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To evaluate the additive value of autoantibodies in identifying systemic sclerosis (SSc) patients with high complication risk.Patients entering the Combined Care In SSc cohort, Leiden University Medical Centre between April 2009 and May 2016 were included. Subgroups of patients were determined using hierarchical clustering, performed on Principal Component Analysis scores, 1) using baseline data of demographic and clinical variables only and 2) with additional use of antibody status. Disease-risk within subgroups was assessed by evaluating 5-year mortality rates. Clinical and autoantibody characteristics of obtained subgroups were compared.In total 407 SSc patients were included, of which 91% (n=371) fulfilled ACR/EULAR 2013 criteria for SSc. Prevalences of autoantibodies were: anti-centromere 37%, anti-topoisomerase (ATA) 24%, anti-RNA polymerase III 5%, anti-fibrillarin 4% and anti-Pm/Scl 5%. Clinical cluster analysis identified 4 subgroups, with two subgroups showing higher than average mortality (resp. 17% and 7% vs. total group mortality of 4%). ATA-positivity ranged from 10 to 21% in low-risk groups and from 30 to 49% among high-risk groups. Adding autoantibody status to the cluster process resulted in 5 subgroups with 3 showing higher than average mortality. Still, 22% of ATA- positive patients were clustered into a low-risk subgroup, while the total number of patients stratified to a high-risk subgroup increased.Autoantibodies only partially contribute to risk-stratification and clinical subsetting in SSc. The current findings confirm that not all ATA-positive patients have worse prognosis and as such, additional biomarkers are needed to guide clinical follow-up in SSc.

Objective Although anticitrullinated protein antibody (ACPA)-positive and ACPA-negative rheumatoid arthritis (RA) have different aetiopathology, the clinical presentation at the time of diagnosis is similar. This study evaluated whether there are phenotypic differences in the symptomatic pre-RA phase. Methods Patients with arthralgia included in the Leiden clinically suspect arthralgia cohort who developed arthritis during follow-up were studied (n=67). Symptoms at symptom onset, symptoms and signs at presentation with arthralgia and time to arthritis development were compared between ACPA-positive and ACPA-negative patients. Results In ACPA-negative patients (n=37), the location of initial symptoms less often included the lower extremities (22% vs 50%, p=0.014). At presentation with arthralgia, ACPA-positive patients had a longer symptom duration (median 22 vs 14 weeks, p=0.005), less tender joints (mean 5 vs 9, p=0.007) and less difficulty making a fist (11% vs 43%, p=0.004). However, after presentation with arthralgia, ACPA-positive patients developed arthritis more quickly (median 6 vs 18 weeks, p=0.015). A partial least squares regression analysis showed clustering of ACPA-positive and ACPA-negative patients based on the above-mentioned clinical variables. Conclusion This study is the first showing that ACPA-positive and ACPA-negative patients have clinical differences in the symptomatic phase preceding clinical arthritis. This contributes to the notion that ACPA-positive and ACPA-negative RA develop differently.

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.

Background Genetic and environmental risk factors for rheumatoid arthritis (RA) are population dependent and may affect disease expression. Therefore, we studied tender and swollen joint involvement in patients newly diagnosed with RA in four countries and performed a subanalysis within countries to assess whether the influence of autoantibody positivity affected disease expression. Methods Patients with symptom duration

Objectives Moderate alcohol consumption is protective against rheumatoid arthritis (RA) development and associated with lower levels of systemic inflammation in RA and in the general population. We therefore hypothesised that moderate alcohol consumption is associated with less severe local inflammation in joints in RA, detected by MRI. Since asymptomatic persons can have low-grade MRI-detected inflammation, we also hypothesised that alcohol consumption is associated with the extent of MRI inflammation in asymptomatic volunteers. Methods 188 newly presenting patients with RA and 192 asymptomatic volunteers underwent a unilateral contrast-enhanced 1.5T MRI of metacarpophalangeal, wrist and metatarsophalangeal joints. The MRIs were scored on synovitis, bone marrow oedema and tenosynovitis; the sum of these yielded the MRI inflammation score. MRI data were evaluated in relation to current alcohol consumption, categorised as non-drinkers, consuming 1–7 drinks/week, 8–14 drinks/week and >14 drinks/week. Association between C reactive protein (CRP) level and alcohol was studied in 1070 newly presenting patients with RA. Results Alcohol consumption was not associated with the severity of MRI-detected inflammation in hand and foot joints of patients with RA (P=0.55) and asymptomatic volunteers (P=0.33). A J-shaped curve was observed in the association between alcohol consumption and CRP level, with the lowest levels in patients consuming 1–7 drinks/week (P=0.037). Conclusion Despite the fact that moderate alcohol consumption has been shown protective against RA, and our data confirm a J-shaped association of alcohol consumption with CRP levels in RA, alcohol was not associated with the severity of joint inflammation. The present data suggest that the pathophysiological mechanism underlying the effect of alcohol consists of a systemic effect that might not involve the joints.

Although rheumatoid arthritis (RA) is a chronic, persistent autoimmune disease, 10 to 15% of RA patients achieve sustained disease-modifying antirheumatic drug (DMARD)-free remission over time. The biological mechanisms underlying the resolution of persistent inflammation in RA are still unidentified, and there is a lack of prognostic markers. It is well established that increased serum levels of gamma interferon-induced protein 10 (IP-10) are associated with (acute) increased inflammatory responses (e.g., in leprosy). In order to assess the potential of IP-10 as a diagnostic tool for inflammatory episodes of RA, we performed a retrospective study and assessed IP-10 levels in longitudinally banked serum samples obtained from patients upon first diagnosis of RA. The selection consisted of 15 persistent RA patients and 19 patients who achieved DMARD-free sustained remission. IP-10 levels, measured by use of a user-friendly quantitative lateral flow assay (LFA), showed up to 170-fold variation interindividually, and baseline IP-10 levels could not be differentiated between the two patient groups. However, a difference in the change in IP-10 levels between the first and last visits (ΔIP-10) was observed ( P = 0.003) between DMARD-free (median ΔIP-10, −662 pg/ml [decrease]) and persistent (median ΔIP-10, 468 pg/ml [increase]) RA patients. Moreover, intraindividual changes in IP-10 levels during the course of disease corresponded to the disease activity score (DAS) ( P = 0.05). These data indicate that IP-10 is associated with disease activity and perseverance of RA. The association of IP-10 with DAS indicates that this tool may be a practical diagnostic aid to help in monitoring disease progression in RA patients and may also find applications in other chronic diseases with exacerbated inflammatory episodes.

OBJECTIVES: Magnetic resonance imaging (MRI) is recommended in the diagnostic process of rheumatoid arthritis (RA), to detect joint damage early. MRI-detected erosions are also present in symptom-free controls, especially at older age. It is unclear if RA-specific MRI-detected erosions can be distinguished from ‘physiological’ erosions in symptom-free individuals. This study compared MRI-detected erosions of RA-patients with healthy controls and with other arthritides. METHODS: 589 newly-presenting early arthritis patients (238 RA, 351 other arthritides) and 193 symptom-free controls underwent contrast-enhanced 1.5T MRI of unilateral metacarpophalangeal- and metatarsophalangeal(MTP)-joints. Total erosion score (according to RAMRIS), number, severity, location of erosions and simultaneous presence of MRI-detected inflammation (synovitis and/or bone marrow edema) were compared; participants were categorized in three age-groups (

ObjectivesSince the 2007 recommendations for the management of early arthritis have been presented, considerable research has been published in the field of early arthritis, mandating an update of the 2007 European League Against Rheumatism (EULAR) recommendations for management of early arthritis.MethodsIn accordance with the 2014 EULAR Standardised Operating Procedures, the expert committee pursued an approach that was based on evidence in the literature and on expert opinion. The committee involved 20 rheumatologists, 2 patients and 1 healthcare professional representing 12 European countries. The group defined the focus of the expert committee and target population, formulated a definition of ‘management’ and selected the research questions. A systematic literature research (SLR) was performed by two fellows with the help of a skilled librarian. A set of draft recommendations was proposed on the basis of the research questions and the results of the SLR. For each recommendation, the categories of evidence were identified, the strength of recommendations was derived and the level of agreement was determined through a voting process.ResultsThe updated recommendations comprise 3 overarching principles and 12 recommendations for managing early arthritis. The selected statements involve the recognition of arthritis, referral, diagnosis, prognostication, treatment (information, education, pharmacological and non-pharmacological interventions), monitoring and strategy. Eighteen items were identified as relevant for future research.ConclusionsThese recommendations provide rheumatologists, general practitioners, healthcare professionals, patients and other stakeholders with an updated EULAR consensus on the entire management of early arthritis.

We thank Mankia et al 1 for their interest in the European League Against Rheumatism (EULAR) definition of arthralgia suspicious for progression to rheumatoid arthritis (RA).2 The authors agree with the taskforce that derivation of criteria for imminent RA is an ambitious next step and that such criteria will probably consist of a combination of clinical, serological and imaging biomarkers.1 In this light we appreciate the work the authors have done to identify serological and imaging markers that are predictive in patients with anti-citrullinated protein antibody (ACPA)-positive arthralgia. While studies on blood and imaging markers in arthralgia are relatively frequent, only few studies have addressed the symptoms and …

We read the letter from Rothschild with interest.1 We agree that we need more data and better evidence on: (1) how to determine the risk of patients with arthralgia progressing to ‘true RA’ and on (2) whether or not Disease Modifying AntiRheumatic Drug (DMARD) treatment is better than placebo in this phase. Both points were discussed in our Viewpoint.2 Cost–benefit analyses can only be performed afterwards. Rothschild seems to …

Objective.Undifferentiated arthritis (UA) is a common form of arthritis. According to the Assessment of Spondyloarthritis international Society (ASAS) criteria for peripheral spondyloarthritis (pSpA), HLA-B27 can be used to help classify patients with pSpA. We tested whether HLA-B27 is increased in patients diagnosed with UA.Methods.Prevalence of HLA-B27 was compared between healthy controls and patients with UA. SpA features were compared between HLA-B27-positive and -negative UA, and SpA.Results.We found 10.1% of UA (38/375) versus 7.2% (403/5584) of controls were HLA-B27-positive (OR 1.5, 95% CI 1.0–2.1; p = 0.037). HLA-B27-positive patients with UA had more SpA features than HLA-B27-negative patients (mean 1.6, SD 1.0, and 0.9 SD 0.6; p < 0.001), but patients with SpA had significantly more SpA features (mean 4.5, SD 1.5; p < 0.001). Family history and preceding infection were features more common in HLA-B27-positive than in HLA-B27-negative UA (15.8% vs 1.3%, p = 0.04 and 15.8% vs 2.6%, p = 0.04). After HLA-B27 testing, 21 additional patients (5.6%) with UA could potentially have been classified with pSpA according to the ASAS criteria.Conclusion.HLA-B27 is more common in patients with UA than in controls. However, the yield of HLA-B27 testing in UA is low. Our results suggest that HLA-B27 testing should be reserved for patients with additional SpA features.

BackgroundThe 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.Methods102 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.ResultsMRI 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 (pConclusionsSubclinical 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.

With great interest, we read the recently published report by Poppelaars et al in which no excess mortality was observed in 155 patients with rheumatoid arthritis (RA) from the COmbinatie therapie Bij Rheumatoide Artritis (COBRA)-trial, who received early intensive treatment, compared with the general population (Standardised mortality rate (SMR) 0.80 (0.59–1.06)).1 The question whether mortality in RA has normalised is debated, as contradicting results have been published.2–8 In many of the studies on mortality, two important factors are not sufficiently taken into account: follow-up duration and disease subtypes. This might explain the conflicting results. Because thus far none of the reported studies incorporated both factors in the analyses, it is too soon to conclude that mortality is ‘normal’ again, as we will show here. We compliment the authors on emphasising the importance of a long follow-up duration by showing in their meta-analysis that excess mortality in RA becomes fully apparent after >10 years. This implies that previous studies that reported on normalisation of mortality had insufficient follow-up to reach this conclusion.2–5 Some studies with a short follow-up duration even showed a seemingly decreased …

Objectives There are conflicting reports concerning the association between alcohol consumption and RA. We performed a case-control study to investigate the association of alcohol consumption with RA as well as with other forms of arthritis. To assess whether alcohol consumption affects long-term disease outcome, we also investigated its association with radiographic progression and sustained drug-free remission in RA. Methods Patients with arthritis and various diagnoses including RA, OA, ReA, SpA and PsA were compared with 5868 controls from the general population. The association of disease with alcohol consumption was analysed by logistic regression analysis. Results Alcohol consumption was inversely associated with not only RA [odds ratio (OR) 0.28, 95% CI 0.23, 0.35] but also OA (OR 0.31, 95% CI 0.16, 0.62) and other forms of arthritis (OR 0.34, 95% CI 0.24, 0.48). A higher degree of systemic inflammation, reflected by the ESR and CRP level, was associated with a smaller proportion of patients consuming alcohol. There was no dose-response relationship between the amount of alcohol consumed and the presence of arthritis. The extent of joint destruction and the rate of sustained drug-free remission were not affected by alcohol consumption. Conclusion Arthritis patients report less alcohol consumption than controls, regardless of the type of arthritis. This suggests that alcohol may either protect against different kinds of arthritis or that the inverse association between alcohol and arthritis may be secondary to disease development, with arthritis patients being less inclined to consume alcohol due to their decreased general well-being.

Background Rheumatoid arthritis (RA) beginning at older age differs from younger-onset RA by several clinical characteristics. Existing data on the association between age of onset and prevalence of autoantibodies are conflicting. Therefore this study determined this association in five cohorts. Furthermore, the association between age of onset and characteristics of the anti-citrullinated protein antibodies (ACPA)-response was explored. Materials and methods 3,321 1987-positive RA-patients included in the Leiden-EAC, BARFOT, ESPOIR, Umea and Lund cohorts were studied on age at diagnosis and presence of ACPA, rheumatoid factor (RF) and anti-carbamylated protein (anti-CarP) antibodies at disease presentation. Logistic regression analyses were performed and effect sizes were summarised in inverse-weighted meta-analyses. ACPA-level was studied within all cohorts and ACPA-isotypes, ACPA-fine-specificity and ACPA-avidity index and clinical characteristics were studied in the Leiden-EAC. Results From the age of fifty onwards, the proportion of ACPA-positive patients decreased with a higher age of onset (OR 0.96 per 1-year increase in age, 95% CI 0.95–0.97). Similar observations were done for RF and anti-CarP. ACPA-level, number of ACPA-isotypes, ACPA-fine-specificity and avidity in ACPA-positive RA-patients were similar in different age-categories. RA-patients older at disease-onset were less often smokers, had higher acute phase reactants and had more often a (sub)acute onset of symptoms. Conclusions Characteristics of the ACPA-response in ACPA-positive RA-patients appeared not age-dependent. The proportion of ACPA-negative RA-patients increased with higher age. The associations with clinical features suggest that part of the ACPA-negative RA-patients with onset at higher age have differences in etiopathology. Further biologic studies are needed to promote personalised medicine in RA.

Early initiation of treatment in patients with inflammatory arthritis at risk of persistence and/or erosive progression is important because it is associated with a reduced rate of progression of joint damage and functional disability. It has been proposed that a window of opportunity exists, during which disease processes are less matured and disease modification can be more effective. The phase of arthralgia preceding clinical arthritis is likely to be an important part of this window of opportunity, during which treatment might prevent progression to clinical arthritis. Several proof-of-concept trials in individuals with arthralgia are now evaluating this hypothesis. Central to such trials is the ability to identify groups at high risk of rheumatoid arthritis (RA) in whom preventive treatment can be tested. This review describes the relevance of adequate prediction making, as well as the accuracy of different types of predictors (including imaging and serological markers) with their value in predicting the progression of arthralgia to arthritis. Despite promising results, studies have been performed in heterogeneous patient populations and most findings have not been validated in independent studies. Future observational or preventive studies should be conducted with homogeneous patient groups (eg, patients fulfilling the European League Against Rheumatism criteria for arthralgia at risk of RA) in order to increase interstudy comparability and to allow result validation.

Background Rheumatoid arthritis (RA) consists of two syndromes, one autoantibody-positive and one autoantibody-negative. Existing data on the relation between age of onset and prevalence of autoantibodies were conflicting. Therefore this multicohort study assessed the age of onset in relation to the presence of autoantibodies. The association with characteristics of the anti-citrullinated protein antibodies (ACPA) response was also explored. Methods The 1987 criteria-positive RA patients included in the Leiden EAC, BARFOT, ESPOIR, Umeå and Lund cohorts (n = 3321) were studied at presentation for age of onset and the presence of ACPA, rheumatoid factor (RF) and anti-carbamylated protein (anti-CarP) antibodies. Logistic regression analyses were performed; effect sizes were summarized in inverse-weighted meta-analyses. Within ACPA-positive RA, ACPA level was studied in all cohorts; ACPA isotypes, ACPA fine specificity and ACPA avidity index and clinical characteristics were studied in the Leiden EAC. Results From the age of 50 onward, the proportion of ACPA-negative RA patients increased with age in the five cohorts. Similar observations were made for RF and anti-CarP. The composition of the ACPA response did not change with increasing age of onset with respect to titer, isotype distribution, fine specificity and avidity index. With increasing age of onset, RA patients smoked less often, had higher acute phase reactants and more often had a sub(acute) symptom onset. Conclusions Data of five cohorts revealed that with older age of onset ACPA-negative RA is more frequent than ACPA-positive RA, while characteristics of ACPA-positive RA as judged by the composition of the ACPA response appeared not age dependent. Further biologic studies are needed to characterize the pathogenesis of ACPA-negative polyarthritis at older age and to promote personalized treatment decisions in ACPA-negative patients in daily practice. Electronic supplementary material The online version of this article (doi:10.1186/s13075-017-1324-y) contains supplementary material, which is available to authorized users.

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, 06% of the patients were ACPA positive and 01% 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.

Objectives Anticitrullinated protein antibodies (ACPA) are specific for rheumatoid arthritis (RA) and have been implicated in disease pathogenesis. Previously we have shown that ACPA display a considerably lower avidity as compared with antibodies against recall antigens. Nonetheless, ACPA-avidity did vary between patients. As antibody mediated effects are influenced by antibody-avidity, we now investigated ACPA-avidity in relation to biological activity and clinical outcome. Methods We determined the avidity of ACPA and related this with severity of joint damage in two Dutch early-RA cohorts containing 199 and 132 patients respectively. Differences in effector functions of low- and high-avidity ACPA were studied. Results Extensive variation in ACPA-avidity between patients was observed. This allowed the analysis of the relationship between avidity and severity. The presence of low-avidity ACPA is associated with a higher rate of joint destruction. This finding was replicated in an independent cohort. Analysis of the properties of low-versus high-avidity ACPA revealed that low-avidity ACPA are less hampered in their ability to bind ‘new’ citrullinated antigens. Although no differences could be observed regarding cellular activation via Fc-γ receptors, low-avidity ACPA were more potent in activating the complement system. Conclusions Patients with low-avidity ACPA display a higher rate of joint destruction. Low-avidity ACPA display a higher potency to interact with more citrullinated antigens in time and show that low-avidity ACPA are more potent in complement activation. These data indicate that (low) avidity impacts on the biological activity of ACPA and associates with a worse radiological outcome.

Objectives. To determine whether molecular remission defined by a multi-biomarker disease activity (MBDA) score predicts a reduced risk of joint damage progression, and whether the MBDA score can augment existing classifications of remission. Methods. The study examined 271 visits for 163 RA patients in the Leiden Early Arthritis Cohort. The MBDA score and other variables from each visit were evaluated for prediction of progression [change in Sharp–van der Heijde Score (ΔSHS) >3] over the ensuing 12 months. Positive likelihood ratios (PLRs) for non-progression were calculated for remission based upon DAS based on 28-joint counts and CRP (DAS28-CRP

OBJECTIVES MRI sensitively detects inflammation, but the clinical relevance of MRI-detected inflammation is undetermined in early arthritis. Therefore, the aim of this cross-sectional study was to investigate the association between MRI-detected inflammation of hands and feet and functional disability in early arthritis. METHODS Five hundred and fourteen early arthritis patients, consecutively included in the Leiden Early Arthritis Clinic, were studied. At baseline a unilateral 1.5 T MRI of the wrist, MCP and MTP joints was performed and functional disability was measured using the HAQ. MRIs were scored for tenosynovitis, synovitis and bone marrow oedema (BME) by two readers. The sum of these types of MRI-detected inflammation yielded the total MRI-inflammation score. Linear and nonlinear regression analyses were performed with HAQ as outcome. RESULTS The total MRI-inflammation score was associated with the HAQ score (β = 0.014, P < 0.001), as were tenosynovitis (β = 0.046, P < 0.001), synovitis (β = 0.039, P < 0.001) and bone marrow oedema scores (β = 0.015, P < 0.001) separately. Analysing these three types of MRI-detected inflammation in one multivariable model revealed that only tenosynovitis was independently associated with the HAQ score (β = 0.039, P < 0.001). Also after correction for age, gender, joint counts, CRP and auto-antibodies, this association remained significant (β = 0.034, P < 0.001). MRI-detected inflammation at wrists or MCP joints associated significantly with impairments in hand functioning (e.g. difficulties with opening milk cartons or jars). Exploring the relation between MRI-detected inflammation and HAQ scores showed no evidence of a floor effect, suggesting that even low scores of MRI-detected inflammation are functionally relevant. CONCLUSION MRI-detected inflammation, and tenosynovitis in particular, is associated with functional disability. This demonstrates the functional relevance of MRI-detected inflammation in early arthritis.

International audience; OBJECTIVES:The 2010 ACR/EULAR criteria were derived to classify rheumatoid arthritis (RA) earlier in time. Previous studies indeed observed that the 2010 criteria were fulfilled earlier than the 1987 criteria. This study determined whether the 2010 criteria perform equally in early classification of autoantibody-positive and autoantibody-negative RA.METHODS:From the total Leiden-EAC (n = 3448) and ESPOIR (n = 813) RA patients who fulfilled the 1987 RA criteria at 1 year but not at presentation were selected (n = 463 and n = 53, respectively), as these patients were classified with delay with the 1987 criteria. These RA patients were studied on fulfilling the 2010 criteria at baseline (as 2010 positivity indicated that these RA patients were earlier identified) and these analyses were stratified for patients with and without anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF). Analyses were repeated for DMARD start within the first year as reference for RA (instead of fulfilling the 1987 criteria).RESULTS:In the EAC, 75% of the selected RA patients did already fulfill the 2010 criteria at baseline. In ESPOIR this was 57%, indeed demonstrating early classification with the 2010 criteria. Among the selected autoantibody-positive RA patients of the EAC, 93% was already identified at baseline with the 2010 criteria. Within autoantibody-negative RA this was 51% (p < 0.001), indicating that 49% of autoantibody-negative RA patients were not early classified with the 2010 criteria. Similarly, within autoantibody-positive RA patients in ESPOIR 92% were 2010 positive at baseline, whereas this was only 25% within autoantibody-negative RA (p < 0.001), indicating that 75% of autoantibody-negative RA patients were not early classified with the 2010 criteria. Similar results were obtained when DMARD start was the reference for RA.CONCLUSIONS:The 2010 criteria perform well in the early identification of autoantibody-positive RA, but autoantibody-negative RA patients are still frequently missed with these criteria. This implies that other diagnostics are required for ACPA-negative patients.

Background The contribution of smoking to rheumatoid arthritis (RA) is hypothesized to be mediated through formation of anti-citrullinated protein antibodies (ACPA). In RA, however, autoantibodies such as ACPA, rheumatoid factor (RF), and anti-carbamylated protein antibodies (anti-CarP) often occur together, and it is thus unclear whether smoking is specifically associated with some autoantibodies rather than others. We therefore investigated whether smoking is only associated with ACPA or with the presence of multiple RA-related autoantibodies. Methods A population-based Japanese cohort (n = 9575) was used to investigate the association of smoking with RF and anti-cyclic citrullinated peptide antibodies (anti-CCP2) in individuals without RA. Furthermore, RA patients fulfilling the 1987 criteria from three early arthritis cohorts from the Netherlands (n = 678), the United Kingdom (n = 761), and Sweden (n = 795) were used. Data on smoking, RF, anti-CCP2, and anti-CarP were available. A total score of autoantibodies was calculated, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by logistic regression. Results In the population-based non-RA cohort, no association was found between smoking and one autoantibody (RF or anti-CCP2), but smoking was associated with double-autoantibody positivity (OR 2.95, 95% CI 1.32–6.58). In RA patients, there was no association between smoking and the presence of one autoantibody (OR 0.99, 95% CI 0.78–1.26), but smoking was associated with double-autoantibody positivity (OR 1.32, 95% CI 1.04–1.68) and triple-autoantibody positivity (OR 2.05, 95% CI 1.53–2.73). Conclusions Smoking is associated with the concurrent presence of multiple RA-associated autoantibodies rather than just ACPA. This indicates that smoking is a risk factor for breaking tolerance to multiple autoantigens in RA. Electronic supplementary material The online version of this article (doi:10.1186/s13075-016-1177-9) contains supplementary material, which is available to authorized users.

The relevance of early identification of rheumatoid arthritis (RA) is acknowledged for several decades. Over time the interpretation of early has changed: in the early 1990s a symptom duration

Human leucocyte antigen (HLA)-DRB1*13 alleles are associated with protection from anticitrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA). It is, however, unknown at which phase of disease development (seroconversion, ACPA maturation, disease onset or outcome) these alleles are most important. We therefore examined the effect of HLA-DRB1*13 on: ACPA presence (systemic autoimmunity associated with RA) in individuals with and without RA, on ACPA characteristics and on clinical outcome measures.The effect of HLA-DRB1*13 on ACPA presence in subjects with or without RA (non-RA) was assessed in the Swedish twin registry (n=10 748). ACPA characteristics were studied in patients with ACPA-positive RA from the Swedish Epidemiological Investigation of RA (EIRA, n=1224) and the Dutch Leiden Early Arthritis Clinic (EAC, n=441). Disease activity at inclusion and disease outcome (disease-modifying antirheumatic drugs (DMARD)-free sustained remission and radiographic progression) was assessed in patients with RA from the EAC.HLA-DRB1*13 is associated with protection from ACPA-positive RA (prevalence 16% vs 28% in ACPA-negative non-RA), but not with significant protection from ACPA in individuals without RA (prevalence: 22%, p value 0.09). HLA-DRB1*13 is associated with lower ACPA-levels (EIRA: 447 U/ml versus 691 U/ml, p value= 0.0002) and decreased citrullinated epitope recognition (EIRA: p0.0001). No association between HLA-DRB1*13 and disease activity or outcome was found.These data indicate that HLA-DRB1*13 mainly affects the onset of ACPA-positive RA in ACPA-positive non-RA individuals. In RA, HLA-DRB1*13 influences ACPA characteristics but not the disease course. This implies that therapeutic strategies aimed at emulating the HLA-DBR1*13 protective effect may be most effective in ACPA-positive healthy individuals at risk for RA.

Background In rheumatoid arthritis (RA) bone marrow edema (BME, osteitis) and anti-citrullinated protein antibodies (ACPA) are associated with radiographic progression. ACPA have been associated with BME, but it is unknown if this association is confined to ACPA and BME. We performed cross-sectional analysis of the association of ACPA, rheumatoid factor (RF) and anti-carbamylated protein (anti-CarP) antibodies with BME and other types of inflammation (synovitis, tenosynovitis) detected by magnetic resonance imaging (MRI). Methods Disease-modifying antirheumatic drug (DMARD)-naïve patients with early arthritis (n = 589), included in the Leiden Early Arthritis Clinic cohort, underwent contrast-enhanced 1.5 T MRI of unilateral wrist, metacarpophalangeal and metatarsophalangeal-joints at baseline. BME, synovitis and tenosynovitis were scored by two readers. ACPA, rheumatoid factor (RF) and anti-CarP were determined at baseline. Results In univariable analyses ACPA-positive patients had higher BME scores than ACPA-negative patients (median 4.5 vs. 2.0, p

Patients with clinically suspect arthralgia (CSA) have, according to their rheumatologists, an increased risk of rheumatoid arthritis (RA), but their actual outcome is unexplored. This longitudinal study investigated (1) progression from CSA to clinically detectable arthritis and (2) associations of clinical factors, serological factors (among which are anticitrullinated peptide antibodies (ACPAs)) and MRI-detected subclinical inflammation with arthritis development.150 patients with CSA were followed for ≥6 months. At baseline, clinical and serological data were collected and unilateral 1.5 T-MRI of metacarpophalangeal (MCP), wrist and metatarsophalangeal (MTP) joints was made. MRI scoring was done according to the RA MRI scoring system. Subclinical MRI inflammation was defined based on MRI results of 193 symptom-free persons.During follow-up (median=75 weeks, IQR=41-106 weeks), 30 patients developed clinical arthritis; 87% did so20 weeks after inclusion. In multivariable analyses, age, localisation of initial symptoms in small and large joints (compared with small joints only), C-reactive protein level, ACPA-positivity and subclinical MRI inflammation significantly associated with arthritis development; ACPA and MRI inflammation were most strongly associated (HR (95% CI) respectively, 6.43 (2.57 to 16.05) and 5.07 (1.77 to 14.50)). After 1-year follow-up, 31% of the patients with MRI inflammation and 71% of the ACPA-positive patients with MRI inflammation had progressed to arthritis. Forty-three per cent of the patients that developed arthritis within 1 year were ACPA-negative; 78% of them had subclinical MRI inflammation at baseline. When MRI inflammation was absent arthritis development was infrequent (6% in all patients with CSA and 3% in ACPA-negative patients with CSA).Subclinical MRI inflammation precedes clinical arthritis with a few months. Subclinical MRI inflammation is, independent of other factors such as ACPA, associated with arthritis development.

Background In the population a high body mass index (BMI) has been associated with slightly increased inflammatory markers. Within rheumatoid arthritis (RA), however, a high BMI has been associated with less radiographic progression; this phenomenon is unexplained. We hypothesized that the phenomenon is caused by an inverse relationship between BMI and inflammation in hand and foot joints with RA. To explore this hypothesis, local inflammation was measured using magnetic resonance imaging (MRI) in early arthritis patients presenting with RA or other arthritides and in asymptomatic volunteers. Methods A total of 195 RA patients, 159 patients with other inflammatory arthritides included in the Leiden Early Arthritis Clinic, and 193 asymptomatic volunteers underwent a unilateral contrast-enhanced 1.5 T MRI scan of metacarpophalangeal, wrist, and metatarsophalangeal joints. Each MRI scan was scored by two readers on synovitis, bone marrow edema (BME), and tenosynovitis; the sum yielded the total MRI inflammation score. Linear regression on log-transformed MRI data was used. Results A higher BMI was associated with higher MRI inflammation scores in arthritides other than RA (β = 1.082, p

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.

Objectives To assess the diagnostic value of MRI for early RA. In some RA patients, a classifiable diagnosis cannot be made at first presentation; these patients present with unclassified arthritis (UA). The use of MRI for early diagnosis of RA is recommended, yet the evidence for its reliability is limited. Methods MRI of hand and foot was performed in 589 early arthritis patients included in the Leiden Early Arthritis Clinic (229 presented with RA, 159 with other arthritides and 201 with UA). Symptom-free controls provided a reference for defining an abnormal MRI. In preliminary investigations, MRI of patients who presented with RA was compared with MRI of symptom-free controls and of patients with other arthritides. Thereafter, the value of MRI in early RA diagnosis was determined in UA patients using the 1-year follow-up on fulfilling the 1987 RA criteria and start of disease-modifying drugs as outcomes. Results Preliminary investigations were promising. Of the UA patients, 14% developed RA and 37% started disease-modifying treatment. MRI-detected tenosynovitis was associated with RA development independent of other types of MRI-detected inflammation [odds ratio (OR) = 7.5, 95% CI: 2.4, 23] and also independent of age and other inflammatory measures (swollen joints, CRP) (OR = 4.2, 95% CI: 1.4, 12.9). Within UA patients, the negative predictive value of abnormal tenosynovitis was 95% (95% CI: 89%, 98%) and the positive predictive value 25% (95% CI: 17%, 35%). The performance was best in the subgroup of UA patients presenting with oligoarthritis (18% developed RA): the positive predictive value was 36% (95% CI: 23%, 52%), the negative predictive value was 98% (95% CI: 88%, 100%), the sensitivity was 93% (95% CI: 70%, 99%) and the specificity was 63% (95% CI: 51%, 74%). Conclusion MRI contributes to the identification of UA patients who will develop RA, mostly in UA patients presenting with oligoarthritis.

The rheumatology field is moving towards identifying individuals with an increased risk for rheumatoid arthritis (RA) at a stage when arthritis is still absent but persons having clinically suspect arthralgia (CSA). Incorporating patients’ views in rheumatologic care is pivotal; however, the views of persons with CSA on their condition are unknown. We aimed to help fill this gap by exploring illness perceptions of persons with CSA and their views on hypothetical prognoses for developing RA. Persons with CSA were invited to participate in a semi-structured focus group discussion. Illness perceptions according to the Common Sense Model (CSM) and four a priori formulated themes were explored in detail during the group discussion. The discussion was audio-taped and transcribed verbatim. Transcripts were analysed in an interpretative phenomenological approach manner, on the basis of the dimensions of the CSM by three researchers independently. The views of four participants with CSA were explored during one focus group discussion. Four dimensions of the CSM were mainly observed: Identity, Consequences, Personal Control and Concern. None of the patients identified themselves as being a patient. They did experience pain and impairments in daily functioning and were concerned that their symptoms would progress. In the absence of physician-initiated treatment, some patients changed lifestyle in order to reduce pain and to promote health. Patients unanimously said that they could not interpret prognostic information on RA development expressed in hypothetical chances. Persons with CSA do not consider themselves patients. Prognostic information related to the development of RA based on risk percentages was considered as not useful by persons with CSA. Understanding of the illness perceptions of persons with CSA by health care professionals might improve medical management and facilitate shared decision-making.

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.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.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 p0.005). 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.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.

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/beta-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.

Autoimmune responses against posttranslationally modified antigens are a hallmark of several autoimmune diseases. For example, antibodies against citrullinated protein antigens (ACPA) have shown their relevance for the prognosis and diagnosis of rheumatoid arthritis (RA), and have been implicated in disease pathogenesis. It is conceivable that other autoantibody systems, recognizing other posttranslationally modified proteins, are also present in RA. Here, we describe the presence of an autoantibody system that discriminates between citrulline- and homocitrulline-containing antigens in the sera of RA-patients. IgG antibodies recognizing carbamylated (homocitrulline-containing) antigens were present in sera of over 45% of RA-patients. Likewise, anticarbamylated protein (anti-CarP) IgA antibodies were observed in 43% of RA-sera. ACPA and anti-CarP antibodies are distinct autoantibodies because, in selected double-positive patients, the anti-CarP antibody binding to carbamylated antigens could be inhibited by carbamylated antigens, but not by control or citrullinated antigens. Similarly, ACPA-binding to citrullinated antigens could only be inhibited by citrullinated antigens. In line with this observation, 16% of ACPA-negative RA-patients, as measured by a standard ACPA assay, harbored IgG anti-CarP antibodies, whereas 30% of these patients tested positive for IgA anti-CarP antibodies. The presence of anti-CarP antibodies was predictive for a more severe disease course in ACPA-negative patients as measured by radiological progression. Taken together, these data show the presence of a unique autoantibody system recognizing carbamylated, but not citrullinated, protein antigens. These antibodies are predictive for a more severe clinical course in ACPA-negative RA-patients, indicating that anti-CarP antibodies are a unique and relevant serological marker for ACPA-negative RA.

To investigate the feasibility of automatic quantification of bone marrow edema (BME) on MRI of the wrist in patients with early arthritis.For 485 early arthritis patients (clinically confirmed arthritis of one or more joints, symptoms for less than 2 years), MR scans of the wrist were processed in three automatic stages. First, super-resolution reconstruction was applied to fuse coronal and axial scans into a single high-resolution 3D image. Next, the carpal bones were located and delineated using atlas-based segmentation. Finally, the extent of BME within each bone was quantified by identifying image intensity values characteristic of BME by fuzzy clustering and measuring the fraction of voxels with these characteristic intensities within each bone. Correlation with visual BME scores was assessed through Pearson correlation coefficient.Pearson correlation between quantitative and visual BME scores across 485 patients was r=0.83, P0.001.Quantitative measurement of BME on MRI of the wrist has the potential to provide a feasible alternative to visual scoring. Complete automation requires automatic detection and compensation of acquisition artifacts. Magn Reson Med 79:1127-1134, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

ObjectiveMRI depicts inflammation and structural damage in rheumatoid arthritis (RA). The validity of MRI-scoring of wrist-joints and metacarpophalangeal-joints according to the RA MRI score(RAMRIS) has been demonstrated. The Outcomes in Rheumatology Clinical Trials (OMERACT) RAMRIS Working Group recently called for validation of the RAMRIS of the metatarsophalangeal (MTP)-joints. Therefore, a systematic literature review was performed to test if the RAMRIS applied to the MTP-joints meets the OMERACT Filter of Truth, Discrimination and Feasibility.MethodsMedical literature databases up to January 2018 were systematically reviewed for studies reporting on RAMRIS applied to MRI of the MTP-joints in RA. To be included, an article had to contain at least one MRI-feature (synovitis, bone marrow oedema (BME), tenosynovitis, erosion, joint space narrowing (JSN)) and one item from the OMERACT Filter: Truth (face, content and construct validity), Discrimination (test-retest reliability, ability to discriminate in trials, longitudinal construct validity and thresholds of meaning) and Feasibility.ResultsOf the 749 retrieved studies, 13 were included, of which 9 provided data on construct validity, 4 on discrimination (3 on reliability, 2 on longitudinal construct validity and 1 on ability to discriminate in trials) and none on feasibility. Construct validity was suggested for BME and erosions, but lacking for synovitis, tenosynovitis and JSN. Data for discrimination remain to be developed for all outcomes.ConclusionAccording to the OMERACT Filter, the validity of the RAMRIS of the forefeet is insufficient in different aspects. A research agenda was determined.

Objective During the last decade, rheumatologists have learned to initiate disease-modifying antirheumatic drugs (DMARDs) early to improve the outcome of rheumatoid arthritis (RA). However, the effect of delay in assessment by a rheumatologist on the outcome of RA has scarcely been explored. The purpose of this study was to examine the association between delay in assessment by a rheumatologist, rates of joint destruction, and probability of achieving DMARD-free remission in patients with RA. Patient characteristics associated with components of delay (by the patient, by the general practitioner [GP], and overall) were assessed. Methods A total of 1,674 early arthritis patients from the Leiden Early Arthritis Clinic cohort were evaluated for patient delay, GP delay, and total delay in assessment by a rheumatologist. Among 598 RA patients, associations between total delay, achievement of sustained DMARD-free remission, and the rate of joint destruction over 6 years followup were determined. Results The median patient, GP, and total delays in seeing a rheumatologist among patients with early arthritis were 2.4 weeks, 8.0 weeks, and 13.7 weeks, respectively. Among all diagnoses, those diagnosed as having RA or spondylarthritis had the longest total delay (18 weeks). Among the RA patients, 69% were assessed in ≥12 weeks; this was associated with a hazard ratio of 1.87 for not achieving DMARD-free remission and a 1.3 times higher rate of joint destruction over 6 years, as compared with assessment in

OBJECTIVES In order to allow personalized medicine, adequate prediction of disease outcome is required. In early undifferentiated arthritis (UA), prediction of the development of RA is crucial, and in case of RA predicting the severity of the disease course may guide individualized treatment decisions. METHODS A total of 570 UA patients and 676 RA patients included in the Leiden Early Arthritis Clinic cohort were studied for baseline characteristics. The disease outcomes studied were fulfillment of the 1987 ACR-RA criteria and arthritis persistence in UA patients and the rate of radiological joint destruction and achieving sustained DMARD-free remission in RA patients. RESULTS Predictive factors for fulfillment of the 1987 ACR-RA criteria and for persistent arthritis in UA were largely similar. Risk factors for a severe rate of joint destruction were: older age (P

Rheumatoid arthritis (RA) is characterized by inflammatory arthritis and localized destruction of bone and cartilage. The severity of joint destruction is highly variable between patients and, according to the findings of twin studies, substantially influenced by genetic factors (1). Nevertheless, the precise contribution of genetic factors has yet to be determined. To date, only a small number of genetic risk factors have been identified, and apart from HLA, the association of none of these factors with RA severity has been convincingly replicated. In contrast, the genetics of susceptibility to RA has been considerably boosted, largely due to the findings of genome-wide association studies. In addition to the HLA–DRB1 shared epitope alleles, several new susceptibility factors have been identified, and their association with RA has been independently replicated: PTPN22, TRAF1/C5, OLIG3/TNFAIP3, and STAT4. Intriguingly, for many of these genetic risk factors, the associations are confined to RA patients positive for anti–citrullinated protein antibody (ACPA). It remains unknown whether genetic factors also affect the severity of joint destruction in ACPA-positive and ACPA-negative RA in different ways. Nonetheless, compelling evidence demonstrates that ACPA-positive RA patients have a more destructive disease course than do ACPA-negative RA patients. A recent meta-analysis of 2 genome-wide association studies identified 6 new risk loci (rs4810485 [CD40], rs1678542 [KIF5A/PIP4K2C], rs42041 [CDK6], rs2812378 [CCL21], rs4750316 [PRKCQ], and rs3890745 [MMEL1/TNFRSF14]) as susceptibility factors for autoantibody-positive RA (2). In the present study, we investigated the association between these single-nucleotide polymorphisms (SNPs) and the rate of radiologic joint destruction in RA patients and in ACPA-positive RA in particular using a large longitudinal cohort. A cohort of ACPA-positive RA patients was used for replication analysis. We found that a genetic variant in the CD40 gene is associated with the rate of joint destruction in ACPA-positive RA patients.

The majority of genetic risk factors for rheumatoid arthritis (RA) are associated with anticitrullinated protein antibody (ACPA)-positive RA, while far fewer genetic risk factors have been identified for ACPA-negative RA. This study was undertaken to quantify the contribution of genetic risk factors in general, and of the predisposing HLA-DRB1 shared epitope (SE) alkies in particular, to the ACPA-positive and ACPA-negative subsets of RA, by computing their heritability and assessing the contribution of the HLA SE alleles. Methods. One hundred forty-eight RA twin pairs, in which at least 1 twin of each pair had RA, were tested for ACPAs and typed for HLA-DRB1 genotypes. Heritability was assessed in a logistic regression model including a bivariate, normally distributed random effect, representing the contribution of unobserved genetic factors to RA susceptibility, with the correlation of the random effects fixed according to twin zygosity. The contribution of the HLA SE alleles to genetic variance was assessed using a similar model, except that estimates were based on genotype-specific population prevalences. Results. The heritability of RA among the twin pairs was 66% (95% confidence interval [95% CI] 44-75%). For ACPA-positive RA, the heritability was 68% (95% CI 55-79%), and for ACPA-negative RA it was 66% (95% CI 21-82%). Presence of the HLA SE alleles explained 18% (95% CI 16-19%) of the genetic variance of ACPA-positive RA but only 2.4% (95% CI 1.6-10%) of the genetic variance of ACPA-negative RA. Conclusion. The heritability of ACPA-positive RA is comparable with that of ACPA-negative RA. These data indicate that genetic predisposition plays an important role in the pathogenesis of ACPA-negative RA, for which most individual genetic risk factors remain to be identified. © 2009, American College of Rheumatology.

Objective Remission has become an attainable goal of rheumatoid arthritis (RA) treatment, especially since the advent of biologic antirheumatic therapy. Because little is known about patients who achieve disease remission with conventional treatment, we used 2 large independent inception cohorts to study the prevalence of and predictive factors for disease-modifying antirheumatic drug (DMARD)–free sustained remission after treatment with conventional therapy. Methods Remission of disease was assessed in 454 patients from the Leiden Early Arthritis Clinic (EAC) and in 895 patients from the British Early Rheumatoid Arthritis Study (ERAS) who fulfilled the American College of Rheumatology 1987 revised criteria for the classification of RA and were treated with conventional therapy. Sustained DMARD-free remission was defined as fulfilling the following criteria for at least 1 year: 1) no current DMARD use, 2) no swollen joints, and 3) classification as DMARD-free remission by the patient's rheumatologist. Predictive factors were identified by Cox regression analysis. Results Sustained DMARD-free remission was achieved by 68 of 454 patients (15.0%) in the Leiden EAC and by 84 of 895 patients (9.4%) in the ERAS. Six factors were associated with sustained DMARD-free remission in both cohorts: acute onset, short symptom duration before inclusion, not smoking, little radiographic damage at baseline, absence of IgM rheumatoid factor (IgM-RF), and absence of HLA shared epitope alleles. In the ERAS, low disease activity at baseline was also predictive of remission. Multivariate analyses revealed symptom duration and the absence of autoantibodies (anti–cyclic citrullinated peptide 2 and IgM-RF) as independent predictors. Conclusion Sustained DMARD-free remission in RA patients treated with conventional therapy is not uncommon. Symptom duration at presentation and the absence of autoantibodies are associated with sustained DMARD-free remission.

Objective The decision to start disease-modifying antirheumatic drugs in patients with recent-onset undifferentiated arthritis (UA) is complicated by a varied natural disease course in which the disease in one-third of patients progresses to rheumatoid arthritis (RA), whereas 40–50% of patients experience spontaneous remission. Recently, a prediction rule was developed to estimate the chance of progression to RA in individual patients presenting with UA. This study investigates the accuracy of this prediction rule in independent cohorts of patients with UA. Methods In 3 cohorts of patients with recent-onset UA, from the UK, Germany, and The Netherlands, the prediction score and the corresponding chance of developing RA were calculated. These data were compared with the observed disease outcome after ≥1 year of followup. Positive predictive values (PPVs) and negative predictive values (NPVs) were calculated and the overall discriminative ability of the prediction rule was assessed using area under the receiver operating characteristic curves (AUCs). Results Since data on the severity of morning stiffness were not available in all validation cohorts, the prediction rule was rederived with the duration of morning stiffness as a substitute. The AUC for this rule was 0.88 (SEM 0.015). For each validation cohort, the AUC was 0.83 (SEM 0.041), 0.82 (SEM 0.037), and 0.95 (SEM 0.031) in the British, German, and Dutch cohorts, respectively. The NPV (for a prediction score ≤6) in these 3 cohorts was 83%, 83%, and 86%, respectively; the PPV (for a prediction score ≥8) was 100%, 93%, and 100%, respectively. Conclusion The recently derived prediction rule, when applied to 3 independent cohorts of patients with UA, has an excellent discriminative ability for assessing the likelihood of progression to RA. Application of this rule will allow individualized treatment decision-making for patients with UA.

There is increasing evidence that common genetic variants can contribute to general immune dysregulation and susceptibility to noninfectious inflammatory diseases. The cytotoxic T-lymphocyte-associated protein 4 (CTLA4) has been associated with Graves disease, type 1 diabetes (T1D), Addison’s disease, celiac disease and rheumatoid arthritis (RA) with odds ratios (ORs) ranging from 1.1 to 1.5 (1). In addition, a missense SNP, rs2476601, in the intracellular tyrosine phosphatase, PTPN22, has been found to be a risk factor (OR = 1.4–2.0) for a number of autoimmune diseases including RA, T1D, autoimmune thyroid disease and systemic lupus erythematosis (SLE) (1) while variants in the third intron of the transcription factor, STAT4, have been associated with risk to both RA and SLE (OR = 1.2–1.8) (2). Finally, the recent plethora of whole genome association (WGA) publications suggests common variants in other genes such as PTPN2 and IL2RA may contribute to risk of multiple noninfectious inflammatory diseases (3,4).

To identify rheumatoid arthritis risk loci in European populations, we conducted a meta-analysis of two published genome-wide association (GWA) studies totaling 3,393 cases and 12,462 controls. We genotyped 31 top-ranked SNPs not previously associated with rheumatoid arthritis in an independent replication of 3,929 autoantibody-positive rheumatoid arthritis cases and 5,807 matched controls from eight separate collections. We identified a common variant at the CD40 gene locus (rs4810485, P = 0.0032 replication, P = 8.2 x 10(-9) overall, OR = 0.87). Along with other associations near TRAF1 (refs. 2,3) and TNFAIP3 (refs. 4,5), this implies a central role for the CD40 signaling pathway in rheumatoid arthritis pathogenesis. We also identified association at the CCL21 gene locus (rs2812378, P = 0.00097 replication, P = 2.8 x 10(-7) overall), a gene involved in lymphocyte trafficking. Finally, we identified evidence of association at four additional gene loci: MMEL1-TNFRSF14 (rs3890745, P = 0.0035 replication, P = 1.1 x 10(-7) overall), CDK6 (rs42041, P = 0.010 replication, P = 4.0 x 10(-6) overall), PRKCQ (rs4750316, P = 0.0078 replication, P = 4.4 x 10(-6) overall), and KIF5A-PIP4K2C (rs1678542, P = 0.0026 replication, P = 8.8 x 10(-8) overall).

Objectives. To evaluate the multi-biomarker disease activity (MBDA) score as a predictor of radiographic progression and compare it with other risk factors among patients with established RA receiving non-biologic DMARDs. Methods. For 163 patients with RA, we assessed 271 visits for MBDA score (scale of 1−100), clinical data and subsequent 1-year radiographic progression (change in Sharp−van der Heijde score [SHS]). Scatter plot and non-parametric quantile regression curves evaluated the relationship between the MBDA score and change in SHS. Changes in joint space narrowing and erosions were compared among MBDA categories with Wilcoxon rank-sum tests. The ability of the MBDA score to independently predict progression was determined by multivariate models and cross-classification of MBDA score with other risk factors. Generalized estimating equation methodology was used in model estimations to adjust for same-patient visits, always ≥1 year apart. Results. Patient characteristics included 67% female, 66%/67% RF+/anti-CCP+; mean age 55 years, MBDA score 43 (moderate = 30−44); median disease duration 4.6 years, SHS 23. Radiographic progression was infrequent for low MBDA scores. Relative risk for progression increased continuously as the MBDA score increased, reaching 17.4 for change in SHS >5 with MBDA scores ≥60. Joint space narrowing and erosion progression were associated with MBDA score. MBDA score was associated with radiographic progression after adjustments for other risk factors. MBDA score significantly differentiated risk for progression when swollen joint count, CRP or DAS28–CRP was low, and among seropositive patients. Conclusion. MBDA score enhanced the ability of conventional risk factors to predict radiographic progression in patients with established RA receiving non-biologic DMARDs.