Jessica A. B. van Nies

Association of a Single-Nucleotide Polymorphism in CD40 With the Rate of Joint Destruction in Rheumatoid Arthritis

OBJECTIVE The severity of joint destruction in rheumatoid arthritis (RA) is highly variable from patient to patient and is influenced by genetic factors. Genome-wide association studies have enormously boosted the field of the genetics of RA susceptibility, but risk loci for RA severity remain poorly defined. A recent meta-analysis of genome-wide association studies identified 6 genetic regions for susceptibility to autoantibody-positive RA: CD40, KIF5A/PIP4K2C, CDK6, CCL21, PRKCQ, and MMEL1/TNFRSF14. The purpose of this study was to investigate whether these newly described genetic regions are associated with the rate of joint destruction. METHODS RA patients enrolled in the Leiden Early Arthritis Clinic were studied (n=563). Yearly radiographs were scored using the Sharp/van der Heijde method (median followup 5 years; maximum followup 9 years). The rate of joint destruction between genotype groups was compared using a linear mixed model, correcting for age, sex, and treatment strategies. A total of 393 anti-citrullinated protein antibody (ACPA)-positive RA patients from the North American Rheumatoid Arthritis Consortium (NARAC) who had radiographic data available were used for the replication study. RESULTS The TT and CC/CG genotypes of 2 single-nucleotide polymorphisms, rs4810485 (CD40) and rs42041 (CDK6), respectively, were associated with a higher rate of joint destruction in ACPA-positive RA patients (P=0.003 and P=0.012, respectively), with rs4810485 being significant after Bonferroni correction for multiple testing. The association of the CD40 minor allele with the rate of radiographic progression was replicated in the NARAC cohort (P=0.021). CONCLUSION A polymorphism in the CD40 locus is associated with the rate of joint destruction in patients with ACPA-positive RA. Our findings provide one of the first non-HLA-related genetic severity factors that has been replicated.

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.

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.

Improved treatment strategies reduce the increased mortality risk in early RA patients

OBJECTIVE A higher mortality rate in patients with RA than in the general population has been reported in most series. Treatment strategies for RA have improved dramatically over the last decades, resulting in less inflammation and joint damage. We investigated whether this change in treatment corresponds to reversal of excess mortality by studying a large inception cohort of early RA patients exposed to different treatment strategies. METHODS Six hundred and eighty-four RA patients included in the Leiden Early Arthritis Clinic between 1993 and 2008 were studied. Treatment was different for three inclusion periods. From 1993 to 1995 patients were treated with NSAIDs and only late in their disease with DMARDs. From 1996 to 1998 patients were promptly treated with HCQ or SSZ. From 1999 to 2008 patients were immediately treated with MTX monotherapy or in combination with other disease-modifying drugs. Life/death status was tracked nationally using the civic registries. Mortality rates were compared with the general Dutch population. RESULTS In Periods 1 and 2, increased standardized mortality rates were found, 1.35 (95% CI 0.94, 1.93) and 1.23 (95% CI 0.91, 1.67), respectively, while a decreased standardized mortality rate was found for patients included in 1999-2006 [0.49 (95% CI 0.31, 0.77)]. Age of onset [hazard ratio (HR) 1.10 (95% CI 1.07, 1.13)], erosive disease [HR 2.03 (95% CI 1.22, 3.37)], high CRP level [HR 1.09 (95% CI 1.01, 1.18)], smoking [HR 2.39 (95% CI 1.31, 4.38)] and higher baseline HAQ score [HR 1.53 (95% CI 1.06, 2.20)] associated with mortality. CONCLUSION Current treatment strategies for early RA, such as that given in inclusion Period 3, might contribute to the reversal of excess mortality in RA.

Identification of a genetic variant for joint damage progression in autoantibody-positive rheumatoid arthritis

Background Joint destruction is a hallmark of autoantibody-positive rheumatoid arthritis (RA), though the severity is highly variable between patients. The processes underlying these interindividual differences are incompletely understood. Methods We performed a genome-wide association study on the radiological progression rate in 384 autoantibody-positive patients with RA. In stage-II 1557 X-rays of 301 Dutch autoantibody-positive patients with RA were studied and in stage-III 861 X-rays of 742 North American autoantibody-positive patients with RA. Sperm-Associated Antigen 16 (SPAG16) expression in RA synovium and fibroblast-like synoviocytes (FLS) was examined using Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) and immunohistochemistry. FLS secrete metalloproteinases that degrade cartilage and bone. SPAG16 genotypes were related to matrix metalloproteinase (MMP)-3 and MMP-1 expression by FLS in vitro and MMP-3 production ex vivo. Results A cluster of single nucleotide polymorphisms (SNPs) at 2q34, located at SPAG16, associated with the radiological progression rate; rs7607479 reached genome-wide significance. A protective role of rs7607479 was replicated in European and North American patients with RA. Per minor allele, patients had a 0.78-fold (95% CI 0.67 to 0.91) progression rate over 7 years. mRNA and protein expression of SPAG16 in RA synovium and FLS was verified. FLS carrying the minor allele secreted less MMP-3 (p=1.60×10−2). Furthermore, patients with RA carrying the minor allele had lower serum levels of MMP-3 (p=4.28×10−2). In a multivariate analysis on rs7607479 and MMP-3, only MMP-3 associated with progression (p=2.77×10−4), suggesting that the association between SPAG16-rs7607479 and joint damage is mediated via an effect on MMP-3 secretion. Conclusions Genetic and functional analyses indicate that SPAG16 influences MMP-3 regulation and protects against joint destruction in autoantibody-positive RA. These findings could enhance risk stratification in autoantibody-positive RA.

Rheumatoid factor and anti-citrullinated protein antibody positivity, but not level, are associated with increased mortality in patients with rheumatoid arthritis: results from two large independent cohorts

IntroductionThis study aimed to investigate rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) status and levels as predictors of mortality in two large cohorts of patients with early inflammatory arthritis (EIA).MethodsData from the Norfolk Arthritis Register (NOAR) and Leiden Early Arthritis Clinic (EAC) cohorts were used. At baseline, patients had demographic data and smoking status recorded; RF, ACPA and inflammatory markers were measured in the local laboratories. Patients were flagged with national death registers until death or censor date. Antibody status was stratified as negative, low or high positive by RF and ACPA levels individually. In addition, patients were grouped as seronegative, RF positive, ACPA positive or double antibody (RF and ACPA) positive. Cox regression models explored associations between antibody status and mortality adjusting for age, sex, smoking status, inflammatory markers and year of enrolment.ResultsA total of 4962 patients were included, 64% were female. Median age at onset was 56 (NOAR) and 54 (EAC) years. In NOAR and EAC respectively, 35% and 42% of patients were ACPA/RF positive. When antibody status was stratified as negative, low or high positive, there were no consistent findings between the two cohorts. Double antibody positivity was associated with excess mortality in both cohorts compared to seronegative patients: NOAR and EAC respective adjusted HR (95% confidence interval) 1.35 (1.09 to 1.68) and 1.58 (1.16 to 2.15).ConclusionsPatients with EIA who are seropositive for both RF and ACPA have increased mortality compared to those who are single positive or seronegative. Antibody level in seropositive patients was not consistently associated with excess mortality.

Improved early identification of arthritis: evaluating the efficacy of Early Arthritis Recognition Clinics

Objective Only 31% of Dutch rheumatoid arthritis (RA)-patients visit a rheumatologist within 12 weeks after symptom onset; this is mainly due to delay at the level of the general practitioner (GP). In order to reduce delay of GPs in identifying early arthritis, we initiated an Early Arthritis Recognition Clinic (EARC). Methods EARCs were initiated at the Leiden and Groningen University Medical Centers. At this EARC, patients filled in a questionnaire about their symptoms, followed by a short visit with only a full joint examination by an experienced rheumatologist. If arthritis was present the patient got an appointment the same week at the regular outpatient clinic. The main outcome parameter was the GP-delay; the secondary outcome parameter was the total delay. In both centres, patients included in early arthritis clinics that had arrived via regular referrals served as control group. Results Four hundred patients visited the Leiden EARC and 212 patients the Groningen EARC. Arthritis was detected in 42% and 49% respectively. The median GP-delay for these arthritis patients was 2.0 (0.4–7.3) and 2.0 (0.4–10.0) weeks and the median total delay 8.6 (3.6–22.3) and 10.6 (3.1–30.8) weeks respectively. At these two clinics 59% and 51% of all arthritis patients and 65% and 53% of the patients that were subsequently diagnosed with undifferentiated arthritis or RA were seen within 12 weeks after symptom onset. In the Leiden and Groningen control groups that arrived via regular referrals, only 32% and 38% were seen within 12 weeks time. Conclusions The EARC increased the early identification of arthritis and RA.

Reasons for medical help-seeking behaviour of patients with recent-onset arthralgia

Objective Patient delay in seeking medical help may cause suboptimal use of the therapeutic window in rheumatoid arthritis. We aimed to assess the motivations and the urgency with which patients with arthralgia seek medical help. Methods 612 patients with arthralgia—visiting two Dutch Early Arthritis Recognition Clinics—were studied. Patients filled out a questionnaire with questions on their symptoms and their reasons for seeking medical help. Comparisons were made for patients with short or prolonged patient delay, patients with and without arthritis, age and gender. Results The median symptom duration was 4 weeks. A prolonged delay in seeking help was associated with a gradual onset of symptoms (78%) and the perception that symptoms would not be serious or would go away (16% and 48%, respectively). Arthralgia patients who promptly sought medical help more often had an acute onset of symptoms and more frequently reported impairments at work or in daily functioning than patients who postponed seeking help (all p<0.005). Patients with and without arthritis generally had similar reasons for seeking help. The proportion of patients who had a prolonged patient delay was comparable between male and female subjects and between age categories. Particularly younger patients postponed seeking help because they thought their symptoms would disappear spontaneously. Conclusions This large-scale study observed several reasons and symptom characteristics influencing the help-seeking behaviour of persons with arthralgia. These data can be helpful to define strategies aiming at early identification of arthritis.

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.

Anaemia to predict radiographic progression in rheumatoid arthritis

The severity of rheumatoid arthritis (RA) is highly variable between patients and currently known risk factors explain only part of this variance. Much research is dedicated to identify additional new risk factors. Such factors may shed light on the processes underlying progression of RA and many risk factors together may enable risk stratification and individualised treatment of RA. With interest we read the study by Möller et al, showing that patients with RA with anaemia have more severe radiological progression. Although anaemia in RA is generally considered to be a consequence of chronic inflammation, this recent study based on patients with RA included in the Swiss SCQM-databaseobserved that the association between anaemia and joint damage was independent of the association between disease activity (measured with the Disease Activity Score including the 28-swollen joint count and erythrocyte sedimentation rate (DAS28ESR) and clinical Disease Activity Index (cDAI)) and joint damage. This led to the presumptions that anaemia in RA captures disease processes that are unmeasured by established disease activity markers (eg, subclinical inflammation) and that evaluation of the haemoglobin level may help to identify patients with rapid radiological progression. Since in science replication of findings is relevant to ascertain the validity, we evaluated the association between anaemia at first presentation and disease severity over 7 years in 676 patients with early RA included in the Leiden Early Arthritis Clinic. Two outcome measures were studied. First, radiological progression; 3502 sets of hand and feet radiographs were made with yearly intervals and scored according to the Sharp-van der Heijde method by one reader (ICC 0.91). Second, disease persistency was assessed by evaluating its counterpart, achieving disease-modifying antirheumatic drugs (DMARD)-free sustained remission. Analyses were done using multivariate normal regression analysis and Cox regression. All analyses were adjusted for age, gender and treatment strategy. The haemoglobin level was determined at first presentation. WHO definitions for the presence and severity of anaemia were used. Of the patients with RA, 24.1% had anaemia at first presentation. These patients were older and had a higher swollen joint count (SJC), erythrocyte sedimentation rate (ESR) and C reactive protein (table 1). Patients with anaemia had more severe joint damage progression (β=1.03, p=0.012, indicating a 1.03 higher rate of joint destruction per year, which equals 1.03=23% more joint damage after 7 years). Similar to Möller et al, we also adjusted for ESR, SJC and rheumatoid factor (RF); this did not affect the association (β=1.03, p=0.040) (figure 1A). When evaluating the three haemoglobin categories a ‘dose-dependent’ effect was observed (β=1.03, p=0.002). Also this association was significant after adjusting for ESR, SJC and RF (β=1.02, p=0.032) (figure 1B). All analyses remained significant when the C reactive protein was included as covariate instead of the ESR (data not shown). Patients with anaemia tended to achieve DMARD-free remission less often than patients without anaemia (HR 0.57, 95% CI 0.34 to 0.95, p=0.031), also after adjusting for ESR, SJC and RF (HR 0.59, 95% CI 0.34 to 1.02, p=0.056) (figure 1C). Analysis on this population-based inception cohort revealed that within RA anaemia is independently associated with radiographic progression. As clinical inflammation in RA may predominantly affect the feet, we evaluated a 66-SJC that—in contrast to the DAS28ESR and cDAI used by Möller et al—included the MTP joints. Nonetheless, we also observed that anaemia independently predicted disease severity. This may indicate that anaemia indeed reflects subclinical inflammation. Future studies are required to unravel this association.