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JCR: Journal of Clinical Rheumatology:
doi: 10.1097/RHU.0b013e31822c53ad
Case Reports

Refractory Adult-Onset Still Disease Successfully Treated With Abatacept

Ostrowski, Rochella A. MD; Tehrani, Rodney MD; Kadanoff, Ruth MD

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From the Loyola University Medical Center, Maywood; and Edward Hines, Jr VA Hospital, Hines, IL.

The authors declare no conflict of interest.

Correspondence: Rochella A. Ostrowski, MD, Loyola University Medical Center, 2160 S First Ave, Maywood, IL 60153. E-mail:

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Adult-onset Still disease (AOSD) is an inflammatory condition of unknown etiology that responds to glucocorticosteroids and disease-modifying antirheumatic drugs, particularly methotrexate. However, disease refractory to conventional treatment has led to the reported use of biologic therapy including tumor necrosis factor α inhibitors (infliximab, etanercept, and adalimumab), anakinra, rituximab, and tocilizumab. We report the successful use of abatacept in the treatment of a patient with AOSD manifested by polyarthritis, rash, fevers, elevated liver function tests, and ferritin levels refractory to treatment with methotrexate and hydroxychloroquine. Remission has been maintained for 35 months with the addition of abatacept administered once monthly. There is evidence that T-cell activity plays an important role in the autoimmune activity of AOSD, and modulation of CD28 costimulation of T cells by abatacept has specific immunosuppressive actions that make it an appealing alternative therapeutic option for refractory AOSD.

Adult-onset Still disease (AOSD), an inflammatory condition of unknown etiology, is characterized by fever, evanescent rash, arthritis, and multiorgan involvement. Additional features include sore throat, hepatosplenomegaly, lymphadenopathy, leukocytosis, elevated liver enzymes, and high serum ferritin levels.

No randomized controlled trials evaluating different treatment modalities of AOSD exist, most likely because of the rarity of the disorder, which has an incidence of 0.16 per 100,000.1 Mild disease is treated with nonsteroidal anti-inflammatory drugs, often with the addition of glucocorticosteroids. Disease-modifying antirheumatic drugs (DMARDs) are eventually required in many patients. The most commonly used DMARD is methotrexate, with a response rate of 88%.2 Other DMARDs used in AOSD include cyclosporine A, hydroxychloroquine, gold, penicillamine, azathioprine, and cyclophosphamide, with an overall response rate of 40%3 (Table 1). Corticosteroid monotherapy carries a response rate of 63%, but it has been suggested that glucocorticosteroids are less effective in patients with chronic articular disease compared with those with nonchronic disease, but that biologic therapies are highly effective in both corticosteroid-resistant and DMARD-resistant AOSD.4

Table 1
Table 1
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Abatacept, a CTLA4 Ig fusion molecule that blocks the interaction between CD80/86 and CD28, is effective in the treatment of rheumatoid arthritis. It is also used for juvenile idiopathic arthritis.

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We report the successful use of abatacept in the treatment of a patient with AOSD refractory to treatment with methotrexate and hydroxychloroquine. The patient is a 31-year-old Hispanic man who presented with a 1-year history of seronegative inflammatory polyarthritis, fevers, maculopapular rash, sore throat, and elevated liver function tests. He was initially treated by his previous physician with hydroxychloroquine, methotrexate up to 15 mg weekly, and courses of prednisone with doses ranging from 10 to 20 mg daily. At the time of presentation, he was receiving etanercept 25 mg subcutaneously twice a week for 1 month, and methotrexate had been discontinued for the same duration of time because of persistently elevated liver transaminases. In addition, he had tapered himself off of his 20-mg daily prednisone maintenance dose 1 month before presentation.

The patient had a temperature of 39.6°C, heart rate of 133 beats/min, respiratory rate of 20 breaths/min, and blood pressure of 134/72 mm Hg. He had cervical lymphadenopathy, effusions in bilateral knees with decreased range of motion secondary to pain, tenderness to palpation at bilateral elbows, and an erythematous maculopapular rash involving the face, chest, upper arms, and thighs bilaterally. Laboratory tests revealed a leukocytosis of 14.5 × 109 cells/L with 75% neutrophils. The alanine aminotransferase was elevated at 112 U/L and aspartate aminotransferase at 28 U/L. Sedimentation rate was 27 mm/hr, and a C-reactive protein level was elevated at 26.1 mg/dL (normal level, ≤1.0 mg/dL). A ferritin level at that time was markedly elevated at 11,169 ng/mL and reached a level of 32,773 ng/mL.

The diagnosis of AOSD was suspected, so further workup was performed to exclude other etiologies for the patient's symptoms. Antinuclear antibody and extracted nuclear antigen panel were negative, as were antimyeloproliferative and antiproteinase 3 antibodies. An extensive infectious disease workup was unrevealing including HIV, viral hepatitis, Epstein-Barr virus, and varicella zoster virus serologies, in addition to antistreptolysin O titers. A hematology evaluation that included serum protein electrophoresis, peripheral flow cytometry, and bone marrow biopsy did not reveal a lymphoproliferative disorder. Rheumatoid factor, antinuclear antibody, anti-SSA, anti-SSB, anti-Smith, anti-RNP, and anti-native DNA antibodies were not present. Anti-cyclic citrullinated peptide antibodies were not tested for. Liver biopsy showed severe, predominantly large vesicular fatty change with mild periportal chronic inflammation and minimal portal and focal periportal fibrosis. A diagnosis of AOSD was made based on the criteria set forth by Yamaguchi et al.5 and the exclusion of other hematologic and infectious etiologies.

The patient was restarted on prednisone 40 mg daily and continued on etanercept and hydroxychloroquine. However, he subsequently developed bacterial pneumonia, and the etanercept was held. The patient refused to restart etanercept after resolution of the pneumonia because of concern for recurrence of infectious complications. Although increasing prednisone to 50 mg daily led to improvement in the patient's AOSD symptoms, the development of recurrent fevers (38.9°C) when prednisone was decreased prompted the reinstitution of methotrexate. As a result, methotrexate was restarted and titrated up to 17.5 mg weekly but eventually maintained at 10 mg weekly because of elevations of his liver transaminases. Prednisone was slowly reduced and maintained at 2.5 to 5 mg daily for 30 months. The ferritin, C-reactive protein, erythrocyte sedimentation rate, and aspartate aminotransferase levels normalized, but the alanine aminotransferase level remained elevated between 65 and 105 U/L and was attributed to underlying fatty liver.

Remission was maintained for 4 years. Four months after he was completely weaned off prednisone, rash, arthralgias, and fevers recurred. Symptoms resolved after the reintroduction of prednisone at 20 mg daily, but methotrexate could be not increased to greater than 12.5 mg weekly because of the patient's underlying fatty liver and presence of fibrosis on his liver biopsy. The inability to decrease the prednisone dose without recurrence of symptoms led to the consideration of more aggressive treatment. The patient refused to start a tumor necrosis factor α inhibitor because of his history of pneumonia while on etanercept, and he was not amenable to medications requiring self-administration of injections including anakinra. Subsequently, he agreed to a trial of abatacept. After negative testing for latent tuberculosis and viral hepatitis, the patient received abatacept 750 mg intravenously at week 0, 2 weeks, and then every 4 weeks. The patient's symptoms resolved after 1 month, and the prednisone was successfully discontinued by the sixth month after the initiation of abatacept. An attempt to discontinue the methotrexate 1 year after starting abatacept resulted in a relapse of the patient's symptoms, and the methotrexate was reinstituted with a temporary course of prednisone. Thirty-five months after starting abatacept, the patient continues to be in remission while on maintenance doses of abatacept, oral methotrexate 7.5 mg weekly, and hydroxychloroquine 400 mg daily.

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With the recent availability of new biologic therapies, successful use of the anti-CD20 monoclonal antibody, rituximab,6 as well as the tumor necrosis factor α inhibitors,7,8 has been reported in AOSD. The interleukin 1 (IL-1) receptor antagonist, anakinra, has also been used as therapy in AOSD.9-11 Recently, tocilizumab, one of the newest biologics approved for use in rheumatoid arthritis, has been effective in the treatment of a patient with AOSD that was refractory to anakinra.12 There is only one other report in the literature, by Quartuccio et al,13 of treatment with abatacept for refractory AOSD. In contrast to the case we describe, their patient was also refractory to adalimumab, infliximab, anakinra, and cyclosporine. In addition, the patient reported by Quartuccio et al.13 was maintained for up to 9 months on adalimumab in addition to methotrexate, leflunomide, and low-dose prednisone. Our patient has been maintained on abatacept, methotrexate, and hydroxychloroquine for 35 months, and a total of 22 months without glucocorticosteroids. This case report provides additional information regarding the potential for sustained remission in AOSD while on abatacept.

The effectiveness of abatacept in AOSD in our patient suggests that targeting T-cell costimulation is a viable treatment option for patients with AOSD. Interleukin 18 and interferon γ (IFN-γ), cytokines that reflect TH1 activity, are elevated in patients with AOSD. Interleukin 18 potentiates both the development of TH1-type immune responses and the production of IFN-γ in T cells and natural killer cells and appears to correlate with activity of the disease.14 Furthermore, patients with untreated AOSD have elevated TH1 cytokine levels in both peripheral blood and tissue biopsies of both the evanescent rash and synovium.15

Abatacept modulates CD28-mediated T-cell costimulation that is necessary for T-cell activation. In murine studies, this molecule suppresses production of IFN-γ and IL-17, in addition to reducing the migration of T cells into B-cell follicles and thereby reducing antibody responses.16 Recent data also demonstrate that CTLA4 Ig increases CD4+C25+Foxp3+ regulatory T-cell populations in mice with collagen-induced arthritis.17

In conclusion, we report a case of AOSD refractory to methotrexate and hydroxychloroquine who was successfully treated by the addition of abatacept. There is evidence that T-cell activity plays an important role in the autoimmune activity of AOSD, and modulation of CD28 costimulation of T cells by abatacept has specific immunosuppressive actions that make it an appealing therapeutic option for AOSD. Currently, abatacept is used only for rheumatoid arthritis, but we propose that abatacept may be an alternative agent for the treatment of refractory AOSD.

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1. Magadur-Joly G, Billaud E, Barrier JH, et al. Epidemiology of adult Still's disease: estimate of the incidence by a retrospective study in west France. Ann Rheum Dis. 1995;54:587-590.

2. Fautrel B, Borget C, Rozenberg S, et al. Corticosteroid sparing effect of low dose methotrexate treatment in adult Still's disease. J Rheumatol. 1999;26:373-378.

3. Efthimiou P, Paik PK, Bielory L. Diagnosis and management of adult onset Still's disease. Ann Rheum Dis. 2006;65:564-572.

4. Franchini S, Dagna L, Salvo F, et al. Efficacy of traditional and biologic agents in different clinical phenotypes of adult-onset Still's disease. Arthritis Rheum. 2010;62:2530-2535.

5. Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult Still's disease. J Rheumatol. 1992;19:424-430.

6. Ahmadi-Simab K, Lamprecht P, Jankowiak C, et al. Successful treatment of refractory adult onset Still's disease with rituximab. Ann Rheum Dis. 2006;65:1117-1119.

7. Benucci M, Li GF, Del Rosso A, et al. Adalimumab (anti-TNF-alpha) therapy to improve the clinical course of adult-onset Still's disease: the first case report. Clin Exp Rheumatol. 2005;23:733.

8. Kumari R, Uppal SS. Prolonged remission in adult-onset Still's disease with etanercept. Clin Rheumatol. 2006;25:106-108.

9. Debiais S, Maillot F, Luca L, et al. Efficacy of anakinra in a case of refractory Still disease. J Clin Rheumatol. 2008;14:357-358.

10. Kalliolias GD, Georgiou PE, Antonopoulos IA, et al. 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;66:842-843.

11. Naumann L, Feist E, Natusch A, et al. IL1-receptor antagonist anakinra provides long-lasting efficacy in the treatment of refractory adult-onset Still's disease. Ann Rheum Dis. 2010;69:466-467.

12. Perdan-Pirkmajer K, Praprotonik S, Tomsic M. A case of refractory adult-onset Still's disease successfully controlled with tocilizumab and a review of the literature. Clin Rheumatol. 2010;29:1465-1467.

13. Quartuccio L, Maset M, De Vita S. Efficacy of abatacept in a refractory case of adult-onset Still's disease. Clin Exp Rheum. 2010;28:265-267.

14. Kawashima M, Yamamura M, Taniai M, et al. Levels of interleukin-18 and its binding inhibitors in the blood circulation of patients with adult-onset Still's disease. Arthritis Rheum. 2001;44:550-560.

15. Chen DY, Lan JL, Lin FJ, et al. Predominance of TH2 cytokine in peripheral blood and pathological tissues of patients with active untreated adult onset Still's disease. Ann Rheum Dis. 2004;63:1300-1306.

16. Platt AM, Gibson VB, Patakas A, et al. Abatacept limits breach of self-tolerance in a murine model of arthritis via effects on the generation of T follicular helper cells. J Immunol. 2010;185:1558-1567.

17. Ko H, Cho M, Lee S, et al. CTLA4-Ig modifies dendritic cells from mice with collagen-induced arthritis to increase the CD4+CD25+Foxp3+ regulatory T cell population. J Autoimmun. 2010;34:111-120.

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XVII Congress of Pan America League Against Rheumatism

April 12-18, 2012

Punta Cana, Dominican Republic

Hard Rock Café and Casino

Contact: PANLAR Dominican Republic 2012

Plaza Hache, 2° nivel, Ave. John F. Kennedy,

Santo Domingo, Dominican Republic.

Phone: (809) 563-4631

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Still disease; abatacept; CTLA4 Ig; arthritis

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