Systemic Therapy Outperforms Intraocular Implant for Treating Uveitis

Active Clinical Trials // Publications // Research News // Uveitis // May 31 2017

Uveitis is characterized by inflammation inside the eye and is a leading cause of vision loss in the working population. The Multicenter Uveitis Steroid Treatment Trial compared the effectiveness and risks of systemic therapy consisting of corticosteroids and immunosuppressive drugs versus a long-lasting fluocinolone corticosteroid intraocular implant (developed by Bausch & Lomb) over a period of seven years. Systemic therapy preserved vision of patients with uveitis better– and had fewer adverse outcomes – than the intraocular implant. After seven years, visual acuity on average remained stable among participants on systemic therapy, but declined by an average of six letters (about one line on an eye chart) among participants that had the implant.

This National Eye Institute / National Institutes of Health funded study was performed by a network of investigative sites in the U.S. with a site in England and another in Australia. 255 patients were enrolled. The University of Wisconsin Fundus Photograph Reading Center, within the Department of Ophthalmology and Visual Science, was responsible for the determination of morphological outcomes throughout the study.

Dr. Michael Altaweel has directed this study at the Reading Center and served in the study leadership for the last 12 years. “Uveitis affects every structure within the eye, ranging from development of cataract, to glaucoma, to macular edema, and inflammatory scarring of the retina. The Reading Center assesses such changes without knowledge of treatment assignment so that we can provide an unbiased comparison of two treatment strategies. In this study, we found that a major difference in outcome and management recommendations are based on secondary effects of treatment, primarily the development of glaucomatous change in the optic nerve associated with the corticosteroid implant. Macular edema was initially better controlled with the implant but by 7 years, systemic therapy achieved better control. Chorioretinal lesions affecting central vision became more common in the implant group, affecting visual acuity”.

At seven years, with better visual acuity outcome in the systemic treatment group, less ocular adverse effects, minimal difference between groups in systemic side effects, and better cost-effectiveness, the systemic treatment approach becomes favored as the first choice for treatment. The fluocinolone implant controls inflammation better for about five years and has a role in treating patients when systemic therapy fails to control inflammation adequately or is not tolerated. The findings were published this month in the Journal of the American Medical Association.

“The results of this study are applicable to a wide range of physicians, as the initial approach to managing severe uveitis is now more likely to involve a Rheumatologist or Internist in conjunction with an Ophthalmologist, unless a Uveitis subspecialist is available. Following expert-panel guidelines, patients avoided most of the adverse outcomes that concern physicians when treating long-term with systemic corticosteroids and immunosuppressive drugs.”notes Dr. Altaweel. “ The findings are applicable to other fields of Medicine using such treatment strategies for systemic inflammatory diseases”.

“The MUST trial results will have immediate public health impact, helping clinicians and their patients make informed decisions about uveitis treatment,” said Sangeeta Bhargava, Ph.D., Program Director at the National Eye Institute.

Reference: John Kempen, Michael Altaweel, Janet Holbrook, Elizabeth Sugar, Jennifer Thorne, and Douglas Jabs for the Multicenter Uveitis Steroid Treatment (MUST) Trial and Follow-up Study. Association Between Long-lasting Fluocinolone Acetonide Intravitreous Implant vs. Systemic Anti-inflammatory Therapy and Visual Acuity at Seven Years Among Patients with Intermediate, Posterior, or Panuveitis. JAMA. 2017;317(19):1993-2005. doi:10.1001/jama.2017.5103

This study was supported by NEI grants U10EY014656 (Dr. Altaweel), U10EY014655 (Dr. Jabs), U10EY014660 (Dr.Holbrook), and Additional support was provided by Research to Prevent Blindness (New York, New York), the Paul and Evanina Mackall Foundation (New York, New York) and the Lois Pope Life Foundation (New York, New York). Bausch & Lomb provided support to the study in the form of donation of fluocinolone implants for patients randomized to implant therapy who were uninsured or otherwise unable to pay for implants, or were located at a site where implants could not be purchased (e.g., in the United Kingdom).

Concerns about potential adverse effects of systemic corticosteroid and immunosuppressive therapy drove the development of an intraocular implant to treat uveitis locally thus avoiding systemic side effects. The fluocinolone intraocular implant, developed by Bausch & Lomb, became FDA-approved in 2004. Early data suggested the implant was very effective at controlling inflammation and had local ocular side effects. The Multicenter Uveitis Steroid Treatment Trial was undertaken to evaluate whether this implant treatment was an improvement over systemic therapy for management of intermediate, posterior and panuveitides.

Researchers recruited 255 uveitis patients at 23 sites (21 in the U.S., one in the U.K., and one in Australia) and randomly assigned them to receive the fluocinolone implant or systemic treatment with corticosteroids (prednisone) and immunosuppressive drugs (such as methotrexate or mycophenolate mofetil). Systemic corticosteroids reduce acute inflammation effectively but have potential systemic adverse effects when used at a high dose for a long time. The immunosuppressive drugs inhibit pathological immune responses, thus reducing the amount of corticosteroids needed over the long-term, mitigating such side effects.

Through the first two years, the visual acuity remained about the same in the two groups (results published in 2011). At seven years, visual acuity on average remained stable in the systemic group (one letter better than baseline) but declined about six letters in the implant group. The researchers found that implant-treated eyes had reactivations of uveitis after about five years, about two years later than expected. Reactivations of uveitis at this point coincided with a decline in visual acuity, on average, by six and seven years after randomization. The loss of vision in the implant group appears to have been due to increased damage in the retina and choroid (a tissue rich in blood vessels lying underneath the retina).

With respect to side effects, patients in the implant group were more likely to develop ocular adverse outcomes like cataracts, intraocular pressure elevation that required treatment with medicine and often surgery, and glaucoma. Patients receiving systemic therapy had increased risk of needing treatment with antibiotics, possibly due to immunosuppression, but otherwise did not have significant increases in the risk of adverse outcomes such as high blood pressure or diabetes. Combining immunosuppressants with systemic corticosteroids allows clinicians to use lower doses of corticosteroids over the long term, thus avoiding many common side effects of high dose corticosteroids. Risks of the immunosuppressants themselves can be controlled by monitoring for potential toxicities and dose adjustment when necessary.

National Eye Institute: Contact: Viviane Callier or Joe Balintfy