The Paradox of Bone and Beyond: Clinical studies of early Spondylarthropathies

Lems, W.F. [Promotor]Dijkmans, B.A.C. [Copromotor]Horst-Bruinsma, I.E. van der [Copromotor

Bone formation rather than inflammation reflects Ankylosing Spondylitis activity on PET-CT: a pilot study

INTRODUCTION: Positron Emission Tomography - Computer Tomography (PET-CT) is an interesting imaging technique to visualize Ankylosing Spondylitis (AS) activity using specific PET tracers. Previous studies have shown that the PET tracers [(18)F]FDG and [(11)C](R)PK11195 can target inflammation (synovitis) in rheumatoid arthritis (RA) and may therefore be useful in AS. Another interesting tracer for AS is [(18)F]Fluoride, which targets bone formation. In a pilot setting, the potential of PET-CT in imaging AS activity was tested using different tracers, with Magnetic Resonance Imaging (MRI) and conventional radiographs as reference. METHODS: In a stepwise approach different PET tracers were investigated. First, whole body [(18)F]FDG and [(11)C](R)PK11195 PET-CT scans were obtained of ten AS patients fulfilling the modified New York criteria. According to the BASDAI five of these patients had low and five had high disease activity. Secondly, an extra PET-CT scan using [(18)F]Fluoride was made of two additional AS patients with high disease activity. MRI scans of the total spine and sacroiliac joints were performed, and conventional radiographs of the total spine and sacroiliac joints were available for all patients. Scans and radiographs were visually scored by two observers blinded for clinical data. RESULTS: No increased [(18)F]FDG and [(11)C](R)PK11195 uptake was noticed on PET-CT scans of the first 10 patients. In contrast, MRI demonstrated a total of five bone edema lesions in three out of 10 patients. In the two additional AS patients scanned with [(18)F]Fluoride PET-CT, [(18)F]Fluoride depicted 17 regions with increased uptake in both vertebral column and sacroiliac joints. In contrast, [(18)F]FDG depicted only three lesions, with an uptake of five times lower compared to [(18)F]Fluoride, and again no [(11)C](R)PK11195 positive lesions were found. In these two patients, MRI detected nine lesions and six out of nine matched with the anatomical position of [(18)F]Fluoride uptake. Conventional radiographs showed structural bony changes in 11 out of 17 [(18)F]Fluoride PET positive lesions. CONCLUSIONS: Our PET-CT data suggest that AS activity is reflected by bone activity (formation) rather than inflammation. The results also show the potential value of PET-CT for imaging AS activity using the bone tracer [(18)F]Fluoride. In contrast to active RA, inflammation tracers [(18)F]FDG and [(11)C](R)PK11195 appeared to be less useful for AS imaging

Problems in Work Participation and Resource Use Should Not Be Underestimated in Patients with Early Spondyloarthritis

Objective. To explore the effect of early spondyloarthritis (SpA) on worker participation and to investigate variables associated with work outcomes as well as the effect on resource use. Methods. Patients included in an early SpA cohort completed a questionnaire comprising items on employment status, sick leave, presenteeism, and resource use. Logistic regressions were used to investigate the associations between work status and clinical characteristics, and linear regressions were used to investigate the association between at-work productivity loss and clinical characteristics. Resource use across patient groups with different employment status was investigated with linear regression analyses. Results. One hundred forty patients participated in our study. Of the patients, 69% were male, the mean age was 41 years, and the disease duration was 4.8 years. Twenty-six patients (19%) were not employed because of SpA. Among 114 employed patients, sick leave was reported in 28% in the previous year. Forty-one percent of the patients reported reduced productivity at work. Multivariable regression analyses showed that high Bath Ankylosing Spondylitis Metrology Index and Ankylosing Spondylitis Quality of Life score were associated with not being employed and with reduced productivity at work. Annual costs of productivity loss attributable to sick leave and presenteeism amounted to (sic)2000 per patient. Patients who reported sick leave show a higher (health-related) resource use. Conclusion. After only 5 years of diagnosis, a considerable proportion of patients with SpA is not employed, and those working have substantial sick leave and productivity loss. Among patients reporting sick leave, resource use is higher. Alertness to work participation even in patients with a short disease duration is urgently needed

High frequency of vertebral fractures in early spondylarthropathies

Summary We demonstrated that vertebral fractures (VF) are commonly found in early SpA. Patients with VF had lower lumbar BMD than patients without VF. VF remained frequently 'unrecognized' and untreated. VF have been associated with more back pain, reduced Qol, and increased risk of future fractures which stresses the importance of recognition also in early stage SpA. Introduction VF are a common complication of longstanding ankylosing spondylitis (AS). However, data of VF in early AS patients and in other spondylarthropathies (SpA) are scarce. Therefore we examined the prevalence of VF in early SpA patients and investigated the associations between VF and demographic and disease-related variables. Methods SpA patients were included consecutively and radiographs of the spine were made. VF were assessed according to the method of Genant et al.: fractures were defined as reduction of ≫20% of the vertebrae. Descriptive statistics, t-tests and logistic regression analyses were used to study the relationship between VF and demographic and disease-related variables, radiographic damage and BMD. Results A total of 113 early SpA patients were included with a disease duration of 7 months, a mean age of 37 years. Seventeen patients (15%) had at least one VF. Fourteen patients had one VF, three patients had two VF. Most VF were located at Th6-Th8. In patients with VF, bone mineral density (BMD) of lumbar spine was lower than BMD of patients without VF (t-test: p=0.043). Axial Psoriatic Arthritis (PsA) was significantly associated with a higher risk for VF (odds ratio [OR]: 4.62, 95% confidence interval [CI] 1.15-18.58, p=0.031). No significant associations were found with disease activity variables nor with radiographic severity. Conclusion In a group of 113 early, young SpA patients, 15% already had at least one VF. Most VF were asymptomatic, undetected by routine diagnostic procedures and located at the mid-thoracic spine. The VF were associated with low BMD of the lumbar spine and with axial PsA. © International Osteoporosis Foundation and National Osteoporosis Foundation 2012

IL10 GGC haplotype is positively and HLA-DQA1*05-DQB1*02 is negatively associated with radiographic progression in undifferentiated arthritis

Objective. In rheumatoid arthritis (RA), many genetic markers, such as the shared-epitope (SE) alleles, are described in association with radiographic progression, but limited data are available on undifferentiated arthritis (UA). We investigated whether single-nucleotide polymorphisms (SNP) and haplotypes in immune response genes and HLA class II alleles are associated with radiographic progression in patients with early UA. Methods. Progression of radiographic damage was determined in white Dutch patients with early UAafter 2 years of followup. Severe progression was defined as an increase in Sharp/van der Heijde Score ≥ 5 points after 2 years of followup. The remainder was classified as mild. These SNP were genotyped by Taqman technology: tumor necrosis factor (TNF) -1031, -863, -857, -308, -238; lymphotoxin-α (LTA) +368, +252; interleukin 10 (IL10) -2849, -1082, -819; IL1A-889, IL1B -31, +3953; and IL1RN +2018. Carriage of SE alleles and HLA-DQA1*05-DQB1*02 haplotype was established. These markers were analyzed in relation to radiographic progression. Results. Forty-eight out of 151 patients with early UA had severe radiographic progression. Severe radiographic progression was associated with an increased carrier frequency of SE alleles (OR 5.12, 95% CI 2.0-13.1, p < 0.001) and IL10 GGC haplotype (OR 2.8, 95% CI 1.4-5.8, p = 0.003). Mild radiographic progression was associated with the HLA-DQA1*05-DQB1*02 haplotype (OR 0.3, 95% CI, 0.1-0.8, p = 0.013) and with allele TNF -308A (OR 0.4, 95% CI, 0.2-0.9, p = 0.02). Conclusion. The SE and the IL10 GGC haplotype are associated with severe progression of radiographic damage, in contrast to the DQA1*05-DQB1*02 haplotype and the TNF -308A allele, which are associated with mild radiographic progression in early UA. The Journal of Rheumatology Copyright © 2010. All rights reserved

Is Treatment in Patients With Suspected Nonradiographic Axial Spondyloarthritis Effective? Six-Month Results of a Placebo-Controlled Trial

OBJECTIVE: To investigate the efficacy of 16-week treatment with etanercept (ETN) in patients with suspected nonradiographic axial spondyloarthritis (SpA). METHODS: Tumor necrosis factor inhibitor-naive patients with inflammatory back pain with at least 2 SpA features and high disease activity (Bath Ankylosing Spondylitis Disease Activity Index score ≥4), without the requirement of a positive finding on magnetic resonance imaging (MRI) of the sacroiliac (SI) joint and/or elevated C-reactive protein (CRP) level, were randomized (1:1) to receive ETN (n = 40) or placebo (n = 40) for 16 weeks and subsequently were followed up for a further 8 weeks (to 24 weeks from baseline) without study medication. The primary end point was the Assessment of SpondyloArthritis international Society 20 (ASAS20) response at 16 weeks. Secondary end points included the Ankylosing Spondylitis Disease Activity Score (ASDAS) and changes in disease parameters, including the Bath Ankylosing Spondylitis Metrology Index (BASMI), CRP level, erythrocyte sedimentation rate (ESR), and Spondyloarthritis Research Consortium of Canada index scores (MRI of the SI joint), after 16 and 24 weeks. RESULTS: Patient characteristics at baseline were comparable between the ETN and placebo groups. At 16 weeks, there was no significant difference in the percentage of patients exhibiting ASAS20 response between the ETN group (6 patients [16.7%]) and the placebo group (4 patients [11.1%]) (relative risk 0.7 [95% confidence interval 0.2-2.2], P = 0.5). Only the ESR showed more improvement in the ETN group compared to the placebo group at 16 weeks (decreases of 2.2 mm/hour and 1.4 mm/hour, respectively), but the difference did not reach statistical significance. Between 16 and 24 weeks, without study medication, the BASMI, CRP level, and ESR had worsened to a greater extent in the ETN group compared to the placebo group, with the difference being significant for the CRP level. CONCLUSION: This study shows that in patients with suspected nonradiographic axial SpA with high disease activity but without the requirement of a positive finding on SI joint MRI and/or elevated CRP level, treatment with ETN is not effective