Our results indicate that within each anatomic location, there are significant differences in the perceived effectiveness of corticosteroid-sparing treatments for controlling ocular inflammation and allowing a successful corticosteroid taper.
Though they do not receive the highest favorability ratings for effectiveness, the most commonly used and most preferred drugs are from the antimetabolite class. Respondents indicate that the long-used methotrexate is their most common first choice corticosteroid-sparing therapy for all anatomic locations of uveitis, with only mild concerns for safety and tolerability. Even given the choice of any other drug disregarding cost and availability, most would still prefer to prescribe methotrexate for anterior uveitis. Methotrexate, however, was the only drug in which there was a significant difference in effectiveness ratings by anatomic location. For intermediate and posterior/panuveitis, respondents would prefer to use mycophenolate mofetil; the main reason for not prescribing mycophenolate initially seems to be cost. These trends were seen when looking at first choices for most commonly used and most preferred treatments and when evaluating the full ranking data using a Bradley–Terry model. This is a well-developed method of rank-ordering items based on how each respondent ranks each item in relation to the others, and may provide a more relevant estimate of the relative usage and preference within our survey population by incorporating more in-depth information [6
Even with the recent availability of generic mycophenolate mofetil, the cost per month is still more than double that of methotrexate. According to Medicare reimbursement rates, a 1-month supply of maintenance dose methotrexate (25 mg per week) costs $50.55, and an equivalent supply of generic mycophenolate mofetil (1 g twice a day) costs $118.50 [7
]. Retrospective studies by the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study Research Group, the largest such studies to date, have reported corticosteroid-sparing success rates at 6 months with methotrexate and mycophenolate for posterior/panuveitis at 21% and 41%, respectively [8
]. Another study, comprised mostly of patients with posterior/panuveitis, reported success rates of 42% with methotrexate compared to 79% with mycophenolate mofetil [10
]. There have been no controlled trials comparing methotrexate and mycophenolate mofetil for any anatomic location to confirm the differences found in retrospective studies. Azathioprine, the third antimetabolite option, was the least popular of the three among our respondents. Published retrospective studies report similar effectiveness rates to those of methotrexate for uveitis, but discontinuations due to safety and tolerability may be more frequent [9
]. Azathioprine is also widely used in rheumatologic diseases and organ transplantation. Randomized trials comparing methotrexate to azathioprine have shown similar effectiveness for treating ANCA-associated vasculitis [13
] and myasthenia gravis [14
], and mixed results in rheumatoid arthritis with one small trial showing similar effectiveness [15
] and another showing greater effectiveness with methotrexate [16
]. Mycophenolate mofetil was shown to be more effective than azathioprine in a randomized trial of patients with Crohn’s disease [17
] and for cardiac transplantation [18
], but trials in lupus nephritis [19
] and renal transplantation [20
] found no significant differences.
Despite being the least used and least preferred as first-line corticosteroid-sparing treatment, the biologic drugs adalimumab and infliximab and the alkylating agent cyclophosphamide received the overall highest effectiveness ratings based on both medians and percent of respondents giving a favorable response. Actual use and preference, however, do not match these reported beliefs. In fact, adalimumab, infliximab, and cyclophosphamide are infrequently used and preferred as initial corticosteroid-sparing treatment, even if cost and availability are not an issue. In the case of adalimumab and infliximab, respondents cited a number of reasons not to prescribe these treatments, including cost, insufficient long-term data, concerns with safety and tolerability, and difficulty of administration. Adalimumab is given by subcutaneous injections and infliximab by intravenous infusions. Despite the overwhelming opinion that cyclophosphamide is effective, it was the least preferred drug, primarily due to concern for the safety of the patient. Cyclophosphamide has been associated with an increased risk of malignancy, infertility, and other undesirable side effects, so this finding was not surprising [21
]. Cyclosporine, a calcineurin inhibitor, was not commonly used and rarely preferred as first-line corticosteroid-sparing therapy because of safety and tolerability concerns and some doubt as to its effectiveness. Previous publications report widely varying rates of success with cyclosporine for uveitis, and there is evidence of high rates of side effects including nephrotoxicity [22
This study does have limitations. It is possible that those who chose to participate in the survey are somehow different from those who did not, which would affect the generalizability of our results to all uveitis specialists or even to the members of the listservs as a whole. The sample size raises the question of whether the responses collected in this study reflect actual practice patterns of uveitis specialists, though studies have shown surveys with similar response rates (about 25%) to have comparable results to those with higher response rates [23
]. Increased sample size could have been achieved by including a broader sample of ophthalmologists in the study, but this would have potentially compromised our goal of eliciting opinions from uveitis specialists with extensive experience with immunomodulatory therapy. The respondents were all uveitis specialists, and the majority had greater than 10 years of practice experience, likely indicating the respondent group had a high level of expertise in this subject area. This is also highlighted by the fact that 100% of respondents reported maximum oral corticosteroid doses of 10 mg/day or less as acceptable maintenance levels, demonstrating familiarity with the SUN guidelines on the use of immunosuppressives [3
]. This is in contrast with the population of a recent survey focusing on corticosteroid use in which steroid-sparing immunosuppressives were rarely used and an average prednisone maintenance dose of 34 mg/day was reported [26
]. In addition, as the vast majority of the respondents in our survey practice in the USA, reported practice patterns and preferences may be specific to the USA and could be different in other countries.
Perceptions of effectiveness and negative aspects of each treatment could be affected in a number of ways. Although general guidelines for the use of immunomodulatory treatment of noninfectious uveitis have been established, uveitis specialists may differ in the way they use each treatment (varying maintenance doses, etc). They may also treat patients with varying disease severities and etiologies of uveitis, which could affect perceptions about each treatment. It is also important to note that this survey reported usage and preferences based on anatomical location of inflammation rather than any associated disease entity. For patients with severe uveitis-related complications or a known associated inflammatory disease such as juvenile idiopathic arthritis or Behcet’s, the nature of the results may have been different. Other factors such as co-management with a rheumatologist and age of the patient population may also affect practice patterns.
Additionally, not all immunomodulatory drugs currently used to treat uveitis were included in the survey; omitted treatments include the calcineurin inhibitors tacrolimus and sirolimus, the alkylating agent chlorambucil, and newer biologic agents such as golimumab or certolizumab. Etanercept was also not included; though etanercept has been commercially available since 1999 and is used to treat various systemic inflammatory conditions, a number of studies have indicated that this particular TNF-alpha inhibitor is likely not effective for controlling ocular inflammation [27
]. There was initially some concern in the rheumatology literature that etanercept may even induce ocular inflammation, but more recent findings support the continued use of etanercept therapy for inflammatory diseases with the caveat that patients developing uveitis may require a change in treatment regimen [30
]. We chose to include treatments which have been most commonly reported in the literature to ensure that most respondents would have some experience with each, making comparisons between them possible.
Despite potentially mitigating factors, the results of this survey were striking. They raise questions that warrant further study, including the possibility of variable effectiveness by anatomic location for some treatments, and also highlight factors that uveitis specialists feel limit the practical use of each immunomodulatory treatment. These results may help guide future research comparing treatment effectiveness for initial corticosteroid-sparing therapy in noninfectious uveitis.