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Careful co-monitoring of patients with ocular inflammation increases positive outcomes
Long-term use of corticosteroids is still common despite safe and effective immunosuppressive agents.
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Ophthalmologists and chemotherapists must collaborate more effectively to determine the best drug regimen for each patient with an ocular manifestation stemming from an autoimmune disease, experts say. Many ophthalmologists are not taking full advantage of the immunosuppressive agents available to treat ocular inflammation in these patients, according to an expert panel.
Corticosteroids have been the traditional therapy for ocular inflammation for 4 decades, said C. Stephen Foster, MD, founder of the Ocular Immunology and Uveitis Foundation. Although corticosteroids are effective, their long-term use can increase the risk of cataract, glaucoma and other ocular and systemic side effects.
Meeting in 1999 and 2000, a panel of experts determined that the most appropriate management strategy for ocular inflammation was combination therapy – corticosteroid therapy coupled with an immunosuppressive agent. The panel concluded that this strategy was not being applied frequently enough in this population. The panel’s findings were published in a landmark article in the American Journal of Ophthalmology in 2000.
“The evidence is very strong on the safety and efficacy of [immunosuppressive] agents in the care of patients with ocular inflammatory diseases that are autoimmune,” Dr. Foster said in an interview with Ocular Surgery News. “Evidence also suggests strongly that nowhere near enough of that type of practice is being done. There is a crying need for increasing amounts of education throughout ophthalmic circles for this shift in paradigm.”
The end goal with combination therapy is to reduce the dose of the corticosteroid and eventually wean the patient off the immunosuppressive agent, Dr. Foster said. The ideal prognosis is that an individualized drug regimen can “re-educate” a patient’s immune system and produce a quiet eye that no longer requires treatment, he said.
“Experience tells us that the likelihood is very high that the immune system has been provided with the opportunity and setting to be re-educated,” Dr. Foster said. “We’ve had a huge number of patients that, once they have achieved that goal of no flare-ups, are successfully withdrawn off steroids and immunosuppressants without a recurrence of the disease.”
Comanagement is key
Dr. Foster said that individualized treatment and close patient monitoring are crucial because of the increased risk of toxicity and side effects that corticosteroids carry.
Comanagement of patient care is key to safe and successful combination therapy, he said. The chemotherapist’s role is to monitor safety and the patient’s drug tolerance based on laboratory tests, and the ophthalmologist’s role is to monitor the efficacy of the drug regimen, he said.
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“The ophthalmologist makes the determination that the current recipe isn’t working, if the patient still requires a steroid, a higher dose of a medication or a change in medication,” he said. “He will also determine how often he wants to see that patient.”
Ideally the chemotherapist sees the patient about every 6 weeks, and the ophthalmologist sees the patient every 2 to 6 weeks, Dr. Foster said.
Durable remission
Problems arise when communication is infrequent between the chemotherapist and the ophthalmologist, Dr. Foster said. Sometimes the two specialists may not communicate for more than a year, he said. By that time, it may be that the patient requires a dosage change.
“In most of those instances, the ophthalmologist and the chemotherapist have not been communicating adequately,” he said.
Ideally, the chemotherapist alerts the ophthalmologist when a patient is not responding to the prescribed immunosuppressant dose. For example, if a patient is not improving after taking methotrexate 25 mg for more than 1 year, the chemotherapist should know the dosage is not enough to induce remission, Dr. Foster said.
“The question then is whether or not to increase the dose. The chemotherapist makes that decision based on the patient’s tolerance and blood parameters,” he said.
Finding a drug regimen that quiets the eye with no corticosteroids may take up to 1.5 years, Dr. Foster said. After the eye is quiet, Dr. Foster recommended keeping the patient on the therapy for 2 years, providing there are no negative effects.
Although finding the right regimen is time-consuming, many patients are able to achieve durable remission – quiescence and discontinuation of therapy, he said.
“With these patients, it is a matter of constant modification, but the end goal is incredibly simple: ... no inflammation on no steroid,” Dr. Foster said. “You need to be on a drug or combination of drugs that don’t include steroids and that keep you from having flare-ups of the uveitis, scleritis or peripheral ulcerative keratitis.”
Common drugs
The expert panel that authored the AJO article, led by Douglas A. Jabs, MD, recommended that ophthalmologists weigh the evidence on corticosteroid and immunosuppressant drugs. Not all of the drugs have an ample body of evidence supporting their use, and some are used off-label to treat the eye, the panel noted.
A high dose of oral corticosteroids should not be administered beyond 1 month, the authors said.
Prednisone is the most commonly used corticosteroid, the authors said. The average dose is 60 mg to 80 mg for an adult. If more than 10 mg daily is required, an immunosuppressant agent should be added, and the ophthalmologist should begin tapering the corticosteroid, they said.
Patients taking corticosteroids should have their blood pressure and glucose monitored every 3 weeks, and they should have bone mineral density, blood cholesterol and lipids monitored annually, according to the article. The panel recommended that patients taking steroids also take supplements containing 1500 mg of calcium and 800 IU of vitamin D daily to avoid bone density loss. Those taking nonsteroidal anti-inflammatory drugs along with a corticosteroid should be monitored for gastrointestinal problems, the authors said.
With methylprednisolone, another popular corticosteroid, potential side effects include arrhythmia, cardiovascular collapse, myocardial infarction and severe infection when administered intravenously.
Second-line therapy
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The delicate tinkering with the drug regimen begins if corticosteroids are insufficient to subdue the inflammation, Dr. Jabs and colleagues said. Adding an immunosuppressant agent to the corticosteroid is the second line of therapy. Immunosuppressant agents can be combined with antimetabolites, T-cell inhibitors and alkylating agents.
Immunosuppressant agents may also be used initially with high-dose oral corticosteroids, which should later be tapered from the regimen.
Antimetabolites used commonly in the eye include azathioprine, methotrexate and mycophenolate mofetil. T-cell inhibitors include cyclosporine and tacrolimus. Alkylating agents include cyclophosphamide and chlorambucil.
Alkylating agents can be combined with corticosteroids but should not be used in combination with other immunosuppressant drugs because of toxicity, according to the article. Malignancy is another concern with alkylating agents, and patients may be at increased risk for developing bladder cancer, skin cancer and myeloproliferative malignancies.
Patients taking immunosuppressant agents also need to be closely monitored for toxicity and side effects, he said.
Advances in treatment
There are several drugs that have been used successfully off-label in patients unresponsive to standard treatment, Dr. Foster said.
“Most drugs that are immunosuppressants or anti-inflammatory agents, physicians began to turn to them for off-label use, such as for lupus, rheumatoid disease and ocular inflammatory disease. It clearly is a major advance in our armamentarium we can use to save vision in otherwise destructive inflammatory disease,” he said.
Dr. Foster uses dacliximab, intravenous immunoglobulin and infliximab as off-label treatments for treatment of ocular inflammation. These drugs have been successful in ocular applications anecdotally, but expense and lack of insurance coverage often keeps ophthalmologists from administering them, he said.
Other new therapies include TNF inhibitors, interferon alpha and monoclonal antibodies, according to a 2004 article in Seminars in Arthritis and Rheumatism. Some experimental treatments such as retinal S-antigen and HLA-peptide-mimicking retinal autoantigen have been studied in separate trials. Monoclonal antibodies have been used successfully in reported cases.
Intravitreal implants that release the corticosteroid cyclosporine are being evaluated. The Food and Drug Administration approved Bausch & Lomb’s Retisert (fluocinolone acetonide) implant for use in chronic noninfectious posterior uveitis in April.
Genetic factors
Genetic research has identified several genes linked to the development of autoimmune diseases, Dr. Foster said.
Research has identified the gene HLAb27 as a genetic risk factor for the development of uveitis, inflammatory bowel disease and ankylosing spondylitis, he said.
“Birdshot retinochoroidopathy probably has the highest genetic linkage of any autoimmune disease known. The HLAa29 gene is a risk factor for developing birdshot, and virtually 97% of patients with birdshot are HLAa29 positive,” he said.
Dr. Foster has done extensive research on ocular cicatricial pemphigoid and has linked the HLADQ beta star 0301 gene with it. He said the gene is overrepresented in patients with ocular cicatricial pemphigoid.
Patients with these genes are predisposed to autoimmune disease and develop them when exposed to a certain microbe, he said. People without the gene may acquire the infection but recover without the immune system continuing its attack on the body afterwards.
“The B27 person’s immune system fights off the germ, but at the same time launches an attack against the person’s own tissues, including the eye tissues, producing uveitis,” he said.
For Your Information:References:
- C. Stephen Foster, MD, can be reached at the Ocular Immunology and Uveitis Foundation, Massachusetts Eye Research Surgery Institute, 5 Cambridge Center, 8th Floor, Cambridge, MA 02142; 617-742-6377; fax: 617-227-1185; e-mail: fosters@uveitis.org.
- Douglas A. Jabs, MD, can be reached at the Wilmer Ophthalmological Institute, 550 N Broadway, Suite 700, Baltimore, MD 21205; 410-955-1966; fax: 410-955-0629; e-mail: djabs@jhmi.edu.
- Jabs DA, Rosenbaum JT, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendation of an expert panel. Am J Ophthal. 2000;130:492-513.
- Pras E, Neumann R, et al. Intraocular inflammation in autoimmune diseases. Semin Arthritis Rheum. 2004;34:602-609.
- Jeanne Michelle Gonzalez is an OSN Staff Writer who covers all aspects of ophthalmology.