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Refractory adult onset Still’s disease and hypersensitivity to non-steroidal anti-inflammatory drugs and cyclo-oxygenase-2 inhibitors: are biological agents the solution?
  1. E H J G Aarntzen,
  2. P L C M van Riel,
  3. P Barrera
  1. Department of Rheumatology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
  1. Correspondence to:
    Dr P Barrera
    p.barrerareuma.umcn.nl

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Adult onset Still’s disease (AOSD) is an autoimmune disorder characterised by periodic high fever, arthritis, and typical evanescent rashes. Non-steroidal anti-inflammatory drugs (NSAIDs) are the preferred treatment. In severe cases several disease modifying antirheumatic drugs, thalidomide, and intravenous immunoglobulin have been used. More recently, successful treatment with tumour necrosis factor α (TNFα) blocking agents1,2 and interleukin (IL) 1 neutralisation3 has also been reported.

Hypersensitivity to NSAIDs, often characterised by urticaria, angio-oedema, and asthma, has been well documented, and several studies indicate that anaphylactic reactions are related to the inhibition of cyclo-oxygenase-1 (COX-1) enzyme4–6 and that selective COX-2 inhibitors can be safe in these patients. Here we report a case of AOSD complicated by coexisting hypersensitivity to acetaminophen (paracetamol), aspirin, NSAIDs, and also to selective COX-2 inhibitors. TNFα neutralisation controlled the fever, but not the AOSD related rashes and polyarthritis or the anaphylactic reactions to NSAIDs and COX-2 inhibitors. Treatment with IL1 receptor antagonist led to full remission of the AOSD.

CASE REPORT

A patient, with known AOSD for 22 years, was admitted to our centre with a 3 week history of spiking high fever, chills, skin rash, cough, and a sore throat. Physical examination disclosed a typical AOSD related rash, polyarthritis, and enlarged inguinal lymph nodes without hepatosplenomegaly. Laboratory examination showed an increased acute phase reaction and a normochromic normocytic anaemia; white blood cell count, platelet count, and liver function tests were normal. Serological tests for viral infections, toxoplasma, Bartonella, blood and urine culture rheumatoid factor, and antinuclear antibodies were all negative.

In the past the AOSD had followed a polycyclic course, which had been successfully treated with several NSAIDs alone or in combination with acetaminophen for 10 years. In 1993, she developed an allergic reaction with angio-oedema to naproxen (fig 1), and later also to acetaminophen and sodium salicylate. Methotrexate was used for the next 10 years, but frequently corticosteroids were needed to treat the AOSD exacerbations. To avoid chronic use of corticosteroids, etanercept was started in May 2003 and the corticosteroids were tapered. This led to exacerbations of a mild polyarthritis and worsening of the rash but no fever. Because selective COX-2 inhibitors may be safe in patients with intolerance to NSAIDs,4,5 rofecoxib was successfully added to etanercept without intolerance. However, a second challenge with rofecoxib resulted in severe angio-oedema and urticarial rash and the same occurred after challenges with celecoxib and etoricoxib. IL1 receptor antagonist was started in December 2004, leading to a full remission of all AOSD related symptoms despite the withdrawal of long term steroid treatment.

Figure 1

 Angio-oedema after NSAID ingestion. Reproduced with the patient’s permission.

DISCUSSION

Our case illustrates that TNFα blocking agents are only partially effective in the treatment of refractory AOSD. Partial or limited efficacy of these agents has also been also observed in patients with systemic onset juvenile idiopathic arthritis.7,8 Our case and several other reports suggest that it is not TNFα but IL1 which has a pivotal role in the pathogenesis of AOSD3 and systemic onset juvenile idiopathic arthritis.9 In these diseases and in other rare disorders with a single amino acid mutation in the NALP-3 gene which results in increased IL1 secretion, IL1 blockade seems to be the preferred treatment.10

Furthermore, our case suggests that hypersensitivity to NSAIDs is not exclusively mediated by COX-1 blockade, but can also be provoked by selective COX-2 inhibitors that can function as haptens, resulting in anaphylaxis upon next exposure.5 Our case shows that these reactions are not mediated by TNFα and not altered by TNFα neutralisation.

REFERENCES

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Footnotes

  • Competing interests: none

  • Published Online First 13 July 2005

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