Purpose
To calculate the incidence rates of ocular complications and vision loss in HLA-B27-associated uveitis and to explore the effect of chronic inflammation on clinical outcomes.
Design
Retrospective longitudinal cohort study.
Methods
The clinical records of 99 patients (148 uveitis-affected eyes) with HLA-B27-associated uveitis seen at a tertiary care center were included. The main outcome measures were ocular complications (posterior iris synechiae, band keratopathy, posterior subcapsular [PSC] cataracts, ocular hypertension, hypotony, cystoid macular edema, and epiretinal membrane) and vision loss. Anterior chamber inflammation was defined as ≥1+ grade inflammation. Chronic uveitis was defined as persistent inflammation with relapse in <3 months after discontinuing treatment or requiring medications to suppress inflammation for >3 months after reviewing the patient’s entire clinical course.
Results
The clinical course was most commonly acute/recurrent (75%) or chronic (20%). The most common complications to develop during follow-up were ocular hypertension (0.10/eye-year) and PSC cataracts (0.09/eye-year). In multivariate analysis, the presence of posterior synechiae at presentation, inflammation, corticosteroid-sparing therapy, corticosteroid injections, chronic disease, and male gender were associated with a statistically significant increased risk of developing vision loss (20/50 or worse). Chronic disease course was associated with a 7-fold increased risk of visual impairment (hazard ratio [HR] = 6.8, P < .0001). The presence of inflammation during follow-up was associated with an increased risk of developing visual impairment (HR = 6.2, P < .0001). In multivariate analysis, chronic disease course and topical corticosteroids were associated with an increased risk of developing any incident ocular complication (HR = 2.2, P = .04 and HR = 3.3, P = .01, respectively).
Conclusions
Poorly controlled inflammation was associated with the development of ocular complications including vision loss. Patients with chronic inflammation were also at greater risk of complications.
Human leukocyte antigen (HLA)-B27-associated uveitis is the most commonly diagnosed cause of acute anterior uveitis (AAU). Within the general population in North America and Europe, the prevalence of HLA-B27 is approximately 8% to 10%, but the prevalence of the HLA-B27 allele in patients with AAU is much higher, ranging from 15% to 60%. The typical characteristics of HLA-B27-associated uveitis have been well described in the literature: young age of onset, unilateral or unilateral alternating inflammation, presence of hypopyon or fibrin in the anterior chamber, development of posterior synechiae, and occurring frequently in the setting of systemic spondyloarthropathies like ankylosing spondylitis and reactive arthritis.
While most patients with HLA-B27-associated uveitis have acute or recurrent inflammation, some patients may develop chronic inflammation. Approximately 5% to 19% of patients with HLA-B27-associated uveitis develop chronic inflammation lasting longer than 3 months or requiring chronic therapy to suppress inflammation. This range may be explained by differences in recruitment methodology and potential differences in definitions of chronic disease; some studies only included patients with acute anterior uveitis at presentation and excluded those who presented with chronic HLA-B27-associated uveitis. Chronic HLA-B27-associated uveitis may represent a large proportion of chronic noninfectious uveitis cases; in 1 study, HLA-B27-associated uveitis was the largest known disease entity, representing 37% of all chronic noninfectious uveitis. However, little is known about how the degree of inflammation and chronic clinical course are associated with visual acuity loss and complications.
Previous longitudinal studies on HLA-B27-associated uveitis have not reported the incidence rates of ocular complications. A few retrospective cohort studies have utilized long-term follow-up to characterize extraocular manifestations and gender differences in patients with HLA-B27-associated uveitis. It has also been reported that the prognosis for patients with HLA-B27-associated uveitis is less favorable than for HLA-B27-negative patients with idiopathic anterior uveitis. Determining the incidence rates of ocular complications in HLA-B27-associated uveitis would be helpful in comparing the prognosis of this disease to other types of uveitis.
The purpose of our study was to calculate the incidence rates of ocular complications and vision loss in a cohort of 104 consecutive patients with HLA-B27-associated uveitis and to explore the effect of inflammation and chronicity on clinical outcomes.
Methods
Study Population
In this retrospective longitudinal cohort study, the clinical records of 104 consecutive patients with HLA-B27-associated uveitis who were examined at the F.I. Proctor Foundation at the University of California, San Francisco, between April 8, 1999 and November 20, 2008 were reviewed. All patients with anterior uveitis in our practice undergo standard screening, which routinely includes a complete blood count, serologic tests for syphilis, a purified protein derivative skin test, chest radiography, and HLA-B27 test. In certain cases, additional tests are performed, including serum angiotensin-converting enzyme level, antinuclear antibody, and urine beta-2 microglobulin. The diagnosis of HLA-B27-associated uveitis required the presence of anterior uveitis and the HLA-B27 allele without any other known reason to have uveitis. Of the 104 HLA-B27-positive patients evaluated, 5 patients were excluded because their uveitis was linked to another disease not associated with HLA-B27 (2 sarcoidosis, 2 juvenile idiopathic arthritis, 1 HLA-A29+); thus, 99 patient records were analyzed.
Data Collection
Every clinic visit was entered into a database. Data included demographic characteristics, ophthalmologic examination results, associated systemic diseases, and medications. Only available data were analyzed. Uveitis was categorized as unilateral in the same eye, unilateral alternating, or bilaterally concomitant. The characteristics of uveitis were analyzed according to definitions of the Standardization of Uveitis Nomenclature (SUN) criteria. For examinations prior to publication of the SUN criteria in 2005, the chart findings were translated into SUN terms for our analyses. Clinical course was described as acute, recurrent, chronic, or indeterminate. Chronic uveitis was defined as persistent inflammation with relapse in <3 months after discontinuing treatment or requiring medications to suppress inflammation for >3 months duration. The entire medical record was reviewed in order to determine chronicity; if a patient initially had recurrent disease and developed chronic disease over the course of follow-up, the patient’s clinical course was recorded as chronic disease. If any medications were required to control inflammation for greater than 3 months, the uveitis was classified as chronic. The only circumstance in which the clinical course was defined as indeterminate was if patients were on corticosteroid-sparing medications at presentation for their systemic disease as well as ocular inflammation and it was not possible to determine whether or not the patients’ inflammation would be controlled without medications. The visual acuity used was the best spectacle-corrected visual acuity from Snellen charts.
The spondyloarthropathies that were included as HLA-B27-associated systemic diseases were anklyosing spondylitis, reactive arthritis, inflammatory bowel disease, psoriatic arthritis, and undifferentiated spondyloarthropathies. The systemic diagnoses were all verified by a rheumatologist. All patients were treated according to the degree of intraocular inflammation using a stepladder corticosteroid-sparing therapeutic algorithm.
Statistical Analysis
For all analyses, including incidence rates of complications and proportional hazard models, only uveitis-affected eyes were included in the analyses. For analysis of vision loss, Snellen fractions were converted into the logarithm of minimal angle of resolution (logMAR). Incidence rates were calculated as the number of events in an affected eye per eye-years at risk. If a patient had a cataract at presentation in only his affected eye or had bilateral cataracts in both of his affected eyes, the patient was no longer at risk; however, if a patient had 1 cataract in only 1 of 2 affected eyes, he or she remained at risk. The Fisher exact and Mann-Whitney tests were used to compare baseline characteristics between groups.
A Cox proportional hazards model was used to analyze risk factors for development of vision loss and complications while accounting for varying lengths of follow-up. The outcomes analyzed were time to development of any incident ocular complication that was not present at baseline or time to development of new vision loss (20/50 or worse and 20/200 or worse). For the analyses of any incident complication, the following were included: posterior iris synechiae, band keratopathy, posterior subcapsular (PSC) cataracts (≥ trace opacity), ocular hypertension (>21 mm Hg), hypotony (<6 mm Hg), cystoid macular edema, and epiretinal membrane. The outcomes of vision loss represented the first time a patient developed vision loss; patients who had vision loss at presentation were excluded. The presence of chronic disease at any time during follow-up, HLA-B27-associated systemic disease, race, and gender were used as binary predictors in the Cox model. We adjusted for duration of uveitis prior to presentation to our clinic because patients may present at varying stages of their disease. In addition, we conducted a sensitivity analysis using staggered entry.
Time-updated variables were used to reflect treatment and inflammation at each visit. The presence of any oral corticosteroid, corticosteroid injections, topical corticosteroid drops, corticosteroid-sparing therapy (including methotrexate, mycophenolate mofetil, cyclosporine, cyclophosphamide, infliximab, adalimumab, etanercept, and sulfasalazine), and grade of inflammation were recorded at each visit and analyzed in the Cox model as time-dependent covariates accounting for variation over the course of follow-up. Updating the variable in the analyses over time accounts for changing treatment. Therefore, overall treatment course is used as a predictor, not just 1 time point (ie, at presentation). Similarly, overall inflammation course was used, not just inflammation at presentation or average inflammation over the patient’s course. The presence of inflammation ≥1+ anterior chamber cells was used as a dichotomous time-dependent covariate in the Cox proportional hazards model. The “robust feature” was used to account for multiple visits per patient. All analyses were performed using Intercooled Stata 9.0 statistical software (Stata Corp, College Station, Texas, USA).
Results
Study Population
Characteristics at presentation are summarized in Table 1 . The patients were 57% (56/99) male and the majority self-identified as Caucasian (75% [73/97]) or East Asian (15% [15/97]). The median age of onset of uveitis was 31 years and the median presenting vision was 0.10 logMAR, or approximately 20/25. The mean follow-up time was 2.1 years, with 53% of patients having at least 6 months of follow-up. Among all 99 HLA-B27 patients, the course was most commonly acute or recurrent (75% [74/99]), followed by chronic (20% [20/99]). The clinical course was defined as indeterminate in 5 patients who were on corticosteroid-sparing medications at presentation for their systemic disease as well as ocular inflammation and for whom it was not possible to determine whether or not the patients’ inflammation would be controlled without medications. Nineteen out of 20 patients classified as having chronic uveitis fulfilled SUN criteria for chronic inflammation at the time of presentation to our clinic. Only 1 patient in the cohort had recurrent disease on presentation and later developed chronic disease. There were no patients who required greater than 3 months of treatment initially who were then able to taper off of all medications successfully.
| n/N a | % | |
|---|---|---|
| Demographics | ||
| Male | 56/99 | 57 |
| Caucasian | 73/97 | 75 |
| East Asian | 15/97 | 15 |
| South Asian | 5/97 | 5 |
| Hispanic | 3/97 | 3 |
| African-American | 3/97 | 3 |
| Native American | 3/97 | 3 |
| Nongranulomatous | 97/99 | 98 |
| Median age of uveitis onset, years (range) | 31 (4–84) | |
| Median presenting logMAR vision b | 0.1 (−.12 to 2.0) | |
| Clinical course c | ||
| Acute | 13/94 | 14 |
| Recurrent | 61/94 | 65 |
| Chronic | 20/94 | 21 |
| Laterality of uveitis d | ||
| Unilateral | 50/96 | 52 |
| Unilateral alternating | 37/96 | 39 |
| Bilateral concomitant | 9/96 | 9 |
| HLA-B27 systemic disease | ||
| Any HLA-B27 disease e | 44/99 | 44 |
| Ankylosing spondylitis | 30/99 | 30 |
| Reactive arthritis | 7/99 | 7 |
| Inflammatory bowel disease | 2/99 | 2 |
| Psoriatic arthritis | 1/99 | 1 |
| Other spondylarthropathy | 6/99 | 6 |
a n/N indicates number/total number of patients assessed.
b Best spectacle-corrected visual acuity at presentation is expressed in logarithm of the minimal angle of resolution (logMAR) in uveitis-affected eyes only.
c Clinical course could not be determined in 5 patients.
d Laterality could not be determined in 3 patients for whom unilateral alternating and bilateral uveitis could not be distinguished.
e Two patients had 2 HLA-B27-associated diseases (1 patient had ankylosing spondylitis and inflammatory bowel disease; 1 patient had ankylosing spondylitis and reactive arthritis).
The proportion of patients with recurrent and chronic inflammation was similar within the group of patients with greater than 6 months of follow-up: recurrent (60% [31/52]) and chronic (31% [16/52]). The largest proportion of HLA-B27 patients had unilateral uveitis (52% [50/96]), followed by unilateral alternating (39% [37/96]) and bilateral concomitant (9% [9/96]). The inflammation was nongranulomatous (98% [97/99]) and anterior (96% [95/99]). Nearly half of the patients had an HLA-B27-associated systemic disease (44% [44/99]), and the most common systemic diseases were ankylosing spondylitis (30% [30/99]) and reactive arthritis (7% [7/99]).
Table 2 compares the characteristics of those HLA-B27 uveitis patients with chronic disease to those without chronic inflammation. The demographic characteristics and the HLA-B27 systemic disease breakdowns were not statistically different between the 2 groups. The patients with chronic disease were more likely to have bilateral disease and there was a trend toward patients with chronic disease having worse baseline visual acuity.
| Acute/Recurrent Patients a (n = 74)% (no) | Chronic HLA-B27 Patients (n = 20 b )% (no) | P Value c | |
|---|---|---|---|
| HLA-B27 systemic disease | |||
| Any HLA-B27 disease | 41 (30) | 50 (10) | .450 |
| Ankylosing spondylitis | 26 (19) | 30 (6) | .700 |
| Reactive arthritis | 4 (3) | 15 (3) | .110 |
| Psoriatic arthritis | 1 (1) | 0 (0) | >0.999 |
| Inflammatory bowel disease | 1 (1) | 5 (1) | .381 |
| Other spondylarthropathy | 6 (5) | 5 (1) | >0.999 |
| Demographics | |||
| Male | 57 (42) | 50 (10) | .592 |
| Caucasian | 78 (56) | 70 (14) | .717 |
| Asian | 18 (13) | 5 (1) | .289 |
| Nongranulomatous | 0 (0) | 10 (2) | .045 |
| Median age of uveitis onset, years (range) | 33 (11–58) | 28 (5–85) | .203 |
| Median presenting logMAR vision (range) | 0.1 (0–1.0) | 0.18 (0–1.9) | .094 |
| Laterality of uveitis | |||
| Unilateral | 51 (38) | 45 (9) | .501 |
| Unilateral alternating | 42 (30) | 30 (6) | .324 |
| Bilateral concomitant | 4 (3) | 25 (5) | .012 |
a Acute/Recurrent includes 13 patients with acute inflammation and 61 patients with recurrent disease. The 5 patients whose clinical course could not be determined were excluded.
b The 20 patients with chronic inflammation include 19 patients who had chronic disease from their first presentation to our clinic and the 1 patient who initially had recurrent disease but developed chronic disease during follow-up.
Of the 148 total affected eyes, the most common ocular complications at presentation were vision loss of 20/50 or worse (26 eyes, 18%), posterior synechiae (25 eyes, 17%), and PSC cataract (20 eyes, 14%). Only 12 eyes (8%) had a visual acuity that was 20/200 or worse at presentation. Nearly a third of patients had received oral corticosteroids (30%) or corticosteroid injections in either eye (26%) prior to presentation at our clinic. Twenty-six patients had been treated with at least 1 corticosteroid-sparing therapy prior to presentation. Ocular inflammation was the driving force for starting corticosteroid-sparing therapy in 23 of these patients. Prior to presentation, the most frequently used corticosteroid-sparing therapies were sulfasalazine (10% [10/99]), methotrexate (9% [9/99]), and etanercept (7% [7/99]).
During follow-up, 41 patients (41% [41/99]) were treated with oral corticosteroids. Additionally, 42 patients (42% [42/99]) received at least 1 corticosteroid-sparing therapy. The most common corticosteroid-sparing therapies were methotrexate (18% [18/99]), sulfasalazine (17% [17/99]), adalimumab (7% [7/99]), and etanercept (7% [7/99]). Twenty-six eyes out of the 148 total affected eyes received at least 1 corticosteroid injection during follow-up.
Incidence of Ocular Complications and Vision Loss
Incidence rates of ocular complications and vision loss are given in Table 3 . The most common complications to develop during follow-up were ocular hypertension and PSC cataracts: the incidence rate of high intraocular pressure (IOP) was 0.10/eye-year (EY) and the rate of development of PSC cataract was 0.09/EY. Development of posterior synechiae (0.05/EY) and vision loss 20/50 or worse during at least 1 visit (0.06/EY) was relatively common in this population. Of the 148 affected eyes, there were 92 eyes at risk for developing vision loss after excluding those patients with 20/50 or worse vision at presentation as well as patients without necessary follow-up time, and 15 of those 92 eyes developed vision loss. Seventy-three percent of those eyes (11/15) that developed vision loss to 20/50 or worse improved to better than 20/50 by last visit. Median time to first improvement was 3 months, although approximately 50% (6/11) eyes that improved had multiple episodes of vision loss, and approximately 20% (2/11) required cataract surgery.
| Event | n/N a | Rate/EY (95% CI) b |
|---|---|---|
| Any ocular complication | 21/53 | 0.224 (0.146–0.344) |
| Elevated intraocular pressure (>21 mm Hg) | 25/102 | 0.102 (0.069–0.151) |
| Posterior subcapsular cataracts (≥ trace opacity) | 20/99 | 0.091 (0.059–0.143) |
| Posterior synechaie | 12/89 | 0.053 (0.030–0.094) |
| Epiretinal membrane | 7/109 | 0.022 (0.011–0.047) |
| Cystoid macular edema | 5/109 | 0.016 (0.007–0.039) |
| Band keratopathy | 3/109 | 0.010 (0.003–0.030) |
| Hypotony (<6 mm Hg) | 2/110 | 0.006 (0.001–0.025) |
| Vision loss 20/50 or worse | 15/92 | 0.062 (0.037–0.102) |
| Vision loss 20/200 or worse | 7/100 | 0.023 (0.011–0.049) |
a n/N indicates number of events/number of eyes at risk.
b Incidence rate is number of events in an affected eye per eye-years at risk.
Other complications such as hypotony, cystoid macular edema, and blindness (20/200 or worse) were more rare. Of the 100 eyes at risk to develop blindness, there were 7 that developed a visual acuity of 20/200 or worse over the course of follow-up. Fifty-seven percent of eyes (4/7) that developed 20/200 or worse vision improved to better than 20/200 by last visit. Median time to first improvement was 5 months, although 75% of the eyes that improved required cataract surgery.
Risk Factors of Visual Acuity Loss and Incident Complications Among Eyes Affected With HLA-B27-Associated Uveitis
Risk factors for vision loss (20/50 or worse) are presented in Table 4 . During the follow-up period, 15 of 92 eyes developed vision loss to 20/50 or worse. In a univariate analysis of risk factors for vision loss, the predictors included duration of uveitis prior to presentation, gender, ethnicity (Caucasian vs other), presence of HLA-B27 systemic disease, posterior synechiae, ocular hypertension, chronic disease course, oral corticosteroids, topical corticosteroids, corticosteroid injections, corticosteroid-sparing therapy, and inflammation. The presence of posterior synechiae at presentation, inflammation during follow-up, oral corticosteroids, corticosteroid injections, and topical corticosteroids were statistically significant risk factors for vision loss. Inflammation during the course of follow-up was associated with an increased risk of developing visual impairment (20/50 or worse) (hazard ratio [HR] = 10.2, P < .0001). Chronic disease course and corticosteroid-sparing therapy were each associated with a nearly 3-fold increased risk of vision loss but did not meet statistical significance (95% confidence interval [CI] = 0.93 to 7.7, P = .07 and CI = 0.93 to 7.8, P = .07, respectively).
