bell DA.
The development of rheumatoid arthritis after recombinant hepatitis B vaccination. J
Reumatol 1998;25:1687-1693.
14. Tudela P, Marti S, Bonanl J. Systemic lupus
erythematosus and vaccination against hepatitis B. Nephron 1992;62:236.
15. Finielz P, Lam-Kam-Sang LF. Systemic lupus
erythematosus and thrombocytopenic purpura in two members of the same family. Nephrol Dial
Transplant 1998;13:2420-2421.
16. Guiseriz J. Systemic lupus erythematosus
following hepatitis B vaccine. Nephron 1996;74:441.
17. Mamoux V, Dumont C. Lupus erythemateux dissemine
et vaccination contre l'hepatite B. Arch Pediatr 1994;1:307-308.
18. Grezard P, Chafi M, Philippot V, Perrot
H, Faisant M. Cutaneoius lupus erythematosus and buccal aphthosis after hepatitis B
vaccination in a 6-year-old child. Ann Dermatol Venereol 1996;123:657-659.
19. Weibel RE, Bemor DE. Chronic arthropathy and
musculoskeletal symptoms associated with rubella vaccines. A review of 124 claims
submitted to the National Vaccine Injury Compensation Program. Arthritis Rheum
1996;39:1529-1534.
20. Ray P, Black S, Shinefield H, Dillon A,
Schwalbe J, Holmes S, Hadler S, Chen R, Cochi S, Wassilak S. Risk of chronic arthropathy
among women after rubella vaccination. Vaccine Safety Datalink Team. JAMA
1997;278:551-556.
21. Howson CP, Fineberg HV. Adverse events following
pertussis and rubella vaccines. Summary of a report of the Institute of Medicine. JAMA
1992;267;392-396.
22. Howson CP, Katz M, Johnston RB Jr, Fineberg HV.
Chronic arthritis after rubella vaccination. Clin Infect Dis 1992;15:307-312.
23.Mitchell LA, Tingle AJ, MacWilliam L, Horne C,
Keown P, Gaur LK, Nepom GT. HLA-DR class II associations with rubella vaccine-induced
joint manifestations. J Infect Dis 1998;177:5-12.
24. Mitchell LA, Tingle AJ, Grace M, Middleton P,
Chalmers AC. Rubella virus vaccine associated arthropathy in postpartum immunized women:
influence of preimmunization serologic status on development of joint manifestations. J
Rheumatol 2000;27:418-423.
25. Nussinovitch M, Harel L, Varsano I. Arthritis
after mumps and measles vaccination. Arch Dis Child 1995;72:348-349.
26. Thurairajan G, Hope-Ross MW, Situnayake RD,
Murray PI. Polyarthropathy, orbital myositis and posterior scleritis: an unusual adverse
reaction to influenza vaccine. Br J Rheumatol 1997;36:120-123.
27. Maillefert JF, Tonolli-Serabian I, Cherasse A,
Demoux AL, Tavernier C, Piroth L. Arthritis following combined vaccine against diphtheria,
polyomyelitis and tetanus toxoid. Clin Exp Rheumatol 2000;18:255-256.
28. Adachi JA, D`Alessio FR, Ericsson CD. Reactive arthritis associated
with typhoid vaccination in travelers: report of two cases with negative HLA-B27. J Travel
Med 2000;7:35-36.
29. Older SA, Battafarano DF, Enzenauer RJ, Krieg AM. Can immunization
precipitate connective tissue disease? Report of five cases of systemic lupus
erythematosus and review of the literature. Sem Arthritis Rheum 1999;29:131-139.
30. Kennedy JR. Reactive arthritis: the result of an anti-idiotypic
immune response to a bacterial lipopolysaccharide antigen where the idiotype has the
immunological appearance of a synovial antigen. Med Hypotheses 2000;54:723-725.
31. Hogenesch H, Azcona-Olivera J, Scott-Montcrieff C, Snyder PW,
Glickman LT. Vaccine-induced autoimmunity in the dog. Adv Med Vet 1999;41:733-747.
Address for Correspondence: Prof. Yehuda Shoenfeld,
Department of Medicine B,
Tel Hashomer, Ramat Gan 52621, Israel
Tel: 972-3-5302652
Fax: 972-3-5352855 .