This review of the literature offers an insight into the current treatment strategies of uveitis. The approach to treatment of uveitis depends upon the etiology, location and severity of the inflammation.
The etiology of uveitis can stem from an autoimmune reaction to system disease such as cancer or infection among other inflammatory diseases, or it can be a local ocular reaction. The spectrum of possibilities often presents a diagnostic challenge for the ophthalmologist and as alluded to above, treatment and prognosis varies depending on the correct diagnosis. History and physical examination play an initial key role more so than laboratory tests in most cases of uveitis.
The type and location of intraocular inflammation with associated findings will help narrow down the differential diagnosis. For instance, is the uveitis anterior, posterior or diffuse? Most types of anterior uveitis are sterile inflammatory reactions that are commonly idiopathic and secondly caused by HLA-B27 positive associated diseases. Intermediate uveitis may be associated with systemic disease or infection. Many posterior uveitis cases are caused by infections.
In addition to location of the inflammation, it is also important to determine whether the uveitis is granulomatous or non-granulomatous.
Pain, redness and photophobia are the typical presenting signs and symptoms of acute uveitis. Keratic precipitates may be present, as well as a hypopyon if severe. The presence of posterior synechiae indicates long-standing disease.
A systemic inflammatory disorder must also be considered so patients should be asked about symptoms related to their skin, lungs, GI, musculoskeletal, GU and CNS.
Most would say that ordering a slew of laboratory tests in every patient with uveitis is a waste of time and money. Rather, it makes more sense to rule out certain diseases, and then let the patient’s medical history and the physical examination guide your choice of lab tests.
Treatment
Therapy for uveitis should be aimed at the underlying condition and symptomatic treatment to suppress the inflammation. Treatment should be initiated within 24 hours of the onset of uveitis.
Corticosteroids:
Corticosteroids have been the mainstay of treatment for uveitis by inhibition of proinflammatory transcription factors and the suppression of prostaglandin and interleukin synthesis. There are a slew of topical steroids used for anterior uveitis, including Durezol, Pred Forte, Lotemax and FML.
Although topical steroids can be very effective, one must monitor the patient for increased intraocular pressure. If the IOP rises, it may be wise to start pressure lowering medications rather than tapering the steroids, which can lead to rebound inflammation. Rimexalone is a lower potency topical steroid than prednisolone acetate, which can be as effective, yet associated with a lower risk of pressure spikes.1
Intravitreal steroids are used for posterior uveitis. Triamcinolone (Trivaris) is FDA approved for intraocular inflammation, providing 3-7 months of beneficial effects. Drawbacks, of course, include cataracts, which can be as high as 15-30% after one injection, and an elevated IOP.
Intravitreal Dexamethasone Implant (Ozurdex):
A dexamethasone intravitreal implant (Ozurdex), by Allergan, is approved and indicated to treat noninfectious uveitis affecting the posterior segment. This implant is an alternative to ophthalmic steroids that have to be administered several times per day. The implant also overcomes the short duration of intravitreal steroid injections. Ozurdex has a biodegradable material combined with the steroid. It is injected into the vitreous and releases the medication over 6 months.
Intravitreal Fluocinolone Acetonide Implant (Retisert):
Retisert is an implant made by Bausch & Lomb that releases medication over approximately 30 months, but is not biodegradable, cannot be injected into the vitreous, but rather must be surgically implanted, and is associated with more side effects including a high rate of cataract formation and almost guaranteed elevation in IOP.
Anti-TNF-alpha:
Adalimumab, a humanized monoclonal anti-TNF-alpha, has been successful in the treatment of uveitis. The effectiveness of another drug in the same class, infliximab, has been reported in refractory sarcoidosis, as well as other types of intraocular inflammation. Erckens, et al. published a study using adalimumab in refractory sarcoidosis as well.
Methotrexate:
Long used for intraocular lymphomas, methotrexate has more recently been applied to uveitis. Advantages include reduction of intraocular inflammation without the increase in IOP seen with steroids. Results are apparent within a week and last approximately 4 months.
Anti-interleukins:
Studies have shown that anti-interleukins have considerable efficacy in otherwise refractory uveitis. These drugs may be associated with high costs and long-term risks, so should be managed and administered under a multidisciplinary group.
Sirolimus:
This drug under phase III trials (SAKURA: Study Assessing double-masKed Uveitis tReAtment) by Santen, is delivered as an intravitreal injection and has immunosuppressive, anti-angiogenic and other effects for the treatment of chronic non-infectious uveitis. Sirolimus is an inhibitor of T cell activation and binds to intracellular receptors known as immunophilins. Sirolimus targets a serine-threonine kinase so functions as a non-calcineurin inhibitor of T cells.
In an early study of subconjunctival or intravitreal sirolimus in 30 patients with noninfectious uveitis, visual acuity improved or stabilized in 80% of patients and vitreous haze improved in all cases with active uveitis at baseline. All 20 patients receiving corticosteroid therapy at the start of the study had reduced doses at 6 months. Of reported SAEs, none were judged to be the result of Sirolimus administration.2
Zhang et al studied the use of systemic rapamycin in mice that were immunized to induce uveitis. They found that administration of low dose rapamycin exacerbated uveitis, whereas high dose rapamycin attenuated ocular inflammation, revealing a paradoxical role for this drug in uveitis in a dose-dependent manner.3
In addition to posterior uveitis, Sen et al. studied subconjunctival injections of sirolimus for the treatment of chronic active anterior uveitis with success. They treated 5 patients with a single 30 uL subconjunctival injection of sirolimus. Three patients showed at least a 2-step decrease in inflammation within 4 weeks and 2 patients showed a 1-step decrease in inflammation within the same time frame. No recurrence was seen during the 4-month follow up.4
Surgery:
Reasons to perform surgery in cases of uveitis include diagnostic tissue sampling, visual rehabilitation and removal of a cataract to monitor the posterior segment.
When uveitis is unresponsive to medical therapy, a vitrectomy may be necessary to clear the opacifications. As well, retinal or optic disc neovascularization may lead to vitreous hemorrhage requiring a vitrectomy.
Intraocular inflammation stimulates fibrous tissue proliferation, making the formation of an epiretinal membrane more likely. Membrane peeling may be helpful in these cases. Optimally, medical treatment is implemented to eliminate inflammation prior to surgery to enhance successful outcomes (approximately 3 months prior to surgery). Approximately 1-2 days preoperatively, topical prednisolone acetate 1% is administered every 1 – 2 hours, +/- systemic steroids. Intraoperative steroids are also commonly used.
A vitrectomy may be necessary in cases of epiretinal membrane or retinal detachment associated with uveitis. The role of vitrectomies in the face of uveitis may expand as new intraocular drug delivery devices are developed.
Research is constantly being performed to define novel ways to treat this difficult disease. In the future we are sure to see new steroid-alternatives with innovative delivery technology to avoid some of the more common side effects of the currently available treatments.
- 10 Clinical Pearls for Treating Uveitis – Susan Wittenberg, MD, Aug 2008, AAO
- Quan D Nguyen, Mohamed A Ibrahim, Anthony Watters, Millena Bittencourt, Jithin Yohannan, Yasir J Sepah, James P Dunn, Joel Naor, Naveed Shams, Ovais Shaikh, Henry A Leder and Diana V Do. Ocular Tolerability and Efficacy of Intravitreal and Subconjunctival Injections of Sirolimus in Patients with Non-infectious Uveitis: Primary Six-Month Results of the SAVE Study. Journal of Ophthalmic Inflammation and Infection. 2012 [submitted]. 1 Quan D Nguyen, Mohamed A Ibrahim, Anthony Watters, Millena Bittencourt, Jithin Yohannan, Yasir J Sepah, James P Dunn, Joel Naor, Naveed Shams, Ovais Shaikh, Henry A Leder and Diana V Do. Ocular Tolerability and Efficacy of Intravitreal and Subconjunctival Injections of Sirolimus in Patients with Non-infectious Uveitis: Primary Six-Month Results of the SAVE Study. Journal of Ophthalmic Inflammation and Infection. 2012 [submitted].
- Zhang Z, Wu X, Duan J, Hinrichs D, Wegmann K, et al. 2012 Low Dose Rapamycin Exacerbates Autoimmune Experimental Uveitis. PLoS ONE 7(5):e36589).
- Sen HN, Larson TA, Meleth AD, Smith WM, Nussenblatt RB. Subconjunctival Sirolimus for the Treatment of Chronic Active Anterior Uveitis: Results of a Pilot Trial. American Journal of Ophthalmology 153(6):1038-1042. June 2012