Rheumatoid vasculitis following influenza vaccination

P. Iyngkaran, V. Limaye, C. Hill, D. Henderson, K. D. Pile and M. Rischmueller

Department of Rheumatology, The Queen Elizabeth Hospital, Woodville, South Australia 5011, Australia

SIR, Yearly influenza vaccination is currently recommended for patients with rheumatoid arthritis (RA) [1]. Case reports, however, suggest an association between influenza vaccination and the development or exacerbation of chronic autoimmune disorders such as RA, systemic lupus erythematosus (SLE) [2] and vasculitis [35].

We describe a case of systemic flare of pre-existing RA concurrent with the first onset of cutaneous vasculitis following influenza vaccination.

A 29-yr-old female smoker with a 12-yr history of seropositive erosive RA presented with a polyarticular flare in addition to burning pain and bluish discoloration of the tips of several fingers and toes. Two weeks prior to the onset of symptoms she received Fluvax (CSL Limited, Australia) containing A/Johannesberg/82/96, A/Sydney/5/97 and B/Harbin/7/94 (B/Beijing/184/93-like). She had been vaccinated on one previous occasion 2 yr earlier with Fluvax containing A/Texas/36/91, A/Johannesberg/33/94 and B/Beijing/184/93. For 12 months prior to presentation her arthritis was well controlled with weekly oral methotrexate (10 mg) and fortnightly intramuscular gold aurothioglucose (50 mg). Previous disease-modifying agents included hydroxychloroquine, auranofin and D-penicillamine; she had never used corticosteroids. Although her disease was widespread, no extra-articular manifestations were previously apparent, including rheumatoid nodules and vasculitis.

Florid synovitis was evident in her metacarpophalangeal and metatarsophalangeal joints, left elbow, shoulder and knee. Numerous subungual splinter haemorrhages were noted in addition to dusky cyanosis of the tips of several fingers of the right hand and toes of the left foot. Heart sounds were normal with a pericardial rub. Examination was otherwise unremarkable.

Laboratory studies revealed: normal urine chemistry; haemoglobin 12.0 g/dl; white cell count 11.2x109/l (76% neutrophils); erythrocyte sedimentation rate (ESR) 120 mm/h (NR: 0–20); C-reactive protein (CRP) 144 mg/l (<10); rheumatoid factor 121 kU/l (<30); serum alanine aminotransferase (ALT) 71 U/l (0–55); C3 1.22 g/l (0.8–1.5); C4 0.24 g/l (0.2–0.4); antinuclear antibodies 1/40 homogeneous; positive antineutrophil cytoplasmic antibodies (immunofluorescence); negative enzyme-linked immunosorbent assay for anti-myeloperoxidase and anti-proteinase 3; and normal serum protein electrophoresis. Anticardiolipin antibodies and cold agglutinins were not detected. Doppler arterial pressures at her wrists and ankles were normal. Perfusion studies suggested small vessel disease in the affected digits, and digital subtraction arteriograms revealed changes consistent with small vessel vasculitis (Fig. 1A and BGo).



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FIG. 1. (A and B) Angiographic findings 5 weeks following influenza vaccination in a patient with pre-existing rheumatoid arthritis with no previous extra-articular manifestations. Following right common femoral artery puncture, a catheter was placed in the brachial artery for digital subtraction angiographic (DSA) runs of the right hand followed by cross-over technique with the catheter placed in the left superficial femoral artery for DSA runs of the left foot. In the right arm (A), there is normal flow in the radial and ulnar arteries. There is loss of the superficial palmar arch and poor flow to the digital arteries, more marked on the radial aspect. Absence of improvement post-glyceryl trinitrate (GTN) injection indicated no component of arterial spasm. In the left leg there was normal flow to the ankle. Distal to the ankle, there is segmental occlusion of the dorsalis pedis artery (B, arrow) with poor collateralization and no significant plantar supply seen. No flow is seen to the digits. (C and D) Digital infarcts 9 weeks following influenza vaccination in the right hand (C) and left foot (D).

 
The patient was treated with topical nitrates, low-dose aspirin and oral nifedipine, in addition to her regular medications. Over the next 2 weeks she developed increasing arthralgia and early morning stiffness, bilateral knee effusions, and digital ulceration and infarction of the second to fifth digits of the right hand (Fig. 1CGo) and left third toe. Radial and ulnar pulses were palpable with no detectable dorsalis pedis. Alkaline phosphatase was 259 U/l (NR: 30–110); serum aspartate aminotransferase 164 U/l (0–45); {gamma}-glutamyl transferase 241 U/l (0–50) and ALT 627 U/l. A single intravenous bolus of 1000 mg methylprednisolone resulted in improvement of symptoms. Oral prednisolone at 75 mg and cyclophosphamide at 100 mg daily were prescribed and methotrexate ceased. At 2 weeks her digits and joints were less painful and peripheral pulses were normal, but capillary return was diminished with new infarcts affecting the left second to fourth fingertips and second and fifth toes (Fig. 1DGo). Her ESR was 20 mm/h and CRP 7 mg/l. At 2 months the patient was asymptomatic with no evidence of synovitis and with normal liver function tests. The gangrenous areas demarcated and separated over the ensuing 8 months. At 10 months the digits were well perfused with minor pulp atrophy. Prednisolone and cyclophosphamide were gradually withdrawn and methotrexate recommenced at 22 months, with subsequent re-emergence of polyarthritis.

Several studies of the safety and efficacy of influenza vaccination in patients with rheumatic diseases, including RA and SLE, have reported no increase in incidence or activity following vaccination [1, 68], thus leading to the recommendation that patients with RA should be included in standard immunization programmes [1]. Despite this, anecdotal cases continue to be reported of autoimmune phenomena following influenza vaccination, including SLE, RA, pericarditis and various forms of vasculitis [25]. As noted by others, studies of vaccine safety have generally followed the effects of a single vaccination, with no trials to date assessing the safety of repeated annual vaccinations as currently recommended [2]. Furthermore, as indicated by these authors, viral components included in vaccines vary from year to year, with evidence that some influenza vaccines are more commonly associated with autoimmune complications than others. Established associations between infectious agents such as rubella, Ross river and hepatitis C viruses and inflammatory arthritis suggest a potential role for the immunological presentation of viral proteins in enhancing inflammatory activity in RA. Indeed, virus-specific antibody-producing B lymphocytes have been isolated from the synovium of patients with RA following influenza vaccination [9]. These observations raise the possibility that virus-specific B and T lymphocytes resident within mononuclear infiltrates in inflamed joints may be activated following systemic viral infection or vaccination, and thus contribute to localized inflammation in RA.

We report the first case, to our knowledge, of vasculitis following influenza vaccination in a patient with pre-existing RA. Although methotrexate and gold have rarely been implicated as causes of vasculitis, in our patient a cause-and-effect relationship with influenza vaccination is suggested by the proximity of her clinical manifestations to the date of vaccination. Proof of such a relationship, however, is not available at this time. Although yearly influenza vaccination is now recommended for patients with RA, a paucity of long-term studies address the influence of repeated vaccination upon both the incidence and exacerbation of pre-existing systemic rheumatic diseases. If a true increase in relative risk exists, albeit small, then an increased frequency of such complications might be anticipated. Although for the vast majority of patients the benefits of regular influenza vaccination are likely to far exceed its potential risks, we would advise appropriate monitoring of individuals with known systemic rheumatic diseases, early reporting of suspected adverse events associated with vaccination and consideration of large prospective studies to determine the actual risks of currently recommended vaccination protocols.

Notes

Correspondence to: M. Rischmueller, Department of Rheumatology, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, South Australia 5011, Australia. E-mail: maureen.rischmueller{at}nwahs.sa.gov.au Back

References

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Accepted 28 November 2002





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