Lyme Vaccine Linked to Autoimmune Arthritis

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By Alex Otto in the January 200l issue of PHARMACY TODAY
SmithKline Beechan To Defend Vaccine In Class Action Suit

Concerns are growing that SmithKline Beecham's Lyme vaccine (LYMErix) may cause irreversible autoimmune arthritis in some patients. About 15% of the nearly 400 LYMErix adverse events reported to FDA in 1999 involved rheumatologic
symptoms ranging from muscle pain and acing joints to severe arthritis.

The reports suggest that a concern raised in preapproval hearings-the possib- ility that the vaccine could trigger degenerative autoimmune disease-may not have been unfounded. Although patients who received the vaccine during trials were no more likely than others to develop long-term rheumatologic or neurologic disorders, vaccine recipients were significantly more likely to report arthralgia and myalgia within 30 days of administration.

SmithKline Beecham stands by the safety of its vaccine, currently the only one on the market for Lyme disease. "We are aware that this debate is out there about this theoretical risk," the company told PHARMACY TODAY. "But we are not seeing any unusual, unexpected patterns," she said, noting that the rates of rheumatologic disease among LYMErix patients are similar to those in the general population. The vaccine is about 80% effective in preventing Lyme
disease and has been administered to 440,000 patients since its approval in 1998.

DEEP QUESTIONS ABOUT SURFACE ANTIGENS

The concerns about arthritis hinge on human leukocyte antigen DR4 (HLA-DR4), a surface protein found on white blood cells in about 10% to 30% of the pop- ulation. It is easily detected by a blood test, but the test costs $300.

A class action lawsuit has been filed against SmithKline by scores of patients who developed severe arthritis after getting the vaccine. The suit alleges that LYMErix triggers degenerative autoimmune disease in HLA-DR4-positive patients and that SmithKline knew of the association before its vaccine was approved but failed to warn doctors.

The spokesperson denies the charge. "We looked at it in our clinical trials, specifically at this idea that people who tested positive for the HLA-DR4 were more likely to develop arthritis than anyone else, and found no evidence of it", she said. The company plans a vigorous defense of its product.

But a handful of rheumatologists are already refusing to give the vaccine to their patients, among them Andra Gaito, MD, president of the International Lyme and Associated Diseases Society. Gaito has treated 22 patients who deve loped severe, crippling rheumatologic disorders following vaccination. A colleague of hers at Yale has treated 40 such patients.

"The rheumatology community was suspicious of this vaccine to begin with," Gaito said. "Before it was ever approved, there were reports published of autoimmune reactions in rats, mice, and other lab animals. It doesn't seem limited to DR4 positive patients. There is such a clear-cut problem here that this (product) needs to come off the market."

In response to such concerns, FDA recently said it would investigate all cases of vaccine-associated arthritis, a step that indicates heightened concern. The agency usually only investigates life-threatening vaccine complications.

PREAPPROVAL TESTIMONY

LYMErix was generally recommended as safe and effective for adults when approved in 1998, but FDA panelists in preapproval hearings were concerned that it could trigger autoimmune reactions in HLA-DRA4-positive patients.

Two HLA-DR4-positive study patients, did, in fact, develop joint pain that lasted for months after being immunized. FDA wondered if these cases pointed to a potential problem and if the clinical trials had been powerful enough to detect one if it existed.

"I am not sure that we have the answer to your question," a SmithKline researcher told the panelists, but the agency was assured that if the vaccine "induces joint symptoms, it must be a rare phenomenon, much rarer than the (HLA=-DR4 trait) itself." The idea of testing patients for the trait was mentioned, but dismissed as "very difficult." Concern about HLA-DR4 status was deemed more academic than practical, the company researcher argued.

"The concern is more than academic if this vaccine were to be delivered to millions of people," a FDA panelist shot back. "We don't know for a fact that the vaccine elicited either one of these episodes of arthritis and paresthesias, but I think we are all worried about that. I am left with uncertainties about whether these two cases are in fact a signal of something that we would have seen if we had been able to follow (patients) longer.

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 vaccination.

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

SEVERE RHEUMATIC DISORDERS ASSOCIATED WITH HEPATITIS B
VIRUS (HBV) VACCINATION

S. Laoussadi, V. Sayag-Boukris, C.-J. Menkes, André Kahan

Department of Rheumatology A, Cochin Hospital, Paris V University, Paris,
France

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

RHEUMATIC DISORDERS DEVELOPED AFTER HEPATITIS B
VACCINATION

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
vaccination.

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 arthritis.

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.

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