SURVEY OF OPHTHALMOLOGY VOLUME 56 NUMBER 6 NOVEMBER–DECEMBER 2011 MAJOR REVIEW Systemic Therapy With Conventional and Novel Immunomodulatory Agents for Ocular Inflammatory Disease Khayyam Durrani, MD, Fouad R. Zakka, MD, Muna Ahmed, MD, Mohiuddin Memon, MD, Sana S. Siddique, MD, and C. Stephen Foster, MD Massachusetts Eye Research and Surgery Institution, Cambridge, Massachusetts, USA; Ocular Immunology and Uveitis Foundation, Cambridge, Massachusetts, USA; and Harvard Medical School, Department of Ophthalmology, Boston, Massachusetts, USA Abstract. Ocular inflammatory disease is the third leading cause of blindness in the United States. In addition to the conventional immunomodulatory agents, which include antimetabolites, alkylating agents, and antibiotics such as cyclosporine, many of which have been used in the treatment of this disease for decades, several new treatment modalities have emerged within the past 10 years. We review in detail the characteristics, safety, and efficacy of the conventional immunomodulators, the more novel agents such as the biologics, and investigational drugs that appear promising in the treatment of ocular inflammatory disease. (Surv Ophthalmol 56:474--510, 2011. Ó 2011 Elsevier Inc. All rights reserved.) Key words. immunomodulatory therapy antimetabolites alkylating agents biologics uveitis scleritis keratitis pemphigoid I. Introduction A. BACKGROUND: THE RATIONALE FOR Approximately 37 million people in the world are IMMUNOMODULATORY THERAPY blind, and at least 161 million people are visually A major advance was made in 1950 with the impaired or have ongoing progressive disease that may discovery of the effectiveness of corticosteroid therapy eventually result in blindness.243 Uveitisasacauseof for uveitis.122 Since then, corticosteroids have been blindness is substantially underestimated, particularly in extensively employed topically, periocularly, intravi- developing countries, where data-keeping may ascribe treally, and systemicaly, in most cases with short term blindness to cataract, glaucoma or macular disease success, in the management of patients with ocular when, in fact, uveitis had produced the cataract or inflammation. An estimated 35% of patients with the glaucoma or the macular disturbance. The in- uveitis suffer significant vision loss.307 Sadly, the cidence of uveitis in industrialized countries is approx- prevalence of significant vision loss secondary to imately 17 cases per 100,000 population-- an estimated uveitis has remained largely unchanged since the 38,000 new cases each year in the United States, publication of Gordon and McLean’s seminal paper122 with a total of 2.3 million individuals afflicted.307,326 It on corticosteroid use more than 50 years ago. is an under-recognized fact that uveitis is the third The challenge and duty of the ophthalmologist, leading cause of blindness in the United States.258 therefore, extend beyond corticosteroid treatment. 474 Ó 2011 by Elsevier Inc. 0039-6257/$ - see front matter All rights reserved. doi:10.1016/j.survophthal.2011.05.003 TREATMENTS FOR OCULAR INFLAMMATORY DISEASE 475 The use of immunomodulatory therapy for ocular TABLE 1 inflammatory disease dates to 1951, only a year after General Categorization of Indications for corticosteroids were uced, when Roda-Perez described Immunosuppressive Chemotherapy the successful treatment of a patient with progressive, steroid-resistant uveitis with nitrogen mustard.250 Over Strong Behc¸et disease with retinal involvement the ensuing half century, a series of publications from Sympathetic ophthalmia Europe and North America have shown that immu- Vogt-Koyanagi-Harada syndrome nomodulatory therapy can be sight-saving in many Rheumatoid necrotizing scleritis or peripheral types of ocular inflammatory disease. Given these data ulcerative keratitis and the well-known ocular and systemic side effects of Wegener granulomatosis Relapsing polychondritis with scleritis long-term corticosteroid therapy, we advocate limiting Juvenile idiopathic arthritis--associated iridocyclitis steroid use with ocular inflammatory disease. By using unresponsive to conventional therapy a stepladder, algorithmic approach to therapeusis to Ocular cicatricial pemphigoid achieve the goal of freedom from inflammation, while Bilateral Mooren ulcer producing no major medication-induced side effects, Relative Intermediate uveitis the ophthalmologist will help to reduce blindness Retinal vasculitis with central vascular leakage secondary to uveitis. Severe chronic iridocyclitis In 2000, a panel of experts consisting of 12 ocular Questionable immunologists, rheumatologists, and pediatricians Intermediate uveitis in children assessed the world’s literature to determine the Sarcoid-associated uveitis inadequately responsive to steroid strength of evidence that immunosuppressive che- Keratoplasty with multiple rejections motherapy is both safe and effective in ocular inflammatory disease.138 Their conclusions extend the consensus achieved by the International Uveitis discussed herein. The patient should have no Study Group 15 years earlier, and we support their inflammation and should be off all steroids, with recommendations. We have expanded the list of the aim of achieving a sustained remission of entities that we believe constitute strong indications inflammation even after immunomodulatory ther- for use of immunosuppressive therapies (Table 1). apy is discontinued. Immunosuppressive agents, except for the condi- tions listed in Table 1, typically represent the final rung in our stepladder approach to the medical treatment of ocular inflammatory disease. Once the II. Conventional Immunomodulatory decision to treat with an immunomodulatory agent Agents in Ocular Inflammatory Disease is made, care must be taken to ensure that the Table 2 provides a representational list of conven- patient is adequately suppressed, but is spared the tional immunomodulators discussed in this section potentially serious consequences of drug toxicity. In that are used for therapy in ocular inflammatory the hands of physicians trained in their use and disease. monitoring, the administration of immunosuppres- sive agents appears to produce fewer serious adverse effects than the chronic use of systemic steroids. A. ANTIMETABOLITES Such therapy should be managed by a physician 1. Methotrexate who is, by virtue of training and experience, an expert in the use of such drugs and in the a. Introduction and Mechanism of Action monitoring of the patient for side effects and their Methotrexate, a folic acid analog, first came treatment. Most ophthalmologists are not trained to into use in 1958 to treat leukemia. Methotrexate do this and collaboration between the ophthalmol- competitively binds and inactivates the enzyme ogist and chemotherapist, usually an oncologist or dihydrofolate reductase (DHFR). Dihydrofolate re- hematologist, is required. ductase plays a key role in converting dietary folic acid Outcomes studies now show unequivocally that to reduced folates (dihydrofolate and tetrahydrofo- immunosuppressive chemotherapy should have late), which are metabolically active. The folates take a much more prominent role in the care of patients part in thymidylate and purine synthesis, as well as in with uveitis than it does at present. We feel the the metabolism of histidine and in the conversion of prevalence of blindness secondary to uveitis will be homocysteine to methionine. Antiangiogenic prop- reduced only if increasing numbers of ophthalmol- erties, inhibition of cytokine production, cellular and ogists limit the total amount of corticosteroids and humoral immunosuppression, and the inhibition of use systemic therapeutics in a stepladder fashion as DHFR and other folate-dependent enzymes may TABLE 2 476 Surv Ophthalmol 56 (6) November--December 2011 Conventional Immunomodulators: Clinical Outcomes for Therapy in Ocular Inflammatory Disease (Representative Studies) Permanent Mean Side Effects Damage No. of Mean Follow-up Requiring Due to Drug Diagnosis Patients Age (years) (months) Success Failure Discontinuation Side Effects Study Notes MTX Chronic 11 42 12b 6 (55%)d n/a n/a n/a Bom37 noninfectious uveitis MTX Sarcoidosis, sarcoidosis- 11 (20 eyes) 38 19a 18 eyes (90%) 2 eyes 2 pts. (18%) n/a Dev79 suspect (10%) MTX Noninfectious ocular 384 47 9 66% 34% 16% n/a Gangaputra114 Success 5 sustained control of inflammation inflammation; 58% on # 10 mg steroid MTX TINU 6 24 20 100% n/a n/a n/a Gion115 Results are of 4 of 6 pts. on MTX; Success 5 control of uveitis MTX Noninfectious uveitis 14 36 8 79% 21% n/a n/a Holz135 Failure 5 no improvement MTX Uveitis, scleritis 39 27 22 31 (79%)e 6 (15%) 10 (26%) n/a Kaplan- Messas144 MTX Uveitis 17 27 range, 61--285 14 (82%) 3 (18%) n/a n/a Lazar163 Particular improvement in daysa sympathetic ophthalmia MTX OCP, drug-induced 17 (34 eyes) 73 30 15 pts. 2 (12%) 4 (24%) n/a McCluskey189 OCP 30 eyes (88% OCP) (100% drug-induced OCP) MTX Chronic noninfectious 160 33 16 122 (76%) 27 (17%) 29 (18%) n/a Samson265 14 on MTX þ CSA, 1 on MTX uveitis þ Plaquenil þ pred, 1 on leflunomide þ MTX MTX Chronic uveitis 22 42 11 16 (73%) 6 (27%) n/a n/a Shah285 MTX Noninfectious orbital 14 (24 eyes) 50 43f 9 (64%) 1 (7%) 2 (14%) n/a Smith296 90% success in those with inflammatory disease adequate trial MTX JIA 7 10 n/a 86% 14% n/a n/a Weiss338 Success 5 decreased inflammation CSA Serpiginous 7 34 49 93% 7% n/a n/a Araujo13 Success 5 improved (21%) þ choroidopathy unchanged (71%) CSA Behc¸et 14 31 n/a 76% 24% n/a n/a Atmaca16 Success 5 improved