Article Date: 1/1/2010

Intraocular Inflammatory Disorders Update
PEER REVIEWED

Intraocular Inflammatory Disorders Update

OLGA M. CERON, MD ∙ DAVID M. HINKLE, MD ∙ C. STEPHEN FOSTER, MD

Intraocular inflammatory disorders encompass a broad spectrum of disease in which the eye or various parts of the eye may be attacked by white blood cells leading to severe visual impairment. In the posterior segment, uveitis, macular edema, vasculitis and retinal detachments contribute to loss of vision. Intermediate uveitis, posterior uveitis and panuveitis are responsible for the majority of visual disability in patients with ocular inflammatory disease. The sight-threatening complications of uveitis include glaucoma, retinopathy and macular edema.1,2

EPIDEMIOLOGY, ETIOLOGY AND DIAGNOSIS

Uveitis is the third leading cause of blindness worldwide and accounts for 10% of vision loss in the United States and up to 15% worldwide.3,4 It is among the array of autoimmune disorders with retinal manifestations (Table 1).5

In addition to a through clinical exam, multiple technologies assist clinicians in their diagnoses and monitoring of patients with ocular inflammatory disease. Optical coherence tomography can assess the macula for edema and for its response to therapy. OCT has gained increasing importance in the diagnosis and evaluation of patients with ocular inflammatory disease. Fluorescein angiography is also useful in elucidating pathology in the retina and its vasculature.

A tailored approach to laboratory testing and selective medical consultation is also key in finding the etiology contributing to inflammation. 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-wavelength automated perimetry isolates the scotopic, koniocellular retinal ganglion cell pathway and may detect scotoma up to five years earlier than standard achromatic perimetry.

Full-field electro retinography is a crucial test in the monitoring of birdshot retinochorioretinopahy (Figure 1). 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.5

Figure 1. Birdshot chorioretinopathy with petalloid macular edema imaged by fluorescein angiography.

Olga M. Ceron, MD, David M. Hinkle, MD, and C. Stephen Foster, MD, are partners at the Massachusetts Eye Research and Surgery Institution in Cambridge, MA. Dr. Hinkle reports financial interest in Sirion Therapeutics, and Dr. Foster reports interest in Abbott, Alcon, Allergan, Bausch & Lomb, Eyegate, Genentech, Inotech, Inspire, Ista Pharmacuticals, LUX Biosciences, Merrimack Pharmaceuticals, Novartis, Sirion, and Therakine. Dr. Ceron reports no financial interest in any products mentioned in this article. She can be reached via e-mail at omchmd@gmail.com.

MANAGEMENT

The aim of ocular inflammatory treatment is to prevent visual loss, discomfort and ocular morbidity. 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. 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.

Corticosteroids have been considered the standard of care for ocular inflammatory disease, but with the advent of new agents, this is changing as the use of noncorticosteroid immunomodulatory agents3–8 in selected pa tients with uveitis allows for improved control and decreased risk of corticosteroid-induced side effects.

Autoimmune uveitis is a treatable condition that may require the use of systemic immunomodulatory medication to halt its progression. Immunosuppressive agents were reserved for treatment, sight-threatening, steroid resistant uveitis or for use in patients who had developed unacceptable steroid induced adverse effects. Now, instead of being regarded as merely steroid sparing, these drugs are often used as first-line agents for a variety of disease with destructive ocular sequele.

Our paradigm3–6 for treating ocular inflammation is based on a limited tolerance to corticosteroid use and a more proactive approach to corticosteroid-sparing immunomodulatory therapy, in an effort to induce a durable remission of ocular inflammatory disease off all corticosteroids. This paradigm provides a “step-ladder” algorithm,3-6 providing the ophthalmologist the opportunity to reduce the aggressiveness of steroid therapy and also incorporate newer immunomodulatory agents:

The algorithm's steps are as follows:

  1. Initial treatment with corticosteroids and/or directly to immunomodulation therapy (see step 4) with gradual steroid withdrawal.
  2. Systemic nonsteroidal anti-inflammatory drugs for selected indications.
  3. Peripheral retinocryopexy or laser photocoagulation in certain patients with intermediate uveitis or pars planitis.
  4. Systemic immunomodulators.
  5. Therapeutic pars plana vitrectomy.

We are strong proponents of aggressive early treatment with immunomodulatory chemotherapy to slow or arrest the progression of vision-threatening diseases.

The International Uveitis Study Group9 established guidelines for the treatment of severe ocu lar inflammatory diseases. Immunomodulatory therapy is indicated as first-line treatment of Behçet disease with retinal involvement, sympathetic ophthalmia (Figure 2), rheumatoid sclerouveitis and Vogt-Koyanagi-Harada (VKH; Figure 3) syndrome (Table 2).

Figure 2. Fundus photo of sympathetic ophthalmia with an exudative retinal detachment.

Figure 3. Fluorescein angiogram of Vogt-Koyangi-Harada with serous retinal detachment and multiple pinpoint hyperfluorescent dots with leakage.

Immunomodulatory therapy alone, or as a steroid-sparing agent, is superior to corticosteroid mono therapy in the prevention of vision loss in VKH syndrome. In addition, the American Uveitis Society consensus panel found good evidence for immuno-suppressive therapy in the treatment of Behçet disease, birdshot retinochoroidopathy, juvenile idiopathic arthritis, Multifocal choroiditis and panuveitis, serpiginous choroidopathy, sympathetic ophthalmia and VKH syndrome. The panel suggested that steroid-sparing therapy should be considered for most chronic ocular in flammatory disorders.

Regardless of the form of autoimmunity, any autoimmune disease affecting the eye may require systemic therapy (Table 3); the components of the immune system reside not in the eye, but rather are systemic and therefore regulation of those components will require systemic therapy.3

When standard treatment fails to halt progression, physicians may turn to more targeted therapeutic modalities.3, 6, 7,10–12

SIDE EFFECTS OF TREATMENT MODALITIES

For many years, patients and clinicians have been concern ed that use of immunosuppressive therapies for ocular inflammatory disease might incur a risk of long-term adverse effects (Table 4).13

In order to evaluate this concern, the Systemic Immuno-suppressive Therapy for Eye Disease (SITE) cohort study was conducted.14 It was a multicenter study across the United States funded by National Institutes of Health and was comprised of five different sites: Casey Eye Institute; Massachusetts Eye Research and Surgery Institute and Massachusetts Eye and Ear Infirmary; National Eye Institute; Scheie Eye Institute; and Wilmer Eye Institute. It is the largest databank in existence for the study of ocular inflammatory diseases treated with corticosteroids and sys temic immunomodulatory therapy.

The SITE study was a classic chart-review study and not a clinical trial. The goal was to determine whether the long-term use of systemic immunosup-pressive therapy for eye diseases leads to a higher risk of malignancy or death. It was our understanding that it does not, but our single-center data were limited to 518 patients with follow-up considerably shorter than that of the SITE study. This SITE study answers this question, which people have been asking since the introduction of such therapy in the late 1970s.

The idea was to “pool together” all the patients from the five largest uveitis referral centers across the United States and to then analyze all of them together. The reason for taking such a large number of patients was to allow us to detect even a small increase in the development of cancer or malignancy. In summary, our results suggest that metho trexate, azathio-prine, mycophenolate mofetil, cyclosporine A, dapsone and systemic corticosteroids given to patients with ocular inflammatory diseases do not increase the risk of overall or cancer mortality. Alkylating agents did not significantly increase the risk of overall mortality, but our results could be consistent with a small to moderate in crease in cancer mortality risk with these agents.

Our findings suggesting substantially increased overall and cancer mortality following tumor necrosis factor-inhibitor therapy should not be taken as conclusive unless supported by more data over a longer time period.

The Multicenter Uveitis Steroid Treatment (MUST) trial is a multicenter randomized clinical trial comparing two treatments for patients with vision-threatening noninfectious intermediate uveitis, posterior uveitis or panuveitis. Its primary aim is to evaluate local therapy with fluocinolone acetonide intraocular implant in affected eyes vs standard therapy, which is systemic corticosteroid therapy supplemented, when indicated, by corticosteroid-sparing potent immunomodulator therapy. The goal is to see which approach is better for preventing vision loss. Completion of the study is expected in December 2011.

CONCLUSION

Currently, multiple clinical trials (Table 5) are ongoing to continue to elucidate treatment options for the complex therapeutic regimens for autoimmune ocular inflammatory disease to provide effective treatment and a safer side effect profile. Novel biologics targeting interleukin (IL)-17 show promise.12 While the management of patients with ocular inflammatory disease remains challenging, it is exciting to care for patients with ocular inflammatory disease as we enter a new frontier of unprecedented translation of basic science research into increasingly targeted therapeutics.5 RP

REFERENCES

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  3. Foster CS. Advances in the diagnosis and treatment of uveitis. Paper Presented at: 80th Annual Meeting of the Association for Research in Vision and Ophthalmology; April 27–May 1, 2008; Fort Lauderdale, FL.
  4. Foster CS. Ocular autoimmune disease: an introduction. Ocular Immunology and Uveitis Foundation Web site. http://www.uveitis.org/patient/articles/articles/auto.html. Accessed December 23, 2009.
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  7. 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 U S A. 1999;96:7462-7466.
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  9. Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immuno-suppressive drugs in patients with ocular inflammatory disorders: recommendation of an expert panel. Am J Ophthalmol. 2000;130:492-513.
  10. Bloch-Michel E, Nussenblatt RB. International Uveitis Study Group recommendations for the evaluation of intraocular inflammatory disease. Am J Ophthalmol. 1987;103:234-235
  11. Lindstrom R. The pharmacologic and pathophysiologic rationale for using NSAIDs in ocular inflammatory disease and ocular surgery. Int Ophthalmol Clin. 2006;46:7-11.
  12. Koenders, M. Joosteen L, Van den Berg W. Potential new targets in arthritis therapy: interleukin (IL) −17 and its relation to tumour necrosis factor and IL-1 in expermential arthritis. Ann Rheum Dis. 2006;65(Suppl 3):iii29-332006;65.
  13. Lane L, Tamesis R, Rodriguez A, et a. Systemic immunosuppressive therapy and the occurrence of malignancy in patients with ocular inflammatory disease. Ophthalmology. 1995;102:1530-5.
  14. Kempen J et al. Overall and cancer related mortality among patients with ocular inflammatory treated with immunosuppressive drugs: retrospective cohort study. BMJ. 2009;339:b2480.


Retinal Physician, Issue: January 2010