I.J. Berg

Efficacy of High Intensity Exercise on Disease Activity and Cardiovascular Risk in Active Axial Spondyloarthritis: A Randomized Controlled Pilot Study

Background Physical therapy is recommended for the management of axial spondyloarthritis (axSpA) and flexibility exercises have traditionally been the main focus. Cardiovascular (CV) diseases are considered as a major health concern in axSpA and there is strong evidence that endurance and strength exercise protects against CV diseases. Therefore, the aim of this study was to investigate the efficacy of high intensity endurance and strength exercise on disease activity and CV health in patients with active axSpA. Methods In a single blinded randomized controlled pilot study the exercise group (EG) performed 12 weeks of endurance and strength exercise while the control group (CG) received treatment as usual. The primary outcome was the Ankylosing Spondylitis (AS) Disease Activity Score (ASDAS). Secondary outcomes included patient reported disease activity (Bath AS Disease Activity Index [BASDAI]), physical function (Bath AS Functional Index [BASFI]), and CV risk factors measured by arterial stiffness (Augmentation Index [Alx]) and Pulse Wave Velocity [PWV]), cardiorespiratory fitness (VO2 peak) and body composition. ANCOVA on the post intervention values with baseline values as covariates was used to assess group differences, and Mann Whitney U-test was used for outcomes with skewed residuals. Results Twenty-eight patients were included and 24 (EG, n = 10, CG, n = 14) completed the study. A mean treatment effect of −0.7 (95%CI: −1.4, 0.1) was seen in ASDAS score. Treatment effects were also observed in secondary outcomes (mean group difference [95%CI]): BASDAI: −2.0 (−3.6, −0.4), BASFI: −1.4 (−2.6, −0.3), arterial stiffness (estimated median group differences [95% CI]): AIx (%): −5.3 (−11.0, −0.5), and for PVW (m/s): −0.3 (−0.7, 0.0), VO2 peak (ml/kg/min) (mean group difference [95%CI]: 3.7 (2.1, 5.2) and trunk fat (%): −1.8 (−3.0, −0.6). No adverse events occurred. Conclusion High intensity exercise improved disease activity and reduced CV risk factors in patients with active axSpA. These effects will be further explored in a larger trial. Trial Registration ClinicalTrials.gov NCT01436942

The Impact of Newer Biological Disease Modifying Anti-Rheumatic Drugs on Cardiovascular Risk Factors: A 12-Month Longitudinal Study in Rheumatoid Arthritis Patients Treated with Rituximab, Abatacept and Tociliziumab

Objectives To assess whether treatment with one of three novel biological DMARDs; rituximab, abatacept or tocilizumab reduce cardiovascular disease (CVD) risk factors in patients with rheumatoid arthritis (RA). Methods This is an open, observational and prospective study with visits at baseline, 3, 6, and 12 months. Patients were assigned to receive rituximab, abatacept or tocilizumab according to clinical indications assessed by an independent rheumatologist. Disease activity was quantified by the disease activity score (DAS28) and extensive ultrasonography. CVD risk was assessed by total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), blood pressure and arterial stiffness measurements [pulse wave velocity (PWV) and augmentation index (AIx)]. Within group change in disease activity and CVD risk over 3 months was explored using paired samples bivariate tests. Predictors of change in CVD risk at 3 months were identified in linear regression models. Changes in CVD risk markers over the 12- month follow-up in patients receiving rituximab were assessed by mixed models repeated analyses. Results 24 patients on rituximab, 5 on abatacept and 7 on tocilizumab were included. At 3 months PWV was significantly reduced in the tocilizumab group only, but at 12 months rituximab patients showed a significant reduction in PWV. Reduced inflammation at 3 months was associated with increased TC and HDL-c in the entire cohort. Conclusion Treatment with tocilizumab and rituximab reduces PWV, a marker of CVD risk, in patients with RA.

Circulating levels of inflammatory cytokines and cytokine receptors in patients with ankylosing spondylitis: a cross-sectional comparative study

Objectives: Insight into the most important inflammatory pathways in ankylosing spondylitis (AS) could be of importance in risk stratification and the development of treatment strategies. Therefore, we aimed to compare circulating levels of inflammatory biomarkers between AS patients and controls, and explore associations between these biomarkers and clinical measures of disease activity. Method: In a cross-sectional study, 143 AS patients were compared with 124 population controls. Blood samples were analysed by immunoassays for interleukin (IL)-6, IL-17a, IL-23, soluble tumour necrosis factor receptor 1 (sTNF-R1) and 2 (sTNF-R2), and osteoprotegerin (OPG). Disease activity was measured by the AS Disease Activity Score (ASDAS) and the Bath AS Disease Activity Index (BASDAI). Results: Analysis of covariance (ANCOVA) demonstrated elevated plasma levels of sTNF-R1 [geometrical mean 0.94 (95% CI 0.88–1.00) vs. 0.83 (95% CI 0.78–0.89) ng/mL, p < 0.01] and OPG (2.3, 95% CI 2.1–2.4 vs. 2.0, 95% CI 1.9–2.2 ng/mL, p = 0.02) and, although not significant, of IL-23 (122, 95% CI 108–139 vs. 106, 95% CI 93–120 pg/mL, p = 0.07) in AS patients vs. controls. More AS patients had a high level of sTNF-R2 than controls (22 vs. 1, p < 0.01). No differences between the groups were seen for IL-6 and IL-17a. In patients, no significant associations were seen between inflammatory markers and disease activity measures after adjusting for personal characteristics. Conclusion: Significantly higher plasma levels of sTNF-R1, sTNF-R2, and OPG and numerically but non-significantly higher levels of IL-23 were found in AS patients compared to controls, indicating that these cytokines and cytokine receptors are important inflammatory pathways. Clinical measures of disease activity were not significantly correlated with circulating inflammatory markers.

CRP and ASDAS are associated with future elevated arterial stiffness, a risk marker of cardiovascular disease, in patients with ankylosing spondylitis: results after 5-year follow-up

Objective To identify factors associated with elevated arterial stiffness in a 5-year follow-up of patients with ankylosing spondylitis (AS). Methods C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), Bath AS disease activity index (BASDAI) and AS disease activity score (ASDAS) were recorded in 2003, and arterial stiffness (Augmentation Index (AIx) and pulse wave velocity (PWV)) in 2008/2009. Patients were grouped into quartiles according to baseline CRP, ESR and BASDAI and four ASDAS groups. Trend analyses were performed using ANCOVA (AIx/PWV as dependent variable) with separate models for CRP, ESR, BASDAI and ASDAS (age and gender adjusted). Independent predictors of future AIx and PWV levels were identified in multivariate linear regression models. Results In total, 85 patients participated. Increasing baseline values of CRP, ESR and ASDAS were associated with elevated AIx on follow-up (p(trend) 0.01, 0.05 and 0.04, respectively). Similar non-significant patterns were seen for PWV. In the multivariate analyses, baseline CRP and ASDAS were independently associated with future elevated AIx (p=0.03 and0.02, respectively). In the multivariate PWV model, results for CRP and ASDAS were non-significant. Conclusions Baseline CRP and ASDAS were associated with future elevated arterial stiffness measured as AIx, supporting that disease activity is related to future risk of cardiovascular disease in patients with AS.

Serum inflammatory biomarkers fail to identify early axial spondyloarthritis: results from the SpondyloArthritis Caught Early (SPACE) cohort

Introduction Decreasing the diagnostic delay in axial spondyloarthritis (axSpA) remains a major challenge. Here, we assessed the value of serum inflammatory biomarkers to distinguish early axSpA from other pathologies in a large cohort of patients referred with early back pain. Methods Serum c reactive protein (CRP), erythrocyte sedimentation rate (ESR) and calprotectin were determined in the SPondyloArthritis Caught Early (SPACE) cohort (n=310), an early back pain inception cohort. Additionally, explorative serum biomarkers derived from the literature (interleukin-27 (IL-27), human β-defensin-2 (hBD-2) and lipcolin-2 (LCN-2)) were determined by ELISA in full-blown patients with ankylosing spondylitis (AS) (n=21) and healthy controls (n=20). Results Serum CRP and ESR levels were not elevated in early axSpA versus ‘control’ back pain patients. Serum calprotectin was elevated in early axSpA versus controls (p=0.01) but failed to identify early axSpA at the individual level (positive predictive value of 38.7%). As to explorative biomarkers, serum levels of IL-27 were not detectable, and hBD-2 and LCN-2 serum levels were not elevated in full-blown AS versus healthy controls (p=0.572, p=0.562, respectively). Therefore, these markers were not further determined in the SPACE cohort. Conclusions None of the candidate serum inflammatory markers were useful as diagnostic markers in the early phase of axSpA.

Uveitis is associated with hypertension and atherosclerosis in patients with ankylosing spondylitis: A cross-sectional study

OBJECTIVES Uveitis is the most common extra-articular manifestation in patients with ankylosing spondylitis (AS), but the literature describing AS patients with a history of uveitis is limited. The objective was to examine if a history of uveitis in patients with AS is associated with increased disease activity and functional impairment and to investigate whether uveitis is associated with an increased frequency of cardiovascular comorbidities, defined here as hypertension and atherosclerosis. METHODS Data were recorded cross-sectionally through patient interviews, blood samples, clinical examination, and questionnaires. Carotid plaques were identified by ultrasonography. AS disease activity and function were compared across categories of uveitis using ANCOVA analyses. Associations between uveitis and hypertension and atherosclerosis [atherosclerotic cardiovascular disease (CVD) and/or carotid plaque] were analyzed in multivariate logistic regression models. RESULTS Of 159 patients with AS (61.6% male, mean age 50.5 years), 84 (52.8%) had experienced one or more episodes of uveitis. AS disease activity was higher in patients with a history of uveitis, statistically significant for functional impairment [Bath AS Functional Index (BASFI)] [mean difference (95% CI)] lnBASFI = 0.2 (0.0-0.3), p = 0.05. Patients with uveitis had an increased odds ratio [OR (95% CI)] for hypertension [3.29 (1.29-8.41), p = 0.01] and atherosclerosis [2.57 (1.15-5.72), p = 0.02]. CONCLUSIONS AS patients with a history of uveitis had non-significantly higher disease activity and significantly higher functional impairment. A history of uveitis was associated with hypertension as well as atherosclerosis. These results may be important in identifying AS patients with elevated risk of CVD but should be confirmed in longitudinal cohorts.

Anti-CD74 antibodies have no diagnostic value in early axial spondyloarthritis: data from the spondyloarthritis caught early (SPACE) cohort

BackgroundAnti-CD74 IgG antibodies are reported to be elevated in patients with axial spondyloarthritis (axSpA). This study assessed the diagnostic value of anti-CD74 antibodies in patients with early axSpA.MethodsAnti-CD74 IgG and IgA antibodies were first measured in an exploratory cohort of patients with radiographic axSpA (138 patients with ankylosing spondyloarthritis (AS)) and 57 healthy controls and then were measured in patients with early axSpA (n = 274) and with non-SpA chronic back pain (CBP) (n = 319), participating in the spondyloarthritis caught early (SPACE) prospective cohort study of patients under 45 years old with early back pain (for ≥ 3 months, but ≤ 2 years).ResultsIn the exploratory cohort, anti-CD74 IgG antibodies were present in 79.7% of patients with AS vs. 43.9% of healthy controls (p < 0.001). Anti-CD74 IgA antibodies were present in 28.5% of patients with AS vs. 5.3% of healthy controls (p < 0.001). In the SPACE cohort, anti-CD74 IgG antibody levels were present in 46.4% of the patients with axSpA vs. 47.9% of the patients with CBP (p = 0.71). Anti-CD74 IgA antibodies were present in 54.7% of the patients with axSpA and 37.0% of the patients with CBP (p < 0.001). This resulted in a positive predictive value of 58.8% (compared to a prior probability of 46.2%) and a negative predictive value of 59.1% (compared to a prior probability of 53.8%). In a regression model, total serum IgA was associated with axSpA odds ratio (OR) 1.19, p < 0.001) whereas anti-CD74 IgA was not (OR) 1.01, p = 0.33). Furthermore, anti-CD74 IgA was associated with sacroiliitis on magnetic resonance imaging (MRI) (OR) = 2.50, p = 0.005) and heel enthesitis (OR) = 2.56, p = 0.002).ConclusionsAlbeit anti-CD74 IgA is elevated in patients with early axSpA, this elevation is not sufficiently specific to yield significant diagnostic value in patients under 45 years old presenting with early back pain.

Presence of multiple spondyloarthritis (SpA) features is important but not sufficient for a diagnosis of axial spondyloarthritis: data from the SPondyloArthritis Caught Early (SPACE) cohort

Objectives Concerns have been raised about overdiagnosis of axial spondyloarthritis (axSpA). We investigated whether patients with chronic back pain (CBP) of short duration and multiple SpA features are always diagnosed with axSpA by the rheumatologist, and to what extent fulfilment of the Assessment of SpondyloArthritis International Society (ASAS) axSpA criteria is associated with an axSpA diagnosis. Methods Baseline data from 500 patients from the SPondyloArthritis Caught Early cohort which includes patients with CBP (≥3 months, ≤2 years, onset <45 years) were analysed. All patients underwent full diagnostic workup including MRI of the sacroiliac joints (MRI-SI) and radiograph of sacroiliac joints (X-SI). For each patient, the total number of SpA features excluding sacroiliac imaging and human leucocyte antigen B27 (HLA-B27) status was calculated. Results Before sacroiliac imaging and HLA-B27 testing, 32% of patients had ≤1 SpA feature, 29% had 2 SpA features, 16% had 3 SpA features and 24% had ≥4 SpA features. A diagnosis of axSpA was made in 250 (50%) of the patients: 24% with ≤1 SpA feature, 43% with 2 SpA features, 62% with 3 SpA features and 85% with ≥4 SpA features. Of the 230 patients with a positive ASAS classification 40 (17.4%) did not have a diagnosis of axSpA. HLA-B27 positivity (OR 5.6; 95% CI 3.7 to 8.3) and any (MRI-SI and/or X-SI) positive imaging (OR 34.3; 95% CI 17.3 to 67.7) were strong determinants of an axSpA diagnosis. Conclusions In this cohort of patients with CBP, neither the presence of numerous SpA features nor fulfilment of the ASAS classification criteria did automatically lead to a diagnosis axSpA. Positive imaging was considered particularly important in making a diagnosis of axSpA.

Is the current ASAS expert definition of a positive family history useful in identifying axial spondyloarthritis? Results from the SPACE and DESIR cohorts

BackgroundThe Assessment of SpondyloArthritis international Society (ASAS) definition of a positive family history (PFH) of spondyloarthritis (SpA) includes the following diseases in first- or second-degree relatives: ankylosing spondylitis (AS), acute anterior uveitis (AAU), reactive arthritis (ReA), inflammatory bowel disease (IBD), and psoriasis. However, it is not known if a PFH for each of these diseases contributes to making a diagnosis of axSpA, sacroiliitis on imaging, or fulfilling the ASAS criteria in patients presenting with chronic back pain (CBP). Therefore, the aim of this study was to assess which SpA diseases in family members are associated with human leukocyte antigen B27 (HLA-B27) and axial spondyloarthritis (axSpA) in CBP patients.MethodsCBP patients suspected of axSpA from the SPACE (n = 438) and the DESIR (n = 647) cohort were asked about the presence of SpA diseases in first- or second-degree relatives (AS, AAU, ReA, IBD, and psoriasis). The associations between a PFH and HLA-B27, sacroiliitis on imaging (magnetic resonance imaging (MRI) or radiographs), axSpA diagnosis, and ASAS classification in CBP patients were assessed.ResultsIn the SPACE and the DESIR cohort, a PFH of AS (odds ratio (OR) 5.9 (95% confidence interval (CI) 3.5–9.9), and OR 3.3 (95% CI 2.1–5.2)) and a PFH of AAU (OR 9.8 (95% CI 3.3–28.9) and OR 21.6 (95% CI 2.9–160.1)) were significantly associated with presence of HLA-B27. Furthermore, in both cohorts a PFH of AS and a PFH of AAU were positively associated with fulfilment of the ASAS criteria, but not with sacroiliitis on imaging. In SPACE but not in DESIR a PFH of AAU was positively associated with axSpA diagnosis. In both cohorts a PFH of ReA, IBD, or psoriasis was not positively associated with HLA-B27 positivity, sacroiliitis on imaging, axSpA diagnosis, or meeting the ASAS criteria for axSpA.ConclusionsIn our cohorts, a PFH of AS or AAU is useful for case-finding of axSpA as this is correlated with HLA-B27 carriership. However, as a PFH of ReA, IBD, or psoriasis does not contribute to identifying axSpA in CBP patients, these data suggest that the widely used ASAS definition of a PFH of SpA should be updated.Trial registrationTrial registration number, NCT01648907. Registered on 20 July 2012.

Frequency of Impaired Spinal Mobility in Patients with Chronic Back Pain Compared to Patients with Early Axial Spondyloarthritis

Objective. To examine the frequency of impaired spinal mobility in patients with chronic back pain of short duration and to compare it with the frequency of impaired spinal mobility in patients with axial spondyloarthritis (axSpA), possible SpA, and no SpA. Methods. The SpondyloArthritis Caught Early (SPACE) cohort includes patients with chronic back pain (≥ 3 mos, ≤ 2 yrs, onset < 45 yrs). Spinal mobility was assessed with lateral spinal flexion, chest expansion, cervical rotation, occiput-to-wall distance, and lumbar flexion. Hip mobility was assessed with intermalleolar distance. Mobility measures were defined as impaired if below the 5th percentile reference curve from general population, adjusted for age and height when appropriate. Proportions of patients categorized with impaired mobility were examined with chi square. Results. In total, 393 patients with chronic back pain were included: 142 axSpA, 140 possible SpA, and 111 no SpA. Impairment in ≥ 1 mobility measure was present in 66% of all patients. The most frequently impaired mobility measure was lateral spinal flexion (40%), followed by chest expansion (22%), cervical rotation (18%), intermalleolar distance (17%), lumbar flexion (15%), and occiput-to-wall distance (11%). No statistically significant differences in proportion of patients with impaired spinal mobility were found between patients with axSpA and the other subgroups in any of the tests. Conclusion. Two out of 3 patients with chronic back pain of short duration had impaired spinal mobility compared to the general population. Impaired spinal mobility occurs as often in patients with early axSpA as in other forms of chronic back pain.