Calprotectin is an acute-phase protein produced by monocytes and neutrophils in the circulation and inflamed tissues. Calprotectin seems to be more sensitive than CRP, being able to detect minimal residual inflammation and is a candidate biomarker in inflammatory diseases. High serum levels are associated with some severe manifestations of rheumatic diseases, such as glomerulonephritis and lung fibrosis. Calprotectin levels in other fluids, such as saliva and synovial fluid, might be helpful in the diagnosis of rheumatic diseases. Of interest is also the potential role of calprotectin as a target of treatment. AbstractCalprotectin is a heterodimer formed by two proteins, S100A8 and S100A9, which are mainly produced by activated monocytes and neutrophils in the circulation and in inflamed tissues. The implication of calprotectin in the inflammatory process has already been demonstrated, but its role in the pathogenesis, diagnosis, and monitoring of rheumatic diseases has gained great attention in recent years. Calprotectin, being stable at room temperature, is a candidate biomarker for the follow-up of disease activity in many autoimmune disorders, where it can predict response to treatment or disease relapse. There is evidence that a number of immunomodulators, including TNF-a inhibitors, may reduce calprotectin expression. S100A8 and S100A9 have a potential role as a target of treatment in murine models of autoimmune disorders, since the direct or indirect blockade of these proteins results in amelioration of the disease process. In this review, we will go over the biologic functions of calprotectin which might be involved in the etiology of rheumatic disorders. We will also report evidence of its potential use as a disease biomarker.

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BackgroundA definition of difficult-to-treat/refractory rheumatoid arthritis (RA) (RRA) has not been established yet, nevertheless, RRA is commonly associated with the resistance to multiple bDMARDs [1,2,3].ObjectivesThe objective was to evaluate the rate of RRA according to three definitions, the agreement between the definitions and major determinants of such definitions in a large monocentric cohort of RA patients.MethodsWe included RA patients treated with any bDMARD (>=1 year), who started bDMARDs after 2001. Considered definitions of RRA were: B-RAA, according to Buch [3], failure of >=1 anti-cytokine (TNF and/or IL6 ihnibitor) and >=1 cell-targeted (B-cell and/or T-cell ihnibitor) bDMARD; KF-RAA, according to Kearsley-Fleet [2], exposed to >=3 bDMARDs classes; DH-RRA, according to de Hair [1], signs and/or symptoms suggestive of inflammatory RA activity (in the study we assumed DAS28>=3.2 or extra-articular manifestations) and failure of >=1 csDMARD and >=2 bDMARDs. Agreement was measured with Cohen’s kappa. To assess variables independently associated with RRA, multivariate regression analysis was used including variables achieving p<0.10 in univariate analysis.ResultsPatients included in the study were 572. B-RRA was observed in 165 (28.8%), KF-RRA in 96 (16.8%) and DH-RRA in 57 (10.0%). DH-RRA was the most stringent definition. Agreement between the definition was fair: DH-RRA and B-RRA kappa=0.330, p<0.001; DH-RRA and KF-RRA kappa=0.260, p<0.001; B-RRA and KF-RRA kappa=0.275, p<0.001. Most common last bDMARD choice in RRA patients differed according to the definition: B-RRA mostly adalimumab (30.9%) (p<0.001), KF-RRA tocilizumab (78.1%) (p<0.001), DH-RRA tocilizumab (33.3%) or abatacept (31.6%) (p<0.001) (Figure). Multivariate analysis revealed that, as expected, all definitions were affected by the number of bDMARDs, and DH-RRA also by the disease activity. Mean PDN daily dose was associated with B-RRA; lower BMI with KF-RRA; the start of bDMARD treatment in earlier years with KF-RRA and DH-RRA; and radiographic progression (in the 24 months before the study) with DH-RRA (Table).ConclusionRRA was observed in a 20-30% of RA patients, slightly higher compared to previous evidence [1,2]. Characteristics of patients fulfilling different RRA definitions are diverse. Particularly, disease severity (disease activity and structural damage) was not associated with RRA if the definition considers only the exposure to bDMARDs. Given the large time span of the study period, RRA patients were more frequently those who started bDMARDs in earlier years.References[1] de Hair MJH, et al. Rheumatology2018;57:1135-1144.[2]. Kearsley-Fleet L, et al. Ann Rheum Dis 2018;77:1405–1412.[3] Buch MH. Ann Rheum Dis 2018;77:966–969. Table. Factors associated with three definitions of difficult-to-treat/refractory rheumatoid arthritis (RRA), multivariate analysis. OR (95% C.I.) p value B-RRA No. bDMARDs 18.77 (11.06;31.85)p<0.001Current bDMARDp<0.001Prednisone daily doseper 5 mg increase2.15 (1.17;2.15)0.014Model Constantp<0.001...

Background::In recent years several biosimilars (BS) of tumour necrosis factor inhibitors (TNF-i) were introduced. At the Padova University Hospital the first BS of etanercept (bsETN) was available in October 2016 and the BS of adalimumab (bsADA) was available in November 2018.Objectives:The objectives of the study were to evaluate the rate of bioriginator-biosimilar (BO-BS) switch in all patients with rheumatoid arthritis (RA), psoriatic arthritis (PSA) and axial spondiloarthritis (axSpA) in the cohort of the Padova University Hospital and to examine factors favouring BO-BS switch. Secondly, we investigated survival of BO-BS switch and BO treatment and factors associated with longer treatment survival.Methods:We considered all patients on ETN originator (boETN) treatment when the first bsETN was available (1st October 2016) and all patients on ADA originator (boADA) when bsADA was available (1st November 2018). Patients were followed until 30 August 2019 and were classified as BO-BS switchers if they underwent a switch from either boETN or boADA to BS during the follow-up, otherwise they were considered as continuing BO treatment. Factors associated with BO-BS switch were tested with a multivariable regression analysis. To test the survival of the BO-BS switch and of the BO treatment, Cox regression analysis was used including all variables achiving a p<0.10 in univariate analysis tested with Log-rank test and Kaplan-Meier curves.Results:Among 1208 patients (553 RA, 433 PSA, 215 axSpA), 560 (46.3%) patients switched to bsETN (391) or bsADA (169). Mean disease duration was 16 (14.2) years and mean duration of the bDMARD treatment was 96.3 (56.8) months. After adjustment for potential confounders, factors associated with BO-BS switch were a longer disease duration, a shorter duration of previous bDMARD treatments and diagnosis (Tab.1) RA patients had almost a 3 fold increased likelihood of being switched to BS compared to PSA and axSPA, while difference between PSA and axSPA was not significant.Following Cox regression analysis we observed a longer drug survival in BO-BS switchers compared to those continuing with BO (HR 1.38; 95% C.I. 1.2-1.58; p<0.001) (Fig. 1). A longer drug survival was also associated with a longer disease duration (.15years: HR 1.75; 95% C.I. 1.5-2; p<0.001), longer mean duration of previous bDMARDs (.5years: HR 4.1; 95% C.I. 3.5-4.7; p<0.001), and diagnosis (RA vs PSA: HR 1.22; 95% C.I. 1.02-1.47; p=0.030; RA vs axSpA: HR 0.89 95% C.I. 0.067-0.97; p=0.023; PSA vs axSpA: HR 0.66; 95% C.I. 0.57-0.77; p<0.001) (Fig 2).Figure 1.Kaplan-Meier curves for treatment survival, Log-rank test.Figure 2.Kaplan-Meier curves for treatment survival in all patients, Log-rank tesConclusion:BO-BS switch was undertaken in almost half of the patients. Patients with longer disease duration and longer bDMARD duration, were the most likely to be switched successfully to BS. BO-BS switching does not affect the survival of the treatment, indeed, it provides sustained effectiveness particularly if undertaken in patients with stable disease activity.Table 1.Factors associated with BO-BS switch, multivariate regression analysis.Disclosure of Interests:DAVIDE ASTORRI: None declared, Francesca Ometto: None declared, LARA FRISO: None declared, BERND RAFFEINER: None declared, Costantino Botsios: None declared, Andrea Doria Consultant of: GSK, Pfizer, Abbvie, Novartis, Ely Lilly, Speakers bureau: UCB pharma, GSK, Pfizer, Janssen, Abbvie, Novartis, Ely Lilly, BMS

Background:The 5-item Compliance Questionnaire for Rheumatology (CQR5) allows the identification of patients likely to be high adherers (HAs) to anti-rheumatic treatment (i.e. taking ≥80% of their medications correctly), or “low” adherers (LAs). An Italian version of the questionnaire was validated (I-CQR5) [1].Objectives:The objective was to investigate what factors are associated with high treatment adherence according to I-CQR5 in RA patients treated with biologic DMARDs (bDMARDs).Methods:RA patients (with disease duration >1 year, undergoing treatment with ≥1 self-administered biological disease-modifying anti-rheumatic drug (bDMARD), willing and capable of completing the questionnaire unaided) were enrolled in the study. I-CQR5 were anonymous and clinical data were collected from the local database. Factors included were demographic, social characteristics of the patients, clinical and treatment variables. Factors achieving a p<0.10 in univariate analysis were included in a multivariate regression analysis.Results:Among 604 RA patients, 193 patients were included in the validation analysis. Median age of the patients was 57 years (46-65), 142 (73.4%) were females, median disease duration was 15 years (9-21); 82 (42.7%) patients were treated with low dose bDMARDs; 174 (91.1%) patients were in low disease activity or remission (Fig.1). HAs were 40.9% (79/193) of patients: 100% (193/193) of patients treated with bDMARDs and 22.4% (57/193) of those treated with bDMARDs in combination with conventional synthetic DMARDs. Female gender, no employment, lower education level, positive Rheumatoid Factor and/or Anti-Citrullinated Peptides Antibodies, low bDMARD dose, higher patient-VAS were significantly more frequent in LAs compared with HAs. In the multivariate analysis, employment was also positively and significantly associated with high adherence: OR 2.89 (1.3-6.44), p=0.009 (Tab.1).Conclusion:As previously reported only one third of RA patients treated with bDMARDs were found to be HAs to treatment according to the I-CQR5. Employment status was the major determinant, increasing by almost 3-fold the likelihood of being adherent. Education level and female gender might be also taken into account as factors influencing treatment adherence.Reference:[1] Ometto F., et al. Treatment adherence in rheumatoid arthritis italian patients using a validated version of the 5-item compliance questionnaire for rheumatology (I-CQR5). EULAR18-4294.Table Multivariate regression analysis. Factors associated with HA to anti-rheumatic treatment according to I-CQR5. OR (95% C.I.) p Male gender2.05 (0.9-4.66)0.086Employment2.89 (1.3-6.44)0.009Patient-VAS (per 10-unite increase)0.95 (0.83-1.09)0.453Model constant0.035OR odds ratio, C.I. confidence interval, VAS visual analogic scale.Disclosure of Interests:None declared

BackgroundGender differences may contribute to treatment tailoring in rheumatoid arthritis (RA) patients. Observational data shows a trend toward worse disease activity and worse response to treatment in females. Only few data are available specifically focused on differences in drug use according to gender.ObjectivesTo evaluate gender differences in treatment approaches in RA patients treated with bDMARDs (biological DMARDs)MethodsWe included RA patients aged ≥18 years, with disease duration ≥1 years, with a stable bDMARD treatment (≥12 months) in a monocentric cohort in the North-East of Italy. Social, demographic, and clinical features in addition to treatments were considered. To assess variables independently associated with gender, all variables achieving a p<0.20 in univariate analysis were included in a multivariate regression model.ResultsAmong 721 RA patients, 514 patients were eligible for the analysis and 407 were females. Compared with males, females had a lower BMI, a higher DAS28, a higher number of conventional synthetic DMARDs (csDMARDs) used before the start of bDMARDs, a higher number of bDMARDs with different mechanism of action (MoA), a larger use of prednisone and a lower rate of combination with MTX (Table 1). After adjustment for confounding factors, females had an increased probability of taking ≥ 2 DMARDs before bDMARDs (OR 2.21, 95% CI 1.25-3.93, p=0.007) and a lower BMI (per 5-unit increase, OR 0.70, 95% CI 0.56-0.87, p=0.001) compared to males (Figure 1).ConclusionIn a cohort of Italian RA patients, females were treated with a higher number of csDMARDs before starting a bDMARD compared to males and a trend toward the use of more bDMARDs with different MoA. Further insight is needed regarding possible differences in the accessibility to bDMARD treatment and reasons for unsatisfactory treatment control in females.Abstract THU0123 – Figure 1Abstract THU0123 –Table 1Disclosure of InterestsNone declared

Background:Three definitions of refractory rheumatoid arthritis (RRA) have been proposed: Buch’s (B-RRA), i.e. failure of ≥1 anti-cytokine and ≥1 cell-targeted bDMARD [1]; Kearsley-Fleet’s (KF-RRA), i.e. exposure to ≥3 bDMARDs classes [2]; De Hair’s (DH-RRA), i.e. signs and/or symptoms of RA activity and failure of ≥1 csDMARD and ≥2 bDMARDs [3].Objectives:To evaluate the rate of RRA according to the three definitions in a monocentric cohort with two cross-sectional analyses in 2012 and 2019. We investigated also the major determinants of each definition. Secondary objective was to evaluate the most frequent treatments in RRA patients.Methods:Patients affected by RA followed at Padova University Hospital were included at two different time points. In the 2012 cohort patients on bDMARDs on 31stDecember 2012 and in the 2019 cohort patients on b/target synthetic DMARDs (tsDMARD) on 1stMarch 2019. Factors independently associated with RRA definitions were tested with multivariable regression analysis, including all variables achieving a p<0.10 in the univariate analysis.Results:We included 260 patients in the 2012 cohort and 571 in the 2019 cohort. Rate of RRA in 2012 cohort was: 23 (8.8%) B-RRA, 57 (21.9%) KF-RRA and 12 (4.6%) DH-RRA; rate of RRA in 2019 cohort was: 165 (28.9%) B-RRA, 96 (16.8%) KF-RRA and 57 (10%) DH-RRA. Following multivariate regression analysis, in the 2012 cohort a significant association was found between number of bDMARDs treatment and all RRA definitions [Tab.1]. Also in the 2019 cohort the variable associated with all RRA definitions was the number of bDMARDs treatment [Tab.2]. Both in 2012 and 2019, IL6-inhibitors were more frequently prescribed in RRA patients; instead TNF inhibitors were less frequently prescribed in RRA.Conclusion:Rate of RRA in the 2019 cohort was 10-30% which is higher compared to the 2012 cohort. This might be explained by the fact that RRA definitions are mainly affected by the number of bDMARDs. Thus, an accurate RRA definition should consider not only the number of treatments but also the current disease activity.References:[1]Buch MH. Ann Rheum Dis 2018;77:966–969[2]Kearsley-Fleet L, et al. Ann Rheum Dis 2018;77:1405–1412[3]De Hair MJH et al. Rheumatology 2018;57:1135-1144Table 1.Factors associated with three definitions of RRA in the 2012 cohort, multivariate analysisCharacteristicsOR (95% C.I.)p valueB-RRACRPper mg/L increase0,81 (0,68-0,95)0,011HAQper unit increase3,28 (0,85-12,54)0,84Combination with any csDMARD4,61 (0,65-32,59)0,124bDMARD treatment durationper year increase0,58 (0,52-1,03)0,114No bDMARDs91,0 (7,87-1055,58)<0,001Model constant0,009KF-RRAPDNper mg increase1,49 (0,87-2,56)0,144DAS28per unit increase4,22 (1,4-12,71)0,011No bDMARDs- (0-0)0,99Model constant0,989DH-RRACombination with any csDMARD6,24 (0,69-56,61)0,614Comorbidity12,82 (0,46-1122,91)0,065No bDMARDsper unit increase6,25 (2,75-121,39)0,003Model constant0,002B-RRArefractory RA according to Buch,KF-RRArefractory RA according to Kearsley-Fleet,DH-RRArefractory RA according to De HairTable 2.Factors associated with three definitions of RRA in the 2019 cohort, multivariate analysisCharacteristicsOR (95% C.I.)p valueB-RRANo. bDMARDs18.77 (11.06;31.85)p<0.001PDN daily doseper 5 mg increase2.15 (1.17;2.15)0.014Model Constantp<0.001KF-RRABMIper 5 unit increase0.61 (0.35;1.05)0.072No. bDMARDs8.69 (5.16;14.64)p<0.001bDMARD treatment start yearper year increase0.92 (0.84;1.01)0.087Model Constant0.069DH-RRANo. bDMARDs3.9 (2.67;5.71)p<0.001bDMARD treatment start yearper year increase0.91 (0.83;0.99)0.026DAS28per 0.6 unit increase5.55 (3.34;9.23)p<0.001RX progression2.7 (1.21;6.03)0.015Model Constant0.04B-RRArefractory rheumatoid arthritis according to Buch,KF-RRArefractory rheumatoid arthritis according to Kearsley-Fleet,DH-RRArefractory rheumatoid arthritis according to De Hair,RX progression(mTSS ≥0,5 over the last 24 months)Disclosure of Interests:LARA FRISO: None declared, Francesca Ometto: None declared, DAVIDE ASTORRI: None declared, Costantino Botsios: None declared, Andrea Doria Consultant of: GSK, Pfizer, Abbvie, Novartis, Ely Lilly, Speakers bureau: UCB pharma, GSK, Pfizer, Janssen, Abbvie, Novartis, Ely Lilly, BMS

ObjectivesTo investigate etanercept (ETN) serum levels and anti-etanercept antibodies (AEA) and evaluate whether ETN levels are associated with SDAI remission in rheumatoid arthritis patients in DAS28 remission treated with full-dose (25 mg twice weekly) and low-dose (25 mg once weekly) ETN.MethodsWe selected 70 patients in stable (≥12 months) full-dose (35) or low-dose (35) ETN, in remission (DAS28<2.6 for ≥12 months) and with a treatment duration ≥5 years. AEA and basal ETN levels were tested by ELISA. A cut-off >142AU/ml was adopted for defining positive AEA. A concentration of ETN ≥3.1μg/mL was considered as a high ETN level [1]. Multivariate regression analysis was used to investigate whether high ETN levels were associated with SDAI remission.ResultsOne blood sample in the low-dose group resulted inadequate. AEA were present in 1 patient in low-dose (1/34, 2.9% low-dose ETN vs 0/35, 0% full-dose ETN, p=0.507). Full-dose and a lower weight were associated with high ETN levels: 15/35, 42.9% vs 3/34, 8.8% p=0.001 and 55.0 kg (57.0;80.0) and 65.0 (51.0;69.8), p=0.014 for high and low ETN levels respectively. Lower ETN levels, low-dose and a longer low-dose duration were associated with SDAI remission but were not confirmed with multivariate regression (Table 1).Table 1.Predictors of SDAI RemissionAll PatientsUnivariate AnalysisMultivariate Regression AnalysisNo SDAI remissionSDAI remissionp valueOR (95% CI)p valueNumber694920Females†58 (84.1%)41 (83.7%)17 (85.0%)0.602Age (years)*61.80 (52.54; 69.68)66.46 (58.62; 72.84)59.27 (47.54; 68.61)0.070per year increase1.01 (0.92; 1.11)0.782Weight (kg)*63.00 (55.00; 77.50)63.50 (59.00; 79.75)56.00 (53.00; 74.50)0.574Positive rheumatoid factor or anti-citrullinated peptides†46 (66.67%)35 (71.43%)11 (55.00%)0.1510.59 (0.09; 3.92)0.586Disease duration (years)*17.08 (13.48; 25.27)17.47 (13.23; 22.71)16.51 (11.61; 31.38)0.963ETN treatment duration (years)*9.50 (6.92; 11.05)8.70 (6.46; 11.02)9.68 (7.79; 11.42)0.667Low-dose ETN duration (years)*6.74 (5.73; 8.70)6.35 (4.75; 8.48)8.14 (6.74; 9.05)0.031per year increase1.31 (0.89; 1.94)0.168Full-dose Etanercept35 (50.7%)29 (59.2%)6 (30.0%)0.0260.408 (1.06; 1.57)0.191Basal ETN serum levels (μg/mL)*2.22 (1.27; 3.36)1.32 (0.66; 2.47)1.48 (1.26; 1.98)0.781Positive anti-ETN antibodies†1 (1.4%)1 (2.0%)0 (0%)0.710High ETN level (≥3.1 μg/mL)†1.65 (1.00; 2.89)2.34 (1.24; 3.54)1.59 (1.28; 2.24)0.426Concomitant MYX use†17 (%)13 (24.5%)4 (25.0%)0.603Prednisone daily dose*2.50 (0.00; 5.00)2.50 (0.00; 3.63)0.50 (0.00; 2.50)0.338HAQ*1.00 (0.60; 1.25)1.00 (0.75; 1.43)0.41 (0.24; 0.78)<0.001per unit increase0.04 (0.00; 1.04)0.053DAS28*2.11 (1.36; 2.35)2.23 (2.02; 2.47)1.10 (0.87; 1.15)<0.001*Median (interquartile range); †number (percentage).ConclusionsAEA are almost absent in patients in stable remission, patient with full-dose ETN and lower weight have higher ETN levels. ETN levels are not predictive of SDAI remission.ReferencesDaïen CI, Daïen V, Parussini E, et al. Etanercept concentration in patients with rheumatoid arthritis and its potential ...