Eva Klingberg

Osteoporosis in ankylosing spondylitis - prevalence, risk factors and methods of assessment

IntroductionOsteoporosis can be a complication of ankylosing spondylitis (AS), but diagnosing spinal osteoporosis can be difficult since pathologic new bone formation interferes with the assessment of the bone mineral density (BMD). The aims of the current study were to investigate prevalence and risk factors for reduced BMD in a Swedish cohort of AS patients, and to examine how progressive ankylosis influences BMD with the use of dual-energy x-ray absorptiometry (DXA) of the lumbar spine in different projections.MethodsMethods of assessment were questionnaires, back mobility tests, blood samples, lateral spine radiographs for syndesmophyte grading (mSASSS), DXA of the hip, radius and lumbar spine in anteroposterior (AP) and lateral projections with estimation of volumetric BMD (vBMD).ResultsAS patients (modified New York criteria), 87 women and 117 men, mean age 50 ± 13 years and disease duration 15 ± 11 years were included. According to World Health Organization (WHO) criteria 21% osteoporosis and 44% osteopenia was diagnosed in patients > = 50 years. Under age 50 BMD below expected range for age was found in 5%. Interestingly lateral lumbar DXA showed significantly lower BMD and revealed significantly more cases with osteoporosis as compared with AP DXA. Lumbar vBMD was not different between sexes, but women had significantly more lumbar osteoporosis measured with AP DXA (P < 0.001). Men had significantly higher mSASSS (P < 0.001). Low BMD was associated with high age, disease duration, mSASSS, Bath Ankylosing Spondylitis Metrology Index (BASMI), inflammatory parameters and low body mass index (BMI). Increasing mSASSS correlated significantly with decreasing lateral and volumetric lumbar BMD, while AP lumbar BMD showed tendency to increase.ConclusionsOsteoporosis and osteopenia is common in AS and associated with high disease burden. Lateral and volumetric lumbar DXA are more sensitive than AP DXA in detecting osteoporosis and are less affected by syndesmophyte formation.

Vertebral Fractures in Ankylosing Spondylitis Are Associated with Lower Bone Mineral Density in Both Central and Peripheral Skeleton

Objective. To study the prevalence and risk factors for vertebral fractures (VF) in ankylosing spondylitis (AS) and the relation between VF, measures of disease activity, and bone mineral density (BMD) in different measurement sites. Methods. Patients with AS (modified New York criteria) underwent examination, answered questionnaires, and gave blood samples. Lateral spine radiographs were scored for VF (Genant score) and syndesmophyte formation through modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). BMD was measured with dual-energy x-ray absorptiometry in the hip, radius, and lumbar spine in anteroposterior and lateral projections with estimation of volumetric BMD (vBMD). Results. Two hundred four patients (57% men) with a mean age of 50 ± 13 years and disease duration 15 ± 11 years were included. VF were diagnosed in 24 patients (12%), but were previously noted clinically in only 3 of the 24. Patients with VF were significantly older (p = 0.004), had longer disease duration (p = 0.011), higher Bath Ankylosing Spondylitis Metrology Index (p = 0.011), mSASSS (p = 0.035), and Bath Ankylosing Spondylitis patient global score-2 (BASG-2) (p = 0.032) and were more often smokers (p = 0.032). All women with a VF were postmenopausal. BMD was significantly lower at all measuring sites in the patients with VF. In logistic regression, high BASG-2, low BMD in femoral neck, and low lumbar vBMD were independently associated with presence of VF. Conclusion. VF in AS are common but are often not diagnosed. VF are associated with advanced age, longstanding disease, impaired back mobility, syndesmophyte formation, and lower BMD in both the central and peripheral skeleton. BMD in the femoral neck, total hip, and estimated vBMD showed the strongest association with VF.

Bone microarchitecture in ankylosing spondylitis and the association with bone mineral density, fractures, and syndesmophytes

IntroductionOsteoporosis of the axial skeleton is a known complication of ankylosing spondylitis (AS), but bone loss affecting the peripheral skeleton is less studied. This study on volumetric bone mineral density (vBMD) and bone microarchitecture in AS was conducted to compare peripheral vBMD in AS patients with that in healthy controls, to study vBMD in axial compared with peripheral bone, and to explore the relation between vertebral fractures, spinal osteoproliferation, and peripheral bone microarchitecture and density.MethodsHigh-resolution peripheral quantitative computed tomography (HRpQCT) of ultradistal radius and tibia and QCT and dual-energy x-ray absorptiometry (DXA) of lumbar spine were performed in 69 male AS patients (NY criteria). Spinal radiographs were assessed for vertebral fractures and syndesmophyte formation (mSASSS). The HRpQCT measurements were compared with the measurements of healthy controls.ResultsThe AS patients had lower cortical vBMD in radius (P = 0.004) and lower trabecular vBMD in tibia (P = 0.033), than did the controls. Strong correlations were found between trabecular vBMD in lumbar spine, radius (rS = 0.762; P < 0.001), and tibia (rS = 0.712; P < 0.001).When compared with age-matched AS controls, patients with vertebral fractures had lower lumbar cortical vBMD (-22%; P = 0.019), lower cortical cross-sectional area in radius (-28.3%; P = 0.001) and tibia (-24.0%; P = 0.013), and thinner cortical bone in radius (-28.3%; P = 0.001) and tibia (-26.9%; P = 0.016).mSASSS correlated negatively with trabecular vBMD in lumbar spine (rS = -0.620; P < 0.001), radius (rS = -0.400; p = 0.001) and tibia (rS = -0.475; p < 0.001) and also with trabecular thickness in radius (rS = -0.528; P < 0.001) and tibia (rS = -0.488; P < 0.001).Adjusted for age, syndesmophytes were significantly associated with decreasing trabecular vBMD, but increasing cortical vBMD in lumbar spine, but not with increasing cortical thickness or density in peripheral bone. Estimated lumbar vBMD by DXA correlated with trabecular vBMD measured by QCT (rS = 0.636; P < 0.001).ConclusionsLumbar osteoporosis, syndesmophytes, and vertebral fractures were associated with both lower vBMD and deteriorated microarchitecture in peripheral bone. The results indicate that trabecular bone loss is general, whereas osteoproliferation is local in AS.

Biomarkers of Bone Metabolism in Ankylosing Spondylitis in Relation to Osteoproliferation and Osteoporosis

Objective. To identify biomarkers for bone metabolism in patients with ankylosing spondylitis (AS) and to determine the relationship between these biomarkers and disease activity, back mobility, osteoproliferation, and bone mineral density (BMD). Methods. Serum levels of Wingless protein (Wnt-3a), Dickkopf-1 (DKK-1), sclerostin, soluble receptor activator of nuclear factor-κB ligand (sRANKL), and osteoprotegerin were assessed using ELISA. Ankylosing Spondylitis Disease Activity Score-C reactive protein, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis patient global score, and C-reactive protein (CRP) were used as disease activity measures, and Bath Ankylosing Spondylitis Metrology Index (BASMI) as a measure of spinal mobility. Lateral spine radiographs were scored for chronic AS-related changes (mSASSS). BMD was measured with dual-energy x-ray absorptiometry. Results. Two hundred four patients with AS (NY criteria; 57% men), with a mean age of 50 ± 13 years and disease duration 15 ± 11 years, and 80 age and sex-matched controls were included. The patients with AS had significantly higher serum levels of Wnt-3a (p < 0.001) and lower levels of sclerostin (p = 0.014) and sRANKL (p = 0.047) compared with the controls. High CRP was associated with low sclerostin (rS = −0.21, p = 0.003) and DKK-1 (rS = −0.14, p = 0.045). In multiple linear regression analyses, increasing BASMI and mSASSS were independently associated with older age, male sex, high CRP, and elevated serum levels of Wnt-3a. In addition, mSASSS remained associated with a high number of smoking pack-years after adjusting for age. Low BMD of femoral neck was associated with high mSASSS after adjusting for age. Conclusion. Serum levels of Wnt-3a are elevated in AS and associated with increased BASMI and mSASSS, independent of age, indicating that Wnt-3a could be a biomarker for the osteoproliferative process.

Calprotectin in ankylosing spondylitis--frequently elevated in feces, but normal in serum.

Abstract Objectives. To investigate indirectly the prevalence of intestinal inflammation in ankylosing spondylitis (AS) patients by assessing the levels of fecal calprotectin, to study levels of serum calprotectin in AS, and to correlate the concentrations of calprotectin in feces and serum with reported gastrointestinal symptoms, medication, and measures of disease activity. Methods. All patients fulfilling the Modified New York criteria of AS at the study centers were invited to participate. The patients answered questionnaires concerning medication, symptoms, and disease activity. Physical examination was performed, including back mobility tests. Samples of stools and blood were collected and analyzed for fecal and serum calprotectin. Results. Elevated levels of fecal calprotectin (>50 mg/kg) was found in 140 of 205 AS patients (68%). Levels of fecal calprotectin were associated with increasing age, disease duration, ESR, CRP, and serum calprotectin, but not with gastrointestinal symptoms. Fecal calprotectin was higher in patients using NSAIDs, salicylates, and proton pump inhibitors, but lower in patients using methotrexate and infliximab. Serum calprotectin levels were normal or low in 98% of AS patients and not different from the levels in healthy blood donors. Serum calprotectin levels were positively associated with ESR, CRP, WBC, and PLT. Conclusions. Two-thirds of AS patients had elevated levels of fecal calprotectin, without associated gastrointestinal symptoms. Serum calprotectin was mostly normal in AS, in contrast to various other inflammatory rheumatic diseases. We suggest that fecal calprotectin may be a marker for subclinical intestinal inflammation in AS and should be measured after stopping NSAIDs, but further endoscopic studies are needed.

Genetic variants in CARD8 but not in NLRP3 are associated with ankylosing spondylitis.

Objectives: The NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome is important for interleukin-1beta (IL-1β) processing as part of an innate immune response. Caspase recruitment domain family, member 8 (CARD8) is an inhibitor of nuclear factor kappa B (NF-κB) and possibly also a part of the NLRP3 inflammasome. The objective of this study was to evaluate one single nucleotide polymorphism (SNP) in CARD8 and three SNPs in NLRP3 in ankylosing spondylitis (AS) susceptibility and disease phenotype. Method: We recruited 492 AS patients from Southern Sweden fulfilling the modified New York criteria for AS, and assessed phenotypic characteristics from medical records and questionnaires. Patients with psoriasis or clinically overt inflammatory bowel disease (IBD) were excluded, as were patients without human leucocyte antigen B27 (HLA-B27). Three NLRP3 SNPs (rs35829419, rs4353135, and rs10733113) and one SNP in CARD8 (rs2043211) were genotyped by commercially available TaqMan assays, and the results compared at genotype and allele levels to those of 793 population-based controls. In a subgroup of the patients (n = 169), faecal calprotectin was assessed as a marker of subclinical intestinal inflammation. Results: The minor allele (A) of CARD8-C10X (rs2043211) was associated with a decreased risk of AS in a dominant model [odds ratio (OR) 0.74, 95% confidence interval (CI) 0.54–0.94, p = 0.012] and at the allelic level (OR 0.81, 95% CI 0.68–0.97, p = 0.02), but was not associated with levels of faecal calprotectin. There was no association regarding NLRP3 SNPs and AS susceptibility, and none of the investigated SNPs were associated with iritis, anti-tumour necrosis factor (anti-TNF) therapy, or peripheral joint involvement. Conclusion: In a Swedish population, the minor allele of CARD8-C10X is associated with a decreased risk of AS, but not with levels of faecal calprotectin or disease phenotype.

Aortic Regurgitation Is Common in Ankylosing Spondylitis: Time for Routine Echocardiography Evaluation?

OBJECTIVES The aim of this study was to assess the prevalence of aortic regurgitation and any relation to disease activity and specific human leukocyte antigen (HLA)-B27 subtypes in patients with ankylosing spondylitis. METHODS Transthoracic echocardiography was performed in 187 patients (105 men), mean age (SD) 50 (13) years, and mean disease duration 24 (13) years, and was related to demographic, clinical, radiographic, electrocardiographic, and laboratory data. RESULTS Aortic regurgitation was found in 34 patients (18%; 95% confidence interval [CI], 12%-24%): mild in 24, moderate in 9, and severe in one. The prevalence was significantly higher than expected from population data. Conduction system abnormalities were documented in 25 patients (13%; 95% CI, 8%-18%), and significantly more likely in the presence of aortic regurgitation (P = .005), which was related to increasing age and longstanding disease, and increased from ~20% in the 50s to 55% in the 70s. It was also independently associated with disease duration, with higher modified Stoke Ankylosing Spondylitis Spine Score, and with a history of anterior uveitis. HLA-B27 was present in similar proportions in the presence vs absence of aortic regurgitation. For comparison, clinically significant coronary artery disease was present in 9 patients (5%; 95% CI, 2%-8%). CONCLUSION Patients with ankylosing spondylitis frequently have cardiac abnormalities, but they more often consist of disease-related aortic regurgitation or conduction system abnormalities than manifestations of atherosclerotic heart disease. Because aortic regurgitation or conduction abnormalities might cause insidious symptoms not easily interpreted as of cardiac origin, we suggest that both electrocardiography and echocardiography evaluation should be part of the routine management of patients with ankylosing spondylitis.

The use of complementary and alternative medicine in outpatients with inflammatory rheumatic diseases in Sweden

Objectives: To study the use of complementary and alternative medicine (CAM) drugs and methods in patients with inflammatory rheumatic diseases, at rheumatology clinics in western Sweden, and to investigate possible associations between CAM-using habits and other characteristics of the patients. Methods: Randomly selected rheumatology outpatients were asked to complete questionnaires about CAM usage, diagnoses, medication, quality of life (using the 36-item Short Form Health Survey, SF-36), fatigue (using the 20-item Multiple Fatigue Inventory, MFI-20), the Health Assessment Questionnaire (HAQ), and visual analogue scales (VAS) for global health, pain, and fatigue. Result: A total of 200 patients were included, 137 women and 63 men, mean age 55±16 and 54±15 years, respectively. Ongoing CAM use was reported by 58 patients (29%): 45 (22.5%) were taking CAM drugs, 20 (10%) were using CAM methods. Altogether 130 patients (65%) had used CAM at some time of their lives; 103 patients (51%) had used CAM drugs ever and 90 patients (45%) had used CAM methods ever. Women used more CAM drugs compared with men. Younger patients used more CAM. CAM use was associated with parameters indicating poorer health, mental component score (MCS) and physical component score (PCS) of SF-36, and VAS for global health and fatigue. Ongoing CAM method was associated with less use of immunomodulatory drugs. Conclusion: CAM use is widespread among rheumatology patients in Sweden. A total of 65% of the patients had experience of CAM treatment. Female sex, younger age, and poor health were associated with CAM utilization.

Prevalence of diastolic dysfunction in patients with ankylosing spondylitis : a cross-sectional study

Objectives: To determine the prevalence of diastolic dysfunction (DD) in patients with ankylosing spondylitis (AS) by following recommended criteria from the American Society of Echocardiography (ASE) and using single variables reflecting DD. Method: A total of 187 patients with AS (105 men; mean age 51 ± 13 years; mean duration of disease 15 ± 11 years) fulfilled the inclusion criteria and underwent pulsed-wave and tissue Doppler imaging. Results: By following ASE recommended criteria, we observed that 12% of patients with AS had mild DD. We also compared single standard Doppler values with normal age-stratified reference values and showed a wide variation in the number of patients with AS outside the 95% confidence interval (CI) of normal values depending on the variable chosen (ranging from 1.1% to 30.5%). Conclusions: By following recommended criteria, our cross-sectional study shows that DD was infrequent and mild in patients with AS.

The variation in free 25-hydroxy vitamin D and vitamin D binding protein with season and vitamin D status

Purpose Serum 25-hydroxy vitamin D [25(OH)D] varies greatly with season at northern latitudes. The purpose of this study was to determine if the seasonal variations in serum total 25(OH)D are followed by a concomitant variation in free 25(OH)D or if the variation is damped by alterations in the binding capacity of DBP. Methods Serum was collected from 540 healthy blood donors (60% men; mean age 41 ± 13 years) during 12 months and analyzed for total 25(OH)D, directly measured free 25(OH)D, vitamin D-binding protein (DBP) and albumin. Calculated free 25(OH)D was estimated. Results The UV-B radiation during the sampling month was positively correlated with the serum levels of total 25(OH)D (r = 0.355, P < 0.001), directly measured free (r = 0.336, P < 0.001) and calculated free 25(OH)D (r = 0.275, P < 0.001), but not with DBP and albumin. The percentage of free 25(OH)D was higher during the winter months than that during the summer months (0.020 ± 0.005% vs 0.019 ± 0.004%; P = 0.007) and higher in participants with a serum 25(OH)D below 25 nmol/L than that in participants with a serum 25(OH)D above 75 nmol/L (0.031 ± 0.007% vs 0.017 ± 0.003%; P < 0.001). iPTH was correlated with directly measured free 25(OH)D (r = −0.226; P < 0.001), but only weakly with calculated free 25(OH)D (r = −0.095; P = 0.027). Conclusions Directly measured free serum 25(OH)D was highly correlated with total serum 25(OH)D and followed the same seasonal variation, whereas the serum concentrations of DBP and albumin were stable. The fluctuation in free 25(OH)D was only marginally damped with an increase in the percentage of free 25(OH)D during the winter months and in participants with vitamin D deficiency.