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Range of uveitis treatments set to expand

Issue: January 10, 2015

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Uveitis refers to a collection of diseases characterized by intraocular inflammation. Treatment varies depending on the specific uveitic disease, the location of the inflammation, severity and duration of disease.

“The uveitides represent probably over 30 separate diseases, which are highly variable in disease course, treatment and prognosis,” Douglas A. Jabs, MD, MBA, said.

For anterior uveitis, patients may experience pain or discomfort, redness in the eye or photophobia, and potentially decreased vision; for posterior uveitis, patients may experience any number of effects on their vision, including floaters or floating spots, decreased vision, distorted vision and decreased field, in addition to changes in color vision or night vision, depending on the type of uveitis, OSN Retina/Vitreous Board Member Glenn J. Jaffe, MD, said.

Slit lamp examination and indirect ophthalmoscopy can identify anterior chamber inflammatory cells and vitreous haze, which are indicators of active inflammation, but identifying the specific disease is key to managing the disease.

When treating inflammatory cells in the anterior chamber that are typical of anterior uveitis, Glenn J. Jaffe, MD, prefers aggressive topical corticosteroid therapy.

Source: Keaton T

Treatment options

“Currently, only corticosteroid is approved for the treatment of uveitis in the United States, both as an oral form or as a local therapy form with a sustained-release intravitreal implant,” Quan Dong Nguyen, MD, MSc, said.

Quan Dong Nguyen

The most common type of uveitis seen by a general ophthalmologist is anterior uveitis, which is easier to manage because it is typically amenable to treatment with topical corticosteroids, according to Jabs. However, some anterior uveitides are chronic and therefore require long-term suppressive corticosteroid therapy.

“Many times, though, ophthalmologists attempt to stop corticosteroid therapy rather than continuing it at a certain low level to suppress the disease,” Jabs said. “This is likely the most common mistake I observe with chronic anterior uveitis.”

The comprehensive ophthalmologist should refer patients with the more severe classes of uveitis — posterior uveitis and panuveitis — to uveitis specialists, according to Jabs.

“These patients typically require immunosuppression often from the start,” Jabs said.

Another consideration in management is whether the uveitis is infectious or not, according to Nguyen,whose experience has yielded an approximately 40% rate of infectious uveitis cases vs. 60% noninfectious.

Szilárd Kiss

Szilárd Kiss, MD, said it is important to ensure the correct diagnosis of uveitis, initially differentiating infectious from noninfectious causes.

“If the etiology is noninfectious and only the eye is affected, use a modality that minimizes the side effects while at the same time providing the necessary efficacy,” Kiss said.

Sometimes, combination therapy is prudent; for example, a patient may already be on immunomodulatory therapy for a systemic disease and encounter a flare of local uveitis that requires intermittent steroid therapy vs. long-term steroid therapy, he said.

Treatment options range from steroid drops to immunosuppressive drugs to sustained local steroid therapy via drug-release implants. Several promising new therapies are also in clinical trials.

“Steroids remain the first line of therapy for most uveitides,” Kiss said, noting that steroids can be administered via topical drops, sub-Tenon’s injection and intravitreal solid implant.

Anterior uveitis

Anterior uveitis typically entails treating inflammatory cells in the anterior chamber, for which Jaffe prefers aggressive topical corticosteroids. For anything greater than 1+ cells, he usually prescribes either hourly Pred Forte (prednisolone acetate ophthalmic suspension, Allergan) or every 2 hours Durezol (difluprednate ophthalmic emulsion 0.05%, Alcon).

“For severe cases, I may prescribe more frequently, but it is difficult for patients to comply,” Jaffe said.

Along with either prednisolone or difluprednate, Jaffe uses a cycloplegic, usually homatropine but at times atropine for more severe cases until the inflammation subsides.

“My strategy is to hit the anterior uveitis really hard in the beginning so that the inflammation will quiet down,” he said. “Once the inflammation is quiet, it is easier to taper the medications. By undertreating, it is harder to achieve control.”

For severe iridocyclitis, caused by human leukocyte antigen B27-associated uveitis with ankylosing spondylitis, for instance, Jaffe may treat with a periocular steroid injection with a shorter-acting steroid.

Kiss has seen good results with difluprednate for anterior uveitis. In one case of severe anterior uveitis and flare in the anterior chamber, Kiss prescribed difluprednate every 2 hours for 3 days, with nearly complete resolution of the inflammation. The drops were then slowly tapered over several weeks.

However, Kiss noted that it is important to take into account the side effect profile in addition to the efficacy, even with topical therapy.

Posterior uveitis

For inflammation that affects more posterior ocular structures, such as pars planitis or anterior vitritis, topical therapy may not be sufficient and a sub-Tenon’s injection may be warranted. Kiss said his preferred sub-Tenon’s injection is Triesence (triamcinolone acetonide injectable suspension 40 mg/mL, Alcon). Typically, patients require an injection once every 3 to 4 months, but for more posterior uveitis, such as vasculitis, noninfectious retinitis or choroiditis, further therapy is needed.

“You need to treat inside the eye. Giving patients drops or even sub-Tenon’s injections is probably not going to be an effective treatment strategy,” Kiss said.

For intravitreal administration, Kiss’ preference is Ozurdex (dexamethasone intravitreal implant 0.7 mg, Allergan), which he has used since 2009. The implant typically lasts 4 to 7 months in most patients with uveitis and can be administered repeatedly via an in-office intravitreal injection.

If inflammation cannot be controlled long term without causing an unacceptable increase in IOP or if drops are needed more frequently than two or three times daily, then Jaffe considers an immunosuppressive medication such as Rheumatrex (methotrexate, Dava Pharmaceuticals).

For posterior uveitis, drops are not sufficient, Jaffe said. For these patients, he starts either oral steroids or more commonly local steroid therapy given as an injection.

“I usually begin with a posterior sub-Tenon’s Kenalog (triamcinolone acetonide injectable suspension, Bristol-Myers Squibb) injection, and for particularly severe cases, I might give intravitreal preservative-free triamcinolone acetonide,” he said.

For patients who likely will require either frequent injections or long-term oral steroids, Jaffe’s first choice for alternative therapy is an intraocular sustained-release drug delivery system, primarily Retisert (fluocinolone acetonide intravitreal implant 0.59 mg, Bausch + Lomb), which is placed surgically and lasts up to 3 years. For shorter duration, Ozurdex or preservative-free intravitreal triamcinolone acetonide 4 mg can be reinjected every 3 to 6 months, according to Jaffe.

Sunil K. Srivastava

Sunil K. Srivastava, MD, said, “We have really good data suggesting the effectiveness of Retisert, with the caveat that 100% of those patients will develop cataracts and a significant number, somewhere between 20% and 40%, will require glaucoma surgery intervention for chronic elevation of IOP, usually within 12 to 18 months of implanting the device.”

Clinicians are interested in more data on using dexamethasone implants over a longer period of time and the complication rates, specifically for cataracts and glaucoma, Srivastava said.

“There has been no head-to-head study with Ozurdex, and it is unclear how many injections of Ozurdex you need to control chronic uveitis really well,” Srivastava said.

For a chronic noninfectious uveitis confined to the eye, such as birdshot chorioretinopathy, Kiss will use the fluocinolone acetonide implant despite the high incidence of cataract and glaucoma and the need for surgical placement.

“For the right patient, Retisert can be a sight-saving and life-changing option,” Kiss said.

Furthermore, fluocinolone acetonide may be an appropriate alternative to systemic treatments associated with bleeding or bone marrow suppression in selected patients, Nguyen said.

Immunomodulatory treatment

Clinicians who are not comfortable administering systemic immunomodulatory agents should refer the patient early in the course of the uveitis, according to Kiss.

“Steroids are good for short-term therapy and in treating exacerbations; however, if someone has inflammation over the medium to long term, you have to move beyond steroids. For example, some conditions, like birdshot, require systemic immunomodulatory treatment much earlier than most ophthalmologists imagine,” he said.

Other alternatives for Jaffe’s patients who need frequent injections or oral steroids long term include Rheumatrex, CellCept (mycophenolate mofetil, F. Hoffmann-La Roche) or Imuran (azathioprine, GlaxoSmithKline), depending on the patient and the specific disease, which act as steroid-sparing medications to wean patients off prednisone, in particular.

Jabs was the lead author of a 2000 article in the American Journal of Ophthalmology on guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders, and he said that fundamental principles of use remain similar.

“What we have learned since then is that there are some very specific diseases where it is inadequate to try corticosteroids alone and certainly not with regional corticosteroid injections,” he said.

In cases such as birdshot chorioretinitis, multifocal choroiditis with panuveitis, Behçet’s disease, serpiginous choroiditis, and Vogt-Koyanagi-Harada syndrome in chronic and possibly acute phase, immunosuppression should be used from the start, Jabs said.

“Available data suggest that these diseases cannot be controlled on doses of prednisone alone low enough for long-term use and that immunosuppression reduces the likelihood of ocular complications and visual loss,” he said.

The guidelines would now be revised to include the use of biologics such as tumor necrosis factor (TNF)-alpha inhibitors in the treatment of uveitis, particularly for Behçet’s disease, for which TNF-alpha inhibitors seem effective, Jabs said.

Jabs is the chair of the ongoing Multicenter Uveitis Steroid Treatment Trial Research Group, which authored a 2011 article in Ophthalmology that compared the relative effectiveness of systemic corticosteroids plus immunosuppression with Retisert. Both therapies at 24 months among the 255 randomized patients resulted in improved visual acuity, an increase of 3.2 letters and 6 letters, respectively, and residual active uveitis rates of 29% and 12%, respectively. The implication of a lower residual active uveitis rate for Retisert is that the implant would have a role to play in treating inflammation that is poorly controlled by systemic therapy, Jabs said.

The study found no increased risk of systemic side effects in patients treated with oral systemic corticosteroids and immunosuppression vs. Retisert, except that those patients given systemic treatment were slightly more likely to receive antibiotics for an infection. The use of adequate immunosuppression to successfully taper prednisone to 7.5 mg daily or less is also important.

“Studies in rheumatoid arthritis have shown that over the intermediate term (months to years), prednisone at that dose has no increased risk of side effects,” Jabs said.

A cross-sectional study performed by Nguyen and colleagues of treatment patterns for noninfectious uveitis that appeared in Ophthalmology showed that “non-uveitis-trained ophthalmologists are using too much prednisone and not enough immunosuppression in general,” Jabs said.

A separate retrospective cohort study in the British Medical Journal concluded that patients with uveitis who were given immunosuppressive drugs and corticosteroids had no long-term increased risk of mortality or cancer mortality (with the possible exception of alkylating agent therapy) compared with controls, Jabs said.

“If you have to give a patient immunosuppression for years, it is safe,” he said.

Chronic uveitis

Information on the safety of systemic immunosuppressive medications is better now than in years past, Srivastava said, but there is also more data on the effectiveness of sustained delivery of local therapy.

A number of clinical trials on how to treat chronic uveitis are enrolling or will soon complete enrolling.

“Short-term injections such as triamcinolone or Ozurdex can be an effective choice, in some cases, for chronic uveitis patients with flare-up,” Srivastava said. “However, the best data for more long-term therapy, includes systemic immunosuppression and the fluocinolone acetonide implant (Retisert).”

The data on repeated intravitreal implants or sub-Tenon’s injections are still short term, he said, in the 1-year range rather than out to 2 or 3 years.

In addition, Srivastava said that data strongly suggest that systemic medications are clinically effective in controlling uveitis in 60% to 70% of patients with any one drug.

“The safety profile of these drugs is also quite good, with the majority of patients able to tolerate the medicine and stay on it,” he said.

Targeted therapies

In the future, ophthalmologists can expect more targeted therapies for uveitis and nonsteroidal local treatments to avoid the complications of steroids.

Srivastava is intrigued by the pending data of intravitreal nonsteroidal sirolimus (Santen Pharmaceutical Co. Ltd.) in patients with noninfectious posterior segment uveitis. The immunomodulator has the same active ingredient as Rapamune (sirolimus, Pfizer) for renal transplant patients.

Furthermore, Clearside Biomedical has developed a suprachoroidal injection system “to inject steroids into a different space of the eye, with the hopes of controlling inflammation without having some of the complications of steroids,” Srivastava said.

In addition, Xoma is in clinical trials for gevokizumab, an injectable systemic interleukin-1 blocker, and AbbVie is finalizing a clinical trial looking at injectable Humira (adalimumab) for treatment of uveitis in addition to arthritis, according to Srivastava. Humira is a TNF inhibitor.

“TNF is a pro-inflammatory protein that is thought to contribute to inflammation in uveitis, so the drug, which blocks TNF, may be effective to treat uveitis,” Jaffe said.

Jaffe is an investigator in a multicenter randomized trial of Iluvien (injectable fluocinolone acetonide implant, Alimera Sciences/pSivida) for uveitis “that potentially could last for 3 years,” he said. Using a specialized injector and a 25-gauge needle, the implant is placed through the pars plana and into the vitreous cavity, where it usually sits in the vitreous base. Iluvien was approved by the U.S. Food and Drug Administration in 2014 for the treatment of diabetic macular edema.

“I like Iluvien for uveitis because it can be given in the clinic. You do not need to take the patient to the operating room,” Jaffe said. It releases a steroid with a broad anti-inflammatory effect and also has an effect on blood vessel permeability to decrease leakage of blood vessels.

“Iluvien also has the potential for fewer side effects, especially the pressure response compared to Retisert,” he said.

As new drugs are approved by the FDA for the treatment of rheumatic diseases, “I think many of those drugs may have a role to play in the treatment of ocular disease,” Jabs said.

One promising drug for a variety of eye diseases is Rituxan (rituximab, Genentech).

“It seems to work well for scleritis and for ocular mucous membrane pemphigoid, so it might be beneficial for uveitis because it targets and reduces the number of B cells,” Jabs said.

Some of the therapies that target inflammatory cytokines may also play a role in treating uveitis.

Nguyen said study results for several local and systemic treatments should soon be reported. Nguyen is the lead author of the first published paper on locally delivered sirolimus for intermediate, posterior or pan-uveitis, which appeared in 2013 in the Journal of Ophthalmic Inflammation and Infection.

“The therapy is local immunosuppression,” he said. “Patients may only have eye inflammation, so sirolimus could be very helpful.”

Nguyen noted that he and his team were the first clinician scientists in the world to evaluate subconjunctival and intravitreal sirolimus for non-infectious intermediate, posterior or pan-uveitis.

At 6-month follow-up, all 30 study patients with uveitis showed a reduction in vitreous haze of one or more steps compared with baseline, and 40% had a reduction of at least two steps of vitreous haze. There were no drug-related systemic adverse events.

Nguyen said he is encouraged by clinical trials of Actemra (tocilizumab, Genentech) and sarilumab (Sanofi/Regeneron Pharmaceuticals), both of which are inhibitors of interleukin-6 delivered systemically via monthly injections.

“Tocilizumab has already been approved by the FDA for treatment of rheumatoid arthritis, among other indications,” Nguyen said. The drug can be delivered by a subcutaneous or intravenous injection, whereas sarilumab is available only as subcutaneous delivery. Nguyen chairs the multicentered STOP-UVEITIS study of tocilizumab for uveitis and serves on the steering committee for the SATURN study evaluating sarilumab in uveitis.

“IL-6 plays a major role in the pathophysiology of uveitis and thus there may be potential therapeutic role for an IL-6 inhibitor,” Nguyen said. – by Bob Kronemyer

At what point should anterior uveitis be considered ‘chronic’ or recalcitrant to treatment and referred to a uveitis specialist?

Sooner than 3 months if no response to corticosteroids

Gary N. Holland

By convention, chronic uveitis is defined as intraocular inflammation that lasts for 3 months or longer; however, patients should be referred to uveitis specialists if inflammation does not respond to corticosteroid treatment much sooner than 3 months. Corticosteroids are used to achieve immediate control of inflammation, while long-term control of chronic uveitis is best maintained by immunosuppressive drugs, regardless of the location of inflammation in the eye.

With few exceptions, when a systemic corticosteroid is required for treatment of uveitis, it should be considered a bridge therapy while immunosuppressive drugs, which can take 2 months or longer for full effect, are being started. Short courses of oral corticosteroids can also be tried as a means of regaining control of uveitis if an occasional exacerbation of inflammation occurs while a patient is receiving immunosuppressive drug therapy, but frequent courses of high-dose oral corticosteroid is not an acceptable long-term treatment strategy because of the potential for severe systemic side effects.

As a general rule of thumb, if there is no response to frequent topical corticosteroids (prednisolone acetate 1%, given every 1 to 2 hours while awake) or 1 mg/kg of oral prednisone over a 1- to 2-week period, the patient should be referred for additional evaluation and alternative therapy. I prefer that patients not receive oral corticosteroid at this dose for longer than 1 month.

Another indication for referral is exacerbation of inflammation with attempts to taper oral corticosteroids (to 7.5 mg prednisone daily or less) or topical corticosteroids (to two drops of prednisolone acetate 1% or less daily).

In some cases, immunosuppressive drugs will allow discontinuation of corticosteroids altogether.

Gary N. Holland, MD, is a professor of ophthalmology and the Jack H. Skirball Chair in Ocular Inflammatory Diseases, UCLA Stein Eye Institute. Disclosure: Holland serves on medical advisory boards for Genentech, Novartis, Santen and Xoma.

Three months is ‘magic number’ for referral

C. Stephen Foster

For those of us who are specifically fellowship trained in the diagnosis and treatment of uveitis, 3 months of inflammation is the magic number for chronic anterior uveitis and at which point the patient should be referred to a uveitis specialist. These patients have typically been initially treated with topical corticosteroid drops to quiet their uveitis; however, by tapering the drops, the uveitis returns, prompting an increase in the number of drops per day. Tapering occurs once again, usually more slowly. But the uveitis returns and the treatment cycle repeated. By the time you reach 3 months, it is time to refer the patient to someone who is specially trained to manage stubborn cases of uveitis. Open-ended chronic use of steroid eye drops is a bad strategy.

A uveitis specialist may dig a little deeper than a primary ophthalmologist in seeking an underlying cause. Over the course of managing patients during the first year by a specialist, there are many instances of what was originally believed to be no specific underlying cause to blame, when in fact there is a specific underlying cause to blame for the patient’s stubborn inflammation, despite the primary care ophthalmologist having done a wonderful job of taking the patient’s history, conducting an examination and putting together a reasonable battery of laboratory tests, including whether or not the patient has the HLA-B27 gene, which is notorious for being associated with recurrent anterior uveitis.

We have any number of cases every single year in which, in reality, the patient’s underlying uveitis is not idiopathic or autoimmune, but infectious. The two most infamous infections that escape detection before referral are late latent secondary syphilis, in which the patient has no prior knowledge of contracting syphilis but had been infected typically many years earlier, and herpes simplex virus, in which the patient may or may not know of having been colonized with herpes simplex.

C. Stephen Foster, MD, is founder and CEO of the Ocular Immunology and Uveitis Foundation, Cambridge, Mass. Disclosure: Foster has received grants for clinical research from Xoma, AbbVie, Novartis and EyeGate Pharmaceuticals.