Debbie M. Boeters

The 2010 ACR/EULAR criteria are not sufficiently accurate in the early identification of autoantibody-negative rheumatoid arthritis: Results from the Leiden-EAC and ESPOIR cohorts

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.

Longitudinal IP-10 serum levels are associated with the course of disease activity and remission in rheumatoid arthritis

ABSTRACT 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.

The prevalence of ACPA is lower in rheumatoid arthritis patients with an older age of onset but the composition of the ACPA response appears identical

BackgroundRheumatoid 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.MethodsThe 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.ResultsFrom 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.ConclusionsData 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.

Are MRI-detected erosions specific for RA? A large explorative cross-sectional study

Objectives 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 patients with RA with healthy controls and with other arthritides. Methods 589 newly presenting patients with early arthritis (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 the Rheumatoid Arthritis MRI Scoring System), number, severity, location of erosions and simultaneous presence of MRI-detected inflammation (synovitis and/or bone marrow oedema) were compared; participants were categorised in three age groups (<40, 40–59, ≥60). Results Patients with RA had statistically significant higher total erosion scores than controls but scores of individual persons largely overlapped. Grade ≥2 erosions and MTP5 erosions were specific for RA (specificity 98%–100% and 90%–98% for different age groups). MTP1 erosions were only specific if aged <40 (specificity 98%) and erosions with inflammation if aged <60 (specificity 91%–100%). ≥1 of the mentioned erosion characteristics were present in 29% of patients with RA. Comparing patients with RA with other arthritides revealed that grade ≥2 erosions and MTP5 erosions remained specific for RA (specificity ≥89%) as well as MTP1 erosions if aged <40 (specificity 93%), in contrast to erosions combined with inflammation (specificity 49%–85%). Conclusions Total erosion scores of individual persons were largely overlapping. Erosion characteristics specific for RA were identified, but were infrequently present. Caution is needed not to overestimate the value of MRI erosions in the diagnostic process.

Does the presence of magnetic resonance imaging-detected osteitis at diagnosis with rheumatoid arthritis lower the risk for achieving disease-modifying antirheumatic drug-free sustained remission: results of a longitudinal study

BackgroundAlthough infrequent, some rheumatoid arthritis (RA) patients achieve disease-modifying antirheumatic drug (DMARD)-free sustained remission. The absence of RA-specific autoantibodies, such as anticitrullinated protein antibodies (ACPA), is known to be associated with this outcome but further mechanisms underlying the chronic nature of RA are largely unknown. Magnetic resonance imaging (MRI)-detected bone marrow edema (BME), or osteitis, strongly predicts erosive progression and is associated with ACPA positivity. Therefore, we hypothesized that the presence of MRI-detected osteitis is also predictive of not achieving DMARD-free sustained remission and that the presence of osteitis mediates the association between ACPA and DMARD-free sustained remission.MethodsA 1.5 T unilateral hand and foot MRI was performed at disease presentation in 238 RA patients, evaluating BME, synovitis, and tenosynovitis (summed as MRI inflammation score). DMARD-free sustained remission, defined as the absence of clinical synovitis after DMARD cessation that persisted during the total follow-up, was assessed (median follow-up 3.8 years). Associations between the different MRI-detected inflammatory features and this outcome were studied. A mediation analysis was performed to study whether the presence of BME mediated the association between ACPA and DMARD-free sustained remission. Finally, patterns of MRI-detected inflammation with regard to DMARD-free sustained remission were studied using partial least squares (PLS) regression.ResultsForty-six (19.3%) patients achieved DMARD-free sustained remission. ACPA positivity associated independently with remission (hazard ratio (HR) 0.16, 95% confidence interval (CI) 0.06–0.39). In contrast, no associations were observed between MRI-detected BME (HR 0.99, 95% CI 0.94–1.03), or other MRI inflammatory features, and achieving DMARD-free sustained remission. Thus, the presence of BME did not mediate the association between ACPA and DMARD-free sustained remission. Furthermore, a PLS analysis revealed that patients who did or did not achieve remission could not be distinguished by patterns of MRI-detected inflammation.ConclusionsAt disease presentation, osteitis, as well as other MRI-detected inflammatory features, was not associated with achieving DMARD-free sustained remission over time. Thus, imaging predictors for joint damage and disease persistence differ. The processes mediating RA chronicity remain largely unsolved.

Evaluation of the predictive accuracy of MRI-detected erosions in hand and foot joints in patients with undifferentiated arthritis

Radiographic erosions are a clear hallmark of rheumatoid arthritis (RA). The European League Against Rheumatism (EULAR) definition of radiographic erosive disease has a high specificity, and its fulfilment alone is sufficient to classify RA.1 However, the sensitivity of radiography to detect erosions early in the disease is low. Other imaging techniques, such as MRI, are more sensitive to detect erosions than radiography and are therefore recommended by a EULAR imaging task force.2 To determine the specificity of MRI-detected erosions, we recently compared erosions in the metacarpophalangeal (MCP) and metatarsophalangeal (MTP) joints (scored according to the RA MRI Scoring System (RAMRIS)3) of patients presenting with RA with those of symptom-free persons and patients presenting with arthritides other than RA.4 MRI-detected erosions were present in all groups; therefore, the specificity of the presence of any MRI-detected erosions was low. By evaluating different erosion features, a few features were identified as specific for RA; these were severe erosions (grade ≥2, defined as >10% of bone eroded), erosions in MTP5 and erosions in MTP1 in persons aged <40. A subsequent and clinically relevant question is whether MRI-detected erosions in patients presenting with undifferentiated arthritis (UA) are valuable in predicting future progression to RA. This was explored to a limited extent in our previous study but as the number of patients with UA was limited (n=192), the predictive value of the different ‘RA-specific …

The use of MRI-detected synovitis to determine the number of involved joints for the 2010 ACR/EULAR classification criteria for Rheumatoid Arthritis – is it of additional benefit?

Objective To assess the value of MRI-detected synovitis to determine the number of involved joints on the performance of the 2010-ACR/EULAR classification criteria for rheumatoid arthritis (RA). Methods 277 patients with a clinical suspicion of RA consecutively included in the Leiden Early Arthritis Clinic (EAC)-cohort underwent 1.5T MRI of MCP-, wrist- and MTP-joints. Test characteristics of the 2010-criteria were calculated when the number of involved joints was determined with and without including MRI-detected synovitis. Two outcomes were studied: disease modifying anti-rheumatic drug (DMARD)-initiation and 1987-criteria fulfilment during the first year. Results At baseline, 143 patients were classified as RA. When MRI-detected synovitis was considered, 14 patients additionally fulfilled the 2010-criteria. Of these, 64% (9/14) started DMARDs. When MRI-detected synovitis was also used to determine the number of involved joints the sensitivity changed from 62% to 67%, the specificity from 90% to 84% and the AUC from 0.76 to 0.75. The net reclassification index was −2.4%. When fulfilling the 1987-criteria was used as outcome, results were similar. Conclusion We found no scientific support that the use of MRI-detected synovitis is of additional benefit for the performance of the 2010 classification criteria.

Which patients presenting with arthralgia eventually develop rheumatoid arthritis? The current state of the art

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.

FRI0131 The 2010 acr/eular criteria are insufficiently accurate in the early identification of autoantibody-negative rheumatoid arthritis: results from the leiden-eac and espoir cohorts

Background The 2010-ACR/EULAR criteria were derived to classify 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 the early detection of autoantibody-positive and autoantibody-negative RA. Objectives To compare the performance of the 2010-criteria between autoantibody-positive and autoantibody-negative RA within two different early arthritis cohorts. 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=515 and n=53, respectively). These RA-patients were studied on the presence of ACPA and RF, and on fulfilling the 2010-criteria at baseline, as 2010-positivity indicated that these RA-patients were earlier identified. Results In the EAC, 67% of the selected RA-patients did already fulfil 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, 85% was identified at baseline already with the 2010-criteria. Within autoantibody-negative RA this was 45% (p<0.001). Similarly within autoantibody-positive RA-patients in ESPOIR 92% was 2010-positive at baseline, whereas this was only 25% within autoantibody-negative RA (p<0.001). 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. As it has been demonstrated that early treatment initiation is beneficial for the outcome of ACPA-negative RA as well, other diagnostics are required for the early identification of ACPA-negative RA. Disclosure of Interest None declared

AB0012 In the elderly acpa-negative ra is more prevalent than acpa-positive ra while the composition of the acpa-response appears identical

Background Rheumatoid arthritis (RA) consists of two syndromes, one autoantibody-positive and one autoantibody-negative. This multi-cohort 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. Objectives 1) determine the association between age of RA-onset and the presence of ACPA, rheumatoid factor (RF) and anti-carbamylated protein (anti-CarP) antibodies, 2) study if age of onset was associated with characteristics of the ACPA-response, 3) substantiate previously reported associations between age of onset and clinical characteristics. Methods 3,321 1987-positive RA-patients included in the Leiden-EAC, BARFOT, ESPOIR, Umeå and Lund cohorts were studied at presentation on age of onset and the presence of ACPA, RF and 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 fifty onwards, the proportion of ACPA-negative RA-patients increased in Dutch, Swedish and French cohorts. Similar observations were done 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 a sub(acute) symptom onset. Conclusions Data of five cohorts revealed that with higher 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. Although more biologic studies are needed to characterize the pathogenesis of ACPA-negative polyarthritis at older age, the present data can promote personalized treatment decisions in ACPA-negative patients in daily practice. Disclosure of Interest None declared