An Overview of Uveitis and Its Management

Release Date: April 1, 2011

Expiration Date: April 30, 2013

FACULTY:

Brenda Wood, BPharm, PharmD
Clinician and Medical Writer
San Diego, Califorina

FACULTY DISCLOSURE STATEMENTS:

Dr. Wood has no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy
acpePostgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 0430-0000-11-011-H01-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

GOAL:

To provide pharmacists with an overview of uveitis and its treatment strategies.

OBJECTIVES:

After completing this activity, the participant should be able to:

  1. Compare and contrast the anatomy and physiology of the normal eye with that of the various forms of uveitis.
  2. Discuss the pathophysiology, diagnosis, goals of therapy, and general treatment strategies for uveitis.
  3. Describe pharmacologic management of uveitis.

Uveitis is defined as an inflammatory process affecting either the iris, the ciliary body, or the choroid layer of the eye.1 The iris is the pigmented portion of the eye.2 Muscles that control the iris are responsible for changing the size of the pupil depending on the amount of light present. The ciliary body is where the aqueous humor is produced.3 Between the sclera and the retina lies the choroid layer, which consists of blood vessels and connective tissue. Uveitis is characterized as either anterior uveitis, intermediate uveitis, posterior uveitis, or panuveitis.1 The most common type of uveitis is anterior, which is defined as an inflammation from the iris to the ciliary body. Inflammation from the ciliary body to the periphery of the retina is termed intermediate uveitis, and posterior uveitis involves inflammation of the choroid layer, retina, and retinal vessels. Finally, panuveitis is inflammation of the iris, the ciliary body, and the choroid areas.1

The most common form of intraocular inflammation is uveitis.4 Significant vision loss can occur in up to 35% of children and adults with uveitis.1,5 Vision loss associated with uveitis is caused by cataract, chorioretinal scarring, cystoid macular edema, inflammatory optic neuropathy, retinal detachment, retinal vascular occlusions, secondary glaucoma, and inflammatory cell debris in the vitreous space or vitreous hemorrhage.6 Total blindness in the United States as a result of uveitis accounts for 10% to 15% of all cases.7 There have been two recent studies in the U.S. that address the incidence and prevalence of uveitis.8,9 The incidence of uveitis has been reported to be 25 to 52 cases per 100,000 person-years, while the prevalence has been reported to be 69 to 115 per 100,000 persons.8,9 The Northern California Epidemiology of Uveitis Study suggested that the incidence of uveitis increased with age. This is in contrast to other published epidemiology studies, which report the highest incidence as between ages 25 and 44 years.8 One epidemiology study in the Veterans Affairs Medical Centers of the Pacific Northwest did not see a statistically significant difference in incidence as it relates to gender.8 However, Braakenburg et al suggest that human leukocyte antigen (HLA)-B27–associated systemic disease is more prevalent in men than in women and may be related to the severity of the systemic disease seen in males.10 Examples of HLA-B27–associated systemic diseases include systemic spondyloarthropathies such as ankylosing spondylitis and reactive arthritis. Uveitis in children is slightly more common in girls than in boys, which may be due to a higher incidence of juvenile idiopathic arthritis seen in girls.5

Pathophysiology and Etiology

Uveitis may be due to an infection; however, about half of all cases are idiopathic. The idiopathic cases are diagnosed as or presumed to be associated with systemic autoimmune diseases.5,11 TABLE 1 lists some of the infectious and noninfectious systemic causes of uveitis.12 The International Uveitis Study Group provides a broader classification of uveitis that is characterized by the terms infectious, noninfectious, and masquerade (neoplastic or nonneoplastic).13 HLA-B27–related idiopathic uveitis is the most common diagnoses for uveitis and occurs frequently in the setting of systemic spondyloarthropathies, such as ankylosing spondylitis and reactive arthritis.8,14 Higher rates of infectious uveitis associated with tuberculosis are seen in developing countries versus developed countries.15 The most common systemic disease in the West associated with uveitis in children is juvenile idiopathic arthritis.5 Secondary iatrogenic uveitis may be seen after ocular surgery or ocular trauma.16

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The inflammation seen in uveitis is a result of a disruption of the blood-ocular barrier, which results in infiltration of leukocytes and protein leakage. Animal models have been used to understand disease pathogenesis. Studies of retinal S-antigen in mice support the idea that this antigen is causally involved in human uveitis, and from animal experiments it was seen that tumor necrosis factor (TNF) alpha is proinflammatory in noninfectious uveitis.4 New methods of treatment may result from animal model studies and may target modification of the immune system with anticytokine monoclonal antibodies, cytokine antagonist therapy, TNF alpha therapy, intravenous immunoglobulin therapy, antigen-specific therapy, antiadhesion molecules, antimajor histocompatibility complex II, and gene therapy.4 However, these therapies need to be further tested in human patients with uveitis. Now and in the future, providers may be using these experimental therapies to avoid the long-term effects of corticosteroid agents.

Patient Presentation

Patients with acute anterior uveitis generally present with one or all of the following symptoms: a red eye, pain in the eye, sensitivity to light, and blurred vision. No discharge is found in uveitis, and the pupil may be smaller or distorted as a result of muscle spasms of the sphincter of the iris.12 Other forms of uveitis may present in a similar fashion except for uveitis associated with juvenile idiopathic arthritis. These cases may be asymptomatic, making it more important for early detection and treatment. Posterior uveitis can be bilateral, and in these cases may have painless loss of vision and no redness. If inflammation is present in the vitreous space, floaters may be present.12 The course of the disease can be acute, which results in a sudden onset that lasts less than 3 months, or recurrent, in which repeated episodes are separated by remissions of greater than or equal to 3 months’ duration during which no treatment was received. Finally, the course can be chronic, where relapses occur less than 3 months after treatment is stopped. To understand the characteristic of uveitis in terms of onset, duration, and course, see TABLE 2.12,17

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Goals of Therapy

The goal of treatment is to rapidly resolve the inflammation, resulting in the return of vision.12 In the case of chronic uveitis, the goal of therapy is to cure the patient in addition to preserving sight.1 A thorough evaluation by an ophthalmologist should be done as soon as possible.18 It is important to determine if the uveitis is isolated or part of a systemic disorder. Additional symptoms that might signify involvement of a systemic disorder include back pain, joint pain, stiffness, diarrhea, and mouth ulcers. All patients with acute anterior uveitis (uveitis that affects vision and is defined by the site of the inflammation) will require treatment, as will the majority of those with other active forms of uveitis (a majority of active cases of uveitis affect vision). Thus, if the inflammation associated with uveitis is not threatening the eyesight, treatment may not be needed for some chronic forms.12 In order to resolve the inflammation, however, it is important that the drug and route of administration adequately penetrate to the site of inflammation in the eye.

Overview of Treatment

The accepted practice in treating first-time episodes of uncomplicated uveitis flare-ups is to use a corticosteroid, either topical, oral, or other.1,15 Severe cases may require a combination of oral, topical, periocular, or intravitreal corticosteroids. In extreme cases where vision is threatened, IV steroids for 3 days may be required. Cycloplegic agents may be used at the onset of acute uveitis to prevent pain and photophobia.18 If uveitis is not resolved within 4 weeks of the use of high-dose (60-80 mg/day) oral prednisone or if no response is seen within 2 to 4 weeks of high-dose oral prednisone, then an immunosuppressive agent should be added.15 Steroid-sparing medications are recommended when the ocular inflammation does not improve with high-dose corticosteroids or the inflammation recurs upon steroid tapering. However, if oral nonsteroidal anti-inflammatory drugs (NSAIDs) are ineffective, then immunosuppressive therapy is the last line of treatment. Oral methotrexate may be a good first choice as an immunosuppressant because it is dosed once weekly, is typically tolerated by patients, and is more affordable compared to some of the other immunosuppressant agents. If the patient is unable to tolerate methotrexate, alternative oral agents include azathioprine, cyclosporine, mycophenolate mofetil, chlorambucil, and leflunomide. If the uveitis is resistant to these agents and is sight threatening, the patient may require injectable therapy with biologicmodifying agents such as adalimumab, infliximab, daclizumab, rituximab, and interferon alfa-2a.1,15 If the patient has received immunosuppressive or biologic agents for 2 years without a recurrence, the medication can be tapered and discontinued. Patients are noted to be cured if they did not have a recurrence for 5 years after discontinuation of therapy.1

Treating Infection-Related Uveitis

The goal of therapy in treating infection-related uveitis is to treat the underlying infection, which may require systemic treatment if the uveitis is a result of tuberculosis, syphilis, or Lyme disease. In addition to systemic treatment for these cases, intravitreal agents may be used.12 Topical and systemic steroids are used in treating patients with infectious uveitis. It is thought that the immune response to the infection has a role in the inflammation, which results in visual loss and damage. However, topical steroids should be used with caution in patients with herpes simplex because uveitis should be done with caution as a worsening may be seen in the corneal epithelial.12

Treating Noninfectious Uveitis

Tapering courses of topical, periocular steroid injections or systemic steroids are used in treating noninfectious acute anterior uveitis. Steroids, either topical or systemic, should be used for the shortest duration possible to resolve inflammation and restore vision. Periocular and systemic steroids may be reserved for severe cases of acute uveitis.12 Cycloplegic agents such as cyclopentolate, homatropine, scopolamine, and atropine are immediately initiated. Cycloplegic agents block nerve impulses to the pupillary sphincter and ciliary muscles, relieving pain and photophobia. They also help prevent the formation of posterior synechiae in the acute setting.12,19 Synechiae formation may cause severe angle-closure glaucoma.16 In an article by Gordon, it was recommended that homatropine 2%-5% be the cycloplegic agent of choice because of the longer duration of cycloplegia (10-48 hours of paralysis of the ciliary muscle) and mydriasis (6 hours to 4 days of pupil dilation). With homatropine, the onset of cycloplegia is 30 to 90 minutes and the onset of mydriasis is 10 to 30 minutes. It may be dosed at 1 drop three times per day while it is needed.18 Multiple doses of scopolamine and atropine are required to maintain effectiveness and therefore may not be used as commonly.1 The most commonly used topical steroid is prednisolone acetate 1% eye drop. The initial dose may be 1 drop in the affected eye every hour for acute anterior uveitis.18 Topical steroids in general should be slowly tapered after 2 weeks of treatment.

Oral NSAIDs may be used as a steroid-sparing strategy. A small percentage of patients (1%) can experience an increase in intraocular pressure when exposed to topical steroids. In this case, it is recommended that patients receive rimexolone or loteprednol since these do not raise the intraocular pressure as much as prednisolone.20 Oral steroids may be used for acute ocular inflammation and given for 1 week followed by a taper. If the inflammation is chronic, oral steroids may be used for 2 to 4 weeks prior to tapering. See TABLE 3 for oral prednisone dosing and tapering in acute and chronic inflammation. If the total duration of oral steroids is less than 3 weeks, there may not be an effect on the hypothalamicpituitary axis. It is important not to provide too quick of a taper, as this can result in a rebound of the ocular inflammation. In cases where inflammation is being treated for longer durations with oral corticosteroids, the hypothalamic-pituitary axis may not return for 6 to 12 months after tapering. Patients may want to carry an alert card or bracelet to notify health professionals that they have taken or are taking oral corticosteroids. These patients should receive a dose of corticosteroids if they become injured or unconscious. Generally, high-dose oral prednisone 60-80 mg/day is not given for greater than 1 month; however, if the inflammation recurs during the taper, resume prednisone at the higher dose for another month, then taper to above the threshold of recurrence. Some practitioners will change the dosing schedule to every other day if chronic therapy is needed, but this may be less effective.15

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Use of IV, Periocular, Intravitreal, or Corticosteroid Implants

In the case of very extreme uveitis in which the inflammation needs to be rapidly controlled, methylprednisolone 1 g IV per day for 3 days followed by oral steroid therapy is recommended. Periocular steroid injections are depot injections, which are intended for an extended duration of effect.1 Intravitreal injections have been shown to have an effect for 3 to 6 months. Intraocular steroid implants may also be used for chronic uveitis and deliver steroids for 6 months or 30 months depending on the implant used.1,21 The injections and implants are used to treat posterior uveitis and may be used for intermediate uveitis.12,22,23

NSAIDS, Immunosuppressants, and Biologic Agents

A major goal in treating patients with uveitis is to limit the use of steroids as much as possible. Therefore, steroid-sparing strategies are important and include the use of oral NSAIDS, chemotherapeutic medications, or biologic-modifying medications, all of which affect inflammation directly. These strategies are necessary to avoid the complications of chronic steroid use, such as cataract and glaucoma.1 See TABLES 4 and 5 for the immunosuppressive and biologic agents used to treat uveitis and minimize the use of steroids.1,24,25 Lee and Foster recommend that both azathioprine and mycophenolate mofetil be alternatives to methotrexate.1 Cyclosporine produces anti-inflammatory effects within days, which may provide a benefit over other agents that take weeks to take effect, and more data are available on the use of oral cyclosporine for treating uveitis than on tacrolimus and sirolimus. It is important to note that the ocular form of cyclosporine, Restasis, cannot be used to treat uveitis. Chlorambucil and cyclophosphamide may also be used to treat uveitis.

tbl4

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The Massachusetts Eye Research and Surgery Institution suggests that empiric evidence in its clinic showed effectiveness with leflunomide in treating steroidresistant uveitis. The biologic agents subcutaneous adalimumab and intravenous infliximab have been effective in treating uveitis in patients with Behcet’s syndrome, juvenile idiopathic arthritis, and ankylosing spondylitis. Another widely use biologic agent used for treating uveitis in Behcet’s syndrome is interferon alfa2a.15,26 The exact mechanism for reducing inflammation with the biologic agents is not known. Therefore, though the agents may be effective in treating systemic disease, they are not necessarily effective in treating uveitis.26 Both IV daclizumab and IV rituximab have shown efficacy in treating uveitis in some patients.1 Currently, none of the biologic agents adalimumab, infliximab, daclizumab, and rituximab have FDA indications for the treatment of uveitis. Etanercept has had mixed results in treating uveitis, and some cases were reported to trigger ocular inflammation.27

The Role of the Pharmacist

Pharmacists are the front line when it comes to interactions with patients; therefore, it is important that the serious and sight-threatening nature of uveitis be understood and explained. A patient presenting with some or all of the following symptoms should immediately be seen by an emergency department physician or by an ophthalmologist: painful eye, photophobic eye, red eye, blurred vision, or distorted and/or small pupil.12,17 See TABLE 6 for questions you can ask when a patient comes to the pharmacy with a chief complaint related to the eye.28 It should be communicated to the patient that uveitis, if not treated promptly, can result in vision loss or permanent total blindness. However, there are effective prescription medications such as topical and oral steroids and other agents that the physician can prescribe to treat the uveitis. If a patient is to receive topical or oral corticosteroids, emphasize that these medications must be used and tapered exactly as prescribed by the physician so as not to result in a return of the uveitis. Warn the patient also of the untoward dangers associated with the decreased function of the hypothalamic-pituitary axis.

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Patients should advise all health care professionals that they are taking or have taken steroids and when. Make sure patient counseling covers the use and tapering of all steroids. An example of a dosing and tapering regimen may be found in TABLE 3.15 Advise the patient to monitor for higher blood pressure, fluid retention, blood sugar increases, high cholesterol, osteoporosis, glaucoma, and cataracts. More aggressive blood sugar and blood pressure treatment may be needed while receiving steroids. Conversely, patients with insulin-dependent diabetes, psychosis, myopathy, pancreatitis, or aseptic necrosis of the bone may require the addition of an immunosuppressant to reduce the daily dose of prednisone. Other side effects may include mood changes, anxiety, insomnia, decreased wound healing, and easy bruising. If a patient is to receive steroids, confer with the physician as to the need for calcium (1,500 mg/day) and vitamin D (800 IU/day) to prevent osteoporosis. Doses of oral prednisone 60 mg/day for the first month and above 20 mg/day for the first 6 months can result in a 15% to 20% risk of aseptic necrosis of the bone. The risk of gastrointestinal ulcers is not increased to any substantial degree; therefore, the use of H2 blockers is not recommended. Appropriate contraception should be used by women of child-bearing age who are to receive any immunosuppressive agents due to the teratogenic nature of these agents. There is also a possible increased risk of malformation if men father children while they are receiving methotrexate. If any of the immunosuppressive or biologic-modifying agents are to be used, counsel patients on those specific side effects and refer them to their physician for monitoring. See TABLES 4 and 5 for some significant side effects associated with these medications. It is paramount that patients take these medications exactly as prescribed by their physician and do not abruptly discontinue them as this can result in the return of the uveitis. The physician will advise patients as to when is the right time for these medications to be discontinued.15

CONCLUSION

Uveitis is the most common form of ocular inflammation.4 It accounts for 10% to 15% of all cases of total blindness in the U.S. and is a result of infection or, in half the cases, is idiopathic. Idiopathic cases are suspected to be autoimmune.8,11 The highest incidence is seen in persons 25 to 44 years of age, and the condition and may be more prevalent in men than women and in girls versus boys.5,8 The course of uveitis is characterized as sudden or insidious and may be limited in duration, lasting 3 months or less, or persistent, lasting longer than 3 months.12,17 The goals of therapy are to resolve inflammation, spare vision, and, in the case of chronic or persistent uveitis, bring about a cure.1,12 First-line therapy for treating acute uveitis consists of topical or systemic steroids.1,15 In the acute setting, cycloplegic ocular drops such as homatropine may be used to relieve pain and prevent photophobia and synechiae formation.18,19 Steroids should be used for the shortest duration possible and slowly tapered to prevent an ocular inflammation flare. If high-dose (adult dose 60-80 mg/day) oral prednisone has not produced a response or resolved the uveitis within 2 to 4 weeks, an immunosuppressive agent such as methotrexate, azathioprine, cyclosporine, mycophenolate mofetil, chlorambucil, or leflunomide should be added.1,15 Finally, if the uveitis is resistant to the immunosuppressive agents, then biologic-modifying agents such as adalimumab, infliximab, daclizumab, rituximab, or interferon alfa-2a may be required.1,15 None of the biologic-modifying agents are FDA approved for treating uveitis; however, clinical trials are under way.29 Though the use of immunosuppressant agents is recognized as a steroid-sparing strategy for uveitis, none of them have an FDA indication for uveitis. However, several formulations of corticosteroids have an FDA indication for treating uveitis.22,23,30

REFERENCES

  1. Lee FF, Foster CS. Pharmacology of uveitis. Expert Opin Pharmacother. 2010;11(7):1135-1146.
  2. MayoClinic Web site. Iritis. Feb 10, 2009. www.mayoclinic.com/health/iritis/DS01128/METHOD=print. Accessed November 7, 2010.
  3. MayoClinic Web site. Uveitis. March 16, 2010. www.mayoclinic.com/health/uveitis/DS00677. Accessed November 7, 2010.
  4. Srivastava A, Rajappa M, Kaur J. Uveitis: mechanisms and recent advance in therapy. Clinica Chimica Acta. 2010;411:1165-1171.
  5. Cunningham ET Jr. Uveitis in children. Ocul Immunol Inflamm. 2000;8:251-261.
  6. Durrani OM, Tehrani NN, Marr JE, et al. Degree, duration and causes of visual loss in uveitis. Br J Ophthalmol. 2004;88:1159-1162.
  7. IUSG Web site. What is uveitis? 2007. http://www.iusg.net/page7/What_is_Uveitis.html. Accessed December 12, 2010.
  8. Suhler EB, Lloyd MJ, Choi DC, et al. Incidence and prevalence of uveitis in Veterans Affairs Medical Centers of the Pacific Northwest. Am J Ophthalmol. 2008;146:890-896.
  9. Gritz DC, Wong IG. Incidence and prevalence of uveitis in Northern California. Ophthalmology. 2004;111:491-500.
  10. Braakenburg AM, de Valk HW, de Boer J, et al. Human leukocyte antigenB27 associated uveitis: long-term follow-up and gender differences. Am J Ophthalmol. 2008;145(3):472-479.
  11. Rothova A, Buitenhuis HJ, Meenken C, et al. Uveitis and systemic disease. Br J Ophthalmol. 1992;76:137-141.
  12. Guly CM, Forrester JV. Investigation and management of uveitis. BMJ. 2010:34;821-826.
  13. Deschenes J, Murray PI, Rao NA, et al. International Uveitis Study Group (IUSG) clinical classification of Uveitis. Ocul Immunol Inflamm. 2008;16:1-2.
  14. Loh AR, Acharya NR. Incidence rates and risk factors for ocular complications and vision loss in HLA-B27-associated uveitis. Am J Ophthalmol. 2010;150:534-542.
  15. Jabs DA, Rosenbaum JT, Foster CS et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol. 2000;130:492-513.
  16. Farooqui SZ, Foster SC. Uveitis, classification. November 20, 2008. http:// emedicine.medscape.com/article/1208936-overview. Accessed December 12, 2010.
  17. Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the first international workshop. Am J Ophthalmol. 2005;140:509-516.
  18. Gordon K III. Iritis and uveitis. August 13, 2009. http://emedicine.medscape.com/article/798323-overview. Accessed November 27, 2010.
  19. Al-Fawaz A, Levinson R. Uveitis, anterior, nongranulomatus. Feb 24, 2010. http://emedicine.medscape.com/article/1209595-print. Accessed November 27, 2010.
  20. Novack GD, Howes J, Crockett RS, Sherwood MB. Change in intraocular pressure during long-term use of loteprednol etabonate. J Glaucoma.1998;7(4):266-269.
  21. Jaffe GJ, McCallum RM, Branchaud B, et al. Long-term follow-up results of a pilot trial of a fluocinolone acetonide implant to treat posterior uveitis. Ophthalmology. 2005;112(7):1192-1198.
  22. Retisert [package insert]. Madison, NJ: Bausch & Lomb; 2009.
  23. Ozurdex [package insert]. Irvine, CA: Allergan; 2010.
  24. Clinicaltrials.gov Web site. Leflunomide and uveitis. March 3, 2008. http://clinicaltrials.gov/ct2/show/NCT00001863?term=leflunomide+and+uveitis&rank=1. Accessed March 1, 2011.
  25. Gueudry J, Wechsler B, Terrada C, et al. Long-term efficacy and safety of low-dose interferon alpha 2a therapy in severe uveitis associated with Behcet disease. Am J Ophthalmol. 2008;146:837-844.
  26. Okada AA. The dream of biologics in uveitis. Arch Ophthalmol. 2010;128(5):632-635.
  27. Smith JR, Levinson RD, Holland GN, et al. Differential efficacy of tumor necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease. Arthritis Rheum. 2001;45(3):252-257.
  28. Elton M. Ocular conditions from A to Z(ii). Pharm J. 2007;278:255-258.
  29. Clinicaltrials.gov Web site. Uveitis. http://clinicaltrials.gov/ct2/results?term=uveitis. Accessed December 17, 2010.
  30. Facts & Comparisons Online Edition. June 2010. Oral prednisone and ophthalmic prednisolone acetate. http://online.factsandcomparisons.com/index.aspx. Accessed December 17, 2010.

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