Association Between Long-Lasting Intravitreous Fluocinolone Acetonide Implant vs Systemic Anti-inflammatory Therapy and Visual Acuity at 7 Years Among Patients With Intermediate, Posterior, or Panuveitis

Abstract

Importance: A randomized clinical trial comparing fluocinolone acetonide implant vs systemic corticosteroids and immunosuppression for treatment of severe noninfectious intermediate, posterior, and panuveitides did not result in a significant difference in visual acuity at 2 and 4.5 years; longer-term outcomes are not known.

Objective: To compare the association between intravitreous fluocinolone acetonide implant vs systemic therapy and long-term visual and other outcomes in patients with uveitis.

Design, setting, and participants: Nonprespecified 7-year observational follow-up of the Multicenter Uveitis Steroid Treatment (MUST) randomized clinical trial comparing the alternative treatments. Follow-up was conducted in tertiary uveitis subspecialty practices in the United States (21), the United Kingdom (1), and Australia (1). Of 255 patients 13 years or older with intermediate, posterior, or panuveitis (active within ≤60 days) enrolled in the MUST trial between December 6, 2005, and December 9, 2008, 215 consented to ongoing follow-up through at least 7 years postrandomization (last visit, February 10, 2016).

Interventions: Participants had been randomized to receive a surgically placed intravitreous fluocinolone acetonide implant or systemic corticosteroids supplemented by immunosuppression. When both eyes required treatment, both eyes were treated.

Main outcomes and measures: Primary outcome was change from baseline in best-corrected visual acuity in uveitic eyes (5 letters = 1 visual acuity chart line; potential range of change in letters read, -121 to +101; minimal clinically important difference, 7 letters), analyzed by treatment assignment accounting for nonindependence of eyes when patients had 2 uveitic eyes. Secondary outcomes included potential systemic toxicities of corticosteroid and immunosuppressive therapy and death.

Results: Seven-year data were obtained for 161 uveitic eyes (70% of 90 patients assigned to implant) and 167 uveitic eyes (71% of 90 patients assigned to systemic therapy) (77% female; median age at enrollment, 48 [interquartile range, 36-56] years). Change in mean visual acuity from baseline (implant, 61.7; systemic therapy, 65.0) through 7 years (implant, 55.8; systemic therapy, 66.2) favored systemic therapy by 7.2 (95% CI, 2.1-12) letters. Among protocol-specified, prospectively collected systemic adverse outcomes, the cumulative 7-year incidence in the implant and systemic therapy groups, respectively, was less than 10%, with the exceptions of hyperlipidemia (6.1% vs 11.2%), hypertension (9.8% vs 18.4%), osteopenia (41.5% vs 43.1%), fractures (11.3% vs 18.6%), hospitalization (47.6% vs 42.3%), and antibiotic-treated infection (57.4% vs 72.3%).

Conclusions and relevance: In 7-year extended follow-up of a randomized trial of patients with severe intermediate, posterior, or panuveitis, those randomized to receive systemic therapy had better visual acuity than those randomized to receive intravitreous fluocinolone acetonide implants. Study interpretation is limited by loss to follow-up.

Trial registration: clinicaltrials.gov Identifier: NCT00132691.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Kempen reported serving as a consultant for AbbVie, Alcon, Allergan, Can-Fite, Clearside, Lux Biosciences, Roche, Sanofi Pasteur, Santen, Vitae, and Xoma; receiving other investigator-initiated grants from EyeGate Pharma, the Lions Club International Foundation, the US Food and Drug Administration, Research to Prevent Blindness, and the National Eye Institute; and paid service for the National Institute of Allergy and Infectious Diseases (Study Section) and the Office of AIDS Research (advisory committee member) since beginning work on the project in 2002. Dr Thorne reported serving as a board member for AbbVie; serving as a consultant for Allergan, Gilead, Xoma, and Santen; and receiving grants from Allergan and NightstaRx. Drs Altaweel, Holbrook, Sugar, and Jabs reported no potential conflicts of interest. Conflict of interest disclosures for the remainder of the MUST Research Group are on file at the MUST Coordinating Center.

Figures

Figure 1.. Flow of Multicenter Uveitis Steroid Treatment (MUST) Follow-up Study

Losses to follow-up by 2, 4.5, and 7 years are indicated. Some participants missed the 2-, 4.5-, or 7-year visits but completed subsequent visits and hence remained in follow-up. aFor a number of patients with uveitis in both eyes, one eye required little or no treatment. Hence, a total of 38 eyes either belonged to these 7 patients or were mildly affected second eyes for which implant therapy was not indicated.

Figure 2.. Distribution of Best-Corrected Visual Acuity Among Uveitic Eyes Assigned to Receive Intravitreous Fluocinolone Acetonide Implant or Systemic Therapy

Best-corrected visual acuity results in standard letters are given for the first 7 years of follow-up; Snellen equivalents are provided for key cutpoints on the right hand side of the plot (20/20 = 85 letters; 20/40 = 70 letters; 20/100 = 50 letters; 20/200 = 35 letters). Count fingers (CF), hand motion (HM), or light perception (LP) and no light perception (NLP) are assigned values of −10 and −25 letters, respectively, because these levels of visual acuity are much lower than reading 1 letter on the chart; these values are included in the summary estimates. The middle line of each box indicates the median; ends of each box indicate the interquartile range (IQR). The whiskers cover the shorter of 1.5 times the IQR or the interval to the maximal or minimal value. Circles below whiskers indicate outlier values; numbers below circles indicate the number of eyes with a visual acuity of count fingers, hand motion, or light perception and no light perception. Change from baseline transiently favored implant at 6 months (P = .03) and favored systemic therapy from year 6 onward (P < .045).

Figure 3.. Proportion of Uveitic Eyes With Uveitis Activity and Macular Edema Over Time

Regarding uveitis activity, there were statistically significant differences from 6 months through 54 months, favoring implant therapy; differences were not statistically significant thereafter. For macular edema, there were statistically significant differences only at 6 months (favoring implant therapy) and 72 months (favoring systemic therapy). See also Table 2.