Steroid-sparing Effects of Etanercept in a Patient with Steroid-dependent Adult-onset Still s Disease

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1 CASE REPORT Steroid-sparing Effects of Etanercept in a Patient with Steroid-dependent Adult-onset Still s Disease Yasuhiro Kiyonaga, Keisuke Maeshima, Chiharu Imada, Miwa Haranaka, Koji Ishii and Hirotaka Shibata Abstract We herein report the case of an 84-year-old man with steroid-dependent adult-onset Still s disease (AOSD) whose daily steroid dose was successfully tapered after etanercept treatment. The corticosteroids worked well initially, and the patient went into remission promptly; however, he suffered a relapse due to steroid tapering. Because treatment with cyclosporine and methotrexate was ineffective, reducing the steroid dose was difficult, and the corticosteroids induced myopathy and diabetes. However, steroid tapering was accomplished in combination with etanercept therapy, and the patient s steroid-induced side effects disappeared. Etanercept should therefore be considered as a steroid-sparing treatment option in patients with steroid-responsive, steroid-dependent AOSD. Key words: adult-onset Still s disease (AOSD), steroid-sparing effect, etanercept, elderly patient () () Introduction Adult-onset Still s disease (AOSD) is a systemic inflammatory disorder characterized by spiking fevers, evanescent skin rashes, polyarthralgia, negative autoantibodies, leukocytosis, liver dysfunction and hyperferritinemia. The clinical course of patients with AOSD may be classified as characterized by either the chronic articular disease type or systemic disease type (SD type) without chronic articular involvement. Nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids and disease-modifying antirheumatic drugs (DMARDs) are used to control the fever, arthritis and systemic manifestations of this disorder. Steroid monotherapy is used to achieve satisfactory control of the disease in more than three-fourths of patients with SD-type AOSD (1). In steroid-resistant or steroid-dependent patients, the initiation of immunosuppressant therapy is often sufficient to control the disease activity. Tumor necrosis factor (TNF) inhibitors, originally developed to treat rheumatoid arthritis (RA), have been reported to be efficacious in treating AOSD, particularly in patients who exhibit an inadequate response to corticosteroids (2, 3). However, the efficacy of etanercept (ETN), a human recombinant soluble TNF receptor, for the treatment of AOSD remains controversial. We herein report the case of an 84-year-old man with steroid-responsive, steroiddependent SD-type AOSD refractory to methotrexate (MTX) and cyclosporine (CyA), whose daily steroid dose was effectively tapered after treatment with ETN. Case Report In May 2011, an 84-year-old Japanese man suffering from a fever (39.0 ) and arthralgia of the hip and knee joints was admitted to a local hospital. An autoimmune disease was suspected, as antibiotics were ineffective. The patient also reported a history of interstitial pneumonia (IP) five years earlier. Although his symptoms were relieved with the short-term administration of prednisolone (PSL; 20 mg/day), he experienced exacerbation of the disease in July His symptoms quickly disappeared following the resumption of PSL therapy (15 mg/day); however, he relapsed when the steroid dose was tapered in August. A blood examination revealed an elevated white blood cell (WBC) count of /L with 87.1% neutrophils. The levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), C- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Japan Received for publication August 2, 2013; Accepted for publication December 23, 2013 Correspondence to Dr. Keisuke Maeshima, maeshima@oita-u.ac.jp 1209

2 16 5, ,500 4,000 3,500 3, , ,000 1,500 1, Aug.2011 Oct.2011 Dec.2011 Feb.2012 Apr.2012 Jun.2012 Aug Figure. Clinical course of the patient. PSL: prednisolone, mpsl: methylprednisolone, CyA: cyclosporine, MTX: methotrexate, ETN: etanercept reactive protein (CRP) and ferritin were 57 (normal, 10-40) IU/L, 88 (normal, 5-40) IU/L, 7.0 (normal, <0.2) mg/dl and 3,544 (normal ) ng/ml, respectively. No abnormal shadows were evident on chest computed tomography. The PSL dose was increased to 30 mg/day, after which the patient s symptoms and laboratory data improved (Figure). The steroid therapy, however, induced myopathy, and he developed glucose intolerance. The dose of PSL was subsequently decreased, which resulted in further elevation of the CRP and ferritin levels. The patient was referred to our hospital for a further evaluation and treatment in October AOSD was diagnosed in accordance with the criteria published by Yamaguchi et al. (4). The patient fulfilled three of the four major criteria for the disorder (fever, arthralgia and leukocytosis) and two of the four minor criteria (hepatic dysfunction and negativity for rheumatoid factor and antinuclear antibodies). The introduction of CyA (100 mg/day) treatment with an increased dose of steroids improved the CRP and ferritin levels. The trough serum concentration of CyA was 131 ng/dl. Simultaneously, the administration of insulin was initiated to manage the patient s hyperglycemia resulting from steroid-induced diabetes. Because the patient s CRP level increased slightly in association with PSL tapering, MTX therapy was introduced in January 2012, albeit without any significant effects on the CRP level. Meanwhile, the development of steroid-induced myopathy, diabetes and hypogammaglobulinemia made steroid tapering imperative. In March 2012, the patient s fever and arthralgia recurred and the CRP level increased to 15.0 mg/dl. The dose of PSL was 15 mg/day at that time. We decided to introduce ETN after obtaining informed consent from the patient and his family. The dose of CyA was discontinued, and treatment with ETN (50 mg/week) was initiated following the administration of methylprednisolone (mpsl; 125 mg/ day), after which the patient s symptoms promptly resolved and the CRP and ferritin levels markedly decreased to within the normal ranges. Although the patient relapsed following the discontinuation of ETN in July 2012, the readministration of ETN again induced remission. The dose of PSL was gradually tapered to 9 mg/day without relapse. The patient s steroid-induced myopathy and hypogammaglobulinemia resolved, and he eventually required less insulin therapy. As of July 2013, he remained in remission with no complications, including infection. Discussion The present patient was an elderly Japanese man with steroid-responsive, steroid-dependent AOSD whose daily steroid dose was successfully tapered after ETN treatment. Despite the high effectiveness of corticosteroids in controlling the clinical manifestations of AOSD, a subset of patients require the administration of intermediate- or highdose prednisone for maintenance therapy (steroid-dependent patients) despite the concomitant use of DMARDs, such as MTX, CyA or azathioprine. MTX has been broadly accepted as a first-choice therapy for steroid-dependent or steroid-resistant AOSD. CyA is also considered to be one of the most effective drugs for treating AOSD (1). However, when these drugs are ineffective or contraindicated, patients are forced to continue larger doses of corticosteroids in order to maintain disease remission, most of whom (particularly elderly patients) suffer from steroid-induced side effects. Although an insufficient starting dose of steroids (less than 40 mg/day of prednisone) has been reported to be a risk factor for relapse (5), physicians often encounter AOSD 1210

3 Table. ETN Treatment for Refractory AOSD Reference Year Age Sex DMARDs before ETN Biologics before ETN Dose(Starting dose) Outcome Female MTX, CQ, gold, CY, D-penicillamine None 25mg 2 doses ineffective Male(2) Female(10) at least 1 DMARDs None 25mg 2-3/week effective(7) ineffective(5) Female HCQ, gold None 25mg 2/week effective Female None None 25mg 2/week effective Male MTX, CyA, SSZ, HCQ None 25mg 2/week effective Male(3) Female(7) MTX(3), AZA(1), IVIG(1) IFX(1) 25mg 2/week effective(8) ineffective(2) Female MTX, CyA, SSZ, IVIG IFX 25mg 2/week ineffective Female MTX None 25mg 2/week ineffective Male MTX None 25mg 2/week effective Male MTX, CyA, AZA, gold IFX 25mg 2/week effective Male MTX, IVIG None 25mg 2/week effective Female MTX, CyA, AZA, HCQ IFX 25mg 2/week ineffective Male MTX, CyA IFX 25mg 2/week ineffective Female MTX None 25mg 2/week ineffective n.d. None None 25mg 3/week ineffective Female None None 25mg 2/week effective Female MTX, gold, LEF, talidomide IFX, ANK 50mg 1/week ineffective Female MTX, SSZ, LEF, BUC IFX 25mg 2/week ineffective Male None None 25mg 3 doses ineffective Female CyA None 25mg 2/week effective Male MTX ANK 50mg 1/week ineffective Male MTX ADA 50mg 1/week ineffective Female MTX ADA 50mg 1/week ineffective Female MTX, HCQ None 25mg 2/week ineffective Male(1) Female(3) DMARDs(n.d.) IFX(2) n.d. effective(1) ineffective(3) Female MTX, CyA, TAC IFX 50mg 1/week effective Male MTX, CyA, TAC TCZ 50mg 1/week effective Female MTX,AZA AKN 25mg 2/week ineffective ADA : adalimumab, AKN : anakinra, AZA: azathioprine, BUC : bucillamine, CQ : chloroquine, CY : cyclophosphamide, CyA : cyclosporine A, DMARDs : disease- modifying antirheumatic drugs, IFX : infliximab, IVIG : intravenous immunoglobulin, LEF : leflunomide, MMF : mycophenolate mofetil, n.d. : not described, TAC : tacrolimus TCZ : tocilizumab, SSZ : sulfasalazine patients in whom the dose of steroids should be minimized for various reasons in actual clinical practice, as observed in our patient. At present, a growing body of literature has documented the efficacy of biologic agents in treating AOSD refractory to conventional agents, such as corticosteroids (1); however, reports regarding the steroid-sparing ability of ETN in steroid-responsive, steroid-dependent patients with AOSD are rare. Several previous immunological studies have shown that TNF-alpha plays a pivotal role in the pathogenesis of AOSD (6), and TNF inhibitors, which are highly effective against RA, can be expected to have potential therapeutic benefits in patients with AOSD. ETN has been proven to be effective in treating patients with moderately to severely active RA who exhibit an inadequate clinical response to DMARDs both as monotherapy and in association with MTX (7, 8). ETN has also shown efficacy in patients with other inflammatory disorders, including AOSD. We searched for published data regarding the use of ETN in the setting of AOSD and found 28 papers describing 51 patients (2, 3, 9-34). Table details the profiles, therapies and outcomes of all patients with AOSD treated with ETN. The mean age was 35.7 years, and most patients were women (70.0%). ETN was used at a dose of 50 mg weekly in most patients. Most patients exhibited an inadequate response to corticosteroids as induction therapy; however, the efficacy of corticosteroids could not be assessed accurately in many cases due to the lack of detailed information. Whether the patient had the chronic articular disease type or SD type was also not assessed in many cases. Treatment with ETN resulted in significant clinical and serological improvements in 26 of the 51 patients, although effectiveness was variably defined. Among the elderly patients (more than 60 years of age ), two of the four patients responded to ETN (2, 26, 28, 33). We did not observe any correlations between the response to ETN and age or gender. Only two of the 12 patients who switched from other TNF inhibitors, such as infliximab or adalimumab, responded to ETN (3, 13, 16, 18, 19, 23, 24, 28, 29, 31, 32), suggesting that physicians should avoid the use of ETN in patients with an inadequate response to other TNF inhibitors. Three patients requiring discontinuation of ETN due to infection have been reported (3, 12, 30). Many reports have demonstrated the marked efficacy of anakinra, a recombinant human interleukin-1 receptor antagonist, in AOSD patients, with the efficacy being maintained over the long term (35). The drug, however, is not currently available in Japan. Although tocilizumab (TCZ), an anti-interleukin-6-receptor monoclonal antibody, has been used with success in Japan (31), we chose to administer ETN in the present case for the following reasons. One, we speculated that ETN would be relatively safe in our patient. 1211

4 Aaltonen et al. reported that ETN may be the best choice considering the safety profiles of TNF inhibitors in RA patients (36). Because the half-life of ETN is the shortest of several biological agents approved in Japan, ETN therapy is expected to be relatively more manageable from the viewpoint of adverse events. In addition, the risk of adverse events induced by ETN treatment is comparable between patients 65 years of age and younger patients (37), indicating that it may not necessarily be appropriate to consider avoiding the use of ETN because the patient is older. On the other hand, an age 65 years has been suggested to be a risk factor for the development of serious infections in RA patients treated with TCZ (38). Furthermore, all ETNspecific anti-drug antibodies (ADAs) are thought to be nonneutralizing, in contrast to other TNF inhibitors. For example, infliximab (anti-tnf-alpha chimeric monoclonal antibody)-specific, adalimumab (anti-tnf-alpha human monoclonal antibody)-specific and/or certolizumab pegol (a pegylated Fab fragment of an anti-tnf-alpha humanized monoclonal antibody)-specific ADAs are able to neutralize the agent, resulting in clinical nonresponsiveness to treatment (39). Therefore, although the reintroduction of most TNF inhibitors after a rest period carries a higher risk of further formation of ADAs, the reintroduction of ETN is associated with a lower risk. In fact, we were able to safely continue the administration of ETN for more than one year in this case, including the reintroduction of therapy after a rest period, with a concomitant reduction in the burden on the patient due to corticosteroid dose tapering. Second, we wished to prevent reductions in the CRP level resulting from TCZ treatment, as the CRP level was the most sensitive marker of the disease activity in our patient. As CRP production is primarily induced by the cytokine interleukin (IL)-6, TCZ strongly inhibits the production of CRP, independent of the disease activity. This case report suggests that treatment with ETN may allow for the tapering of the dose of corticosteroids in selected patients with steroid-dependent AOSD. Since the pathogenesis of AOSD is very heterogeneous with a variable clinical course, the clinical benefits of ETN in patients with AOSD are inconsistent. However, we believe that it is important to bear in mind that ETN is one treatment option for steroid-dependent AOSD and its use should be considered in elderly patients in order to reduce the dose of steroids as much as possible, particularly when immunosuppressants, such as MTX and/or CyA, are ineffective. We therefore would like to emphasize the need to pay close attention to minimizing the risk of possible subsequent infection, particularly when high-dose corticosteroids are administered together. Further investigation is required to confirm the efficacy and safety of ETN in controlled clinical trials. The authors state that they have no Conflict of Interest (COI). References 1. Franchini S, Dagna L, Salvo F, Aiello P, Baldissera E, Sabbadini MG. Efficacy of traditional and biologic agents in different clinical phenotypes of adult-onset Still s disease. Arthritis Rheum 62: , Husni ME, Maier AL, Mease PJ, et al. Etanercept in the treatment of adult patients with Still s disease. Arthritis Rheum 46: , Fautrel B, Sibilia J, Mariette X, Combe B, Club Rhumatismes et I. Tumour necrosis factor alpha blocking agents in refractory adult Still s disease: an observational study of 20 cases. Ann Rheum Dis 64: , Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult Still s disease. J Rheumatol 19: , Kong XD, Xu D, Zhang W, Zhao Y, Zeng X, Zhang F. Clinical features and prognosis in adult-onset Still s disease: a study of 104 cases. Clin Rheumatol 29: , Fujii T, Nojima T, Yasuoka H, et al. Cytokine and immunogenetic profiles in Japanese patients with adult Still s disease. Association with chronic articular disease. Rheumatology (Oxford) 40: , Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. AnnInternMed130: , Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 340: , Stern A, Riley R, Buckley L. Worsening of macrophage activation syndrome in a patient with adult onset Still s disease after initiation of etanercept therapy. J Clin Rheumatol 7: , Asherson RA, Pascoe L. Adult onset Still s disease: response to Enbrel. Ann Rheum Dis 61: , Serratrice J, Granel B, Disdier P, Weiller PJ, Dussol B. Resolution with etanercept of nephrotic syndrome due to renal AA amyloidosis in adult Still s disease. Am J Med 115: , La Montagna G, Valentini G. Listeria monocytogenes meningitis in a patient receiving etanercept for Still s disease. Clin Exp Rheumatol 23: 121, Vasques Godinho FM, Parreira Santos MJ, Canas da Silva J. Refractory adult onset Still s disease successfully treated with anakinra. Ann Rheum Dis 64: , 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 52: , Kumari R, Uppal SS. Prolonged remission in adult-onset Still s disease with etanercept. Clin Rheumatol 25: , Thonhofer R, Soleiman A, Kriessmayr M, et al. Decrease of proteinuria in a patient with adult-onset Still s disease and glomerulonephritis after anti-tnfalpha therapy. Scand J Rheumatol 35: , Kuek A, Weerakoon A, Ahmed K, Ostör AJ. Adult-onset Still s disease and myocarditis: successful treatment with intravenous immunoglobulin and maintenance of remission with etanercept. Rheumatology (Oxford) 46: , Kötter I, Wacker A, Koch S, et al. Anakinra in patients with treatment-resistant adult-onset Still s disease: four case reports with serial cytokine measurements and a review of the literature. Semin Arthritis Rheum 37: , Murakami K, Fujii T, Yukawa N, et al. Successful treatment of a patient with refractory adult Still s disease by tacrolimus. Modern Rheumatol 17: , Ruiz PJ, Masliah E, Doherty TA, Quach A, Firestein GS. Cardiac death in a patient with adult-onset Still s disease treated with the 1212

5 interleukin 1 receptor inhibitor anakinra. Ann Rheum Dis 66: , Gianella S, Schaer DJ, Schwarz U, et al. Retinal microangiopathy and rapidly fatal cerebral edema in a patient with adult-onset Still s disease and concurrent macrophage activation syndrome. Am J Hematol 83: , Yang DH, Chang DM, Lai JH, et al. Etanercept as a rescue agent in patient with adult onset Still s disease complicated with congestive heart failure. Rheumatol Int 29: 95-98, De Bandt M, Saint-Marcoux B. Tocilizumab for multirefractory adult-onset Still s disease. Ann Rheum Dis 68: , Yoshimura M, Makiyama J, Koga T, et al. Successful treatment with tocilizumab in a patient with refractory adult-onset Still s disease (AOSD). Clin Exp Rheumatol 28: , Kaneko K, Kaburaki M, Muraoka S, et al. Exacerbation of adultonset Still s disease, possibly related to elevation of serum tumor necrosis factor-alpha after etanercept administration. Int J Rheum Dis 13: e67-e69, Sumida K, Ubara Y, Hoshino J, et al. Etanercept-refractory adultonset Still s disease with thrombotic thrombocytopenic purpura successfully treated with tocilizumab. Clin Rheumatol 29: , Perdan-Pirkmajer K, Praprotnik S, Tomsic M. A case of refractory adult-onset Still s disease successfully controlled with tocilizumab and a review of the literature. Clin Rheumatol 29: , Rech J, Ronneberger M, Englbrecht M, et al. Successful treatment of adult-onset Still s disease refractory to TNF and IL-1 blockade by IL-6 receptor blockade. Ann Rheum Dis 70: , Thonhofer R, Hiller M, Just H, Trummer M, Siegel C, Dejaco C. Treatment of refractory adult-onset Still s disease with tocilizumab: report of two cases and review of the literature. Rheumatol Int 31: , Ostrowski RA, Tehrani R, Kadanoff R. Refractory adult-onset still disease successfully treated with abatacept. J Clin Rheumatol 17: , Suematsu R, Ohta A, Matsuura E, et al. Therapeutic response of patients with adult Still s disease to biologic agents: multicenter results in Japan. Modern Rheumatol 22: , Maeshima K, Ishii K, Iwakura M, et al. Adult-onset Still s disease with macrophage activation syndrome successfully treated with a combination of methotrexate and etanercept. Modern Rheumatol 22: , Kato T, Noguchi K, Uehara M, et al. Angioedema of the periorbital region that developed during treatment with etanercept in a case of refractory adult-onset Still s disease. Intern Med 51: , Quismorio A, Brahmbhatt B, Houng M, Panush RS. Etanercept allergy and anaphylaxis. J Rheumatol 39: , Giampietro C, Ridene M, Lequerre T, et al. Anakinra in adultonset Still s disease: long-term treatment in patients resistant to conventional therapy. Arthritis Care Res 65: , Aaltonen KJ, Virkki LM, Malmivaara A, Konttinen YT, Nordstrom DC, Blom M. Systematic review and meta-analysis of the efficacy and safety of existing TNF blocking agents in treatment of rheumatoid arthritis. PLoS ONE 7: e30275, Fleischmann R, Baumgartner SW, Weisman MH, Liu T, White B, Peloso P. Long term safety of etanercept in elderly subjects with rheumatic diseases. Ann Rheum Dis 65: , Koike T, Harigai M, Inokuma S, et al. Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: interim analysis of 3881 patients. Ann Rheum Dis 70: , van Schouwenburg PA, Rispens T, Wolbink GJ. Immunogenicity of anti-tnf biologic therapies for rheumatoid arthritis. Nat Rev Rheumatol 9: , The Japanese Society of Internal Medicine