Evaluating processes underlying the predictive value of baseline erosions for future radiological damage in early rheumatoid arthritis.

OBJECTIVES: Baseline erosions are characteristic for rheumatoid arthritis (RA) and predictive for a severe disease course. The mechanisms leading to baseline erosions being a strong predictor for radiological progression are unknown. We aimed to increase this understanding by mediation analyses in an observational cohort and a cross-sectional MRI study. METHODS: 3256 hands and feet radiographs of 653 early RA patients assessed during 7 years of disease were scored using the Sharp-van der Heijde method. Mediation models and multivariate regression analyses were used to explore the association between baseline erosions, other predictors and radiological damage over time. 603 joints (MCP2-5 and MTP1-5) of 67 RA patients underwent 1.5 T MRI at baseline. Data on MRI inflammation were compared with clinical inflammation and baseline radiological erosions. RESULTS: Patients with baseline erosions had, at any point in time during 7 years, 3.45 times more joint damage than patients without erosions (p<0.001, 95% CI 3.00 to 3.98). Baseline erosions were an independent predictor and not a mediator between symptom duration, systemic or local clinical inflammation (erythrocyte sedimentation rate (ESR), swollen joint count (SJC)) or autoantibodies (anti-citrullinated-peptide antibodies, rheumatoid factor) and radiological damage. Subclinical MRI inflammation was studied in relation to erosions, revealing that 83% of the non-swollen joints with baseline erosions had subclinical MRI inflammation compared with 25% of the non-swollen joints without baseline erosions (OR 15.2 95% CI 3.1 to 102.1). The association between MRI inflammation and baseline erosions was independent of symptom duration, ESR, SJC and autoantibodies. CONCLUSIONS: Baseline erosions are a predictor for future joint damage, independent of known predictors as time, autoantibodies or clinical measurable inflammation. Subclinical inflammation is suggested as an underlying mechanism.

Aiming for a simpler early arthritis MRI protocol: can Gd contrast administration be eliminated?

PURPOSE: To evaluate whether intravenous gadolinium (Gd) contrast administration can be eliminated when evaluating synovitis and tenosynovitis in early arthritis patients, thereby decreasing imaging time, cost, and invasiveness. MATERIALS AND METHODS: Wrist MRIs of 93 early arthritis patients were evaluated by two readers for synovitis of the radioulnar, radiocarpal, and intercarpal joints, according to the Rheumatoid Arthritis MRI Scoring method (RAMRIS), and for tenosynovitis in ten compartments. Scores of MRI images without Gd contrast enhancement were compared to scores obtained when evaluating all, including contrast-enhanced, MRI images as reference. Subsequently, a literature review and pooled analysis of data from the present and two previous studies were performed. RESULTS: At the individual joint/tendon level, sensitivity to detect synovitis without Gd contrast was 91 % and 72 % for the two readers, respectively, with a specificity of 51 % and 81 %. For tenosynovitis, the sensitivity was 67 % and 54 %, respectively, with a specificity of 87 % and 91 %. Pooled data analysis revealed an overall sensitivity of 81 % and specificity of 50 % for evaluation of synovitis. Variations in tenosynovitis scoring systems hindered pooled analyses. CONCLUSION: Eliminating Gd contrast administration resulted in low specificity for synovitis and low sensitivity for tenosynovitis, indicating that Gd contrast administration remains essential for an optimal assessment. KEY POINTS: • Eliminating gadolinium contrast administration results in low specificity for synovitis • For tenosynovitis, sensitivity is low without gadolinium contrast administration • Gadolinium contrast administration remains essential for evaluating synovitis and tenosynovitis in early arthritis.

Aiming for a shorter rheumatoid arthritis MRI protocol: can contrast-enhanced MRI replace T2 for the detection of bone marrow oedema?

PURPOSE: To determine whether T1 post-gadolinium chelate images (T1Gd) can replace T2-weighted images (T2) for evaluating bone marrow oedema (BME), thereby allowing a shorter magnetic resonance imaging (MRI) protocol in rheumatoid arthritis (RA). MATERIAL AND METHODS: In 179 early arthritis patients and 43 advanced RA patients, wrist and metacarpophalangeal joints were examined on a 1.5-T extremity MRI system with a standard protocol (coronal T1, T2 fat-saturated and coronal and axial T1 fat-saturated after Gd). BME was scored according to OMERACT RAMRIS by two observers with and without T2 images available. Agreement was assessed using intraclass correlation coefficients (ICCs) for semi-quantitative scores and test characteristics with T2 images as reference. RESULTS: Agreement between scores based on T2 and T1Gd images was excellent ICC (0.80-0.99). At bone level, sensitivity and specificity of BME on T1Gd compared to T2 were high for both patient groups and both readers (all ≥80 %). CONCLUSION: T1Gd and T2 images are equally suitable for evaluating BME. Because contrast is usually administered to assess (teno)synovitis, a short MRI protocol of T1 and T1Gd is sufficient in RA. KEY POINTS: • Bone marrow oedema scores are equal on T2 and T1-Gd-chelate enhanced sequences. • Agreement between scores based on T2 and T1-Gd-chelate images was excellent. • Sensitivity and specificity for presence of bone marrow oedema were high. • A short protocol without T2 images suffices in rheumatoid arthritis patients.

MRI of hand and foot joints of patients with anticitrullinated peptide antibody positive arthralgia without clinical arthritis.

BACKGROUND: Anticitrullinated peptide antibodies (ACPA) and acute phase reactants may be increased before arthritis becomes clinically detectable, suggesting that the processes underlying rheumatoid arthritis (RA) start preclinically. Whether local inflammation occurs in the preclinical phase is unknown. Therefore, we studied the small joints of ACPA positive arthralgia patients for local subclinical inflammation. METHODS: Imaging was performed using 1.5 T extremity MRI. Painful hand or foot joints of 21 ACPA positive arthralgia patients without clinical arthritis were imaged. For comparison, hand and foot joints of 22 ACPA positive RA patients and 19 symptom free controls were studied. Within ACPA positive arthralgia patients, painful and symptom free joint regions were imaged. Scoring was performed according to the Outcome Measures in Rheumatology Clinical Trials (OMERACT) Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) method. Analyses were performed on joint region level and focused on inflammation (synovitis plus bone marrow oedema). RESULTS: The mean combined inflammation scores of the metacarpophalangeal/proximal interphalangeal joints of controls, painful joints of ACPA positive arthralgia patients and ACPA positive RA patients were 0.1, 0.7 and 3.7, respectively (p<0.001). Likewise, the mean combined inflammation scores of the wrist were 0.9, 2.3 and 10.3, respectively (p<0.001) and that of the metatarsophalangeal joints 0.5, 0.9 and 3.8, respectively (p=0.10). At the MCP joints, the combined inflammation score was significantly correlated with C reactive protein and erythrocyte sedimentation rate levels (rs=0.83 and rs=0.78, respectively) CONCLUSIONS: The present data suggest that local subclinical inflammation occurs in ACPA positive arthralgia patients.

Genetic studies on components of the Wnt signalling pathway and the severity of joint destruction in rheumatoid arthritis.

BACKGROUND: Progression of joint destruction in rheumatoid arthritis (RA) is partly heritable; knowledge of genetic factors may increase our understanding of the mechanisms underlying joint destruction. The activity of the Wnt/ß-catenin pathway influences osteoblast differentiation. Dickkopf-1 (Dkk-1) and sclerostin (Sost) are negative regulators and lipoprotein receptor-related protein-5 (LRP-5) and Kremen-1 are transmembrane receptors involved in this pathway. OBJECTIVE: To study variants in the genes encoding these proteins in relation to progression of joint destruction. METHODS: 1418 patients with RA of four cohorts with 4885 sets of hands and feet x-rays were studied. Explorative analyses were performed on 600 patients with RA from Leiden on single nucleotide polymorphisms (SNPs) tagging Dkk-1, Sost, Kremen-1 and LRP-5. SNPs significantly associating with joint damage progression were subsequently genotyped in cohorts from Groningen (NL), Sheffield (UK) and Lund (Sweden). Data were summarised in meta-analyses. Serum levels of functional Dkk-1 and sclerostin were measured and studied in relation to genotypes. RESULTS: In the first cohort, six Dkk-1, three Sost, one Kremen-1 and 10 LRP-5 SNPs were significantly associated with radiological progression of joint destruction. Three Dkk-1 SNPs were associated significantly with progression of joint damage in the meta-analysis, also after correction for multiple testing (rs1896368, rs1896367 and rs1528873). Two Sost SNPs tended to significance (rs4792909 and rs6503475, p=0.07 after false discovery rate correction). Gene-gene interactions between SNPs on Dkk-1 and Sost were seen. Serum levels of Dkk-1 were significantly correlated with the genotypes in rs1896368 (p=0.02). CONCLUSIONS: Patients with RA carrying risk alleles of genetic variants in Dkk-1 have higher serum levels of functional Dkk-1 and more progressive joint destruction over time.

Risk of rheumatoid arthritis development in patients with unclassified arthritis according to the 2010 ACR/EULAR criteria for rheumatoid arthritis.

OBJECTIVE: Early recognition and treatment of RA is associated with an improved outcome. The 2010 ACR/EULAR criteria for RA identify RA patients earlier than the 1987 ACR criteria. Nevertheless, we recently observed that 24% of the 2010 unclassified arthritis (UA) patients develop RA during follow-up. Here we studied this frequency in other cohorts and evaluated the prognostic accuracy of ACPA and the Leiden prediction rule in 2010 UA patients. METHODS: The 2010 UA patients from three Early Arthritis Clinics were studied: 776 from Leiden, 121 from Birmingham and 322 from Amsterdam. Fulfilment of the 1987 ACR criteria during follow-up was studied as the primary outcome. DMARD prescription during the year and having a persistent course of arthritis over 7 years were studied as secondary outcomes in one cohort. The presence of ACPA and the prediction score at baseline were evaluated in relation to these outcomes. RESULTS: In the three cohorts, 24%, 26% and 12%, respectively, of the 2010 UA patients fulfilled the 1987 criteria after 1 year. However, some of these patients already fulfilled the 1987 criteria at baseline. In 1987 and 2010 UA patients, 15%, 21% and 9%, respectively, developed RA (1987) at 1 year. In these patients, 0-6% of the patients were ACPA positive and 0-1% had high prediction scores. Consequently a large majority of the UA patients with an unfavourable outcome was not recognized by these prognostic tools. CONCLUSION: A proportion of 2010 UA patients progress to RA. ACPA and the Leiden prediction rule are not useful in identifying these patients. These results imply that other predictive markers should be developed for 2010 UA patients.

Evaluation of magnetic resonance imaging-detected tenosynovitis in the hand and wrist in early arthritis.

OBJECTIVE: Magnetic resonance imaging (MRI) is a sensitive method to detect inflammation in rheumatoid arthritis (RA), visualizing synovitis, bone marrow edema, and tenosynovitis. The prevalence of MRI-detected tenosynovitis and its diagnostic value in early arthritis are unclear. This study was undertaken to identify the frequency of MRI-detectable tenosynovitis at the metacarpophalangeal (MCP) and wrist joints in early arthritis and the association of these with RA and the severity of RA. METHODS: A total of 178 patients with early arthritis underwent unilateral 1.5T extremity MRI at baseline. The MCP and wrist joints were scored using the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring system and Haavardsholm's tenosynovitis score. Sixty-nine patients fulfilled the American College of Rheumatology/European League Against Rheumatism 2010 classification criteria for RA during the first year and were compared with the non-RA patients. Among the RA patients, comparisons were made with regard to anti-citrullinated protein antibody (ACPA) positivity and radiographic progression during year 1. RESULTS: Of all patients, 65% had MRI-detected tenosynovitis. RA patients had tenosynovitis more often than non-RA patients (75% versus 59%; P = 0.023). The flexor tendons at MCP5 and the extensor tendons at MCP2 and MCP4 and in extensor compartment I of the wrist were more frequently affected in RA patients than in other patients (odds ratios 2.8 [95% confidence interval (95% CI) 1.2-7.0], 9.1 [95% CI 1.9-42.8], 14.2 [95% CI 1.7-115.9], and 4.0 [95% CI 1.4-11.1], respectively). These associations were independent of local MRI synovitis. Specificities were all ≥82%. Within the group of RA patients, tenosynovitis scores were not associated with ACPA positivity or radiographic progression. CONCLUSION: MRI-detected tenosynovitis is commonly seen in early arthritis. The flexor tendons at MCP5, the extensor tendons at MCP2 and MCP4, and the first extensor compartment of the wrist are more often affected in RA, independent of local synovitis.

Are rheumatoid arthritis patients discernible from other early arthritis patients using 1.5T extremity magnetic resonance imaging? a large cross-sectional study.

OBJECTIVE: Magnetic resonance imaging (MRI) is increasingly used in rheumatoid arthritis (RA) research. A European League Against Rheumatism (EULAR) task force recently suggested that MRI can improve the certainty of RA diagnosis. Because this recommendation may reflect a tendency to use MRI in daily practice, thorough studies on the value of MRI are required. Thus far no large studies have evaluated the accuracy of MRI to differentiate early RA from other patients with early arthritis. We performed a large cross-sectional study to determine whether patients who are clinically classified with RA differ in MRI features compared to patients with other diagnoses. METHODS: In our study, 179 patients presenting with early arthritis (median symptom duration 15.4 weeks) underwent 1.5T extremity MRI of unilateral wrist, metacarpophalangeal, and metatarsophalangeal joints according to our arthritis protocol, the foot without contrast. Images were scored according to OMERACT Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) by 2 independent readers. Tenosynovitis was also assessed. The main outcome was fulfilling the 1987 American College of Rheumatology (ACR) criteria for RA. Test characteristics and areas under the receiver-operator-characteristic curves (AUC) were evaluated. In subanalyses, the 2010 ACR/EULAR criteria were used as outcome, and analyses were stratified for anticitrullinated protein antibodies (ACPA). RESULTS: The ACR 1987 criteria were fulfilled in 43 patients (24.0%). Patients with RA had higher scores for synovitis, tenosynovitis, and bone marrow edema (BME) than patients without RA (p < 0.05). ACPA-positive patients had more BME (median scores 6.5 vs. 4.25, p = 0.016) than ACPA-negative patients. For all MRI features, the predictive value for the presence of RA was low (< 50%). For all MRI features the AUC were < 0.70. Patients who fulfilled ACR/EULAR 2010 criteria but not ACR87 criteria for RA had less synovitis than patients who were positive for RA according to both sets of criteria (p = 0.029). CONCLUSION: Although patients with RA had higher scores of MRI inflammation and ACPA-positive patients had more BME, the severity of MRI inflammation assessed according to RAMRIS does not accurately differentiate patients with RA from other early arthritis patients.

Serum pyridinoline levels and prediction of severity of joint destruction in rheumatoid arthritis.

OBJECTIVE: Previous studies indicated that pyridinoline, a collagen crosslink in cartilage and bone, might be a good marker to predict joint destruction in patients with rheumatoid arthritis (RA), although large prospective studies are lacking. We evaluated the predictive value of serum pyridinoline levels for joint destruction, both at baseline for longterm prediction and during the disease course for near-term prediction. METHODS: Patients with early RA from the Leiden Early Arthritis Clinic were studied. Radiographs at baseline and yearly during 7 years of followup were scored according to the Sharp-van der Heijde Scoring (SHS) method. Pyridinoline serum levels at baseline and during followup were measured by ELISA. The association between baseline pyridinoline levels and difference in SHS over 7 years was tested, with a multivariate normal regression model. Second, the association between pyridinoline levels determined during the disease course and progression of SHS over the next year was tested with a multivariable linear regression analysis. RESULTS: Studying baseline pyridinoline serum levels in 437 patients revealed that the mean SHS over 7 years was 6% higher for every higher pyridinoline level (nmol/l) at baseline (p = 0.001). Subsequently, during followup (n = 184 patients) the progression in SHS in the upcoming year was 17% higher for every higher nmol/l pyridinoline level (p = 0.001). The area under the receiver-operation characteristic curve for rapid radiological progression was 0.59. CONCLUSION: Increased pyridinoline serum levels, both at baseline and during the disease course, are associated with more severe joint destruction during the coming year(s), although the predictive accuracy as a sole predictor was moderate.

Associations between APOE genotypes and disease susceptibility, joint damage and lipid levels in patients with rheumatoid arthritis.

OBJECTIVE: Apolipoprotein E (APOE) genotypes are associated with cardiovascular disease (CVD) and lipid levels. In rheumatoid arthritis (RA), an association has been found with disease activity. We examined the associations between APOE genotypes and disease susceptibility and markers of disease severity in RA, including radiographic joint damage, inflammatory markers, lipid levels and cardiovascular markers. METHOD: A Norwegian cohort of 945 RA patients and 988 controls were genotyped for two APOE polymorphisms. We examined longitudinal associations between APOE genotypes and C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) as well as hand radiographs (van der Heijde Sharp Score(SHS)) in 207 patients with 10 year longitudinal data. Lipid levels, cardiovascular markers and history of CVD were compared across genotypes in a cross sectional study of 136 patients. Longitudinal radiological data of cohorts from Lund and Leiden were available for replication. (N = 935, with 4799 radiographs). RESULTS: In the Norwegian cohort, associations between APOE genotypes and total cholesterol (TC) and low-density lipoproteins (LDL) were observed (ε2 < ε3/ε3 < ε4, p = 0.03 and p = 0.02, respectively). No association was present for acute phase reactant or CVD markers, but a longitudinal linear association between APOE genotypes and radiographic joint damage was observed (p = 0.007). No association between APOE genotypes and the severity of joint destruction was observed in the Lund and Leiden cohorts, and a meta- analysis combining all data was negative. CONCLUSION: APOE genotypes are associated with lipid levels in patients with RA, and may contribute to dyslipidemia in some patients. APOE genotypes are not consistently associated with markers of inflammation or joint destruction in RA.

Effect of CYP2C9 polymorphisms on prescribed dose and time-to-stable dose of sulfonylureas in primary care patients with Type 2 diabetes mellitus.

AIMS: Sulfonylureas are mainly metabolized by the enzyme CYP2C9. Two allelic variants, CYP2C9*2 and CYP2C9*3, result in decreased metabolic capacity and have been associated with elevated sulfonylurea serum levels. However, most of the available data originates from pharmacokinetic analyses performed in healthy individuals. In this study, the effect of CYP2C9*2 and CYP2C9*3 alleles on prescribed dose and time-to-stable dose of sulfonylureas was investigated. MATERIALS & METHODS: A group of 207 incident sulfonylurea users treated in four university affiliated primary care centers were identified. The effect of the CYP2C9*2 and CYP2C9*3 alleles on prescribed dose and time-to-stable dose was then assessed. RESULTS: No significant effects of the CYP2C9*2 and CYP2C9*3 alleles were found. However, a trend towards a lower stable glimepiride dose for carriers of the CYP2C9*3 allele was observed. CONCLUSION: Genotyping for the CYP2C9*2 and CYP2C9*3 alleles currently appears to have no clinical implications for dosing of sulfonylureas in primary care patients with Type 2 diabetes mellitus.