Uveitis is an inflammation inside the eye. Uveitis can cause loss of vision if it is not treated. The standard treatment when uveitis is severe has been oral corticosteroids. Sometimes drugs that suppress the immune system are also used to increase the effect of oral corticosteroids, or reduce the dose that is needed. These drugs are called immunosuppressive drugs. A newer treatment is an implant filled with 0.59 mg of corticosteroid medicine called fluocinolone acetonide. The implant is surgically placed into the back of the eye. The implant slowly releases the medicine to reduce the inflammation. The FDA (Food and Drug Administration) approved the implant in April 2005
This study is being done to learn more about uveitis and to compare the effectiveness of uveitis treatments by continuing follow-up of patients who took part in the MUST Trial (IRB study # 14616). The main purpose of this study is to compare how the two uveitis treatments used in the MUST Trial work over a longer period of time. The two treatments are the same as the ones in the MUST Trial; either local treatment with an implant filled with the corticosteroid medicine fluocinolone acetonide, or systemic treatment with corticosteroid and if needed other immunosuppressive medicines taken by mouth. Enough information was collected in the MUST Trial to compare how well these two treatments work for the first 2 years of treatment. More information is needed to find out which treatment approach will give better results over the long term. Knowing the long-term effectiveness and safety of these treatments is important because the kinds of uveitis being studied usually need to be treated for many years. In addition to comparing the effectiveness of treatments, this study is being done to get information about what happens to patients with different types of uveitis over time. This information may help researchers understand uveitis better and may suggest ways of improving treatment.
Uveitis, in clinical usage, refers to an array of intraocular inflammatory diseases. In 1990, uveitis was estimated to be responsible for about 10% of visual impairment in the western world, and approximately 30,000 new cases of legal blindness per year in the United States. Vision loss due to uveitis is likely to have a greater impact per case than vision loss from age-related eye diseases, because uveitis most commonly occurs during early to mid-adulthood, resulting in disability during the working years. Common causes of vision loss in uveitis include cystoid macular edema (CME), media opacities such as cataract or vitreous debris, retinal injury, and secondary glaucoma. The visual acuity of patients with severe uveitis tends to fluctuate over time, particularly if control of the uveitis is not consistently maintained. In developed countries, the majority of intermediate uveitis and panuveitis cases, and about one-half the posterior uveitis cases are presumed to be autoimmune, based on the absence of evidence for infection, and a salutary response to corticosteroid and other anti-inflammatory therapies. Non-infectious uveitides encompass a variety of syndromes, each with specific diagnostic features. However, if a case is established to be non-infectious, corticosteroids are the mainstay of treatment in most instances, regardless of which specific syndrome is diagnosed. The appropriate treatment approach for these conditions depends on two characterizations: 1) whether the clinical course of the uveitis is episodic and spontaneously remitting (with or without intermittent recurrences) versus chronic; and 2) what the anatomic localization of the inflammation is. The former distinction is determined by observing the clinical course of the disease over time, to determine whether remissions occur. The anatomic localization of inflammation is determined by clinical examination. According to the International Uveitis Study Group method for anatomic classification, as updated by the Standardization of Uveitis Nomenclature Working Group, uveitides may be classified in the following categories: anterior uveitis, intermediate uveitis, posterior uveitis, or panuveitis. In anterior uveitis, inflammation affects primarily the anterior segment; in intermediate uveitis, inflammation affects primarily the vitreous/pars plana region, with or without mild anterior chamber reaction; in posterior uveitis, the choroid and retina primarily are affected, often with overlying vitritis; and in panuveitis, multiple parts of the eye are affected, typically including significant anterior chamber and vitreous inflammation. Many cases of anterior uveitis follow the acute-remitting pattern. However, intermediate uveitis, posterior uveitis, and panuveitis often follow the course of a chronic disease. Although intermediate uveitis is in some cases a mild disease, a substantial proportion of patients with this condition eventually require systemic corticosteroid therapy to adequately control their disease. Clinical experience suggests that most cases of posterior uveitis and panuveitis require chronic, suppressive systemic corticosteroid therapy to control inflammation adequately. Standard treatment of uveitis: Although anterior uveitis often is responsive to topical corticosteroid therapy, the poor penetration of eyedrops into the posterior segment of the eye makes this approach inappropriate as the primary treatment for intermediate uveitis, posterior uveitis, and panuveitis, except in rare instances. Periocular injection of long-acting corticosteroid preparations is a convenient and often effective approach to controlling inflammation in the posterior segment, particularly when either a limited duration of therapy or adjunctive therapy is desired. However for chronic disease, the difficulty predicting when therapeutic benefit from the injected corticosteroid depot may wane makes it difficult to avoid intermittent exacerbations of the inflammatory disease, each with the potential to cause vision loss. Therefore, oral corticosteroids are the mainstay of therapy for chronic, vision-threatening, non-infectious intermediate uveitis, posterior uveitis, and panuveitis. Even for intermediate uveitis, often a less severe disease than posterior uveitis or panuveitis, approximately 50% of patients ultimately will require oral corticosteroids. Oral corticosteroid therapy has potential side effects. The side effects of short-term therapy, even at high doses, are reversible, relatively mild, and typically well-tolerated (e.g., insomnia, mood swings, Cushingoid facies). However, long-term therapy with doses higher than 10-15 mg/day of prednisone incurs the risk of more substantial side effects, including hyperglycemia, hypertension, hyperlipidemia, osteoporosis, and (in children) growth retardation. Therefore, in cases of chronic uveitis that require long-term administration of oral corticosteroids at moderate to high dosage, immunosuppressive agents typically are added for their corticosteroid-sparing (and in the case of alkylating agents, remittive) effects. In addition, for certain specific uveitis syndromes, initial immunosuppressive therapy is warranted based on evidence suggesting improved outcomes. The immunosuppressive agents effective for treatment of uveitis that are most commonly used include the antimetabolites azathioprine, methotrexate, and mycophenolate mofetil; the T-cell inhibitors cyclosporine and tacrolimus; and the alkylating agents chlorambucil and cyclophosphamide. Each of these agents, in turn, has the potential to cause different kinds of side effects, requiring monitoring. However, because such side effects typically are reversible, a regimen that is effective in controlling uveitis and tolerable for intermediate- to long-term therapy usually can be determined. Fluocinolone acetonide implant therapy for non-infectious uveitis: Because non-infectious uveitis is commonly localized to the eye, a local therapy approach that accomplishes long-term control of inflammation and avoids systemic side effects would be an appealing prospect. The fluocinolone acetonide implant (0.59 mg, Bausch & Lomb, Inc., Tampa, FL) is such a treatment, and was FDA-approved in May 2005. It is a matrix consisting of the corticosteroid, fluocinolone acetonide, coated in a polyvinyl alcohol and silicone laminate attached to a polyvinyl alcohol strut. In vivo, fluocinolone acetonide filters out into the vitreous cavity through a diffusion port, delivering drug to the vitreous with approximately zero order kinetics (0.3-0.4 μg/day) as long as solid drug remains inside, except for a brief period with a higher rate of drug delivery (0.6 μg/day) in the first month. The version marketed is designed to deliver the medication for 30-36 months, and can be replaced if needed. In a phase 2/3 clinical trial comparing 0.59 to 2.1 mg versions of the implant, 278 eyes were randomly assigned to receive one of the two versions of the fluocinolone acetonide implant. Patients were selected to have asymmetric disease, and the contralateral eye was treated by withdrawal of therapy until reactivation occurred, followed by best medical judgment (trying to avoid systemic therapy). Only pooled results for both implant dosages are available, although results were similar for the two dosages (Glenn Jaffe, verbal communication, May 2, 2005, ARVO Annual Meeting presentation of these results). Essentially all treated eyes initially obtained complete control of uveitis. During follow-up, reactivation of uveitis occurred at or prior to 2 years after implantation in 12% of study eyes, versus 59.7% in these eyes in the year prior to enrollment, and 50.0% in contralateral eyes at 2 years. Use of systemic, periocular, and topical corticosteroid therapy for treatment of uveitis in implanted eyes was significantly reduced, whereas use of periocular and topical corticosteroids in contralateral eyes increased significantly. Visual acuity was stabilized or improved in the majority of treated eyes, with 24.3% improving by 3 or more lines, compared with 5.3% of contralateral eyes. Nearly all eyes with a natural lens (i.e. had not already undergone cataract surgery with implantation of an IOL) receiving implants developed cataract, with 89.4% undergoing cataract extraction by 2 years, vs. 13.3% of fellow eyes. A substantial number of implanted eyes developed intraocular pressure elevation, with 53.7% requiring eye drops to lower intraocular pressure at the two year time point, vs 20.2% in contralateral eyes. In addition, 30.6% of implanted eyes required glaucoma filtration surgery versus 0.4% of contralateral eyes, by two years' follow-up. Additional safety data from phase 1/2 studies of other disease indications showed other rare complications, including retinal detachments, optic neuropathy that resolved after implant removal, and small numbers of cases that reported floaters, hypotony, dislocated implant, discomfort, and conjunctival thinning (< 5% each). There were also few cases of a retinal vein occlusion syndrome, which manifested as visual disturbances, disc edema, and intraretinal hemorrhages, all of which occurred after cataract surgery in post-vitrectomy eyes with age-related macular degeneration; all resolved after implant removal. There also were several cases of mild vitreous hemorrhage. The product label also reports that procedural complications from implant surgery can occur, including "cataract fragments in the eye post-op, implant expulsion, injury, mechanical complication of implant, migration of implant, post-op complications, post-op wound complications, and wound dihiscense." Post-operatively, some patients reported symptoms of "reduced visual acuity...blurred vision, abnormal sensation in the eye, eye irritation...pruritis, vitreous floaters...increased tearing...dry eye...photopsia, and eye swelling." The MUST Trial Follow-up Study is a cohort study of patients who enrolled in the MUST Trial. A similar prospective design to that used in the MUST Trial will be used in the MUST Trial Follow-up Study and, while the data collection schedule has been reduced to collect the minimum data needed to ascertain study objectives, the new data will be comparable to the data obtained during the trial phase. The study will not dictate which uveitis treatment should be used; remaining on the randomly assigned treatment is not required. However, based upon current follow-up information, we expect that 90% of enrolled patients will remain in the MUST Trial Follow-up Study and few will elect to change treatments since most are not experiencing uveitis flares. In keeping with good clinical practice, study ophthalmologists will be encouraged to follow the treatment guidelines used in the MUST Trial. These guidelines, written by uveitis experts, are generally accepted as the standard of care. Patients will be enrolled who participated in the MUST Trial will be recruited and re-enrolled into the MUST Trial Follow-up Study at approximately 23 clinical centers and randomized on a 1:1 basis to one of the two treatment groups. Participants will be followed until death, participant withdrawal, or a common study closeout. Participants will be seen at baseline, one month after randomization, three months after randomization, and every three to six months thereafter for data collection. Both ophthalmological and medical data will be collected to evaluate the outcomes of treatment of the uveitis, the complications of the uveitis, and complications of therapy. Selected laboratory data related to the complications of systemic corticosteroid therapy will be collected