H.W. van Steenbergen

Disease-modifying antirheumatic drug-free sustained remission in rheumatoid arthritis: an increasingly achievable outcome with subsidence of disease symptoms

Objective Disease-modifying antirheumatic drug (DMARD)-free sustained remission, the sustained absence of synovitis after cessation of DMARD therapy, is a relevant long-term outcome of rheumatoid arthritis (RA) if (1) its occurrence is promoted by treatment and (2) this status reflects resolution of symptoms and disability. This study investigated both items. Methods 1007 patients with RA diagnosed between 1993 and 2011, included in the Leiden Early Arthritis Clinic, were studied on achieving DMARD-free sustained remission. Patients included in 1993–1995 were initially treated with non-steroidal anti-inflammatory drugs, in 1996–1998 mild DMARDs were started early, from 1999 onwards methotrexate was initiated promptly and from 2005 onwards disease activity score (DAS)-steered treatment was common. Remission rates were compared using Kaplan–Meier curves and Cox proportional regression. Results In total, 155 patients achieved DMARD-free sustained remission. Specific treatment strategies were significantly associated with achieving remission (p<0.001). Cox regression adjusted for anticitrullinated protein antibody/rheumatoid factor, swollen joint count, erythrocyte sedimentation rate, C-reactive protein revealed HRs for DMARD-free sustained remission of 1.13 (95% CI 0.48 to 2.64) in patients diagnosed in 1996–1998, 2.39 (1.07 to 5.32) in patients treated with early methotrexate (inclusion 1999–2004) and 3.72 (1.60 to 8.62) in those treated early with methotrexate and DAS-steered therapy (inclusion 2005–2011). At the time of remission, the Health Assessment Questionnaire was at the level of the general population (median 0.13, IQR 0–0.63). Also, patient-rated visual analogue scale (VAS) morning stiffness, fatigue, pain and disease activity were low (median (IQR) mm, 14 (2–27), 10 (0–47), 6 (0–20), 7 (0–20), respectively). Conclusions More intensive treatment strategies increased the chance for DMARD-free sustained remission, indicating that RA chronicity can be influenced. Patients with RA achieving DMARD-free sustained remission have a normalised functional status.

The association between anti-carbamylated protein (anti-CarP) antibodies and radiographic progression in early rheumatoid arthritis: a study exploring replication and the added value to ACPA and rheumatoid factor

Objective Anti-carbamylated protein (anti-CarP) antibodies are reported to associate with more radiographic progression within the total rheumatoid arthritis (RA) population and anti-citrullinated peptide antibody (ACPA)-negative subgroup. We explored the association of anti-CarP with radiographic progression in RA and aimed to replicate the association and evaluate the added value of anti-CarP antibodies in relation to ACPA and rheumatoid factor (RF). Methods 576 Swedish and 628 Dutch patients with RA (2394 and 3247 sets of radiographs, respectively) were longitudinally studied. Replication was restricted to the Swedish patients. In both cohorts, the association of anti-CarP with radiographic progression was determined in strata of patients with similar ACPA and RF status; results of both cohorts were combined in fixed-effect meta-analyses. The net percentage of patients for whom the radiographic progression in 5 years was additionally correctly classified when adding anti-CarP to a model including ACPA and RF was evaluated. Results Anti-CarP associated with radiographic progression in the total Swedish RA population (beta=1.11 per year, p=8.75×10−13) and in the ACPA-negative subgroup (beta=1.14 per year, p=0.034). Anti-CarP associated with more radiographic progression in the strata of ACPA-positive/RF-negative, ACPA-negative/RF-positive and ACPA-positive/RF-positive patients with RA (respective p values 0.014, 0.019 and 0.0056). A model including ACPA and RF correctly classified 54% and 57% of the patients; adding anti-CarP to this model did not increase these percentages (54% and 56% were correctly classified). Conclusions Anti-CarP antibodies associated with more severe radiographic progression in the total and ACPA-negative RA population. Anti-CarP-positivity had a statistically significant additive value to ACPA and RF, but did not improve correct classification of patients.

Anticitrullinated protein antibodies and rheumatoid factor are associated with increased mortality but with different causes of death in patients with rheumatoid arthritis: a longitudinal study in three European cohorts.

Objective Patients with rheumatoid arthritis (RA)-related autoantibodies have an increased mortality rate. Different autoantibodies are frequently co-occurring and it is unclear which autoantibodies associate with increased mortality. In addition, association with different causes of death is thus far unexplored. Both questions were addressed in three early RA populations. Methods 2331 patients with early RA included in Better Anti-Rheumatic Farmaco-Therapy cohort (BARFOT) (n=805), Norfolk Arthritis Register (NOAR) (n=678) and Leiden Early Arthritis Clinic cohort (EAC) (n=848) were studied. The presence of anticitrullinated protein antibodies (ACPA), rheumatoid factor (RF) and anticarbamylated protein (anti-CarP) antibodies was studied in relation to all-cause and cause-specific mortality, obtained from national death registers. Cox proportional hazards regression models (adjusted for age, sex, smoking and inclusion year) were constructed per cohort; data were combined in inverse-weighted meta-analyses. Results During 26 300 person-years of observation, 29% of BARFOT patients, 30% of NOAR and 18% of EAC patients died, corresponding to mortality rates of 24.9, 21.0 and 20.8 per 1000 person-years. The HR for all-cause mortality (95% CI) was 1.48 (1.22 to 1.79) for ACPA, 1.47 (1.22 to 1.78) for RF and 1.33 (1.11 to 1.60) for anti-CarP. When including all three antibodies in one model, RF was associated with all-cause mortality independent of other autoantibodies, HR 1.30 (1.04 to 1.63). When subsequently stratifying for death cause, ACPA positivity associated with increased cardiovascular death, HR 1.52 (1.04 to 2.21), and RF with increased neoplasm-related death, HR 1.64 (1.02 to 2.62), and respiratory disease-related death, HR 1.71 (1.01 to 2.88). Conclusions The presence of RF in patients with RA associates with an increased overall mortality rate. Cause-specific mortality rates differed between autoantibodies: ACPA associates with increased cardiovascular death and RF with death related to neoplasm and respiratory disease.

Magnetic Resonance Imaging-Detected Features of Inflammation and Erosions in Symptom-Free Persons From the General Population.

The use of magnetic resonance imaging (MRI)–detected inflammation and joint damage in the diagnosis of rheumatoid arthritis is recommended by a European League Against Rheumatism imaging task force. This recommendation is based on the sensitivity of MRI and not on specificity. Knowledge of the prevalence of MRI‐detected features in symptom‐free persons, however, is pivotal when considering MRI for diagnostic purposes.

The effects of rheumatoid factor and anticitrullinated peptide antibodies on bone erosions in rheumatoid arthritis

With interest we read the article by Hecht et al 1 who studied the associations of anticitrullinated peptide antibodies (ACPA) and rheumatoid factor (RF) with bone erosions in rheumatoid arthritis (RA). The background of this study was that ACPAs directed against citrullinated vimentin induce differentiation of osteoclasts, indicating that ACPA has a direct effect on bone resorption.2 No biological data are available on whether RF also affects bone cells and, given the overlap between ACPA-positivity and RF-positivity, the authors wanted to distinguish the association between RF and bone erosions from the association between ACPA and bone erosions. In a cross-sectional study, high-resolution peripheral quantitative CT (HR-pQCT) images of metacarpophalangeal (MCP) 2–4 joints of 238 patients with RA were made and groups of patients with different combinations of autoantibodies were compared. The authors observed mainly differences in erosive burden in patients with both antibodies compared with those without antibodies. In a subgroup analysis, they also reported a higher erosive burden in ACPA+/RF+ patients compared with ACPA+/RF− patients. Based on their findings the authors suggested that RF may act as an enhancer of bone loss in ACPA-positive patients. HR-pQCT is an interesting tool that admits …

Fatigue in rheumatoid arthritis; a persistent problem: a large longitudinal study

Objective Fatigue is prevalent and disabling in rheumatoid arthritis (RA). Surprisingly, the long-term course of fatigue is studied seldom and it is unclear to what extent it is influenced by inflammation. This study aimed to determine the course of fatigue during 8 years follow-up, its association with the severity of inflammation and the effect of improved treatment strategies. Methods 626 patients with RA included in the Leiden Early Arthritis Clinic cohort were studied during 8 years. Fatigue severity, measured on a 0–100 mm scale, and other clinical variables were assessed yearly. Patients included in 1993–1995, 1996–1998 and 1999–2007 were treated with delayed treatment with disease-modifying antirheumatic drugs (DMARDs), early treatment with mild DMARDs and early treatment with methotrexate respectively. After multiple imputation, the serial measurements were analysed using linear quantile mixed models. Results Median fatigue severity at baseline was 45 mm and remained, despite treatment, rather stable thereafter. Female gender (effect size=4.4 mm), younger age (0.2 mm less fatigue/year), higher swollen and tender joint counts (0.3 mm and 1.0 mm more fatigue/swollen or tender joint) and C reactive protein-levels (0.1 mm more fatigue per mg/L) were independently and significantly (p<0.05) associated with fatigue severity over 8 years. Although improved treatment strategies associated with less severe radiographic progression, there was no effect on fatigue severity (p=0.96). Conclusions This largest longitudinal study on fatigue so far demonstrated that the association between inflammation and fatigue is statistically significant but effect sizes are small, suggesting that non-inflammatory pathways mediate fatigue as well. Improved treatment strategies did not result in less severe fatigue. Therefore, fatigue in RA remains an ‘unmet need’.

MR‐detected features of inflammation and erosions occur in symptom‐free persons from the general population

The use of magnetic resonance imaging (MRI)–detected inflammation and joint damage in the diagnosis of rheumatoid arthritis is recommended by a European League Against Rheumatism imaging task force. This recommendation is based on the sensitivity of MRI and not on specificity. Knowledge of the prevalence of MRI‐detected features in symptom‐free persons, however, is pivotal when considering MRI for diagnostic purposes.

Association of Valine and Leucine at HLA–DRB1 Position 11 With Radiographic Progression in Rheumatoid Arthritis, Independent of the Shared Epitope Alleles but Not Independent of Anti–Citrullinated Protein Antibodies

For decades it has been known that the HLA–DRB1 shared epitope (SE) alleles are associated with an increased risk of development and progression of rheumatoid arthritis (RA). Recently, the following variations in the peptide‐binding grooves of HLA molecules that predispose to RA development have been identified: Val and Leu at HLA–DRB1 position 11, Asp at HLA–B position 9, and Phe at HLA–DPB1 position 9. This study was undertaken to investigate whether these variants are also associated with radiographic progression in RA, independent of SE and anti–citrullinated protein antibody (ACPA) status.

OP0172 Characterising Arthralgia in the Preclinical Phase of Rheumatoid Arthritis Using Magnetic Resonance Imaging

Background The phase of arthralgia is the earliest moment to clinically recognize patients who will develop Rheumatoid Arthritis (RA). Previous imaging studies in the phase of arthralgia without clinical arthritis showed that subclinical inflammation precedes RA development. It is unknown which symptoms and characteristics relate to subclinical joint inflammation as measured by MR-imaging. Among all arthralgia patients, those with Clinically Suspect-type Arthralgia (CSA) are suspect to progress to arthritis according to the clinical judgment of their rheumatologists. Objectives We determined the symptoms and characteristics of patients with Clinically Suspect Arthralgia that had inflammation on MRI. Methods 102 patients with CSA and without clinical arthritis were included. At baseline, they filled questionnaires, underwent joint counts and unilateral 1.5T MRI of MCP2-4, wrist and MTP1-5 joints. Synovitis, bone marrow edema (BME) and tenosynovitis were scored according to the RAMRIS method. Symptoms and signs were related to MRI-inflammation (based on MRI-scores in symptom free controls, a sum of the scores for synovitis, BME and tenosynovitis ≥3 was considered as positive for MRI-inflammation). Whether certain clinical characteristics and MRI-inflammation frequently occurred together was studied by Partial Least Squares regression. All CSA patients were followed longitudinally. Results 44% of the CSA patients had subclinical MRI-inflammation. Synovitis was the most prevalent inflammatory feature on MRI (20%). Patients with MRI-inflammation were older and more frequent anti-citrullinated peptide antibodies (ACPA)-positive than patients without MRI-inflammation (p<0.001 and 0.049 respectively). A combination of symptoms and characteristics (including subacute symptom onset, initial localization in large joints, or in lower extremities, morning stiffness ≥60 minutes, elevated acute phase reactants and presence of autoantibodies) explained 42% of the variance in MRI-inflammation. Hence, no specific combination of characteristics was found to be discriminative for the presence of subclinical inflammation. Despite a still limited follow-up duration, 35% of the patients with MRI-detected subclinical inflammation that were followed for at least four months developed clinical arthritis or RA. Conclusions Subclinical inflammation as measured by MRI is present in 44% of CSA patients. A combination of symptoms/characteristics incompletely differentiated patients with and without MRI-inflammation. Follow-up will reveal which characteristics relate to RA development. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.2092

Evaluation of the association between anticarbamylated protein antibodies and the longitudinal course of functional ability in rheumatoid arthritis.

Clinically relevant joint destruction has now become infrequent in patients with newly diagnosed rheumatoid arthritis (RA), while other disease outcomes such as functional ability and disease persistence have become more important. Recently, novel auto-antibody reactivities have been identified in RA, with the ultimate aim to better characterise patients with RA. Anticarbamylated protein (anti-CarP) antibodies were recently identified and associated with more severe radiographic progression,1 but the association with other outcomes was unexplored. With great interest we read the study by Humphreys et al ,2 reporting more severe functional disability in anti-CarP positive patients with inflammatory polyarthritis. According to the reported unadjusted β-coefficient (95% CI), patients with anti-CarP antibodies had 0.21 (0.14 to 0.29) higher scores on the Health Assessment Questionnaire (HAQ) during a median follow-up duration of 8 years. This association was statistically independent of the presence of anticitrullinated peptide antibodies (ACPA) and rheumatoid factor (RF). In general replication …