C-reactive protein polymorphisms influence serum CRP-levels independent of disease activity in ankylosing spondylitis.

OBJECTIVES: C-reactive protein (CRP) levels are frequently used to determine disease activity in patients with ankylosing spondylitis (AS), but these levels may not reflect disease activity. We therefore investigated the influence of common single-nucleotide polymorphisms (SNPs) in the CRP gene on CRP levels in AS patients. Additionally, the relation between CRP levels and BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) was examined. METHODS: This exploratory cross-sectional study included 189 Dutch AS patients. CRP SNPs rs2794521, rs3091244, rs1800947 and rs876538 were genotyped and haplotypes constructed. Linear regression analysis was used for the association between SNPs and CRP levels, with correction for confounders non-steroidal anti-inflammatory drugs use, body mass index, smoking, age, gender and disease activity (BASDAI). RESULTS: Only 52% of AS patients with a high disease activity (BASDAI ≥4) showed a high CRP level (≥10mg/L), whereas the others did not. In AS patients, CRP levels changed with different genotypes, with genotype CA of tri-allelic (C>T>A) SNP rs3091244 showing higher CRP levels in comparison with genotype CC (CA: 18.6 mg/L vs. CC: 8.3 mg/L; p=0.02). Carriers of haplotype 5 (tagged by allele A of rs3091244) had a higher risk to express a CRP ≥10 mg/L (OR=2.9, 95%CI 1.0-8.3; p=0.05) when compared with non-carriers. CONCLUSIONS: In AS, patients with high disease activity often do not show corresponding high CRP levels. We found that CRP levels vary with different CRP genotype in AS patients. Carrying distinct genetic variants might play a role in certain AS patients who show low CRP levels despite high disease activity (as well as high CRP levels with low disease activity). This observation may be important for the interpretation of disease activity scores that incorporate CRP levels, like the ASDAS.

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.

Presence of active MRI lesions in patients suspected of non-radiographic axial spondyloarthritis with high disease activity and chance at conversion after a 6-month follow-up period.

OBJECTIVES: The primary aim is to evaluate signs of inflammation on MRI of sacroiliac joints (SIJ)/spine in inflammatory back pain (IBP) patients suspected of nr-axSpA with high disease activity. Secondary aims are to describe the onset of new inflammatory lesions at MRI after 6 months and to evaluate gender differences in the presence of inflammation. METHOD: Consecutively, patients with IBP with at least two spondyloarthritis features, high disease activity (BASDAI ≥ 4), and who were TNFi naïve, had a MRI of SIJ and spine. In the absence of active lesions, MRI was repeated after 6 months. MRI images were scored according to the Spondyloarthritis Research Consortium of Canada method. RESULTS: Sixty-nine patients were included (53% female), of whom 39% showed signs of inflammation at the first MRI: 30.9% of the SIJ, 19.1% of the spine and 2.4% at both sites, irrespective of the CRP levels. Males more often showed inflammatory signs at the MRI of the SIJ and spine compared with females (45.5% vs. 33.3%). Consistently, the median SPARCC score was higher in males: for SIJ 14.0 (IQR 2.3-25.0) and for spine 11.5 (IQR 8.5-25.6). Only one patient (4.7%) without baseline inflammatory signs showed active lesions of SIJ after 6 months. CONCLUSIONS: Almost 40% of the IBP patients suspected of nr-axSpA, with high disease activity, showed inflammatory lesions on MRI of SIJ and/or spine, which occurred more often in males compared with females. In the majority (95.3%), an MRI without inflammatory lesions remained negative after 6 months despite high disease activity.Key Points• Forty percent of inflammatory back pain patients with high disease activity showed inflammatory signs on MRI of the SIJ and/or spine.• Only 4% of baseline MRIs without inflammatory signs at baseline conversed to an MRI with inflammatory signs after 6 months.• Male inflammatory back pain patients with high disease activity showed more often inflammatory signs on MRI compared with females.

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 [18F]FDG and [11C](R)PK11195 can target inflammation (synovitis) in rheumatoid arthritis (RA) and may therefore be useful in AS. Another interesting tracer for AS is [18F]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 [18F]FDG and [11C](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 [18F]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 [18F]FDG and [11C](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 [18F]Fluoride PET-CT, [18F]Fluoride depicted 17 regions with increased uptake in both vertebral column and sacroiliac joints. In contrast, [18F]FDG depicted only three lesions, with an uptake of five times lower compared to [18F]Fluoride, and again no [11C](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 [18F]Fluoride uptake. Conventional radiographs showed structural bony changes in 11 out of 17 [18F]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 [18F]Fluoride. In contrast to active RA, inflammation tracers [18F]FDG and [11C](R)PK11195 appeared to be less useful for AS imaging.

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 UA after 2 years of followup. Severe progression was defined as an increase in Sharp/van der Heijde Score > or = 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-alpha (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.