Key Points
Question
What is the effect of adalimumab on patient-reported visual functioning in uveitis?
Findings
In a post hoc analysis of the VISUAL-1 and VISUAL-2 trials, including 217 patients in VISUAL-1 and 226 patients in VISUAL-2, the 25-item National Eye Institute Visual Function Questionnaire composite score assessing patient-reported visual functioning within longitudinal models showed significant differences between the adalimumab and placebo arms.
Meaning
These findings suggest that adalimumab is associated with clinically meaningful improvements in visual functioning for patients with noninfectious intermediate uveitis, posterior uveitis, and panuveitis.
Abstract
Importance
Adalimumab was recently approved for the treatment of noninfectious intermediate uveitis, posterior uveitis, and panuveitis.
Objective
To assess the effect of adalimumab on the visual functioning and quality of life in patients with corticosteroid-dependent noninfectious intermediate uveitis, posterior uveitis, and panuveitis.
Design
A post hoc analysis of clinical trials of adults with active (VISUAL-1) and inactive (VISUAL-2) noninfectious intermediate uveitis, posterior uveitis, and panuveitis was conducted in the United States, Canada, Europe, Israel, Australia, Latin America, and Japan. A total of 217 patients (110 adalimumab, 107 placebo) in VISUAL-1 and 226 patients (115 adalimumab, 111 placebo) in VISUAL-2 were studied using intent-to-treat analyses. The clinical trials were conducted between August 10, 2010, and May 14, 2015.
Interventions
In VISUAL-1 and VISUAL-2, patients were randomized to receive adalimumab, 80-mg, subcutaneous loading dose followed by 40 mg every other week or placebo for 80 weeks. All patients underwent prednisone tapering, with patients in VISUAL-1 receiving an initial prednisone burst.
Main Outcomes and Measures
The 25-item National Eye Institute Vision Function Questionnaire (NEI VFQ-25) composite score questionnaire assessed the impact of visual impairment from the patient’s perspective; scores on the questionnaire range from 0 to 100, with higher scores indicating better vision-related quality of life. The change in NEI VFQ-25 from best state achieved prior to week 6 (VISUAL-1) and from baseline state (VISUAL-2) to the final or early termination visit was determined in each group and statistically compared using analysis of variance. The temporal effects of adalimumab and placebo on NEI VFQ-25 were investigated using a longitudinal model.
Results
Of the 217 patients in VISUAL-1, 124 (57.1%) were women; the mean (SD) age was 42.7 (14.9) years. Of the 226 patients in VISUAL-2, 138 (61.1%) were women; the mean (SD) age was 42.5 (13.4). In VISUAL-1, the change from final score to best score in NEI VFQ-25 was −1.30 for adalimumab and −5.50 for placebo—a difference of 4.20 (95% CI, 1.04 to 7.36; P = .01) associated with adalimumab compared with placebo. In VISUAL-2, the change from baseline NEI VFQ-25 was 3.36 for adalimumab and 1.24 for placebo—a difference of 2.12 (95% CI, −0.81 to 5.04; P = .16). In both trials, the longitudinal models showed a significant difference in NEI VFQ-25 between adalimumab and placebo of 3.07 (95% CI, 2.09 to 4.06; P < .001) and 4.66 (95% CI, 0.05 to 9.26; P = .048) in the VISUAL-1 (74.15 vs 71.08) and VISUAL-2 (82.39 vs 77.73) trials, respectively.
Conclusions and Relevance
This post hoc analysis suggests that adalimumab is associated with statistically significant and clinically meaningful improvements in patient-reported visual functioning for patients with noninfectious intermediate uveitis, posterior uveitis, and panuveitis.
Trial Registration
clinicaltrials.gov Identifiers: NCT01138657 (VISUAL-1) and NCT01124838 (VISUAL-2)
This analysis of the VISUAL-1 and VISUAL-2 clinical trials evaluates the effect of adalimumab on visual functioning and quality of life in patients with noninfectious intermediate uveitis, posterior uveitis, and panuveitis.
Introduction
Noninfectious uveitis is a group of intraocular inflammatory disorders. Patients with uveitis can experience significant visual impairment that may result in partial or complete loss of vision. The annual incidence of uveitis is estimated to be between 17 and 52 per 100 000 individuals. In particular, uveitis is responsible for an estimated 10% of cases of blindness in the United States, including 30 000 new cases of legal blindness each year. Uveitis can affect people of any age, but it most commonly develops in people between the ages of 20 and 59 years and is a major cause of visual morbidity in the working age group. The impact of disease is significant in terms of health care utilization and costs as well as ocular morbidity.
The Standardization of Uveitis Nomenclature criteria categorizes uveitis based on the primary anatomic location of inflammation. Anterior uveitis is the most common type of uveitis and accounts for 50% to 90% of uveitis cases. Intermediate and posterior uveitis account for 1% to 15% and 4% to 19% of uveitis cases, respectively. Patients with untreated intermediate and posterior uveitis are at increased risk of developing significant and sometimes permanent vision loss. In fact, posterior uveitis accounts for more vision loss than other more prevalent forms of the disease.
The current standard of care for uveitis is corticosteroids. However, long-term use of moderate to high doses of corticosteroids can result in serious adverse events, including both ocular morbidity, such as glaucoma and cataracts, and systemic adverse events, including impaired glucose tolerance, hypertension, osteoporosis, and infections.
Adalimumab, an anti-inflammatory drug that binds to tumor necrosis factor, was recently approved for the treatment of noninfectious intermediate uveitis, posterior uveitis, and panuveitis. Two phase 3 clinical trials, VISUAL-1 and VISUAL-2, have been conducted among patients with active and inactive uveitis, respectively. VISUAL-1 assessed clinical outcomes in patients requiring 10 to 60 mg/d of oral prednisone (or oral corticosteroid equivalent) for active noninfectious intermediate, posterior, and panuveitis, while VISUAL-2 assessed clinical outcomes for patients with inactive noninfectious intermediate uveitis, posterior uveitis, and panuveitis requiring 10 to 35 mg/d of oral prednisone to maintain an inactive state. In both trials, adalimumab significantly lowered the risk for uveitic flare or vision loss with low safety concerns.
Uveitis has a substantial effect on individuals’ physical, professional, psychological, and social functioning in day-to-day life. Commonly associated symptoms of uveitis include decreased vision, eye pain, redness, light sensitivity or photophobia, and floaters. Several studies have focused on the effect of uveitis symptoms on quality-of-life outcomes. Given that both uveitis and corticosteroid therapy are related to an increased likelihood of complications, it may be difficult to determine disease vs treatment effect on comorbidity and quality of life. Moreover, noninfectious uveitis is associated with a number of systemic disorders, including Behçet disease, juvenile idiopathic arthritis, rheumatoid arthritis, Vogt-Koyanagi-Harada disease, sarcoidosis, ankylosing spondylitis, psoriatic arthritis, and multiple sclerosis. Consequently, the impact of uveitis symptoms and associated comorbidities generally results in lower health-related and vision-related quality of life (VRQoL) compared with quality of life in healthy adults. The objective of this research was to evaluate the effect of adalimumab beyond clinical end points, focusing on patient-reported VRQoL.
Methods
Patient Population and Study Design
The patient population consisted of participants enrolled in the VISUAL-1 and VISUAL-2 clinical trials—2 phase 3, randomized, double-masked, placebo-controlled multicenter studies with parallel study designs conducted between August 10, 2010, and May 14, 2015. VISUAL-1 required patients to have had active disease in at least 1 eye despite at least 2 weeks of oral prednisone (or oral corticosteroid equivalent) at a dose of 10 to 60 mg/d. Active uveitis was defined as at least 1 of the following factors in at least 1 eye: active inflammatory, chorioretinal, or retinal vascular lesions; anterior chamber cell grade of 2+ or higher; and/or vitreous haze grade of 2+ or higher. To be included in VISUAL-2, patients were required to have had inactive disease for at least 28 days prior to the baseline visit, to be receiving between 10 and 35 mg/d of oral prednisone, and to have a documented history of experiencing at least 1 uveitis flare within 18 months of the screening visit.
The studies were conducted in accordance with the protocol, International Council for Harmonization guidelines, applicable regulations, and guidelines governing clinical study conduct, the ethical principles of the Declaration of Helsinki, and all applicable local regulations. The trial protocols for the VISUAL 1 and VISUAL 2 were approved by an independent ethics committee or institutional review board at each site. Participants in the clinical trials provided written informed consent. The primary efficacy and safety results from the VISUAL-1 and VISUAL-2 trials and the trial protocols have been reported elsewhere.
Patients in the VISUAL-1 trial were randomized to adalimumab or placebo in a 1:1 ratio via an interactive voice and web response system using a computer-generated random assignment sequence stratified by baseline immunosuppressant treatment. Patients randomized to adalimumab received an 80-mg subcutaneous loading dose of adalimumab followed by 40 mg every other week starting at week 1, and patients randomized to placebo received a matching placebo subcutaneous injection according to the same schedule. Both arms also received a standardized, open-label oral prednisone burst of 60 mg/day at study entry followed by a protocol-defined mandatory taper schedule in which all participants continuing in the study discontinued prednisone intake no later than week 15. Patients randomized to adalimumab in VISUAL-2 received an 80-mg loading dose followed by 40-mg doses every other week. Patients were not given a burst dose of oral prednisone at the start of the trial nor were patients on a uniform tapering schedule. Instead, each patient was assigned to a different schedule depending on the starting prednisone dose (10-35 mg/d). All patients discontinued oral prednisone at or before week 19 (eTable 1, eTable 2, and eFigure 1 in the Supplement). Both trials concluded at the prespecified 80-week time point.
As the primary clinical end point of the VISUAL-1 (treatment failure) trial was assessed for the first time at week 6, 14 patients (9 adalimumab and 5 placebo) who dropped out through week 6 were excluded from the analysis. All other patients in the intent-to-treat population were included in the analysis. In VISUAL-2, the difference in the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) scores from the baseline visit to the final or early termination visit was compared between adalimumab and placebo using analysis of variance. Five patients (1 adalimumab and 4 placebo) did not have a baseline or final or early termination score and were excluded from this analysis.
Visual Functioning
Assessment of VRQoL was conducted using the NEI VFQ-25, which measures important aspects of visual functioning as well as social functioning and emotional well-being. The NEI VFQ-25 consists of 25 items presented in Likert scale format in which patients are asked to rate the level of severity of particular visual symptoms or difficulty of activities, such as driving or reading ordinary print in newspapers. The questionnaire generates a general health subscale in addition to the following 11 VRQoL subscales: general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, and peripheral vision. Finally, an overall composite score is calculated, serving as a mean of the 11 vision-related subscales. Scores range from 0 to 100, with higher scores indicating better VRQoL. The reliability and validity of the NEI VFQ-25 have been established in noninfectious uveitis. Meaningful change thresholds were generated for each subscale of the NEI VFQ-25 using best-corrected visual acuity (BCVA) categories of 5 to 9 letters.
Statistical Analysis
Analysis of Variance
To assess the effect of adalimumab on patient-reported VRQoL, the change in NEI VFQ-25 composite score was analyzed and compared between adalimumab and placebo participants using analysis of variance. In VISUAL-1, the change in the NEI VFQ-25 composite score from best state achieved prior to week 6 to the final/early termination visit was compared to account for the initial corticosteroid burst. In VISUAL-2, the change in the NEI VFQ-25 composite score from baseline to the final/early termination visit was compared. To increase the sample size and the power of the results, missing values of the NEI VFQ-25 after early termination visits were imputed with the last observation carried forward. All analyses were conducted using SAS, version 9.3 (SAS Institute) and R, version 3.1 (R Foundation). As a sensitivity analysis, the Holm-Bonferroni method was used to correct for multiple comparisons controlling the familywise error rate at P = .05.
Longitudinal Analysis
To investigate and compare the temporal effects of adalimumab and placebo on the NEI VFQ-25 in a manner that makes use of all NEI VFQ-25 measurements per patient across time (a patient can have up to 23 NEI VFQ-25 measurements during the trial), a generalized estimating equations longitudinal model was used to account for correlations between repeated measurements. The model also includes terms to capture the nonlinear trajectories in the NEI VFQ-25 composite score as well as the effect of adalimumab vs placebo.
Specifically, the temporal change of NEI VFQ-25 composite score of a patient is modeled as follows:
| NEI VFQ-25 = β0 + β1 adalimumab + β2T + β3D + β4D • adalimumab + ε (1), |
where adalimumab is a categorical variable indicating whether the patient was receiving adalimumab and T is the number of days after randomization. In VISUAL-1, the variable was set to 0 if T was less than 42 days and set to T-42 if T was 42 days or more. In VISUAL-2, D was set to 0 if T was less than 56 days or set to T-56 if T was 56 days or more. Finally, ε is an error term modeled with an exchangeable covariance matrix for each patient (ie, within-patient observations are equally correlated). This model formulation is parsimonious yet complex enough to account for different temporal profiles of the NEI VFQ-25 scores before and after days 42 and 56, respectively, and different profiles (ie, separate slopes) for the adalimumab and placebo arms after days 42 and 56 (via the interaction term β4D • adalimumab). In addition, to account for the large difference in mean NEI VFQ-25 scores at baseline between the adalimumab and placebo arm patients in VISUAL-2, the intercept term β1 adalimumab was included only for the analysis of the VISUAL-2 data.
Day 42 was identified as the switching point in the model of NEI VFQ-25 for VISUAL-1 because patients who dropped out through week 6 were excluded from the analysis. Furthermore, the switching point was designed to capture the expected rise in visual functioning that patients would experience in the weeks immediately following the corticosteroid burst. Similarly, a switching point at week 8 for VISUAL-2 was included since there were no NEI VFQ-25 measurements at week 6 but rather at week 8. Missing NEI VFQ-25 values were imputed via last observation carried forward.
Responsiveness
To help quantify the relevance of changes in the NEI VFQ-25, thresholds for responsiveness on the NEI VFQ-25 were derived using the BCVA response levels of 5 or more letters (minimal deterioration based on distribution-based meaningful change threshold). In VISUAL-1, the minimum important difference in the NEI VFQ-25 was −3.26 or worse (ie, an NEI VFQ-25 difference exceeding −3.26 corresponds to a ≥5 letter worsening in BCVA); in VISUAL-2, the minimum important difference was −0.95 or worse. Cumulative distribution function curves were calculated as cumulative change on the NEI VFQ-25 total scores for all available changes from the best state achieved (prior to week 6) for VISUAL-1 and from baseline for VISUAL-2 to subsequent time points by treatment.
Results
VISUAL-1
Demographic and baseline characteristics of the 217 participants in the intent-to-treat population are summarized in Table 1. The mean (SD) age was 42.7 (14.9) years, and 124 participants (57.1%) were women. Patients had uveitis for a mean of 45.53 (62.54) months; 47 participants (21.7%) had intermediate uveitis, and 73 (33.6%) and 97 (44.7%) had posterior and panuveitis, respectively. The baseline NEI VFQ-25 composite score was 68.11.
Table 1. Baseline Values for Patients in the VISUAL-1 and VISUAL-2 Trials.
| Baseline Demographics | Mean (SD) | |
|---|---|---|
| Adalimumab | Placebo | |
| VISUAL-1 | ||
| Intent-to-treat population, No. | 110 | 107 |
| Age, y | 42.7 (15.6) | 42.6 (14.2) |
| Women, No. (%) | 59 (53.6) | 65 (60.7) |
| White, No. (%) | 89 (80.9) | 86 (80.4) |
| Uveitis duration, mo | 40.20 (51.25) | 51.01 (72.17) |
| Component score | ||
| SF-36 mental | 46.56 (11.58) | 49.42 (11.62) |
| SF-36 physical | 49.32 (8.52) | 47.62 (8.74) |
| NEI VFQ-25 total score | 68.45 (19.67) | 67.77 (18.50) |
| VISUAL-2 | ||
| Intent-to-treat population, No. | 115 | 111 |
| Age, y | 42.85 (12.93) | 42.22 (13.98) |
| Women, No. (%) | 66 (57.4) | 72 (64.9) |
| White, No. (%) | 96 (83.5) | 94 (84.7) |
| Uveitis duration, mo | 59.52 (64.50) | 62.87 (67.65) |
| Component score | ||
| SF-36 mental | 48.89 (10.86) | 46.10 (13.24) |
| SF-36 physical | 49.51 (8.55) | 48.49 (10.42) |
| NEI VFQ-25 total score | 78.01 (15.81) | 75.29 (17.74) |
Abbreviations: NEI VFQ-25, 25-item National Eye Institute Visual Function Questionnaire; SF-36, Short Form–36 Health Survey.
Adalimumab-treated patients had a smaller mean decline in 11 of 12 NEI VFQ-25 scores from best score achieved before week 6 to the final/early termination visit (Figure 1). Moreover, patients treated with adalimumab also showed statistically significant improvements in the following subcomponents: general vision (∆ = 6.20; 95% CI, 1.46 to 10.95; P = .011), ocular pain (∆ = 10.02; 95% CI, 4.90 to 15.15; P < .001), near vision (∆ = 5.12, P = .036), and mental health (∆ = 5.25, P = .033). In addition, adalimumab-treated patients had statistically significant improvement relative to placebo in terms of change in NEI VFQ-25 composite score between final/termination and best state before week 6 (−1.30 vs −5.50; ∆ = 4.20; 95% CI, 1.04 to 7.36; P = .01). Sensitivity analyses were performed comparing the difference in all scores from the best score achieved before week 6 with weeks 32, 48, and 64 instead of the final visit. The analyses indicate that the results do not change substantially with time (eFigure 2 in the Supplement).
Figure 1. Differences in the 25-Item National Eye Institute Visual Function Questionnaire and Its 12 Subcomponents Between Adalimumab and Placebo.
Twelve subcomponents of the questionnaire in VISUAL-1 (A) and VISUAL-2 (B) trials. Scores on the questionnaire range from 0 to 100, with higher scores indicating better vision-related quality of life.
aPer protocol P <.05.
bStatistical significance after adjustment for multiple comparisons.
Figure 2 shows the mean NEI VFQ-25 composite score over time for the adalimumab and placebo arms in VISUAL-1. The model (Table 2) estimated that, on average, patients experienced a mean increase of 6.14 (0.05) in NEI VFQ-25 composite score over the first 6 weeks of the corticosteroid burst. There was a statistically significant treatment effect on the rate of NEI VFQ-25 decrease over time, with the NEI VFQ-25 scores of placebo patients declining by a mean of 0.25 ( = 30 • [β2 + β3]) each month after week 6 compared to a mean decline of 0.08 ( = 30 • [β2 + β3 + β4]) for patients receiving adalimumab. The estimated mean difference in the NEI VFQ-25 composite score at week 80 between adalimumab and placebo participants was 3.07 (95% CI, 2.09-4.06; P < .001).
Figure 2. Mean 25-Item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) Score vs Time in Each Treatment Arm .
Composite scores in the VISUAL-1 (A) and VISUAL-2 (B) trials. Error bars indicate SEs; dashed lines, the end of the corticosteroid tapering period.
Table 2. Regression Results of the NEI VFQ-25 Among Patients Receiving Adalimumab vs Placebo in the VISUAL-1 and VISUAL-2 Trialsa.
| Characteristic | Mean (95% CI) | P Value |
|---|---|---|
| VISUAL-1 | ||
| Intercept (β0) | 69.09 (66.43 to 71.74) | <.001 |
| Time (β2) | 0.146 (0.129 to 0.163) | <.001 |
| Time after wk 6 (β3) | −0.154 (−0.172 to −0.137) | <.001 |
| Time after wk 6 × adalimumab (β4) | 0.006 (0.004 to 0.008) | <.001 |
| Adalimumab vs placebo at wk 80b | 3.07 (2.09 to 4.06) | <.001 |
| VISUAL-2 | ||
| Intercept (β0) | 76.50 (73.91 to 79.88) | <.001 |
| Intercept × adalimumab (β1) | 2.87 (−1.73 to 7.47) | .22 |
| Time (β2) | 0.049 (0.037 to 0.060) | <.001 |
| Time after wk 8 (β3) | −0.052 (−0.064 to −0.041) | <.001 |
| Time after wk 8 × adalimumab (β4) | 0.003 (0.002 to 0.005) | <.001 |
| Adalimumab vs placebo at wk 80b | 4.66 (0.047 to 9.262) | .048 |
Abbreviation: NEI VFQ-25, 25-item National Eye Institute Visual Function Questionnaire.
Coefficient estimates were obtained using general estimating equations and 95% CIs were calculated from empirical SE estimates.
Adalimumab vs placebo at week 80 is the estimated difference in NEI VFQ-25 scores between adalimumab and placebo patients at the end of the study (week 80).
Figure 3 shows the proportion of patients deteriorating by a clinical relevant threshold of at least 5 words on the BCVA in VISUAL-1. The proportion of patients deteriorating was significantly higher for those in the placebo arm compared with adalimumab patients (47.06% vs 30.69%; P = .02).
Figure 3. Deterioration and Cumulative Distribution Function Change in the 25-Item National Eye Institute Visual Function Questionnaire (NEI VFQ-25).
A, Change between final visit and best state achieved before week 6 in VISUAL-1. B, Change between final visit and baseline in VISUAL-2. MID indicates minimally important difference.
VISUAL-2
Demographic and baseline characteristics of the 226 participants in the intent-to-treat population are summarized in Table 1. The mean age was 42.5 (13.4) years, and 138 participants (61.1%) were female. Patients had uveitis for a mean of 61.16 months; 47 (20.8%) of the participants had intermediate uveitis, 73 (32.3%) had posterior uveitis, 103 (45.6%) had panuveitis, and 3 (1.3%) had both intermediate and posterior uveitis. The baseline NEI VFQ-25 score was numerically (but not significantly) higher for adalimumab-treated patients.
Adalimumab-treated patients had a smaller mean decline in 9 of 12 NEI VFQ-25 scores from baseline score to the final/early termination visit (Figure 1). Patients treated with adalimumab showed statistically significant improvements in the general vision (∆ = 6.46; 95% CI, 2.33 to 10.60; P = .003) and mental health (∆ = 5.55, P = .022) subcomponents. In addition, adalimumab-treated patients had an improvement compared with placebo in terms of change between final and baseline NEI VFQ-25 composite scores (3.36 vs 1.24; ∆ = 2.12; 95% CI, -.81 to 5.04; P = .16). Sensitivity analyses performed comparing the difference in all scores from baseline with weeks 32, 48, and 64 also indicated that the results did not change substantially with time (eFigure 3 in the Supplement).
Figure 2 shows the mean NEI VFQ-25 composite score over time for the adalimumab and placebo arms in VISUAL-2. The model (Table 2) estimated that patients experienced an increase of 2.72 (0.15) in NEI VFQ-25 composite score over the first 8 weeks. As in VISUAL-1, there was a statistically significant treatment effect on the rate of NEI VFQ-25 decrease over time, with the NEI VFQ-25 scores of patients receiving placebo declining by a mean of 0.126 ( = 30 • [β2 + β3]) each month after week 8 compared with a mean decline of 0.02 ( = 30 • [β2 + β3 + β4]) for patients receiving adalimumab. The estimated mean difference in NEI VFQ-25 composite score at week 80 between adalimumab and placebo participants was 4.66 (95% CI, 0.05-9.26; P = .048).
Figure 3 shows the proportion of patients deteriorating by a clinical relevant threshold of at least 5 words on the BCVA in VISUAL-2. The proportion of patients deteriorating was higher for those in the placebo arm compared with patients receiving adalimumab (32.71% vs 23.48%; P = .14).
Discussion
Uveitis is one of the leading causes of ocular morbidity and blindness in the United States. Severe uveitis often requires systemic treatment with corticosteroids or other immunosuppressive agents, which may lead to a wide array of adverse events. Thus, there exists a need for alternative therapies that demonstrate not only clinical benefits and safety but also a positive effect on the patient’s VRQoL. This post hoc analysis demonstrates that adalimumab treatment was associated with significantly better maintenance of NEI VFQ-25 scores compared with placebo, corroborating the positive effects of reducing the severity of uveitis symptoms in VRQoL.
Adalimumab has been associated with improved health-related quality of life in patients with Crohn disease, psoriasis, rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis, ulcerative colitis, and hidradenitis suppurativa. We now have evidence that adalimumab is an effective and safe treatment option for noninfectious uveitis. In the present study, we employ data from VISUAL-1 and VISUAL-2 to evaluate the effect of adalimumab on patient-reported outcomes in patients with noninfectious intermediate uveitis, posterior uveitis, and panuveitis. In particular, we used the NEI VFQ-25, a reliable and validated measure of visual functioning and general health.
In this analysis, adalimumab-treated patients in VISUAL-1 achieved improvements in 11 of the 12 domains of NEI VFQ-25 compared with patients who received placebo. The more substantial improvements were observed in total score, general vision, ocular pain, near vision, and mental health. Similarly, adalimumab-treated patients in VISUAL-2 improved in 9 of the 12 NEI VFQ-25 domains, compared to placebo patients, with significant improvements observed in general vision and mental health.
In addition, the longitudinal analyses performed on both VISUAL-1 and VISUAL-2 data indicate that levels of NEI VFQ-25 decrease at a lower rate in adalimumab patients than in placebo patients, suggesting an association between adalimumab treatment and better maintenance of VRQoL. Adalimumab-treated patients in both trials consistently demonstrated greater maintenance of the NEI VFQ-25 composite scores during the last 60 weeks of the trial. These results are important because VRQoL provides a metric of a patients’ vision-related well-being and may be more clinically meaningful than general health-related quality-of-life measurement tools.
Limitations
This study has limitations in that all analyses were performed on a clinical trial population, which may not be representative of the broader uveitis population. Because corticosteroids are the standard of care, patients who receive placebo would have instead been treated with corticosteroids outside the trial and may have experienced a different trajectory of visual functioning. The clinical trials contained a heterogeneous uveitis population without information on which groups were responsive to treatment. Also, although the formulation of the longitudinal model was both parsimonious and flexible, other formulations could be proposed (eg, adding spline terms). In fact, the main results presented here were robust to more complex model specifications. In addition, to increase the statistical power of our analyses, we used the LOCF imputation method, which is a standard practice in clinical trial analyses. However, an observed case analysis or other imputation methods can be used, and all imputation procedures require assumptions about the underlying missing data mechanism.
Conclusions
When evaluating novel treatments for uveitis, it is essential to investigate clinical end points as well as patient-reported quality of life. The analyses in this study provide evidence that patients with noninfectious uveitis treated with adalimumab experience statistically significant and clinically meaningful improvements in VRQoL compared with those who receive placebo. Therefore, this analysis supports the use of adalimumab as a promising new treatment option, having demonstrated improvements in both clinical and visual functioning outcomes in patients with active and inactive uveitis.
eTable 1. VISUAL-1 Tapering Schedule
eTable 2. VISUAL-2 Tapering Schedule
eFigure 1. Number of Patients Remaining in VISUAL-1 and VISUAL-2 at Each Week
eFigure 2. Change in NEI VFQ-25 Scores From Best Score Achieved Before Week 6 to Visit in Weeks 32, 48, 64, and 80 in VISUAL-1
eFigure 3. Change in NEI VFQ-25 Scores From Baseline to Visit in Weeks 32, 48, 64, and 80 in VISUAL-2
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable 1. VISUAL-1 Tapering Schedule
eTable 2. VISUAL-2 Tapering Schedule
eFigure 1. Number of Patients Remaining in VISUAL-1 and VISUAL-2 at Each Week
eFigure 2. Change in NEI VFQ-25 Scores From Best Score Achieved Before Week 6 to Visit in Weeks 32, 48, 64, and 80 in VISUAL-1
eFigure 3. Change in NEI VFQ-25 Scores From Baseline to Visit in Weeks 32, 48, 64, and 80 in VISUAL-2
