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Corticosteroids have long been the mainstay of treatment for uveitis, but these drugs are known to carry the risk of serious side effects. Is treatment with steroid-sparing immunosuppressants the solution?
That’s the opinion of the expert panel that published “Guidelines for the Use of Immunosuppressive Drugs in Patients With Ocular Inflammatory Disorders” in 2000. The panel recommended the addition of immunosuppressants if inflammation cannot be controlled at a dosage of 10 mg per day or less of prednisone—or its equivalent—within three months.1
Yet many ophthalmologists are reluctant to use immunosuppressive therapies, in part because of lingering concerns about cancer and other perceived risks, especially for younger patients. Some ophthalmologists appear to be unaware of the guidelines (see “Ideal vs. Real: Corticosteroid Prescribing Patterns”). As a result, far too many uveitis patients are being maintained on long-term corticosteroids and, thus, are at increased risk of such side effects as cataracts, glaucoma, diabetes, hypertension, hyperlipidemia and osteoporosis.
For many physicians, the most pressing question is whether immunosuppressive therapy raises the risk of cancer in patients with noninfectious uveitis. Based on currently available information, the answer appears to be no, with a few caveats.
It’s important to note that much of the evidence on increased cancer risk with immunosuppressants does not come from studies of patients with inflammatory eye disease. Rather, it is drawn from studies of transplant patients, whose need for intense systemic immunosuppression places them at heightened cancer risk compared with uveitis patients. Given that limitation, here’s an overview of what we know now.
An increase in risk. The alkylating agents cyclophosphamide and chlorambucil show the strongest evidence to date of an increased risk of malignancy. “Alkylating agents are curative, but the evidence is fairly persuasive that they cause cancer,” said John H. Kempen, MD, PhD, associate professor of ophthalmology and epidemiology at the University of Pennsylvania in Philadelphia.
In a review of the existing evidence, Dr. Kempen and his colleagues concluded that these drugs increase the risk of bladder cancer (cyclophosphamide only), leukemia, lymphoma, skin cancer and, possibly, overall cancer.2 Nonetheless, they say, use of these drugs may be appropriate for severe, vision-threatening disease, in which the risk of blindness without treatment is much higher than the risk of cancer with treatment.
In addition, Dr. Kempen said, it might be possible to use alkylating agents as suggested in a follow-up report on short-term, high-dose chlorambucil therapy for sight-threatening uveitis.3 “There were no lymphomas or skin cancers in their cohort, so there might be a lower risk with that approach.”
A mixed picture. Overall, the calcineurin inhibitors cyclosporine and tacrolimus and the antimetabolite azathioprine do not appear to increase long-term cancer risk, except in certain high-risk patients, particularly those who have received organ transplants. There may be a higher risk of nonmelanoma skin cancer with cyclosporine and azathioprine, but “it’s possible that’s in a post-transplant situation” and thus not applicable to uveitis patients, Dr. Kempen said. In any event, he recommends that patients using these drugs should wear sunscreen and be monitored for the possible development of skin cancer.
The evidence is even less conclusive regarding the use of tumor necrosis factor (TNF) inhibitors, such as etanercept and infliximab. Most rheumatology studies provide strong evidence of safety in terms of cancer, with the notable exception of a meta-analysis of clinical trials, which reported a higher risk of cancer.4
Looking specifically at ophthalmology, Dr. Kempen and his colleagues reported that TNF inhibitors increased total and cancer mortality in patients with uveitis and other ocular inflammatory diseases in the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) study.5 However, the researchers cautioned that their data were limited by the study’s methodology and need to be confirmed in other studies. “Patients with severe disease that puts them at higher risk of cancer might have been treated more often with TNF inhibitors, which might explain the observation,” said Dr. Kempen, adding that more information will be forthcoming from SITE in approximately three years.
Negligible risk. Methotrexate, mycophenolate mofetil and daclizumab appear to have the lowest risk of carcinogenicity, based on existing evidence. “This is especially true with methotrexate,” Dr. Kempen said. “Its safety is well established, and it might even lower the risk of heart disease.”
The larger context. “To begin with, the important thing is that we’re not comparing these drugs with topical therapy such as Pred Forte; if a patient responded to that, the discussion would be over,” said Debra A. Goldstein, MD, director of the uveitis service and professor of ophthalmology at the University of Illinois in Chicago. “We’re looking at preventing the loss of visual function. If someone has lost vision in one eye, we know that we have to proceed aggressively in the other eye. If a person has perfect vision, then we can proceed at a much slower pace. Unfortunately, we have no therapy that’s perfectly safe and perfectly efficacious.”
For Dr. Kempen, the take-home message is one of safety. “For years, physicians have worried about cancer risk with these drugs, but the risks have been overstated. If these drugs are needed, you shouldn’t avoid using them based on current information.” Moreover, he noted an irony: “People are hesitant and uncomfortable with using immunosuppressants, yet they manage patients on prednisone for longer periods of time, despite the greater risks with prednisone.”
Other Safety Considerations
But cancer is not the only factor in considering the use of immunosuppressive therapies. Uveitis specialists emphasize the need to conduct a thorough assessment of each individual. “With every patient, you have to weigh the drug choice along with his or her lifestyle and any other preexisting medical conditions,” Dr. Goldstein said. She noted that several other situations, including the following, also affect the choice of therapy.
Pregnancy. Several immunosuppressants are contraindicated during pregnancy, including cyclophosphamide, chlorambucil and methotrexate.
Dr. Goldstein commented that methotrexate is “absolutely contraindicated in pregnancy or in any female patient who may become pregnant—or even in a male patient who may impregnate someone.” She pointed out that methotrexate is “one of the few FDA Category X drugs and, in fact, can be used to terminate pregnancy, as in the case of an ectopic pregnancy.”
Dr. Goldstein added, “I fully counsel all patients on the serious risk to the fetus should they become pregnant during treatment [with methotrexate] and ask that they use two forms of birth control while they are taking the drug and for at least three months after it is stopped.”
Other immunosuppressive agents have been used successfully during pregnancy, Dr. Goldstein said. “However, I prefer not to use systemic immunosuppression during pregnancy. Thankfully, many uveitis patients will experience relative quiescence during pregnancy and flare up only after delivery. Other patients can be managed with local therapy, such as periocular or intraocular corticosteroids. I contact each patient’s obstetrician in order to discuss risks and benefits of any systemic, local or topical therapy.”
Postpartum period. The risks of drug side effects are not confined to pregnancy; some drugs, such as methotrexate, are also contraindicated for women who want to breast-feed their infants. “Treatment may need to be modified based on the mother’s desire to nurse,” Dr. Goldstein said.
Treatment also may need to be modified if a patient experiences a postpartum uveitis flare. “There seems to be a relative immunosuppression of uveitis during the third trimester of pregnancy, when there’s a lot of circulating progesterone—and progesterone is an anti-inflammatory,” Dr. Goldstein said. “It’s in the ‘fourth trimester,’ those first three months after delivery, when uveitis can flare and we get into trouble.”
In children. There is no age limit or threshold for the use of immunosuppressive therapy. “I often have to use immunosuppressants in young children,” Dr. Goldstein said. With regard to potential side effects, “The toxicity of corticosteroids is even more significant in children than it is in adults, as systemic corticosteroids can result in growth retardation in kids,” she said.
Moreover, she noted, children may be more susceptible than adults to the effects of topical corticosteroids in terms of developing cataracts or glaucoma; and if cataract or glaucoma surgery becomes necessary, it may be more problematic in children. For these reasons, many children with chronic uveitis need steroid-sparing immunosuppressive therapy, she said. “For example, children in my practice with uveitis related to juvenile idiopathic arthritis often require systemic immunosuppression.” Dr. Goldstein’s first choice in these patients is usually methotrexate, “as it has a long track record of safety and does not appear to increase cancer risk when used in children.”
In young adults. Technically, immunosuppressants can be used in teenagers and young adults. However, Dr. Goldstein said that she’s reluctant to use methotrexate in this age group because of the risk of liver problems. “I always assume that college kids drink too much, so drugs like methotrexate that have hepatotoxic side effects aren’t ideal choices.”
Taking It Step by Step
Do uveitis specialists generally follow a stepladder approach to treatment? “We all do, whether or not we call it that,” Dr. Goldstein said. “In most cases, we’re looking for a steroid-sparing effect.”
However, she noted that the stepladder is inappropriate for some types of uveitis. “We’re more aggressive to start with in cases of retinal vasculitis or Behçet disease. We don’t go stepwise. We know we have to go to biologics as first-line therapy.”
This type of aggressive stance is in keeping with the guidelines. As the panel noted, “Selected diseases, because of their poor natural history, are candidates for immunosuppressive drug therapy from the onset. These include Behçet disease with posterior segment involvement and mucous membrane pemphigoid with ocular involvement.”1
1 Jabs, D. A. et al. Am J Ophthalmol 2000;130(4):492–513.
2 Kempen, J. H. et al. Am J Ophthalmol 2008;146(6):802–812.
3 Birnbaum, A. D. et al. Ophthalmology 2010:117(7):1466–1466.e1.
4 Bongartz, T. et al. JAMA 2006;295(21):2275–2285.
5 Kempen, J. H. et al. BMJ 2009;339:b2480.
Drs. Goldstein and Kempen report no related financial interests.
IDEAL VS. REAL: Corticosteroid Prescribing Patterns
Uveitis treatment guidelines issued by an expert panel1 are not being followed as thoroughly as they should, a study published earlier this year found.2
In a cross-sectional, multicenter study conducted in the United States, researchers surveyed 60 ophthalmologists and three rheumatologists who routinely manage patients with noninfectious uveitis. Of the 63 physicians in the study, 47 (75 percent) “did not use/were not aware” of the guidelines. Of the remaining 16 physicians who “do use/are aware” of the guidelines, 15 reported that they “always/often” adhere to them.
In addition, a total of 580 patients with noninfectious uveitis were randomly selected for analysis. All told, 62 percent of the patients received systemic corticosteroids.
As the researchers noted, this real-world look at physician prescribing patterns reveals that far too many patients are being treated and maintained on high doses of corticosteroids rather than being moved to steroid-sparing therapy.
1 Jabs, D. A. et al. Am J Ophthalmol 2000;130(4):492–513.
2 Nguyen, Q. D. et al. Ophthalmology 2011;118(1):184–190.