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Abatacept for Refractory Juvenile Idiopathic Arthritis-Associated Uveitis — A Case Report To the Editor: Juvenile idiopathic arthritis (JIA) is a well recognized cause of uveitis in childhood. The overall prevalence of JIA-associated uveitis has been reported to be as high as 34%1. Uveitis is characterized by anterior chamber cellular infiltration and aqueous flare. Severe vision-compromising complications such as cataracts, iritis, band keratopathy, posterior synechiae, hypotony, and glaucoma occur in more than 30% of affected individuals and may result in blindness1. Topical corticosteroids are the mainstay of treatment for uveitis; however, prolonged topical use may result in cataracts or glaucoma, while protracted systemic use has significant side effects. Treatment options also include disease modifying antirheumatic drugs (DMARD) such as cyclosporine and mycophenolate, and anti-tumor necrosis factor (TNF) agents such as adalimumab and infliximab. TNF-α is an important cytokine in the inflammatory process occurring in children with JIA. Animal model studies have shown that TNF-α mediated inflammation occurs in autoimmune uveitis2,3. While adalimumab has been effective for the majority of patients, no treatment has been 100% successful4,5. Abatacept is a soluble fusion protein consisting of the extracellular domain of human cytotoxic T lymphocyte antigen 4 (CTLA4) linked to the modified FC domain of human IgG1. It avidly binds to CD80/CD86 on antigen-presenting cells, blocks the CD28 costimulatory signal, and results in T cell inactivation. It has proven effective in patients with refractory rheumatoid arthritis and efficacious and safe in adults6. There are no published reports of its use to treat children for uveitis. A 16-year-old Hispanic girl with psoriatic arthritis and IgA deficiency was diagnosed with uveitis at 5 years of age. Her right eye had normal visual acuity (VA) of 20/20, while her left eye VA was 20/100 with synechiae, band keratopathy, and cataract. She was initially treated with topical steroids and beta-blocker ophthalmic drops without improvement. At 6 years of age, she started taking methotrexate (10 mg/m2) and prednisone 10 mg. Cyclosporine was added 1 year later because of persistent uveitis with scarring. She required a penetrating keratoplasty for band keratopathy. She was maintained with cyclosporine, methotrexate, both systemic and topical steroids, and a mydriatic for 2 years. Mycophenolate was then added because of progression of the ocular inflammation. Methotrexate was discontinued. When she was 8 years old, she was taking cyclosporine 5 mg/kg/day, mycophenolate 500 mg twice daily, prednisone 5 mg, and topical steroids. Infliximab infusions were initiated with stabilization of her eye inflammation. She underwent a trans pars plana vitrectomy for severe vitritis and removal of an inflamed vitreous to reduce inflammation. Infliximab therapy was discontinued after 1 year because of infusion-related dyspnea and tachycardia. She was maintained with prednisone 15 mg, cyclosporine 5 mg/kg/day, and mycophenolate 500 mg twice daily. Four months later, she developed back and shoulder pain and a scalp and nail rash. Skin biopsy revealed findings were consistent with psoriasis, which improved on topical medication. Magnetic resonance imaging of the spine did not reveal disc protrusion, canal stenosis, or nerve root compression. Her uveitis remained very active. At 10 years of age, cyclosporine was increased to 7 mg/kg/day, and she was maintained with prednisone 15 mg, mycophenolate 500 mg twice daily, and topical steroid drops. Daclizumab 2 mg/kg intravenously (IV) was given monthly for 6 months without response. She received etanercept (0.4 mg/kg/dose twice/wk) for 3 months when she was 11 years old without improvement in her uveitis. Mycophenolate was discontinued and monthly cyclophosphamide (750 mg/m2) was given for 5 months without effect. She then received 2 infusions of rituximab (600 mg/m2) followed 24 h later by cyclophosphamide (750 mg/m2) over 2 weeks. Although her uveitis initially improved, she had recurrent inflammation 6 months after her first course of rituximab and cyclophosphamide. At that time, she was taking prednisone 2.5 mg, cyclosporine 4 mg/kg, sulfasalazine 500 mg twice daily, diclofenac 50 mg twice daily, and topical steroids. Two additional infusions of cyclophosphamide and rituximab were given 2 weeks apart without sustained improvement. Because of her continuing active uveitis and risk of permanent bilateral visual loss, abatacept infusions were started at 10 mg/kg IV (500 mg). Infusions were given at 0, 2, and 4 weeks, and every 4 weeks thereafter. There was a rapid decrease in her ocular inflammation and improvement in her eye disease, resulting in reduction of her medication doses to prednisone 5 mg and cyclosporine 2.5 mg/kg, and discontinuation of sulfasalazine and diclofenac. There have been no increased infections or adverse reactions. After 18 months of therapy her uveitis remains well controlled and she has experienced no complications of the abatacept. There is decreased inflammation of her left eye, and the retina can be visualized through her transplanted cornea. Her visual acuity has been maintained at 20/25 bilaterally. CTLA4-Ig administration inhibits development of organ-specific autoimmune disease in a variety of model systems (e.g., collagen-induced arthritis, autoimmune oophoritis, and experimental antiglomerular basement membrane autoimmune glomerulonephritis). Experiments have also shown that blockade of the interaction between the B7 family of cell-surface molecules (CD80/86) and CD28 by CTLA4-Fc reduced the incidence and severity of autoimmune anterior uveitis in experimental models7,8. Although the role of peripheral and intraocular T lymphocytes in uveitis is uncertain9,10, this single observation suggests abatacept may represent a useful new alternative and therapeutic approach for treating patients with refractory autoimmune uveitis. SHEILA ANGELES-HAN, MD, Hospital for Special Surgery, Pediatric Rheumatology; THOMAS FLYNN, MD, Columbia University, Edward S. Harkness Eye Institute; THOMAS LEHMAN, MD, Hospital for Special Surgery, Pediatric Rheumatology, 535 East 70th St., New York, NY 10021, USA. Address reprint requests to Dr. Lehman; E-mail: goldscout@aol.com
2. Nakamura S, Yamakawa T, Sugita M, et al. The role of tumor necrosis factor-alpha in the induction of experimental autoimmune uveoretinitis in mice. Invest Ophthalmol Vis Sci 1994;35:3884-9. [MEDLINE] 3. Sartani G, Silver PB, Rizzo LV, et al. Anti-tumor necrosis factor alpha therapy suppresses the induction of experimental autoimmune uveoretinitis in mice by inhibiting antigen priming. Invest Ophthalmol Vis Sci 1996;37:2211-8. [MEDLINE] 4. Vazquez-Cobian LB, Flynn T, Lehman TJA. Adalimumab therapy for childhood uveitis. J Pediatr 2006;149:572-5. [MEDLINE] 5. Foeldvari I, Nielsen S, Kummerle-Deschner J, et al. Tumor necrosis factor-alpha blocker in treatment of juvenile idiopathic arthritis-associated uveitis refractory to second-line agents: results of a multinational survery. J Rheumatol 2007;34;1146-50.[MEDLINE] 6. Genovese MC, Becker JC, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med 2005;353:1114-23. [MEDLINE] 7. Shao H, Woon MD, Nakamura S, et al. Requirement of B7-mediated costimulation in the induction of experimental autoimmune anterior uveitis. Invest Ophthalmol Vis Sci 2001;42:2016-21. [MEDLINE] 8. Silver PB, Hathcock KS, Chan CC, Wiggert B, Caspi BR. Blockade of costimulation through B7/CD28 inhibits experimental autoimmune uveoretinitis, but does not induce long-term tolerance. J Immunol 2000;165:5041-7. [MEDLINE] 9. Deschenes J, Char DH, Kaleta S. Activated T lymphocytes in uveitis. Br J Ophthalmol 1988;72:83-7. [MEDLINE] 10. Wang XC, Norose K, Yano A, Ohta K, Segawa K. Two-color flow cytometric analysis of activated T lymphocytes in aqueous humor of patients with endogenous vs. exogenous uveitis. Curr Eye Res 1995;14:425-33. [MEDLINE]
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