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A dearth of uveitis specialists and widespread lack of familiarity with published treatment guidelines leave treatment gaps and less-than-optimal care for many patients.
Most people with noninfectious uveitis are treated by comprehensive ophthalmologists, many of whom are unfamiliar with established treatment guidelines outlining the role of corticosteroids and immunomodulatory therapy (IMT). But it’s not just nonspecialists who sometimes fail to follow treatment recommendations. Although these guidelines were published a dozen years ago,1 their application varies widely, according to recent studies: While uveitis specialists generally demonstrate good compliance,2 many other ophthalmologists, including retina specialists, do not use, or are not even aware of, the guidelines.3
Unfamiliarity with the guidelines often leads to improper treatment because doctors may be reluctant to prescribe adequate corticosteroid dosages initially due to concerns about side effects. Paradoxically, this may lead to patients being kept on too high a dose of corticosteroids for too long after multiple failed attempts to taper them off the drugs.
Physicians may not realize that successful corticosteroid tapering can usually be achieved with the addition of an immunomodulatory agent to the patient’s regimen. Often referred to as corticosteroid-sparing agents, these drugs include azathioprine, methotrexate, mycophenolate mofetil, cyclosporine, cyclophosphamide, and others. In the last decade, the newer biologic response modifiers, such as tumor necrosis factor (TNF) inhibitors, have also secured a place in the treatment arsenal for noninfectious uveitis (see below).
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However, because many ophthalmologists are not comfortable using IMT, a significant segment of patients with noninfectious uveitis may not be receiving optimal care. Here is a closer look at current practices and how they can be improved with appropriate use of a variety of anti-inflammatory regimens.
When Guidelines Are Unknown or Ignored
In an editorial published in the Journal of Ophthalmic Inflammation and Infection,4 Emmett T. Cunningham Jr., MD, PhD, MPH, director of the uveitis service at California Pacific Medical Center in San Francisco and adjunct clinical professor of ophthalmology at Stanford University School of Medicine, examined the findings of several surveys of physicians who manage patients with noninfectious uveitis. His review of the survey responses revealed a striking lack of consensus and consistency in the treatment of these patients.
Excessive maintenance. For example, in a 2011 study, Nguyen and colleagues surveyed 60 ophthalmologists (about a third of whom were uveitis specialists) and three rheumatologists about their management of noninfectious uveitis.3 The results revealed that patients were often placed on maintenance dosages of corticosteroids that were three to four times the recommended maximal dosage of less than 10 mg per day. Further, only 12 percent of patients were prescribed IMT to bring systemic corticosteroid dosages into the target range. Perhaps most surprisingly, 75 percent of the physicians participating in this survey responded that they “did not use/were not aware of” uveitis treatment guidelines.
Uveitis—Not One Disease but Many
The first step in achieving optimal treatment is to determine what, exactly, you’re dealing with. Douglas A. Jabs, MD, MBA, professor and chairman of ophthalmology at Mount Sinai School of Medicine in New York, said that uveitis comprises about 30 separate diseases, each with its own course and treatment needs. “The type of uveitis most commonly seen by nonspecialists is acute anterior uveitis. It is episodic, potentially recurrent, and typically requires six to eight weeks of topical corticosteroids. At that point, you can stop treatment, and the patient will have, on average, one attack a year.”
Hone the diagnosis to choose the treatment. However, Dr. Jabs emphasized, the treatment paradigm used to treat acute anterior uveitis is absolutely wrong for the more severe, chronic uveitides, which typically require more than topical corticosteroids. Distinguishing between an acute, recurrent process and a chronic process is critical for matching the appropriate treatment to the disease.
“Some diseases are spontaneously remitting, have a good prognosis, and don’t need treatment—multiple evanescent white dot syndrome is one such disease,” Dr. Jabs said. “Others need antimicrobial treatment. Ocular toxoplasmosis, for example, requires treatment with antimicrobial agents plus or minus corticosteroids, depending on the location of the lesion. Diseases that require immunosuppression, like birdshot retinochoroidopathy, need treatment with oral corticosteroids plus an immunosuppressive drug. All three of these diseases are called posterior uveitis under a kind of lumping rubric. But just think how different the treatments are for these diseases. That’s why it is so critical to make the correct diagnosis.”
Corticosteroids: Hit Hard, Taper Fast
Dr. Cunningham noted that the guidelines for treating noninfectious uveitis call for controlling inflammation with corticosteroids—topical, systemic, or periocular—but also acknowledged the drugs’ potential toxicity, especially when given systemically.
“Corticosteroids are important drugs, and they are our primary drug for achieving rapid control,” said Dr. Cunningham. “But corticosteroids are often used at too high a dose and for too long. We try to get adults to 7.5 to 10 milligrams per day or less within three months. The guidelines do not take into account children, who are much more vulnerable to corticosteroids and who can experience profound growth retardation as a result of corticosteroid treatment. So the need is even greater to bring the dosage down in children as quickly as possible.”
Dr. Cunningham tells his residents, “Corticosteroids are great—they are cheap, potent, and fast acting, but many doctors don’t treat aggressively enough early on. As a result, they don’t achieve complete control and then can’t taper the corticosteroids to below the target dose of 7.5 to 10 milligrams per day. That’s why you see patients on 30 or 40 milligrams per day for six or more months, leading to toxicity.”
Consequences of Inadequate Treatment
When members of the American Uveitis Society were asked in a survey to name the number-one treatment error they see among patients referred to them, undertreatment won hands down. “Most ophthalmologists are keenly aware of the side effects of corticosteroids—including both the drops and systemic therapy—and they are worried about using them,” said Nisha Acharya, MD, associate professor of ophthalmology and director of the uveitis service at the University of California, San Francisco.
Too little ... “As a result, they may undertreat patients, either with the number of drops prescribed or with inadequate oral corticosteroid dosages. With oral corticosteroids, an ophthalmologist may prescribe the drugs but then do a really fast taper or start the patient on doses that are lower than advisable.”
Dr. Acharya added that the problem with undertreatment is that you are exposing patients to possible side effects from corticosteroids with little likelihood of achieving a good response. “In the end, patients have to be put on longer treatment courses and may eventually need an increased steroid dose.”
Or too long. The other big issue is that patients are often maintained on corticosteroids too long. “This is different from undertreatment,” she said, which “involves how you approach and prescribe your corticosteroid treatment and what doses and tapering schedule you use. But the challenge is what to do when patients are not able to taper off corticosteroids because of chronic inflammation.”
The problem of intermittent control. Uveitis specialists often see patients who should have been put on immunomodulatory therapy but were not. “In these instances, a patient may be kept on oral corticosteroids indefinitely or be given intermittent periocular or intraocular corticosteroid injections in an attempt to keep the inflammation quiet,” Dr. Acharya said. “Chronic corticosteroid use, especially at high doses, can lead to systemic complications, such as bone thinning, diabetes, hypertension, and ulcers. Corticosteroid injections are also associated with the development of cataracts and glaucoma.
“The problem with intermittent corticosteroid injection is that you are not continuously suppressing the inflammation,” Dr. Acharya added. “You are suppressing it, waiting for the inflammation to flare up, and then injecting again. This ‘sawtooth’ pattern of inflammation is problematic because each flare-up can cause more damage to the structures of the eye, often with permanent negative consequences.
“Our goal for patients with chronic inflammation is to find a safe and effective long-term therapy, and we don’t consider high-dose oral corticosteroids to be a long-term option,” she continued. “So we typically move on to systemic immunomodulatory agents, either the traditional agents or the new biologics. There are a lot of options now, including the option of using a corticosteroid implant.”
Intravitreal Implants vs. Systemic Therapy
An intravitreal corticosteroid implant, such as Retisert (fluocinolone acetonide, 0.59 mg), can provide long-term therapy for chronic noninfectious posterior uveitis. Retisert relies on microtechnology to create a tiny drug reservoir that delivers the medication directly to the back of the eye. “Retisert is extremely effective,” Dr. Acharya said. “It releases the corticosteroid into the eye for about two-and-a-half years.”
The Multicenter Uveitis Steroid Treatment (MUST) trial5 compared the efficacy and safety of the fluocinolone implant and systemic corticosteroid therapy. The researchers found that implant therapy was as effective as systemic steroid treatment in preserving or improving vision at two years. Moreover, although both treatment approaches controlled the inflammation in the majority of patients, implant therapy reduced inflammation more quickly and was slightly more effective than systemic corticosteroids and immunosuppression (88 percent vs. 71 percent). Dr. Jabs noted that the better control of inflammation with the implant also suggests a role for it for patients in whom systemic therapy fails to control the inflammation.
However, the implant has the potential to cause glaucoma and cataract. “About 50 percent of patients develop elevated intraocular pressure, and 16 percent of patients may develop glaucoma within two years—and cataract develops in almost everyone,” Dr. Acharya said. “But patients who do not want systemic therapy may prefer to use an intravitreal implant and deal with these side effects. The elevated pressure is manageable, although some patients may need glaucoma surgery.” In MUST, 25 percent of the eyes with implants developed IOP elevations that required surgery, versus 4 percent in the systemic therapy group.
Regarding the comparison of side effects between the implant and systemic groups, Dr. Jabs noted that it is not a matter of “all or none; the differences are more or less.” For example, cataract occurred in 45 percent of systemically treated patients, and elevated IOP in about 19 percent at two years.
A dexamethasone intravitreal implant (Ozurdex) is also available. This implant, which lasts about six months, was approved in 2009 to treat macular edema following branch retinal vein occlusion or central retinal vein occlusion; and in 2010 it received FDA approval for noninfectious uveitis.
These corticosteroid-sparing drugs are an integral component of long-term management of noninfectious uveitis. The classic categories include antimetabolites (azathioprine, methotrexate, mycophenolate mofetil), leukocyte-signaling, or calcineurin, inhibitors (cyclosporine, tacrolimus, sirolimus), and alkylating agents (chlorambucil, cyclophosphamide). More recently, biologic response modifiers such as TNF-alpha inhibitors, including adalimumab (Humira), etanercept (Enbrel), infliximab (Remicade), and golimumab (Simponi), have joined the list of options for ocular inflammation.
The uveitis specialists surveyed by Esterberg and Acharya most commonly reported using methotrexate as their initial corticosteroid-sparing therapy, with mycophenolate mofetil as their second choice. Apart from efficacy, physicians’ preferences were influenced by such factors as safety, cost, availability, and ease or difficulty of administration.2
Biologic response modifiers hold promise. These agents, which inhibit cytokines, have the potential to precisely target and suppress inflammation in noninfectious uveitis.
Eric B. Suhler, MD, MPH, associate professor of ophthalmology at Oregon Health & Science University in Portland, noted that the number of biologics is increasing dramatically.
“It’s an exciting time because biologics are just exploding, and there are so many potential therapeutic targets that we are learning to interfere with in various ways,” said Dr. Suhler, who is also chief of ophthalmology at the Portland VA Medical Center and codirector of OHSU’s uveitis clinic. “We are improving in the breadth of targets as well as in the way we can deliver care.
“Initially, almost all of the biologics were developed to be given intravenously. The most commonly used of these is the TNF blocker infliximab. More recently, subcutaneous options have become increasingly prevalent and can be given at longer intervals. Adalimumab, another TNF blocker commonly utilized for uveitis, can be given subcutaneously every two weeks. Some recently developed TNF blockers can be dosed at monthly intervals, but these are less well studied for uveitis.”
Concerns about side effects. Dr. Suhler noted that TNF blockers have been in use for about a decade in rheumatology and oncology. “We have found them to be extremely beneficial in treating uveitis, albeit with concerns about side effects like infections and malignancies.
“With TNF blockers, we don’t usually see the side effects often associated with other agents used to treat noninfectious uveitis,” he said. “But there is a controversy in the rheumatology literature about how much, if at all, TNF blockers increase a patient’s risk of developing a malignancy.
“The SITE [Systemic Immunosuppressive Therapy for Eye Disease] study6 found that over 25 years of follow-up, individuals with inflammatory diseases treated with anti-TNF agents had an approximately threefold risk of dying of cancer compared with patients not treated with TNF blockers,” Dr. Suhler continued. “This is consistent with some of the findings in the rheumatology literature, though other rheumatology studies have refuted this increase in risk. These agents also probably double the risk of serious infections.”
Dr. Suhler added that these findings were less robust than other results from the SITE study because of the shorter follow-up and smaller patient cohort with these medications. “Nonetheless,” he said, “these safety concerns, as well as the cost, are the reasons that TNF inhibitors typically are not used as first-line drugs unless the uveitis is very severe.”
Simplifying Immunomodulatory Drug Categories
|Dr. Cunningham offered his own informal groupings of immunomodulatory medications for noninfectious uveitis based on strength, safety, and tolerability. These simple categories can provide a starting point for an ophthalmologist who is considering prescribing corticosteroid-sparing agents.
Weaker but Safer. The “weaker but safer” group includes the antimetabolites methotrexate, mycophenolate mofetil, and azathioprine.
“These agents all seem to be in the same range of control, which, interestingly, is not complete control even in expert hands,” Dr. Cunningham said. “The decision to select one of the antimetabolites depends on the relative indications and contraindications for a given patient, as well as how comfortable the physician is with using the medication.” He noted that methotrexate may not be a good choice for a patient with a history of chronic hepatitis or alcoholic liver disease, for example, because it is metabolized by the liver.
The most important factor in choosing a drug is determining how much potency is needed. “If I am treating with corticosteroids and have not achieved control, or if I put a patient on high-dose corticosteroids and the disease comes back quickly as I taper the dose, I know that I need a significant amount of extra potency.
“There is a group of disorders that, out of the gate, we recognize as being particularly difficult to control. These include sympathetic ophthalmia and Wegener granulomatosis, which tend to require the early addition of an immunosuppressive agent.”
Stronger and Less Safe. Historically, the “stronger and less safe” category included alkylating agents such as chlorambucil and cyclophosphamide, Dr. Cunningham said. “We still use these for certain disorders, such as Wegener granulomatosis and some collagen vascular diseases. But in recent years, the trend has been to use biologics, most importantly, the TNF inhibitors. We use TNF inhibitors when the antimetabolites are insufficient or the patient is intolerant of them. TNF inhibitors can be added to antimetabolites.”
Leukocyte-Signaling Inhibitors. Dr. Cunningham also discussed leukocyte-signaling inhibitors (often referred to as calcineurin inhibitors or T-cell inhibitors). These agents include cyclosporine and tacrolimus. Based on his overview of surveys on uveitis treatment,1 Dr. Cunningham noted that cyclosporine was rarely preferred and seldom used, primarily because of tolerability concerns. “Doctors don’t seem to like these drugs and, I believe, with good reason,” he said. “The small amount of evidence we have suggests that cyclosporine may not be as effective as the antimetabolites, and yet it has a lot of side effects, including high blood pressure, hair growth, gingival hyperplasia, and kidney damage.”
Uveitis specialists generally have less experience with tacrolimus, and the therapeutic window is clearly narrower than for cyclosporine, but some studies have reported promising results with this agent.
1 Cunningham ET Jr. J Ophthalmic Inflamm Infect. 2012;2(2):61-63.
Putting Treatment Risks Into Perspective
“Properly used, immunosuppression is relatively safe,” Dr. Jabs said. “The MUST trial,5 which randomized patients to prednisone plus immunosuppression or the fluocinolone acetonide implant, found no increased risk of systemic side effects among those who received oral corticosteroids plus immunosuppression. The one exception was that patients given prednisone were prescribed antibiotics more often for infections, although these individuals were not hospitalized more frequently than other patients.
“The group assigned to oral corticosteroids plus immunosuppression used the drugs in a manner consistent with published recommendations, including aggressive tapering of prednisone to less than 10 mg per day,” Dr. Jabs added. “The side effects over a period of years—maybe not decades—at 7.5 mg or less of prednisone per day are very minimal. So it is a tolerable dose if you can taper it down, and immunosuppression is the way to get the dose down to that level.”
Dr. Jabs added that the SITE cohort study found no increased risk of mortality, cancer-related mortality, or probably even cancer per se, with antimetabolites or calcineurin inhibitors.6 “Those drugs are safe in the long term,” he said, “and we have 25-year follow-up in that study, with lots of power to pick up small differences. So the more conventional small-molecule immunosuppression is probably safe in the long term.”
When one looks carefully at individual drugs and different regimens, Dr. Jabs said, any one drug works about 50 to 70 percent of the time, and any approach works 70 to 85 percent of the time, but nothing works 100 percent of the time. “That’s why it’s important to have access to someone who knows how to use multiple treatments and knows when to move on to drug 2 or drug 3 if the first drug doesn’t work. You can’t rigidly stick with a single approach and expect it to work with everyone. This is where you move out of the science and into the art of medicine.”
1 Jabs DA et al. Am J Ophthalmol. 2000;130(4):492-513.
2 Esterberg E, Acharya NR. J Ophthalmic Inflamm Infect. 2012;2(1):21-28.
3 Nguyen QD et al. Ophthalmology. 2011;118(1):184-190.
4 Cunningham ET Jr. J Ophthalmic Inflamm Infect. 2012;2(2):61-63.
5 The MUST Trial Research Group. Ophthalmology. 2011;118(10):1916-1926.
6 Kempen JH et al. BMJ. 2009;339:b2480. doi:10.1136/bmj.b2480.
Meet the Experts
|NISHA ACHARYA, MD Associate professor of ophthalmology and director of the uveitis service at the University of California, San Francisco. Disclosure: Receives grant support from Bausch + Lomb and is a consultant for GlaxoSmithKline and Xoma.
EMMETT T. CUNNINGHAM JR., MD, PHD, MPH Director of the uveitis service at California Pacific Medical Center in San Francisco and adjunct clinical professor of ophthalmology at Stanford University School of Medicine. Disclosure: Is a partner in Clarus Ventures.
DOUGLAS A. JABS, MD, MBA Professor and chairman of ophthalmology at Mount Sinai School of Medicine in New York. Disclosure: Is a consultant for Abbott, Alcon, Allergan, Applied Genetic Technologies, Corcept Therapeutics, Genentech, Genzyme, GlaxoSmithKline, Novartis, Regeneron, and Roche.
ERIC B. SUHLER, MD, MPH Associate professor of ophthalmology at Oregon Health & Science University and chief of ophthalmology at the Portland VA Medical Center. Disclosure: Is a consultant for Abbott and Lux Bio and receives grant support from Abbott, Bristol-Myers Squibb, EyeGate, Genentech, Lux Bio, and Novartis.