Validation of the self-administered comorbidity questionnaire adjusted for spondyloarthritis: results from the ASAS-COMOSPA study.

OBJECTIVE: To confirm validity of the Self-administered Comorbidity Questionnaire modified for patients with SpA (mSCQ), and assess whether validity improves when adding items on extra-articular manifestations (EAMs), i.e. uveitis, psoriasis, and IBD, and osteoporosis and fractures. METHODS: Data from the Assessment in SpondyloArthritis international Society COMOrbidities in SPondyloArthritis study were used. Criterion validity of presence of EAMs, osteoporosis and fractures was assessed as agreement (kappa) between patients' self-reported and physician-confirmed disease. Construct validity of the mSCQ including EAMs, osteoporosis and/or fractures (SpA-SCQ) was assessed by testing hypotheses about correlations with demographics, physical function, work ability, health utility and disease activity, and was compared with construct validity of the rheumatic disease comorbidity index. RESULTS: In total, 3984 patients contributed to the analyses. Agreement between patient-reported and physician-reported EAMs was substantial to almost perfect (uveitis ĸ = 0.81, IBD ĸ = 0.73, psoriasis ĸ = 0.86). Agreement for osteoporosis (ĸ = 0.38) and fractures (ĸ = 0.39) was fair. As hypothesized, the mSCQ correlated moderately to weakly with age, physical function, work limitations and health utility, and very weakly with disease activity. In contrast to our hypothesis, adding EAMs, osteoporosis and/or fractures to the mSCQ decreased correlations with several external constructs, especially among patients with peripheral SpA. Correlations with the different constructs were stronger for the both mSCQ and SpA-SCQ (rBASFI = 0.34; rEQ-5D = -0.33) compared with the rheumatic disease comorbidity index (rBASFI = 0.24; rEQ-5D = -0.21). CONCLUSION: The mSCQ is a valid self-report instrument to assess the influence of comorbidities on health outcomes in patients with SpA. Adding EAMs and/or osteoporosis or fractures does not improve validity of the mSCQ.

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.

Which aspects of health are most important for patients with spondyloarthritis? A Best Worst Scaling based on the ASAS Health Index.

OBJECTIVE: The aim was to investigate the importance of aspects of health for patients with axial SpA (axSpA) and to explore differences across different subgroups. METHODS: A Best Worst Scaling exercise was conducted in patients with axSpA from 20 countries (10 patients per country) worldwide. Using the 17 items of the Assessment of SpondyloArthritis international Society Health Index, a set of 17 choice tasks was generated. Patients had to indicate in each choice task the most and least important out of four varying items. The hierarchical Bayes method was used to estimate the relative importance score for each item (summing to 100). Subgroup comparisons were performed for relevant demographic (gender, age, work status, geographical area and education) and disease characteristics (SpA phenotype, disease duration and disease activity) using one-way analysis of variance or the Mann-Whitney U-test. RESULTS: The experiment was completed by 199 patients with axSpA [117 (58.8%) men, mean (sd) age 42.3 (13.6) years, mean (sd) disease duration 11.1 (11.2) years, 130 (65.3%) AS]. The highest relative importance was assigned to pain (14.2; 95% CI: 13.8, 14.6), sleep (10.3; 95% CI: 9.6, 11.0), being exhausted (9.6; 95% CI: 9.0, 10.3), standing (9.25; 95% CI: 8.5, 10.0) and motivation to do anything that requires physical effort (8.7; 95% CI: 8.1, 9.3). The lowest relative importance was assigned to sexual relationships, toileting, contact with people, driving and washing hair. Differences between subgroups were small or in aspects with lower importance. CONCLUSION: A clear gradient was seen in the importance of the different aspects of health that impact functioning of patients with axSpA. Differences between subgroups were small or non-existent. These findings help to align clinical care to patients' needs.

Fluctuations in patient reported disease activity, pain and global being in patients with ankylosing spondylitis.

OBJECTIVE: To evaluate in patients with AS (i) the fluctuation in self-reported disease activity (BASDAI), patient global well-being [visual analogue scale (VAS)-global] and spinal pain (VAS-pain) during 2 years of follow-up on a group level and (ii) the clinical relevance of these fluctuations on a patient level. METHODS: Dutch patients from the Outcome in AS International Study cohort completed patient-reported outcome measures every 2 months over 2 years. On the group level, mixed linear models were used to analyse whether the outcome measures were constant over time. On a patient level, relevant changes in scores were assessed by the frequency in which changes would exceed predefined cut-off values (>1.0 or >2.0 on a 0-10 scale) during the 2 years of follow-up using 2-, 4-, 6-, 12- or 24-month assessments. RESULTS: Ninety patients [median age 47.3 years (sd 11.4), 67.8% male, symptom duration 25.2 years (sd 11.3)] were included. On the group level, the outcome measures remained constant over time. However, large fluctuations were found on the patient level. For example, using 2 month intervals, 92% and 69% of the patients had at least one change of > 1.0 or > 2.0, respectively, in the BASDAI during the 2 year follow-up. When prolonging the interval, the proportion of changes exceeding the cut-off decreased, indicating that information is lost. Similar results were found for the VAS-global and VAS-pain. CONCLUSION: Substantial fluctuations in BASDAI, VAS-global and VAS-pain were found in individuals over time. With longer intervals, fewer fluctuations were observed, indicating that relevant changes might be missed.

Do extra-articular manifestations influence outcome in ankylosing spondylitis? 12-year results from OASIS.

OBJECTIVES: To assess in patients with ankylosing spondylitis (AS) whether extra-articular manifestations (EAMs) are associated with worse functioning, worse quality of life (QoL), and more radiographic damage over time. METHODS: 12-year follow-up data from the Outcome in Ankylosing Spondylitis International Study were used, complemented with data on EAMs extracted from medical charts. Functioning was assessed by the BASFI and physical component of the SF-36, QoL by ASQoL and EuroQoL, and radiographic damage by the mSASSS. Generalised estimating equations analyses were made to assess whether EAMs were associated with these outcomes over time. RESULTS: 216 patients were included (154 (71%) men, mean age 43.6 years (SD 12.7), mean symptom duration 20.5 years (SD 11.7), and mean follow-up 8.3 years (SD 4.3). In total, 58 (26.9%) patients had acute anterior uveitis (AAU), 24 (11.1%) inflammatory bowel disease (IBD), and 14 (6.5%) psoriasis. Univariably, IBD was associated with worse BASFI over time (B=1.26, 95%-CI 0.13 to 2.39, p=0.03), but not in a multivariable model. Furthermore, in a multivariable model, IBD was associated with EuroQoL over time (B=2.93, 95%-CI 0.14 to 5.72, p=0.04). Univariably, psoriasis was associated with radiographic damage (B=-7.25, 95%-CI -14.38 to -0.12, p=0.05) and ASQoL (B= -1.94, 95%-CI -3.32 to -0.57, p<0.01) over time, but not in a multivariable model. AAU was not associated with any outcome over time. CONCLUSIONS: In this longstanding AS cohort, the presence of EAMs was not associated with functional disability, QoL or radiographic damage over time, except for IBD, which was associated with a better EuroQoL.

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.

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.

Aspects of validity of the self-administered comorbidity questionnaire in patients with ankylosing spondylitis.

OBJECTIVES: To evaluate criterion and construct validity of the self-administered comorbidity questionnaire (SCQ) in patients with AS. METHODS: The SCQ and indices of disease activity, physical function, health-related quality of life (HRQoL) and work disability were administered to 98 patients with AS. Criterion validity was assessed by the agreement between the SCQ answers and comorbidities identified in medical records. Construct validity was assessed by correlating the SCQ with the Charlson index and MichaudWolfe index; by correlating the SCQ with demographics, physical function, HRQoL and AS-related disease activity; and by exploring the contribution of comorbidity to these outcomes while adjusting for clinical-demographic characteristics. Furthermore, a modified version of the SCQ (mSCQ) was evaluated for the same aspects of validity, after removing rheumatic conditions. RESULTS: Agreement was moderate to perfect for most conditions (k 0.471.00), except for ulcer disease, depression and OA (k 0.140.15). The correlation between the SCQ and Charlson and MichaudWolfe indices was 0.24 and 0.39 respectively, and between the mSCQ and both indices 0.36 and 0.53. Both SCQ and mSCQ correlated weakly to moderately with age, physical function and HRQoL (0.240.45). The SCQ also correlated weakly with disease activity (0.27) while the mSCQ did not (0.17). In multivariable analysis, both SCQ and mSCQ contributed independently to physical function, HRQoL and work disability, while the MichaudWolfe and Charlson indices did not. CONCLUSION: The SCQ is a promising instrument to determine comorbidities and to understand the impact on health outcomes in patients with AS. Excluding rheumatic conditions from the SCQ (mSCQ) improved validity.

Development of one general and six country-specific algorithms to assess societal health utilities based on ASAS HI.

Objective: Health utilities represent preference values that persons attach to health states. This study aims to develop one general and six country-specific algorithms to calculate societal preference values for health of patients with spondyloarthritis (SpA), as assessed by the disease-specific Assessment of SpondyloArthritis international Society Health Index (ASAS HI). Methods: A survey was performed in random population samples from six European countries. In a best-worst choice experiment, subjects were asked to indicate repeatedly which of 4 random aspects of the 17-item ASAS HI was were most and least important. Bayesian analysis provided the relative importance of each of the 17 items. To rescale the relative importance scores on the absolute utility scale between 0 and 1, participants additionally completed two lead time trade-off experiments, one for 'severe SpA' and one for 'best health' without SpA. Six country-specific algorithms and one general algorithm were derived. The general algorithm was tested in 199 patients with axial SpA (axSpA). Results: 3039 subjects, mean age 47 years (SD 15) and 52% female completed the experiments. The population's health utility value for SpA varied between - 0.24 for 'worst' SpA (country range -0.35 to 0.03), and 0.88 for 'best' health (country range 0.81 to 0.90). Among 199 patients with axSpA, the mean utility was 0.36 (SD 0.30, range -0.24 to 0.88) and discriminated well between patients having high (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4) or low (BASDAI < 4) disease activity (0.18 (SD 0.24) vs 0.51(SD 0.27), p<0.01). Conclusion: One general and six country-specific algorithms are available to convert scores from the ASAS HI into disease-specific societal utility values.

Valuing Treatment With Infliximab for Ankylosing Spondylitis Using a Willingness-to-Pay Approach.

OBJECTIVE: To investigate willingness to pay (WTP) for treatment with infliximab by patients with ankylosing spondylitis (AS) and explore factors associated with WTP. METHODS: Data from 85 patients participating in the European AS Infliximab Cohort (EASIC) open-label extension of the AS Study for the Evaluation of Recombinant Infliximab Therapy (ASSERT) were used. WTP was included at baseline in EASIC and comprised a hypothetical scenario exploring whether the patient would be willing to pay for beneficial effects of infliximab and, if so, what amount they would be willing to pay per administration. Factors associated with WTP were explored using zero-inflated negative binomial (ZINB) regressions. RESULTS: Of the 85 patients, 63 (74.1%) were willing to pay, and among these, the mean amount they were willing to pay per administration was €275 (median €100 [interquartile range €50-200]). Multivariable ZINB analysis showed that Assessment of SpondyloArthritis international Society criteria for 20% improvement (ASAS20) response was associated with a 7-fold lower likelihood to pay 0 euros (odds ratio [OR] 0.14 [95% confidence interval (95% CI) 0.03-0.71]) and a 3-fold increase in the amount willing to pay (exp(ß) = 3.32 [95% CI 1.44-7.69]). In addition, the country of residence was associated with a lower likelihood to pay 0 euros (OR 0.07 [95% CI 0.02-0.36]), while increased age was associated with the amount willing to pay (exp(ß) = 1.05 [95% CI 1.01-1.09]). CONCLUSION: In a hypothetical scenario, three-quarters of patients with AS receiving long-term infliximab stated that they were willing to pay an out-of-pocket contribution for this treatment. Treatment response contributed to the willingness as well as to the amount patients were willing to pay.

Reduction in Spinal Radiographic Progression in Ankylosing Spondylitis Patients Receiving Prolonged Treatment With Tumor Necrosis Factor Inhibitors.

OBJECTIVE: To evaluate the course of spinal radiographic progression for up to 8 years of followup in a large cohort of ankylosing spondylitis (AS) patients treated with tumor necrosis factor (TNF) inhibitors. METHODS: Consecutive patients from the Groningen Leeuwarden AS cohort starting TNF inhibitors between 2004 and 2012 were included. Baseline and biannual radiographs were randomized with radiographs of TNF-naive AS patients and scored in chronologic order according to modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). The course of radiographic progression (linear or nonlinear) was investigated using generalized estimating equations. Primary analysis was performed in patients with complete data over 4, 6, and 8 years of followup. Sensitivity analysis was performed after single linear imputation of missing radiographic data and after adjusting for patient characteristics with possible influence on radiographic progression. RESULTS: At baseline, median mSASSS of 210 included AS patients was 2.8 (interquartile range 0.0-12.0), mean ± SD mSASSS 10.0 ± 15.5. During the first 4 years, radiographic progression followed a linear course (estimated mean progression rate was 1.7 for 0-2 and 2-4 years). A deflection from a linear course was found in patients with complete and imputed data over 6 and 8 years. The estimated mean 2-year progression rate reduced from 2.3 to 0.8 in patients with complete 8-year data. The same pattern was found after adjustment for baseline mSASSS scores, presence of syndesmophytes, sex, HLA-B27 status, age, symptom duration, smoking duration, body mass index, disease activity, and nonsteroidal antiinflammatory drug use. CONCLUSION: This observational cohort study in AS patients receiving long-term TNF inhibitors showed a reduction in spinal radiographic progression after more than 4 years of followup.

Do patients with ankylosing spondylitis adapt to their disease? Evidence from a 'then-test' in patients treated with TNF inhibitors.

OBJECTIVE: To investigate whether patients with ankylosing spondylitis (AS) adapt to their disease, using the 'then-test'. METHODS: Data from patients participating in the AS Study for Evaluation of Recombinant Infliximab Therapy (ASSERT) and continuing in the European AS Infliximab Cohort (EASIC) were used. At 5 assessments in EASIC, patients were asked to rerate their global well-being before the start of infliximab in ASSERT. The patients evaluated their past situation by using a 'then-test' ('retrospective patient global'). Initial and retrospective patient global were compared using a paired t test, and mixed linear models investigated whether the retrospective score of well-being was stable at all follow-up assessments in EASIC. Linear regression analysis explored whether treatment response was associated with the difference between the initial and retrospective score ('gap') while adjusting for possible confounders. RESULTS: 86 patients (mean age 39.8 years (SD=10.4), mean disease duration 10.8 years (SD=8.5)) contributed to the current analyses. At the time of starting infliximab, patients judged their global at 7.0 (SD=1.6), and with the 'then-test' at 7.2 (SD=2.3) (p=0.45). Time elapsed did not influence the 'then-test' (p=0.13). Multivariably, the gap was irrespective of treatment response, but associated with initial patient global (p<0.01) and initial Bath AS Disease Activity Index (p=0.02). CONCLUSIONS: Patients with AS accurately judged their global well-being before starting treatment with tumour necrosis factor inhibition, even though substantial time had elapsed. The difference between initial and retrospective judgment was irrespective of treatment response. In this setting, the 'then-test' could not prove adaptation in AS. TRIAL REGISTRATION NUMBER: NCT01286545.