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Biologic Therapy for Posterior Uveitis and Panuveitis by Sirichai Pasadhika, MD; Eric B

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Biologic Therapy for Posterior Uveitis and Panuveitis by Sirichai Pasadhika, MD; Eric B MEDICAL RETINA FEATURE STORY Biologic Therapy for Posterior Uveitis and Panuveitis BY SIRICHAI PASADHIKA, MD; ERIC B. SUHLER, MD, MPH; AND EMMETT T. CUNNINGHAM, JR., MD, PHD, MPH iologic response modifiers (often referred to as WHEN TO USE BIOLOGICS IN UVEITIS biologics) are proteins produced by recombi- Corticosteroids are still the mainstay of treatment nant DNA or monoclonal antibody technology for most patients with uveitis.4 In a minority of cases, designed to block specific mediators of the cell- corticosteroid-sparing immunosuppressive drugs (eg, Bmediated immune response. They are mostly either metrothexate, mycophenolate mofetil, azathioprine, recombinant antibodies or antibody-derived proteins. cyclosporine, tacrolimus, and cyclophosphamide) and Monoclonal antibodies (mAb), when used as medica- biologics (Table 1) may be required to control inflam- tions, are given a generic name ending in “-mab.” An mation in recalcitrant or chronic diseases. Due to their antecedent “u” (-umab) indicates a human antibody (eg, costs and long-term safety profiles, biologics are not adalimumab), whereas “xi” (-ximab) indicates a mixed routinely recommended as first-line therapy in most human-murine (chimeric) antibody (eg, infliximab). patients. We generally follow a stepladder approach of Fusion proteins containing receptor domains are given treatment, beginning with corticosteroid therapy (top- a generic name ending in “-cept” (eg, etanercept). In ical, local and/or systemic), and followed by immuno- general, fully humanized antibodies are less likely than suppressive agents and then biologics.5 Biologics are chimeric antibodies to cause hypersensitivity reactions or generally reserved for cases where more conventional to elicit neutralizing antibody formation. immunosuppression has either failed or been poorly Systemically administered biologics are approved tolerated due to adverse effects. Situational exceptions by the US Food and Drug Administration for several for the early use of biologics may be made for Behçet immune-mediated diseases, including rheumatoid arthri- disease (BD)-related uveitis, in which a number of clini- tis, inflammatory bowel disease, and juvenile idiopathic cal studies have shown that infliximab may be rapidly arthritis (JIA). Biologics have also been used off-label for effective for controlling vision-threatening disease. ocular inflammatory diseases, including uveitis. The most commonly used systemic biologics for ocular condi- WHEN NOT TO USE BIOLOGICS IN UVEITIS tions to date are tumor necrosis factor-alpha (TNF-a) Systemic biologics, including TNF-a inhibitors and inhibitors, including infliximab (Remicade; Centocor daclizumab, are potent immunosuppressives, and, like Ortho Biotech, Inc.) and adalimumab (Humira; Abbott other immunosuppressives, they are not recommend- Laboratories), and the interleukin-2 (IL-2) antagonist ed for the treatment of infectious uveitis. Class effects daclizumab (Zenapax; Roche). In a randomized con- of TNF-a blockers prominently include risk of serious trolled trial, the anti-TNF fusion protein etanercept infection, most significantly including reactivation of (Enbrel; Amgen, Inc., and Pfizer, Inc.) ) was no more tuberculosis and fungal infections, and increased risk effective than placebo at controlling anterior uveitis of malignancy. Both of these side effects appeared to in patients with JIA.1 Infliximab and adalimumab are be dose-related. Other uncommon but potentially generally believed to be more effective than etanercept severe side effects include initiation or worsening for treating ocular inflammatory disorders.2,3 However, of demyelinating disease, congestive heart failure, no head-to-head studies comparing the various TNF-a thromboembolic events, and lupus-like reactions. inhibitors have been performed. Less serious side effects include hypersensitivity reac- 74 RETINA TODAY APRIL 2012 MEDICAL RETINA FEATURE STORY tions, headache, flu-like symptoms, and gastrointestinal had a greater median ocular attack rate (1.27 attacks/ adverse effects.6,7 year) than those receiving placebo (0.27 attacks/year). Furthermore, the placebo group experienced a greater BIOLOGICS FOR UVEITIS ASSOCIATED WITH reduction in immunosuppressive agents.19 POSTERIOR SEGMENT DISEASE This review focuses on biologic therapy for uveitis SARCOIDOSIS associated with posterior segment pathology. The most Sarcoidosis is a multisystem granulomatous disorder commonly reported clinical studies of the use of sys- with systemic and ocular manifestations. Uveitis is the temic biologics to date are for BD, and these include most common ocular involvement, ranging from mild randomized clinical trials, retrospective case series, and iridocyclitis to severe panuveitis. Corticosteroids are reports. Results regarding the use of biologics for other the mainstay of therapy. Immunomodulators are use- forms of uveitis have come primarily from retrospective ful in refractory cases. The TNF-a inhibitors may also case reports and series. be effective in treating sarcoidosis-related systemic diseases and uveitis.20,21 However, in patients receiv- BEHÇET DISEASE ing TNF-a inhibitors for treatment of other immune- BD may cause chronic, relapsing occlusive vasculitis mediated diseases, multiple case reports and series and uveitis as well as dermatologic, rheumatologic, gas- suggest that TNF-a inhibitors (infliximab,22-26 etaner- trointestinal, and neurologic manifestations. Infliximab cept,22,25 and adalimumab25-27) may cause sarcoidosis- has been reported to be a rapid and very effective like disease with pulmonary,23,24,28 renal,23 ocular,22 and therapy for the treatment of BD-related panuveitis,8-11 cutaneous26 involvement. Etiology remains unclear, posterior uveitis, and retinal vasculitis.12,13 Associated but drug-induced sarcoidosis is likely a class effect of neovascularization of the optic disc may regress after TNF-a inhibitors.29 Therefore, we recommend caution infliximab therapy.14 when considering use of a TNF-a inhibitor in patients Sfikakis and colleagues reported that in a prospective with sarcoidosis-related ocular diseases. study of 25 patients with BD-related uveitis, the majority of patients (> 90%) experienced resolution of vitritis, reti- SYMPATHETIC OPHTHALMIA nitis, retinal vasculitis, and cystoid macular edema (CME) Sympathetic ophthalmia (SO) is a chronic, bilateral, within 28 days after initiation of infliximab therapy and granulomatous panuveitis with frequent exacerbations. often as early as within 1 week of initial treatment.12 Initial treatment with systemic corticosteroids as well as However, in some patients with initial response, inflix- prompt and aggressive immunomodulation is strongly imab may become less effective in controlling uveitis recommended to control inflammation and prevent attacks after 1 year of therapy.15 ocular morbidity. Due to chronicity of the disease, long- A recent retrospective study of 11 patients with term immunosuppression is almost always indicated, BD-related uveitis showed that adalimumab led to often with multiple immunosuppressive agents, includ- complete resolution of inflammation in 10 (91%) of ing alkylating agents in severe cases.5 11 patients and an improvement in visual acuity of Despite aggressive corticosteroid-sparing therapy, more than 3 lines in 17 (81%) of 21 eyes with an aver- adequate control of inflammation may not be age follow-up of 10.8 months.16 Adalimumab may also achieved. Gupta et al recently reported a case of a be effective in patients who are intolerant of or refrac- 7-year-old patient with SO following severe ocular tory to previous infliximab therapy.16,17 Patients with trauma complicated by retained intraocular foreign quiescent uveitis after infliximab infusions may suc- body and endophthalmitis in one eye.30 SO devel- cessfully switch to adalimumab injections to maintain oped at 6 weeks after the injury. All attempts to taper disease remission and prevent relapses.18 prednisone to 7.5 mg/day or less failed despite con- Although the TNF-a inhibitors infliximab and adali- current use of cyclosporine, mycophenolate mofetil, mumab may provide excellent therapeutic outcomes and intravenous daclizumab (2 mg/kg every 2 weeks). in BD-related uveitis, an interleukin-2 (IL-2) antago- Daclizumab was replaced by infliximab (10 mg/kg nist, daclizumab, failed to improve visual outcomes in every 4 weeks), and the uveitis was well-controlled BD-related uveitis compared with standard immuno- with subsequent discontinuation of cyclosporine, suppressive therapy.19 In a prospective, randomized prednisone, and mycophenolate at 13, 17, and 24 study, 9 patients received daclizumab and 8 patients months after initiation of infliximab, respectively. No received intravenous placebo, with a median follow-up published data on the use of other biologics for SO are of 15 months. The patients treated with daclizumab currently available. APRIL 2012 RETINA TODAY 75 MEDICAL RETINA FEATURE STORY TABLE 1. CHARACTERISTICS, DOSAGE, ROUTES OF ADMINISTRATION, AND SIDE EFFECTS FOR SELECTED BIOLOGIC AGENTS. Generic Names Specific Dosages Routes Approved Systemic Indications Selected Side Effects (Trade Names) Targets 1. Tumor necrosis factor (TNF)-a inhibitors Infliximab TNF-a 3 to 5 mg/kg loading at week IV Rheumatoid arthritis, psoriatic Susceptibility to infec- (Remicade) 0, 2, and 6, then maintenance arthritis, ankylosing spondylitis, tions, including reacti- 3 to 10 mg/kg every 4 to 8 Crohn’s disease (adult and pedi- vation of tuberculosis, weeks; maximal
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