Management of Juvenile Idiopathic Arthritis–Associated Uveitis
PracticeUpdate: Dr. Ackert, will you please give us some background information on juvenile idiopathic arthritis–associated uveitis?
Dr. Ackert: Juvenile idiopathic arthritis (JIA) was previously known as juvenile rheumatoid arthritis. It refers to a group of arthritides of unknown etiology that occur in the pediatric population. Onset is prior to age 16 years.1 Typically, patients with JIA begin to experience symptoms of pain and swelling in a few of the larger joints. Laboratory testing is often performed in the course of rheumatologic evaluation, and includes testing for antinuclear antibody (ANA) and rheumatoid factor (RF) markers.2 Patients with positive ANA and negative RF findings are those most predisposed to development of uveitis .1
JIA-associated uveitis is a co-existent condition and is the most common cause of pediatric uveitis in the United States.3 It is a chronic, bilateral, non-granulomatous anterior uveitis seen in an otherwise white and quiet eye. In the majority of cases, the uveitis is diagnosed within 4 years of the arthritis diagnosis, although ocular findings may precede symptoms of arthritis. Because patients may not experience visual symptoms, follow-up with frequent screening exams is recommended. The screening exams typically show the aforementioned anterior uveitis, but additional ocular complications, such as cataracts, band keratopathy, and glaucoma often occur.3 Children who are diagnosed with JIA before the age of 7 years are recommended for follow-up with an ophthalmologist or uveitis specialist every 3 to 4 months for ocular examination; those presenting after the age of 7, or those who are RF positive and ANA negative, are recommended for follow-up every 6 months.4
PracticeUpdate: What is your approach to treatment?
Dr. Ackert: Initially, we try to control the inflammation with topical drops given at a relatively high dose and then taper the medication. A dose of one drop three times per day or less is acceptable in terms of the side effects of corticosteroid-induced glaucoma or cataracts.5
If the patient requires more than four drops every day to adequately control anterior chamber inflammation—meaning that inflammation is defined as grade 0 or no activity—oral medication is often prescribed. Oral corticosteroids are of limited benefit in the pediatric population due to associated side effects that include growth retardation. If corticosteroids are used, the dose should be tapered to less than 0.15 mg/kg body weight within 4 weeks and drug use limited to 3 months.6 Therefore, many specialists recommend systemic immunosuppression as the next step for control of the uveitis.6 The initial choice is usually an anti-metabolite, typically methotrexate, which we start at a dose of 15 mg/week and escalate as clinically indicated up to 25 mg/week. We administer methotrexate for approximately 6 to 8 weeks to gain full efficacy. After that time, if there is still inflammation, we often use an additional medication, often an anti–tumor necrosis factor alpha (TNF-alpha) agent, to gain control.6 These decisions are made in collaboration with the rheumatologist in order to try to control both the eye disease and arthritic systemic disease with as few medications as possible.
PracticeUpdate: What are the most promising new therapies and where do they fit into the treatment paradigm?
Dr. Ackert: Immunosuppressive agents are effective steroid-sparing agents for control of uveitis and have a low rate of adverse effects if used and monitored properly.7 In general, they have significantly lowered the risk of visual loss secondary to JIA-associated uveitis.8 Disease-modifying anti-rheumatic drugs (DMARDs), in particular TNF-alpha inhibitors, have been shown to be safe and effective in the treatment of more aggressive forms or arthritis and uveitis refractive to treatment with topical corticosteroids and anti-metabolites.
Ideally, we’re looking for medications that are safe for patients in the pediatric population and that gain control of both the ocular and systemic disease with as few adverse effects as possible. The New England Journal of Medicine recently published a randomized trial examining tocilizumab, a new biologic agent aimed against the anti-interleukin-6 receptor.9 The study reported efficacy in terms of controlling JIA refractory to other treatment modalities. In addition, anti-interleukin 6 receptor antibodies have been shown to be effective in controlling experimental models of uveitis,10 and there is a small case series that has shown these agents to be effective in gaining control of JIA-associated uveitis refractory to other DMARDs.11
PracticeUpdate: What else should ophthalmologists be aware of regarding this disease?
Dr. Ackert: Ophthalmologists should understand the need for referral to an uveitis specialist given the risk for visual impairment and the frequent need for immunosuppression to adequately control the eye disease. It is also important to be mindful of related complications—including band keratopathy, cataracts, and glaucoma—and make a referral to the appropriate sub-specialist as necessary.
References
1. Petty RE, Southwood TR, Manners P, et al. International league of associations for rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31(2):390–392.
2. Ravelli A, Felici E, Magni-Manzoni S, et al. Patients with antinuclear antibody-positive juvenile idiopathic arthritis constitute a homogeneous subgroup irrespective of the course of joint disease. Arthritis Rheum. 2005;52(3):826–832.
3. Foster CS. Diagnosis and treatment of juvenile idiopathic arthritis-associated uveitis. Curr Opin Ophthalmol. 2003;14(6):395–398.
4. American Academy of Pediatrics Section on Rheumatology and Section on Ophthalmology. Guidelines for ophthalmologic examinations in children with Juvenile Rheumatoid Arthritis. Pediatrics. 1993;92(2):295-296.
5. Thorne JE, Woreta FA, Dunn JP, et al. Risk of cataract development among children with juvenile idiopathic arthritis-related uveitis treated with topical corticosteroids. Opthalmology. 2010;117(7):1436-1441.
6. Heiligenhaus A, Michels H, Schumacher C,et al; German Ophthalmological Society; Society for Childhood and Adolescent Rheumatology; German Society for Rheumatology. Evidence-based, interdisciplinary guidelines for anti-inflammatory treatment of uveitis associated with juvenile idiopathic arthritis. Rheumatol Int. 2012;32(5):1121-1133.
7. Multicenter Uveitis Steroid Treatment (MUST) Trial Research Group, Kempen JH, Altaweel MM, Holbrook JT,et al. Randomized comparison of systemic anti-inflammatory therapy versus fluocinolone acetonide implant for intermediate, posterior, and panuveitis: the multicenter uveitis steroid treatment trial. Ophthalmology. 2011;118(10):1916-1926.
8. Gregory AC, Kempen JH, Daniel E, et al. Risk factors for loss of visual acuity among patients with uveitis associated with juvenile idiopathic arthritis: The Systemic Immunosuppressive Therapy for Eye Diseases Study. Ophthalmology. 2013;120(1):186-192.
9. De Benedetti F, Brunner HI, Ruperto N, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367(25):2385-2395.
10. Yoshimura T, Sonoda K-H, Ohguro N, Ohsugi Y, Ishibashi T, Cua DJ et al. Involvement of Th17 cells and the effect of anti-IL6 therapy in autoimmune uveitis. Rheumatology. 2009. 48:347-354.
11. Tappeiner C, Heinz C, Ganser G, Heiligenhaus A. Is Toclizumab an effective treatment of refractory uveitis associated with juvenile idiopathic arthritis? J Rheumatol. 2012 Jun;39(6):1294-1295.
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