A prospective chohort study on bone formation and bone loss in ankylosing spondylitis

Background and objectives: Patients with ankylosing spondylitis (AS) have an increased risk of bone loss with development of osteoporosis and vertebral fractures (VFs) but also spinal new bone formation with growth of bony spurs (syndesmophytes) between the vertebrae. Measurements of spinal bone mineral density (BMD) by the routine method dual-energy x-ray absorptiometry (DXA) in anteroposterior (AP) projection can be difficult to interpret due to the spinal new bone formation. The general aims of this thesis were to study the development of bone loss and new bone formation over 5 years in patients with AS and to assess factors associated with the changes. Methods: The studies included in this thesis are based on a cohort of patients with AS according to the modified New York criteria recruited from three rheumatology clinics in western Sweden. Patients completed the same protocol at baseline and at the 5-year follow-up with assessment of BMD with DXA at the hip (femoral neck, total hip), the spine (AP, lateral) and total radius and spinal radiographs for grading of AS related spinal alterations and VFs. A group of men were randomized in an age-adjusted algorithm to undergo high-resolution peripheral quantitative computed tomography (HRpQCT) at the ultra-distal radius and tibia for assessment of volumetric BMD (vBMD), cortical area and microarchitecture. Serum hepatocyte growth factor (s-HGF) was analyzed with enzyme-linked immunosorbent assay (ELISA) in the total cohort. Results: Over 5 years, there were significant decreases in femoral neck BMD and tibia vBMD. Decreases were associated with signs of inflammation. In contrast, BMD at the total hip and the spine AP and lateral projections increased. Use of bisphosphonates was associated with increases in BMD at all measured sites except tibia. Use of tumor necrosis factor inhibitors (TNFi) was associated with increases in BMD at AP spine and tibia. Only three patients developed new VFs. AS related spinal alterations increased significantly with higher increases in men compared to women. New predictors identified for spinal radiographic progression were obesity in both sexes and use of bisphosphonates and impaired mobility in women. Among previously known predictors, baseline AS related spinal alterations was shared by sexes, whereas baseline elevated CRP and smoking were predictors in men. The biomarker s-HGF was identified as a novel independent predictor of spinal radiographic progression in men. Conclusion: The studies in this thesis suggest that the best site to assess bone loss in patients with longstanding AS is at the femoral neck and that inflammation has a negative impact on bone loss and development of AS related spinal alterations and thus is an important treatment target. The studies give further reasons to counsel the patients to stop smoking and to encourage obese patients to weight loss. Treatments with bisphosphonates and TNFi had a positive impact on BMD. Further studies are suggested regarding the role of bisphosphonates in relation to spinal radiographic progression and whether s-HGF can be useful as a predictor for spinal radiographic progression

A longitudinal study of fecal calprotectin and the development of inflammatory bowel disease in ankylosing spondylitis

Background: Patients with ankylosing spondylitis (AS) are at increased risk of developing inflammatory bowel disease (IBD). We aimed to determine the variation in fecal calprotectin in AS over 5 years in relation to disease activity and medication and also to study the incidence of and predictors for development of IBD. Methods: Fecal calprotectin was assessed at baseline (n = 204) and at 5-year follow-up (n = 164). The patients answered questionnaires and underwent clinical evaluations. At baseline and at 5-year follow-up, ileocolonoscopy was performed in patients with fecal calprotectin = 500 mg/kg and = 200 mg/kg, respectively. The medical records were checked for diagnoses of IBD during the follow-up period. Results: Fecal calprotectin &gt; 50 mg/kg was found in two-thirds of the patients at both study visits. In 80% of the patients, fecal calprotectin changed by &lt; 200 mg/kg between the two measuring points. Baseline fecal calprotectin was positively correlated with Ankylosing Spondylitis Disease Activity Score based on C-reactive protein, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, C-reactive protein, erythrocyte sedimentation rate, and fecal calprotectin at 5-year follow-up. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with higher fecal calprotectin, and 3-week cessation of NSAIDs resulted in a drop of a median 116 mg/kg in fecal calprotectin. The use of tumor necrosis factor (TNF) blockers was associated with lower fecal calprotectin at both visits, but the users of TNF receptor fusion proteins had significantly higher fecal calprotectin than users of anti-TNF antibodies at 5-year follow-up. The 5-year incidence of Crohn's disease (CD) was 1.5% and was predicted by high fecal calprotectin. Conclusions: Fecal calprotectin was elevated in a majority of the patients and was associated with disease activity and medication at both visits. CD developed in 1.5% of the patients with AS, and a high fecal calprotectin was the main predictor thereof. The results support a link between inflammation in the gut and the musculoskeletal system in AS. We propose that fecal calprotectin may be a potential biomarker to identify patients with AS at risk of developing IBD.CC BY 4.0</p

Physical function and sex differences in radiographic axial spondyloarthritis : a cross-sectional analysis on Bath Ankylosing Spondylitis Functional Index

Background: Physical function is an important determinant of health-related quality of life in radiographic axial spondyloarthritis patients (r-axSpA). To improve the basis of effective healthcare efforts, we aimed to investigate which demographic and disease-related factors that influence Bath Ankylosing Spondylitis Functional Index (BASFI) in r-axSpA patients overall and stratified by sex. Furthermore, we sought to explore differences between sexes regarding separate BASFI questions and also to explore which factors that may contribute to these differences. Methods: This observational cross-sectional study included patients fulfilling the modified New York criteria for Ankylosing Spondylitis. Patients were assessed with 66/68 joint count and Bath Ankylosing Spondylitis Metrology Index (BASMI) measurements. Lateral X-rays were performed for Modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-Reactive Protein (CRP), and BASFI were registered. Multivariable linear regression analyses were used to investigate which factors that associate with BASFI. Results: A total of 353 r-axSpA patients were included, mean age 52.2 ± 12.7 years, 62.3% males. No significant sex difference was seen in BASFI scores (2.7 ± 2.0 in males vs 2.9 ± 2.1 in females). Age, body mass index, ASDAS-CRP, BASMI or mSASSS, fatigue, and tenderness were found to associate independently with BASFI in different models (R 2 0.53–0.63). Investigation of separate BASFI questions revealed that the ability to look over shoulder was worse in males than females (mean 4.43 ± 3.37 vs 3.74 ± 3.06, p = 0.05) and most strongly correlated with mSASSS and BASMI among separate BASFI questions (r = 0.53, p &lt; 0.001; r = 0.62, p &lt; 0.001). The ability to climb stairs was worse in females than males (mean 2.49 ± 2.77 vs 1.54 ± 2.32, p &lt; 0.001). Conclusions: No difference between male and female r-axSpA patients was seen in BASFI despite significant sex differences in BASMI, mSASSS, and CRP levels. Our results underline the impact of fatigue and tenderness on BASFI. The ability to climb stairs without a handrail was scored worse among females compared to males. Furthermore, the ability to look over the shoulder was worse in males than females and closely related to spinal mobility and structural spinal changes

Factors related to health-related quality of life in ankylosing spondylitis, overall and stratified by sex

Background: Ankylosing spondylitis (AS) begins early in life and often leads to reduced physical function, but less is known about the impacts it has on health-related quality of life (HRQoL). The aims of this study were to assess HRQoL using the Short Form-36 (SF-36) in a cohort of patients with AS compared with controls and to examine associations between SF-36 scores and spinal radiographic changes, physical function, disease activity and demographic data overall and stratified by sex. Methods: A cohort of patients with AS from Western Sweden were assessed using the Modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) with spinal radiographs, clinical examination and questionnaires, including the Bath Ankylosing Spondylitis Metrology Index, Bath Ankylosing Spondylitis Functional Index (BASFI), Ankylosing Spondylitis Disease Activity Score-C-reactive protein (ASDAS-CRP), Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Patient Global (BASG) and SF-36. Each patient's SF-36 results were compared with those of five age-matched and sex-matched persons (n=1055) from the SF-36 Swedish normative population database. Associations between SF-36 physical component summary (PCS) and mental component summary (MCS) scores and disease-related and demographic factors were investigated using univariate and multivariable ogistic regression analyses with PCS and MCS below/above their respective median values as dependent variables. Results: A total of 210 patients, age (median, IQR) 49.0 (21.2) years, symptom duration 24.0 (21.0) years, men 57.6% and HLAB27 87.1% were included. Patients with AS scored significantly lower (p&lt;0.001) compared to controls in all SF-36 domains and component summaries; PCS 42.4 (14.5) in AS versus 52.4 (11.8) in controls and MCS 47.9 (20.0) in AS versus 54.1 (10.1) in controls. Both men and women scored significantly lower in PCS compared with MCS. Multivariable logistic regression analyses revealed that living without a partner (OR 2.38, 95% CI 1.00-5.67), long symptom duration (year in decade OR 1.66, 95% CI 1.16-2.37), higher BASFI (OR 1.98, 95% CI 1.46-2.70) and ASDAS 2.1 (OR 3.32, 95% CI 1.45-7.62) were associated with worse PCS, while living without a partner (OR 3.04, 95% CI 1.34-6.91), fatigue (visual analogue scale for global fatigue greater than the median (OR 6.36, 95% CI 3.06-13.19) and ASDAS 2.1 (OR 2.97, 95% CI 1.41-6.25) with worse MCS. Some differences between sexes were observed in the results. Conclusions: The patients with AS had significantly lower HRQoL compared with controls. PCS was more affected compared to MCS in both sexes. Both disease-related and demographic factors were associated with HRQoL, partly overlapping for PCS and MCS. Factors associated with HRQoL showed some differences between sexes. By modifying factors, such as ASDAS-CRP and fatigue, HRQoL may potentially be improved. Trial registration: ClinicalTrials.gov, NCT00858819. Registered on 9 March 2009. Last updated on 28 May 2015

Elevated serum level of hepatocyte growth factor predicts development of new syndesmophytes in men with ankylosing spondylitis

OBJECTIVES: To study baseline serum hepatocyte growth factor (s-HGF) as a predictor of spinal radiographic progression overall and by sex and to analyse factors correlated to changes in s-HGF in patients with AS. METHODS: At baseline and the 5-year follow-up, s-HGF was analysed with ELISA. Spinal radiographs were graded according to modified Stoke Ankylosing Spondylitis Spinal Score. Radiographic progression was defined as ≥2 modified Stoke Ankylosing Spondylitis Spinal Score units/5 years or development of ≥1 syndesmophyte. Logistic regression analyses were used. RESULTS: Of 204 baseline participants, 163 (80%) completed all examinations at the 5-year follow-up (54% men). Baseline s-HGF was significantly higher in men who developed ≥1 syndesmophyte compared with non-progressors, median (interquartile range) baseline s-HGF 1551 (1449-1898) vs 1436 (1200-1569) pg/ml, P = 0.003. The calculated optimal cut-off point for baseline s-HGF ≥1520 pg/ml showed a sensitivity of 70%, a specificity of 69% and univariate odds radio (95% CI) of 5.25 (1.69, 14.10) as predictor of development of ≥1 new syndesmophyte in men. Baseline s-HGF ≥1520 pg/ml remained significantly associated with development of ≥1 new syndesmophyte in men in an analysis adjusted for the baseline variables age, smoking, presence of syndesmophytes and CRP, odds radio 3.97 (1.36, 11.60). In women, no association with HGF and radiographic progression was found. Changes in s-HGF were positively correlated with changes in ESR and CRP. CONCLUSION: In this prospective cohort study elevated s-HGF was shown to be associated with development of new syndesmophytes in men with AS

Occurrence and relative risks for non-vertebral fractures in patients with ankylosing spondylitis compared with the general population : a register-based study from Sweden

OBJECTIVES: To estimate the incidence of non-vertebral fractures in ankylosing spondylitis (AS) compared with the general population. METHODS: Nationwide register-based cohort study including patients with AS (n=11 611, 65% men, mean age 48 years), and matched general population controls (n=58 050). Five prespecified fracture outcomes: (1) non-vertebral; (2) fracture of the proximal humerus, distal forearm or hip; (3) proximal humerus; (4) distal forearm and (5) hip) were identified through register linkages with follow-up 2007-2016. We used Poisson regression to calculate incidence rates (IRs), number of fractures per 1000 person-years at risk and IR ratios (IRRs), overall and by sex and age. IRRs were adjusted for history of any prior fracture. RESULTS: IRs (men/women) for non-vertebral fracture in AS were 11.9 (95% CI 11.0 to 12.9)/14.5 (95% CI 13.1 to 16.1) and in controls 10.0 (95% CI 9.7 to 10.4)/11.8 (95% CI 11.1 to 12.4), IRR (men/women) 1.2 (95% CI 1.1 to 1.3)/1.2 (95% CI 1.1 to 1.4). IRs (men/women) for fractures of the humerus, forearm or hip in AS were 4.0 (95% CI 3.5 to 4.6)/6.3 (95% CI 5.4 to 7.3) and in controls 2.7 (95% CI 2.5 to 2.9)/5.5 (95% CI 5.1 to 6.0), IRR (men/women) 1.5 (95% CI 1.3 to 1.7)/1.1 (95% CI 0.9 to 1.3). IRRs were statistically significantly elevated in men with AS versus controls for forearm fracture (1.4 (95% CI 1.1 to 1.7)) and hip fracture (1.8 (95% CI 1.4 to 2.3)), whereas not in women with AS where the IRRs were 1.1 (95% CI 0.9 to 1.4) and 1.0 (95% CI 0.6 to 1.4). For humerus fracture, IRRs were 1.4 (95% CI 0.99 to 1.9) in men with AS versus controls and 1.1 (95% CI 0.8 to 1.6) in women. CONCLUSIONS: Both men and women with AS have a slightly higher risk of non-vertebral fractures than the general population. A statistically significantly higher risk of fractures of the proximal humerus, distal forearm or hip was found in men with AS in comparison to general population, where the relative risk was especially pronounced for hip fracture

Cardiac conduction disturbances in patients with ankylosing spondylitis : results from a 5-year follow-up cohort study

Objectives: To describe electrocardiographic (ECG) development in patients with ankylosing spondylitis (AS) and identify associations between baseline characteristics and cardiac conduction disturbances (CCD) at 5-year follow-up. Methods: In a longitudinal cohort study, 172 patients (54% men, mean age (SD) of 50 (13) years at baseline) with AS underwent ECG, physical examination, questionnaires and laboratory testing at baseline and at 5-year follow-up. Descriptive statistics and univariate and age- and sex-adjusted logistic regression analyses were used. CCD included both atrioventricular and intraventricular blocks. Results: Twenty-three of the 172 patients (13.4%) had a CCD at follow-up. Eight patients had developed a new CCD and eight had normalised their ECG. In the age- and sex-adjusted analyses, CCD at baseline (OR 24.8, 95% CI 7.3 to 84.5), male sex (OR 6.4, 95% CI 2.0 to 20.8), history of anterior uveitis (OR 4.4, 95% CI 1.3 to 14.5), higher ASDAS-CRP (OR 2.3, 95% CI 1.3 to 4.0), greater waist circumference (OR 1.3, 95% CI 1.1 to 1.6, per 5 cm), and medication with antiplatelets (OR 7.0, 95% CI 1.5 to 31.8) and beta-blockers (OR 3.4, 95% CI 1.0 to 11.5) were associated with a CCD at follow-up. Higher age and longer symptom duration were highly correlated and were both associated with a CCD at follow-up. Conclusions: The presence of CCD in AS is in part dynamic and associated with both AS and non-AS characteristics. Our results suggest that patients especially prone to present with CCDs are older men with a previous CCD, longer symptom duration, higher AS disease activity, a history of anterior uveitis and medication reflecting cardiovascular disease

Additional file 2 of Physical function and sex differences in radiographic axial spondyloarthritis: a cross-sectional analysis on Bath Ankylosing Spondylitis Functional Index

Additional file 2: Supplementary Table 2. Multivariable linear regression analyses exploring factors associated with BASFI QN8 and BASFI QN7. BASMI was used instead of mSASSS in the BASFI QN8 model, mSASSS was used instead of BASMI in the BASFI QN7 model

Additional file 4 of Physical function and sex differences in radiographic axial spondyloarthritis: a cross-sectional analysis on Bath Ankylosing Spondylitis Functional Index

Additional file 4: Supplementary Table 4. Multivariable linear regression models investigating influencing factors of BASFI in two geographically separated cohorts of r-axSpA patients