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Effective Treatment of Steroid Refractory Adult-onset Still's Disease with Anakinra To the Editor: We describe rapid and sustained response of a 44-year-old woman with steroid-refractory adult-onset Still's disease (AOSD) to treatment with the interleukin 1 (IL-1) receptor antagonist anakinra as a first-line immunosuppressive therapy. The fast mode of action compared to conventional disease modifying antirheumatic drugs (DMARD) and tumor necrosis factor (TNF) inhibitors paired with an acceptable safety profile had prompted us to initiate a primary IL-1 receptor-blocking therapy. The rapid clinical response (cessation of fever within 12 h) and normalization of elevated acute-phase laboratory measures within a few days, together with recent data suggesting a crucial role of IL-1 in the pathogenesis of systemic-onset juvenile rheumatoid arthritis and AOSD, encourage first-line therapy with anakinra in these patients. A 44-yr-old Caucasian woman was transferred to our emergency department from a community hospital due to a 2-week history of high-spiking fever recurring every day with temperature peaks of 41šC in the evening. The fever had not been responsive to treatment with antibiotics and was associated with systemic inflammatory symptoms including chills, ubiquitous arthralgias, myalgias, especially in the lower limbs, and a non-itching exanthema. Before the acute onset of the disorder, she had never experienced similar symptoms or any other health problem. She denied visits to foreign countries in the past months. At examination we found a middle-aged woman in reduced condition with fever (41šC), pharyngitis, conjunctivitis, mild hepatosplenomegaly, heart rate of 100 per minute, and a systolic heart murmur. We noted a non-itching salmon-colored rash, which was most prominent at the extremities (Figure 1) and resolved within 48 h. Clinically, no joint swelling or synovitis was found. Laboratory testing revealed elevated C-reactive protein (CRP) and erythrocyte sedimentation rate, leukocytosis, normocytic anemia, elevated lactate dehydrogenase (LDH), and slightly raised liver enzymes (Figure 2). Suspecting AOSD, we observed extremely high levels of serum ferritin (51,100 ng/ml, normal range 10–120 ng/ml) and increased concentrations of soluble IL-2 receptors (6061 U/ml, normal range 223–710 U/ml). A bone marrow aspiration was performed to exclude an underlying malignancy and to detect possible hemophagocytosis. Cytology revealed solely a hypercellular bone marrow, and flow-cytometry showed an overexpression of CD38 and CD11c on monocytes, indicating immunoactivation and an activated T-cell population (partly HLA-DR+, CD38+, CD25+). Serological analysis indicated no infection with Treponema pallidum, Borrelia, parvovirus, rubella, HIV, hepatitis B virus (HBV), HCV, HAV, Epstein Barr virus, cytomegalovirus, or human herpesvirus 6. Blood cultures and urinalysis had been negative 3 times. A chest radiograph, abdominal ultrasound, computerized tomography scan of the perinasal sinuses, and transesophageal echocardiography were unremarkable, despite a mild splenomegaly and marginal insufficiency of the aortic valve. Serum electrophoresis showed a polyclonal gammopathy and an acute-phase response. No evidence was found for any other rheumatic disorder, and antinuclear antibodies and rheumatoid factors were negative.
Since the patient met all classification criteria for AOSD1 and no evidence for any other autoimmune disorder, malignancy, or infectious disease was found, steroid therapy with oral prednisolone 1 mg/kg body weight in addition to 1.5 g aspirin was initiated; this had no effect on signs and symptoms. After 3 days of unsuccessful oral prednisolone, intravenous pulses of 250 mg prednisolone per day were given. In spite of the dose escalation, the fever recurred every day with a peak in the evening and resistance to treatment with paracetamol, metamizol, and diclofenac. In view of this primary response failure to steroids, we decided to begin additional immunosuppressive therapy with anakinra. Indeed, within a few hours of a single subcutaneous application of 100 mg anakinra, the fever subsided and the patient experienced a complete remission of clinical symptoms, with normalization of laboratory findings after a few days (Figure 2). In parallel with the dramatic clinical improvement, the concentration of serum ferritin diminished rapidly from 51,100 to 3480 ng/ml after 10 days of therapy. Similarily, CRP, LDH, and leukocyte counts returned to normal values. Within 6 weeks of treatment the serum ferritin normalized completely. Prednisolone was tapered below 7.5 mg/day within 3 months. After 6 months, low-dose prednisolone was discontinued, and the time interval between the anakinra applications was gradually increased. Currently, after 8 months of treatment, the patient remains in remission receiving anakinra 100 mg subcutaneously 3 times weekly. AOSD was first described by Bywaters in 19712 and represents a rare systemic inflammatory disorder with an estimated incidence of 1 to 2 cases per million inhabitants per year in Western Europe3. Due to this low incidence, few data on diagnosis and therapy derived from case reports and limited retrospective studies are available4. The etiology of AOSD remains elusive. Currently, the hypothesis of an exacerbated immune response based on a dysregulation of cytokine-mediated signaling cascades is favored5. IL-1 appears to play a central pathogenic role in systemic inflammatory disorders like juvenile and adult-onset Still's disease and periodic fever syndromes6,7. IL-1-mediated inflammatory activity is mirrored by a remarkable elevation of ferritin level, which is upregulated by this proinflammatory cytokine8. After very promising effects of anti-IL-1 receptor therapy in children with systemic-onset juvenile rheumatoid arthritis7, successful treatment of AOSD with anakinra has been described in single case reports and a series of 4 patients who did not respond adequately to conventional DMARD or anti-TNF-a therapy (methotrexate, cyclosporine, sulfasalazine, infliximab, or etanercept)9,10. Recently, Kalliolias, et al reported a prompt response and longterm steroid-sparing effect of anakinra in 3 patients that had previously required high steroid doses to control disease activity and in one patient who was refractory to methotrexate and etanercept11. Anakinra presents several advantages over conventional DMARD, with a faster response and a favorable safety profile with fewer opportunistic infections compared to TNF inhibitors; the prompt, sustained clinical response and subsequent improvement of laboratory measures in our patient encourage further use of anakinra as a first-line therapy in severe steroid refractory AOSD. Yet a longer observation time and larger series of patients will be needed to determine optimal length of treatment course, longterm outcomes, and complications with anakinra. Moreover, the cost-effectiveness of IL-1 receptor blockade for severe AOSD has to be evaluated, weighing the expected delay of response to DMARD in severe steroid-refractory AOSD compared to the costs of anakinra and potential side effects of both treatment strategies. Additional anti-IL-1 strategies with improved pharmacokinetics, such as the IL-1 TRAP (soluble IL-1 receptor that binds and neutralizes IL-1), are being developed and may provide clinical advantages due to a longer application interval. JUDITH MAIER, MD; GABRIELE BIRKENFELD, MD; JOCHEN PFIRSTINGER, MD; JÜRGEN SCHÖLMERICH, MD, Professor; Department of Internal Medicine I, University Hospital, Regensburg; MARTIN FLECK, MD, Professor, Department of Rheumatology/Clinical Immunology, Asklepios-Clinic, Bad Abbach; HILKE BRÜHL, PD, MD, Department of Internal Medicine I, University Hospital, Regensburg, Germany. Address reprint requests to Dr. H. Brühl, Department of Internal Medicine I, University of Regensburg, 93042 Regensburg, Germany. E-mail: hilke.bruehl@klinik.uni-regensburg.de 2. Bywaters EGL. Still's disease in the adult. Ann Rheum Dis 1971;30:121-33. 3. Magadur-Joly G, Billaud E, Barrier JH. Epidemiology of adult Still's disease: estimate of the incidence by a retrospective study in west France. Ann Rheum Dis 1995;54:587-90. [MEDLINE] 4. Efthimiou P, Paik PK, Bielory L. Diagnosis and management of adult onset Still's disease. Ann Rheum Dis 2006;65:564-72. [MEDLINE] 5. Choi JH, Su CH, Lee YM, Suh YJ, Lee SK. Serum cytokine profiles in patients with adult onset Still's disease. J Rheumatol 2003;30:2422-7. [MEDLINE] 6. Dinarello CA. Blocking IL-1 in systemic inflammation. J Exp Med 2005;201:1355-9. [MEDLINE] 7. Pascual V, Allantaz F, Arce E, Punaro M, Banchereau J. Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. J Exp Med 2005;201:1479-86. [MEDLINE] 8. Rogers JT, Bridges KR, Durmowicz GP, Glass J, Auron PE, Munro HN. Translational control during the acute phase response. Ferritin synthesis in response to interleukin-1. J Biol Chem 1990;265:14572-8. [MEDLINE] 9. Godinho Vasques FM, Santos Parreira MJ, Canas da Silva J. Refractory adult onset Still's disease successfully treated with anakinra. Ann Rheum Dis 2005;64:647-8. [MEDLINE] 10. Fitzgerald AA, LeClercq SA, Yan A, Homik JE, Dinarello CA. Rapid responses to anakinra in patients with refractory adult-onset Still's disease. Arthritis Rheum 2005;52:1794-803. [MEDLINE] 11. Kalliolias GD, Georgiou PE, Antonopoulos IA, Andonopoulos AP, Liossis SC. Anakinra treatment in patients with adult-onset Still's disease is fast, effective, safe and steroid sparing: experience from an uncontrolled trial. Ann Rheum Dis 2007;66:842-3. [MEDLINE]
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