PEER REVIEWED

Autoimmune Inflammatory Vitreoretinal Disease: Pathogenesis, Progression, and Treatment

DAVID M. HINKLE, MD · C. STEPHEN FOSTER, MD

Our stepladder approach, including a brief synopsis of many of the medications typically employed for treatment of ocular inflammatory disease, appeared in the March 2007 issue of Retinal Physician. Enhanced understanding of the pathogenesis and progression of uveitis is leading to targeted therapies with less potential toxicity and greater efficacy for the most recalcitrant cases of ocular inflammatory disease. Additional therapeutic options, including off-label use of currently available medications and ongoing clinical research studies of promising new drugs and devices will also be reviewed. The trend in uveitis management toward evidence-based medicine is reflected by an increasing number of ongoing randomized, controlled clinical trials. There are 24 randomized, controlled clinical trials currently registered at www.clinicaltrials.gov and an additional 10 nonrandomized or open label trials in progress.

TREATMENT HISTORY

The pathogenesis of autoimmune uveitis is still being elucidated. Based on histopathologic findings in experimental autoimmune uveitis (EAU), uveitis is believed to be a T-lymphocyte–mediated disease process in most cases. This discovery explained the earliest successful treatment efforts with steroid-sparing agents, including methotrexate, azathioprine, and cyclophosphamide in the 1950s and 1960s, and led to the utilization of more specific T-cell inhibitors (cyclosporine, tacrolimus, rapamycin [Rapamune, Wyeth], and daclizumab [Zenapax, Roche]), first in EAU and then in the treatment of patients with birdshot retinochoroidopathy, retinal vasculitis, and other forms of intermediate and posterior uveitis in the 1980s and 1990s.^1,2

Autoreactive T cells develop due to deficient peripheral T-cell–anergy mechanisms and may lead to retinal autoimmunity in some patients.³ Several retinal antigens, including arrestin (S-antigen), interphotoreceptor binding protein, and tyrosinase-related proteins, may be initiators of autoimmune retinopathy.⁴ Once T cells are presented such antigen by cells resident in ocular tissue (macrophage, vascular endothelium, pigment epithelium, and Müller cell), a costimulatory signaling cascade leads to upregulation of receptors on the T-cell surface and production of a number of proinflammatory cytokines including interferon gamma, tumor necrosis factor, interleukin (IL)-6, and IL-17.⁵ The response is a combined humoral and cell-mediated event. Deposition of complement, recruitment of additional inflammatory cells, and collateral destruction of adjacent ocular tissue occur as the immune system attempts to eradicate the "self" protein misidentified as "foreign" antigen.⁶

Attempts to induce tolerance to inciting antigens achieved limited success in patients with rheumatoid arthritis and multiple sclerosis.^7,8 Following the favorable results of a pilot study in 1 patient with pars planitis and another with Behçet disease, a phase 1/2 trial of oral bovine retinal S-antigen in the treatment of uveitis was completed. Although the trials were underpowered to demonstrate statistically significant efficacy, there was a trend toward longer time to flare-up and the ability to reduce immunosuppressant medications.⁹ The time and expense associated with production of bovine retinal S-antigen also limited widespread adoption of this treatment option.

Figure 1. Late-phase fluorescein angiogram demonstrating retinal vasculitis in Behçet syndrome patient.

When tolerance mechanisms fail, the autoimmune response leads to progressive inflammation and tissue damage. An inflammatory cell infiltrate develops in a manner similar to the normal wound-healing response. This manifests clinically as an increase in retinal and choroidal vascular permeability (edema), vitreous organization, and ultimately neovascularization, fibrosis, and contraction.

PATIENT MANAGEMENT

Frequently, the natural history of this autoimmune response is progressive vision loss. Uveitis currently accounts for 10% of vision loss in the United States.¹⁰ A survey performed a century ago implicated uveitis as the cause of blindness in 14% of US cases.¹¹ Intermediate uveitis, posterior uveitis, and panuveitis are responsible for the majority of visual disability in patients with ocular inflammatory disease. Although intermediate uveitis is anecdotally ascribed a favorable prognosis, one-fourth of patients suffer visual impairment or loss. Roughly half of patients with posterior or panuveitis in the same study suffered similar outcomes.¹²

The introduction of corticosteroid treatment 50 years ago effected little change on the level of visual impairment; many patients with uveitis are intolerant or refractory to corticosteroid therapy or suffer ongoing damage due to chronic low-grade inflammation during attempts to taper corticosteroids.

We are strong proponents of aggressive early treatment with immunomodulatory chemotherapy to slow or arrest the progression of these blinding diseases. The International Uveitis Study Group established guidelines for the treatment of severe ocular inflammatory disease 2 decades ago.¹³ Immunomodulatory therapy is indicated as first-line treatment of Behçet disease with retinal involvement (Figure 1), sympathetic ophthalmia, rheumatoid sclerouveitis, and Vogt-Koyanagi Harada (VKH) syndrome (Table 1). Immunomodulatory therapy alone, or as a steroid-sparing agent, is superior to corticosteroid monotherapy in the prevention of vision loss in VKH syndrome.¹⁵ In addition, the American Uveitis Society consensus panel found good evidence for immunosuppressive therapy in the treatment of the conditions listed in Table 2 and suggested that steroid-sparing therapy should be considered for most chronic ocular inflammatory disorders.¹⁵

Birdshot retinochoroidopathy highlights the importance of monitoring disease activity with multiple modalities to detect progressive disease activity or complications that place a patient at higher risk of vision loss. Properly managed, birdshot patients may suffer visual impairment, but most retain functional vision (Figure 2). When poorly managed, birdshot is a blinding disease with an end stage resembling tapetoretinal degeneration.¹⁶

Figure 2. Color fundus photograph of the left eye of a patient with a 26-year history of birdshot retinochoroidopathy demonstrating optic nerve pallor and extensive chorioretinal atrophy and scarring. Visual acuity is 20/40 in the left eye and 20/30 in the less-affected right eye, with no angiographic cystoid macular edema or retinal vasculitis in either eye. (Right eye is not shown.)

Birdshot patients frequently experience floaters, nyctalopia, and peripheral visual-field disturbances despite "normal" central visual acuity (VA). Symptoms tend to wax and wane without objective changes in the VA, vitreous, or fundus appearance.

Fluorescein angiography (FA) may disclose occult retinal vasculitis, optic papillitis, and cystoid macular edema (CME). Comorbid CME, which may persist despite excellent control of inflammation, is a leading cause of severe, permanent vision loss in uveitic eyes, including those with anterior uveitis.¹⁷ Optical coherence tomography greatly improves the ability to detect this vision-robbing complication and monitor response to therapy for CME (Figure 3). Indocyanine green angiography is particularly helpful in evaluating the extent of choroiditis present and, in our experience, frequently reveals more extensive involvement than that seen on FA. Similarly, short-wave-length–automated perimetry isolates the scotopic, koniocellular retinal ganglion cell pathway and may detect scotoma up to 5 years earlier than standard achromatic perimetry.¹⁸

Figure 3. Optical coherence tomography demonstrating uveitic cystoid macular edema before and after intravitreal bevacizumab (Avastin, Genentech) injection.

Full-field electroretinography is a crucial test in the monitoring of birdshot. The bright scotopic response amplitude and 30-Hz photopic flicker implicit times are sensitive, objective, and reproducible indicators of retinal dysfunction that enable physicians to quantify disease progression and adjust treatment accordingly.¹⁹

NEWER TREATMENT MODALITIES

When standard treatment fails to halt progression, physicians may turn to more targeted therapeutic modalities. Daclizumab is a humanized immunoglobulin G monoclonal antibody to CD25 of the IL-2 receptor. Antibody binding inhibits T lymphocyte activation. Daclizumab is indicated for the treatment of renal allograft rejection. Its safety and efficacy in the treatment of intermediate and posterior uveitis were first reported in 1999.²⁰ We find it effective in the treatment of posterior uveitis, particularly in birdshot retinochoroidopathy patients intolerant or refractory to combination cyclosporine and mycophenolate mofetil (CellCept, Roche).^{21, 22} Cereon Genomics (Cambridge, United Kingdom) has plans for conducting a proof of concept trial of basiliximab (Simulect), another IL-2 receptor monoclonal antibody, for noninfectious uveitis later this year.

Lux Biosciences (Jersey City, NJ) is conducting a double-masked, randomized, controlled phase 3 clinical trial of LX211 in the treatment of uveitis. The LUMINATE trial, with 43 sites in North America, Europe, and India, holds the promise of providing patients with the first Food and Drug Administration (FDA)-approved systemic medication for the treatment of uveitis. LX 211 is a calcineurin inhibitor that blocks T-cell–signal transduction in a manner similar to cyclosporine. Subcutaneous injections of LX211 successfully prevented or reversed EAU in male Lewis rats.²³ LX211 demonstrated safety and efficacy in prevention renal allograft rejection and control of psoriasis in phase 2 clinical trials and appears to have a much larger therapeutic window, with a more favorable side-effect profile than earlier calcineurin inhibitors.²⁴

The elusive promise of a nontoxic therapeutic agent for ocular inflammatory disease remains on the horizon. Pregnant women tend to experience fewer exacerbations of uveitis and other autoimmune diseases, particularly during the third trimester.²⁵ This phenomenon correlates with serum alpha-fetoprotein levels. Merrimack Pharmaceuticals (Cambridge, MA) is conducting a single-center, double-masked, randomized, controlled phase 2 clinical trial of MM-093, a recombinant human alpha-fetoprotein (AFP), in the treatment of sarcoidosis associated uveitis and birdshot retinochoroidopathy at our institution. AFP improved symptoms in rheumatoid arthritis and psoriasis patients during phase 2 clinical trials.²⁶

There are ongoing efforts to deliver corticosteroids to ocular tissues in a controlled, sustained, and targeted manner, thereby avoiding a plethora of well-known side effects associated with systemic administration, repeated intraocular injections, and tissue destruction induced by recurrent inflammation as intraocular levels diminish during tapering or elimination. Posurdex (Allergan, Irvine, CA), an implantable biodegradable dexamethasone implant, demonstrated efficacy in the treatment of macular edema secondary to uveitis, diabetes, and retinal vein occlusion in phase 2 trials.²⁷ Dexamethasone release occurs for up to 6 months following a single injection. A double-masked, placebo-controlled phase 3 trial for the treatment of intermediate and posterior uveitis is recruiting patients in uveitis centers across the United States.

The National Eye Institute-sponsored MUST trial is recruiting patients with uveitis for a randomized trial of systemic therapy vs an implantable fluocinolone acetonide implant (Retisert, Bausch & Lomb, Rochester, NY) at 24 centers in the United States, United Kingdom, and Australia. Steady-state fluocinolone release occurs for approximately 30 to 36 months.

We favor Retisert implantation combined with vitrectomy for diagnostic and therapeutic purposes.^28,29 Because cataract is a guaranteed side effect of Retisert implantation and glaucoma requiring surgery for adequate control of intraocular pressure (IOP) develops in up to 30% of eyes post-implantation, we very much favor, if at all possible, reserving this therapy for patients with unilateral uveitis who have not shown elevated IOPs following aggressive corticosteroid therapy. Patients with uveitis who are aphakic or pseudophakic are especially good candidates.

Finally, a long-awaited preservative-free formulation of triamcinolone acentonide has received FDA approval, allaying concerns over the ocular toxicity of alcohol-preserved formulations, as well as the potential for unpredictable dilution or contamination of washed suspensions. Triesence (Alcon, Fort Worth, TX) is indicated for visualization during vitrectomy and treatment of sympathetic ophthalmia, temporal arteritis, uveitis, and ocular inflammatory conditions unresponsive to topical corticosteroids. We welcome a safer treatment option for severe, vision-threatening intraocular inflammation, but we hasten to discourage event-based treatment strategies that are associated with poor long-term outcomes due to cumulative damage from recurrent or chronic inflammation.^30,31

CONCLUSION

While the management of patients with ocular inflammatory disease remains challenging, it is truly exciting to care for patients with ocular inflammatory disease as we witness a period of unprecedented translation of basic science research into increasingly targeted clinical therapeutics. RP

REFERENCES

1. Nussenblatt RB, Rodrigues MM, Wacker WB, et al. Cyclosporin A: Inhibition of experimental autoimmune uveitis in Lewis rats. J Clin Invest. 1981;67: 1228-1231.
2. Mochizuki M, Nussenblatt RB, Kuwabara T, Gery I. Effects of cyclosporine and other immunosuppressive drugs on experimental autoimmune uveoretinitis in rats. Invest Ophthalmol Vis Sci. 1985;26:226-232.
3. Lambe T, Leung JC, Ferry H, et al. Limited peripheral T cell anergy predisposes to retinal autoimmunity. J Immunol. 2007;178:4276-4283.
4. Gery I, Nussenblatt RB, Chan CC, Caspi RR. Autoimmune diseases of the eye. In: Theofilopoulos AN, Bona CA, eds. The Molecular Pathology of Autoimmune Diseases. New York, NY: Taylor and Francis; 2002:978-998.
5. Peng Y, Han G, Shao H, Wang Y, Kaplan HJ, Sun D. Characterization of IL-17+ interphotoreceptor retinoid-binding protein-specific T cells in experimental autoimmune uveitis. Invest Ophthalmol Vis Sci. 2007;48:4153-4161.
6. Montalvo V, Chan CC, Gery I, et al. Complement deposits on ocular tissues adjacent to sites of inflammation. Curr Eye Res. 2007;32:917-922.
7. Trentham D, Dynesius-Trentham R, Orav E, et al. Effects of oral administration of type II collagen on rheumatoid arthritis. Science. 1993;261:1727-1730.
8. Weiner H, Mackin G, Matsui M, et al. Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis. Science. 1992;259:1321-1324.
9. Nussenblatt RB, Gery I, Weiner HL, et al. Treatment of uveitis by oral administration of retinal antigens: results of a phase I/II randomized masked trial. Am J Ophthalmol. 1997;123:684-687.
10. Nussenblatt RB. The natural history of uveitis. Int Opthalmol. 1997;14:303.
11. Taylor HR. LXIII Edward Jackson Memorial Lecture: Eye Care: Dollars and Sense. Am J Ophthalmol. 2007;143:1-8.
12. Rothova A, Suttorp-van Schulten MS, Treffers WF, Kijlstra A. Causes and frequency of blindness in patients with intraocular inflammatory disease. Br J Ophthalmol. 1996;80:332-336.
13. Bloch-Michel E, Nussenblatt RB. International Uveitis Study Group recommendations for the evaluation of intraocular inflammatory disease. Am J Ophthalmol. 1987;103:234-235.
14. Paredes I, Ahmed M, Foster CS. Immunomodulatory therapy for Vogt- Koyanagi-Harada patients as first-line therapy. Ocul Immunol Inflamm. 2006;14:87-90.
15. Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendation of an expert panel. Am J Ophthalmol. 2000;130:492-513.
16. Rothova A, Van Schooneveld MJ. The end stage of birdshot retinochoroidopathy. Br J Ophthalmol. 1995;79:1058-1059.
17. Lardenoye CW, van Kooij B, Rothova A. Impact of macular edema on visual acuity in uveitis. Ophthalmology. 2006;113:1446-1449.
18. Landers JA, Goldberg I, Graham SL. Detection of early visual field loss in glaucoma using frequency-doubling perimetry and short-wavelength automated perimetry. Arch Ophthalmol. 2003;121:1705-1710.
19. Zacks DN, Samson CM, Loewenstein J, Foster CS. Electroretinograms as an indicator of disease activity in birdshot retinochoroidopathy. Graefes Arch Clin Exp Ophthalmol. 2002;240:601-607.
20. Nussenblatt RB, Peterson JS, Shiffman R, et al. Treatment of noninfectious intermediate and posterior uveitis with the humanized anti-Tac mAb: a phase I/II clinical trial. Proc Natl Acad Sci USA. 1999;96:7462-7466.
21. Papaliodis GN, Chu D, Foster CS. Treatment of ocular inflammatory disorders with daclizumab. Ophthalmology. 2003;110:786-789.
22. Sobrin L, Huang JJ, Kristen W, Kafkala C, Choopong P, Foster CS. Daclizumab for treatment of birdshot chorioretinopathy. Arch Ophthalmol. 2008:126: 186-191.
23. Cunningham M, Li Z, Chan CC, et al. Subcutaneous Injections of LX211 Prevent and Reverse Experimental Autoimmune Uveoretinitis in Rats. Poster presented at: Annual Meeting of the Association for Vision and Research in Ophthalmology; May 6-10, 2007; Fort Lauderdale, FL.
24. Bissonnette R, Papp K, Poulin Y, et al. A randomized, multicenter, double-blind, placebo-controlled phase 2 trial of ISA247 in patients with chronic plaque psoriasis. J Am Acad Dermatol. 2006;54:472-478.
25. Kump LI, Cervantes-Castañeda RA, Androudi SN, Foster CS, Christen WG. Patterns of exacerbations of chronic non-infectious uveitis in pregnancy and puerperium. Ocul Immunol Inflamm. 2006;14:99-104.
26. Pollard LC, Murray J, Moody M, et al. A randomised, double-blind, placebo-controlled trial of a recombinant version of human alpha-fetoprotein (MM-093) in patients with active rheumatoid arthritis. Ann Rheum Dis. 2007;66:687-689.
27. Kuppermann BD, Blumenkranz MS, Haller JA, et al. Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema. Arch Ophthalmol. 2007;125:309-317.
28. Diamond JG, Kaplan HJ. Uveitis: effect of vitrectomy combined with lensectomy. Ophthalmology. 1979;86:1320-1329.
29. Kaplan HJ, Diamond JG, Brown SA. Vitrectomy in experimental uveitis. II. Method in eyes with protein-induced uveitis. Arch Ophthalmol. 1979;97: 336-339.
30. Durrani, Tehrani NN, Marr JE, et al. Degree, duration, and causes of visual loss in uveitis. Br J Ophthalmol. 2004;88:1159-1162.
31. Dana MR, Merayo-Lloves J, Schaumberg DA, Foster CS. Prognosticators for visual outcome in sarcoid uveitis. Ophthalmology. 1996;103:1846-1853.