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Research Article

Rapid responses to anakinra in patients with refractory adult-onset Still's

disease

Avril A. Fitzgerald 1, Sharon A. LeClercq 2, Yan 2, Joanne E.

Homik 3, A. Dinarello 4 * 1University of Calgary, Calgary, Alberta,

Canada

2Royal andra Hospital, Edmonton, Alberta, Canada

3University of Alberta, Edmonton, Alberta, Canada

4University of Colorado Health Sciences Center, Denver

*Correspondence to A. Dinarello, University of Colorado Health

Sciences Center, 4200 East Ninth Avenue, B168, Denver, CO 80262Dr. Dinarello

has

received consulting fees of less than $10,000 from Amgen.

Funded by:

NIH; Grant Number: AI-15614, HL-68743, CA-046934

Abstract

Objective To assess the efficacy of anakinra treatment in patients with

adult-onset Still's disease (AOSD) that is refractory to corticosteroids,

methotrexate (MTX), and etanercept.

Methods Four patients with AOSD were treated with prednisone and MTX and 2

patients were also treated with etanercept for worsening symptoms and

indicators of systemic inflammation. White blood cells (WBCs), C-reactive

protein

(CRP) levels and/or erythrocyte sedimentation rate, and ferritin levels were

measured and, in 1 patient, serum creatinine levels were determined. Treatment

with anakinra at 100 mg/day was initiated.

Results The index patient's disease was refractory to treatment with

prednisone (30 mg/day) and MTX, with spiking fevers, rash, synovitis, a serum

ferritin level of 8,400 ng/ml (normal 200), and a CRP level of 86 mg/liter

(normal

<8). Levels of interleukin-1 (IL-1), IL-1, IL-6, IL-1 receptor antagonist,

and IL-18 were elevated. Just prior to anakinra treatment, the WBC count was

14,600/mm3, the CRP level was 86 mg/liter, and the ferritin level was 573

ng/ml, with daily spiking fevers to 104°F, rash, and swollen joints. Within

hours

of the first injection, the patient was afebrile and asymptomatic; within

days, the WBC count, ferritin level, and CRP level decreased into the normal

range. On 2 occasions, anakinra was withheld. Within a few days, the WBC count

rose to >20,000/mm3 with prominent neutrophilia, the CRP level rose to >200

mg/liter, and the ferritin level rose to >3,000 ng/ml. Upon restarting

anakinra, the patient became afebrile, the WBC count fell to 8,000/mm3, the CRP

level fell to <3 mg/liter, and the ferritin level fell to <300 ng/ml. Three

additional patients with refractory AOSD who experienced rapid reductions in

fever, symptoms, and markers of inflammation when treated with anakinra are

reported.

Conclusion Refractory AOSD appears to be IL-1-mediated since anakinra

decreases hematologic, biochemical, and cytokine markers and also produces

rapid

reductions in systemic and local inflammation. Reported efficacy of tumor

necrosis factor-blocking therapies in AOSD may be due to a reduction in IL-1.

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