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Adult onset Still’s disease: response to Enbrel
  1. R A Asherson1,
  2. L Pascoe1
  1. 1Rheumatic Diseases Unit, Department of Medicine, The Groote Schuur Hospital and the University of Cape Town School of Medicine, Cape Town, South Africa and The Rosebank Clinic, Johannesburg, South Africa
  1. Correspondence to:
    Dr R A Asherson, Johannesburg Consulting Offices, Rosebank Clinic (Suite 21), Sturdee Avenue, Johannesburg 2196, South Africa;
  1. H G Kraetsch2,
  2. B Manger2
  1. 2Department of Internal Medicine III, Institute for Clinical Immunology, Krankenhausstr 12, D-91054 Erlangen, Germany

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    Over the past year several publications have appeared recording the use of tumour necrosis factor (TNF) blockers, particularly infliximab (Revellex) in the treatment of adult onset Still’s disease (AOSD), a condition often resistant to a variety of treatments.

    We wish to report a favourable response to etanercept (Enbrel) in a single patient who has proved resistant to a wide variety of agents over a 10 year period and who has had several, very serious complications of this condition, including the development of cardiac amyloidosis.

    The patient, a 35 year old nursing sister, was initially diagnosed with AOSD at the age of 23 and was treated with non-steroidal anti-inflammatory drugs, salicylates, methotrexate, antimalarial drugs (chloroquine), and d-penicillamine. On this regimen she developed frequent flares and side effects to most of the disease modifying antirheumatic drugs to which she had been exposed—for example, antimalarial drugs resulted in the loss of peripheral vision in her right eye. Intramuscular gold injections (Myocrisin) were then given but also to no avail. High dose steroids (3g daily over five days intravenously (IV)) given at 6–8 weekly intervals caused weight gain and Cushing’s syndrome. Attacks of myalgic pain affecting the neck, shoulders, and mid-back areas were common, and were present throughout her illness. Eventually this was diagnosed as fibromyalgia.

    At the age of 29 she was admitted to hospital with severe dyspnoea and chest pain. She tested positive for cytomegalovirus and coxsackievirus B. Steroids were ineffective and an emergency tracheotomy was performed in 1996. She was admitted to the intensive care unit with severe surgical emphysema, bilateral pneumothoraces, pleural effusions, and a pericardial effusion. She was kept sedated for most of her admission. The tracheotomy tube was removed but had to be reinserted owing to the collapse of both arytenoid cartilages. Eventually a Montgomery stent (permanent tracheotomy) was inserted and this remained in situ until 1999, some three years later. Treatment was started with daily oral cyclophosphamide. This resulted in severe neutropenia which required Neupogen as the white cell count had fallen to 1×109/l. Extensive alopecia also developed. Steroids were again given in a dose of 1 g twice weekly. Then she consulted a different rheumatologist (RAA) when she was admitted to the intensive care unit again with pericarditis and effusion, pleural effusions, peritonitis (polyserositis), hepatosplenomegaly, and a restrictive cardiomyopathy, which was later diagnosed as being due to amyloid. Gastroscopy showed reflux oesophagitis with ulceration and severe candidiasis. Severe bone marrow depression with thrombocytopenia (15×109/1) necessitated intravenous gammaglobulin (Polygam) treatment, which was ineffective.

    It was decided to attempt plasmapheresis combined with cyclophosphamide at 6–8 weekly intervals. Although the frequency of relapses was markedly reduced, she developed pseudomonas infection and the line had to be removed. Myocarditis was treated with β blockers (Sotacor 160 mg twice a day).

    In February 1999 treatment with cyclosporin 125 mg twice a day and methotrexate 50 mg weekly was started. This resulted in fair but not complete control. Liver functions were measured weekly, but the high doses of methotrexate were well tolerated. Because of side effects, the cyclosporin had to be discontinued. The relapses were not as severe or as frequent as previously. IV cyclosphosphamide, together with mesna and zofran were given every 6–8 weeks. However, relapses occurred more frequently again requiring high dose steroids. Thalidomide was then attempted but even with minimal doses peripheral neuropathy ensued and it had to be discontinued. Premature ovarian failure was then diagnosed.

    In 2000 treatment with Defibrotide, an experimental anticytokine preparation, was started. This was ineffective. It was then decided to give etancercept (Enbrel) for “flares only, combined with intramuscular steroid (Depo-Medrol 160 mg biweekly before and at the time of the flare; flares were anticipated by subjective symptomatology (sore throat, sweats, fatigue, polyarthralgias, vasculitic skin lesions) as well as by rises in the C reactive protein, erythrocyte sedimentation rate, white blood cell count, and serum ferritin levels. Methotrexate was maintained at 25 mg weekly, as recommended by the manufacturers. On this regimen, flares occurred every 3–4 months only. Enbrel was then given once weekly together with steroids twice weekly.

    On 29 June 2000 she sustained a fracture of her skull complicated by a subarachnoid bleed; a tympanomastoidectomy was required. She discontinued all her drugs in November 2000 and sustained a massive flare requiring admission to hospital. She decided to discontinue her methotrexate because of side effects and continued with the Enbrel twice weekly. No flares occurred. She ran out of Enbrel in November 2001 for one week and again had to be admitted to hospital with a “flare”necessitating IV steroid and cyclophosphamide once again. When supplies of Enbrel were again unavailable she used only one injection weekly and once again, in January developed a severe “flare” necessitating admission to hospital and IV steroid (4 g), on this occasion without cyclophosphamide.

    This case demonstrates several important points in the management of recalcitrant AOSD as well as clinical features occurring in the course of the disease.

    Each “flare” was heralded by the appearance of vasculitic skin lesions accompanied by severe arthralgias and frank arthritis, in addition to systemic features such as night sweats and fatigue. No typical rash of Still’s disease ever appeared. Her temporomandibular joints were affected more severely than any others and eventually required total replacement. Chondritis, as evidenced by collapse of both arytenoid cartilages was an early feature of the disease. After about 10 years, amyloid cardiomyopathy had developed. Severe recurrent attacks of fibromyalgia complicated her management. Local injections of 1% lidocaine were effective for this condition as well as a variety of analgesics.

    A number of differing therapeutic regimens were tried in an attempt to control the disease. They all succeeded only partially. These included plasmapheresis, high dose methotrexate (as high as 50 mg weekly without ill effects), and IV boluses of cyclophosphamide.

    High dose steroids were usually required to control major flares and intramuscular steroids together with Enbrel seemed to control minor flares and were preferable to daily oral steroids. Side effects necessitating withdrawal of drugs developed after cyclosporin and thalidomide treatment. Infection complicated and required the discontinuation of plasmapheresis. Defibrotide, an experimental anticytokine compound, useful in the treatment of the catastrophic antiphospholipid syndrome was ineffective in this condition.1 IV gammaglobulins were also ineffective.

    The use of Enbrel revolutionised control of the disease. However, a reduction of the dose to one injection weekly instead of the recommended two was ineffective and major relapses occurred. The use of TNFα antagonists in the treatment of AOSD dates back to 1997 when it was first suggested by Stambe and Wickes, who documented the use of thalidomide in a 44 year old woman unresponsive to the usual treatment, although in this particular patient the TNFα levels were low.2 Hoshino et al found high levels of TNFα as well as interferon γ and interleukin 6 in 12 patients with AOSD.3

    Elliott et al in 1998 used infliximab effectively in a patient with juvenile rheumatoid arthritis and systemic features.4 The first paper demonstrating its usefulness in AOSD was that of Cavagna et al in 2001.5 It was shown that long intervals between infusions resulted in relapses and that reduction of the interval of administration from eight to four weekly was effective. Skin reactions (for example, urticaria) were prevented by the administration of antihistamines before the infusions. Kraetsch et al also in 2001 treated six patients with a diagnosis of AOSD with infliximab. The fevers, arthralgias, myalgias, hepatosplenomegaly, and rash resolved in all six patients after the first course of treatment with the compound.6 All serological abnormalities also returned to normal. Up to the time of publication of that series, treatment had been given for between five and 28 months.

    It seems now that infliximab and entanercept have revolutionised the treatment of recalcitrant AOSD and should not be withheld from any patients who do not initially respond to conventional treatments which may have included cyclophosphamide7 and cyclosporin,8 both of which have been used in the treatment of this condition. High dose steroids combined with cyclophosphamide, on occasion, aborted the acute episodes in this patient but resulted in side effects of steroid overdosage.

    Our patient had a number of unusual features of the disease and her response to anti-TNF treatment has been nothing short of dramatic.


    Authors’ response

    The authors report an interesting case of a patient with severe adult onset Still’s disease refractory to multiple conventional treatments. A reduction of disease activity was not achieved until treatment with the tumour necrosis factor (TNF) antagonist etanercept at a dose of 25 mg twice weekly was started. After a period of treatment with the dose approved for the treatment of rheumatoid arthritis a marked improvement of the patient’s symptoms was seen. Subsequent reduction of the dose to a weekly administration of 25 mg etanercept was followed by a relapse of the disease. Treatment had to be re-escalated to the original dose of 25 mg etanercept twice weekly. Again, a relevant reduction of disease activity was achieved. Up to now treatment with etanercept 25 mg twice weekly is effective and well tolerated by the patient.

    The case demonstrates again that treatment directed against TNFα is an effective treatment for adult onset Still’s disease. Up to now, promising data have been presented only for treatment with infliximab.1–3 To our knowledge, this is the first published case of successful treatment of adult onset Still’s disease (AOSD) with the TNF receptor construct etanercept, suggesting that inhibition of TNFα is a potential approach to treatment of this disease. Additionally, as seen with several patients treated with infliximab, the case again underlines the need to give continuously a “minimum dose” of this drug to maintain the achieved remission of AOSD.