Rapid response to anakinra in patients with refractory Adult Onset Still’s Disease (AOSD)

Rapid response to anakinra in patients with refractory Adult Onset Still’s Disease (AOSD)

Category:  16 RA-treatment and gene therapyA. A. Fitzgerald1, S. A. LeClercq2, Alexander Yan2, J. E. Homik3, Charles A. Dinarello4. 1University of Calgary, Calgary, AB, Canada; 2Royal Alexandra Hospital, Edmonton, AB, Canada; 3University of Alberta, Edmonton, AB, Canada; 4University of Colorado, Denver, CO

Presentation Number: 335

Poster Board Number: 336

Purpose. To assess the effect of anakinra in the treatment of refractory AOSD.

Methods

Four patients with AOSD were treated with prednisone, methotrexate and, in two, etanercept for worsening symptoms and parameters of systemic inflammation. Prior to anakinra, levels of CRP and/or ESR were measured. In one patient (index case), pre- and post anakinra treatment levels of cytokines were determined. All patients were treated with 100 mg of subcutaneous anakinra daily. Following initiation of therapy, biochemical, hematological and clinical parameters were measured.

Results

The index case, a 39 y/o female diagnosed with AOSD had a ferritin level of 8,400 ng/ml and CRP of 99 mg/L. On prednisone (30 mg) she had persistent spiking fever and rash. Cytokine levels were IL-1 beta, 10.1 and 3.9; IL-6, 702 and 629; IL-1Ra 2112 and 1922; IL-1 alpha 82 and 102; IL-18 2558 and 2238 pg/mL. Spiking the patient’s serum with recombinant IL-1 beta did not reveal interfering substances. IL-18 levels remained markedly elevated. Methotrexate was added with little improvement. Prior to anakinra, WBC was 14,600, CRP 86 mg/L and ferritin 573 ng/mL with daily spiking fevers to 104 F, rash and swollen joints. Within hours of the first anakinra injection, the patient defervesced and continued afebrile and asymptomatic while treated with anakinra. After 40 days of anakinra, WBC, ferritin and CRP had returned to within normal range. After 3 months, anakinra was withheld to evaluate a febrile episode. Within 3 days, WBC rose to 21,400 (83% neutrophils), CRP to 224 and ferritin to 1,618. Anakinra was restarted and within 4 hours the patient was afebrile; arthritis and rash resolved one day later and WBC fell to 8,000 and CRP to 55.6. Three additional patients with active AOSD refractory to prednisone and methotrexate experienced similar rapid reductions in fever, local and systemic symptoms with anakinra. Elevated WBC and markers of acute phase response also decreased rapidly. Etanercept had been tried in the pre-anakinra drug regimen in 2 patients without benefit.

Conclusions

Despite the lack of elevated levels of circulating IL-1, the rapid falls in clinical, hematological and biochemical markers of systemic disease when blocking IL-1 activity in refractory AOSD reveals that the disease is primarily mediated by IL-1 and not TNF. Reports of success with TNF blocking therapy in AOSD may be due to a reduction in IL-1.
Commercial Relationship:  A.A. Fitzgerald, None; S.A. LeClercq, None; A. Yan, None; J.E. Homik, None; C.A. Dinarello, None.

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