J. Joly

Methotrexate in combination with other DMARDs is not superior to methotrexate alone for remission induction with moderate-to-high-dose glucocorticoid bridging in early rheumatoid arthritis after 16 weeks of treatment: the CareRA trial

Objectives To compare the efficacy and safety of intensive combination strategies with glucocorticoids (GCs) in the first 16 weeks (W) of early rheumatoid arthritis (eRA) treatment, focusing on high-risk patients, in the Care in early RA trial. Methods 400 disease-modifying antirheumatic drugs (DMARD)-naive patients with eRA were recruited and stratified into high risk or low risk according to classical prognostic markers. High-risk patients (n=290) were randomised to 1/3 treatment strategies: combination therapy for early rheumatoid arthritis (COBRA) Classic (methotrexate (MTX)+ sulfasalazine+60 mg prednisone tapered to 7.5 mg daily from W7), COBRA Slim (MTX+30 mg prednisone tapered to 5 mg from W6) and COBRA Avant-Garde (MTX+leflunomide+30 mg prednisone tapered to 5 mg from W6). Treatment modifications to target low-disease activity were mandatory from W8, if desirable and feasible according to the rheumatologist. The primary outcome was remission (28 joint disease activity score calculated with C-reactive protein <2.6) at W16 (intention-to-treat analysis). Secondary endpoints were good European League Against Rheumatism response, clinically meaningful health assessment questionnaire (HAQ) response and HAQ equal to zero. Adverse events (AEs) were registered. Results Data from 98 Classic, 98 Slim and 94 Avant-Garde patients were analysed. At W16, remission was reached in 70.4% Classic, 73.6% Slim and 68.1% Avant-Garde patients (p=0.713). Likewise, no significant differences were shown in other secondary endpoints. However, therapy-related AEs were reported in 61.2% of Classic, in 46.9% of Slim and in 69.1% of Avant-Garde patients (p=0.006). Conclusions For high-risk eRA, MTX associated with a moderate step-down dose of GCs was as effective in inducing remission at W16 as DMARD combination therapies with moderate or high step-down GC doses and it showed a more favourable short-term safety profile. EudraCT number: 2008-007225-39.

Reference curve and diagnostic sensitivity for a new ultrasound device for the phalanages, the DBMsonic 1200, in Belgian women

Abstract: Quantitative ultrasound (US) applied in bone mass measurements is promising because it is a radiation-free and cheap technique that may provide information on bone quality. The DBMsonic 1200 (IGEA, Carpi) is such a new ultrasound device that measures mean amplitude-dependent speed of sound through the distal metaphyses of the four proximal phalanges (nondominant hand). We determined the standarded precision and constructed a reference curve for Belgian women. The diagnostic sensitivity was tested in established osteoporotic patients with at least one vertebral fracture, expressed as area under the curve (ROC) and compared with other bone mass measurement techniques such as dual-energy X-ray absorptiometry (DXA) and US of the heel. For a group of 93 women with different pathologies, the standardized precision obtained was 4.2 ± 4.3%. Within this group, the standardized precision was 3.7 ± 3.1% for 28 normals and 5.8 ± 4.9% for 12 osteoporotic patients. The reference curve was constructed in 310 normal women (age range 21–84 years). The diagnostic sensitivity of this ultrasound device was compared with that obtained with spinal DXA and proximal femur results of the same individuals, as well as with ultrasound measurements of the calcaneus, and investigated in the osteoporotic patients older than 50 years and in age-matched controls. The area under the curve was 80.3% (SE 3.9%) for the DBMsonic 1200, 77.4% (SE 1.4%) for DXA of the spine, 79.5% (SE 3.9%) for DXA of the femoral neck and 70.1% (SE 4.9%) for US of the heel. Our data show an acceptable and comparable standardized precision in relation to other available data for the same device. In the group of osteoporotic women over 50 years of age we have found similar diagnostic sensitivity for the US measurements of the phalanges as for DXA of the lumbar spine and femoral neck. There is a minor, but no significantly higher diagnostic sensitivity than for ultrasound of the calcaneus. We conclude that this tool is promising for discriminating normal and osteoporotic female patients.

Diagnostic Sensitivity of Peripheral Quantitative Computed Tomography Measurements at Ultradistal and Proximal Radius in Postmenopausal Women

Peripheral quantitative computed tomography (pQCT) is a bone densitometry technique that is able to provide real volumetric bone density values not only of the total but also of trabecular and cortical bone separately. Normal reference curves were constructed with cross-sectional data obtained in 275 postmenopausal women (50-85 years), measured at 4% of the ulnar length (ultradistal region), and data for total, trabecular, and cortical bone density were obtained. In these postmenopausal subjects, continuously significant (p < 0.0001) age-dependent declines in bone density of 1.14%, 1.1%, and 0.57% for total, trabecular, and cortical bone, respectively, were observed while similar declines of 0.9%, 0.9%, and 0.4% per year since menopause, respectively, were found. The estimated mechanical stability index also showed linear dependencies with decreases of 0.84%/year and 0.6%/year since menopause (p < 0.0001). A more proximal acquisition at 15% of the ulnar length, an almost pure cortical region, resulted in linear declines of 0.41%/year and 0.27%/year (p < 0.0001) for the cortical bone and the mechanical stability index with significant changes of -0.27% and -0.23% per year, respectively, since menopause. Covariance analysis showed similar age dependencies of the different bone indices obtained in both regions of interest except for the stability index. A significant size adaptation of the bone with age was also observed, which was seen in the relationships of the trabecular and cortical bone areas to age and to bone density. Diagnostic sensitivity of all parameters for established osteoporosis was assessed by receiver operating characteristic (ROC) curves, comparing 99 patients with at least one fracture to the reference population. The area under these curves was highest in the ultradistal pure trabecular density of the radius (75%), followed by stability index (72%) and the area of cortical bone (65%) of the proximal site. No distinguishing power was seen for the cortical bone density values obtained in either the ultradistal (51%) or proximal radius (52%).

A detailed analysis of treatment delay from the onset of symptoms in early rheumatoid arthritis patients

Objectives: A treatment delay of more than 12 weeks can negatively affect treatment response in rheumatoid arthritis (RA). Our aim was to quantify the different stages of delay before RA treatment in different rheumatology centres and to explore influencing factors. Method: A total of 156 disease-modifying anti-rheumatic drug (DMARD)-naive early RA patients were included from eight practices: one academic hospital, five general hospitals, and two private practices. Eight different types of delay were defined from symptom onset until treatment initiation. Information on the duration of each stage of delay was collected from the patient, their general practitioner (GP), and patient files at the rheumatology practice. Patient/GP demographics and disease activity/severity parameters were recorded. Results: The median total delay from symptom onset until treatment initiation was 23 weeks whereas patient-, GP- and rheumatologist-related median delay was 10, 4, and 7 weeks, respectively. Only 21.6% of the patients had a total delay of less than 12 weeks. The total median delay in private rheumatology practices was less than in academic and general hospitals (p < 0.001). Furthermore, RA patients treated within 12 weeks of symptom onset showed a higher level of disease activity. The duration of rheumatologist-related delay was inversely correlated with disease activity parameters. Patients with morning stiffness were treated, on average, 3 weeks sooner than those without morning stiffness (p < 0.006). Conclusions: In only one out of five early RA patients was treatment initiated within 12 weeks of symptom onset, as recommended. Patient-related delay contributed most to overall delay. Disease activity and type of rheumatology centre are pivotal determinants of delay.

Factors influencing the prescription of intensive combination treatment strategies for early rheumatoid arthritis

Objectives: Despite the availability and demonstrated effectiveness of intensive combination treatment strategies (ICTS) for early rheumatoid arthritis (RA), a discrepancy seems to exist between theoretical evidence and actual prescription in daily practice. The purpose of this study was to explore and identify the factors influencing the prescription of ICTS. Method: This study involved rheumatologists and nurses participating in the Care for Rheumatoid Arthritis (CareRA) trial, a multicentre randomized controlled trial (RCT) comparing different ICTS for early RA with conventional disease-modifying anti-rheumatic drugs (DMARDs) plus step-down glucocorticoids (GCs). A qualitative study was carried out using individual semi-structured interviews. Each interview was recorded, transcribed literally, and analysed thematically. In addition, observations at outpatient clinics were used to clarify the interpretation of the results. Results: We interviewed 26 rheumatologists and six nurses and observed five outpatient visits. Identified facilitators included available scientific evidence, personal faith in treatment strategy, staff support, and low treatment costs. Rheumatologists had no doubts about the value of methotrexate (MTX) but some questioned the value of combination strategy, others the effectiveness and/or the dosage of individual compounds. Additional barriers for prescribing ICTS included need for patient education, fear for patients’ preconceptions, concerns about applicability to the individual patient, difficulties with breaking routine, interference with organizational structures and processes, time constraints, and lack of financial support. Conclusions: A heterogeneous set of factors highlights the complexity of prescribing ICTS for early RA in daily clinical practice. Future improvement strategies should stimulate the facilitators while at the same time addressing the barriers. The generalizability of these findings to other health care systems needs further examination.

Effectiveness of methotrexate with step-down glucocorticoid remission induction (COBRA Slim) versus other intensive treatment strategies for early rheumatoid arthritis in a treat-to-target approach: 1-year results of CareRA, a randomised pragmatic open-label superiority trial

Objectives Combining disease-modifying antirheumatic drugs (DMARDs) with glucocorticoids (GCs) is an effective treatment strategy for early rheumatoid arthritis (ERA), yet the ideal schedule and feasibility in daily practice are debated. We evaluated different DMARD combinations and GC remission induction schemes in poor prognosis patients; and methotrexate (MTX) with or without GC remission induction in good prognosis patients, during the first treatment year. Methods The Care in ERA (CareRA) trial is a 2-year investigator-initiated randomised pragmatic open-label superiority trial comparing remission induction regimens in a treat-to-target approach. DMARD-inexperienced patients with ERA were stratified into a high-risk or low-risk group based upon presence of erosions, disease activity, rheumatoid factor and anticitrullinated protein antibodies. High-risk patients were randomised to a COBRA Classic (MTX + sulfasalazine + prednisone step-down from 60 mg), COBRA Slim (MTX + prednisone step-down from 30 mg) or COBRA Avant Garde (MTX + leflunomide + prednisone step-down from 30 mg) scheme. Low-risk patients were randomised to MTX tight step-up (MTX-TSU) or COBRA Slim. Primary outcome was the proportion of patients in 28 joint disease activity score calculated with C-reactive protein remission at week 52 in an intention-to-treat analysis. Secondary outcomes were safety and effectiveness (ClinicalTrial.gov identifier NCT01172639). Results 98 COBRA Classic, 98 COBRA Slim (high risk), 93 COBRA Avant Garde, 47 MTX-TSU and 43 COBRA Slim (low risk) patients were evaluated. Remission was achieved in 64.3% (63/98) COBRA Classic, 60.2% (59/98) COBRA Slim (high risk) and 62.4% (58/93) COBRA Avant Garde patients at W52 (p=0.840); and in 57.4% (27/47) MTX-TSU and 67.4% (29/43) COBRA Slim (low risk) patients (p=0.329). Less adverse events occurred per patient with COBRA Slim (high risk) compared with COBRA Classic or COBRA Avant Garde (p=0.038). Adverse events were similar in MTX-TSU and COBRA Slim (low risk) patients (p=0.871). At W52, 76.0% patients were on DMARD monotherapy, 5.2% used GCs and 7.5% biologicals. Conclusions MTX with a moderate-dose GC remission induction scheme (COBRA Slim) seems an effective, safe, low-cost and feasible initial treatment strategy for patients with ERA regardless of their prognostic profile, provided a treat-to-target approach is followed. Trial registration numbers EudraCT-number 2008-007225-39 and NCT01172639; Results.

Are illness perception and coping style associated with the delay between symptom onset and the first general practitioner consultation in early rheumatoid arthritis management? An exploratory study within the CareRA trial.

Objectives: Persons who are later diagnosed with early rheumatoid arthritis (ERA) often delay their first contact with a health professional after symptom onset. Besides initial symptoms, psychosocial characteristics of individuals may influence their help-seeking behaviour. We explored the role of disease characteristics, illness perception, and coping in patient-related delay before treatment initiation in recently diagnosed patients with ERA. Method: This exploratory, cross-sectional study included 112 patients with ERA from the Care for early RA (CareRA) trial for whom complete data on patient-related delay, coping, and illness perception were available. In addition to baseline sociodemographic and clinical data, the patients’ psychosocial profiles were assessed with the Utrecht Coping List (UCL) and the revised Illness Perception Questionnaire (IPQ-R). Correlations were measured by Spearman’s rho. Using regression analyses, we weighted the association of variables with patient-related delay. Results: Patient-related delay was positively correlated with perceptions of causality including psychological attributions (r = 0.301, p = 0.001), risk factors (r = 0.189, p = 0.045), immunity (r = 0.261, p = 0.005), and passive coping (r = 0.222, p = 0.018). It was negatively correlated with the 28 swollen joint count (SJC28; r = −0.194, p = 0.040), perceptions of treatment control (r = −0.271, p = 0.004), and illness coherence (r = −0.208, p = 0.028). Clinical and psychosocial variables explained 15% and 18%, respectively, of the variability in patient-related delay. Conclusions: Aside from a lower SJC, a longer patient-related delay was correlated with a passive coping style, a strong conviction of symptom causality, poor expected treatment control, and a feeling of limited illness coherence. Psychosocial aspects influence individuals’ help-seeking behaviour and are worth considering when aiming for a reduction in ERA treatment delay.

OP0180 Remission Induction with Dmard Combinations and Glucocorticoids is not Superior to Remission Induction with MTX Monotherapy and Glucocorticoids: Week 52 Results of the High-Risk Group from the Carera Trial

Background To date, intensive DMARD combination therapy with glucocorticoids (GCs) is the most effective treatment approach for the management of early Rheumatoid Arthritis (eRA). The ideal content of the combination and the dose of GCs are however not yet known. Objectives To compare different intensive combination treatment strategies associated with GCs in eRA patients with a poor prognosis at week (W)52 in the CareRA trial. Methods CareRA is a two year prospective investigator-initiated multicenter RCT rooted in daily practice. DMARD naïve eRA patients were stratified into a high or low-risk group based on classical prognostic markers (presence of erosions, rheumatoid factor, anti-cyclic citrullinated protein and DAS28(CRP). High-risk patients (n=290) were randomized to 1 of 3 treatment strategies. 1) Cobra Classic (n=98): Methotrexate (MTX)+Sulphasalazine+60mg prednisone tapered weekly to 7.5mg daily from W7 2) Cobra Slim (n=98): MTX+30mg prednisone tapered to 5 mg daily from W6 3) Cobra Avant-Garde (n=94):MTX+Leflunomide +30mg prednisone tapered to 5 mg daily from W6 From W28, GCs were tapered in all patients and stopped at W34. A predefined treat to target approach was applied. From W40, we aimed for DMARD monotherapy. Efficacy measures were proportions of DAS28(CRP) remission, good EULAR response, clinically meaningful HAQ response, HAQ=0 (ITT analysis). Radiographic progression was measured via the Sharp Van der Heijde score. Adverse events related to therapy (AEs) were registered. Missing data were imputed by last observation carried forward. Results Remission rates were 64.3%, 60.2% and 62.8% in the Classic, Slim and Avant-Garde group respectively (p=0.837). Also no other efficacy outcomes did not differ between groups. 82% of X-ray images were available at baseline. Radiographic progression was minimal. SvH scores were 1.3±2.1, 1.3±2.5 and 1.0±1.4 at baseline and changed over 52 weeks 0.3±0.5, 0.4±1.1 and 0.3±0.6 in the Classic, Slim and Avant-Garde group respectively (p=0.581). The total numbers of AEs were 182 in 65 Classic patients, 125 in 64 Slim patients and 174 in 72 Avant-Garde patients (p=0.026). Serious AEs were reported in 3 Classic, 2 Slim and 3 Avant-Garde patients. Conclusions High rates of remission were achieved at week 52 with csDMARDs and GCs in all remission induction schemes. Cobra Slim showed comparable efficacy with less adverse events compared to DMARD combinations with moderate or high GC dosages. Disclosure of Interest None declared

THU0117 Low-Risk Patients Also Benefit from Remission Induction Treatment in Early Rheumatoid Arthritis: Week 52 Results from the Carera Trial

Background Early intensive treatment to target is recommended in severe early Rheumatoid Arthritis (eRA). However, data are lacking in patients presenting without markers of poor prognosis. Objectives To compare Methotrexate (MTX) with or without Glucocorticoid (GC) remission induction in a tight control setting over 52 weeks in low-risk patients with eRA. Methods CareRA is a two year prospective investigator-initiated multicenter RCT rooted in daily practice. DMARD naïve eRA patients were stratified into a high or low-risk group according to classical prognostic markers (presence of erosions, rheumatoid factor, anti-cyclic citrullinated protein and disease activity). In the low-risk arm, 43 patients were randomized to 15mg MTX monotherapy following a Tight Step Up (MTX-TSU) approach and 47 patients to a Cobra Slim schedule (MTX+30mg prednisone tapered to 5mg daily from W6). GCs were tapered from W28 and stopped at W34. A predefined treat to target approach was applied. Efficacy measures were proportions of DAS28(CRP) remission, good EULAR response, clinically meaningful HAQ response, HAQ=0 and Area Under the Curve (AUC) for DAS28(CRP) (ITT analysis). Radiographic progression was measured via the Sharp Van der Heijde (SvH) method. Adverse events related to therapy (AEs) were registered. No power was calculated in this explorative study. Missing data were imputed via last observation carried forward. Results Remission rates at week 52 were 57.4% and 67.4% in the MTX-TSU and Cobra Slim group respectively (p=0.329). MTX-TSU patients had a higher AUC for DAS28(CRP) than Cobra Slim patients over 52 weeks of treatment (p=0.017). No other efficacy scores differed between groups. 76% of X-ray images were available at baseline. Radiographic progression was minimal. SvH scores were 0.7±1.1 and 0.9±1.5 at baseline and changed over 52 weeks 0.2±0.3 and 0.3±0.4 in the MTX-TSU and Cobra Slim group respectively (p=0.184). The numbers of AEs were 48 in 27 MTX-TSU patients and 49 in 20 Cobra Slim patients (p=0.871). Two serious AEs (pulmonary infection and anemia) were registered in the Cobra Slim group. We observed numerically more treatment adaptations and IM/IA GC injections in MTX-TSU patients. Conclusions Both RA therapies achieved high remission rates in a tight control setting at week 52. However, remission induction with Cobra Slim resulted in a more rapid and sustained disease control. MTX with or without GC remission induction showed a comparable safety profile. Disclosure of Interest None declared

THU0137 Associated with A Glucocorticoid Bridging Scheme, Methotrexate is as Effective Alone as in Combination with Other DMARDS for Early Rheumatoid Arthritis, with Fewer Reported Side Effects: 16 Weeks Remission Induction Data from the Carera Trial

Background In line with the window of opportunity theory, intensive DMARD combination therapy with glucocorticoids (GCs) is probably the most effective treatment approach for early Rheumatoid Arthritis (eRA), but the ideal content of the combination and the dose of GCs is not yet known. Objectives To compare the efficacy and safety of intensive treatment strategies associated with GCs at week (W)16, focusing on high risk patients. Methods CareRA is a prospective two-year investigator-initiated multicenter RCT rooted in daily practice. In this trial, 400 DMARD naïve eRA patients were stratified into high or low risk according to classical prognostic markers such as the presence of erosions, RF/ACPA and disease activity. High risk patients were randomized to 1/3 treatment strategies: COBRA Classic (MTX+ Sulphasalazine + 60mg GCs tapered to 7.5mg daily from W7), COBRA Slim (MTX + 30mg GCs tapered to 5 mg from W6) and COBRA Avant-Garde (MTX + Leflunomide + 30mg GCs tapered to 5 mg from W6). Treatment modifications to target low disease activity were mandatory from W8 onwards, if desirable and feasible according to the rheumatologist. The primary outcome was remission (DAS28(CRP) <2.6) at W16 (ITT analysis). Secondary endpoints were good EULAR response, clinically meaningful HAQ response and HAQ=0. Area under the curve (AUC) for DAS28(CRP) and proportion of treatment adaptations and GC injections were calculated. Adverse events (AEs) were registered. Missing data were imputed by the maximum likelihood method. Results 290 patients were stratified as high risk: 98 Classic, 98 Slim and 94 Avant-Garde patients. Remission was achieved in 70.4% COBRA CLASSIC patients, 73.5% COBRA SLIM patients, 68.1% COBRA AVANT-GARDE patients (p=0.713) at W16. No significant differences between groups were shown in the proportion with a good EULAR response, clinically meaningful HAQ response and HAQ=0 (all p>0.05). The AUC for DAS28(CRP) in the 3 treatment arms was equal (p=0.521). No difference in treatment adaptions or GCs injections was found at W16.Until W16, therapy related AEs were reported in 61.2% of Classic, in 46.9% of Slim and in 69.1% of Avant-Garde patients (p=0.006). Conclusions At W16, MTX associated with a moderate step-down dose of GCs was as effective as DMARD combination therapies with moderate or even high step down GC doses in high-risk eRA. The short-term safety profile of MTX with GCs alone was more favorable. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.2137