EyeNet Magazine


 
Clinical Update: Uveitis
Understanding Uveal Inflammation
By Leslie Burling-Phillips, Contributing Writer
 
 

On the surface, uveitis appears to be fairly straightforward. “You see uveitis, use steroids,” is a common refrain. In fact, however, there are dozens of potential causes of uveitis, and many of them respond either incompletely or not at all to corticosteroids. Thus it’s critical to have a correct diagnosis in order to choose the appropriate therapy. Infections can cause uveitis, for example, and treating infectious uveitis without appropriate antimicrobial therapy can actually make the inflammation worse. Similarly, there are well-recognized masquerade syndromes that can mimic uveitis, most notably neoplastic disorders such as intraocular lymphoma in the elderly and leukemia and retinoblastoma in the young.

“Sifting through the seemingly endless variables to identify the underlying cause of the inflammation can be a tremendous challenge because there are so many different causes. Some are associated with systemic diseases that are not typically considered by ophthalmologists. Most are noninfectious and are presumed to be autoimmune, but infectious and neoplastic causes of uveitis also exist,” explained 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.

The goals of uveitis treatment are straightforward:

  • Relieve the associated discomfort.
  • Restore vision and prevent any future vision loss.
  • Identify and treat the underlying cause of the inflammation.


Corticosteroids: The Mainstay of Therapy

“Although the side effects are numerous and can be significant, most specialists agree that corticosteroids are almost always the first line of therapy for any patient with uveitis unless there is a contraindication. After nearly 60 years, this is still the best treatment available for uveitis in terms of efficacy and the ability to control the disease quickly,” said Russell W. Read, MD, associate professor of ophthalmology and director of the uveitis/ocular inflammatory diseases service at the University of Alabama at Birmingham.

In most patients with anterior uveitis, the inflammation is noninfectious and is part of an autoimmune process related to human leukocyte antigen (HLA) B-27. This is generally treated with topical corticosteroids, quite often with 1 percent prednisolone acetate, although prednisolone sodium phosphate or dexamethasone may also be used, and rimexolone, loteprednol and fluoro- metholone may be used when the inflammation is mild. Whichever agent is chosen, relatively high doses that are tapered as the inflammation subsides are required rather than an initially low dose that may need to be gradually increased to control the inflammation. Treatment may also need to be adjusted according to the severity of the inflammation, the presence of relative contraindications and the patient’s history and response to therapy.

Topical treatment sometimes not enough. For severe uveitis, systemic corticosteroids are often prescribed and pose some well-known side effects. In addition to weight gain, elevated blood sugars, osteoporosis and systemic hypertension, patients may also experience adrenal suppression or insufficiency, leukocytosis, myopathy and hypokalemia. As a result, blood pressure, serum electrolytes and fasting glucose levels should be monitored regularly. In addition, children are particularly sensitive to the growth-stunting effects of corticosteroids and so their exposure should be limited. In some patients, periocular or intraocular corticosteroid injections may be necessary. A number of safety issues and side effects must then be considered. With an injection administered to the outside of the eye, for example, there are risks of ptosis, IOP elevation, cataract formation and inadvertent globe perforation. Similarly, with an injection administered into the eye, there are risks of endophthalmitis, trauma to the lens, retinal detachment or tear, or vitreous hemorrhage.


Immunosuppressives: When Corticosteroids Falter

In patients who do not respond or are refractory to corticosteroid treatment, or who have vision-threatening cases of uveitis, immunosuppressive agents may be necessary to manage the inflammation. Several classes of immunosuppressive drugs are available:

  • Antimetabolites (methotrexate, azathioprine, mycophenolate mofetil, etc.),
  • Inhibitors of leukocyte signaling (cyclosporine, tacrolimus),
  • Alkylating or DNA cross-linking agents (cyclophosphamide, chlorambucil) and
  • Biologic agents (most notably the tumor necrosis factor inhibitors infliximab, etanercept and adalimumab).

Toxicity and efficacy play tag. The challenge of immunosuppressive therapy is determining how much inflammation is present, identifying the underlying condition involved, and, according to Dr. Read, “understanding the continuum of potency and side effects, with increasing efficacy but increasing side effects as one moves forward.” Dr. Cunningham agreed. “Antimetabolites are the weakest, but safest, group of immunosuppressive agents. We have a lot of experience with them, particularly methotrexate and azathioprine. We know what side effects to anticipate and we can use them comfortably. Leukocyte signaling inhibitors, such as cyclosporine and tacrolimus, are more potent than the antimetabolites and produce more side effects. The alkylating or DNA cross-linking agents, including cyclophosphamide and chlorambucil, are most potent of all and have the most serious side effects, including secondary cancers and hemopoietic abnormalities, and so are generally reserved for patients with life- or vision-threatening conditions, such as those with systemic vasculitis.”

With big guns, be extra careful. The fourth type of immunosuppressive agents—the biologic agents, typified by the tumor necrosis factor inhibitors—are also reserved for treating patients who are refractory to other treatments and have severe vision-threatening inflammation. “The TNF inhibitors are relatively new. We’re just learning how to use them. It’s clear that some patients do quite well with them whereas others show little or no therapeutic response. Unfortunately, it is difficult to predict which patients will or will not respond well. As with the alkylating agents, there is a hefty side effect profile, including the reactivation of tuberculosis, increased risk of severe infection, including sepsis, lymphoma and demyelinating disease,” said Dr. Cunningham.

Keep patients in the loop. Owing to the significant number of side effects associated with the use of any of the immunosuppressive agents, patients must understand the potential risks prior to beginning treatment. Women should be advised not to become pregnant, and all patients should be carefully monitored for any adverse reactions. While the potential side effects are serious, said Dr. Read, “there is a false perception that immunosuppressive medications are going to make patients sick, or make their hair fall out. In fact, that’s not the case if they are used correctly. In my clinic, patients are given blood tests every six to eight weeks to monitor liver and kidney function. We also monitor blood counts to make sure they are not having any problems with treatment. The vast majority of people do just fine with no significant abnormalities.”


A Correct Diagnosis Is Critical

“Most important, I think, is coming up with an accurate diagnosis, since infectious uveitis requires a very different treatment from noninfectious uveitis, and the treatment for both infectious and noninfectious uveitis is, in turn, very different from what would be considered to be an appropriate therapy for one of the masquerade syndromes. Once the patient is found to have a noninfectious uveitis, then corticosteroids are usually sufficient,” said Dr. Cunningham. “But for those patients who either respond incompletely to or are intolerant of corticosteroids,” he added, “then a reasonable alternative is the use of one or more of the noncorticosteroid immunosuppressive agents or newer biologic agents. And since these medications can produce serious side effects, my recommendation is always to use them in close collaboration with both a uveitis specialist and a rheumatologist or an internist who is comfortable with dosing and monitoring these agents. Use of immunosuppressive agents is as much an art as a science.”
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Dr. Cunningham reports no financial interests. Dr. Read is participating in a Lux clinical trial.
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For an extensive list of corticosteroids and immunosuppressive agents, with toxicity profiles and monitoring recommendations, click here.

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