Ocular Immunology & Inflammation, 2015; 23(2): 135–143 ! Informa Healthcare USA, Inc. ISSN: 0927-3948 print / 1744-5078 online DOI: 10.3109/09273948.2013.874445
ORIGINAL ARTICLE
Quality of Life in Patients with Noninfectious Uveitis Treated with or without Systemic Anti-inflammatory Therapy Wei Gui, BS1, Matthew Dombrow, MD2, Inna Marcus, MD3, Meredith H. Stowe, PhD2, Baylah Tessier-Sherman, MPH2, Elizabeth Yang, MD1, and John J. Huang, MD1 1
Department of Ophthalmology and Visual Science, Yale University, New Haven, Connecticut, USA, School of Medicine, Yale University, New Haven, New Haven, Connecticut, USA, and 3Duke Eye Center, Duke University, Durham, North Carolina, USA
2
ABSTRACT Purpose: To compare vision-related (VR-QOL) and health-related quality of life (HR-QOL) in patients with noninfectious uveitis treated with systemic anti-inflammatory therapy versus nonsystemic therapy. Methods: A prospective, cross-sectional study design was employed. VR-QOL and HR-QOL were assessed by the 25-Item Visual Function Questionnaire (VFQ-25) and the Short Form 12-Item Health Survey (SF-12), respectively. Multivariate regression analysis was performed to assess the VR-QOL and HR-QOL based on treatment. Results: Among the 80 patients, the median age was 51 years with 28 males (35%). The adjusted effect of treatment modality on VR-QOL or HR-QOL showed no statistically significant difference in all subscores of VFQ-25 or physical component score (PCS) and mental component score (MCS) of SF-12. Systemic therapy did not compromise VR-QOL or HR-QOL compared to nonsystemic therapy. Conclusions: Systemic therapy can be effectively used to control serious cases of noninfectious uveitis without significant relative adverse impact on quality of life. Keywords: Quality of life, SF-12, systemic therapy, uveitis, VFQ-25
Uveitis is a major cause of visual impairment in developed countries, responsible for an estimated 30,000 new cases of legal blindness annually, and causes 2.8–10% of cases of blindness in the workingage population in the United States alone.1 Early diagnosis and treatment are important to prevent vision-threatening complications of uveitis, which include cataract, glaucoma, retinopathy, optic neuropathy, macular edema, and phthisis.2,3 Current commonly used treatments consist of local agents, including topical corticosteroids, periocular injections of methylprednisolone or triamcinolone, intravitreal injections of triamcinolone, dexamethasone intravitreal implant in a biodegradable matrix lasting 6 months and fluocinolone implant lasting for two and
a half years, and systemic agents, including oral corticosteroids, steroid-sparing immunomodulators, and, more recently, biologics.1 Recently, in the field of ophthalmology, there has been growing interest in quality of life assessment for objectively reflecting the actual impact of disease and the extent of suffering for the patient.4,5 Ocular diseases, including age-related macular degeneration, diabetic macular edema, glaucoma, and optic neuritis, affect the quality of life in patients.6–9 Although quality of life studies in patients with uveitis are present in the literature,1,5,10–14 studies regarding comparisons of uveitis treatment on quality of life are limited.15–17 In addition, there are concerns that the systemic medical treatment for noninfectious
Received 13 June 2013; revised 12 November 2013; accepted 9 December 2013; published online 20 May 2014 Correspondence: John J. Huang, MD, Department of Ophthalmology and Visual Science, Yale University School of Medicine, 40 Temple Street, 3rd Floor, New Haven, CT 06510, USA. E-mail: [email protected]
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136 W. Gui et al. uveitis may further contribute to a lower quality of life due to side effects and associated morbidity. Due to these concerns, ophthalmologists often delay or are reluctant to use such therapy. The recently published large, randomized controlled Multicenter Uveitis Steroid Treatment (MUST) trial of patients with intermediate, posterior, or panuveitis recorded quality of life measures comparing treatment with systemic versus implant therapy.18 Although much information has been gained from this study, key questions remain, including how therapies with known systemic side effects compare to less aggressive treatments for quality of life assessment. The purpose of the present study is to compare the vision-related (VR-QOL) and health-related quality of life (HR-QOL) in patients with noninfectious uveitis receiving systemic anti-inflammatory therapy with those who were not receiving such therapy.
MATERIALS AND METHODS Patient Sample This prospective, cross-sectional study was conducted at the uveitis clinic, Yale Eye Center in the Yale Department of Ophthalmology and Visual Science from March 2011 through May 2013. Eligible patients were aged 18 and older, had a diagnosis of noninfectious uveitis, and were able to communicate effectively in English or through an interpreter. The study was approved by the Yale University Human Investigation Committee (HIC), and written informed consent was obtained from all subjects in accordance with the Declaration of Helsinki.
Data Collection Demographic data collected at the time of visit included age, gender, and medical diseases. All patients underwent a full ophthalmologic examination including visual acuity (VA), applanation tonometry, and slit-lamp biomicroscopy. VA was assessed using the Snellen eye chart retroilluminated at 20 feet. Ocular data collected or determined at the time of visit by a qualified uveitis specialist included diagnosis, location (anterior, intermediate, posterior, or panuveitis), laterality (unilateral or bilateral), activity (quiet or active, predominantly based on the Standardization of Uveitis Nomenclature (SUN) working group classification),19 current treatment, other ocular disease, and past eye surgeries. At the time of the visit, patients had been previously evaluated and were already being treated with appropriate therapy. Treatment modality was divided into 2 categories for subsequent analysis: systemic therapy (immunomodulators, biologics, and/or oral
corticosteroids) or nonsystemic therapy (observation with treatment as needed, topical corticosteroids, periocular injection of triamcinolone, and/or fluocinolone acetonide implant). Patients were classified in the systemic therapy group as long as they were on systemic treatment at the time of the clinic visit. Patients who were not receiving any treatment for uveitis at the time of visit were considered to be treated with observation with treatment as needed and classified in the nonsystemic therapy group. The Snellen VA recorded at the time of exam was converted to the logarithm of the minimum angle of resolution (logMAR) VA. Counting fingers (CF) was converted to +1.98 logMAR and hand motion (HM) was converted to +2.28 logMAR based on the study by Lange et al.20 Light perception (LP) or no light perception (NLP) values were excluded from analysis.21
Quality of Life Assessment The VR-QOL was assessed using the National Eye Institute Visual Functioning Questionnaire (VFQ-25). VFQ-25 is a 25-item questionnaire that is both reliable and valid, containing 12 subscores: general health (1 question), general vision (1 question), ocular pain (2 questions), near activities (3 questions), distance activities (3 questions), social functioning (2 questions), mental health (4 questions), role difficulties (2 questions), dependency (3 questions), driving (2 questions), color vision (1 question), and peripheral vision (1 question).22 Since this study also used a separate questionnaire for HR-QOL, the VFQ-25 general health subscale was not used. Additionally, a VFQ-25 composite score (CS) was calculated by averaging all of the subscale values except the general health subscale. Answers to each of the 25 questions were converted to a 100-point scale with 100 representing the best possible score and 0 representing the worst possible score. The VFQ-25 questionnaire was selected to assess visual functioning because Schiffman et al. have demonstrated its validity for VR-QOL in patients with uveitis.14 The HR-QOL was assessed using the 12-item Short Form Survey (SF-12) derived from the 36-item Short Form Survey (SF-36).23 The SF-12 questionnaire comprises 12 questions addressing 8 general health subscores: physical functioning (2 questions), rolephysical (2 questions), bodily pain (1 question), general health (1 question), vitality (1 question), social functioning (1 question), role-emotional (2 questions), and mental health (2 questions). Based on the variables created by the answers, each variable was multiplied by physical and mental regression weights, which were derived from the general U.S. population, to generate a physical component score (PCS) and a mental component score (MCS). Higher PCS and MCS Ocular Immunology & Inflammation
Quality of Life in Uveitis for Systemic Therapy scores indicate better physical and mental health, respectively. The U.S. population scores were normalized to a mean of 50 and standard deviation of 10.23 The SF-12 questionnaire was selected to evaluate health functioning because it is a validated and shorter version of the survey from which it was derived, the SF-36, one of the best known and most widely validated questionnaires for HR-QOL.14 Schiffman et al. have assessed health functioning using the SF-36 in patients with uveitis and suggest evaluating both VR-QOL and HR-QOL to measure the effect of disease and its therapy on quality of life.14
Statistical Analysis Statistical analysis was performed using SAS v 9.2 (SAS Institute, Cary, NC). To evaluate associations between categorical and continuous variables, in normally distributed samples, Fisher’s exact test and the two-sided Student t-test were used and in nonnormally distributed samples, Cochran-MantelHaenszel statistics and Mann-Whitney U tests were used. Linear regression analysis was performed to determine association of variables with VR-QOL or HR-QOL scores. Multivariate regression was used to evaluate associations between treatment modality and VR-QOL or HR-QOL. A p value 5.05 was considered statistically significant. The study was designed to be able to detect differences in vision-related quality of life by the VFQ-25 and in health-related quality of life by the SF-12 (PCS and MCS scores) in patients treated with systemic versus nonsystemic therapy. The sample size in the study is able to detect a one-sided difference of 11.0, 6.4, and 6.1 points in the VFQ-25 composite score, PCS, and MCS measures, respectively, with 80% power and 95% level of confidence.
RESULTS Demographics and Clinical Characteristics The demographic and clinical characteristics data are summarized in Table 1. Eighty patients with noninfectious uveitis seen at the Yale Eye Center were enrolled in this study. There were 28 males (35.0%) and 52 females (65.0%), with median age of 51 years and range of 18–88 years. The median logMAR VA of the better-seeing eye, worse-seeing eye, and worst recorded VA were 0.1 (range of 0.1–0.9), 0.3 (range of 0–2.3), and 0.8 (range of 0 to no light perception), respectively. Thirty-four patients (42.5%) were treated with systemic therapy. Anterior uveitis (48.8%) and panuveitis (28.8%) were the most common locations of disease. Uveitis was bilateral in 71.2% of patients, and the median duration of disease was 2.7 years with a range of 0.02–56 years. Disease was active in !
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22.5% of patients, and the median number of past ocular surgeries was 1 with a range of 0–7. Ocular co-morbidities were present in 82.5% of patients, and medical co-morbidities were present in 77.5% of patients. The most common diagnoses were idiopathic (35.0%), sarcoid (17.5%), and HLA-B27+ (16.2%).
Demographics and Clinical Characteristics by Treatment The demographic and clinical characteristics data categorized by treatment group are also summarized in Table 1. In the systemic therapy group, the median age was 45 years with a range of 18–81 years, and there were 9 males (26.5%) and 25 females (73.5%). In the nonsystemic therapy group, the median age was 52 years with a range of 24–88 years, and there were 19 males (41.3%) and 27 females (58.7%). There were no statistically significant differences between patients treated with or without systemic therapy in age, gender, VA, uveitis location, laterality, duration, activity, total number of ocular surgeries, presence of ocular co-morbidities, and presence of medical co-morbidities.
VFQ-25 and SF-12 Scores VR-QOL and HR-QOL scores are summarized in Figure 1. The median VFQ-25 CS score was 78.6, and the highest median subscores were observed for social functioning (100.0) and color vision (100.0) and the lowest for mental health (62.5). The mean SF-12 PCS and MCS scores were 44.1 and 47.7, respectively. Comparing male and female patients, VFQ-25 subscores were significantly higher in male patients for composite score, ocular pain, near vision, distance vision, mental health, dependency, and driving, but not significantly different for general vision, social functioning, role difficulties, color vision, and peripheral vision (Figure 1). SF-12 component scores were significantly higher for male patients in MCS but not significantly different in PCS (Figure 1).
Bivariate Analysis of Variables Associated with VR-QOL and HR-QOL The linear regression analysis of the association of variables with the CS score of VFQ-25 and the PCS and MCS scores of SF-12 is summarized in Table 2. Gender, VA of the better-seeing eye, VA of the worseseeing eye, and worst recorded VA were identified as variables significantly associated with the CS score of VFQ-25. The presence of medical co-morbidities was the only variable significantly associated with the
138 W. Gui et al. TABLE 1. Demographic and clinical characteristics. All Variable Age (yr) Median Range Gender, n (%) Male Female Visual acuity (VA)a Better eye Median Range Worse eye Median Range Worst recorded Median Range Location, n (%) Anterior Intermediate Posterior Panuveitis Laterality, n (%) Unilateral Bilateral Duration of disease (yr) Median Range Activity, n (%) Active Quiet Ocular surgeries Median Range Ocular co-morbidities, n (%)b None Cataract Glaucoma Epiretinal membrane Age-related macular degeneration Diabetic retinopathy Medical co-morbidities, n (%)c None Hypertension Hyperlipidemia Diabetes Thyroid disease Arthritis Cancer Etiology of disease, n (%) Idiopathic Sarcoid HLA-B27+ Pars planitis Juvenile idiopathic arthritis Vogt-Koyanagi-Harada Acute zonal occult outer retinopathy Birdshot chorioretinopathy Otherd a
No. of patients (%) N = 80
Treatment group Systemic No. of patients (%) N = 34
Nonsystemic No. of patients (%) N = 46
p Value 0.16
51 18–88
45 18–81
52 24–88
28 (35.0) 52 (65.0)
9 (26.5) 25 (73.5)
19 (41.3) 27 (58.7)
0.1 0.1–0.9
0.1 0.1–0.5
0.1 0.1–0.9
0.3 0.0–NLP
0.3 0.0–2.3
0.3 0.0–NLP
0.8 0.0–NLP
0.6 0.1–LP
1 0.0 –NLP
0.17
0.70
0.42
0.58
0.55 39 5 13 23
(48.8) (6.2) (16.2) (28.8)
15 2 7 10
(44.1) (5.9) (20.6) (29.4)
24 3 6 13
(52.2) (6.5) (13.0) (28.3) 0.061
23 (28.8) 57 (71.2)
6 (17.6) 29 (85.3)
17 (37.0) 29 (63.0) 0.76
2.7 0.02–56.0
2.2 0.08–30.6
2.9 0.02–56.0 0.37
18 (22.5) 62 (77.5)
6 (17.6) 28 (82.4)
12 (26.1) 34 (73.9)
1.0 0–7 66 (82.5) 14 (17.5) 35 (43.8) 26 (32.5) 11 (13.8) 2 (2.5) 1 (1.2) 62 (77.5) 18 (22.5) 21 (26.2) 9 (11.2) 8 (10.0) 6 (7.5) 5 (6.2) 5 (6.2)
0.0 0–6 30 (88.2) 4 (11.8) 18 (52.9) 11 (32.4) 7 (20.6) 1 (2.9) 1 (2.9) 27 (79.4) 7 (20.6) 6 (17.6) 2 (5.9) 3 (8.8) 2 (5.9) 2 (5.9) 1 (2.9)
1.5 0–7 36 (78.3) 10 (21.7) 17 (37.0) 15 (32.6) 4 (8.7) 1 (2.2) 0 (0.0) 35 (76.1) 11 (23.9) 15 (32.6) 7 (15.2) 5 (10.9) 4 (8.7) 3 (6.5) 4 (8.7)
0.64
28 14 13 5 4 3 2 2 9
(35.0) (17.5) (16.2) (6.2) (5.0) (3.8) (2.5) (2.5) (11.2)
8 6 5 2 4 3 0 1 5
(23.5) (17.6) (14.7) (5.9) (11.8) (8.9) (0.0) (2.9) (14.7)
20 8 8 3 0 0 2 1 4
0.25
0.73
(43.5) (17.4) (17.4) (6.5) (0.0) (0.0) (4.3) (2.2) (8.7)
VA in logMAR (logarithm of the minimal angle of resolution) notation. Statistical testing for presence or absence of ocular co-morbidities. c Statistical testing for presence or absence of medical co-morbidities. d Includes diagnoses of ANA positive uveitis, antiphospholipid syndrome, Behc¸et, Eales, Fuchs heterochromic iridocyclitis, multifocal choroiditis and uveitis, punctate inner choroidopathy, systemic lupus erythematosus, tubulointerstitial nephritis, and uveitis. LP, light perception; NLP, no light perception. b
Quality of Life in Uveitis for Systemic Therapy SF-12 PCS score, and gender was the only variable significantly associated with the SF-12 MCS score.
Multivariate Analysis of the Effect of Treatment Modality on VR-QOL and HR-QOL The multivariate analysis of the effect of treatment modality on QOL is summarized in Table 3. The VFQ25 subscores models were adjusted for age, gender, VA in the better seeing-eye, location of uveitis, laterality, duration, activity, and presence of ocular 100
Overall
90
Male
80
Female
70 60 50 40 30 20 10 0
FIGURE 1. National Eye Institute Visual Functioning Questionnaire (VFQ-25) and Medical Outcomes Study 12-Item Short Form (SF-12) quality of life scores. Male patients versus female patients (*p50.05). VFQ-25: CS, composite score; GV, general vision; OP, ocular pain; NA, near activities; DA, distance activities; SF, social functioning; MH, mental health; RD, role difficulties; De, dependency; Dr, driving; CV, color vision; PV, peripheral vision. SF-12: PCS, physical component score; MCS, mental component score.
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co-morbidities, which were variables found to be significantly associated with the CS score in the linear regression model (Table 2) or important variables identified in previous quality of life studies in patients with uveitis.24–26 Similarly, the SF-12 component scores models were adjusted for age, gender, VA in the better-seeing eye, duration of uveitis, and presence of medical co-morbidities.5 The median VFQ-25 CS score was 78.6 for both the systemic and nonsystemic treatment groups. For the systemic treatment group, the median of the other VFQ-25 subscores ranged from 62.5 (mental health) to 100.0 (social functioning and color vision) and for the nonsystemic treatment group, the median of the other VFQ-25 subscores ranged from 60.0 (general vision) to 100.0 (social functioning and color vision). The mean SF-12 PCS scores were 44.0 and 44.2 for the systemic and nonsystemic treatment groups, respectively, while the mean SF-12 MCS scores were 45.8 and 49.2 for the systemic and nonsystemic groups, respectively. None of the adjusted VFQ-25 subscores and the SF-12 component scores were significantly different between patients treated with or without systemic therapy. The R2 of the CS score in the VFQ-25 models was 33%, with the R2 for the other subscores ranging from 12 to 40%, and the R2 of the PCS and MCS scores in the SF-12 models were 16 and 18%, respectively.
Subgroup Analysis by Gender Table 4 summarizes the clinical characteristics of uveitis patients in the study by gender. Age was
TABLE 2. Linear regression analysis of variables associated with VFQ-25 and SF-12. VFQ-25
SF-12
Variable
CS b
p Value
PCS b
Age Gender*: female Visual acuity Better eye Worse eye Worst recorded Location* Anterior Intermediate Panuveitis Laterality*: unilateral Mean duration of disease (yrs) Activity*: active Ocular surgeries Ocular co-morbidity*: none Medical co-morbidity*: none
0.150 11.009
0.24 50.05
0.112 2.878
0.13 0.29
0.0490 6.348
32.858 14.594 7.766
50.001 50.001 50.01 0.67
8.268 2.769 0.483
0.14 0.14 0.78 0.15
6.272 3.338 1.033
3.641 2.670 2.946 5.630 0.128 6.646 1.449 9.615 5.702
0.26 0.60 0.22 0.27 0.099 0.29
5.826 4.598 4.781 1.758 0.00940 1.142 0.288 4.463 9.497
p Value
0.55 0.95 0.71 0.70 0.20 50.01
MCS b
2.482 1.190 2.163 1.975 0.183 0.0178 0.713 3.289 3.007
p Value 0.51 50.05 0.27 0.069 0.56 0.49
0.50 0.19 1.00 0.39 0.35 0.35
*For categorical variables, one level was assigned as the reference (b = 0.000), i.e. Male, Posterior, Bilateral, Quiet, Presence of ocular comorbidity, Presence of medical co-morbidity. CS, composite score; PCS, physical component score; MCS, mental component score b, linear regression coefficient. !
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VFQ-25 models adjusted for age, gender, VA in the better seeing-eye, location of uveitis, laterality, duration, activity, and presence of ocular co-morbidities. SF-12 models adjusted for age, gender, VA in the better-seeing eye, duration of uveitis, and presence of medical co-morbidities. CS, composite score; GV, general vision; OP, ocular pain; NA, near activities; DA, distance activities; SF, social functioning; MH, mental health; RD, role difficulties; De, dependency; Dr, driving; CV, color vision; PV, peripheral vision; PCS, physical component score; MCS, mental component score; IQR, interquartile range; SD, standard deviation; R2, proportion of the variation in the dependent factor explained by all of the independent variables in the model.
45.8 (12.2) 49.2 (10.7) 0.34 0.18 44.0 (10.8) 44.2 (12.1) 0.95 0.16 Treatment Systemic 78.6 (23.6) 80.0 (20.0) 81.2 (37.5) 75.0 (29.2) 83.3 (27.1) 100.0 (15.6) 62.5 (43.8) 87.5 (50.0) 91.7 (20.8) 75.0 (37.5) 100.0 (0.0) 75.0 (31.2) Nonsystemic 78.6 (23.8) 60.0 (20.0) 75.0 (40.6) 75.0 (35.4) 75.0 (33.3) 100.0 (25.0) 65.6 (43.8) 87.5 (50.0) 91.7 (33.3) 75.0 (33.3) 100.0 (0.0) 75.0 (25.0) p Value 0.92 0.97 0.44 0.94 0.98 0.75 0.48 0.41 0.25 0.80 0.75 0.91 0.33 0.19 0.15 0.32 0.21 0.12 0.29 0.33 0.40 0.40 0.12 0.22 R2
MCS PCS MH SF DA NA OP GV CS Variable
Median VFQ-25 score (IQR)
TABLE 3. Multivariate analysis of quality of life in patients treated with or without systemic therapy.
RD
De
Dr
CV
PV
Mean SF-12 score (SD)
140 W. Gui et al. significantly higher in male patients compared to female patients. VA in the better-seeing eye was significantly better in male patients compared to female patients, but there were no statistically significant differences when comparing VA in the worse-seeing eye or worst-recorded VA. Female patients were significantly more likely to have bilateral disease as compared to males. No statistically significant differences were observed between male and female patients for all other characteristics, including disease location, duration, activity, total number of past ocular surgeries, and presence of ocular or medical co-morbidities.
DISCUSSION Uveitis is a diverse group of inflammatory ocular diseases known to be an important cause of legal and economic blindness in working-age adults.1 A variety of treatments are available for noninfectious uveitis. Commonly, a stepladder approach of escalating therapy is utilized to treat the various conditions, with the more severe conditions necessitating potent systemic immunomodulators. For most patients with uveitis involving the posterior segment, long-term systemic and immunosuppressive treatments are required to control intraocular inflammation and to avoid vision loss.5 Some clinicians use only various formulations of steroids for treating inflamed eyes, but this approach often leads to undesirable systemic side effects,27 and few data exist for the impact of the various types of treatment on patients’ quality of life. This study presents new data comparing the quality of life in patients who receive systemic therapy versus nonsystemic therapy. Due to the stepladder approach to treatment, systemic immunomodulators are typically reserved for patients with the most severe and refractory uveitis, often with more chronic disease and worse visual acuity, with the expectation that these patients receiving such treatments would fare poorly in terms of VR-QOL and HR-QOL. The MUST study found that the implant group had statistically better general selfreported quality of life outcomes compared with the systemic group, but the extent of the differences was marginal.18 The results in this study show that both VR-QOL and HR-QOL measures (as assessed by VFQ25 and SF-12, respectively) are not significantly different between the two treatment groups despite the systemic group potentially having more severe, chronic, and recalcitrant disease. The VR-QOL results in this study are consistent with a recent publication by Tan et al.,24 which showed that patients on immunosuppressive therapy did not have significantly different VFQ-25 scores compared to those on topical corticosteroids or not on treatment after multiple regression analysis. Meanwhile, the MUST Ocular Immunology & Inflammation
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TABLE 4. Clinical features by gender. Variable Age (yr) Median Range Visual acuity (VA)a Better eye Median Range Worse eye Median Range Worst recorded Median Range Location, n (%) Anterior Intermediate Posterior Panuveitis Laterality, n (%) Unilateral Bilateral Duration of disease (yr) Median Range Activity, n (%) Active Quiet Ocular surgeries Median Range Ocular co-morbidity, n (%) Present None Medical co-morbidity, n (%) Present None Etiology of disease, n (%) Idiopathic Sarcoid HLA-B27+ Pars planitis Juvenile idiopathic arthritis Vogt-Koyanagi-Harada Acute zonal occult outer retinopathy Birdshot chorioretinopathy Otherc
Male No. of patients (%) N = 28
Female No. of patients (%) N = 52
p Value 50.05
57.5 26–88
47.0 18–82 50.05b
0.1 0.1–0.7
0.1 0.1–0.9
0.2 0.0–2.2
0.3 0.0–2.3
0.7 0.0 –NLP
0.8 0.1–NLP
0.65
0.24
0.22 17 1 3 7
(60.7) (3.6) (10.7) (25.0)
22 4 10 16
(42.3) (7.7) (19.2) (30.8) 50.05
12 (42.9) 16 (57.1)
11 (21.2) 41 (78.8) 0.66
1.9 0.02–33.0
3.2 0.08–56.0 0.13
9 (32.1) 19 (67.9)
9 (17.3) 43 (82.7) 0.71
1.0 0–6
1.0 0–7 0.95
23 (82.1) 5 (17.9)
43 (82.7) 9 (17.3)
23 (82.1) 5 (17.9)
39 (75.0) 13 (25.0)
15 5 3 1 0 1 0 1 2
13 9 10 4 4 2 2 1 7
0.47
(53.6) (17.9) (10.7) (3.6) (0.0) (3.6) (0.0) (3.6) (7.1)
(25.0) (17.3) (19.2) (7.7) (7.7) (3.8) (3.8) (1.9) (13.5)
a
VA in logMAR (logarithm of the minimal angle of resolution) notation. Female patients had significantly worse VA in the better-seeing eye. c Includes diagnoses of ANA positive uveitis, antiphospholipid syndrome, Behc¸et, Eales, Fuchs heterochromic iridocyclitis, multifocal choroiditis and uveitis, punctate inner choroidopathy, systemic lupus erythematosus, tubulointerstitial nephritis, and uveitis. NLP, no light perception. b
study found that systemic therapy was associated with relatively little additional systemic morbidity compared with nonsystemic therapy (fluocinolone acetonide implant), and suggested that systemic therapy does not commonly induce morbidity with limited oral corticosteroid doses.18 Overall, these results suggest that treatment with potent systemic therapy does not contribute to a lower quality of life !
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despite well-described potential side effects and morbidity associated with the treatment. In our study population, key differences were detected between male and female patients. Mean VA in the better-seeing eye was significantly worse for female patients. Recent studies demonstrated that VA in the better-seeing eye had a stronger correlation with VR-QOL scores than VA in the worse-seeing
142 W. Gui et al. eye.25,26 In this study, the difference in VA in the better-seeing eye between male and female patients paralleled the differences seen in the VFQ-25 scores, but neither the VA in the worse-seeing eye nor the worst recorded VA were significantly different between male and female patients. The VFQ-25 subscores all were significantly lower for female patients except for general vision, social functioning, role difficulties, color vision, and peripheral vision, suggesting that although female patients rated their overall eyesight, their feeling of accomplishing less or being limited in how long they can work, and their ability to use their vision in social interactions, to pick out and match clothes, and to notice objects off to the side (i.e. questions pertaining to general vision, role difficulties, social functioning, color vision, and peripheral vision on VFQ-25) in a similar manner to male patients, the majority of the VR-QOL, including composite score and near and distance activities, were diminished compared to male patients. For HR-QOL, the MCS score was significantly lower in female patients, but the PCS score was not significantly different, suggesting that the mental health of female patients is affected to a greater degree than physical health relative to male patients in this population of patients with noninfectious uveitis. Although certain standard measures of disease severity, such as duration and activity, were not significantly different between male and female patients in this study, female patients were significantly more likely to have bilateral disease, suggesting greater disease severity in female patients and its strong contribution to the observed lower quality of life scores. In the framework of systemic disease, many publications have reported the increased vigor and activity of the immune responses in females compared with males, leading to the higher incidence of autoimmune diseases in females.28,29 Of note, several studies have also shown a higher preponderance of female patients with uveitis, suggesting that women may be more susceptible to more severe uveitis.30 Additionally, Maca et al. have reported that women appear to suffer more from the psychological strain caused by uveitis.31 There are several limitations to this study. Patients were recruited exclusively from a single subspecialty clinic in the northeastern United States and may not be representative of noninfectious uveitis patients elsewhere. The study was cross-sectional in design and could not accurately delineate temporal associations between variables. The sample size may limit the power to detect small statistically significant differences. The measure of HR-QOL in this study was assessed using SF-12, but it has been said that such generic outcomes questionnaires do not have sufficient content to describe important elements of functioning for patients with ocular diseases.14 However, the comprehensiveness, brevity, reliability,
and validity of the short form questionnaires makes this assessment tool the most appropriate and accepted.5 A subset of patients could have had systemic treatment previously and completed the regime at the time of consultation or had systemic treatment stopped due to side effects. These patients would then be classified under the nonsystemic group, yet the effects of systemic therapy may still be present acting as a possible confounder and potentially affecting quality of life results. Finally, 4 patients were unable to complete the VFQ-25 questionnaire and 2 patients were unable to complete the SF-12 questionnaire, resulting in missing data and potentially introducing bias. Nevertheless, this study represents a detailed analysis focused on patients’ quality of life comparing treatment with or without systemic therapy, which clinicians may incorporate in their own practice. In conclusion, treatment with systemic therapy in patients with noninfectious uveitis did not compromise VR-QOL or HR-QOL compared to nonsystemic therapy. Therefore, clinicians should keep the various forms of systemic therapy in the arsenal of treatment options, understanding that patients’ quality of life measures are preserved they are when used appropriately.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
REFERENCES 1. de Smet MD, Taylor SRJ, Bodaghi B, et al. Understanding uveitis: the impact of research on visual outcomes. Prog Retin Eye Res. 2011;30:452–470. 2. Durrani OM, Meads CA, Murray PI. Uveitis: a potentially blinding disease. Ophthalmologica. 2004;218:223–236. 3. Nguyen QD, Hatef E, Kayen B, et al. A cross-sectional study of the current treatment patterns in noninfectious uveitis among specialists in the United States. Ophthalmology. 2011;118:184–190. 4. Bradley EA, Bradley D, Bartley GB. Evaluating healthrelated quality of life in ophthalmic disease—practical considerations. Arch Ophthalmol. 2006;124:121–122. 5. Miserocchi E, Modorati G, Mosconi P, et al. Quality of life in patients with uveitis on chronic systemic immunosuppressive treatment. Ocul Immunol Inflamm. 2010;18:297–304. 6. Cole SR, Beck RW, Moke PS, et al. The National Eye Institute Visual Function Questionnaire: experience of the ONTT. Optic Neuritis Treatment Trial. Invest Ophthalmol Vis Sci. 2000;41:1017–1021. 7. Gutierrez P, Wilson MR, Johnson C, et al. Influence of glaucomatous visual field loss on health-related quality of life. Arch Ophthalmol. 1997;115:777–784. 8. Linder M, Chang TS, Scott IU, et al. Validity of the visual function index (VF-14) in patients with retinal disease. Arch Ophthalmol. 1999;117:1611–1616. Ocular Immunology & Inflammation
Quality of Life in Uveitis for Systemic Therapy 9. Mangione CM, Gutierrez PR, Lowe G, et al. Influence of age-related maculopathy on visual functioning and healthrelated quality of life. Am J Ophthalmol. 1999;128:45–53. 10. Jalil A, Yin K, Coyle L, et al. Vision-related quality of life and employment status in patients with uveitis of working age: a prospective study. Ocul Immunol Inflamm. 2012;20: 262–265. 11. Murphy CC, Greiner K, Plskova J, et al. Validity of using vision-related quality of life as a treatment end point in intermediate and posterior uveitis. Br J Ophthalmol. 2007;91: 154–156. 12. Murphy CC, Hughes EH, Frost NA, Dick AD. Quality of life and visual function in patients with intermediate uveitis. Br J Ophthalmol. 2005;89:1161–1165. 13. Onal S, Savar F, Akman M, Kazokoglu H. Vision- and health-related quality of life in patients with Behc¸et uveitis. Arch Ophthalmol. 2010;128:1265–1271. 14. Schiffman RM, Jacobsen G, Whitcup SM. Visual functioning and general health status in patients with uveitis. Arch Ophthalmol. 2001;119:841–849. 15. Stanbury RM, Graham EM. Systemic corticosteroid therapy—side effects and their management. Br J Ophthalmol. 1998;82:704–708. 16. Min DI, Monaco AP. Complications associated with immunosuppressive therapy and their management. Pharmacotherapy. 1991;11:S119–S125. 17. Menezo V, Lau C, Comer M, Lightman S. Clinical outcome of chronic immunosuppression in patients with noninfectious uveitis. Clin Exp Ophthalmol. 2005;33:16–21. 18. Multicenter Uveitis Steroid Treatment (MUST) Trial Research Group, Kempen JH, Altaweel MM, et al. Randomized comparison of systemic anti-inflammatory therapy versus fluocinolone acetonide implant for intermediate, posterior, and panuveitis: the multicenter uveitis steroid treatment trial. Ophthalmology. 2011;118: 1916–1926. 19. Jabs DA, Nussenblatt RB, Rosenbaum JT, Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting
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ORIGINAL ARTICLE
Quality of Life in Patients with Noninfectious Uveitis Treated with or without Systemic Anti-inflammatory Therapy Wei Gui, BS1, Matthew Dombrow, MD2, Inna Marcus, MD3, Meredith H. Stowe, PhD2, Baylah Tessier-Sherman, MPH2, Elizabeth Yang, MD1, and John J. Huang, MD1 1
Department of Ophthalmology and Visual Science, Yale University, New Haven, Connecticut, USA, School of Medicine, Yale University, New Haven, New Haven, Connecticut, USA, and 3Duke Eye Center, Duke University, Durham, North Carolina, USA
2
ABSTRACT Purpose: To compare vision-related (VR-QOL) and health-related quality of life (HR-QOL) in patients with noninfectious uveitis treated with systemic anti-inflammatory therapy versus nonsystemic therapy. Methods: A prospective, cross-sectional study design was employed. VR-QOL and HR-QOL were assessed by the 25-Item Visual Function Questionnaire (VFQ-25) and the Short Form 12-Item Health Survey (SF-12), respectively. Multivariate regression analysis was performed to assess the VR-QOL and HR-QOL based on treatment. Results: Among the 80 patients, the median age was 51 years with 28 males (35%). The adjusted effect of treatment modality on VR-QOL or HR-QOL showed no statistically significant difference in all subscores of VFQ-25 or physical component score (PCS) and mental component score (MCS) of SF-12. Systemic therapy did not compromise VR-QOL or HR-QOL compared to nonsystemic therapy. Conclusions: Systemic therapy can be effectively used to control serious cases of noninfectious uveitis without significant relative adverse impact on quality of life. Keywords: Quality of life, SF-12, systemic therapy, uveitis, VFQ-25
Uveitis is a major cause of visual impairment in developed countries, responsible for an estimated 30,000 new cases of legal blindness annually, and causes 2.8–10% of cases of blindness in the workingage population in the United States alone.1 Early diagnosis and treatment are important to prevent vision-threatening complications of uveitis, which include cataract, glaucoma, retinopathy, optic neuropathy, macular edema, and phthisis.2,3 Current commonly used treatments consist of local agents, including topical corticosteroids, periocular injections of methylprednisolone or triamcinolone, intravitreal injections of triamcinolone, dexamethasone intravitreal implant in a biodegradable matrix lasting 6 months and fluocinolone implant lasting for two and
a half years, and systemic agents, including oral corticosteroids, steroid-sparing immunomodulators, and, more recently, biologics.1 Recently, in the field of ophthalmology, there has been growing interest in quality of life assessment for objectively reflecting the actual impact of disease and the extent of suffering for the patient.4,5 Ocular diseases, including age-related macular degeneration, diabetic macular edema, glaucoma, and optic neuritis, affect the quality of life in patients.6–9 Although quality of life studies in patients with uveitis are present in the literature,1,5,10–14 studies regarding comparisons of uveitis treatment on quality of life are limited.15–17 In addition, there are concerns that the systemic medical treatment for noninfectious
Received 13 June 2013; revised 12 November 2013; accepted 9 December 2013; published online 20 May 2014 Correspondence: John J. Huang, MD, Department of Ophthalmology and Visual Science, Yale University School of Medicine, 40 Temple Street, 3rd Floor, New Haven, CT 06510, USA. E-mail: [email protected]
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136 W. Gui et al. uveitis may further contribute to a lower quality of life due to side effects and associated morbidity. Due to these concerns, ophthalmologists often delay or are reluctant to use such therapy. The recently published large, randomized controlled Multicenter Uveitis Steroid Treatment (MUST) trial of patients with intermediate, posterior, or panuveitis recorded quality of life measures comparing treatment with systemic versus implant therapy.18 Although much information has been gained from this study, key questions remain, including how therapies with known systemic side effects compare to less aggressive treatments for quality of life assessment. The purpose of the present study is to compare the vision-related (VR-QOL) and health-related quality of life (HR-QOL) in patients with noninfectious uveitis receiving systemic anti-inflammatory therapy with those who were not receiving such therapy.
MATERIALS AND METHODS Patient Sample This prospective, cross-sectional study was conducted at the uveitis clinic, Yale Eye Center in the Yale Department of Ophthalmology and Visual Science from March 2011 through May 2013. Eligible patients were aged 18 and older, had a diagnosis of noninfectious uveitis, and were able to communicate effectively in English or through an interpreter. The study was approved by the Yale University Human Investigation Committee (HIC), and written informed consent was obtained from all subjects in accordance with the Declaration of Helsinki.
Data Collection Demographic data collected at the time of visit included age, gender, and medical diseases. All patients underwent a full ophthalmologic examination including visual acuity (VA), applanation tonometry, and slit-lamp biomicroscopy. VA was assessed using the Snellen eye chart retroilluminated at 20 feet. Ocular data collected or determined at the time of visit by a qualified uveitis specialist included diagnosis, location (anterior, intermediate, posterior, or panuveitis), laterality (unilateral or bilateral), activity (quiet or active, predominantly based on the Standardization of Uveitis Nomenclature (SUN) working group classification),19 current treatment, other ocular disease, and past eye surgeries. At the time of the visit, patients had been previously evaluated and were already being treated with appropriate therapy. Treatment modality was divided into 2 categories for subsequent analysis: systemic therapy (immunomodulators, biologics, and/or oral
corticosteroids) or nonsystemic therapy (observation with treatment as needed, topical corticosteroids, periocular injection of triamcinolone, and/or fluocinolone acetonide implant). Patients were classified in the systemic therapy group as long as they were on systemic treatment at the time of the clinic visit. Patients who were not receiving any treatment for uveitis at the time of visit were considered to be treated with observation with treatment as needed and classified in the nonsystemic therapy group. The Snellen VA recorded at the time of exam was converted to the logarithm of the minimum angle of resolution (logMAR) VA. Counting fingers (CF) was converted to +1.98 logMAR and hand motion (HM) was converted to +2.28 logMAR based on the study by Lange et al.20 Light perception (LP) or no light perception (NLP) values were excluded from analysis.21
Quality of Life Assessment The VR-QOL was assessed using the National Eye Institute Visual Functioning Questionnaire (VFQ-25). VFQ-25 is a 25-item questionnaire that is both reliable and valid, containing 12 subscores: general health (1 question), general vision (1 question), ocular pain (2 questions), near activities (3 questions), distance activities (3 questions), social functioning (2 questions), mental health (4 questions), role difficulties (2 questions), dependency (3 questions), driving (2 questions), color vision (1 question), and peripheral vision (1 question).22 Since this study also used a separate questionnaire for HR-QOL, the VFQ-25 general health subscale was not used. Additionally, a VFQ-25 composite score (CS) was calculated by averaging all of the subscale values except the general health subscale. Answers to each of the 25 questions were converted to a 100-point scale with 100 representing the best possible score and 0 representing the worst possible score. The VFQ-25 questionnaire was selected to assess visual functioning because Schiffman et al. have demonstrated its validity for VR-QOL in patients with uveitis.14 The HR-QOL was assessed using the 12-item Short Form Survey (SF-12) derived from the 36-item Short Form Survey (SF-36).23 The SF-12 questionnaire comprises 12 questions addressing 8 general health subscores: physical functioning (2 questions), rolephysical (2 questions), bodily pain (1 question), general health (1 question), vitality (1 question), social functioning (1 question), role-emotional (2 questions), and mental health (2 questions). Based on the variables created by the answers, each variable was multiplied by physical and mental regression weights, which were derived from the general U.S. population, to generate a physical component score (PCS) and a mental component score (MCS). Higher PCS and MCS Ocular Immunology & Inflammation
Quality of Life in Uveitis for Systemic Therapy scores indicate better physical and mental health, respectively. The U.S. population scores were normalized to a mean of 50 and standard deviation of 10.23 The SF-12 questionnaire was selected to evaluate health functioning because it is a validated and shorter version of the survey from which it was derived, the SF-36, one of the best known and most widely validated questionnaires for HR-QOL.14 Schiffman et al. have assessed health functioning using the SF-36 in patients with uveitis and suggest evaluating both VR-QOL and HR-QOL to measure the effect of disease and its therapy on quality of life.14
Statistical Analysis Statistical analysis was performed using SAS v 9.2 (SAS Institute, Cary, NC). To evaluate associations between categorical and continuous variables, in normally distributed samples, Fisher’s exact test and the two-sided Student t-test were used and in nonnormally distributed samples, Cochran-MantelHaenszel statistics and Mann-Whitney U tests were used. Linear regression analysis was performed to determine association of variables with VR-QOL or HR-QOL scores. Multivariate regression was used to evaluate associations between treatment modality and VR-QOL or HR-QOL. A p value 5.05 was considered statistically significant. The study was designed to be able to detect differences in vision-related quality of life by the VFQ-25 and in health-related quality of life by the SF-12 (PCS and MCS scores) in patients treated with systemic versus nonsystemic therapy. The sample size in the study is able to detect a one-sided difference of 11.0, 6.4, and 6.1 points in the VFQ-25 composite score, PCS, and MCS measures, respectively, with 80% power and 95% level of confidence.
RESULTS Demographics and Clinical Characteristics The demographic and clinical characteristics data are summarized in Table 1. Eighty patients with noninfectious uveitis seen at the Yale Eye Center were enrolled in this study. There were 28 males (35.0%) and 52 females (65.0%), with median age of 51 years and range of 18–88 years. The median logMAR VA of the better-seeing eye, worse-seeing eye, and worst recorded VA were 0.1 (range of 0.1–0.9), 0.3 (range of 0–2.3), and 0.8 (range of 0 to no light perception), respectively. Thirty-four patients (42.5%) were treated with systemic therapy. Anterior uveitis (48.8%) and panuveitis (28.8%) were the most common locations of disease. Uveitis was bilateral in 71.2% of patients, and the median duration of disease was 2.7 years with a range of 0.02–56 years. Disease was active in !
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22.5% of patients, and the median number of past ocular surgeries was 1 with a range of 0–7. Ocular co-morbidities were present in 82.5% of patients, and medical co-morbidities were present in 77.5% of patients. The most common diagnoses were idiopathic (35.0%), sarcoid (17.5%), and HLA-B27+ (16.2%).
Demographics and Clinical Characteristics by Treatment The demographic and clinical characteristics data categorized by treatment group are also summarized in Table 1. In the systemic therapy group, the median age was 45 years with a range of 18–81 years, and there were 9 males (26.5%) and 25 females (73.5%). In the nonsystemic therapy group, the median age was 52 years with a range of 24–88 years, and there were 19 males (41.3%) and 27 females (58.7%). There were no statistically significant differences between patients treated with or without systemic therapy in age, gender, VA, uveitis location, laterality, duration, activity, total number of ocular surgeries, presence of ocular co-morbidities, and presence of medical co-morbidities.
VFQ-25 and SF-12 Scores VR-QOL and HR-QOL scores are summarized in Figure 1. The median VFQ-25 CS score was 78.6, and the highest median subscores were observed for social functioning (100.0) and color vision (100.0) and the lowest for mental health (62.5). The mean SF-12 PCS and MCS scores were 44.1 and 47.7, respectively. Comparing male and female patients, VFQ-25 subscores were significantly higher in male patients for composite score, ocular pain, near vision, distance vision, mental health, dependency, and driving, but not significantly different for general vision, social functioning, role difficulties, color vision, and peripheral vision (Figure 1). SF-12 component scores were significantly higher for male patients in MCS but not significantly different in PCS (Figure 1).
Bivariate Analysis of Variables Associated with VR-QOL and HR-QOL The linear regression analysis of the association of variables with the CS score of VFQ-25 and the PCS and MCS scores of SF-12 is summarized in Table 2. Gender, VA of the better-seeing eye, VA of the worseseeing eye, and worst recorded VA were identified as variables significantly associated with the CS score of VFQ-25. The presence of medical co-morbidities was the only variable significantly associated with the
138 W. Gui et al. TABLE 1. Demographic and clinical characteristics. All Variable Age (yr) Median Range Gender, n (%) Male Female Visual acuity (VA)a Better eye Median Range Worse eye Median Range Worst recorded Median Range Location, n (%) Anterior Intermediate Posterior Panuveitis Laterality, n (%) Unilateral Bilateral Duration of disease (yr) Median Range Activity, n (%) Active Quiet Ocular surgeries Median Range Ocular co-morbidities, n (%)b None Cataract Glaucoma Epiretinal membrane Age-related macular degeneration Diabetic retinopathy Medical co-morbidities, n (%)c None Hypertension Hyperlipidemia Diabetes Thyroid disease Arthritis Cancer Etiology of disease, n (%) Idiopathic Sarcoid HLA-B27+ Pars planitis Juvenile idiopathic arthritis Vogt-Koyanagi-Harada Acute zonal occult outer retinopathy Birdshot chorioretinopathy Otherd a
No. of patients (%) N = 80
Treatment group Systemic No. of patients (%) N = 34
Nonsystemic No. of patients (%) N = 46
p Value 0.16
51 18–88
45 18–81
52 24–88
28 (35.0) 52 (65.0)
9 (26.5) 25 (73.5)
19 (41.3) 27 (58.7)
0.1 0.1–0.9
0.1 0.1–0.5
0.1 0.1–0.9
0.3 0.0–NLP
0.3 0.0–2.3
0.3 0.0–NLP
0.8 0.0–NLP
0.6 0.1–LP
1 0.0 –NLP
0.17
0.70
0.42
0.58
0.55 39 5 13 23
(48.8) (6.2) (16.2) (28.8)
15 2 7 10
(44.1) (5.9) (20.6) (29.4)
24 3 6 13
(52.2) (6.5) (13.0) (28.3) 0.061
23 (28.8) 57 (71.2)
6 (17.6) 29 (85.3)
17 (37.0) 29 (63.0) 0.76
2.7 0.02–56.0
2.2 0.08–30.6
2.9 0.02–56.0 0.37
18 (22.5) 62 (77.5)
6 (17.6) 28 (82.4)
12 (26.1) 34 (73.9)
1.0 0–7 66 (82.5) 14 (17.5) 35 (43.8) 26 (32.5) 11 (13.8) 2 (2.5) 1 (1.2) 62 (77.5) 18 (22.5) 21 (26.2) 9 (11.2) 8 (10.0) 6 (7.5) 5 (6.2) 5 (6.2)
0.0 0–6 30 (88.2) 4 (11.8) 18 (52.9) 11 (32.4) 7 (20.6) 1 (2.9) 1 (2.9) 27 (79.4) 7 (20.6) 6 (17.6) 2 (5.9) 3 (8.8) 2 (5.9) 2 (5.9) 1 (2.9)
1.5 0–7 36 (78.3) 10 (21.7) 17 (37.0) 15 (32.6) 4 (8.7) 1 (2.2) 0 (0.0) 35 (76.1) 11 (23.9) 15 (32.6) 7 (15.2) 5 (10.9) 4 (8.7) 3 (6.5) 4 (8.7)
0.64
28 14 13 5 4 3 2 2 9
(35.0) (17.5) (16.2) (6.2) (5.0) (3.8) (2.5) (2.5) (11.2)
8 6 5 2 4 3 0 1 5
(23.5) (17.6) (14.7) (5.9) (11.8) (8.9) (0.0) (2.9) (14.7)
20 8 8 3 0 0 2 1 4
0.25
0.73
(43.5) (17.4) (17.4) (6.5) (0.0) (0.0) (4.3) (2.2) (8.7)
VA in logMAR (logarithm of the minimal angle of resolution) notation. Statistical testing for presence or absence of ocular co-morbidities. c Statistical testing for presence or absence of medical co-morbidities. d Includes diagnoses of ANA positive uveitis, antiphospholipid syndrome, Behc¸et, Eales, Fuchs heterochromic iridocyclitis, multifocal choroiditis and uveitis, punctate inner choroidopathy, systemic lupus erythematosus, tubulointerstitial nephritis, and uveitis. LP, light perception; NLP, no light perception. b
Quality of Life in Uveitis for Systemic Therapy SF-12 PCS score, and gender was the only variable significantly associated with the SF-12 MCS score.
Multivariate Analysis of the Effect of Treatment Modality on VR-QOL and HR-QOL The multivariate analysis of the effect of treatment modality on QOL is summarized in Table 3. The VFQ25 subscores models were adjusted for age, gender, VA in the better seeing-eye, location of uveitis, laterality, duration, activity, and presence of ocular 100
Overall
90
Male
80
Female
70 60 50 40 30 20 10 0
FIGURE 1. National Eye Institute Visual Functioning Questionnaire (VFQ-25) and Medical Outcomes Study 12-Item Short Form (SF-12) quality of life scores. Male patients versus female patients (*p50.05). VFQ-25: CS, composite score; GV, general vision; OP, ocular pain; NA, near activities; DA, distance activities; SF, social functioning; MH, mental health; RD, role difficulties; De, dependency; Dr, driving; CV, color vision; PV, peripheral vision. SF-12: PCS, physical component score; MCS, mental component score.
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co-morbidities, which were variables found to be significantly associated with the CS score in the linear regression model (Table 2) or important variables identified in previous quality of life studies in patients with uveitis.24–26 Similarly, the SF-12 component scores models were adjusted for age, gender, VA in the better-seeing eye, duration of uveitis, and presence of medical co-morbidities.5 The median VFQ-25 CS score was 78.6 for both the systemic and nonsystemic treatment groups. For the systemic treatment group, the median of the other VFQ-25 subscores ranged from 62.5 (mental health) to 100.0 (social functioning and color vision) and for the nonsystemic treatment group, the median of the other VFQ-25 subscores ranged from 60.0 (general vision) to 100.0 (social functioning and color vision). The mean SF-12 PCS scores were 44.0 and 44.2 for the systemic and nonsystemic treatment groups, respectively, while the mean SF-12 MCS scores were 45.8 and 49.2 for the systemic and nonsystemic groups, respectively. None of the adjusted VFQ-25 subscores and the SF-12 component scores were significantly different between patients treated with or without systemic therapy. The R2 of the CS score in the VFQ-25 models was 33%, with the R2 for the other subscores ranging from 12 to 40%, and the R2 of the PCS and MCS scores in the SF-12 models were 16 and 18%, respectively.
Subgroup Analysis by Gender Table 4 summarizes the clinical characteristics of uveitis patients in the study by gender. Age was
TABLE 2. Linear regression analysis of variables associated with VFQ-25 and SF-12. VFQ-25
SF-12
Variable
CS b
p Value
PCS b
Age Gender*: female Visual acuity Better eye Worse eye Worst recorded Location* Anterior Intermediate Panuveitis Laterality*: unilateral Mean duration of disease (yrs) Activity*: active Ocular surgeries Ocular co-morbidity*: none Medical co-morbidity*: none
0.150 11.009
0.24 50.05
0.112 2.878
0.13 0.29
0.0490 6.348
32.858 14.594 7.766
50.001 50.001 50.01 0.67
8.268 2.769 0.483
0.14 0.14 0.78 0.15
6.272 3.338 1.033
3.641 2.670 2.946 5.630 0.128 6.646 1.449 9.615 5.702
0.26 0.60 0.22 0.27 0.099 0.29
5.826 4.598 4.781 1.758 0.00940 1.142 0.288 4.463 9.497
p Value
0.55 0.95 0.71 0.70 0.20 50.01
MCS b
2.482 1.190 2.163 1.975 0.183 0.0178 0.713 3.289 3.007
p Value 0.51 50.05 0.27 0.069 0.56 0.49
0.50 0.19 1.00 0.39 0.35 0.35
*For categorical variables, one level was assigned as the reference (b = 0.000), i.e. Male, Posterior, Bilateral, Quiet, Presence of ocular comorbidity, Presence of medical co-morbidity. CS, composite score; PCS, physical component score; MCS, mental component score b, linear regression coefficient. !
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VFQ-25 models adjusted for age, gender, VA in the better seeing-eye, location of uveitis, laterality, duration, activity, and presence of ocular co-morbidities. SF-12 models adjusted for age, gender, VA in the better-seeing eye, duration of uveitis, and presence of medical co-morbidities. CS, composite score; GV, general vision; OP, ocular pain; NA, near activities; DA, distance activities; SF, social functioning; MH, mental health; RD, role difficulties; De, dependency; Dr, driving; CV, color vision; PV, peripheral vision; PCS, physical component score; MCS, mental component score; IQR, interquartile range; SD, standard deviation; R2, proportion of the variation in the dependent factor explained by all of the independent variables in the model.
45.8 (12.2) 49.2 (10.7) 0.34 0.18 44.0 (10.8) 44.2 (12.1) 0.95 0.16 Treatment Systemic 78.6 (23.6) 80.0 (20.0) 81.2 (37.5) 75.0 (29.2) 83.3 (27.1) 100.0 (15.6) 62.5 (43.8) 87.5 (50.0) 91.7 (20.8) 75.0 (37.5) 100.0 (0.0) 75.0 (31.2) Nonsystemic 78.6 (23.8) 60.0 (20.0) 75.0 (40.6) 75.0 (35.4) 75.0 (33.3) 100.0 (25.0) 65.6 (43.8) 87.5 (50.0) 91.7 (33.3) 75.0 (33.3) 100.0 (0.0) 75.0 (25.0) p Value 0.92 0.97 0.44 0.94 0.98 0.75 0.48 0.41 0.25 0.80 0.75 0.91 0.33 0.19 0.15 0.32 0.21 0.12 0.29 0.33 0.40 0.40 0.12 0.22 R2
MCS PCS MH SF DA NA OP GV CS Variable
Median VFQ-25 score (IQR)
TABLE 3. Multivariate analysis of quality of life in patients treated with or without systemic therapy.
RD
De
Dr
CV
PV
Mean SF-12 score (SD)
140 W. Gui et al. significantly higher in male patients compared to female patients. VA in the better-seeing eye was significantly better in male patients compared to female patients, but there were no statistically significant differences when comparing VA in the worse-seeing eye or worst-recorded VA. Female patients were significantly more likely to have bilateral disease as compared to males. No statistically significant differences were observed between male and female patients for all other characteristics, including disease location, duration, activity, total number of past ocular surgeries, and presence of ocular or medical co-morbidities.
DISCUSSION Uveitis is a diverse group of inflammatory ocular diseases known to be an important cause of legal and economic blindness in working-age adults.1 A variety of treatments are available for noninfectious uveitis. Commonly, a stepladder approach of escalating therapy is utilized to treat the various conditions, with the more severe conditions necessitating potent systemic immunomodulators. For most patients with uveitis involving the posterior segment, long-term systemic and immunosuppressive treatments are required to control intraocular inflammation and to avoid vision loss.5 Some clinicians use only various formulations of steroids for treating inflamed eyes, but this approach often leads to undesirable systemic side effects,27 and few data exist for the impact of the various types of treatment on patients’ quality of life. This study presents new data comparing the quality of life in patients who receive systemic therapy versus nonsystemic therapy. Due to the stepladder approach to treatment, systemic immunomodulators are typically reserved for patients with the most severe and refractory uveitis, often with more chronic disease and worse visual acuity, with the expectation that these patients receiving such treatments would fare poorly in terms of VR-QOL and HR-QOL. The MUST study found that the implant group had statistically better general selfreported quality of life outcomes compared with the systemic group, but the extent of the differences was marginal.18 The results in this study show that both VR-QOL and HR-QOL measures (as assessed by VFQ25 and SF-12, respectively) are not significantly different between the two treatment groups despite the systemic group potentially having more severe, chronic, and recalcitrant disease. The VR-QOL results in this study are consistent with a recent publication by Tan et al.,24 which showed that patients on immunosuppressive therapy did not have significantly different VFQ-25 scores compared to those on topical corticosteroids or not on treatment after multiple regression analysis. Meanwhile, the MUST Ocular Immunology & Inflammation
Quality of Life in Uveitis for Systemic Therapy
141
TABLE 4. Clinical features by gender. Variable Age (yr) Median Range Visual acuity (VA)a Better eye Median Range Worse eye Median Range Worst recorded Median Range Location, n (%) Anterior Intermediate Posterior Panuveitis Laterality, n (%) Unilateral Bilateral Duration of disease (yr) Median Range Activity, n (%) Active Quiet Ocular surgeries Median Range Ocular co-morbidity, n (%) Present None Medical co-morbidity, n (%) Present None Etiology of disease, n (%) Idiopathic Sarcoid HLA-B27+ Pars planitis Juvenile idiopathic arthritis Vogt-Koyanagi-Harada Acute zonal occult outer retinopathy Birdshot chorioretinopathy Otherc
Male No. of patients (%) N = 28
Female No. of patients (%) N = 52
p Value 50.05
57.5 26–88
47.0 18–82 50.05b
0.1 0.1–0.7
0.1 0.1–0.9
0.2 0.0–2.2
0.3 0.0–2.3
0.7 0.0 –NLP
0.8 0.1–NLP
0.65
0.24
0.22 17 1 3 7
(60.7) (3.6) (10.7) (25.0)
22 4 10 16
(42.3) (7.7) (19.2) (30.8) 50.05
12 (42.9) 16 (57.1)
11 (21.2) 41 (78.8) 0.66
1.9 0.02–33.0
3.2 0.08–56.0 0.13
9 (32.1) 19 (67.9)
9 (17.3) 43 (82.7) 0.71
1.0 0–6
1.0 0–7 0.95
23 (82.1) 5 (17.9)
43 (82.7) 9 (17.3)
23 (82.1) 5 (17.9)
39 (75.0) 13 (25.0)
15 5 3 1 0 1 0 1 2
13 9 10 4 4 2 2 1 7
0.47
(53.6) (17.9) (10.7) (3.6) (0.0) (3.6) (0.0) (3.6) (7.1)
(25.0) (17.3) (19.2) (7.7) (7.7) (3.8) (3.8) (1.9) (13.5)
a
VA in logMAR (logarithm of the minimal angle of resolution) notation. Female patients had significantly worse VA in the better-seeing eye. c Includes diagnoses of ANA positive uveitis, antiphospholipid syndrome, Behc¸et, Eales, Fuchs heterochromic iridocyclitis, multifocal choroiditis and uveitis, punctate inner choroidopathy, systemic lupus erythematosus, tubulointerstitial nephritis, and uveitis. NLP, no light perception. b
study found that systemic therapy was associated with relatively little additional systemic morbidity compared with nonsystemic therapy (fluocinolone acetonide implant), and suggested that systemic therapy does not commonly induce morbidity with limited oral corticosteroid doses.18 Overall, these results suggest that treatment with potent systemic therapy does not contribute to a lower quality of life !
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despite well-described potential side effects and morbidity associated with the treatment. In our study population, key differences were detected between male and female patients. Mean VA in the better-seeing eye was significantly worse for female patients. Recent studies demonstrated that VA in the better-seeing eye had a stronger correlation with VR-QOL scores than VA in the worse-seeing
142 W. Gui et al. eye.25,26 In this study, the difference in VA in the better-seeing eye between male and female patients paralleled the differences seen in the VFQ-25 scores, but neither the VA in the worse-seeing eye nor the worst recorded VA were significantly different between male and female patients. The VFQ-25 subscores all were significantly lower for female patients except for general vision, social functioning, role difficulties, color vision, and peripheral vision, suggesting that although female patients rated their overall eyesight, their feeling of accomplishing less or being limited in how long they can work, and their ability to use their vision in social interactions, to pick out and match clothes, and to notice objects off to the side (i.e. questions pertaining to general vision, role difficulties, social functioning, color vision, and peripheral vision on VFQ-25) in a similar manner to male patients, the majority of the VR-QOL, including composite score and near and distance activities, were diminished compared to male patients. For HR-QOL, the MCS score was significantly lower in female patients, but the PCS score was not significantly different, suggesting that the mental health of female patients is affected to a greater degree than physical health relative to male patients in this population of patients with noninfectious uveitis. Although certain standard measures of disease severity, such as duration and activity, were not significantly different between male and female patients in this study, female patients were significantly more likely to have bilateral disease, suggesting greater disease severity in female patients and its strong contribution to the observed lower quality of life scores. In the framework of systemic disease, many publications have reported the increased vigor and activity of the immune responses in females compared with males, leading to the higher incidence of autoimmune diseases in females.28,29 Of note, several studies have also shown a higher preponderance of female patients with uveitis, suggesting that women may be more susceptible to more severe uveitis.30 Additionally, Maca et al. have reported that women appear to suffer more from the psychological strain caused by uveitis.31 There are several limitations to this study. Patients were recruited exclusively from a single subspecialty clinic in the northeastern United States and may not be representative of noninfectious uveitis patients elsewhere. The study was cross-sectional in design and could not accurately delineate temporal associations between variables. The sample size may limit the power to detect small statistically significant differences. The measure of HR-QOL in this study was assessed using SF-12, but it has been said that such generic outcomes questionnaires do not have sufficient content to describe important elements of functioning for patients with ocular diseases.14 However, the comprehensiveness, brevity, reliability,
and validity of the short form questionnaires makes this assessment tool the most appropriate and accepted.5 A subset of patients could have had systemic treatment previously and completed the regime at the time of consultation or had systemic treatment stopped due to side effects. These patients would then be classified under the nonsystemic group, yet the effects of systemic therapy may still be present acting as a possible confounder and potentially affecting quality of life results. Finally, 4 patients were unable to complete the VFQ-25 questionnaire and 2 patients were unable to complete the SF-12 questionnaire, resulting in missing data and potentially introducing bias. Nevertheless, this study represents a detailed analysis focused on patients’ quality of life comparing treatment with or without systemic therapy, which clinicians may incorporate in their own practice. In conclusion, treatment with systemic therapy in patients with noninfectious uveitis did not compromise VR-QOL or HR-QOL compared to nonsystemic therapy. Therefore, clinicians should keep the various forms of systemic therapy in the arsenal of treatment options, understanding that patients’ quality of life measures are preserved they are when used appropriately.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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