Celecoxib-induced lupus-like syndrome

P. Poza-Guedes, R. González-Pérez and G. Canto

Allergy Department, Hospital Universitario Doce de Octubre, Madrid, Spain

SIR, We present a 68-yr-old woman with hypercholesterolaemia, hypertension and gonarthrosis without a medical history of atopy or drug allergy. She was treated regularly with atorvastatin (Cardyl®), telmisartan (Pritor®) and piroxicam (Feldene®). Due to gastric dyspepsia, piroxicam was replaced by celecoxib (Celebrex®) 200 mg/day. Two weeks later, she developed generalized arthromyalgias and a non-itching micropapular skin exanthema with central distribution associated with malar rash (Fig. 1Go). Celecoxib was discontinued and oral antihistamines and steroids were given for the next 3 days. The symptoms cleared up within 5 days.



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FIG. 1.
 
The patient gave written consent for the study. Prick and patch skin testing with several cyclooxygenase 2 (COX-2) inhibitors (celecoxib, rofecoxib and nimesulide) had a negative result. Oral challenge test with increasing doses of celecoxib up to the therapeutic dose (200 mg) every 24 h was performed over a period of 3 days, and a central micropapular skin exanthema with malar rash and polyarthralgias developed 5 h after the last provoking dose. Laboratory data showed a normal full blood count, and no evidence of liver or kidney failure was found. Plasma C3 and C4 concentrations, aldolase, C-reactive protein and rheumatoid factor were normal. Testing for antinuclear antibodies (ANA) had a low positive result at 1/40 dilution, but antihistone antibodies (H2A-H2B histone–DNA complex) were negative. No significant radiological abnormalities were found in the chest, elbows, wrists, hands and feet.

The skin biopsy was reported as characteristic of lupus erythematosus (perivascular and perifollicle lymphocytic infiltration in the upper dermis with vacuolar degeneration in the basal layer of the epidermis). MHC class II typing for HLA-DRB1 alleles was performed with the polymerase chain reaction using sequence-specific primers. The predisposing HLA-DR4 subtype (DRB1*0401) was found, as described previously [1]. Clinical and serological follow-up was performed every 4 months for 1 yr after diagnosis. The patient has remained asymptomatic since then, following her regular treatment with atorvastatin and telmisartan. Subsequent good tolerance to non-steroidal anti-inflammatory drugs (NSAIDs) was confirmed by single-blind, placebo-controlled oral challenges with piroxicam (20 mg) and aspirin (1 g). The patient showed negative results in serial ANA profiles.Go

Drug-induced lupus (DIL) resembles clinically idiopathic lupus erythematosus. This syndrome should be suspected in patients without a history of autoimmune disease who develop symptoms or signs similar to those of systemic lupus erythematosus (SLE) in association with drug treatment and show complete reversal after withdrawal of the drug [2]. The first case was described by Hoffmann in 1945 with sulphadiazine [3], although more than 70 drugs had been reported to cause DIL or to exacerbate pre-existing lupus. There is no consensus on the diagnostic criteria, although many of the patients are Caucasians, over 50 yr of age and do not fulfil four of the 11 criteria of the American College of Rheumatology for the classification of SLE [4].

The pathogenesis is not well understood. However, several mechanisms are postulated: lack of immunological tolerance, slow acetylator status, drug–DNA interaction, and probably genetic predisposition [2]. Some HLA patterns have been implicated, with an association between DIL and HLA-DR4 [1]. Recently, Dunphy et al. [5] found at least one HLA-DR4 subtype (DRB1*0401,0408) in nine of 13 patients with minocycline-induced lupus, and they suggest that certain amino acids may form a spatially related epitope that is shared exclusively between certain HLA-DR4 and HLA-DR2 subtypes. NSAIDs are one of the common causes related to DIL. The selective COX-2 inhibitors (celecoxib and rofecoxib) have been introduced as new analgesic and anti-inflammatory agents for the treatment of osteoarthritis. Although these drugs have similar side-effects to other NSAIDs, the lower rate of adverse gastrointestinal effects has promoted their widespread use.

Although antihistone antibodies were negative, there was substantial evidence to confirm the clinical picture, such as the presence of immunogenetic risk factors, reversal of positive ANA, the histopathological findings and the positive provocation with the culprit drug. With the increasing use of COX-2 inhibitors, health-care professionals should be aware of the potential severe side-effects of emerging drugs [6, 7]. To our knowledge this is the first reported case of DIL associated with celecoxib.

Notes

Correspondence to: P. Poza-Guedes. E-mail: pozagdes{at}hotmail.com Back

References

  1. Batchelor JR, Welsh KI, Tinoco RM et al. Hydralazine-induced systemic lupus erythematosus: influence of HLA-DR and sex on susceptibility. Lancet 1980;1:1107–9.[CrossRef][Medline]
  2. Yung RL, Richardson BC. Drug-induced lupus. Rheum Dis Clin North Am 1994;20:61–86.[ISI][Medline]
  3. Hoffman BJ. Sensitivity of sulfadiazine resembling acute erythematosus. Arch Dermatol Syph 1945;51:190–2.[ISI]
  4. Talal EM, Cohen AS, Fries JF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271–7.[ISI][Medline]
  5. Dunphy J, Oliver M, Rands AL, Lovell CR, McHugh NJ. Antineutrophil cytoplasmic antibodies and HLA class II alleles in minocycline-induced lupus-like syndrome. Br J Dermatol 2000;142:461–7.[CrossRef][ISI][Medline]
  6. Verbeiren S, Morant C, Charlanne H, Ajebbar K, Caron J, Modiano P. Celecoxib induced toxicodermia with positive patch-test. Ann Dermatol Venereol 2002;129:203–5.[ISI][Medline]
  7. Schneider F, Meziani F, Chartier C, Alt M, Jaeger A. Fatal allergic vasculitis associated with celecoxib. Lancet 2002;359:852–3.[CrossRef][ISI][Medline]
Accepted 6 December 2002





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