Carmen Stolwijk

Prevalence of extra-articular manifestations in patients with ankylosing spondylitis: a systematic review and meta-analysis

OBJECTIVES Uveitis, psoriasis and inflammatory bowel disease (IBD) are common extra-articular manifestations (EAM) in patients with ankylosing spondylitis (AS); however, summary data of reported prevalence are lacking. The aim of the present study was to summarise the prevalence of EAMs among patients with AS and to identify underlying factors to explain potential heterogeneity of prevalence. METHODS A systematic literature search was performed (Medline, Embase and Cochrane Library) to identify relevant articles. Risk of bias was assessed and data were extracted. Pooled prevalences were calculated. Potential sources of any observed clinical or methodological heterogeneity in the estimates were explored by subgroup and metaregression analysis. RESULTS In the 156 selected articles, 143 reported the prevalence of uveitis (44 372 patients), 56 of psoriasis (27 626 patients) and 69 of IBD (30 410 patients). Substantial heterogeneity was observed in prevalence estimates among all EAMs (I(2)=84-95%). The pooled prevalence of uveitis was 25.8% (95% CI 24.1% to 27.6%), and was positively associated in multivariable metaregression with disease duration (β 0.05, 95% CI 0.03 to 0.08) and random selection of patients (β -0.24, 95% CI -0.43 to -0.04). The pooled prevalence of psoriasis was 9.3% (95% CI 8.1% to 10.6%). The pooled prevalence of IBD was 6.8% (95% CI 6.1% to 7.7%) and was positively associated with the percentage of women in the studies (β 0.02, 95% CI 0.00 to 0.03). Geographical area was associated in multivariable metaregressions with prevalence of all EAMs. CONCLUSIONS EAMs are common in patients with AS. The large heterogeneity between studies can be partly explained by differences in clinical as well as methodological characteristics.

Higher disease activity leads to more structural damage in the spine in ankylosing spondylitis: 12-year longitudinal data from the OASIS cohort

Objectives To analyse the long-term relationship between disease activity and radiographic damage in the spine in patients with ankylosing spondylitis (AS). Methods Patients from the Outcome in AS International Study (OASIS) were followed up for 12 years, with 2-yearly clinical and radiographic assessments. Two readers independently scored the X-rays according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Disease activity measures include the Bath AS Disease Activity Index (BASDAI), AS Disease Activity Index (ASDAS)-C-reactive protein (CRP), CRP, erythrocyte sedimentation rate (ESR), patient’s global assessment and spinal pain. The relationship between disease activity measures and radiographic damage was investigated using longitudinal, autoregressive models with 2-year time lags. Results 184 patients were included (70% males, 83% HLA-B27 positive, mean (SD) age 43 (12) years, 20 (12) years symptom duration). Disease activity measures were significantly longitudinally associated with radiographic progression. Neither medication nor the presence of extra-articular manifestations confounded this relationship. The models with ASDAS as disease activity measure fitted the data better than models with BASDAI, CRP or BASDAI+CRP. An increase of one ASDAS unit led to an increase of 0.72 mSASSS units/2 years. A ‘very high disease activity state’ (ie, ASDAS >3.5) compared with ‘inactive disease’ (ie, ASDAS <1.3) resulted in an additional 2-year progression of 2.31 mSASSS units. The effect of ASDAS on mSASSS was higher in males versus females (0.98 vs −0.06 mSASSS units per ASDAS unit) and in patients with <18 years vs ≥18 years symptom duration (0.84 vs 0.16 mSASSS units per ASDAS unit). Conclusions This is the first study showing that disease activity contributes longitudinally to radiographic progression in the spine in AS. This effect is more pronounced in men and in the earlier phases of the disease.

Evolution of radiographic damage in ankylosing spondylitis: a 12 year prospective follow-up of the OASIS study

Objectives To describe the evolution of radiographic abnormalities of the spine in patients with ankylosing spondylitis (AS). Methods Patients with AS were followed prospectively with 2 yearly radiographs for 12 years. The modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) was scored by two readers (R1 and R2). New syndesmophytes at uninvolved vertebral corners were computed. Radiographic progression was investigated using generalised estimating equations. Results 809 radiographs (presenting 520 at 2 yearly intervals) from 186 patients (70% men, mean age 43 (SD 12) years, mean 20 (SD 12) years since symptom onset and 83% HLA-B27 positive) were included. Mean mSASSS at baseline was 11.6 (16.2). While the course of progression in individual patients was highly variable, and still occurred in patients with decades of symptom duration, mean 2 year progression was 2.0 (3.5) mSASSS units. Over the entire follow-up, at least one new syndesmophyte was found in 55% (R1) and 63% (R2) of patients (38% (R1) and 39% (R2) of all intervals). In 24% of patients (39% of intervals), there was no progression. A progression ≥5 mSASSS units occurred in 22% of patients (or in 12% of intervals). At the group level, a linear time course model fitted the data best, with a constant rate over the entire 12 year interval of 0.98 mSASSS units/year. Radiographic progression occurred significantly faster in men, in HLA-B27 positive patients and in patients with a baseline mSASSS≥10. Conclusions Long term radiographic progression in AS is highly variable in the individual patient, more severe in HLA-B27 positive men and still occurs after decades of disease. At the group level, however, progression in AS follows an approximately linear course.

Epidemiology of Spondyloarthritis

Spondyloarthritis (SpA) represents a group of interrelated diseases with common clinical features and a close association with HLA-B27. Reports of incidence and prevalence of diseases vary depending on methodological differences between studies, the case definition used to classify disease, and the prevalence of HLA-B27 in the population studied. Newly proposed criteria for axial SpA and peripheral SpA present a new approach to facilitate classification of the SpA into 2 main subtypes and the criteria allow earlier detection of patents with inflammatory back pain. These criteria were developed for use in a (specialized) clinical setting and not for large epidemiologic studies.

The global prevalence of spondyloarthritis: A systematic review and meta-regression analysis

To summarize the prevalence of spondyloarthritis (SpA) and its subtypes in the general population, and to identify demographic and methodologic characteristics that might explain heterogeneity in prevalence estimates.

The epidemiology of extra-articular manifestations in ankylosing spondylitis: a population-based matched cohort study

Objective To assess the incidence and risks of common extra-articular manifestations (EAMs), that is, acute anterior uveitis (AAU), psoriasis and inflammatory bowel disease (IBD), in patients with ankylosing spondylitis (AS) compared with population-based controls. Methods All incident patients with AS (n=4101) from the UK Clinical Practice Research Datalink (1987–2012) were matched with up to seven control subjects without AS by year of birth, sex and practice (n=28 591). Incidence rates, cumulative incidence rates and adjusted (adj) HRs for the development of EAMs were calculated, with time-dependent adjustments for age, sex, comorbidity and medication use. Results At diagnosis of AS, the proportion of patients with an EAM was 11.4% for AAU, 4.4% for psoriasis and 3.7% for IBD. Incidence rates of EAMs were 8.9/1000 person-years for AAU, 3.4/1000 person-years for psoriasis and 2.4 /1000 person-years for IBD in AS. The 20-year cumulative incidence was 24.5%, 10.1% and 7.5%, respectively. Risks of EAMs were 1.5-fold to 16-fold increased versus controls, with an adj HR of 15.5 (95% CI 11.6 to 20.7) for AAU, adj HR of 1.5 (95% CI 1.1 to 1.9) for psoriasis and adj HR of 3.3 (95% CI 2.3 to 4.8) for IBD. For psoriasis and IBD, the highest risks were found in the 1st years after diagnosis, while developing AAU continued to be increased also 10 years after diagnosis of AS. Conclusions The risk of, in particular AAU, but also of psoriasis and IBD, is significantly increased in patients with AS compared with controls. Hazard patterns are different for each of the EAMs.

Ankylosing spondylitis and risk of ischaemic heart disease: a population-based cohort study

Objective To investigate the incidence and risk of ischaemic heart disease (IHD) and acute myocardial infarction (AMI), including the role of non-steroidal anti-inflammatory drugs (NSAID), in patients with ankylosing spondylitis (AS) compared with population controls. Methods All patients with newly diagnosed AS (n=3809) from the British Clinical Practice Research Datalink (1987–2012) were matched with up to seven persons without AS by year of birth, gender and practice (n=26 197). Incidence rate ratios (IRR) and HRs for development of IHD and AMI were calculated. Stepwise analyses were performed adjusting for age, gender, comorbidity and drug use, including NSAIDs. Results At baseline, 4.3% of the patients had IHD and 1.8% had AMI compared with 3.4% and 1.4% of the controls, respectively. After exclusion of pre-existing IHD or AMI, the IRRs were 1.18 (95% CI 0.96 to 1.46) and 0.91 (95% CI 0.65 to 1.27) for IHD and AMI, respectively. Compared with controls, the age-gender adjusted HR for developing IHD was 1.20 (95% CI 0.97 to 1.48), and for AMI 0.91 (95% CI 0.65 to 1.28). In female patients, the risk of developing IHD was increased (HR 1.88, 95% CI 1.22 to 2.90), but after adjustment for all possible risk factors only a non-significant trend was found (HR 1.31, 95% CI 0.83 to 2.08). In particular, NSAID use explained this change (HR IHD adjusted for age-gender-NSAID use 1.57, 95% CI 0.99 to 2.48). Conclusions Female patients with AS had an increased age-adjusted risk of developing IHD, but after adjustment for NSAID use only a non-significant trend towards increased risk was found.

Gender-attributable differences in outcome of ankylosing spondylitis: long-term results from the Outcome in Ankylosing Spondylitis International Study

OBJECTIVES To investigate gender-attributable differences regarding clinical outcome [disease activity, physical function and quality of life (QoL)] and radiographic damage in patients with AS over time. METHODS Data from the Outcome in AS International Study were used. Disease activity was assessed by the BASDAI, ASDAS and CRP; physical function by BASFI; QoL by the Short Form-36, Ankylosing Spondylitis Quality of Life (ASQoL) score and European Quality Of Life scale; and radiographic damage by the modified Stoke AS Spine Score (mSASSS). Cross-sectional comparative analyses were done at baseline. Next, separate models were created to assess gender-attributable differences on each outcome measure over time using time-adjusted generalized estimating equations. RESULTS A total of 216 patients [154 (72.3%) males, mean age 43.6 years (s.d. 12.7), symptom duration 20.5 years (s.d. 11.8), mean follow-up duration 8.3 years (s.d. 4.1)] were included. At baseline, male compared with female patients had lower self-reported disease activity (BASDAI 3.2 vs 3.9, P = 0.03) but more radiographic damage (mSASSS 13.8 vs 6.5, P = 0.02). No significant gender-attributable differences in other clinical parameters were found. In multivariable analysis, male gender was significantly associated with a better ASQoL (B = -1.18, 95% CI: -2.17, -0.20, P = 0.02), and in a separate model with a higher mSASSS over time (B = 8.24, 95% CI: 4.38, 12.09, P < 0.01). CONCLUSION In this prospective cohort study, no gender-attributable differences in disease activity or physical function over time were found. However, radiographic damage was more severe in males. Furthermore, males had a better QoL over time.

Lifestyle factors may modify the effect of disease activity on radiographic progression in patients with ankylosing spondylitis: a longitudinal analysis

Objectives To investigate the complex relationship between inflammation, mechanical stress and radiographic progression in patients with ankylosing spondylitis (AS), using job type as a proxy for continuous mechanical stress. Methods Patients from the Outcome in Ankylosing Spondylitis International Study were followed up for 12 years, with 2-yearly assessments. Two readers independently scored the X-rays according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Disease activity was assessed by the AS Disease Activity Score C reactive protein (ASDAS-CRP). The relationship between ASDAS and spinal radiographic progression was investigated with longitudinal analysis, with job type at baseline (physically demanding (‘blue-collar’) versus sedentary (‘white-collar’) labour) as a potential factor influencing this relationship. The effects of smoking status and socioeconomic factors were also investigated. Results In total, 184 patients were included in the analyses (70% males, 83% human leucocyte antigen-B27 positive, 39% smokers, 48% blue-collar workers (65/136 patients in whom data on job type were available)). The relationship between disease activity and radiographic progression was significantly and independently modified by job type: In ‘blue-collar’ workers versus ‘white-collar’ workers, every additional unit of ASDAS resulted in an increase of 1.2 versus 0.2 mSASSS-units/2-years (p=0.014 for the difference between blue-collar and white-collar workers). In smokers versus non-smokers, every additional unit of ASDAS resulted in an increase of 1.9 versus 0.4 mSASSS-units/2-years. Conclusions Physically demanding jobs may amplify the potentiating effects of inflammation on bone formation in AS. Smoking and socioeconomic factors most likely confound this relationship and may have separate effects on bone formation.

Characteristics associated with the presence and development of extra-articular manifestations in ankylosing spondylitis: 12-year results from OASIS

OBJECTIVE The aim of this study was to identify characteristics associated with the presence and development of extra-articular manifestations (EAMs) in a prevalence cohort of patients with AS. METHODS Twelve-year follow-up data from the Outcome in Ankylosing Spondylitis International Study (OASIS) were used. In addition, medical charts were checked for the presence of acute anterior uveitis (AAU), IBD and psoriasis. Demographic, clinical and radiographic characteristics associated with the presence of (any) EAM at baseline or new development during follow-up were identified. RESULTS Two hundred and sixteen patients were included [mean age 43.6 years (s.d. 12.7), 154 (71%) men, mean symptom duration 20.5 years (s.d. 11.7), mean follow-up 8.3 years (s.d. 4.3)]. At baseline, 39 (18%) patients had AAU, 15 (7%) had IBD and 9 (4%) had psoriasis. The history of AAU was univariably associated with increased age [odds ratio (OR) 1.04 (95% CI 1.01, 1.07)], longer symptom duration [OR 1.05 (95% CI 1.02, 1.08)] and more radiographic damage [OR 1.02 (95% CI 1.00, 1.04)]. The history of psoriasis was associated with greater age [OR 1.05 (95% CI 1.00, 1.11)] and lower CRP [OR 0.77 (95% CI 0.59, 1.00)]. At follow-up, 27 patients developed a new EAM. Newly developed IBD was associated with a higher time-varying AS Disease Activity Score [hazard ratio (HR) 2.80 (95% CI 1.43, 5.52)], worse physical function [HR 1.40 (95% CI 1.09, 1.80)] and worse patient global well-being [HR 1.46 (95% CI 1.10, 1.93)]. Newly developed AAU was associated with an elevated time-varying CRP [HR 1.02 (95% CI 1.01, 1.04)]. CONCLUSION Development of EAMs was infrequent in this cohort, despite relatively long follow-up. In particular, markers of disease activity were associated with the development of IBD.