J. A. B. van Nies

What is the evidence for the presence of a therapeutic window of opportunity in rheumatoid arthritis? A systematic literature review

Objective Initiation of DMARD-therapy in the ‘window of opportunity’ is thought to result in a more effective modification of the processes underlying rheumatoid arthritis (RA). We questioned whether this effect is true or hyped and performed a systematic literature review. Methods Medical literature databases up to June 2012 were systematically reviewed for cohort studies and randomised controlled trials reporting outcome data of early RA in relation with symptom duration at treatment initiation. The quality of these studies was assessed by two independent reviewers using a criteria scoring system of 15 items. Studies were dichotomised with the median score (79%) as cut-off. Best-evidence synthesis was applied to determine the level of evidence per outcome category. A meta-analysis was performed on the studies reporting on achieving DMARD-free sustained remission (the reverse of disease persistency). Results Out of 836 screened articles, 18 fulfilled the selection criteria and were not duplicates. Ten were scored as high quality. Remission (various definitions) and radiographic progression were frequently studied outcomes. There was strong evidence for an association between symptom duration and radiographic progression. A meta-analysis on datasets evaluating DMARD-free sustained remission showed that symptom duration was independently associated with such remission; HR 0.989 (95% CI 0.983 to 0.995) per week increase in symptom duration. A moderate level of evidence was observed for other remission outcomes. Conclusions Even when heterogeneity of patients is taken into account, prolonged symptom duration is associated with radiographic progression and a lower chance on DMARD-free sustained remission. These data may support the presence of a ‘window of opportunity’.

Evaluating relationships between symptom duration and persistence of rheumatoid arthritis: does a window of opportunity exist? Results on the Leiden Early Arthritis Clinic and ESPOIR cohorts

Background A prolonged symptom or disease duration at treatment initiation is associated with unfavourable outcomes in rheumatoid arthritis (RA). It is unknown whether this relation is linear, referring to a common ‘the-earlier-the-better principle’, or whether a transient time frame in which the disease is more susceptible to treatment exists, referring to a ‘window of opportunity’. To elucidate this, we evaluated the shape of the associations of symptom duration with persistence of RA. Methods Patients with 1987 RA treated with disease modifying antirheumatic drugs (DMARDs) in the Leiden Early Arthritis Clinic (EAC, n=738) and Evaluation et Suivi de POlyarthrites Indifférenciées Récentes (ESPOIR) (n=533) were studied. Cox proportional hazards regression models using natural cubic splines were performed; the log-HR on DMARD-free sustained remission (the opposite of RA persistence) during 5-year follow-up was plotted against symptom duration. Discrimination was measured using time-dependent receiver operator characteristic curves. Subanalyses were performed stratified for the DMARDs used (methotrexate or other conventional DMARDs) and for anticitrullinated peptide antibody (ACPA). Results 11.5% (85/738) and 5.4% (29/533) of EAC and ESPOIR RA patients achieved DMARD-free sustained remission. In both cohorts and all analyses, the curves depicting the log-HRs on remission in relation to symptom duration were not linear. The symptom duration with optimal discriminative ability was 14.9 weeks (95% CI 12.3 to 16.0; area under the curve (AUC) 0.61) in the EAC and 19.1 weeks (95% CI 12.3 to 28.0; AUC 0.59) in ESPOIR. For ACPA-positive RA, this was 11.4 weeks (95% CI 7.7 to 79.0; AUC 0.56) and for ACPA-negative RA 15.0 weeks (95% CI 9.7 to 48.7; AUC 0.56). Conclusions The association between symptom duration and RA persistence is not linear, suggesting the presence of a confined period in which RA is more susceptible to treatment.

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.

Smoking as a risk factor for the radiological severity of rheumatoid arthritis: a study on six cohorts

Background Smoking is a risk factor for the development of anti -citrullinated protein antibodies (ACPA) positive rheumatoid arthritis (RA). Whether smoking predisposes to severe joint damage progression is not known, since deleterious, protective and neutral observations have been made. Objective To determine the effect of smoking on joint damage progression. Methods Smoking status was assessed in 3158 RA patients included in six cohorts (Leiden Early Arthritis Clinic (Leiden-EAC), BARFOT, Lund, Iceland, NDB and Wichita). In total 9412 radiographs were assessed. Multivariate normal regression and linear regression analyses were performed. Data were summarised in a random effects inverse variance meta-analysis. Results When comparing radiological progression for RA patients that were never, past and current smokers, smoking was significantly associated with more severe joint damage in Leiden-EAC (p=0.042) and BARFOT (p=0.015) RA patients. No significant associations were found in the other cohorts, though a meta-analysis on the six cohorts showed significantly more severe joint damage progression in smokers (p=0.01). Since smoking predisposes to ACPA, analyses were repeated with ACPA as additional adjustment factor. Then the association was lost (meta-analysis p=0.29). Conclusions This multi-cohort study indicated that the effect of smoking on joint damage is mediated via ACPA and that smoking is not an independent risk factor for radiological progression in RA.

MRI-detected subclinical joint inflammation is associated with radiographic progression

Background We recently demonstrated that MRI inflammation is prevalent in clinically non-swollen joints of early arthritis patients. In this study, we assessed the relevance of this subclinical inflammation with regard to radiographic progression. Methods 1130 joints (unilateral metacarpophalangeal 2–5, wrist and metatarsophalangeal 1–5) of 113 early arthritis patients underwent clinical examination and 1.5 T MRI at baseline, and radiographs at baseline and 1 year. Two readers scored the MRIs for synovitis, bone marrow oedema (BME) and tenosynovitis according to Rheumatoid Arthritis (RA) Magnetic Resonance Imaging (MRI) Scoring System (RAMRIS). Radiographic progression over 1 year was determined using the Sharp–van der Heijde scoring method. Results On patient level, BME, synovitis and tenosynovitis were associated with radiographic progression, independent of known risk factors (p=0.003, 0.001 and 0.011, respectively). Of all non-swollen joints (n=932), 232 joints (26%) had subclinical inflammation (≥1 MRI-inflammation feature present). These joints were distributed among 91% of patients. Radiographic progression was present in 4% of non-swollen joints with subclinical inflammation compared to 1% of non-swollen joints without subclinical inflammation (relative risks (RR) 3.5, 95% CI 1.3 to 9.6). Similar observations were done for BME (RR5.3, 95% CI 2.0 to 14.0), synovitis (RR3.4, 95% CI 1.2 to 9.3) and tenosynovitis (RR3.0, 95% CI 0.7 to 12.7) separately. Conclusions Radiographic progression was infrequent, but joints with subclinical inflammation had an increased risk of radiographic progression within year 1. This demonstrates the relevance of MRI-detected subclinical inflammation.

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.

Studying associations between variants in TRAF1-C5 and TNFAIP3-OLIG3 and the progression of joint destruction in rheumatoid arthritis in multiple cohorts

The severity of joint destruction in rheumatoid arthritis (RA) is highly variable between patients. Recent twin and population studies indicated that the severity of joint destruction is influenced by genetic factors.1 ,2 Previously, we reported the association of rs10818488 ( TRAF1-C5 ) and rs675520 ( TNFAIP3-OLIG3 ) with progression of joint destruction.3 ,4 The genes near these loci encode for tumour necrosis factor receptor-associated factor-1 ( TRAF1 ), complement component-5 ( C5 ) and tumour necrosis factor α-induced protein-3 ( TNFAIP3 ; a protein that inhibits NF-κ B activation). A basic principle in genetic association studies is to evaluate multiple cohorts to validate observed findings. We therefore studied both single-nucleotide polymorphisms in several RA cohorts with radiological follow-up data. Six thousand two hundred and eighty-two x-rays of 2666 RA patients were studied: 147 patients from Lund (Sweden), 385 patients from Sheffield (UK), 285 patients from Iceland, 384 patients from the North American Rheumatoid Arthritis Consortium (NARAC), 756 patients from the National Databank of Rheumatic Diseases (NDB), 113 patients from Wichita and 596 patients from the Leiden Early Arthritis Clinic (Leiden-EAC) cohort (table 1). Detailed information on these datasets is provided elsewhere.2 ,5,–,10 …

Association of Genetic Variants in the IL4 and IL4R Genes With the Severity of Joint Damage in Rheumatoid Arthritis: A Study in Seven Cohorts

OBJECTIVE The progression of joint destruction in rheumatoid arthritis (RA) is determined by genetic factors. Changes in IL4 and IL4R genes have been associated with RA severity, but this finding has not been replicated. This study was undertaken to investigate the association between IL4- and IL4R-tagging single-nucleotide polymorphisms (SNPs) and the progression rate of joint damage in RA in a multicohort candidate gene study. METHODS IL4- and IL4R-tagging SNPs (n = 8 and 39, respectively) were genotyped in 600 RA patients for whom 2,846 sets of radiographs of the hands and feet were obtained during 7 years of followup. Subsequently, SNPs significantly associated with the progression of joint damage were genotyped and studied in relation to 3,415 radiographs of 1,953 RA patients; these included data sets from Groningen (The Netherlands), Lund (Sweden), Sheffield (UK), the North American Rheumatoid Arthritis Consortium (US), Wichita (US), and the National Data Bank (US). The relative increase in progression rate per year in the presence of a genotype was determined in each cohort. An inverse variance weighting meta-analysis was performed on the 6 data sets that together formed the replication phase. RESULTS In the discovery phase, none of the IL4 SNPs and 7 of the IL4R SNPs were significantly associated with the joint damage progression rate. In the replication phase, 2 SNPs in the IL4R gene were significantly associated with the joint damage progression rate (rs1805011 [P = 0.02] and rs1119132 [P = 0.001]). CONCLUSION Genetic variants in IL4R were identified, and their association with the progression rate of joint damage in RA was independently replicated.

The PTPN22 susceptibility risk variant is not associated with the rate of joint destruction in anti-citrullinated protein antibody-positive rheumatoid arthritis

A missense single-nucleotide polymorphism in the protein tyrosine phosphatase non-receptor 22 ( PTPN22 ) gene, which encodes a negative regulator of T-cell activation, is an important genetic risk factor for rheumatoid arthritis (RA) susceptibility.1 The association of the PTPN22 susceptibility risk allele and the severity of joint destruction is unclear as a result of contradictory observations.2,–,6 To determine an individual patients rate of joint destruction accurately, it is required that radiological measurements are collected by means of standard procedures, scored quantitatively and sensitively and are repeated in time. Consequently, differences in used measurements and analysis methods may contribute to the occurrence of contrasting findings. Second, although the effect of PTPN22 on RA susceptibility is confined to the anti-citrullinated protein antibody (ACPA)-positive group,2 6 most studies on PTPN22 and joint destruction did not analyse the ACPA-positive subset.2,–,5 The present study studied the effect of the PTPN22 susceptibility risk variant on the rate …

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