By John D. Sheppard Jr., MD, MMSc
Two exceedingly important and reassuring clinical studies have recently confirmed the long-term safety of corticosteroid-sparing systemic immunosuppression for patients with noninfectious ocular inflammatory disease. The Multicenter Uveitis Steroid Treatment (MUST) Trial results were reported in the October 2011 issue of Ophthalmology, and the Systemic Immunosuppression Therapy for Eye Diseases (SITE) cohort study findings were published in the British Medical Journal in 2009.
These studies suggest the obligation of clinicians to deliver uveitis treatment that targets minimizing or eliminating systemic steroids whenever possible while safely controlling inflammation and preserving vision. Armed with this new confirmatory data, ophthalmologists treating uveitis and other ocular inflammatory diseases should be further empowered to prescribe steroid-sparing systemic immunosuppressive drugs or to work closely with uveitis specialists or rheumatologists familiar with their use.
In the MUST Trial, 255 patients (479 eyes) with noninfectious intermediate, posterior or panuveitis were randomized to aggressive systemic immunosuppression therapy or implantation of a fluocinolone intravitreal sustained-release delivery device (Retisert, Bausch & Lomb, Rochester, N.Y.). This implant, which delivers corticosteroid medication locally for about three years, has revolutionized the treatment of the most desperately-afflicted noninfectious uveitis patients.
Both treatment groups experienced improvement over 24 months, although the changes were not significant. However, treatment with the implant achieved inflammatory control faster and more often. This treatment group improved on average by 2.8 letters or more, while visual field sensitivity remained reduced in both groups.
At 24 months, visual acuity had improved by 6.0 letters in the implant group and 3.2 letters in the systemic treatment group. This difference was not statistically different. Vision-related quality of life improved by 11.4 units in the implant group and 6.8 units with systemic therapy (P = 0.043). Only 12 percent of the implant group had residual active uveitis, a significantly smaller proportion than the 29 percent of the systemic therapy group (P = 0.001).
During the two years of follow-up, patients with the implant were more likely to need cataract surgery (80 vs. 31 percent) or treatment for elevated intraocular pressure (61 vs. 20 percent), or to develop glaucoma (16 vs. 4.0 percent). The systemic therapy group had a higher rate of infections requiring prescription treatment (0.60 vs. 0.36 per person/year, P = 0.034), but there were no serious long-term consequences of these infections. Systemic adverse outcomes otherwise were unusual in both groups, with minimal differences between the groups.
Because the systemic therapy was well tolerated, the authors suggest that this approach represents a reasonably safe alternative for localized ocular as well as systemic inflammatory disorders. Without clear differentiation between the results of either systemic or implant therapy, they recommend tailoring treatment choice to the patient’s individual clinical circumstances. For example, systemic therapy should be considered for patients with concomitant active systemic inflammation, such as arthritis or colitis, while local steroid implantation therapy should be considered for those with isolated ocular inflammatory disease, all else being equal. Systemic therapy would likely be the first choice for patients with glaucoma, while implant therapy might be used for those failing systemic therapy.
The retrospective SITE cohort study was conducted to determine whether immunosuppressive treatment adversely affects survival. It included 7,957 individuals with noninfectious ocular inflammation, 2,340 of whom received immunosuppressive drugs during follow-up. They were seen between 1979 and 2005 at five clinical centers. The majority had uveitis.
The results demonstrate that risks for all-cause and cancer-related mortality are not significantly elevated in patients being treated for ocular inflammatory diseases with long-term systemic immunosuppressive agents, such as methotrexate, azathioprine and cyclosporine, nor did they differ when compared with rates for age-matched individuals in the general U.S. population. However, tumor necrosis factor inhibitors were associated with increased overall mortality and cancer mortality. This should be expected from their mechanism of action and warrants further study.
This data clearly differentiates patients with ocular inflammation from those with systemic inflammatory diseases for which the literature does to some extent report increased mortality rates. However, this increased mortality can now be associated with comorbidity of concomitant systemic disease.
Systemic immunosuppression should be strongly considered by uveitis specialists for a wide variety of reasons beyond their now well-established safety profile. Study results indicate that maintenance doses of systemic corticosteroids above 7.5 to 10 mg per day are poorly tolerated. Many conditions respond better to immunosuppression than steroids, including ocular pemphigoid, necrotizing scleritis and serpiginous choroiditis. Also, there is substantial evidence that permanent remission can be induced by agents such as cyclophosphamide or chlorambucil for ocular inflammatory diseases, including pemphigoid and granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis). Anti-metabolites, including methotrexate, aziothioprine (Immuran) and mofetil mycophenoloate (CellCept), have excellent long-term safety profiles for a wide variety of systemic inflammatory conditions in numerous types of patients including children.