J. Inciarte-Mundo

Reducción de dosis de terapias biológicas en enfermedades reumáticas: análisis descriptivo de 153 pacientes en condiciones de práctica clínica

OBJECTIVE To analyze the frequency and characteristics of dose reduction of biological agents in a cohort of patients with chronic arthritis, in clinical practice conditions in a tertiary level hospital. MATERIAL AND METHODS Descriptive, cross-sectional study, which included all patients, followed consecutively during 6 months (June 2011-November 2011), by one investigator, with patients who at least have received one dose of biological agents in 2011. RESULTS We included 153 patients: Rheumatoid arthritis (RA) (n=82), ankylosing spondylitis (n=29), psoriatic arthritis (n=20), and miscellaneous group (n=22). Mean disease duration was 14.9±7.7 years. At the time of analysis, 70 patients (45.7%) were receiving low doses of biological therapy (50% in miscellaneous group group, 50% in psoriatic arthritis, 48.2% in ankylosing spondylitis, and 42.6% in RA). Mean time of dosage reduction was 17.4±17.5 months. The most common biological agents used in low dose were: etanercept, adalimumab and tocilizumab; 57.6%, 54.9% and 40% respectively, in patients with a reduced dose of biological therapy. The patients at low dose of biological therapy compared with standard dose, had similar mean disease duration, but received significantly less DMARDs, glucocorticoids and NSAIDs, and similar biological agent duration. RA patients with reduced biological treatment, at the time of analysis, had higher remission rates versus patients receiving a standard dose (82.9% vs 34%, p<0.0001). The medical decision at the time of analysis was to maintain low-dosage biological treatment in almost all patients. CONCLUSION In our clinical practice, 45.7% of our chronic arthritis patients receive low dose of biological therapy, after achieving remission or low activity at standard doses, maintaining a good control of the disease.

Serum Calprotectin Versus Acute-Phase Reactants in the Discrimination of Inflammatory Disease Activity in Rheumatoid Arthritis Patients Receiving Tumor Necrosis Factor Inhibitors

To compare the accuracy of serum calprotectin and acute‐phase reactants (C‐reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) in stratifying disease activity in rheumatoid arthritis (RA) patients receiving tumor necrosis factor inhibitors (TNFi), and to correlate calprotectin levels with TNFi trough serum levels.

Serum Calprotectin More Accurately Discriminates the Inflammatory Disease Activity of Rheumatoid Arthritis Patients Receiving TNF inhibitors than Acute Phase Reactants

To compare the accuracy of serum calprotectin and acute‐phase reactants (C‐reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) in stratifying disease activity in rheumatoid arthritis (RA) patients receiving tumor necrosis factor inhibitors (TNFi), and to correlate calprotectin levels with TNFi trough serum levels.

Towards optimal cut-off trough levels of adalimumab and etanercept for a good therapeutic response in rheumatoid arthritis. Results of the INMUNOREMAR study

We read with great interest the paper by Chen et al 1 analysing the relationship between therapeutic response to adalimumab and etanercept and serum drug trough levels in 70 patients with rheumatoid arthritis (RA). The authors confirmed a positive association between drug levels and European League Against Rheumatism (EULAR) response. Good responders showed significantly higher drug levels than moderate or poor responders, in line with other studies.2 ,3 The authors calculated (receiver operating characteristic curves) highly sensitive and specific cut-off trough levels of response (1.274 and 1.046 μg/mL for therapeutic response to adalimumab and 1.242 and 0.800 μg/mL for etanercept at 6 and 12 months, respectively). The study also highlights the importance of establishing an optimal cut-off for the …

Is There Subclinical Synovitis in Patients with Palindromic Rheumatism in the Intercritical Period? A Clinical and Ultrasonographic Study According to Anticitrullinated Protein Antibody Status

Objective. To investigate the presence of subclinical synovitis by ultrasound (US) and the clinical phenotype in patients with palindromic rheumatism (PR) according to anticitrullinated protein antibody (ACPA) status. Methods. Fifty-four patients with PR were studied. Clinical, demographic, serological, and therapeutic characteristics were compared in ACPA-positive and ACPA-negative patients. US searching for synovial hypertrophy (SH) and power Doppler signal (PDUS) in 22 joints of the hands was performed in the intercritical period. The results were compared according to ACPA status and with a healthy control group (n = 30). In 10 patients, US was performed during the joint attack. Results. Most patients were female (63%) with a mean disease duration of 11.6 ± 10.7 years. Thirty-six patients (66.7%) were ACPA-positive. ACPA-positive patients had a shorter duration of attacks, a younger age, and less knee involvement at disease onset. US examination showed SH grade ≥ 1 in 79.6% of patients with PR and 50% of controls. Significant US results (SH ≥ 2 or PDUS) were observed in 2.7% and 1.4% of joints assessed and in 33% and 25.9% of patients with PR, respectively. Only 4 patients (7.4%) had US active synovitis (SH ≥ 2 plus PDUS) in at least 1 joint. US assessment showed no significant differences between ACPA-positive and ACPA-negative patients. PDUS was observed in 7 out of 10 patients during attacks. Conclusion. Some differences emerged in the clinical phenotype of PR according to ACPA status. Most patients with PR do not have US subclinical synovitis in the intercritical period, even those who are ACPA-positive.

Clinical and sonographic biomarkers of structural damage progression in RA patients in clinical remission: A prospective study with 12 months follow-up

OBJECTIVE To determine clinical and sonographic biomarkers predicting structural damage progression at 12 months of follow-up as measured by magnetic resonance imaging (MRI) in rheumatoid arthritis (RA) patients in clinical remission. PATIENTS AND METHODS We included patients with RA in clinical remission, defined as 28-joint disease activity score (DAS28)-erythrocyte sedimentation rate (ESR) <2.6 for >6 months. Ultrasound scans of both hands and knees and MRI of the dominant hand were performed at baseline and at 12 months. RESULTS Out of 55 patients, 42 completed the follow-up. Among them, 78% were female, aged (median) 54 years; disease duration was 93 months. In total, 12 (28%) patients were taking oral prednisone, 34 (81%) conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), and 20 (47%) biological therapies. At baseline, 45% fulfilled criteria previously defined for ultrasound-defined active synovitis (UdAS) [PD (power Doppler) signal + synovial hyperplasia ≥2]. Multivariate analysis showed significant associations between baseline MRI erosion score, body mass index (BMI), disease duration, prednisone treatment, absence of biologic and csDMARDs, UdAS, and MRI erosion score progression after 12 months. In an exploratory analysis, serum levels of calprotectin correlated significantly with bone edema progression. CONCLUSIONS We identified clinical and sonographic markers of structural damage progression after 12 months follow-up in patients with RA in clinical remission. Meeting the criteria of ultrasound active synovitis, defined as simultaneous relevant synovial hyperplasia and PD, was associated with erosion progression after 12 months. Calprotectin was associated with bone edema, in an exploratory analysis.

Differing specificities and isotypes of anti-citrullinated peptide/protein antibodies in palindromic rheumatism and rheumatoid arthritis

BackgroundTo analyze differences in the recognition of anti-citrullinated peptide/protein antibody (ACPA) citrullinated epitopes and isotypes in patients with palindromic rheumatism (PR) and rheumatoid arthritis (RA).MethodsACPA fine specificities (citrullinated peptides of enolase, fibrin, and vimentin) and isotypes (IgG, IgM, and IgA) were analyzed in 54 patients with longstanding PR and 54 patients with established RA.ResultsCCP2 tested positive in 66.7% of patients with PR and RA. The ACPA distribution of fine specificities and isotypes differed between PR and RA patients. PR patients had a lower frequency of fine ACPA specificities than RA patients, which was significant in the case of a peptide derived from vimentin (PR 24.1% vs. 59.3% RA; p < 0.001). The mean number of ACPA specificities was lower in PR than in RA patients, and only 25.9% of PR patients recognized ≥2 additional specificities compared with 46.3% of RA patients. Significantly less isotype usage, especially IgA, was observed in PR patients.ConclusionThe ACPA immune response differed in patients with PR and RA, with fewer fine specificities and isotype usage in patients with PR. Some patients with PR may have impaired maturation of the B-cell response against citrullinated peptides with no progression to RA.

FRI0093 Immunogenicity of TNF Inhibitors in Patients with Rheumatoid Arthritis or Polyarticular Psoriatic Arthritis in Clinical Remission or Low Disease Activity: A One-Year Multicentre Prospective Study (The Inmunoremar Study)

Objectives To determine drug trough serum levels and anti-drug antibodies (Ab) in rheumatoid arthritis (RA) or polyarticular psoriatic arthritis (PsA) patients in clinical remission (CR) or low disease activity (LDA) receiving TNF inhibitors [adalimumab (ADA), etanercept (ETN) and infliximab (IFX)], to correlate trough serum levels and Ab with disease flare after a 1-year follow-up, and to determine predictive factors of disease flare. Methods Prospective, multicentre study of RA and PsA patients attended in 3 hospital outpatient clinics (Catalonia, Spain) treated with ADA, ETN or IFX for ≥3 months in CR or LDA measured by DAS28-ESR at ≥2 consecutive visits. Ab and trough serum levels (ELISA Kit Promonitor®, Progenika SA, Spain) were determined at 0, 4, 8 and 12 months. Disease flare was defined as DAS28>3.2 and a delta DAS28 >0.6 during the 1 year follow-up compared with visit 0. Variables collected: demographic data; disease activity, diagnosis; disease duration; biologic drug; reduced dose, and concomitant csDMARD therapy. Differences between patients with and without disease flare were studied by univariate analysis. Multivariate Cox regression analysis was used to establish associations between baseline variables and disease flares. Results 187 patients (RA 103 [57%], PsA 81 [43%]), 66% female, mean age 57±12 years, were included. 138 (74%) patients were in CR, 49 (26%) with LDA, 69 ADA, 83 ETN, and 35 IFX. Mean treatment duration was 60±41 months. 34% and 58% of RA and PsA patients were on reduced doses of TNFi, and 75% and 44% on concomitant csDMARD, respectively. Thirty-two patients (17.1%: 9 ADA, 13 ETN, 10 INF) had a disease flare during follow-up: 15 at month 4, 12 at month 8 and 5 at month 12. Ab (2ADA, 2IFX) were detected in 12.5% of these patients. Patients with disease flares had lower mean baseline trough serum TNFi levels (2.36±0.45 μ/ml vs. 3.92±0.29 μ/ml p<0.01), although the difference was significant only for ADA (2.2±1.4 μ/ml vs. 6.6±4.1 μ/ml p=0.02), higher baseline DAS28 (2.42 vs. 2.04 p<0.001), and CDAI (5.80 vs. 4.15 p=0.001) and a lower frequency of remission (53% vs. 78% =0.003). During flares, trough serum levels of the three TNFi decreased, although the different was significant compared with baselines only in ETN (0.9±1.2 μ/ml vs. 2.3±1.26 μ/ml p=0.02). Cox multivariate analysis showed associations between disease flares and serum levels of TNFi (hazard ratio (HR) =0.84), glucocorticoids use (HR=2.11), and higher DAS28 (HR=2.19) and CDAI (HR=1.14) levels. Other baseline variables were not associated with disease flares. Conclusions Over a one-year follow up disease flares were observed in 17% of RA and PsA patients treated with TNFi for a prolonged period who achieved clinical remission/low disease activity. Anti-drug antibodies explained only 12.5% of disease flares. Low drug trough serum levels and high disease activity levels at baseline were associated with disease flares. References Sanmarti et al. Ann Rheum Dis. 2015 Aug;74(8):e42. Disclosure of Interest R. Sanmarti Grant/research support from: This Study was supported by an Investigator Initiated Research (IIR) from Pfizer (WS2392358), J. Inciarte-Mundo: None declared, P. Estrada-Alarcόn: None declared, M. García-Manrique: None declared, J. Narvaez Grant/research support from: This Study was supported by an Investigator Initiated Research (IIR) from Pfizer (WS2392358), A. Gόmez-Centeno Grant/research support from: This Study was supported by an Investigator Initiated Research (IIR) from Pfizer (WS2392358), J. Rodríguez-Moreno Grant/research support from: This Study was supported by an Investigator Initiated Research (IIR) from Pfizer (WS2392358), M. Pascal: None declared, J. Yagüe: None declared

FRI0063 Predictors of Flare in A Cohort of RA in Remission after 12 Months of Follow-Up

Background Definitive biomarkers have not been identified to predict flares in patients with RA in clinical remission. Objectives To determine clinical, serological and ultrasonografic variables predicting disease relapse at 12 months of follow-up in a cohort of RA patients in clinical remission. Methods We included consecutively RA patients in clinical remission defined as DAS28-ESR <2.6 for >6months evaluated by two independent rheumatologist from our Arthritis Clinic. Complete clinical and biological assessment, determination of serum levels of angiogenic and proinflamatory cytokines, and ultrasound scans of both hands were performed at baseline and after 12 months of follow-up. Risk factors odds ratio (OR) related with 12 months flare were adjusted with multivariate logistic models. Results Sixty patients with RA in remission were included; 78.3% were female. Median age was 53 years (range: 31–74), weight was 67 kg (47–108). Disease and remission mean duration were 111.9 ± 86.4 and 37 months, respectively. 71% of patients were RF positive and 81% were ACPA positive. Patients taking low-dose prednisone, csDMARDs and bDMARDs were 16 (26%), 47 (78%) and 28 (46.7%), respectively. At baseline, 66% had power-doppler (PD) signal and 48% also had synovial hyperplasia grade ≥2, so fulfilling the criteria previously defined of ultrasound defined active sinovitis (UdAS). Twenty-six (43%) patients had disease flare during the follow-up. In the univariate analysis, disease flares were more frequent in patients with PD signal (p=0.056) or UdAS (p=0.117), and significantly less frequent in patients with mild-moderate intake of alcohol. However, in the multivariate analysis, only higher ESR levels (OR: 1.1, 95%CI: 1–1.1), higher weight (OR: 3.1, 95%CI: 1.4–7) and low-dose prednisone treatment (OR: 1.8, 95%CI: 1.2–2.8) were independent risk factors at baseline for disease flares. This model has a sensitivity of 76.9% (95%CI: 56.4–91), a specificity of 76.5% (95%CI: 58.8–89.3), a predictive positive value of 71.40% (95%CI: 52.4–88.4), a predictive negative value of 81.3% (95%CI: 62.7–91.7) and a good predictive power (ROC: 0.849, IC 95%: 74.4–95.4%). We did not find differences between angiogenic or proinflammatory cytokine serum levels and not differences in RAMRIS between patients relapsing or maintaining the remission at baseline. Conclusions This prospective study suggests that higher ESR levels, higher weight and low-dose prednisone treatment are relevant independent risk factors for development of disease flares in patients with RA in clinical remission. However, imaging data (Ultrasound or MRI) or angiogenic/cytokine serum levels were no predictors of flare in this study. Disclosure of Interest None declared

AB0208 Prediction of Flare in Rheumatoid Arthritis and Psoriatic Arthritis Patients with Low Disease Activity Receiving Tnf Inhibitors: Role of Calprotectin and Drug Trough Serum Levels. A One-Year Prospective Cohort Study

Background Calprotectin and TNF antagonist (TNFa) trough serum levels are associated with disease activity. Objectives To determine if calprotectin serum levels or drug trough serum levels predict relapse in RA and PsA patients with low levels of disease activity during TNFa therapy. Methods Prospective 1-year follow-up, single center study (INMUNOREMAR cohort). RA (ACR 1987) and PsA (CASPAR) patients in clinical remission (CR) (DAS28-ESR <2.6) or low disease activity (LDA) (DAS28-ESR <3.2) in ≥2 consecutive visits treated with adalimumab (ADA), etanercept (ETN) or infliximab (IFX) for ≥3 months were included. Demographic data, disease duration, time to initiate csDMARD and bDMARD, time to achieve remission, remission duration, autoantibody status, radiological data, concomitant csDMARD therapy, dose and duration of biological therapy were collected. Clinical and laboratory assessment was made every 4 months and at the time of flare. Calprotectin serum levels (ELISA Kit Calpro AS®) and TNFa trough serum levels (ELISA Kit Promonitor®, Progenika) were determined. Disease flare was defined as DAS28-ESR>3.2 and increase in ΔDAS28-ESR >0.6. Univariate and multivariate regression models were used to identify predictors of disease flare. Results 103 patients (47RA, 56PsA) were included. Mean Age 57 (30–81) years. 78 (75.8%) had CR and 25 (24.2%) LDA. Mean CR/LDA duration was 58 (4–163) months. 36 patients had received treatment with ADA, 50ETN, and 17IFX. Mean biologic treatment duration 61 (7–166) months. 47.4% patients were on monotherapy, 47% on reduced dose, and 17.9% received steroids. 84 patients (91%) remained in CR/LDA for 12 months, and 12 patients (13%; 8 RA, 4 PsA) experienced flares. Patients with flares had a longer time to achieve CR/LDA [CR/LDA (n=81) 3.1 (1–6) months vs. Flare (n=12) 20 (5–31) months, p<0.001], a shorter CR/LDA duration [CR/LDA (n=81) 59 (5–163) months vs. Flare (n=12) 25 (3–134) months, p=0.031], higher calprotectin levels [CR/LDA (n=81) 1.4 (0.6–3.7) μg/mL vs. Flare (n=12) 6 (4.5–7.9) μg/mL, p<0.001], and lower drug trough serum levels [CR/LDA (n=83) 2.6 (0.6–12) μg/mL vs. Flare (n=12) 0.6 (1–1.2) μg/mL; p<0.001], even when analyzed by biologic [ADA CR/LDA (n=30) 7 (0.2–12) μg/mL vs. Flare (n=4) 0.5 (0.4–1) μg/mL; p=0.003; ETN CR/LDA (n=44) 1.5 (0.7–4.7) μg/mL vs. Flare (n=5) 0.8 (0.9–1.2)μg/mL; p=0.039; IFX CR/LDA (n=14) 3.1 (0.5–7.7) μg/mL vs. Flare (n=3) 0.1 (0–1) μg/mL; p=0.021] at baseline. According to the cut-off developed by our group [1], patients with flares had sub-therapeutic baseline drug serum trough levels [CR/LDA (n=22) 26% vs. Flare (n=12) 100%, p<0.001]. Baseline TNFi trough serum levels [hazard ratio (HR) = 0.47], steroid treatment (HR=3.21), time to CR/LDA (HR=1.17), and baseline calprotectin levels (HR=2.38) significantly predicted flare in the univariate analysis but only baseline calprotectin levels significantly predicted flare in the multivariate analysis [HR=2.74 (1.74–4.31); p<0.0001]. Conclusions Calprotectin and TNF trough serum levels are promising biomarkers to predict flare in RA and PsA patients with low disease activity during anti-TNF treatment. References Sanmarti et al. Ann Rheum Dis. 2015 Aug;74(8):e42. Disclosure of Interest J. Inciarte-Mundo Grant/research support from: Hospital Clinic de Barcelona (Premi E. Letang 2013); Catalan Society of Rheumatology (Research Grant 2013), M. Hernández: None declared, V. Ruiz-Esquide: None declared, J. Ramírez: None declared, A. Cuervo: None declared, S. Cabrera-Villalba: None declared, M. Pascal: None declared, J. Yagüe: None declared, J. Cañete: None declared, R. Sanmarti Grant/research support from: This Study was supported by an Investigator Initiated Research (IIR) from Pfizer (WS2392358)