Hanna W. van Steenbergen

A genetic study on C5-TRAF1 and progression of joint damage in rheumatoid arthritis

IntroductionThe severity of joint damage progression in rheumatoid arthritis (RA) is heritable. Several genetic variants have been identified, but together explain only part of the total genetic effect. Variants in Interleukin-6 (IL-6), Interleukin-10 (IL-10), C5-TRAF1, and Fc-receptor-like-3 (FCRL3) have been described to associate with radiographic progression, but results of different studies were incongruent. We aimed to clarify associations of these variants with radiographic progression by evaluating six independent cohorts.MethodsIn total 5,895 sets of radiographs of 2,493 RA-patients included in six different independent datasets from the Netherlands, Sweden, Spain and North-America were studied in relation to rs1800795 (IL-6), rs1800896 (IL-10), rs2900180 (C5-TRAF1) and rs7528684 (FCRL3). Associations were tested in the total RA-populations and in anti-citrullinated peptide antibodies (ACPA)-positive and ACPA-negative subgroups per cohort, followed by meta-analyses. Furthermore, the associated region C5-TRAF1 was fine-mapped in the ACPA-negative Dutch RA-patients.ResultsNo associations were found for rs1800795 (IL-6), rs1800896 (IL-10) and rs7528684 (FCRL3) in the total RA-population and after stratification for ACPA. Rs2900180 in C5-TRAF1 was associated with radiographic progression in the ACPA-negative population (P-value meta-analysis = 5.85 × 10−7); the minor allele was associated with more radiographic progression. Fine-mapping revealed a region of 66Kb that was associated; the lowest P-value was for rs7021880 in TRAF1. The P-value for rs7021880 in meta-analysis was 6.35 × 10−8. Previous studies indicate that the region of rs7021880 was associated with RNA expression of TRAF1 and C5.ConclusionVariants in IL-6, IL-10 and FCRL3 were not associated with radiographic progression. Rs2900180 in C5-TRAF1 and linked variants in a 66Kb region were associated with radiographic progression in ACPA-negative RA.

Characterising arthralgia in the preclinical phase of rheumatoid arthritis using MRI

Background The phase of arthralgia is the earliest moment to clinically recognize patients who may develop Rheumatoid Arthritis (RA). Previous imaging studies in the arthralgia phase have shown that inflammation precedes RA development. It is unknown which symptoms/characteristics relate to subclinical joint inflammation as measured by MRI. Among all patients with arthralgia, those with clinically suspect arthralgia (CSA) are suspected to progress to arthritis according to the clinical judgement of their rheumatologists. We determined the symptoms/characteristics of patients with CSA who had inflammation on MRI. Methods 102 patients with CSA and without clinical arthritis were included. They completed questionnaires, underwent joint counts and unilateral 1.5 T MRI of MCP joints 2–4, wrist and MTP joints 1–5. Synovitis, bone marrow oedema (BME) and tenosynovitis were scored according to the OMERACT rheumatoid arthritis MRI scoring system. Symptoms and signs were related to MRI inflammation (based on MRI scores in symptom-free controls; a sum of synovitis, BME and tenosynovitis scores ≥3 was considered positive). Whether certain clinical characteristics frequently occurred together with MRI inflammation was studied by partial least squares analysis. Results MRI was performed in 93 patients with CSA, 44% of whom had subclinical MRI inflammation. Synovitis was the most prevalent inflammatory feature on MRI (20%). Patients with MRI inflammation were older and were more frequently positive for anti-citrullinated peptide antibodies than patients without MRI inflammation (p<0.001 and 0.049). In PLS analysis, including 16 clinical and serological characteristics as independent variables and MRI inflammation as dependent variable, no clear clusters of patients with and without MRI inflammation were identified. Conclusions Subclinical inflammation as measured by MRI is present in 44% of patients with CSA. A combination of symptoms/characteristics incompletely differentiated patients with and without MRI inflammation.

EULAR definition of arthralgia suspicious for progression to rheumatoid arthritis

Background During the transition to rheumatoid arthritis (RA) many patients pass through a phase characterised by the presence of symptoms without clinically apparent synovitis. These symptoms are not well-characterised. This taskforce aimed to define the clinical characteristics of patients with arthralgia who are considered at risk for RA by experts based on their clinical experience. Methods The taskforce consisted of 18 rheumatologists, 1 methodologist, 2 patients, 3 health professionals and 1 research fellow. The process had three phases. In phase I, a list of parameters considered characteristic for clinically suspect arthralgia (CSA) was derived; the most important parameters were selected by a three-phased Delphi approach. In phase II, the experts evaluated 50 existing patients on paper, classified them as CSA/no-CSA and indicated their level of confidence. A provisional set of parameters was derived. This was studied for validation in phase III, where all rheumatologists collected patients with and without CSA from their outpatient clinics. Results The comprehensive list consisted of 55 parameters, of which 16 were considered most important. A multivariable model based on the data from phase II identified seven relevant parameters: symptom duration <1 year, symptoms of metacarpophalangeal (MCP) joints, morning stiffness duration ≥60 min, most severe symptoms in early morning, first-degree relative with RA, difficulty with making a fist and positive squeeze test of MCP joints. In phase III, the combination of these parameters was accurate in identifying patients with arthralgia who were considered at risk of developing RA (area under the receiver operating characteristic curve 0.92, 95% CI 0.87 to 0.96). Test characteristics for different cut-off points were determined. Conclusions A set of clinical characteristics for patients with arthralgia who are at risk of progression to RA was established.

The Course of Bone Marrow Edema in Early Undifferentiated Arthritis and Rheumatoid Arthritis: A Longitudinal Magnetic Resonance Imaging Study at Bone Level.

In patients with rheumatoid arthritis (RA), bone marrow edema (BME) scores are associated with development of erosions. However, little is known about the course and outcome of BME at bone level. We undertook this study to determine the association of BME and synovitis with the development of erosions in the same bone longitudinally.

Studies on ageing and the severity of radiographic joint damage in rheumatoid arthritis.

IntroductionThe western population is ageing. It is unknown whether age at diagnosis affects the severity of Rheumatoid Arthritis (RA), we therefore performed the present study.Method1,875 RA-patients (7,219 radiographs) included in five European and North-American cohorts (Leiden-EAC, Wichita, Umeå, Groningen and Lund) were studied on associations between age at diagnosis and joint damage severity. In 698 Leiden RA-patients with 7-years follow-up it was explored if symptom duration, anti-citrullinated-peptide-antibodies (ACPA), swollen joint count (SJC) and C-reactive-protein (CRP) mediated the association of age with joint damage. Fifty-six other RA-patients of the EAC-cohort underwent baseline MRIs of wrist, MCP and MTP-joints; MRI-inflammation (RAMRIS-synovitis plus bone marrow edema) was also evaluated in mediation analyses. Linear regression and multivariate normal regression models were used.ResultsAnalysis on the five cohorts and the Leiden-EAC separately revealed 1.026-fold and 1.034-fold increase of radiographic joint damage per year increase in age (β=1.026, 1.034, both p<0.001); this effect was present at baseline and persisted over time. Age correlated stronger with baseline erosion-scores compared to joint space narrowing (JSN)-scores (r=0.38 versus 0.29). Symptom duration, ACPA, SJC and CRP did not mediate the association of age with joint damage severity. Age was significantly associated with the MRI-inflammation-score after adjusting for CRP and SJC (β=1.018, p=0.027). The association of age with joint damage (β=1.032, p=0.004) decreased after also including the MRI-inflammation-score (β=1.025, p=0.021), suggesting partial mediation.ConclusionRA-patients presenting at higher age have more severe joint damage; this might be partially explained by more severe MRI-detected inflammation at higher age.

Autoantibodies to two novel peptides in seronegative and early rheumatoid arthritis

OBJECTIVES Despite recent progress in biomarker discovery for RA diagnostics, still over one-third of RA patients-and even more in early disease-present without RF or ACPA. The aim of this study was to confirm the presence of previously identified autoantibodies to novel Hasselt University (UH) peptides in early and seronegative RA. METHODS Screening for antibodies against novel UH peptides UH-RA.1, UH-RA.9, UH-RA.14 and UH-RA.21, was performed in two large independent cohorts. Peptide ELISAs were developed to screen for the presence of antibodies to UH-RA peptides. First, 292 RA patients (including 39 early patients), 90 rheumatic and 97 healthy controls from UH were studied. Antibody reactivity to two peptides (UH-RA.1 and UH-RA.21) was also evaluated in 600 RA patients, 309 patients with undifferentiated arthritis and 157 rheumatic controls from the Leiden Early Arthritis Clinic cohort. RESULTS In both cohorts, 38% of RA patients were seronegative for RF and ACPA. Testing for autoantibodies to UH-RA.1 and UH-RA.21 reduced the serological gap from 38% to 29% in the UH cohort (P = 0.03) and from 38% to 32% in the Leiden Early Arthritis Clinic cohort (P = 0.01). Furthermore, 19-33% of early RA patients carried antibodies to these peptides. Specificities in rheumatic controls ranged from 82 to 96%. Whereas antibodies against UH-RA.1 were related to remission, anti-UH-RA.21 antibodies were associated with inflammation, joint erosion and higher tender and swollen joint counts. CONCLUSION This study validates the presence of antibody reactivity to novel UH-RA peptides in seronegative and early RA. This might reinforce current diagnostics and improve early diagnosis and intervention in RA.

How do general practitioners identify inflammatory arthritis? A cohort analysis of Dutch general practitioner electronic medical records

OBJECTIVE To examine the symptoms, signs and additional investigations that general practitioners (GPs) used in the process of diagnosing recent-onset inflammatory arthritis. Here, we assumed that the recorded information was crucial in the diagnostic process of arthritis. METHODS A database including electronic medical records of 16 Dutch general practices with 44,350 patients was studied. Patients with an episode of RA and allied conditions according to the International Classification of Primary Care-1 code L88 (here summarized as inflammatory arthritis) in the period 2009-2013 were selected. Frequencies of symptoms, signs and performed additional investigations were evaluated and compared between referred and non-referred patients. RESULTS A total of 126 patients were diagnosed with inflammatory arthritis. Information on symptom duration, symptom location, swelling, loss of function, redness and warmth were recorded in, respectively, 64, 90, 80, 52, 48 and 41% of patients. Information on morning stiffness, family history or the squeeze-test was provided in 20, 18 and 17% of patients. Symmetry, inflammatory type arthralgia and fist closure were not recorded. Acute phase reactants and auto-antibody tests were performed in 40-46% and 8-11%, respectively. Eighty-four patients (67%) were referred to secondary care. Symptoms located in the foot, morning stiffness, family history, myalgia, absence of redness and elevated acute phase reactants were associated with referral (all P < 0.05). CONCLUSION GPs mainly used classical signs of inflammation to diagnose inflammatory arthritis. Other items that are regularly assessed in secondary care (morning stiffness, squeeze-test, family history) were infrequently recorded by GPs.

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.

Predicting the severity of joint damage in rheumatoid arthritis; the contribution of genetic factors

Background The severity of radiologic progression is variable between rheumatoid arthritis (RA) patients. Recently, several genetic severity variants have been identified and were replicated, these belong to 12 loci. This study determined the contribution of the identified genetic factors to the explained variance in radiologic progression and whether genetic factors, in addition to traditional risk factors, improve the accuracy of predicting the severity of radiologic progression. Methods 426 early RA patients with yearly radiologic follow-up were studied. The main outcome measure was the progression in Sharp-van der Heijde score (SHS) over 6 years, assessed as continuous outcome or categorised in no/little, moderate or severe progression. Assessed were improved fit of a linear mixed model analysis on serial radiographs, R2 using linear regression analyses, C-statistic and the net proportion of patients that was additionally correctly classified when adding genetic risk factors to a model consisting of traditional risk factors. Results The genetic factors together explained 12–18%. When added to a model including traditional factors and treatment effects, the genetic factors additionally explained 3–7% of the variance (p value R2change=0.056). The percentage of patients that was correctly classified increased from 56% to 62%; the net proportion of correct reclassifications 6% (95% CI 3 to 10%). The C-statistic increased from 0.78 to 0.82. Sensitivity analyses using imputation of missing radiographs yielded comparable results. Conclusions Genetic risk factors together explained 12–18% of the variance in radiologic progression. Adding genetic factors improved the predictive accuracy, but 38% of the patients were still incorrectly classified, limiting the value for use in clinical practice.

Using a reference when defining an abnormal MRI reduces false-positive MRI results—a longitudinal study in two cohorts at risk for rheumatoid arthritis

Objectives The use of hand and foot MRI in the diagnostic process of RA has been advocated. Recent studies showed that MRI is helpful in predicting progression from clinically suspect arthralgia (CSA) to clinical arthritis, and from undifferentiated arthritis (UA) to RA. Symptom-free persons can also show inflammation on MRI. This study aimed to evaluate if MRI findings in symptom-free volunteers are relevant when defining a positive MRI. Methods Two hundred and twenty-five CSA patients and two hundred and one UA patients underwent MRI of MCP, wrist and MTP joints at baseline and were followed for 1 year on progression to arthritis and RA, respectively, as reported previously. MRI was considered positive if ⩾ 1 joint showed inflammation (called uncorrected definition), or if ⩾ 1 joint had inflammation that was present in < 5% of persons of the same age category at the same location (called 5% corrected definition). Test characteristics were compared for both definitions. Results By using MRI data of symptom-free volunteers as reference, specificity of MRI-detected inflammation increased from 22 to 56% in CSA patients, and from 10 to 36% in UA patients. The sensitivity was not affected; it was 88 and 85% in CSA patients and 93 and 93% in UA patients. The accuracy also increased, from 32 to 60% in CSA patients and 22 to 44% in UA patients. Conclusion The use of a reference population resulted in a substantial reduction of false-positive results, without influencing the sensitivity. Although common for other tests in medicine, this phenomenon is novel for MRI in the early detection of RA.