Detection of bone erosions in rheumatoid arthritis wrist joints with magnetic resonance imaging, computed tomography and radiography

Background

The objectives of the present study were, with multidetector computed tomography (CT) as the reference method, to determine the performance of magnetic resonance imaging (MRI) and radiography for the detection of bone erosions in rheumatoid arthritis wrist bones, and to test whether measuring volumes of erosions on CT and MRI is reproducible and correlated to semiquantitative assessments (scores) of erosions on CT, MRI and radiography.

Methods

Seventeen patients with rheumatoid arthritis and four healthy control individuals underwent CT, MRI and radiography of one wrist, performed on the same day. CT was performed on a Philips Mx8000IDT unit (voxel size 0.4 mm × 0.4 mm × 1 mm) and MRI was performed on a Philips Panorama 0.6T unit (voxel size 0.4 mm × 0.4 mm × 0.4 mm). Images were evaluated separately for erosions in all wrist bones and were scored according to the principles of the Outcome Measures in Rheumatology Rheumatoid Arthritis MRI Scoring System (CT and MRI) and the Sharp/van der Heijde (radiographs) scoring methods. Measurements of erosion volumes of all erosions were performed twice with a 1-week interval.

Results

With CT as the reference method, the overall sensitivity, specificity and accuracy (concordance) of MRI for detecting erosions were 61%, 93% and 77%, respectively, while the respective values were 24%, 99% and 63% for radiography. The intramodality agreements when measuring erosion volumes were high for both CT and MRI (Spearman correlation coefficients 0.92 and 0.90 (both P < 0.01), respectively). Correlations between volumes and scores of individual erosions were 0.96 for CT and 0.99 for MRI, while they were 0.83 (CT) and 0.80 (MRI) for persons' total erosion volume and total score (all P < 0.01).

Conclusion

With CT as the reference method, MRI showed moderate sensitivity and good specificity and accuracy for detection of erosions in rheumatoid arthritis and healthy wrist bones, while radiography showed very low sensitivity. The tested volumetric method was highly reproducible and correlated to scores of erosions.     

Change in CD3 positive T-cell expression in psoriatic arthritis synovium correlates with change in DAS28 and magnetic resonance imaging synovitis scores following initiation of biologic therapy - a single centre, open-label study

Introduction

With the development of increasing numbers of potential therapeutic agents in inflammatory disease comes the need for effective biomarkers to help screen for drug efficacy and optimal dosing regimens early in the clinical trial process. This need has been recognized by the Outcome Measures in Rheumatology Clinical Trials (OMERACT) group, which has established guidelines for biomarker validation. To seek a candidate synovial biomarker of treatment response in psoriatic arthritis (PsA), we determined whether changes in immunohistochemical markers of synovial inflammation correlate with changes in disease activity scores assessing 28 joints (ΔDAS28) or magnetic resonance imaging synovitis scores (ΔMRI) in patients with PsA treated with a biologic agent.

Methods

Twenty-five consecutive patients with PsA underwent arthroscopic synovial biopsies and MRI scans of an inflamed knee joint at baseline and 12 weeks after starting treatment with either anakinra (first 10 patients) or etanercept (subsequent 15 patients) in two sequential studies of identical design. DAS28 scores were measured at both time points. Immunohistochemical staining for CD3, CD68 and Factor VIII (FVIII) was performed on synovial samples and scored by digital image analysis (DIA). MRI scans performed at baseline and at 12 weeks were scored for synovitis semi-quantitatively. The ΔDAS28 of the European League Against Rheumatism good response definition (>1.2) was chosen to divide patients into responder and non-responder groups. Differences between groups (Mann Whitney U test) and correlations between ΔDAS28 with change in immunohistochemical and MRI synovitis scores (Spearman's rho test) were calculated.

Results

Paired synovial samples and MRI scans were available for 21 patients (8 anakinra, 13 etanercept) and 23 patients (8 anakinra, 15 etanercept) respectively. Change in CD3 (ΔCD3) and CD68 expression in the synovial sublining layer (ΔCD68sl) was significantly greater in the disease responders compared to non-responders following treatment (P = 0.005 and 0.013 respectively). ΔCD3, but not ΔCD68 or ΔFVIII, correlated with both ΔDAS28 (r = 0.49, P = 0.025) and ΔMRI (r = 0.58, P = 0.009).

Conclusions

The correlation of ΔCD3 with ΔDAS28 and ΔMRI following biologic treatment in this cohort contributes to the validation of ΔCD3 as a synovial biomarker of disease response in PsA, and supports the further evaluation of ΔCD3 for predictive properties of future clinical outcomes.     

Remission in psoriatic arthritis: is it possible and how can it be predicted?

Introduction

Since remission is now possible in psoriatic arthritis (PsA) we wished to examine remission rates in PsA patients following anti tumour necrosis factor alpha (TNFα) therapy and to examine possible predictors of response.

Methods

Analysis of a prospective patient cohort attending a biologic clinic, between November 2004 and March 2008, was performed prior to commencing therapy and at regular intervals. Baseline clinical characteristics including demographics, previous disease-modifying antirheumatic drug (DMARD) response, tender and swollen joint counts, early morning stiffness, pain visual analogue score, patient global assessment, C reactive protein (CRP) and health assessment questionnaire (HAQ) were collected.

Results

A total of 473 patients (152 PsA; 321 rheumatoid arthritis (RA)) were analyzed. At 12 months remission, defined according to the disease activity score using 28 joint count and CRP (DAS28-CRP), was achieved in 58% of PsA patients compared to 44% of RA patients, significant improvement in outcome measures were noted in both groups (P < 0.05). Analysis of a subgroup of PsA and RA patients matched for DAS28-CRP at baseline also showed higher numbers of PsA patients achieving remission. Linear regression analysis identified the HAQ at baseline as the best predictor of remission in PsA patients (P < 0.001).

Conclusions

DAS28 remission is possible in PsA patients at one year following anti-TNF therapy, at higher rates than in RA patients and is predicted by baseline HAQ.     

Distinct synovial immunopathology in Behçet disease and psoriatic arthritis

Introduction

The aim of the study was to investigate synovial immunopathology differences between early Behçet disease (BD) and psoriatic arthritis (PsA).

Methods

Needle arthroscopy of an inflamed knee joint was performed in patients with early untreated BD (n = 8) and PsA (n = 9). Synovial fluid (SF) was collected for cytokines, perforin, and granzyme analysis. Eight synovial biopsies per patient were obtained for immunohistochemical analysis of the cellular infiltrate (T cells, natural killer cells, macrophages, B cells, plasma cells, mast cells, and neutrophils), blood vessels as well as expression of perforin and granzyme. The stained slides were evaluated by digital image analysis.

Results

The global degree of synovial inflammation was similar in the two types of arthritis. In the analysis of the innate immune cell infiltration, there was a striking neutrophilic inflammation in BD synovitis whereas PsA displayed significantly higher numbers of cells positive for c-kit, a marker of mast cells. As for lymphocytes, CD3⁺ T cells, but neither CD20⁺ B cells nor CD138⁺ plasma cells, were significantly increased in BD versus PsA. Further analysis of the T-lymphocyte population showed no clear shift in CD4/CD8 ratio or Th1/Th2/Th17 profile. The SF levels of perforin, an effector molecule of cytotoxic cells, displayed a significant four- to fivefold increase in BD.

Conclusions

This systematic comparative analysis of early untreated synovitis identifies neutrophils and T lymphocytes as important infiltrating cell populations in BD. Increased levels of perforin in BD suggest the relevance of cytotoxicity in this disease.     

Crossreactive Autoantibodies Directed against Cutaneous and Joint Antigens Are Present in Psoriatic Arthritis

Background

Psoriatic arthritis (PsA) is a chronic inflammatory disease of unknown origin, characterized by erosions and new bone formation. Diagnosis of PsA is mainly clinical and there are no biomarkers available. Moreover in PsA autoantibodies have not been described so far. Indeed an autoimmune origin has been suggested but never proven. Aim of the study was to investigate the possible presence of autoantibodies typically associated with PsA.

Methods

We used pooled IgG immunoglobulins derived from 30 patients with PsA to screen a random peptide library in order to identify disease relevant autoantigen peptides.

Results

Among the selected peptides, one was recognised by nearly all the patients’ sera. The identified peptide (PsA peptide: TNRRGRGSPGAL) shows sequence similarities with skin autoantigens, such as fibrillin 3, a constituent of actin microfibrils, desmocollin 3, a constituent of the desmosomes and keratin 78, a component of epithelial cytoskeleton. Interestingly the PsA peptide shares homology with the nebulin-related anchoring protein (N-RAP), a protein localized in the enthesis (point of insertion of a tendon or ligament to the bone), which represents the first affected site during early PsA. Antibodies affinity purified against the PsA peptide recognize fibrillin, desmocollin, keratin and N-RAP. Moreover antibodies directed against the PsA peptide are detectable in 85% of PsA patients. Such antibodies are not present in healthy donors and are present in 13/100 patients with seroposive rheumatoid arthritis (RA). In seronegative RA these antibodies are detectable only in 3/100 patients.

Conclusions

Our results indicate that PsA is characterized by the presence of serum autoantibodies crossreacting with an epitope shared by skin and joint antigens.     

Monitoring cartilage loss in the hands and wrists in rheumatoid arthritis with magnetic resonance imaging in a multi-center clinical trial: IMPRESS (NCT00425932)

Introduction

Magnetic resonance imaging (MRI) is increasingly being used in clinical trials of rheumatoid arthritis (RA) because of its superiority over x-ray radiography (XR) in detecting and monitoring change in bone erosion, osteitis and synovitis. However, in contrast to XR, the MRI scoring method that was used in most clinical trials did not include cartilage loss. This limitation has been an obstacle to accepting MRI as a potential alternative to XR in clinical trials. Cross-sectional studies have shown MRI to be sensitive for cartilage loss in the hands and wrist; although, longitudinal sensitivity to change has not yet been confirmed. In this study we examined the ability of MRI to monitor change in cartilage loss in patients with RA in a multi-site clinical trial setting.

Methods

Thirty-one active RA patients from a clinical trial (IMPRESS) who were randomized equally into treatment with either rituximab + methotrexate or placebo + methotrexate had MRI of the dominant hand/wrist at baseline, 12 weeks and 24 weeks at 3 clinical sites in the US. Twenty-seven of these patients also had XR of both hands/wrists and both feet at baseline and 24 weeks. One radiologist scored all XR images using the van der Heijde-modified Sharp method blinded to visit order. The same radiologist scored MR images for cartilage loss using a previously validated 9-point scale, and bone erosion using the Outcome Measures in Rheumatology Clinical Trials (OMERACT) RA MRI Score (RAMRIS) blinded to visit order and XR scores. Data from the two treatment arms were pooled for this analysis.

Results

Mean MRI cartilage score increased at 12 and 24 weeks, and reached statistical significance at 24 weeks. XR total Sharp score, XR erosion score and XR joint-space narrowing (JSN) score all increased at 24 weeks, but only XR total Sharp score increased significantly.

Conclusions

To our knowledge, this is the first publication of a study demonstrating MRI''s ability to monitor cartilage loss in a multi-site clinical trial. Combined with MRI''s established performance in monitoring bone erosions in RA, these findings suggest that MRI may offer a superior alternative to XR in multi-site clinical trials of RA.     

PAD4 is not essential for disease in the K/BxN murine autoantibody-mediated model of arthritis

Introduction

Both murine and human genome-wide association studies have implicated peptidyl arginine deiminase (PAD4) as a susceptibility gene in rheumatoid arthritis (RA). In addition, patients with RA commonly have autoantibodies which recognize PAD4 or and/or citrullinated peptides. This study aims to evaluate the role of PAD4 in the effector phase of arthritis.

Methods

PAD4 knock out (KO) and wild type (WT) C57BL/6J mice were injected with K/BxN sera to induce disease. Progression of disease was monitored by measuring paw and ankle swelling and clinical indexes of disease, and pathogenesis was assessed by indexing of clinical progression on paws collected from WT and PAD4 KO mice injected with K/BxN serum. PAD4 activity was determined by visualization of neutrophil extracellular traps (NETs) and immunohistological analysis of histone citrullination.

Results

PAD4 activity is readily detectable in the inflamed synovium of WT but not PAD4 deficient animals, as demonstrated by histone citrullination and NET formation. However, PAD4 WT and KO animals develop K/BxN serum transfer disease with comparable severity and kinetics, with no statistically significant differences noted in clinical scores, swelling, joint erosion or joint invasion.

Conclusions

PAD4 WT and KO mice develop disease in the K/BxN serum transfer model of arthritis with similar severity and kinetics, indicating that PAD4 is dispensable in this effector phase model of disease.     

Differential regulation of osteoclastogenesis by Notch2/Delta-like 1 and Notch1/Jagged1 axes

Introduction

Osteoclastogenesis plays an important role in the bone erosion of rheumatoid arthritis (RA). Recently, Notch receptors have been implicated in the development of osteoclasts. However, the responsible Notch ligands have not been identified yet. This study was undertaken to determine the role of individual Notch receptors and ligands in osteoclastogenesis.

Methods

Mouse bone marrow-derived macrophages or human peripheral blood monocytes were used as osteoclast precursors and cultured with receptor activator of nuclear factor-kappaB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF) to induce osteoclasts. Osteoclasts were detected by tartrate-resistant acid phosphatase (TRAP) staining. K/BxN serum-induced arthritic mice and ovariectomized mice were treated with anti-mouse Delta-like 1 (Dll1) blocking monoclonal antibody (mAb).

Results

Blockade of a Notch ligand Dll1 with mAb inhibited osteoclastogenesis and, conversely, immobilized Dll1-Fc fusion protein enhanced it in both mice and humans. In contrast, blockade of a Notch ligand Jagged1 enhanced osteoclastogenesis and immobilized Jagged1-Fc suppressed it. Enhancement of osteoclastogenesis by agonistic anti-Notch2 mAb suggested that Dll1 promoted osteoclastogenesis via Notch2, while suppression by agonistic anti-Notch1 mAb suggested that Jagged1 suppressed osteoclastogenesis via Notch1. Inhibition of Notch signaling by a gamma-secretase inhibitor suppressed osteoclastogenesis, implying that Notch2/Dll1-mediated enhancement was dominant. Actually, blockade of Dll1 ameliorated arthritis induced by K/BxN serum transfer, reduced the number of osteoclasts in the affected joints and suppressed ovariectomy-induced bone loss.

Conclusions

The differential regulation of osteoclastogenesis by Notch2/Dll1 and Notch1/Jagged1 axes may be a novel target for amelioration of bone erosion in RA patients.     

An image-based method to measure joint deformity in inflammatory arthritis: development and pilot study

Quantifying joint deformity in people with rheumatoid (RA) and psoriatic arthritis (PsA) remains challenging. Here, we demonstrate a new method to measure bone erosions and abnormal periosteal growths, based on the difference between a predicted healthy and actual diseased joint surface. We optimized the method by creating and measuring artificial bone erosions and growths. Then we measured 46 healthy and diseased patient surfaces. We found average sensitivity errors of ≤0.27?mm when measuring artificial erosions and growths. Patients had significantly more bone erosion than healthy subjects. Surface based outcomes are a novel way to interpret and quantify bone changes in PsA and RA.     

Can erosions on MRI of the sacroiliac joints be reliably detected in patients with ankylosing spondylitis? - A cross-sectional study

Introduction

Erosions of the sacroiliac joints (SIJ) on pelvic radiographs of patients with ankylosing spondylitis (AS) are an important feature of the modified New York classification criteria. However, radiographic SIJ erosions are often difficult to identify. Recent studies have shown that erosions can be detected also on magnetic resonance imaging (MRI) of the SIJ early in the disease course before they can be seen on radiography. The goals of this study were to assess the reproducibility of erosion and related features, namely, extended erosion (EE) and backfill (BF) of excavated erosion, in the SIJ using a standardized MRI methodology.

Methods

Four readers independently assessed T1-weighted and short tau inversion recovery sequence (STIR) images of the SIJ from 30 AS patients and 30 controls (15 patients with non-specific back pain and 15 healthy volunteers) ≤45 years old. Erosions, EE, and BF were recorded according to standardized definitions. Reproducibility was assessed by percentage concordance among six possible reader pairs, kappa statistics (erosion as binary variable) and intraclass correlation coefficient (ICC) (erosion as sum score) for all readers jointly.

Results

SIJ erosions were detected in all AS patients and six controls by ≥2 readers. The median number of SIJ quadrants affected by erosion recorded by four readers in 30 AS patients was 8.6 in the iliac and 2.1 in the sacral joint portion (P < 0.0001). For all 60 subjects and for all four readers, the kappa value for erosion was 0.72, 0.73 for EE, and 0.63 for BF. ICC for erosion was 0.79, 0.72 for EE, and 0.55 for BF, respectively. For comparison, the kappa and ICC values for bone marrow edema were 0.61 and 0.93, respectively.

Conclusions

Erosions can be detected on MRI to a comparable degree of reliability as bone marrow edema despite the significant heterogeneity of their appearance on MRI.     

A Comparison of Disease Burden in Rheumatoid Arthritis,Psoriatic Arthritis and Axial Spondyloarthritis

Objective

The main objective of this study was to compare disease burden in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (ax-SpA).

Methods

In this cross-sectional study, all the RA (1093), PsA (365) and ax-SpA (333) patients who visited the out-patient clinic of the Hospital of Southern Norway Trust during the year 2013 were included; the RA patients all had a RA diagnosis verified by the treating rheumatologist, the PsA patients all fulfilled the ClASsification for Psoriatic ARthritis (CASPAR) criteria and the ax-SpA patients all fulfilled the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for ax-SpA. Patient-reported health status, demographic variables, medications, and composite scores of disease activity were assessed. The main analyses were performed using General Linear Models adjusted for age, sex and multiple comparisons. Correlation analyses were performed using Spearman’s rho.

Results

The reported pain, joint pain, patient’s global assessment and fatigue were similar in PsA and ax-SpA, but significantly lower in RA. The 28-joint Disease Activity Score (DAS28) (0.3±0.1, p = 0.003), Clinical Disease Activity Index (CDAI) (1.0±0.4, p = 0.028) and Routine Assessment of Patient Index Data 3 (RAPID3) (0.4±0.1, p = 0.004) were all significantly higher in PsA vs. RA. RAPID3 showed moderate to high correlation with DAS28 (rho = 0.521, p<0.001) and CDAI (rho = 0.768, p<0.001) in RA and PsA, and with Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (rho = 0.902, p<0.001) and Bath Ankylosing Spondylitis Functional Index (BASFI) (0.865, p<0.001) in ax-SpA and PsA.

Conclusion

In conclusion, patient- reported outcome measures were similar in our population of PsA and ax-SpA patients, but significantly lower for the RA patients. Composite disease activity measures were lower in RA than in PsA and ax-SpA, but the magnitude of these differences was small and probably not of clinical significance. Our study indicates that disease burden in RA, PsA and ax-SpA may be more similar than previously demonstrated.     

c-Fms-mediated differentiation and priming of monocyte lineage cells play a central role in autoimmune arthritis

Introduction

Tyrosine kinases are key mediators of multiple signaling pathways implicated in rheumatoid arthritis (RA). We previously demonstrated that imatinib mesylate--a Food and Drug Administration (FDA)-approved, antineoplastic drug that potently inhibits the tyrosine kinases Abl, c-Kit, platelet-derived growth factor receptor (PDGFR), and c-Fms--ameliorates murine autoimmune arthritis. However, which of the imatinib-targeted kinases is the principal culprit in disease pathogenesis remains unknown. Here we examine the role of c-Fms in autoimmune arthritis.

Methods

We tested the therapeutic efficacy of orally administered imatinib or GW2580, a small molecule that specifically inhibits c-Fms, in three mouse models of RA: collagen-induced arthritis (CIA), anti-collagen antibody-induced arthritis (CAIA), and K/BxN serum transfer-induced arthritis (K/BxN). Efficacy was evaluated by visual scoring of arthritis severity, paw thickness measurements, and histological analysis. We assessed the in vivo effects of imatinib and GW2580 on macrophage infiltration of synovial joints in CIA, and their in vitro effects on macrophage and osteoclast differentiation, and on osteoclast-mediated bone resorption. Further, we determined the effects of imatinib and GW2580 on the ability of macrophage colony-stimulating factor (M-CSF; the ligand for c-Fms) to prime bone marrow-derived macrophages to produce tumor necrosis factor (TNF) upon subsequent Fc receptor ligation. Finally, we measured M-CSF levels in synovial fluid from patients with RA, osteoarthritis (OA), or psoriatic arthritis (PsA), and levels of total and phosphorylated c-Fms in synovial tissue from patients with RA.

Results

GW2580 was as efficacious as imatinib in reducing arthritis severity in CIA, CAIA, and K/BxN models of RA. Specific inhibition of c-Fms abrogated (i) infiltration of macrophages into synovial joints of arthritic mice; (ii) differentiation of monocytes into macrophages and osteoclasts; (iii) osteoclast-mediated bone resorption; and (iv) priming of macrophages to produce TNF upon Fc receptor stimulation, an important trigger of synovitis in RA. Expression and activation of c-Fms in RA synovium were high, and levels of M-CSF were higher in RA synovial fluid than in OA or PsA synovial fluid.

Conclusions

These results suggest that c-Fms plays a central role in the pathogenesis of RA by mediating the differentiation and priming of monocyte lineage cells. Therapeutic targeting of c-Fms could provide benefit in RA.     

MRI osteitis predicts cartilage damage at the wrist in RA: a three-year prospective 3T MRI study examining cartilage damage

Introduction

Cartilage damage impacts on patient disability in rheumatoid arthritis (RA). The aims of this magnetic resonance imaging (MRI) study were to investigate cartilage damage over three years and determine predictive factors.

Methods

A total of 38 RA patients and 22 controls were enrolled at t = 0 (2009). After 3 years, clinical and MRI data were available in 28 patients and 15 controls. 3T MRI scans were scored for cartilage damage, bone erosion, synovitis and osteitis. A model was developed to predict cartilage damage from baseline parameters.

Results

Inter-reader reliability for the Auckland MRI cartilage score (AMRICS) was high for status scores; intraclass correlation coefficient (ICC), 0.90 (0.81 to 0.95) and moderate for change scores (ICC 0.58 (0.24 to 0.77)). AMRICS scores correlated with the Outcome MEasures in Rheumatoid Arthritis Clinical Trials (OMERACT) MRI joint space narrowing (jsn) and X-Ray (XR) jsn scores (r =0.96, P < 0.0001 and 0.80, P < 0.0001, respectively). AMRICS change scores were greater for RA patients than controls (P = 0.06 and P = 0.04 for the two readers). Using linear regression, baseline MRI cartilage, synovitis and osteitis scores predicted the three-year AMRICS (R² = 0.67, 0.37 and 0.39, respectively). A multiple linear regression model predicted the three-year AMRICS (R² = 0.78). Baseline radial osteitis predicted increased cartilage scores at the radiolunate and radioscaphoid joints, P = 0.0001 and 0.0012, respectively and synovitis at radioulnar, radiocarpal and intercarpal-carpometacarpal joints also influenced three-year cartilage scores (P-values of 0.001, 0.04 and 0.01, respectively).

Conclusions

MRI cartilage damage progression is preceded by osteitis and synovitis but is most influenced by pre-existing cartilage damage suggesting primacy of the cartilage damage pathway in certain patients.     

Ultrasonography,magnetic resonance imaging,radiography, and clinical assessment of inflammatory and destructive changes in fingers and toes of patients with psoriatic arthritis

The aim of the present study was to assess ultrasonography (US) for the detection of inflammatory and destructive changes in finger and toe joints, tendons, and entheses in patients with psoriasis-associated arthritis (PsA) by comparison with magnetic resonance imaging (MRI), projection radiography (x-ray), and clinical findings. Fifteen patients with PsA, 5 with rheumatoid arthritis (RA), and 5 healthy control persons were examined by means of US, contrast-enhanced MRI, x-ray, and clinical assessment. Each joint of the 2nd–5th finger (metacarpophalangeal joints, proximal interphalangeal [PIP] joints, and distal interphalangeal [DIP] joints) and 1st–5th metatarsophalangeal joints of both hands and feet were assessed with US for the presence of synovitis, bone erosions, bone proliferations, and capsular/extracapsular power Doppler signal (only in the PIP joints). The 2nd–5th flexor and extensor tendons of the fingers were assessed for the presence of insertional changes and tenosynovitis. One hand was assessed by means of MRI for the aforementioned changes. X-rays of both hands and feet were assessed for bone erosions and proliferations. US was repeated in 8 persons by another ultrasonographer. US and MRI were more sensitive to inflammatory and destructive changes than x-ray and clinical examination, and US showed a good interobserver agreement for bone changes (median 96% absolute agreement) and lower interobserver agreement for inflammatory changes (median 92% absolute agreement). A high absolute agreement (85% to 100%) for all destructive changes and a more moderate absolute agreement (73% to 100%) for the inflammatory pathologies were found between US and MRI. US detected a higher frequency of DIP joint changes in the PsA patients compared with RA patients. In particular, bone changes were found exclusively in PsA DIP joints. Furthermore, bone proliferations were more common and tenosynovitis was less frequent in PsA than RA. For other pathologies, no disease-specific pattern was observed. US and MRI have major potential for improved examination of joints, tendons, and entheses in fingers and toes of patients with PsA.     

Only one independent genetic association with rheumatoid arthritis within the KIAA1109-TENR-IL2-IL21 locus in Caucasian sample sets: confirmation of association of rs6822844 with rheumatoid arthritis at a genome-wide level of significance

Introduction

To investigate whether accelerated hand bone mineral density (BMD) loss is associated with progressive joint damage in hands and feet in the first year of rheumatoid arthritis (RA) and whether it is an independent predictor of subsequent progressive total joint damage after 4 years.

Methods

In 256 recent-onset RA patients, baseline and 1-year hand BMD was measured in metacarpals 2-4 by digital X-ray radiogrammetry. Joint damage in hands and feet were scored in random order according to the Sharp-van der Heijde method at baseline and yearly up to 4 years.

Results

68% of the patients had accelerated hand BMD loss (>-0.003 g/cm²) in the first year of RA. Hand BMD loss was associated with progressive joint damage after 1 year both in hands and feet with odds ratios (OR) (95% confidence intervals [CI]) of 5.3 (1.3-20.9) and 3.1 (1.0-9.7). In univariate analysis, hand BMD loss in the first year was a predictor of subsequent progressive total joint damage after 4 years with an OR (95% CI) of 3.1 (1.3-7.6). Multivariate analysis showed that only progressive joint damage in the first year and anti-citrullinated protein antibody positivity were independent predictors of long-term progressive joint damage.

Conclusions

In the first year of RA, accelerated hand BMD loss is associated with progressive joint damage in both hands and feet. Hand BMD loss in the first year of recent-onset RA predicts subsequent progressive total joint damage, however not independent of progressive joint damage in the first year.     

Anti-type II collagen antibodies are associated with early radiographic destruction in rheumatoid arthritis

Introduction

We have previously reported that high levels of antibodies specific for native human type II collagen (anti-CII) at the time of RA diagnosis were associated with concurrent but not later signs of inflammation. This was associated with CII/anti-CII immune complex (IC)-induced production of pro-inflammatory cytokines in vitro. In contrast, anti-cyclic citrullinated peptide antibodies (anti-CCP) were associated both with late inflammation and late radiological destruction in the same RA cohort. We therefore hypothesized that anti-CII are also associated with early erosions.

Methods

Two-hundred-and-fifty-six patients from an early RA cohort were included. Baseline levels of anti-CII, anti-CCP and anti-mutated citrullinated vimentin were analyzed with ELISA, and rheumatoid factor levels were determined by nephelometry. Radiographs of hands and feet at baseline, after one and after two years were quantified using the 32-joints Larsen erosion score.

Results

Levels of anti-CII were bimodally distributed in the RA cohort, with a small (3.1%, 8/256) group of very high outliers with a median level 87 times higher than the median for the healthy control group. Using a cut-off discriminating the outlier group that was associated with anti-CII IC-induced production of proinflammatory cytokines in vitro, baseline anti-CII antibodies were significantly (p = 0.0486) associated with increased radiographic damage at the time of diagnosis. Anti-CII-positive patient had also significantly increased HAQ score (p = 0.0303), CRP (p = 0.0026) and ESR (p = 0.0396) at the time of diagnosis but not during follow-up. The median age among anti-CII-positive subjects was 12 years higher than among the anti-CII-negative patients.

Conclusion

In contrary to anti-CCP, anti-CII-positive patients with RA have increased joint destruction and HAQ score at baseline. Anti-CII thus characterizes an early inflammatory/destructive phenotype, in contrast to the late appearance of an inflammatory/destructive phenotype in anti-CCP positive RA patients. The anti-CII phenotype might account for part of the elderly acute onset RA phenotype with rather good prognosis.     

CD16 (FcRγIII) as a potential marker of osteoclast precursors in psoriatic arthritis

Introduction  

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis characterized by bone erosion mediated by osteoclasts (OC). Our previous studies showed an elevated frequency of OC precursors (OCP) in PsA patients. Here, we examined if OC arise from CD16-positive monocytes in PsA.     

International cohort study of 73 anti-Ku-positive patients: association of p70/p80 anti-Ku antibodies with joint/bone features and differentiation of disease populations by using principal-components analysis

Introduction

An international cohort study of 73 anti-Ku-positive patients with different connective tissue diseases was conducted to differentiate the anti-Ku-positive populations of patients based on their autoantibody profile and clinical signs/symptoms and to establish possible correlations between antibodies against Ku p70 and Ku p80 with autoimmune diseases.

Methods

Sera of anti-Ku-positive patients were collected from six European centers and were all secondarily tested (in the reference center); 73 were confirmed as positive. Anti-Ku antibodies were detected with counter-immunoelectrophoresis (CIE), line immunoassay (LIA), and immunoblot analyses. All clinical and laboratory data were follow-up cumulative data, except for anti-Ku antibodies. Statistical analyses were performed by using R (V 2.12.1). The Fisher Exact test was used to evaluate the association between anti-Ku antibodies and diagnosis, gender, clinical signs, and other observed antibodies. The P values were adjusted for multiple testing. Separation of disease populations based on the presence of antibodies and clinical signs was investigated by principal-components analysis, which was performed by using thr// R's prcomp function with standard parameters.

Results

A 16% higher prevalence of anti-Ku p70 was found over anti-Ku p80 antibodies. In 41 (57%) patients, a combination of both was detected. Five (7%) patients, who were CIE and/or LIA anti-Ku positive, were negative for both subsets, as detected with the immunoblot; 31% of the patients had undifferentiated connective tissue disease (UCTD); 29% had systemic sclerosis (SSc); 18% had systemic lupus erythematosus (SLE); 11% had rheumatoid arthritis; 7% had polymyositis; and 3% had Sjögren syndrome.

Conclusions

A significant positive association was found between female patients with anti-Ku p70 and joint/bone features, and a significant negative association was found between female patients with anti-Ku p80 only and joint/bone features (P = 0.05, respectively). By using the first and the third components of the principal-component analysis (PCA) with 29 parameters evaluated, we observed that the anti-Ku-positive population of UCTD patients had overlapping parameters, especially with SLE, as opposed to SSc, which could be helpful in delineating UCTD patients.