Systemic Therapy with Conventional and Novel Immunomodulatory Agents for Ocular Inflammatory Disease

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.

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 Behçet 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 conditions 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 immunosuppressive 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 2011 November--December (6) 56 Ophthalmol Surv 476 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 Behçet 14 31 n/a 76% 24% n/a n/a Atmaca16 Success 5 improved þ same CSA Endogenous uveitis 30 range, 8--70 36 14/24 (58%) 10/24 17% n/a BenEzra28 Percentages based on 24 pts. (42%) who continued treatment CSA Behçet 12 38 12 7/12 (58%) 3/12 n/a n/a Binder31 Improvement in 58%; but (25%) initial improvement seen in 10/12 pts. 60 CSA Behçet 14 27 42 86% eyes 14% eyes n/a n/a Chavis Success 5 improved þ AL ET DURRANI same CSA Chronic 14 (controlled 45 12 7% 64% n/a n/a De Vries72 4 pts. in CSA group idiopathic trial, 14 lost to f/u uveitis on CSA) CSA Behçet 14 n/a 36 93% eyes 7% eyes n/a n/a Diaz-Llopis80 Success 5 improved þ same RAMNSFROUA NLMAOYDISEASE INFLAMMATORY OCULAR FOR TREATMENTS CSA Endogenous n/a n/a n/a 76% eyes 19% eyes n/a n/a Dick82 CSA þ steroid; Success 5 posterior uveitis improved (39%) þ unchanged (37%) CSA Scleritis 5 32 9 100% n/a n/a n/a Hakin127 CSA þ steroid CSA Noninfectious ocular 373 36 11 52% 48% 11% n/a Kacmaz141 Success 5 sustained inflammation control of inflammation; 36% on # 10 mg steroid CSA Noninfectious uveitis 14 9 27 92% eyes 8% n/a n/a Kilmartin152 Success 5 improved þ eyes unchanged CSA BSCR 21 44 18 55% eyes 19% (eyes) n/a n/a Le Hoang164 CSA Noninfectious 18 40 n/a 44% 39% 11% n/a Leznoff170 Success 5 complete þ uveitis maximum suppression of inflammation (partial not included) CSA Behçet 46 (controlled n/a n/a 91% 2% 2% n/a Masuda183 trial, 46 on CSA) CSA Rheumatoid arthritis 6 54 38 83% 17% n/a n/a McCarthy188 CSA Behçet 8 29 n/a 94% eyes 6% eyes n/a n/a Muftuoglu202 Success 5 improved (75%) þ same (19%) CSA Noninfectious uveitis 17 35 180 6% Nissen210 CSA Noninfectious uveitis 52 35 12 63% at 1 year 12% 14% n/a Nussenblatt211 Failure at 3 mos. listed (success @ 3 mos. 5 79%) CSA Endogenous uveitis 56 38 3 43% n/a n/a n/a Nussenblatt212 Therapeutic endpoint @ 3 mos. CSA Behçet 52 34 38a 69% 31% 17% n/a Ozdal219 Success 5 improved þ same CSA Behçet 12 29 24 100% n/a n/a n/a Ozyazgan220 Success 5 Va stable CSA Autoimmune uveitis 14 31 6 8 (57%) n/a n/a n/a Palestine222 CSA þ Bromocriptine; 2 pts. required pred þ CSA, not included in success CSA Endogenous uveitis 32 33 12 100% n/a n/a n/a Pascalis225 CSA þ steroid þ MTX CSA Behçet 22 31 20a 96% 5% n/a n/a Sajjadi263 Success 5 improved þ same CSA Endogenous 38 42 12 Yes, but not clear Yes, but not 3% Secchi276 noninfectious clear uveitis CSA Behçet 12 30 20 91% eyes 9% n/a n/a Sullu305 Success 5 improved (36%) þ unchanged (54%) CSA Chronic 9 45 17 67% eyes 17% eyes 11% n/a Towler315 CSA þ steroid in some pts. posterior (temporary Success 5 improved uveitis d/c) (61%) þ unchanged (6%); 3 eyes excluded CSA Chronic uveitis 13 41 29 83% eyes at 1 year 17% eyes 1 n/a Towler316 Success 5 improved þ at 1 yr (8%) same; VA improved in 61%, decreased in 17%, same in 22% at 1 year 477 (Continued on next page) TABLE 2 2011 November--December (6) 56 Ophthalmol Surv 478 Continued 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

CSA BSCR 19 46 36 83% eyes 17% eyes 7% n/a Vitale330 1/15 required d/c; 15 pts. in group with CSA alone or in combo, 3rd group on no IMT CSA Scleritis 7 60 8 71% n/a 14% n/a Wakefield331 CSA þ steroid CSA Refractory uveitis 22 41 91% 9% n/a n/a Wakefield332 Success 5 stable þ improved VA CSA Uveitis 15 13 45 75% (at 4 years) 25% (at 4 yrs.) 7% n/a Walton334 CSA þ steroid in some; Success 5 improved þ unchanged CSA Behçet 19 31 51 76% eyes 11% 16% n/a Whitcup339 CSA þ steroid AZA Chronic uveitis 25 29 n/a 92% 8% 7% n/a Andrasch7 AZA Behçet 49 n/a #3 years 94% 2% n/a n/a Ben Ezra27 Success 5 VA 6/120 or better at #3 year f/u; Results CMB (20), AZA (4), and colchicine (18) AZA Choroidal 14 36 15 88% eyes 12% eyes 7% n/a Dees73 neovascularization AZA OCP 18 57 39 100% n/a 17% n/a Foster107 IMT combinations used (AZA, prednisone, CTX) #pts. 5 #pts. on IMT; Success 5 improved þ same AZA Retinal vasculitis 34 41 25a 65% eyes 34% eyes 24% n/a Greenwood124 AZA Serpiginous choroiditis 5 46 13 100% n/a n/a n/a Hooper136 Combination: AZA þ CSA þ pred AZA OCP 9 65 18 56% eyes 44% eyes n/a n/a Mondino198 AZA Chronic uveitis 20 39 n/a 60% 40% n/a n/a Newell208 AZA Noninfectious ocular 145 51 8 62% 38% 24% n/a Pasadhika224 Success 5 sustained inflammation control of inflammation; 47% on # 10 mg steroid AZA Neuroretinitis 7 34 6 72% n/a n/a n/a Purvin238 Success 5 decrease in attack rate AZA OCP 11 68 28 33% 9% eyes 9% n/a Tauber309 Success 5 disease under control

Failure 5 therapeutic failure AL ET DURRANI AZA Behçet 25 32 24 100% n/a n/a n/a Yazici352 Success 5 VA stable; Nos. for pts. with ocular Behçet on AZA MMF Chronic uveitis 54 n/a 7a 94% 6% 18% n/a Baltatzis19 RAMNSFROUA NLMAOYDISEASE INFLAMMATORY OCULAR FOR TREATMENTS MMF Noninfectious ocular 236 47 9 73% 27% 12% n/a Daniel69 Success 5 sustained inflammation control of inflammation; 55% on # 10 mg steroid MMF Intermediate and 18 n/a n/a 72% n/a n/a n/a Greiner125 Success 5 resolved posterior uveitis inflammation; article in German MMF Refractory uveitis 14 43 34a 75% 25% n/a n/a Lau162 Success 5 improved þ same MMF Scleritis 8 46 10 100% n/a 13% n/a Sen280 Success 5 VA improved þ same; scleritis recurred or not controlled in 5 of 8 pts. MMF Uveitis 10 n/a 5 80% n/a n/a n/a Zierhut357 Success 5 no inflammation or decreased recurrence rate; article in German CTX Refractory uveitis 12 n/a 24 100% n/a n/a n/a Buckley42 Success 5 decreased inflammation CTX Peripheral uveitis 16 n/a n/a 100% n/a n/a n/a Buckley43 CTXþ steroid; Success 5 VA improved þ stable (23 eyes of 16 pts.) CTX Wegener 10 n/a 25 100% n/a n/a c Charles59 CTX þ steroid; Success 5 control of scleritis CTX OCP 10 74 14 79% eyes 11% eyes 10% n/a Elder87 Success 5 resolved inflammation; Failure 5 perforation CTX Wegener 85 41 47a 93% 7% n/a n/a Fauci93 CTX þ pred; Results combine systemic þ ocular CTX OCP 10 35 6 80% 20% 30% n/a Galindo- Rodriguez110 CTX Scleritis (RP) 11 52 36 100% n/a 2/5, 40% n/a Hoang-Xuan132 Success 5 no inflammation; 5 pts. on CTX; initial side effects in 2 but later tolerated; so final success 5 100% CTX Behçet 46 28 30 100% n/a n/a n/a Kazokoglu147 Success 5 VA stable; 11% with hemorrhagic cystitis but no indication of d/c CTX Behçet 11 32 24 100% n/a n/a n/a Ozyazgan220 Success 5 no significant change in VA CTX Noninfectious ocular 215 61 74 76% 24% 34% 1 (0.5%) Pujari237 Success 5 sustained inflammation control of inflammation; 61% on # 10 mg steroid; 1 death from PCP 479 (Continued on next page) TABLE 2 2011 November--December (6) 56 Ophthalmol Surv 480 Continued 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

CTX Uveitis 11 40 21 64% 36% n/a n/a Rosenbaum253 CTX Optic neuropathy 3 47 48 83% eyes 17% n/a n/a Rosenbaum256 CTX þ steroid; (SLE) Success 5 stable þ improved VA; Age 5 age at onset of neuropathy CMB Serpiginous 9 55 78 100% n/a n/a n/a Akpek3 Success 5 stable þ choroiditis improved VA; Treatment: CMB or CTX CMB Severe chronic 25 29 22a 92% 8% 8% (d/c 1 (4%) Andrasch7 AZA or CMB þ uveitis or taper) prednisone; 1 death from reticulum cell sarcoma CMB Uveitis 14 36 7 86% 14% 14% n/a Dinning84 1 pt. d/c due to nausea & depression CMB Idiopathic 31 37 12 32% 68% 3% n/a Godfrey116 Success 5 improved uveitis inflammation; Failure 5 indeterminate or no change in inflammation CMB Behçet 11 34 24 93% 7% n/a n/a Mamo179 f/u after control of inflammation; Success 5 decreased inflammation CMB Refractory 28 29 46 82% 18% 25% n/a Miserocchi192 uveitis CMB Behçet 44 30 51 66% 34% n/a n/a Mudun201 CMB Behçet 10 n/a 22a 61% 40% n/a n/a O’Duffy213 Results only for uveitis Unless otherwise specified, the % is given for patients (not eyes). AZA 5 azathioprine; BSCR 5 birdshot chorioretinopathy; CMB 5 chlorambucil; CSA 5 cyclosporine; CTX 5 cyclophosphamide; d/c 5 discontinuation; f/u 5 follow- up; IMT 5 immunomodulatory therapy; JIA 5 juvenile idiopathic arthritis; MMF 5 mycophenolate mofetil; MTX 5 methothrexate; n/a 5 not available; OCP 5 ocular cicatricial pemphigoid; PCP 5 Pneumocystis carinii pneumonia; pred 5 prednisone; RP 5 relapsing polychondritis; SLE 5 systemic lupus erythematosus; TINU 5 tubulointerstitial nephritis and uveitis; VA 5 visual acuity. aDuration of treatment. bPatients received MTX for a minimum of 1 year. c2 patients had pneumonia (due to leukopenia) and 1 died of viral myocarditis possibly related to immunosuppression. d

Patients had decreased number of relapses while on MTX. AL ET DURRANI eFull or partial control of inflammation (10 patients were fully controlled). fFollow-up for 9 responders to MTX. TREATMENTS FOR OCULAR INFLAMMATORY DISEASE 481 collectively explain the therapeutic effect of low-dose hepatotoxicity, a serious side effect. Abnormal liver methotrexate.216 enzymes have been seen in 15% of treated patients.157 When using methotrexate in high doses, as is Risk factors for hepatotoxicity include age and often the case in cancer chemotherapy, folinic acid duration of therapy.333 Low-dose methotrexate may is used to shield normal cells from toxicity. Folinic also result in cutaneous vasculitis, urticaria, photo- acid functions without the need for reduction by sensitivity, alopecia, and cutaneous nodules.337 A DHFR and acts by restoring methionine, thymidy- recent assessment of the long-term risk of malignancy late, and purine biosynthesis. This is unaffected by among patients treated with immunosuppressive the presence of methotrexate.216 Methotrexate has agents from transplant, rheumatologic, autoimmune a relatively high bioavailability in low doses, 100% skin disease, and inflammatory bowel disease cohorts when given intravenously, and may be administered concluded that methotrexate has virtually no long- subcutaneously as well as intramuscularly. Part of the term carcinogenic effects.150 The SITE retrospective drug undergoes hepatic metabolism, and all its cohort study of patients receiving immunosuppres- metabolites are excreted in the urine.216 sive drugs for noninfectious ocular inflammation found no increased risk of overall mortality or b. Use in Ocular Inflammatory Disease cancer-related mortality among patients receiving methotrexate when compared with controls.149 Used widely for rheumatoid diseases and arthritis, Methotrexate is a definite teratogen and must not methotrexate has also been effective in treating be used in pregnant women.216 a large number of ocular inflammatory diseases. In the mid 1960s Wong and associates used intravenous d. Suggested Treatment Protocol in Ocular methotrexate to treat 10 patients with cyclitis who were Inflammatory Disease uncontrolled on corticosteroids.343,344 Nine of 10 showed favorable and rapid improvement. Lazar et al Following a baseline hemogram, liver function then showed that 14 of 17 patients with various tests, blood urea nitrogen (BUN), serum creatinine, corticosteroid-resistant uveitis syndromes achieved and urinalysis, we typically begin treatment with good results with intravenous methotrexate.163 Several methotrexate at a weekly dose of 2.5 to 10 mg, retrospective studies of patients treated with metho- administered orally or intramuscularly, and titrate the dose to the clinical response to a maximum of 50 mg trexate for chronic noninfectious ocular inflammatory 106 disease have since been reported.37,135,144,285 One per week. Three to 6 weeks are required for study conducted by our group demonstrated a control methotrexate to take effect. Complete blood counts of inflammation in 76% of patients at a mean and liver function tests are obtained at 4-week methotrexate dose of 12.3 mg/week. Adverse effects intervals during therapy, and therapy is continued for 2 years after quiescence is achieved, without resulted in the discontinuation of therapy in 7% of 138,165 patients.265 The recently completed Systemic Immu- recurrences, to achieve a durable remission. nosupressive Therapy for Eye Diseases (SITE) multicenter retrospective cohort study reported outcomes 2. Azathioprine in 384 patients treated with methotrexate as the sole a. Introduction and Mechanism of Action non-corticosteroid immunosuppressant for ocular 114 Azathioprine, an imidazolyl derivative of 6- inflammation. Methotrexate was found to effect mercaptopurine, has been widely used as a potent complete cessation of ocular inflammation in 66% of immunosuppressant in organ transplant surgery and patients in this cohort within 1 year, allowing a success- autoimmune disease. Following ingestion, the drug is ful taper of systemic corticosteroids to 10 mg per day or rapidly metabolized to 6-mercaptopurine, which in less in 58% of patients. Although the drug was turn is converted to thioinosine-5-phosphate. The employed to treat a variety of ocular inflammatory latter is a purine analog that acts as a false precursor conditions, most notably anterior uveitis, posterior or for adenine and guanine synthesis, thus interfering panuveitis, and mucus membrane pemphigoid, treat- with DNA, RNA, and eventually protein synthesis in ment success was most common in patients with immunocompetent lymphoid cells in a cell-cycle anterior uveitis and scleritis, attaining a control rate of specific manner.216 The immunosuppressive effects approximately 56% in both groups. of azathioprine, however, are only partly explained by this mechanism. Azathioprine has been shown to c. Side Effects selectively inhibit T-lymphocyte function at therapeu- The side effects of methotrexate (nausea, vomit- tic doses, suppress homing in circulating T-cells, ing, diarrhea, anorexia, and weight loss) are usually selectively decrease the development of monocyte mild and improve after dose reduction. Patients need precursors and the participation of natural killer cells to refrain from alcohol consumption to avoid in the antibody-dependant cytotoxicity reaction, and 482 Surv Ophthalmol 56 (6) November--December 2011 DURRANI ET AL suppress the delayed (type IV) hypersensitivity re- Immunosuppression, including that with azathio- action in renal, skin, and cardiac allografts.56 prine, has been associated with an increased risk of neoplasia, such as lymphomas and skin cancers in b. Use in Ocular Inflammatory Disease transplant recipients and in patients with rheumatoid 227 Azathioprine has been shown to be effective in the arthritis. However, rheumatologic disease itself is associated with an increased risk of malignancy management of scleritis secondary to relapsing 53 polychondritis and as an adjunctive agent in ocular independent of treatment. One study concluded cicatricial pemphigoid.132,269 In our experience, that there is an increased risk related to the duration of exposure to immunosuppressive drugs, including azathioprine has been most effective in juvenile 15 idiopathic arthritis (JIA)-associated iridocyclitis re- azathioprine. Conversely, a study of 755 patients sistant to corticosteroid therapy.131 Reports show administered azathioprine for inflammatory bowel disease and followed for a maximum of 29 years failed a variable efficacy in other uveitic entities, with 65 Newell,208 Andrasch,7 and Moore et al199 finding it to show an increased risk of neoplasia. A recent most effective in patients with intermediate uveitis, critical assessment of the risk of malignancy in organ chronic uveitis of diverse etiologies, and sympathetic transplant and autoimmune disease cohorts applied ophthalmia, respectively. In contrast, Mathews et al to patients with ocular inflammatory disease concluded that azathioprine likely does not increase total found the drug to be only as effective as placebo in 150 chronic iridocyclitis, and others have found it to be cancer risk to a detectable degree. ineffective in sympathetic ophthalmia.180,184 One Other major side effects of azathioprine are bone randomized, controlled trial of azathioprine in marrow suppression, with leukopenia and thrombo- Behçet disease demonstrated its efficacy in decreas- cytopenia occurring more commonly than anemia. This typically develops 1 to 2 weeks after initiation of ing relapses of ocular disease and in the prevention of 293 ocular involvement in patients with systemic dis- therapy. Other potential side effects include ease.352 A later study by our group showed more increased susceptibility to infection, particularly Herpes simplex and zoster reactivation, hepatotoxicity, equivocal results, with only three of eight patients 56 achieving control of ocular inflammation in conjunc- alopecia, gastrointestinal toxicity, and pancreatitis. tion with systemic corticosteroids or cyclosporine.104 We, therefore, do not consider azathioprine to be the d. Suggested Treatment Protocol in Ocular Inflammatory most effective drug for the treatment of ocular Disease manifestations of this disease. In the SITE retrospec- A complete blood count with differential and liver tive cohort study, which included 145 patients treated function tests should be obtained prior to beginning with azathioprine for a wide variety of noninfectious therapy.138 We also perform quantitative testing for ocular inflammatory disease entities, the drug was thiopurine methyltransferase enzyme activity and do found to have controlled inflammation in 62% of not administer azathioprine in patients with low or patients and demonstrated a steroid-sparing effect in absent enzyme activity. The drug is typically prescribed 47% of patients at 1 year.224 Control of inflammation at an initial dose of 2 to 3 mg/kg/day orally and is then was achieved most commonly in patients with in- adjusted based on the clinical response and side termediate uveitis, occurring in 90% of patients with effects.106 The dose should be reduced by 25% in the condition in this group. patients receiving allopurinol. We perform complete hemograms on a weekly basis until drug dosage, c. Side Effects disease activity, and hematologic parameters have stabilized. Complete hemograms and liver function The most common side effect of azathioprine is tests are then performed at 4-week intervals for the gastrointestinal upset, with nausea and vomiting 49 duration of treatment, typically 2 years provided the occurring in approximately 12% of patients. patient is free of ocular inflammation off corticoste- Although prior studies have indicated that these roids, with the goal of achieving a durable remission side effects are generally well tolerated, the SITE following cessation of therapy.106,165 study group found the rate of discontinuation of azathioprine secondary to side effects was 0.16 per 3. Leflunomide person-year, or 24% in this cohort.221,224 Azathio- prine has also been shown to have a higher rate of a. Introduction and Mechanism of Action treatment-related side effects when compared to Leflunomide is a prodrug that is converted to its methotrexate or mycophenolate mofetil, and pa- active metabolite in the liver and gastrointestinal tients have a two-fold risk of not being retained on tract, which in turn inhibits dihydro-orotate de- this medication as compared to methotrexate when hydrogenase, an enzyme involved in de novo used to treat ocular inflammatory disease.17,112 pyrimidine synthesis. Functioning as a tyrosine TREATMENTS FOR OCULAR INFLAMMATORY DISEASE 483 kinase inhibitor, it inhibits T-cell and B-cell re- Although it was ineffective as an antimicrobial, the sponses to interleukin (IL)-2 and inhibits T-cell and active form, mycophenolic acid, was first used as an B-cell proliferation and immunoglobulin produc- immunosuppressant in the 1970s to treat psoriasis.300 tion.108 Leflunomide is used as a disease-modifying By inhibiting monophosphate dehydrogenase, MMF drug in the treatment of active rheumatoid arthritis disrupts the de novo pathway of purine synthesis. This and is being investigated in the management of pathway is used preferentially by B-cells and T- cells to various solid neoplasms. In one randomized, con- synthesize guanosine, required for DNA synthesis.4 In trolled clinical trial, it compared favorably with addition, the drug suppresses antibody synthesis, methotrexate in retarding the radiographic pro- disrupts cell adhesion to vascular endothelium, and gression and improving physical function in patients interferes with lymphocytic chemotaxis. By the 1990s, with rheumatoid arthritis.64 the morpholinoethyl ester of mychophenolic acid, namely, MMF, came into use as an immunosuppres- b. Use in Ocular Inflammatory Disease sant following renal allograft transplantation.33,231 To date, experience in the use of leflunomide in Absorbed well in the gut, MMF is converted to the active mycophenolic acid, which has a half-life of 16 the management of ocular inflammatory disease has 46 been limited. Animal studies have shown lefluno- hours. It is then glucoronidated to phenolic glucor- mide to be more effective than cyclosporine in onide and excreted in the urine. Antacids reduce the inhibiting experimental autoimmune uveitis, and bioavailability of MMF by 15%. the drug has been shown to be as effective as cyclosporine in suppressing corneal allograft re- b. Use in Ocular Inflammatory Disease 66,249 jection in the rat. In patients with sarcoidosis, Our study of 54 patients with chronic ocular leflunomide was shown to decrease ocular inflam- inflammatory disease showed that inflammation was mation in 23 of 28 patients (82%) in one retrospec- 24 controlled in 65% on mycophenolate mofetil mono- tive review. We have used leflunomide successfully therapy.19 A steroid-sparing effect was achieved in in patients unresponsive to, or with a demonstrated 54%, and the drug was also shown to be effective in intolerance to, methotrexate. combination with cyclosporine and methotrexate. A subsequent retrospective case series describing out- c. Side Effects comes of therapy in patients with scleritis and uveitis Common adverse effects seen with leflunomide are who had failed or were intolerant to methotrexate gastrointestinal, particularly diarrhea, occurring in showed that MMF controlled inflammation in 47 of 85 approximately 37% of patients in one study, with patients (55%), with five patients achieving durable upper respiratory tract infections in approximately the remission off all medication.297 The study also showed same percentage of patients, and neurologic effects that patients with scleritis and JIA had less frequent including headache, dizziness, and paresthesias.64 inflammation control. In eight patients with scleritis in Weight loss occurs in approximately 4% of patients.63 remission on systemic corticosteroid therapy,MMF was a successful steroid-sparing agent; however, the drug d. Suggested Treatment Protocol in Ocular Inflammatory did not demonstrate the same desirable effect in Disease controlling active scleritis. A report by Doycheva et al, As mentioned, the literature available on the use of assessing 17 children with intraocular inflammation treated with MMF, showed that a steroid-sparing effect leflunomide in patients with ocular inflammation is 85 limited. Following baseline complete blood counts was achieved with 88% of patients. Mild side effects with differential, and liver function tests, oral le- occurred in 41% of patients and caused one patient to flunomide is used at daily dosages between 0.01 to discontinue the treatment. In the large retrospective 10 mg/kg.165 Complete blood counts and liver function SITE cohort, among 236 patients treated with the drug testingmaythenbeperformedat4-weekintervals.Data for inflammatory eye disease, control of inflammation was achieved in 73% within a year, with a steroid- do not exist regarding the ability of the drug to induce 69 durable remission of ocular inflammation, and thus the sparing effect in 55% at the same time point. Twelve optimal duration of therapy is unknown. percent (12%) of patients in this cohort required discontinuation of therapy because of side effects within the first year. 4. Mycophenolate Mofetil a. Introduction and Mechanism of Action c. Side Effects Mycophenolate mofetil (MMF) is an inosine mono- ThemostcommonsideeffectsofMMFare phosphate dehydrogenase inhibitor initially described gastrointestinal, including diarrhea, nausea, abdomi- as an antibiotic approximately 50 years ago.98 nal pain, and vomiting. Elevations of liver enzymes, 484 Surv Ophthalmol 56 (6) November--December 2011 DURRANI ET AL leukopenia, and lymphocytopenia are reported less granulomatosis, rheumatoid vasculitis, polyarteritis frequently.216 In patients with impaired absorption nodosa, systemic lupus erythematosus, pemphigus and/or metabolism of the drug (as in renal and vulgaris, and cicatricial pemphigoid.39,181,358 gastrointestinal diseases) MMF must be used and dosed with caution. In a retrospective analysis of 106 patients b. Use in Ocular Inflammatory Disease with different forms of chronic uveitis, Siepmann et al concluded mycophenolate mofetil was a safe and Cyclophosphamide is considered the treatment of effective immunosuppressant.290 Similarly, the SITE choice in patients with ocular inflammation second- study group found no increase in overall or cancer- ary to Wegener granulomatosis, polyarteritis nodosa, related mortality in patients treated with the drug peripheral ulcerative keratitis and necrotizing scleritis in rheumatoid arthritis, and relapsing polychon- for ocular inflammation compared to untreated 40,92,100,132 controls.149 dritis. It also has a demonstrated efficacy in bilateral Mooren ulcer, and as a first-line agent in d. Suggested Treatment Protocol in Ocular Inflammatory active, progressive ocular cicatricial pemphigoid and Disease Behçet disease affecting the posterior pole of the eye and viscera.42,100,107 Cyclophosphamide is par- We perform a baseline hemogram with differen- ticularly effective in the management of severe tial and liver function tests before commencing ocular cicatricial pemphigoid, with complete quies- therapy with MMF. The drug is administered orally, cence of inflammation demonstrated in 69% of and patients are counseled that MMF must be patients in a recent report by Saw et al and partial ingested on an empty stomach one hour before or improvement in an additional 21%.269 It has been two hours after meals. Treatment is commenced at used with success in our stepladder approach in the an initial dose of 500 mg twice a day for 2 weeks, management of ocular inflammation in a variety of while monitoring for side effects. This is then entities including intermediate uveitis and ocular increased to the therapeutic dose of 1 g twice inflammation associated with systemic lupus eryth- a day if tolerated. Doses above 3 g/day carry an ematosus and Crohn disease.180 In our experience, increased risk of toxicity, whereas those less than intravenous pulse cyclophosphamide had an efficacy 2 g/day often fail to produce the desired immuno- 106 of approximately 69% in severe or recalcitrant modulatory effect. Patients are then monitored ocular inflammatory disease.86 Of the 215 patients with complete blood counts on a weekly basis for 4 receiving cyclophosphamide for inflammatory eye weeks, then twice monthly for 2 months, followed by 138 disease in the SITE study cohort, 76% achieved monthly testing. Liver function testing is re- control of inflammation at 1 year, and a steroid- peated at monthly intervals for the duration of sparing effect was observed in 61%.237 Similar treatment, usually 2 years, provided the patient is results in time to control of inflammation and free of recurrences of ocular inflammation. steroid-sparing were observed in patients receiving the drug by the oral and intravenous routes in this B. ALKYLATING AGENTS study, although patients receiving the drug orally tended to have a higher rate of control of 1. Cyclophosphamide inflammation. a. Introduction and Mechanism of Action Cyclophosphamide is a cell-cycle nonspecific alky- c. Side Effects lating agent used commonly in cancer chemotherapy Although associated with a variety of potential and for the induction of remission in a host of toxic effects—including leukopenia, hemorrhagic autoimmune disorders and has a mechanism of action cystitis, secondary malignancy, and sterility— similar toothernitrogenmustards, exertinga cytotoxic cyclophosphamide has been shown to have a remark- effect on rapidly proliferating cells by alkylating able safety profile in the rheumatologic and dermato- nucleophilic groups on DNA bases, particularly on logic literature, particularly when used intravenously the 7-nitrogen position of guanine.55 This leads to for limited periods.181 Intravenous pulse administra- cross-linking of DNA bases, abnormal base pairing, tion of cyclophosphamide offers certain advantages and DNA strand breakage. Cyclophosphamide- over oral administration and is likely the route now induced immunosuppression is thought to be medi- preferred by most practitioners in the treatment of ated by a direct cytotoxic effect on immunocompetent ocular inflammation in this country. In addition to the lymphocytes, particularly those that have undergone rapid induction in patients with severe ocular in- genetic differentiation and division. Cyclophospha- flammatory involvement, intravenous pulse adminis- mide has been efficacious in treating a wide variety tration avoids prolonged bladder exposure to the toxic of autoimmune disorders, including Wegener acrolein metabolite, allowing larger yet less frequent TREATMENTS FOR OCULAR INFLAMMATORY DISEASE 485 dosing in patients with hemorrhagic cystitis caused by Therapy is continued for 1 year after quiescence in oral intake and induces only transient neutropenia, an effort to induce a long-term, drug-free remission. making intercurrent infections less likely.86 However, a critical assessment of the literature extrapolating 2. Chlorambucil data from rheumatologic and transplant data sug- a. Introduction and Mechanism of Action gested a clinically important risk of malignancy with alkylating agents, including cyclophosphamide, and Chlorambucil is a nitrogen mustard with a mech- this was thought to be applicable to the ocular disease anism of action similar to cyclophosphamide, setting to at least some extent.150 This report replacing hydrogen ions with alkyl groups on DNA concluded that with appropriate precautions, such as bases. This causes DNA strands to undergo intra- limiting the cumulative dose and ensuring adequate strand crosslinking and DNA-to-protein crosslinking, disrupting DNA replication, transcription, and hydration, the risk of cancer is probably not sufficient 55 to outweigh the benefit in severe, vision-threatening nucleic acid function. Chlorambucil is well absorbed in the gut, with peak serum concentra- disease. The SITE study demonstrated no increase in 207 overall mortality (adjusted hazard ratio [HR], 1.14; tions achieved within one to two hours. The drug 95% confidence interval [CI], 0.81--1.60; p 5 0.45).149 is converted by the liver to phenylacetic acid However, cancer-related mortality was non- mustard, the active metabolite. Both chlorambucil significantly increased, with the 95% CI for alkylating and phenylacetic acid mustard are ultimately hydro- agents as a class narrowly including 1.0 (adjusted HR lyzed to inactive compounds and undergo renal for cyclophosphamide, 1.61; 95% CI, 0.81--3.22; p 5 excretion. Chlorambucil has a half-life of 92 0.17). Cyclophosphamide was discontinued by 33.5% minutes, whereas the phenyl acetic mustard metab- of patients because of side effects within 1 year in this olite has a longer half-life of 145 minutes. cohort.237 Cyclophosphamide is a teratogen and is gonadotoxic, and patients taking the drug must be b. Use in Ocular Inflammatory Disease advised against reproduction. To preserve future Chlorambucil has been used in several uveitic fertility, patients are offered cryopreservation of sperm entities. Studies have primarily been carried out on or eggs prior to treatment, and concomitant the use of this drug in Behçet disease, sympathetic gonadotropin-releasing hormone treatment is admin- ophthalmia, JIA, and serpiginous choroiditis. istered in women of childbearing age.34 Mudun et al investigated the effect of short-term chlorambucil on 44 patients with Behçet-associated uveitis201 and demonstrated a statistically significant d. Suggested Treatment Protocol in Ocular Inflammatory decrease in the mean frequency of recurrences of Disease inflammation, from 4.9 to 0.9 recurrences per year. Complete hemograms including leukocyte differ- The longest duration between recurrences in- entials, and platelet counts, liver function tests, and creased from 4.4 months to 25.7 months, and a urinalysis are obtained prior to commencing short-term chlorambucil therapy was found to be therapy. We typically administer cyclophosphamide effective in controlling ocular manifestations of the intravenously at an initial dose of 1 g/m2 body disease in two-thirds of patients. Similarly, Goldstein surface area.86,138 Complete hemograms are then et al studied 53 patients with uveitis treated with repeated on a weekly basis. As the level of short-term high-dose chlorambucil.119 Treatment leukopenia achieved is a reasonable indicator of durations in this protocol ranged from 2 to 9 the adequacy of immunosuppression, subsequent months at an average daily dose of 20 mg. Seventy dosages of cyclophosphamide are based on the percent (70%) of the patients achieved remission leukocyte count, neutrophil count, and the degree during an average follow-up period of 4 years. Our of change in these values attained by the previous group has reported on 28 patients with otherwise administration of the agent, aiming for leukocyte treatment-resistant noninfectious uveitis, with un- counts between 3,500 and 4,500 cells/mL. We try, derlying etiologies including Behçet disease, JIA, however, to avoid a leukocyte count of less than pars planitis, sympathetic ophthalmia, idiopathic 3,500 cells/mL, a neutrophil count of less than 1,500 uveitis, Crohn disease, and HLA-B27-associated cells/mL, and a platelet count of less than 75,000 uveitis.192 Chlorambucil was administered at a me- cells/mL. Initial dosing of cyclophosphamide is dian daily dose of 8 mg, and the median treatment titrated at 2-week intervals. Once hematologic duration was 12 months. Seven patients had to parameters and disease activity have stabilized, discontinue treatment due to side effects, including infusions are repeated at 3-week to 4-week intervals. two patients who developed temporary amenorrhea, Urinalysis, serum chemistries, and liver function two with progressive leukopenia, two with gastroin- tests are repeated at 4-week intervals during therapy. testinal intolerance, and one patient with infection. 486 Surv Ophthalmol 56 (6) November--December 2011 DURRANI ET AL

A positive clinical response was observed in 19 A second approach that has been described is patients (68%). We concluded that chlorambucil is short-term, high-dose therapy.138 This includes an a safe and effective treatment in otherwise in- initial dose of 2 mg daily for 1 week, followed by tractable uveitis.192 escalation by 2 mg per day each week. Dose escalation is continued until inflammation is com- c. Side Effects pletely suppressed, or until leukocyte counts de- The major side effect of chlorambucil is bone crease to less than 2,400 cells/mL or platelet counts marrow suppression that is usually reversible, but decrease to less than 100,000 cells/mL. Chlorambu- may be protracted, and rarely may lead to irrevers- cil is discontinued if bone marrow toxicity occurs. ible bone marrow aplasia.138 Other side effects The usual duration of this short-term, high-dose include opportunistic infections and reactivation therapy is 3--6 months. of Herpes zoster. Routine prophylaxis for Pneumocystis carinii pneumonia should be considered in all C. ANTIBIOTICS 138 patients receiving chlorambucil therapy. Perma- 1. Cyclosporine nent sterility and amenorrhea may occur.308 In younger women, the amenorrhea and infertility a. Introduction and Mechanism of Action may be reversible, although in older women early Cyclosporine is a fungal antimetabolite developed onset of menopause is typical. In contrast to primarily for use in solid organ transplantation. cyclophosphamide, alopecia and bladder toxicity Although the mechanism of action of cyclosporine do not occur. Chlorambucil is a known teratogen is not fully known, the drug has been shown to and is contraindicated in pregnancy. reversibly inhibit T-cell mediated alloimmune and A study of rheumatoid arthritis patients found autoimmune responses.262,340 Most evidence indi- that 8 of 39 patients developed cutaneous malig- cates that cyclosporine binds to and inhibits nancy during follow-up.226 Similarly, in patients with calcineurin, preventing the nuclear translocation neoplastic disease, chlorambucil treatment has been of nuclear factor of activated T-cells (NFAT). This associated with a significantly higher rate of second- inhibits the signaling cascade from the T-cell ary hematologic malignancy.29,167 Analysis of the receptor to genes encoding multiple lymphokines retrospective cohort of patients in the SITE study such as IL-2 and enzymes necessary for the showed no significant increase in overall mortality in activation of resting T-cells. patients receiving alkylating agents; however, a non- significant increase in cancer-related mortality was b. Use in Ocular Inflammatory Disease observed (adjusted HR for chlorambucil, 2.29; 95% The clinical use of cyclosprine in ophthalmology 5 149 CI, 0.53--9.83; p 0.26). is well established. Palestine et al were the first to report the efficacy of cyclosporine in patients with intractable d. Suggested Treatment Protocol in Ocular Inflammatory uveitis in Behçet disease, Vogt-Koyanagi-Harada Disease syndrome (VKH), sarcoidosis, and sympathetic oph- Following a baseline complete blood count in- thalmia.222 The same group subsequently demon- cluding leukocyte differential and liver function strated that cyclosporine used as monotherapy in tests, we prefer to begin chlorambucil at an oral steroid-resistant patients was effective in decreasing dose of 0.1 mg/kg/day, titrating the dose to inflammation in 15 of 16 patients.211 Masuda et al response and drug tolerance every 3 weeks, for conducted a double blinded study comparing cyclo- a typical maximum daily dose of 6 to 12 mg/day.106 sporine to colchicine in the treatment of Behçet Vigilant monitoring of adverse reactions, including disease and clearly demonstrated the superiority of myelosuppression, must be performed, as described cyclosporine.183 More recently, additional regimens previously for cyclophosphamide, with similar target have been proposed, with cyclosporine being used in parameters for leukocyte, neutrophil, and platelet combination with prednisone or other immunosup- counts. The effect of chlorambucil on the bone pressives to diminish the potential toxicity of the marrow is cummulative and increased vigilance in earlier higher doses used when administered alone. monitoring is required at approximately 3 months Several uncontrolled trials involving small numbers of of treatment, followed by a progressive reduction of patients have also reported on the treatment of the dose over the ensuing 3 to 6 months. Liver birdshot retinochoroidopathy, corneal ulceration, function tests are repeated monthly.138 Treatment is scleral melting, peripheral ulcerative keratitis associ- continued for 1 year of disease-free activity to induce ated with Wegener granulomatosis, and in the pre- a durable remission.192 vention of corneal transplant rejection in high-risk TREATMENTS FOR OCULAR INFLAMMATORY DISEASE 487 eyes.159,191,235,330 The drug, however, has been shown activation by inhibiting calcineurin.275 The drug to be ineffective in the management of ocular binds to an intracellular protein, FK506 binding cicatricial pemphigoid.206,309 In the 373 patients protein-12, which in turn forms a complex with analyzed in the SITE retrospective cohort of patients calcium, calmodulin, and calcineurin. This complex with a variety of ocular inflammatory disease entities, inhibits the activity of calcineurin phosphatase, control of inflammation was accomplished in approx- which in turn prevents the nuclear translocation of imately 52% of patients, and systemic corticosteroid NFAT and leads to the inhibition of T-cell activa- was tapered to # 10 mg/day in 36% at 1 year.141 tion.262 Thus, cyclosporine and tacrolimus share Topical cyclosporine has been successfully used in a common pathway for immunosuppression. It is the treatment of vernal conjunctivitis, ligneous indicated for the prevention of solid-organ allograft conjunctivitis, Sjogren syndrome, and atopic rejection and as rescue therapy in patients with keratoconjunctivitis.32,134 rejection episodes on cyclosporine.20,187,229 c. Side Effects b. Use in Ocular Inflammatory Disease Potential side effects of cyclosporine include hyper- Data reporting the use of tacrolimus in autoim- tension (documented in 50% of patients in a series mune disease, particularly noninfectious uveitis, has of patients undergoing renal transplantation), neph- increased in recent years. Mochizuki and colleagues rotoxicity (reported in approximately 25% of renal demonstrated disease reduction in 76.5% of patients transplant patients, 38% of heart transplant patients, receiving the drug for noninfectious uveitis in an and 37% of liver transplant patients), tremors, open, multicentered clinical trial, with an improve- hirsutism (21--45% of renal transplant patients), and 138,234,248,266 ment in visual acuity occurring in 72.9% of treated hypercholesterolemia. In the SITE co- eyes, and the drug was found to be effective in 7 of 11 hort, patients younger than 40 years of age and those patients who had been refractory to prior treatment receiving 151--250 mg/day were less likely to require with cyclosporine.196 In a prospective randomized discontinuation of cyclosporine because of side 141 trial of 37 patients requiring second-line immuno- effects. Cyclosporine was also not associated with modulatory therapy for posterior segment inflamma- increased risk of mortality or cancer-related mortality 149 tion, tacrolimus was found to be as effective as in this cohort. cyclosporine in decreasing intraocular inflammation, improving visual acuity, and allowing taper of d. Suggested Treatment Protocol in Ocular Inflammatory systemic corticosteroids, and had a lower incidence Disease of side effects when compared with cyclosporine.203 Prior to initiating therapy with cyclosporine, we These outcomes were maintained in a longer term perform a complete hemogram with differential, follow-up study of the same cohort.133 Topical BUN, serum creatinine, creatinine clearance, uri- tacrolimus has been reported to be effective in the nalysis, liver function tests, a fasting lipid profile, management of atopic blepharoconjunctivitis and and obtain baseline blood pressure measurements. giant papillary conjunctivitis.160,329 More recently, the We usually commence treatment at an oral dose of drug has also been shown to be effective when 2.5 mg/kg/day once daily, and increase dosage in administered systemically in the management of increments of 50 mg to a maximum of 5 mg/kg/ severe atopic keratoconjunctivitis.11 day, titrated to the clinical response.106 Blood pressure, serum creatinine, and BUN should be c. Side Effects checked at 2-week intervals while the drug dosage is Similar to cyclosporine, the major dose-limiting being titrated, followed by monthly testing of these side effects of tacrolimus are nephrotoxicity and parameters as well as creatinine clearance, blood hypertension. Renal insufficiency developed in counts, and liver function tests. Fasting lipids are 106,138 28.3% of 53 patients treated with the drug for monitored at 3-month intervals. Treatment is refractory uveitis, but was transient and mild in most continued for 2 years after quiescence to achieve cases.196 Systemic hypertension occurs in approxi- a durable remission after cessation of therapy. mately 47--50% of patients, but is well controlled by a single agent in the majority of patients.230 2. Tacrolimus (FK506) Neurologic side effects may include minor reactions such as headache and paresthesias to major neuro- a. Introduction and Mechanism of Action toxicity including expressive aphasia, seizures, and Tacrolimus, or FK506, is a macrolide antibiotic coma in less than 10% of patients when administered synthesized by the bacterium Streptomyces tsukubaen- intravenously at high doses in renal transplant sis. Like cyclosporine, tacrolimus inhibits T-cell recipients.229 In patients taking the drug orally for 488 Surv Ophthalmol 56 (6) November--December 2011 DURRANI ET AL uveitis, transient meningismus occurred in 12 of 53 Of eight patients with severe noninfectious uveitis, patients and resolved with discontinuation of ther- rapamycin therapy was found to be effective in five, apy.196 The incidence of secondary malignancy in and it was possible to reduce or discontinue patients receiving tacrolimus for rejection prophy- corticosteroid therapy in these responders. Treat- laxis following solid organ transplantation is esti- ment was discontinued in the remaining three mated to be approximately 1.6%.245 T-cell inhibitors patients because of unacceptable side effects. as a class, however, were not associated with increased Buech et al have described the preparation of mortality or cancer-related mortality in a large a microemulsion of rapamycin for potential use as retrospective cohort study of patients receiving this a topical agent.44 They concluded, however, that this class of agents for ocular inflammation.149 formulation did not achieve sufficient concentra- tions in the corneal endothelium and aqueous d. Suggested Treatment Protocol in Ocular Inflammatory humor, and thus was not recommended for the Disease prevention of allograft rejection after corneal trans- Tacrolimus is usually administered orally at a dose plantation or in autoimmune uveitis. They sug- of 0.05 to 0.15 mg/kg/day when used in the gested the formulation may be effective in the treatment of ocular inflammation.138 Baseline tests treatment of inflammatory disorders of the ocular and subsequent monitoring is performed in a man- surface such as keratoconjunctivitis sicca, vernal ner similar to that described for cyclosporine.106 As conjunctivitis, and atopic blepharitis. oral absorption of the drug is variable, trough levels of tacrolimus should also be monitored during c. Side Effects therapy.196 The optimal duration of therapy re- The most common reported side effects of quired to achieve long-term remission is yet to be rapamycin therapy in cardiac transplant patients determined. are infection and edema.200 In Shanmuganathan’s study of patients with ocular inflammation, side effects with rapamycin were mostly reported to be 3. Rapamycin gastrointestinal and cutaneous in nature.287 These a. Introduction and Mechanism of Action included elevated liver enzymes, nausea, abdominal Rapamycin, or sirolimus, is a macrocyclic triene pain, erythema nodosum, scleroderma-like changes, antibiotic synthesized by Streptomyces hygroslopius, seborrheic dermatitis, and eczematous rash. Re- which was first isolated from soil samples. Rapamycin current lower respiratory tract infections and belongs to the same family of immunosuppressive myalgias were also encountered. antibiotics as cyclosporine and FK506 and functions similarly, inhibiting T-cell activity and proliferation d. Suggested Treatment Protocol in Ocular Inflammatory through the interference of IL-2 signal transduc- Disease tion.277 Rapamycin forms a complex by binding to The recommended dosage of rapamycin for the the cytosolic immunophilin, FK binding protein-12. prevention of graft rejection is a loading dose of 6 mg, This complex binds to a target regulatory kinase followed by 2 mg/day, with the dose titrated to trough termed the mammalian target of rapamycin. This, in rapamycin levels, which are monitored throughout turn, prevents cytokine-driven T-cell proliferation, treatment.176 A daily dose of 2 to 6 mg/day, which stops the cell cycle at the G1 phase.193 In administered orally, has been described in one report addition to its immunosuppressive properties, rapa- in the management of ocular inflammatory disease.287 mycin possess antiangiogenic effects.161 Baseline tests and monitoring for renal, hematologic and hepatic adverse effects is performed in a manner b. Use in Ocular Inflammatory Disease similar to that described for cyclosporine treatment. In animal studies, Roberge and colleagues were Studies to establish the long-term efficacy and safety of able to demonstrate that rapamycin was effective in rapamycin in ocular inflammatory disease have yet to the treatment of autoimmune uveoretinitis in be reported. rats.247 Martin and colleagues investigated the combined effect of rapamycin and cyclosporine in 4. Dapsone this model and demonstrated that they acted synergistically in suppressing lymphocyte prolifera- a. Introduction and Mechanism of Action tion.182 Data regarding the use of rapamycin in Dapsone, or 4,40-diaminediphenyl sulfone, is ocular inflammatory disease is limited. Shanmuga- a synthetic sulfone first used in the treatment of nathan and co-workers have studied the efficacy of leprosy in the 1940. Since then, in addition to its rapamycin in the treatment of refractory uveitis.287 efficacy in chloroquine-resistant malaria, cutaneous TREATMENTS FOR OCULAR INFLAMMATORY DISEASE 489 leishmaniasis, and Pneumocystis carinii infection in depending on the clinical response and tolerance, acquired immune deficiency syndrome patients, it to a maximum of 150 mg/day.106 The dose should has also been found to have potent anti- then be reduced gradually once ocular inflamma- inflammatory properties.342 The drug has been tion has been brought under control. Weekly successfully used in the treatment of dermatitis complete blood counts are performed for the initial herpetiformis, bullous pemphigoid, and cicatricial 4 weeks, followed by hemograms every 4--6 weeks pemphigoid153,328 and is thought to mediate its anti- thereafter for the duration of therapy, which is inflammatory activity by stabilizing lysosomal mem- usually indefinite, as most patients relapse when the branes, thus decreasing the release of proteolytic drug is discontinued.106,239 enzymes, and by the inhibition of the myeloperox- idase-H2O2-halide-mediated cytotoxic system in D. MICROTUBULE INHIBITORS neutrophils.346 1. Colchicine b. Use in Ocular Inflammatory Disease a. Introduction and Mechanism of Action Dapsone has been shown to be effective in halting Colchicine is a microtubule inhibitor that binds to the progression of fibrosis in ocular cicatricial tubulin dimers and exerts an antimitotic effect by pemphigoid (OCP).101,269 We recommend use of preventing formation of the mitotic spindle, thus the drug as a first-line agent in patients with mild to halting cell division during metaphase.8,47,313 The moderate slowly progressive OCP in patients con- drug also causes the depolymerization and disap- firmed not to be glucose-6-phosphate dehydroge- pearance of fibrillar microtubules in granulocytes nase (G6-PD)-deficient.309 Dapsone has also been and other motile cells. This results in the inhibition used with variable success in patients with simple or of granulocyte migration and lysosomal degranula- nodular scleritis associated with relapsing polychon- tion, and thus the release of proteolytic enzymes at dritis (RP).132 However, the drug is ineffective in sites of inflammation. necrotizing scleritis associated with RP.103 b. Use in Ocular Inflammatory Disease c. Side Effects Studies indicate that colchicine may have limited The most frequent side effect of dapsone therapy efficacy in the treatment of some ocular manifesta- is methemoglobinemia, which occurs in almost all tions of Behçet disease, either alone or in combina- patients receiving a dose of 200 mg or greater per tion with other immunomodulatory agents.185,194,195 day, but appears less frequently at doses lower than In an early study, Mizushima et al showed that 104 of 2 mg/kg/day.74,89,232 Dose-related hemolysis, usu- 131 patients with Behçet disease responded to ally apparent 3 to 4 weeks after the initiation of colchicine.195 It has been reported that colchicine therapy, rarely warrants discontinuation of the drug. has been used successfully for anterior uveitis at Hemolytic anemia is much more common, more a dose of 1 mg/day; however its efficacy in severe severe, and occurs at lower doses in patients with posterior uveitis is limited.91,194,195 In a study by G6-PD deficiency.205,236,355 In these patients, re- Masuda et al, colchicine was shown to be inferior to duction of G6-PD activity inhibits the production cyclosporine in the treatment of ocular manifesta- of reduced glutathione, which is necessary to reduce tions of Behçet disease, as well as oral aphthous hydrogen peroxide and other oxygen-derived free ulceration, dermal, and genital lesions.183 The drug radicals produced by dapsone. Other rare compli- appears more useful as a prophylactic agent in the cations of therapy include life-threatening agranu- prevention of recurrences in patients with mild locytosis and aplastic anemia, reversible peripheral anterior uveitis in these patients. Nonetheless, neuropathy, toxic hepatitis and cholestatic jaundice, colchicine and cyclosporine have been successfully cutaneous hypersensitivity reactions, and a poten- used in this condition in combination.91 Colchicine tially fatal mononucleosis-like syndrome.342 may also be used alone or in combination with dapsone for the treatment of mild joint symptoms in d. Suggested Treatment Protocol in Ocular Inflammatory patients with ocular manifestations of relapsing Disease polychondritis.169 We recommend baseline G6-PD levels and a hemogram in all patients in whom dapsone therapy is c. Side Effects being considered. The drug is administered orally, When administered in moderate doses, colchicine and treatment is initiated at a dose of 25 mg twice is well tolerated; however, gastrointestinal side daily for 1 week, after which the dose is increased to effects are common.47,313Acute toxicity may result 50 mg twice daily, with further adjustments made in renal failure, vascular damage, hemorrhagic 490 Surv Ophthalmol 56 (6) November--December 2011 DURRANI ET AL gastroenteritis, and ascending paralysis of the not effective in preventing recurrences of uveitis central nervous system. Aplastic anemia, myopathy, compared to infliximab (59% vs 0% of patients, azoospermia, and agranulocytosis are other known respectively), or in controlling inflammation at final potential adverse effects. visit (94% vs 0%, repectively).113 In addition, a review of adverse event registry data by Lim et al demon- d. Suggested Treatment Protocol in Ocular Inflammatory strated a greater number of reported uveitis cases Disease associated with etanercept therapy than with infliximab and adalimumab, and suggested etanercept A complete hemogram with differential, as well as 172 serum chemistries and urinalysis, are performed may be a cause of uveitis. The efficacy of etanercept prior to commencing treatment. Colchicine is in the treatment of ocular inflammatory disease, typically administered orally at a dose of 0.5 to 0.6 therefore, is debatable. Of note, experience with mg two to three times a day in the setting of ocular biologics to date supports the notion that rates of inflammatory disease.106 Complete blood counts, disease-free remission after discontinuation of biologics are lower when compared to conventional serum chemistries, and urinalysis are repeated every 171,292,321 3 months thereafter for the duration of treatment, immunomodulatory agents. which is indefinite if used as monotherapy.106 iii. Side Effects. Reaction at the injection site is the most commonly reported side effect (37%).95 Serious infections and sepsis may be associated with etaner- III. Novel Immunomodulatory Agents cept treatment, with 30 of the estimated 25,000 patients receiving the drug reported to have de- Table 3 provides a representative list of novel veloped life-threatening infections, including sepsis. immunomodulators discussed in this section that Six died within 2 to 16 weeks of initiating treat- are used for therapy in ocular inflammatory disease. ment.272 Live vaccination is contraindicated during etanercept therapy. Rare side effects include pancy- A. ANTIBODIES topenia and aplastic anemia, onset or exacerbation of 1. Tumor Necrosis Factor Inhibitors a central nervous system demyelinating disorder, anaphylactic reactions, and a lupus-like syndrome.76 a. Etanercept In addition, the SITE study found an increased risk of i. Introduction and Mechanism of Action. Etanercept is mortality and cancer-related mortality in patients a dimeric protein composed of soluble tumor taking TNF inhibitors, including etanercept.149 The necrosis factor (TNF) receptor and a human IgG adjusted HR for deaths attributed to cancer in Fc fragment.50,270,345 The drug inhibits binding of patients receiving etanercept for ocular inflamma- both TNF-a and TNF-b to cell surface TNF re- tion was 4.38 (95% CI, 0.96--19.93; p 5 0.031). ceptors, rendering TNF biologically inactive. This Although concerning, these data were considered to results in decreased expression of adhesion mole- be less robust by the investigators as the number of cules responsible for leukocyte migration and de- patients and duration of follow-up in this group were creased synthesis of pro-inflammatory cytokines and considered to be limited. matrix metalloproteinases. iv. Suggested Treatment Protocol in Ocular Inflammatory ii. Use in Ocular Inflammatory Disease. Data regarding Disease. As with all anti-TNF therapies, patients with the use of etanercept for ocular inflammatory disease signs and symptoms of active systemic infection and is variable. Early studies by Smith et al demonstrated are not offered treatment. All candidates for therapy that etanercept was mildly effective in improving are tested for latent tuberculosis by tuberculin skin- inflammation.295 Sfikakis and colleagues found testing, and patients at risk of exposure to hepatitis etanercept to be promising in the treatment of B virus (HBV) also undergo serologic testing to Behçet disease with refractory ocular involvement, identify carriers of HBV.174 With rare exceptions, and Reiff et al concluded that the drug had patients showing evidence of latent TB and HBV a beneficial effect in children with uveitis, improving carriers are excluded from treatment with TNF inflammation in 10 of 16 affected eyes, with similar inhibitor therapy for ocular inflammatory disease. results maintained at 2 years of follow up.241,242,283 Patients with moderate to severe heart failure are Our group concluded, in the only double-masked, also excluded. A baseline hemogram and liver placebo-controlled randomized clinical trial on the function tests are performed prior to treatment subject, that it had no significant efficacy over placebo and repeated at monthly intervals. Patients with in preventing relapses of uveitis in patients being a history of mild heart failure are carefully moni- tapered from methotrexate.105 A subsequent retro- tored for signs and symptoms of worsening cardiac spective analysis of 22 patients treated with TNF function. Etanercept is typically administered as inhibitor therapy demonstrated that etanercept was a subcutaneous injection of 25 mg twice a week for TABLE 3 DISEASE INFLAMMATORY OCULAR FOR TREATMENTS Novel 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 Etanercept JIA 34 13 21 23 (68%) 11 (37%) 1 (3%) n/a Foeldvari99 Success 5$50% decrease in local or oral steroid Etanercept Noninfectious 20 (10 on 48 6 7/10 (70%) 3/10 (30%) 3/10 (30%) n/a Foster105 Success 5 no flare-up during uveitis on etanercept) treatment; no significant MTX taper difference from placebo Etanercept Ocular 22 (9 on 37 18 5/9 (56%) 4/9 (44%) 0 n/a Galor113 Success 5 Quiescence by 3 mos. inflammatory etanercept) disease Etanercept JIA 31 14 20 10 (32%) 21 (68%) 1 (3%) n/a Schmeling273 Success 5 no flare up during treatment Infliximab Refractory uveitis 12 35 17 12 (100%) 0 0 n/a Bodaghi35 Success 5 control of inflammation Infliximab Childhood uveitis 17 11 13 17 (100%) 0 0 n/a Kahn142 High dose infliximab, 10--20 mg/kg/dose Infliximab Childhood uveitis 13 6 21 12 (92%) 1 (8%) 0 n/a Saurenmann268 Success 5$50% decrease in steroid or other IMT Infliximab Behçet 25 33 8 25 (100%) 0 0 n/a Sfikakis284 Success 5 improved inflammation and VA on day 28 Infliximab Refractory uveitis 31 40 24 24/31 (77%) 7/31 (23%) 5/14 (36%) n/a Suhler303,304 Complications: PE, CHF, lupus- at 10 weeks like drug reaction Adalimumab Refractory uveitis 19 34 12 12 (63%) 7 (37%) 0 n/a Diaz-Llopis81 Success 5 controlled inflammation at 12 mos. Adalimumab Ankylosing 1,250 (274 46 8 See notes See notes n/a n/a Rudwaleit260,261 Recurrences decreased from spondylitis with uveitis) 15/100 PYs to 7.4/100 PYs with treatment Adalimumab JIA 20 13 19 7 (35%) 13 (65%) 0 n/a Tynjala323 Success 5 Improved uveitis Daclizumab Recalcitrant ocular 17 35 24 15 (88%) 2 (12%) 1 (6%) n/a Bhat30 Includes uveitis and scleritis inflammation Daclizumab JIA 6 9 13 5 (83%) 1 (17%) 1 (17%) n/a Sen279 Success 5 reduced inflammation at week 12 or on re-induction Daclizumab BSCR 8 50 26 7 (88%) 1 (13%) 2 (25%) n/a Sobrin298 Success 5 stable VA and resolved vitirits; ERG worsened in 3 pts. IVIg BSCR 18 51 32 17 (81%) 1 (19%) 3 (17%) 0 Cassoux52 Success 5 improved inflammation on FA; VA improved in 82% eyes IVIg þ OCP 12 T: 58 T:56 6/6 Treated 0 0 n/a Foster102 6/6 Controls had VA loss and Rituximab C: 63 C: 58 (100%) progression of OCP (Continued on next page) 491 TABLE 3 2011 November--December (6) 56 Ophthalmol Surv 492 Continued

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 IVIg OCP 16 (IVIg: 8, 63 (IvIg) 24 (IvIg) 8/8 (100%) 0 0 n/a Letko168 Total or partial control in 75% conventional of pts. on conventional treatment: 8) treatment IVIg Refractory uveitis 10 43 11 5 (50%) 5 (50%) 1 (10%) n/a Rosenbaum255 Mean age and f/u duration does not include 2 pts. in pilot study IVIg OCP 10 65 35 after 8/8 completing 0/8 completing 0 n/a Sami264 2 pts. did not complete completing treatment treatment (0%) protocol, lost VA treatment (100%) Rituximab Primary Sjogren 30 43 11 Mean LG score n/a 1/20 (5%) n/a Meijer190 p ! 0.05 for LG score; syndrome improved Schirmer’s and TBUT not improved Rituximab Thyroid 12 52 12 Mean CAS and n/a 0 n/a Silkiss291 p ! 0.001 for both scores eye disease TAOS scores improved Rituximab Wegener 10 48 12 10 (100%) 0 0 n/a Taylor310 IFN-a 2a Behçet 50 (9 with uveitis) 32 3 5/6 treated 1/6 treated 0 n/a Alpsoy6 1/3 (33%) improved in pts. (83%) pts. (17%) placebo-treated group IFN-a 2a Behçet and other 45 32 30 19/23 Behçet 4/23 Behçet 1 (2%) n/a Bodaghi36 (83%) (17%) 13/22 other 9/13 other (59%) (41%) IFN-a 2a Noninfectious 24 50 21 21 (88%) 3 (13%) 1 (4%) n/a Deuter77 Success 5 complete or partial uveitic CME resolution electroretinograph IFN-a 2a Behçet 32 30 71 28 (88%) 4 (13%) 0 n/a Gueudry126 Success 5 initial control; relapse rate increased after d/c IFN-a 2a Behçet 50 32 36 46 (92%) 4 (8%) 3 (6%) n/a Kotter156 Side effects requiring d/c were alopecia and diarrhea IFN-a 2a Behçet 44 30 24 (after 40 (91%) 4 (9%) 3 (8%) n/a Tugal- Success 5 partial or complete discontinuation) Tutkun320 response; 36% relapse-free during treatment BSCR 5 birdshot chorioretinopathy; C 5 control group; CAS 5 Clinical Activity Score; CHF 5 congestive heart failure; CME 5 cystoid macular edema; d/c 5 discontinuation; ERG 5 electroretinograph; FA 5 fluorescein angiography; f/u 5 follow-up; IFN-a 2a 5 interferon-a 2a; IMT 5 immunomodulatory therapy; IVIg 5 intravenous immunoglobulin; JIA 5 juvenile idiopathic arthritis; LG 5 lissamine green; MTX 5 methotrexate; n/a 5 not available; OCP 5 ocular cicatricial pemphigoid;

PE 5 pulmonary embolism; PY 5 person-year; T 5 treated group; TAOS 5 Thyroid Associated Ophthalmopathy Scale; TBUT 5 tear breakup time; VA 5 visual acuity. AL ET DURRANI TREATMENTS FOR OCULAR INFLAMMATORY DISEASE 493 a period of 2 years.138 However, our experience fatal.38,120 Caution should be exercised when suggests that sustained remission occurs less com- considering infliximab for individuals with a history monly after the discontinuation of biologics, even of chronic or recurrent infections, mild congestive after this period. heart failure, nervous system disorders, or who live in an area endemic for histoplasmosis. Infliximab is b. Infliximab contraindicated in patients with a clinically signifi- i. Introduction and Mechanism of Action. Infliximab is cant, active infection and moderate to severe a chimeric IgG monoclonal antibody that binds congestive heart failure. As with etanercept, patients a on infliximab should not be immunized with live specifically to TNF- with high affinity and neutralizes 272,282 its biological activity.50,270,345 It is composed of vaccines. As previously discussed, a prospective a human constant and a murine variable region. The trial of patients receiving infliximab for ocular functional activity of TNF-a has been shown to inflammatory disease showed a relatively high in- undergo inhibition by infliximab in a wide variety of cidence of thromboembolism, drug-related lupus- like illness, and a possible relationship to solid in vitro bioassays utilizing human fibroblasts, endo- 303 thelial cells, neutrophils, B-lymphocytes and T-lym- malignancy. Preliminary results from the SITE phocytes, and epithelial cells. Cells expressing retrospective cohort suggest an increased risk of transmembrane TNF-a are bound by infliximab and overall and cancer-related mortality in patients receiving TNF inhibitors, including infliximab, for lysed by complement or effector cells. Unlike etaner- 149 cept, infliximab does not neutralize TNF-b.271 It has ocular inflammation. been shown to be effective in treatment-resistant iv. Suggested Treatment Protocol in Ocular Inflammatory rheumatoid arthritis and inflammatory bowel Disease. Baseline testing is performed as described disease.26,175,178 for etanercept, and patients are screened and ii. Use in Ocular Inflammatory Disease.Dataregarding excluded from TNF inhibitor therapy as previously the efficacy of infliximab in ocular inflammatory discussed. Infliximab is administered intravenously disease have increased in recent years. It has been at an initial dose of 3 mg/kg/day at 0, 2, and 6 weeks, followed by a maintenance dose schedule used effectively in the treatment of the ocular 38,138,299 manifestations of Behçet disease resistant to other of every 8 weeks. Repeat hemograms and imunomodulatory agents, as well as uveitis and liver function tests are performed at the same scleritis secondary to JIA, ankylosing spondylitis, intervals, prior to each infusion. We typically Wegener granulomatosis, sarcoidosis, and Crohn continue treatment for a duration of 2 years once disease.23,35,142,209,240 Suhler et al performed a pro- quiescence is achieved in an effort to attain a sustained remission of ocular inflammation after spective clinical trial of infliximab therapy in patients 165 with refractory uveitis and reported results at 1 and 2 discontinuation of the drug. years of treatment.303,304 Twenty-four (24) of 31 patients (77%) met a composite clinical endpoint c. Adalimumab of clinical success at the first planned outcome i. Introduction and Mechanism of Action. Unlike eta- assessment. Of these patients, 15 completed one year nercept and infliximab, adamimumab is a fully of therapy, and 8 completed 2 years. A higher rate of human IgG1 TNF-a antibody produced by phage- adverse events was reported than in previous display technology.145 It binds specifically to TNF-a, retrospective case series. Of 24 patients treated with blocking its interaction with the cell surface TNF- the drug for 1 year, 3 developed thromboembolism, a receptors p55 and p75, which are expressed on 2 a drug-related lupus-like illness, and 1 each fibroplasts, neutrophils, and vascular endothelial developed a solid malignancy and congestive heart cells. Adalimumab also binds to soluble TNF-a, but failure. Of the eight patients who extended treatment not to TNF-b. Binding of adalimimab with surface to 2 years of therapy, one additional patient de- TNF-a results in lysis of TNF-a expressing cells veloped a drug-related lupus-like illness and two in vitro in the presence of complement. It has been patients developed fatal solid malignancies which shown to be effective in patients with rheumatoid were considered by the authors to have an unclear arthritis, ankylosing spondylitis, JIA, psoriatic arthri- relation to the drug. Seventy-five percent (75%) of tis, and plaque psoriasis.260,267,288,341 patients developed elevated antinuclear antibody ii. Use in Ocular Inflammatory Disease. Adalimumab is titers, which were of unclear clinical significance. being used with increasing frequency in the iii. Side Effects. Pulmonary and extrapulmonary tu- treatment of ocular inflammatory disease. Mushtaq berculosis and invasive fungal and opportunistic et al first described its use for ocular manifestations infections have been observed in patients on of Behçet disease and found it effective in main- infliximab. Some of these infections have been taining remission in patients previously treated with 494 Surv Ophthalmol 56 (6) November--December 2011 DURRANI ET AL infliximab.204 Since then, it has been successful in prevention rejection following solid organ transplan- patients with uveitis secondary to JIA, ankylosing tation. The drug is currently being studied in an spondylitis, refractory uveitis of diverse etiologies international phase III trial to determine its efficacy in including VKH and birdshot chorioretinopathy preventing relapses in multiple sclerosis.347 (BSCR), scleritis secondary to rheumatoid arthritis, ii. Use in Ocular Inflammatory Disease. Buggage et al and orbital pseudotumor.1,81,244,261,323 The recently performed a double-masked, randomized study to completed open-label, multicenter, uncontrolled investigate the safety and efficacy of daclizumab in Review of Safety and Effectiveness with Adalimumab the treatment of the ocular manifestations of Behçet in Patients with Active Ankylosing Spondylitis trial disease.45 Seventeen patients with Behçet disease that enrolled 1,250 patients with active ankylosing with ocular involvement were treated with intrave- spondylitis included 274 patients with a history of nous placebo or daclizumab. The authors con- anterior uveitis.261 This trial showed that adalimu- cluded that there was no evidence suggesting that mab decreased the frequency of recurrences of daclizumab was beneficial in comparison to placebo. anterior uveitis by 51% in all patients, decreasing it Sobrin et al studied the outcomes of daclizumab by 68% in patients with anterior uveitis within 1 year therapy in the management of BSCR.298 Eight prior to the start of therapy, 50% with active uveitis patients with BSCR with refractory disease, or who at the start of therapy, and by 45% in patients with were intolerant to traditional immunomodulatory chronic uveitis. therapy, were reviewed. During a mean follow-up of iii. Side Effects. Injection-site reactions are the most 25.6 months, seven of eight patients demonstrated common side effect, but occur less frequently when a stabilization or improvement in visual acuity and compared to other TNF-a inhibitors.5 As with other a total resolution of vitreous inflammation. Resolu- TNF-a inhibitors, reactivation of tuberculosis and tion of vasculitis on fluorescein angiography was life-threatening fungal and opportunistic infections observed in six patients. Four patients in this study may occur during treatment with adalimumab, and remained free of inflammation while on daclizumab precautions must be taken in patients with a history alone. Gallagher et al treated 23 pediatric patients of chronic or recurrent infection and patients living with uveitis using biological response modifiers.111 in areas endemic for histoplasmosis. Similarly, the Five of these patients were treated with daclizumab. drug should be used with caution in patients with The results showed that an improvement in visual congestive heart failure. TNF-a inhibitors may be acuity occurred in 4 of 10 eyes in the daclizumab related to an increased risk of malignancy, and subset, and 8 of 10 eyes were found to have adalimumab has been associated with a greater risk decreased inflammation. In another study, Yeh of non-melanoma skin cancer.294 et al reported the use of high dose daclizumab in iv. Suggested Treatment Protocol in Ocular Inflammatory five patients with noninfectious intermediate or Disease. Following intial screening, as described for posterior uveitis, and demonstrated an improve- etanercept, adalimumab is administered subcutane- ment in vitreous haze in four of five patients by the ously at a typical dose of 40 mg every other week.261 fourth week of follow-up.353 Sen and colleagues also Monitoring is performed similarly at monthly in- treated six patients with JIA-associated uveitis with tervals, and treatment continued for a period of high dose daclizumab, and found that five achieved 2 years following quiescence, provided the patient control of inflammation by the end of the study, remains free of inflammation during this period. with one patient requiring discontinuation of the drug due to a medication-induced rash.279 2. Anti-IL-2 Receptor Antibodies iii. Side Effects. Daclizumab has been well-tolerated in patients with uveitis.223,279 Potential side effects of a. Daclizumab treatment are lymphadenopathy, psoriasiform i. Introduction and Mechanism of Action. Daclizumab rashes, mild peripheral edema, and infections. A is a humanized monoclonal antibody that targets the meta-analysis of clinical trial results in patients alpha subunit of the IL-2 receptor on the surface of undergoing renal transplantation showed no in- T-lymphocytes.350 It is synthesized by recombinant crease in the risk of malignancy with daclizumab.336 DNA technology. It binds CD25, also known as Tac iv. Suggested Treatment Protocol in Ocular Inflammatory or p55, on the human IL-2 receptor on activated Disease. Prior to treatment with daclizumab, we T-lymphocytes.158 By doing so it inhibits the IL- routinely perform baseline complete hemograms 2--mediated biologic responses of activated lymphoid and liver function tests.298 The drug is administered cells. This reaction inhibits autoreactive T-cells without intravenously at a dose of 1 mg/kg every 2 weeks, suppressing the function of the immune system. The and the dose and frequency of administration are production of daclizumab has been discontinued due then titrated to the clinical response, to a maximum to low market demand as an immunomodulator in the dose of 200 mg.30 Complete blood counts and liver TREATMENTS FOR OCULAR INFLAMMATORY DISEASE 495 function tests are then performed prior to each demyelination showed that polyclonal immunoglob- infusion for a period of 2 years, provided the patient ulins promote remyelination.251 In the clinical is free of ocular inflammation. setting, van Engelen and associates have reported improved vision in patients with stable demyelinating 325 3. Miscellaneous Antibodies optic neuritis who were treated with IVIg. Urcelay et al were the first to report the use of IVIg in two a. Intravenous Immune Globulin patients with OCP refractory to corticosteroids and i. Introduction and Mechanism of Action. Intravenous immunosuppressive agents.324 Both showed a positive immune globulin (IVIg) consists of preparations response to therapy. Our group has studied 10 composed of 97--98% intact immunoglobulin G with patients with severe OCP unresponsive to conven- an IgG subclass distribution akin to that of normal tional therapy and subsequently treated with IVIg. human plasma.302 A trace amount of IgA is Disease progression was controlled in 8 of 10 patients contained in the preparation, and this may cause who completed the study.264 IVIg has also been anti-IgA immunization in patients with total de- employed in patients with Graves ophthalmopathy, ficiencies of that isotype. Donations from a large and three studies have reported positive results with number of individuals (7,000--10,000) contribute to IVIg treatment.10,166,281 Seider et al have reported on the preparation of IVIg. Due to the large number of four patients with ocular Behçet disease refractory to donors, these preparations provide a broad spec- steroids and cyclosporine, subsequently treated with trum of antibody specificities against pathogens. IVIg.278 All four patients showed a positive response IVIg, in addition, contains natural antibodies that to treatment. In patients with pemphigus vulgaris are not generated by prior exposure to external refractive to IVIg therapy and conventional immuno- antigens or active immunization.67 These antibodies suppressives, the addition of rituximab has been are present in IgG, IgA, and IgM isotypes, and their shown to be effective in controlling mucosal in- role remains unchanged throughout life. These flammation.2 Similar positive results with IVIg ther- natural antibodies are considered to be more apy have also been reported in orbital myositis, polyreactive than immune antibodies (directed anterior uveitis associated with Kawasaki disease, against an exogenous antigen). More than one and VKH.51,121,286 mechanism has been proposed for the action of iii. Side Effects. IVIg remains a costly therapeutic IVIg in autoimmune disease: (1) blockage and option. Potential side effects of treatment are modulation of the IgG Fc fragment receptors on aseptic meningitis, thromboembolism, and risk of the surface of macrophages; (2) modulation of transmission of blood-borne infections.171 Other cytokine synthesis and release; (3) modulation of adverse effects include allergic reactions, and the complement system; (4) selection of B- and T- volume overload in patients with borderline con- lymphocyte repertoires; (5) neutralization of circu- gestive heart failure.158 lating autoantibodies; and finally (6) interaction iv. Suggested Treatment Protocol in Ocular Inflammatory with other B- and T-lymphocyte surface mole- Disease. Before commencing treatment, we perform cules.146 It is effective in a wide range of disorders, a complete blood count with differential, and de- including primary immune deficiencies such as termine levels of quantitative immunoglobulins prior common variable immune deficiency, autoimmune to each infusion. If levels are normal, patients receive diseases including autoimmune idiopathic throm- 1 to 2.5 g/kg/cycle of treatment divided over 3 days. bocytopenic purpura and Kawasaki disease, and Premedication is with 650 mg acetaminophen and autoimmune blistering diseases such as pemphigus 50 mg diphenhydramine orally 30 minutes before foliaceus and mucus membrane pemphigoid.158 each infusion.218 A slow, continuous infusion is then ii. Use in Ocular Inflammatory Disease. Sunakawa was administered in an ambulatory setting over a 210--240 one of the first to report a beneficial effect of IVIg in minute period. Infusions are repeated at 2- to 4-week a patient with severe uveitis.306 Since then, the intervals until ocular inflammation has subsided, effectiveness of IVIg has been studied in several types after which infusions are repeated every 5 to 6 weeks of ocular inflammatory disease. One study involving for at least 2 years after remission has been achieved, 18 patients with active BSCR treated solely with IVIg after which therapy may be gradually tapered and demonstrated an improvement in vision in 53.8% of discontinued.218,264 patients and a decrease in 7.7% of patients.166 In this report, macular edema, when present, resolved in half of the eyes to fluorescein angiography with b. Anakinra treatment. Studies to evaluate the role of IVIg therapy i. Introduction and Mechanism of Action. Anakinra is in optic neuritis have also been conducted. Animal a recombinant form of the human IL-1 receptor studies in a virus model of inflammatory antagonist that differs from native human IL-1 496 Surv Ophthalmol 56 (6) November--December 2011 DURRANI ET AL receptor antagonist in that it has an additional antigen on the surface of human B-lymphocytes. methionine residue at its amino terminus.50 It blocks CD20 regulates the early differentiation and matu- the biologic activity of IL-1 by competitively inhibiting ration of B-lymphocytes. It is found on pre-B- the binding of IL-1 to the IL-1 type I receptor.175 lymphocytes, mature B-lymphocytes and B-cells in Anakinra has been approved for patients 18 years or non-Hodgkin lymphoma but not in hematopoietic older suffering from moderately to severely active stem cells, normal plasma cells, or other tissues.318 rheumatoid arthritis.97 It may be used alone or in The Fab portion of rituximab binds with the CD20 conjunction with other disease-modifying antirheu- antigen on B-lymphocytes and the Fc portion binds matic drugs except TNF-a antagonists. with the immune effector cells, inducing cell lysis by ii. Use in Ocular Inflammatory Disease. In ophthal- complement-mediated cytotoxicity, antibody- mology, the use of anakinra has almost exclusively dependent cell-mediated cytotoxicity and induction been limited to animal models. It has been shown to of apoptosis.117 Rituximab therapy results in the prevent rejection of corneal grafts, possibly by directly depletion of B-cells and reduction of IgG and IgM suppressing inflammation and preserving anterior levels for 6 to 12 months following therapy.171 chamber--associated immune deviation.68,139,349 It Rituximab is active against low-grade non-Hodgkin inhibits corneal neovascularization by inhibiting lymphomas, chronic lymphocytic leukemia, and intercellular adhesion molecule-1.356 It also sup- multiple myeloma.54 Its immunosuppressive effects presses allergic eye disease by down-regulating have been shown to be effective in preventing graft eosinophils and other inflammatory cells.148 The rejection following ABO-incompatible kidney trans- role of IL-1 antagonism in Graves disease and uveitis is plantations without splenectomy, systemic lupus under investigation.151,173,254,319 A recent case report erythematosus, autoimmune hemolytic anemia, has described the effectiveness of anakinra in the Waldenstrom macroglobulinemia, and pemphigus treatment of chronic infantile neurological articular vulgaris.2,9,83,123,322 syndrome--associated posterior uveitis recalcitrant to ii. Use in Ocular Inflammatory Disease. A growing TNF inhibitor therapy.312 number of reports indicate rituximab is useful in the iii. Side Effects. The most common reported side treatment of recalcitrant ocular inflammation. To effect of anakinra is injection-site reaction. The risk of date, it has been used successfully in patients with life-threatening infections such as tuberculosis and rheumatoid arthritis--associated scleritis, Wegener other opportunistic infections is a concern, particu- granulomatosis involving the eye and orbit, Behçet larly among debilitated patients and patients with disease with recalcitrant retinal vasculitis, primary dysfunction of immune system.96 Treatment with Sjogren syndrome, and, in combination with IVIg, anakinra is generally associated with small reductions ocular cicatricial pemphigoid.70,102,137,190,310 in total leukocyte, platelet, and absolute neutrophil iii. Side Effects. Rituximab is contra-indicated in blood counts. A small percentage of patients re- patients with IgE-mediated hypersensitivity to murine ceiving anakinra therapy develop marked neutrope- proteins. A severe hypersensitivity reaction may occur nia. The risk of both infections and neutropenia in such patients following an intravenous push or increases significantly with concomitant use of bolus. Serious side effects include infection, sepsis, anti-TNF agents. Contraindications to anakinra use infusion reactions with adult respiratory distress include hypersensitivity to the drug or to Escherichia syndrome, bronchospasm, pulmonary edema, an- coli--derived proteins, active infection, neutropenia, gioedema, tumor lysis syndrome in patients with and concomitant use of anti-TNF agents.96 a high load of malignant cells, severe mucocutaneous iv. Suggested Treatment Protocol in Ocular Inflammatory reactions such as Steven-Johnson syndrome and toxic Disease. A baseline complete blood count with epidermal necrolysis, acute renal failure, and cardiac differential is performed in all patients prior to arrhythmias.57,259 All of these side effects are administering anakinra. In patients with rheuma- potentially fatal.54 toid arthritis, the drug is administered as a sub- iv. Suggested Treatment Protocol in Ocular Inflammatory cutaneous injection of 100 mg/day.118 Subsequent Disease. When administered in combination with monitoring may then be performed at monthly IVIg in patients with recalcitrant ocular cicatricial intervals. Insufficient data exist regarding treatment pemphigoid, we infuse rituximab at a dose of 375 duration required to attain sustained remission. mg/m2 once weekly for 8 consecutive weeks. Thereafter, the drug is administered monthly for 4 months, for a total of 6 months of treatment.102 c. Rituximab Complete hemograms and peripheral blood B-cell þ i. Introduction and Mechanism of Action. Rituximab is levels (CD20 cells) are determined by flow cytom- a genetically engineered murine/human chimeric etry prior to each dose. In this protocol, IVIg is monoclonal IgG antibody directed against CD20 administered as described earlier one month prior to TREATMENTS FOR OCULAR INFLAMMATORY DISEASE 497 initiating rituximab therapy, and then monthly until recommended prior to initiation of treatment. Pa- B-cell levels decrease to within normal limits. tients with an active infection should not be started on Thereafter, IVIg is administered at 6, 8, 10, 12, 14, treatment with tocilizumab. Patients receiving the and 16 weeks.102 drug also have a higher incidence of gastrointestinal perforation, mainly secondary to diverticulitis.217 a. Tocilizumab iv. Suggested Treatment Protocol in Ocular Inflammatory i. Introduction and Mechanism of Action. Tocilizumab Disease. The use of tocilizumab in humans for is a recombinant humanized anti-IL-6 receptor ocular inflammation is not yet reported. In patients monoclonal antibody that has been shown to bind with rheumatoid arthritis in whom treatment is specifically to both soluble and membrane-bound considered, individuals with an active infection are IL-6 receptor and inhibit downstream signaling by excluded, and tuberculin skin-testing is performed. these receptors.327 IL-6 is an inflammatory cytokine Patients with latent tuberculosis requiring cilizumab produced by a variety of cells including T-cells and for rheumatoid arthritis must receive adequate antimycobacterial therapy prior to initiating treat- B-cells, lymphocytes, and monocytes, and is involved 217 in T-cell activation, immunoglobulin secretion, ment. A baseline complete blood count with leukocyte recruitment, and the proliferation and differential and liver function tests are then differentiation of hematopoietic precursor cells.252 performed. In patients with rheumatoid arthritis, It has also been shown to be produced by synovial the drug is infused at an initial dose of 4 mg/kg, and endothelial cells in joints affected by rheuma- increased to 8 mg/kg every 4 weeks based on the toid arthritis.327 Tocilizumab has been shown in clinical response. The duration of treatment re- several randomized double-blind clinical trials to be quired to achieve sustained remission is unknown. effective in the treatment of patients with moderate to severe rheumatoid arthritis, either as monother- B. OTHERS apy or in combination with other disease modifying 1. Interferons antirheumatic drugs, notably in patients who have a. Introduction and Mechanism of Action had an inadequate response to anti-TNF-a therapies.217 It is also effective in polyarticular juvenile Interferons (IFNs) are a group of cytokines rheumatoid arthritis and Castleman disease.186,354 synthesized by a variety of cell types with immuno- ii. Use in Ocular Inflammatory Disease. In the eye, IL-6 modulatory, antiviral, and antiproliferative proper- has been shown to play an important role in the ties. The type I interferons, which include IFN-a and regulation of inflammation in in vivo studies.214,215 IFN-b, are the most clinically relevant in the context In an animal model of lipopolysaccharide-induced of ocular inflammation. IFN-a and IFN-b exert uveitis, elevated IL-6 levels have been found to immunomodulatory effects by increasing the ex- correlate with the development of ocular inflamma- pression of major histocompatibility complex class I surface molecules and by the activation of macro- tion, loss of immune privilege, and the loss of T-cell 130 suppression capacity by the aqueous humor.215 phages and natural killer cells. Two human Interleukin-6 levels have also been found to be recombinant IFN-a peptides, IFN-a 2a and 2b, and elevated in patients with active uveitis.71,109,228 Our two IFN-b peptides, IFN-b 1a and 1b, are routinely used in the management of hepatitis C and multiple group measured levels of IL-6 in the vitreous of 23 130 eyes with active intermediate or posterior uveitis, sclerosis, respectively. and found levels of this cytokine to be significantly increased compared with cadaveric donor con- b. Use in Ocular Inflammatory Disease trols.228 Interestingly, levels of TNF-a, IL-1, and Interferon has been used in patients with ocular IL-2 were not detectable in these eyes with active manifestations of Behçet disease since 1994.94 IFN-a ocular inflammation. No data regarding the efficacy 2a was shown by Alpsoy et al in a randomized of tocilizumab for ocular inflammatory disease have controlled trial of 50 patients (9 of whom had ocular been published. involvement) to be superior to placebo in reducing iii. Side Effects. The most common adverse effects the severity and frequency of relapses of ocular include upper respiratory tract infections, nasophar- inflammation.6 A non-controlled open-label pro- yngitis, headache, hypertension, and a transient ele- spective study of 50 patients with refractory Behçet vation of serum liver enzyme levels.327 Neutropenia, disease with ocular involvement treated with IFN-a thrombocytopenia, and serious infection, including 2a demonstrated a response rate of 92%, with reactivation of tuberculosis, invasive fungal infections, significant improvements in visual acuity and ocular and opportunistic bacterial infections, have been inflammation.156 At an average follow-up of 2.5 reported with therapy.217 Tuberculin skin-testing is years, more than one-third of patients in this trial 498 Surv Ophthalmol 56 (6) November--December 2011 DURRANI ET AL had completed therapy and were free of ocular rheumatoid arthritis have immune responses to inflammation. Two meta-analyses have corroborated native type II collagen, it is unclear whether these findings, with 94% and 95% of patients with collagen reactivity is related to the primary patho- Behçet-related ocular inflammation demonstrating genesis in rheumatoid arthritis or simply reflects a partial or complete response to IFN-a 2a ther- tissue degradation. When injected in animals, type apy.155,359 However, there is some overlap of the II collagen induces an arthritis morphologically cases reviewed in these analyses. In the meta-analysis similar to rheumatoid arthritis. Oral administration performed by Kotter et al, IFN-a 2a appeared more of type II collagen is thought to suppress disease effective than IFN-a 2b in controlling ocular activity in rheumatoid arthritis by inducing oral inflammation.155 tolerance.301 In a randomized double-blind trial of IFN-b 1a is used to prevent recurrences in patients 60 patients with severe active rheumatoid arthritis, with multiple sclerosis, and there is evidence that it study subjects demonstrated a decrease in the is effective in the treatment of intermediate uveitis number of involved joints compared to subjects associated with this condition. A recent case series of receiving placebo, with four patients having com- 13 patients with multiple sclerosis--associated uveitis plete disease remissions.317 However, consistent treated with IFN-b 1a demonstrated improvements efficacy of type II collagen in rheumatoid arthritis in visual acuity, ocular inflammation, and associated has not been demonstrated.21,129 macular edema.25,177 Although data are limited, interferon may also be effective in other uveitis b. Use in Ocular Inflammatory Disease subtypes, including sympathetic ophthalmia and 36,233 Thompson et al treated 16 patients with JIA and idiopathic posterior uveitis. uveitis with chicken type II collagen with equivocal results.314 In that study, four participants experi- c. Side Effects enced improvement in ophthalmic outcomes in The most common adverse effects of interferon terms of anterior chamber inflammation and visual therapy are injection-site reactions. Flu-like symp- acuity, and two participants worsened. Six subjects toms occurred in an average of 88%, mild leukope- demonstrated an improvement in systemic symp- nia in 30%, and alopecia in 10% of patients in one toms of JIA, and no serious or related adverse events meta-analysis.155 Elevation of liver enzymes may were reported. Based on these results, usefulness in occur in a minority of patients, but is typically uveitis therapy was thought to be unlikely, but this reversible. Ischemic heart disease and arrhythmias remains to be seen. may worsen. In addition, depression and suicidal ideation have been reported, and patients should be c. Side Effects counseled to report these symptoms immediately to During phase I and phase II studies of oral type II their prescribing physician. Auto-immune thyroid- collagen treatment in rheumatoid arthritis, adverse itis has also been reported in patients using 130 events did not differ significantly from groups interferon. receiving placebo.21 Adverse events possibly related to treatment are nausea, abdominal pain, and d. Suggested Treatment Protocol in Ocular Inflammatory heartburn.129,289 Disease A complete blood count, liver function tests, and d. Suggested Treatment Protocol in Ocular Inflammatory thyroid function tests should be performed prior to Disease 177 treatment. IFN-a 2a is typically administered at As efficacy of this drug has not been demon- a dose of 3 to 6 million international units, daily to 3 78 strated in humans to date, we believe there is times a week. Repeat hemograms and liver insufficient evidence to recommend therapy at function tests are performed at 4-week intervals, present. and thyroid function testing is performed every 3 months. Treatment is continued with a goal of achieving quiescence of inflammation for a period 3. Pentoxifylline of 2 years before cessation of therapy. a. Introduction and Mechanism of Action Pentoxifylline is a tri-substituted dimethylxan- 2. Type II Collagen thine derivative nonselective phosphodiesterase inhibitor that has been shown to cause vasodilation a. Introduction and Mechanism of Action and inhibit platelet aggregation by inhibiting 22 Type II collagen is a structural protein abundantly thromboxane A2 synthesis. Pentoxyfilline de- present in articular cartilage. Although patients with creases blood viscosity, and, in patients with chronic TREATMENTS FOR OCULAR INFLAMMATORY DISEASE 499 arterial disease, has been known to increase tissue TNF-a and IL-6 release by macrophages, inhibit oxygenation. It also enhances erthrocyte and neu- migration of leukocytes, and downregulate Th1 trophil deformability, and decreases neutrophil function.140,143 It also suppresses cutaneous inflam- adhesion and activation.14,88 Although the precise mation, zymosan-induced inflammation, LPS- mechanism of its immunomodulatory effects are induced TNF-a expression, and collagen-induced still under investigation, inhibition of TNF-a may arthritis.48,154,257,311 play a primary role.75,90 b. Use in Ocular Inflammatory Disease b. Use in Ocular Inflammatory Disease Rolipram has been used in murine models of Pentoxifylline has been known to have several experimental autoimmune uveoretinitis induced by ocular effects. These include increased pulsatile retinal S antigen and lipopolysaccharide induced ocular blood flow, increased blood flow velocity in uveitis in rats, and has been shown to reduce the retinal vessels, protection against retinal ischemia/ severity of intraocular inflammation in these reperfusion injury, and increased choroidal perfu- models.61,348 This effect is independent of IL-10 sion in eyes with ocular hypotension.62,274,335 It has and is thought to be secondary to inhibition of been also been found to be effective in reducing NF-kB translocation and expression of E-selectin, fibroblast proliferation in thyroid ophthalmopathy TNF-a, and IL-6. No clinical data are available to by inhibiting HLA-DR expression and glycosamino- date regarding the use of rolipram in the treatment glycan synthesis induced by inflammatory cytokines of ocular inflammation in humans. including TNF-a, IFN-g and IL-1.18,58 The use of pentoxifylline in ocular inflammatory disease has c. Side Effects 12,351 been limited. A report from Japan decribes its The use of rolipram has been limited by the high use in controlling uveitis in three patients with 351 incidence of nausea and vomiting. Newer second- Behçet disease. generation PDE IV inhibitors such as zardaverine and CDP-840 have been shown to have a much lower c. Side Effects incidence of emesis than rolipram.41,128 Common side effects include gastrointestinal disturbance, nausea, dizziness, and headache. Sim- d. Suggested Treatment Protocol in Ocular Inflammatory ilar to other methylxanthines, pentoxifylline may Disease 246 also cause chest pain and tachycardia. Pentoxifyl- Insufficient data exist regarding the use of line is contraindicated in patients with a history of rolipram in ocular inflammatory disease at present. recent cerebral and retinal hemorrhage and allergy to methylxanthines.335 d. Suggested Treatment Protocol in Ocular Inflammatory IV. Conclusion Disease The use of corticosteroids by Gordon and McLean We believe insufficient evidence of the efficacy of in 1950 was a landmark event that revolutionized pentoxifylline in the treatment of ocular inflamma- the treatment of ocular inflammatory disorders at tion currently exists. the time. The intervening half century has allowed investigators to more clearly identify the pathways 4. Rolipram involved in the systemic immune response, as well as the mechanisms of auto-immunity and immune a. Introduction and Mechanism of Action deviation, unique to the eye. In comparison to Rolipram is a selective inhibitor of cAMP-specific earlier immunomodulators, which may inhibit phosophodiesterase (PDE), PDE IV. Inhibition of several pathways in the immune system by multiple PDE IV, an enzyme that phosphorylates and thus mechanisms, recombinant DNA technology and the deactivates cAMP, results in increased intracellular synthesis of humanized monoclonal antibodies have cAMP levels. Elevation of cAMP leads to down- revolutionized therapy, allowing selectively inhibi- regulation of inflammatory cell activity, possibly by tion of the precise cytokines and receptors that may decreasing free cytosolic calcium mobilized during be involved in specific autoimmune ocular inflam- cell activation. It is thought that PDE IV inhibitors matory conditions. This, hopefully, will open the way reduce the release of cytokines from activated to rational drug design and allow the synthesis of peripheral blood monocytes because there is a cAMP immunomodulators effective in abolishing inflam- response element in the transcription of cytokine mation, but with fewer systemic effects, that preserve genes.197 Rolipram has been shown to suppress the immune system’s capability of warding off 500 Surv Ophthalmol 56 (6) November--December 2011 DURRANI ET AL internal and external pathogens. This, coupled with 7. Andrasch RH, Pirofsky B, Burns RP. 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Outline

I. Introduction 3. Leflunomide A. Background: the rationale for immuno- a. Introduction and mechanism of action modulatory therapy b. Use in ocular inflammatory disease c. Side effects II. Conventional immunomodulatory agents in d. Suggested treatment protocol in ocular ocular inflammatory disease inflammatory disease A. Antimetabolites 4. Mycophenolate mofetil 1. Methotrexate a. Introduction and mechanism of action b. Use in ocular inflammatory disease a. Introduction and mechanism of action c. Side effects b. Use in ocular inflammatory disease d. Suggested treatment protocol in ocular c. Side effects inflammatory disease d. Suggested treatment protocol in ocular inflammatory disease B. Alkylating agents 2. Azathioprine 1. Cyclophosphamide a. Introduction and mechanism of action a. Introduction and mechanism of action b. Use in ocular inflammatory disease b. Use in ocular inflammatory disease c. Side effects c. Side effects d. Suggested treatment protocol in ocular d. Suggested treatment protocol in ocular inflammatory disease inflammatory disease TREATMENTS FOR OCULAR INFLAMMATORY DISEASE 509

2. Chlorambucil iii. Side effects iv. Suggested treatment protocol in ocular a. Introduction and mechanism of action inflammatory disease b. Use in ocular inflammatory disease c. Side effects b. Infliximab d. Suggested treatment protocol in ocular i. Introduction and mechanism of action inflammatory disease ii. Use in ocular inflammatory disease iii. Side effects C. Antibiotics iv. Suggested treatment protocol in ocular 1. Cyclosporine inflammatory disease a. Introduction and mechanism of action c. Adalimumab b. Use in ocular inflammatory disease i. Introduction and mechanism of action c. Side effects ii. Use in ocular inflammatory disease d. Suggested treatment protocol in ocular iii. Side effects inflammatory disease iv. Suggested treatment protocol in ocular 2. Tacrolimus (FK506) inflammatory disease a. Introduction and mechanism of action 2. Anti-IL-2 receptor antibodies b. Use in ocular inflammatory disease c. Side effects a. Daclizumab d. Suggested treatment protocol in ocular i. Introduction and mechanism of action inflammatory disease ii. Use in ocular inflammatory disease 3. Rapamycin iii. Side effects iv. Suggested treatment protocol in ocular a. Introduction and mechanism of action inflammatory disease b. Use in ocular inflammatory disease c. Side effects 3. Miscellaneous antibodies d. Suggested treatment protocol in ocular inflammatory disease a. Intravenous immune globulin 4. Dapsone i. Introduction and mechanism of action ii. Use in ocular inflammatory disease a. Introduction and mechanism of action iii. Side effects b. Use in ocular inflammatory disease iv. Suggested treatment protocol in ocular c. Side effects inflammatory disease d. Suggested treatment protocol in ocular inflammatory disease b. Anakinra i. Introduction and mechanism of action D. Microtubule inhibitors ii. Use in ocular inflammatory disease 1. Colchicine iii. Side effects iv. Suggested treatment protocol in ocular a. Introduction and mechanism of action inflammatory disease b. Use in ocular inflammatory disease c. Side effects c. Rituximab d. Suggested treatment protocol in ocular i. Introduction and mechanism of action inflammatory disease ii. Use in ocular inflammatory disease iii. Side effects III. Novel immunomodulatory agents iv. Suggested treatment protocol in ocular inflammatory disease A. Antibodies d. Tocilizumab 1. Tumor necrosis factor inhibitors i. Introduction and mechanism of action a. Etanercept ii. Use in ocular inflammatory disease i. Introduction and mechanism of action iii. Side effects ii. Use in ocular inflammatory disease 510 Surv Ophthalmol 56 (6) November--December 2011 DURRANI ET AL

iv. Suggested treatment protocol in ocular 3. Pentoxifylline inflammatory disease a. Introduction and mechanism of action b. Use in ocular inflammatory disease B. Others c. Side effects 1. Interferons d. Suggested treatment protocol in ocular inflammatory disease a. Introduction and mechanism of action b. Use in ocular inflammatory disease 4. Rolipram c. Side effects a. Introduction and mechanism of action d. Suggested treatment protocol in ocular b. Use in ocular inflammatory disease inflammatory disease c. Side effects 2. Type II collagen d. Suggested treatment protocol in ocular inflammatory disease a. Introduction and mechanism of action b. Use in ocular inflammatory disease c. Side effects IV. Conclusion d. Suggested treatment protocol in ocular V. Method of literature search inflammatory disease VI. Disclosure