Uveitis refers to inflammation of the uveal tract and may be due to autoimmune or infectious causes. The uvea is the pigmented part of the eye and includes the iris, ciliary body, and choroid. The inflammation can affect and cause damage to multiple tissues in the eye. Depending on where the inflammation is located, we further subdivide the disease into the terms anterior, intermediate, or posterior uveitis or, if involving all three of those locations, panuveitis.

Uveitis is not very common with an incidence of 25 to 341 cases per 100,000 person-years but is the cause of 10% to 15% of cases of blindness in the United States.^1-4 Therefore, prompt treatment and management is important. Choice of therapeutic agent depends on the amount of inflammation, the frequency of flare-ups, and the associated vision loss. Knowing what treatments are available, how they are administered, and their potential side effects allows you to better assess your patients and anticipate their questions or concerns.

Described below are different treatment options for noninfectious uveitis.

Steroids

Steroids are often the first line of therapy for uveitis. They are fast acting and effectively block inflammation. Topical steroids are used most often for anterior uveitis or iritis. The patient administers them in drop form as often as every hour initially and tapered down slowly as inflammation resolves. In general, stopping steroids abruptly carries a risk of recurrent inflammation.

Topical steroid formulations are emulsified — the active portion of the medicine can sink to the bottom of the bottle. Therefore, patients should shake the bottle for about 30 seconds to one minute when administering these drops. Side effects include raised intraocular pressure (IOP) and cataract formation. Common formulations in order of decreasing strength are: difluprednate (Durezol, Novartis), prednisolone acetate, loteprednol (Lotemax, Bausch + Lomb), and fluorometholone (FML, Allergan).

For intermediate and posterior uveitis or severe anterior uveitis, systemic steroids are often used. Dosing for oral prednisone ranges from 0.5 mg to 1 mg per kilogram (patient’s weight) per day, depending on the level of inflammation. For more severe cases, patients may receive intravenous methylprednisolone at a dose of 1 g/day for three days followed by an oral taper. Systemic steroids have several side effects including gastritis, weight gain, raised blood sugar level, diabetes, mood changes, insomnia, avascular necrosis of the hip, bone loss, and hypertension. Oral prednisone should be taken in the morning with food in a single dose. If taking prednisone for longer than a few months, patients should receive vitamin D and calcium supplementation and have bone density testing yearly.

When patients lack associated extraocular inflammation, have unilateral disease, or cannot tolerate systemic medication, they may be good candidates for local periocular or intravitreal steroids. Triamcinolone acetate can be injected into the sub-Tenon’s space and slowly dissipates providing treatment over about three months. Intravitreal preservative-free triamcinolone acetate (Kenalog, Bristol-Myers Squib) can also be injected. Dexamethasone intravitreal implant (Ozurdex, Allergan) lasts about three to four months and can be injected in office. Local steroids are also associated with the development of increased IOP and cataract. The fluocinolone acetonide intravitreal implant (Retisert, Bausch and Lomb), placed in the OR, provides slow release of 0.59 mg of steroid over a period of 300 days. The majority of its recipients require medical treatment for elevated IOP, with nearly 40% going on to require glaucoma drainage device implant. About 90% of patients with the Retisert ultimately need cataract surgery.⁵

Immunomodulatory therapy

Higher doses of oral steroids can control inflammation quite well, but they are not ideal for long term treatment as they can have detrimental health effects. Steroid sparing agents or immunomodulatory therapy can control inflammation, but with a lower side effect profile than systemic steroids. The safety and efficacy of steroid-sparing agents were reviewed in the systemic immunosuppressive therapy for eye diseases (SITE) study.⁶ These agents can be divided into antimetabolites, T-cell inhibitors, alkylating agents and biologics. Depending on the agent used, they are usually prescribed by a uveitis specialist or in conjunction with a rheumatologist. Prior to starting any of these medications, a complete blood count and comprehensive metabolic panel laboratory tests are usually ordered.

The antimetabolites include methotrexate, mycophenolate mofetil, and azathioprine. Side effects include nausea, GI upset, and elevated liver enzymes. Labs are monitored every three months for these medications. T-cell inhibitors are tacrolimus and cyclosporine. Side effects include tremor, bone marrow suppression, and kidney toxicity. Patients on these medications are also monitored every three months.

Alkylators, typically reserved for severe and refractory cases, include cyclophosphamide and chlorambucil. These agents are very strong and are associated with more serious side effects such as an increased risk for malignancy. They are usually monitored with monthly labs. All of these medications are taken orally and divided into several doses per day, except for methotrexate, which is taken weekly and can also be administered by a subcutaneous injection.

Biologic therapies are effective in treating inflammation by targeting inflammatory mediators in the blood. In 2016, adalimumab (Humira, Abbvie) was the first biologic therapy approved for the treatment of non-infectious posterior uveitis.⁷ Humira is self-administered with an autoinjector similar to an EpiPen and is usually taken every two weeks. Most common side effects associated with Humira are pain or irritation at the injection site, and increased risk for infections. Other biologic therapies commonly used in uveitis include infliximab (Remicade, Janssen Biotech) and rituximab (Rituxan, Genentech/Biogen) — these agents are administered by IV infusion.

Surgery

Patients with uveitis may need surgical intervention due to sequelae from inflammation. Complications such as cataract formation and glaucoma are treated with cataract extraction and glaucoma drainage device implant, respectively. Some other consequences of inflammation that may require surgery include epiretinal membrane formation, retinal breaks, and tractional retinal detachment, which may require vitreoretinal surgery. In general eyes should be quiet and without inflammation approximately three months prior to any surgery unless it is an emergency. Steroids should be dosed appropriately to manage inflammation in the perioperative period.

Conclusion

Multiple therapeutic options are available for uveitis, with steroids often used first line. Patients can often achieve adequate control of their disease with minimal side effects. Knowing what therapies are available gives you an advantage with this patient population. OP

REFERENCES:

1. Gritz D. Incidence and prevalence of uveitis in Northern California: The Northern California Epidemiology of Uveitis Study. Ophthalmology. 2004;111:491-500.
2. Acharya NR, Tham VM, Esterberg E, et al. Incidence and prevalence of uveitis. JAMA Ophthalmology. 2013;131:1405.
3. Suhler EB, Lloyd MJ, Choi D, Rosenbaum JT, Austin DF. Incidence and prevalence of uveitis in Veterans Affairs Medical Centers of the Pacific Northwest. Am J Ophthalmol. 2008;146:890-896.
4. Jabs DA. Prevalence of the uveitides in the United States. JAMA Ophthalmol. 2016;134:1245-1246.
5. The Multicenter Uveitis Steroid Treatment (MUST) Trial and Follow-up Study Research Group. Association between longlasting fluocinolone acetonide intravitreous implant vs. systemic anti-inflammatory therapy and visual outcomes at seven years among patients with intermediate, posterior, or panuveitis. JAMA. 2017;317:1993-2005.
6. Kempen JH,Daniel E,Gangaputra S, et al. Methods for identifying long-term adverse effects of treatment in patients with eye diseases: the SITE Cohort Study. Ophthalmic Epidemiol. 2008;15:47-55.
7. Jaffe GJ, Dick AD, Brezin AP, et al. Adalimumab in patients with active non-infectious uveitis. N Engl J Med. 2016;375:932-943.

Jessica E. Weinstein, MD, is a uveitis fellow at the University of Washington. She will pursue additional fellowship training in vitreoretinal surgery at Wake Forest University in July 2018.