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Original Articles

Clinical Associations of Uveitis in Axial Spondyloarthritis Group and Ankylosing Spondylitis Group

Do They Represent the Same Disease?

Wong, Oi Man MBBS, FCOphthHK, FHKAM, FRCSEd, MPH*,†; Tsang, Helen Hoi Lun MBBS, MRCP, FHKCP, FHKAM; Chan, Shirley Chiu Wai MBBS, MRCP; Lee, Kam Ho MBBS, FRCR§; Li, Philip Hei MBBS, MRes, MRCP; Lau, Chak Sing MBChB, FRCP, FHKCP, FHKAM; Chung, Ho Yin MBBS, MRCP, FHKCP, FHKAM

Author Information
JCR: Journal of Clinical Rheumatology: January 2020 - Volume 26 - Issue 1 - p 1–6
doi: 10.1097/RHU.0000000000000869
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Abstract

Uveitis is the inflammation of the uvea—the layer of the eye that consists of the iris, ciliary body, and choroid. Being the fifth leading cause of blindness, uveitis accounts for 10% of blindness in the middle-aged group in the Western world.1 Sequelae of uveitis include cataract, glaucoma, and cystoid macular edema, all of which can cause significant visual impairment. More than half of patients with uveitis have disease onset in their third to fourth decade with significant socioeconomic impact.2

Axial spondyloarthritis (SpA) is a spectrum of rheumatic diseases characterized by inflammation of the spine and sacroiliac (SI) joints, of which ankylosing spondylitis (AS) is the prototype and the most deforming subtype. Other subtypes include psoriatic arthritis, inflammatory bowel disease (IBD)–associated SpA, reactive arthritis, and undifferentiated SpA.

Uveitis is one of the most common extra-articular manifestations of SpA,3,4 with variable prevalence in different SpA subtypes.5 A pooled estimate found a prevalence of uveitis of 25.8% in SpA patients, with increasing rates over the lifetime,2 and lifetime prevalence of 33.2% in AS patients.3 Studies of associations between uveitis and AS are abundant6–8 and have consistently found uveitis associated with AS, human leukocyte antigen (HLA) B27 positivity, and male predominance.9,10 The prevalence of HLA-B27 positivity in uveitis patients was found to be in the range of 19% to 88%, depending on ethnicity.11

The 1984 modified New York (MNY) classification criteria for AS12 required definite sacroiliitis on lumbosacral spine radiograph. However, a shortcoming of this criterion is the exclusion of early-stage axial SpA patients before structural damage is radiographically evident.13

More recently, the 2009 Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axial SpA14,15 were developed to enhance early diagnosis.16 Advances in imaging techniques, and genetic criteria, allowed for axial SpA to be diagnosed at an earlier stage. The core criteria consist of sacroiliitis on imaging (magnetic resonance imaging [MRI] or radiograph) or HLA-B27 positivity, with the addition of other specified SpA features. These new classification criteria indubitably lead to further questions of whether common extra-articular manifestations such as uveitis also occurred at similar rates as in AS patients traditionally classified by the MNY criteria.13

The objectives of this study were to determine the prevalence and associated factors of uveitis in Chinese SpA patients using ASAS criteria and in AS defined by MNY criteria.

MATERIALS AND METHODS

This is a multicenter observational cohort from March 2014 to July 2017. The analysis is a cross-sectional design. Data were locked after July 2017.

Patient Recruitment

Two hundred fifty-two axial SpA patients with back pain were consecutively recruited from 3 rheumatology centers (Queen Mary Hospital, Pamela Youde Nethersole Eastern Hospital, and Tseung Kwan O Hospital). The inclusion criteria included (1) being older than 18 years, (2) fulfillment of ASAS classification criteria for axial SpA, (3) back pain of more than 3 months, and (4) able to sign written consent. Exclusion criteria included (1) pregnancy and (2) inability or refusal to undergo MRI examination.

Clinical and Demographic Data

Clinical data were collected from recruited patients. These included age, sex, smoking and drinking history, back pain duration, family history of SpA, history of IBD, psoriasis, sexually transmitted disease, dysentery preceding back pain, and history of enthesitis. Use of disease-modifying antirheumatic drug (DMARD) and steroid was also determined.

All recruited patients were interviewed to determine history of uveitis. The Hospital Authority Clinical Management System, a centralized computer medical records system in the public medical sector, was used to confirm patients' reports of uveitis. All ophthalmology records in the Hospital Authority Clinical Management System were checked. In cases of discrepancy, patients were reinterviewed for clinical clarification.

Physical examinations were performed to determine tender (68 counts) and swollen (66 counts) joint count and Bath Ankylosing Spondylitis Metrology Index (BASMI).17 Recruited patients completed the following self-rated questionnaires: Bath Ankylosing Spondylitis Disease Activity Index (BASDAI),18 Bath Ankylosing Spondylitis Functional Index (BASFI),19 and Bath Ankylosing Spondylitis Global Index (BASGI).20 Blood parameters included HLA-B27, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). Ankylosing Spondylitis Disease Activity Scores21 were calculated using CRP (ASDAS-CRP) and ESR (ASDAS-ESR) to quantify disease activity.

Radiography

Radiographs of the lumbosacral spine (anteroposterior view) were performed in all recruited patients. All radiographs were interpreted by 2 readers (K.H.L., P.H.L.) to grade the severity of sacroiliitis according to the MNY criteria: grade 0, normal; grade 1, suspicious; grade 2, erosion/sclerosis without joint space change; grade 3, sclerosis/erosion with change in joint space or partial ankylosis; and grade 4, complete fusion. Definite sacroiliitis according to the MNY criteria—bilateral grade 2 sacroiliitis or greater or unilateral grade 3 sacroiliitis or greater—was classified as AS. Discrepancies in scoring were resolved by consensus.

Magnetic Resonance Imaging

All recruited patients underwent whole-spine and bilateral SI joint MRI examinations for short tau inversion recovery (STIR) sequence using a 3-T Achieva scanner (Philips Healthcare, Best, the Netherlands). A torso coil was used to image both the spine and SI joints. The technical parameters for STIR images were as follows: repetition time/echo time = 5000/80 milliseconds, field of view = 150 × 240 mm2, matrix size = 152 × 157, slice thickness = 3.5 mm (with no gap). Other imaging parameters were as follows: repetition time/echo time = 4000/90 milliseconds, field of view = 300 × 241 mm2, matrix size = 124 × 100, slice thickness = 4 mm (with no gap), SENSE factor = 2 along the phase-encoding direction, readout bandwidth = 2289 Hz.

Magnetic resonance imaging of SI joints and spine was scored independently by 2 readers (H.Y.C., S.C.W.C.), blinded to clinical data, according to the Spondyloarthritis Research Consortium of Canada magnetic resonance imaging index Inflammation (SPARCC) SI joint and spine scoring method.22,23 Scorings were checked for agreement.

Statistical Analysis

Statistical analysis was performed with IBM SPSS Statistics software version 21 (SPSS Inc., Chicago, IL). Continuous variables were reported as mean and SD. Odds ratios (ORs) were reported with 95% confidence interval (CI). Independent-samples t test and χ2 test were used for comparison of independent continuous variables and categorical data between patients with and without uveitis. Significantly different variables between groups with and without uveitis were identified and analyzed with univariate logistic regression analyses. Independent variables with p < 0.1 were retested in multivariate logistic regression models (enter mode). The 95% CIs were calculated. Agreements between the 2 readers were checked by correlation coefficient. Unless specified, p < 0.05 was considered significant.

Ethics Approval

The study was approved by the institutional review boards of The University of Hong Kong/Hospital Authority Hong Kong west cluster, Pamela Youde Nethersole Eastern Hospital, and Tseung Kwan O Hospital. (institutional review board no. UW 16-252). It was conducted in accordance with the Declaration of Helsinki and the guidance for good clinical practice (November 30, 2006).

RESULTS

Among the 252 axial SpA patients recruited, 163 (64.7%) were classified as AS. Sixty-seven patients (26.6%) had history of uveitis. Forty-five patients (67.2%) had unilateral involvement, and 10 patients (14.9%) had bilateral involvement. The remaining 12 patients (17.9%) had no record on the involved eye. Eight patients (11.9%) had recurrent uveitis, and 47 patients (70.1%) had single uveitis. The other 12 patients (17.9%) had no record on the number of uveitis attack. In the AS group, 40 patients (24.5%) had uveitis. Twenty-seven patients (67.5%) had unilateral involvement, and 6 patients (15.0%) had bilateral involvement. The remaining 7 patients (17.5%) had no record on the involved eye. Five patients (12.5%) had recurrent uveitis, and 28 patients (70.0%) had single uveitis. The other 7 patients (17.5%) had no record on the number of uveitis attack. Sixty-nine patients (27.5%) were using sulfasalazine. Twenty-nine patients (11.5%) were using DMARDs other than sulfasalazine. None of our studied patients were on steroid. Patients with history of uveitis were older, were predominantly male, and had fewer tender joints, less SI joint inflammation, and higher prevalence of IBD. Baseline characteristics of the axial SpA and AS groups are listed in Tables 1, and 2 respectively. In summary, our axial SpA patients were characterized by long disease duration, high disease activity as reflected by BASDAI, and moderate functional impairment by BASFI.

TABLE 1
TABLE 1:
Baseline Characteristics of Axial SpA Patients
TABLE 2
TABLE 2:
Baseline Characteristics of AS Patients

Agreement of SPARCC scores between 2 readers at SI joints (correlation coefficient, 0.909; p < 0.001) and spinal levels (correlation coefficient, 0.899; p < 0.001) was excellent.

Regression Models

In the axial SpA group, univariate analyses showed that age (OR, 1.05; p < 0.01), back pain duration (OR, 1.05; p < 0.01), HLA-B27 positivity (OR, 8.36; p = 0.004), history of IBD (OR, 5.78; p = 0.05), sulfasalazine treatment (OR, 1.05; p = 0.87), DMARD treatment other than sulfasalazine (OR, 0.85, p = 0.73), tender joint count (OR, 0.83; p = 0.03), ESR (OR, 0.99; p = 0.06), CRP (OR, 0.81; p = 0.06), BASGI (OR, 0.86; p = 0.01), ASDAS-ESR (OR, 0.67; p = 0.01), ASDAS-CRP (OR, 0.65; p = 0.01), and SI joint SPARCC score (OR, 0.92; p = 0.02) were associated with uveitis. Details are shown in Table 3.

TABLE 3
TABLE 3:
Univariate Regression Models of Axial SpA Patients

In the AS subgroup, univariate analyses showed that age (OR, 1.04; p = 0.003), male sex (OR, 3.03; p = 0.01), back pain duration (OR, 1.06; p < 0.001), HLA-B27 positivity (OR, 5.58; p = 0.02), sulfasalazine treatment (OR, 1.25; p = 0.58), DMARD treatment other than sulfasalazine (OR, 1.64; p = 0.33), ESR (OR, 0.98; p = 0.05), BASGI (OR, 0.86; p = 0.04), ASDAS-ESR (OR, 0.62; p = 0.01), ASDAS-CRP (OR, 0.64; p = 0.04), SI joint SPARCC score (OR, 0.86; p = 0.05), and spine SPARCC score (OR, 1.03; p = 0.08) were associated with uveitis. Details are shown in Table 4.

TABLE 4
TABLE 4:
Univariate Regression Models of AS Patients

Two models were built up in multivariate analyses of both the axial SpA and AS groups. One used ASDAS-CRP and the other used ASDAS-ESR as an independent variable. As ESR, CRP, and BASGI were collinear with ASDAS, these variables were not included in multivariate regression models.

In the axial SpA group, multivariate analysis using ASDAS-CRP as independent variable showed uveitis was associated with age (OR, 1.05; p = 0.01), HLA-B27 positivity (OR, 11.79; p = 0.01), and history of IBD (OR, 9.74; p = 0.04). Multivariate analysis using ASDAS-ESR as independent variable showed uveitis was associated with age (OR, 1.05; p = 0.004), HLA-B27 positivity (OR, 13.93; p = 0.04), history of IBD (OR, 14.40; p = 0.02), and ASDAS-ESR (OR, 0.54; p = 0.01) (Table 5).

TABLE 5
TABLE 5:
Multivariate Regression Models of Axial SpA

In the AS group, multivariate analysis using ASDAS-CRP as independent variable showed uveitis was associated with back pain duration (OR, 1.05; p = 0.01) and male sex (OR, 3.46; p = 0.03). Multivariate analysis using ASDAS-ESR as independent variable showed uveitis was associated with back pain duration (OR, 1.05; p = 0.01) and ASDAS-ESR (OR, 0.53; p = 0.02) (Table 6).

TABLE 6
TABLE 6:
Multivariate Regression Models of AS Patients

DISCUSSION

The introduction of biologic therapies precipitated the evolution of the traditional concept of AS. Early diagnosis was required for early treatment with more effective biologic therapies, aiming to arrest the progress of pathological new bone formation. To facilitate early diagnosis, the ASAS classification criteria for axial SpA were introduced in 2009,14,15 which included patients without radiological change in the SI joints. It follows that upon incorporating MRI criteria for sacroiliitis the disease spectrum has widened to include a group of patients who will not progress to AS.24 Therefore, previous studies in uveitis-associated factors in AS may be distinct from those in axial SpA. Our data confirm the proposal.

A large meta-analysis showed higher prevalence of uveitis in AS than nonradiographic axial SpA.25 In our study, the prevalence of uveitis was similar in the axial SpA group (26.6%) and the AS group (24.5%). This was lower than the pooled prevalence of 33.2% in AS reported in a previous systematic review.3 This apparent discrepancy may be explained by the influence of disease duration on the development of uveitis. In previous studies, longer duration of disease was associated with higher rates of uveitis, ranging from 24.7% at 10 to 15 years to 43.0% in more than 30 years of disease.3 Considering the mean duration of back pain of 12.3 to 21.9 years in our study, the 24.5% to 26.6% rate of uveitis was consistent with the pooled data in previous studies. Additional supportive evidence in our study was that older age was independently associated with uveitis in the axial SpA group, and longer duration of disease was independently associated with uveitis in the AS group.

Human leukocyte antigen B27 was associated with uveitis in univariate analyses of both the axial SpA and AS groups and in multivariate analysis of the AS group. Similar genetic clustering of SpA and uveitis has been well documented in several epidemiological studies.3,26,27 The genetic effect of HLA-B27 in the axial SpA group may have been diluted by HLA-B27–negative patients with SI joint inflammation. In fact, current evidence suggests the presence of other associated genetic markers such as HLA-B60, HLA-B61, HLA-DR8, HLA-DRB1, MICA,28 and endoplasmic reticulum aminopeptidase 1 in SpA-related uveitis29 that may steer toward a new pathomechanism linking uveitis and SpA.

The male sex predilection among patients having AS-associated uveitis has been reported.4,9,30 Our data also confirmed a positive association between male sex and uveitis in the AS group. However, this was not found in the axial SpA group. Previous study showed uveitis phenotype in psoriatic arthritis and IBD-related SpA may differ from those of AS.31 The former group is more insidious in onset and female predominant.8,31 Our results provide further evidence that SpA-related uveitis could have several pathomechanisms or even different etiologies. As patients in our cohort had long disease duration, our axial SpA patients without radiological SI joint changes were likely representing a distinct group of diseases from AS. This could provide explanation for the observed differences.

The associations of age and duration of back pain with uveitis are intuitive, reflecting cumulative lifetime occurrences and direct effects of disease progression. A large Korean national cohort had also observed the association between age and uveitis.32

However, counterintuitively, the relationship between SpA disease activity and uveitis was not found in our data. Regression analyses showed no association between uveitis and inflammation in MRI of spinal and SI joints. Having said that, the cross-sectional design does not allow us to assess the true relationship with axial joint activity. In the literature, the reported relationship between disease activity and uveitis was inconsistent. A cross-sectional study in Chinese patients found uveitis to be associated with higher disease activity, as reflected by a higher BASDAI score.6 However, a more recent French study failed to show this association.27 It is worth to note that our study is the first one to use MRI to assess axial joint activity.

Lastly, in the axial SpA group, uveitis was associated with IBD. Although an association between IBD and uveitis has been reported in the past,8,31,33 the robustness of our findings was compromised by the relatively small numbers in the IBD-related SpA group. The finding needs larger size studies to confirm.

Our study had several limitations. First, history of uveitis was based on patients' reports and subject to recall bias and underreporting. We were also not able to determine the severity of uveitis. We attempted to limit the bias by crosschecking in the computerized Clinical Management System. Moreover, the presentation of uveitis in IBD was reportedly more insidious and chronic than that in other SpA subtypes, which may result in unintentional underreporting or underdiagnosis.

Second, the small sample size and retrospective nature affected the power of the study in analyzing its relationship with uveitis. This is in particular to the IBD patients, which precludes a full interpretation as stated previously. A prospective study involving both rheumatologic and ophthalmological assessments for the patients, although requiring more resources, would be ideal in acquiring more comprehensive and accurate data.

In conclusion, the prevalence of uveitis in Chinese was found to be 26.6% in SpA and 24.5% in AS. Independent risk factors for uveitis in SpA were older age, HLA-B27 positivity, and history of IBD. Independent risk factors for uveitis in AS were male sex and duration of back pain. Differences in prevalence and associated risk factors of uveitis may indicate that axial SpA defined by ASAS axial SpA criteria is clinically distinct from AS defined by the MNY criteria. Larger size studies should be performed to confirm our findings. Further researches would also be needed to determine the clinical significance and prognosis of uveitis in ASAS criteria–defined axial SpA patients.

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Keywords:

ankylosing spondylitis; ASAS criteria; axial spondyloarthritis; modified New York criteria; uveitis

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