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Objectives Rheumatic and musculoskeletal diseases (RMDs) require a tailored follow-up that can be enhanced by the implementation of innovative tools. The Digireuma study aimed to test the feasibility of a hybrid follow-up utilizing an electronic patient reported outcomes (ePROs)-based monitoring strategy in patients with RMDs. Methods Adult patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA) were recruited for a 6-month bicentric prospective follow-up consisting of face-to-face and digital assessments. Patients were asked to report disease-specific ePROs on a pre-established basis, and could also report flares, medication changes, and recent infections at any time. Four rheumatologists monitored these outcomes and contacted patients for interventions when deemed necessary. Results from face-to-face and digital assessments were described. Results Of 56 recruited patients, 47 (84%) submitted any ePROs to the digital platform. Most patients with RA were female (74%, median age of 47 years), while 48% of patients with SpA were female (median age 40.4 years). A total of 3,800 platform visits were completed, with a median of 57 and 29 visits in patients with RA and SpA, respectively. Among 52 reported alerts, 47 (90%) needed contact, of which 36 (77%) were managed remotely. Adherence rates declined throughout the study, with around half of patients dropping out during the 6 months follow-up. Conclusion The implementation of a hybrid follow-up in clinical practice is feasible. Digital health solutions can provide granular knowledge of disease evolution and enable more informed clinical decision making, leading to improved patient outcomes. Further research is needed to identify target patient populations and engagement strategies.

Background:Some patients with gout have multiple comorbidities and subcutaneous tophi refractory to conventional monotherapy with urate-lowering treatments (ULT). Uricases may be helpful drugs, but they are not always available. Combined treatment with two potent ULT, such as FBX and BNZ, could achieve a uricase-like effect and be a therapeutic alternative for these patients.Objectives:To evaluate the efficacy and tolerance of the combined treatment of benzbromarone BNZ with FBX in patients with difficult-to-treat (D2T) tophaceous gout.Methods:Multicenter observational study with patients diagnosed with gout according to EULAR/ACR 2015 criteria, subcutaneous tophi, and poor response to standard of care treated with a combination of BNZ and FBX according to a 12-month two-step regimen: FBX monotherapy for the first 6 months (individualized dose optimization), followed by subsequent addition of BNZ (50 mg/day, progressively escalating to 100 mg, whenever possible). Demographic and clinical variables related to gout, cardiovascular risk factors (CVRF), nephrolithiasis, estimated glomerular filtration rate (eGFR), and liver enzymes were collected. A descriptive analysis of the sample was performed using frequencies and percentages for qualitative variables and measures of central tendency and dispersion for quantitative variables. T-test for paired samples was used to analyze changes in uric acid (UA) levels and eGFR.Results:Fifteen patients were recruited from two hospitals, 87% male, with a median age of 59 years (range 43-93), oligo/polyarticular arthritis and a mean of 5.7±3.7 attacks in the year before starting BNZ. Most of them had advanced gout (mean 16.2±8.8 years), with high basal UA levels (mean 10.3±1.7 mg/dl), a marked presence of CVRF (93% hypertension, 73% dyslipidemia, 13% major cardiovascular event, 7% diabetes), and renal impairment (mean eGFR 63.7±23.6 ml/min; mean creatinine 1.21±0.37 mg/dl). Only one patient had a history of nephrolithiasis. Before starting combination therapy, 80% had received monotherapy with a xanthine oxidase inhibitor: 27% allopurinol (median 200 mg/day, range 100-300), 53% FBX (median 100 mg/day, range 40-120). Adding BNZ to FBX treatment resulted in a significant reduction in UA at 12 months (Δ=2.1 mg/dl [95CI: 1.2-2.9], p<0.001), in addition to the initial decrease achieved by FBX alone (Δ=2.3 mg/dl [95CI: 1.1-3.6], p=0.002; Figure 1), with tophi dissolution in 60% (9/15) of patients. The median duration of follow-up was 18 months (range 9-44); median exposure to BNZ 12 months (range 6-38). Reasons for discontinuation of BNZ were tophi dissolution in nine patients, loss of follow-up in three patients and poor clinical tolerance in one patient. There were no serious adverse events, renal colic or significant changes in liver enzymes or kidney function after 12 months compared to baseline values (eGFR12m 61.6 vs eGFRbaseline 63.7 ml/min; n.s.). One death was recorded (no treatment-related; elderly, history of aortic regurgitation).Conclusion:In our sample, the combination of BNZ and FBX was effective in patients with D2T tophaceous gout, with an intensive reduction in UA and rapid tophi dissolution. Combined therapy was well-tolerated by most patients.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Enrique Calvo-Aranda: None declared, Claudia Maria Gomez-Gonzalez: None declared, Marta Novella-Navarro: None declared, Fernando Perez-Ruiz Menarini Central America, Anlylam, Arthriti and Protalix.

Gout is associated with increased cardiovascular risk (CVR). Traditional CVR factors (CVRF) are frequently present in patients with gout, further worsening the prognosis. Several studies have shown that clinical nurse specialist (CNS) contributes effectively to the management of gout. To analyze the detection of CVRF in patients with gout in a rheumatology consultation with CNS and to evaluate short-term changes after a targeted approach. Patients with gout according to ACR/EULAR 2015 criteria referred from Primary/Specialized Care due to poor control of the disease. At the first visit, demographic and clinical variables were collected: age, sex, smoking, alcohol consumption, duration of gout, tophi, comorbidities, urate-lowering treatment (ULT) and concomitant drugs. A blood test and review of previous tests from the last year were performed, as well as measurement of blood pressure (BP), weight and abdominal circumference. Nurse-managed calls were made to monitor home measurements and check adherence/tolerance to pharmacological (start/adjustment of ULT, antihypertensive, lipid-lowering and anti-diabetes drugs) and non-pharmacological approach (gout education, dietary/lifestyle recommendations) initiated at the first visit, according to the Spanish gout guideline and EULAR recommendations for CVR management in rheumatic diseases. We count on multidisciplinary collaboration with other specialists. After 6 months, an in-person visit was made with the same measurements to determine potential changes. A descriptive analysis of the sample was performed. The Wilcoxon test was used to evaluate the variation in the parameters studied. The outcome variable was determined as improvement versus no improvement of the dependent variable. Chi-square and Mann Whitney U tests were used to evaluate the differences. Forty patients who met the inclusion criteria were included. 98% were male, with a median age of 66 (58-75) years, severe gout (83% tophaceous, median duration 7 years) and marked presence of CVRF (smoking 23%, hypertension 78%, dyslipidemia 55%, diabetes 23%), some of them previously undetected (10% hypertensive, 3% dyslipidemic, 3% diabetic), and related comorbidities (ischemic heart disease 8%, cerebrovascular disease 5%, chronic kidney disease 20%). Fifty-five percent were not taking ULT and 53% used non-steroidal anti-inflammatory drugs (NSAIDs) on a regular basis. At the first visit, ULT was started/adjusted in 95% of patients, antihypertensive in 15%, lipid-lowering drugs in 13%, and anti-diabetes drugs in 8%. At 6 months, there was a significant improvement in sUA and BP, and a non-statistically significant weight reduction (Table 1). Serum uric acid (sUA) target was achieved in 93% of patients (37/40 <6 mg/dl, 29/40 <5 mg/dl). The use of NSAIDs was reduced to 5%. Four out of 9 smokers quit. Systolic BP improved in 73% of patients and diastolic BP in 70%. Dietary and habit modifications, therapeutic adjustments and multidisciplinary care were significantly associated with improved BP (p=0.02). In patients with difficult-to-treat gout and high CVR, combined intervention with CNS allows substantial short-term changes in CVRF, a drastic reduction in NSAID consumption and a high percentage of success in achieving the sUA target. [1]Doherty M, et al. Efficacy and cost-effectiveness of nurse-led care involving education and engagement of patients and a treat-to-target urate-lowering strategy versus usual care for gout: a randomised controlled trial. Lancet. 2018;392(10156):1403-1412 Rheumatology Department, Hospital Universitario Infanta Leonor. Enrique Calvo-Aranda Speakers bureau: Menarini, Grünenthal, Claudia Maria Gomez-Gonzalez: None declared, Jose Antonio Angel-Sesmero: None declared, Marta Novella-Navarro: None declared, Patricio Cardoso Peñafiel: None declared. Table 1Anthropometric, blood pressure and serum uric acid changes 6 months after the first visit.Basal6 monthspWeight (kg)87 (77.3-99)85.4 (77-96.3)0.79Abdominal circumference (cm)107 (102-116)108 (103-116)0.81Systolic BP (mm Hg)151 (133.3-162.5)142.5 (124.8-155)0.02Dyastolic BP (mm Hg)88.5 (76.3-95)78.5 (70-86.8)0.01sUA (mg/dl)7.7 (6.6-8.8)4.5 (4.1-5.2)<0.01All variables expressed as median/IQR. BP: blood pressure; sUA: serum uric acid

Background:Difficult-to-manage (D2M) axial spondyloarthritis (axSpA) is an emerging concept, whose definition is yet to be established. The characterisation of these subgroup of patients is relevant, as it may contribute to a broader understanding of the reasons behind treatment failure and to the development of new therapeutic strategies [1].Objectives:To develop a predictive model to forecast patients from the early stages of treatment with b/tsDMARDs.Methods:We analysed data from an observational prospective cohort from La Paz Hospital between 2004-2019 which included patients diagnosed of axSpA initiating a b/tsDMARD, and who fulfilled one of these two definitions: a) D2M: failure to at least 2 b/tsDMARDs, b) good responders (GR): patients remaining their first bDMARD for at least 3 years or withdrawing it because of sustained disease control. Clinical, laboratory, therapy-related information and disease activity measures prior to starting the first b/tsDMARD (baseline), as well as disease activity measures 6-months after initiating it, were collected. Delta-ASDAS was estimated as the difference between baseline and 6-month ASDAS. After excluding the variables with the greater number of missing values, all the variables associated with D2M-axSpA in the univariable regression analyses were selected in order to create Classification And Regression Tree (CART) models. The cohort was randomly split into two independent groups: a training set (80%) and a validation set (20%). Later on, the CART model inputted the most associated factors with D2M-axSpA selecting an optimal cut-off point for classification. Subsequent splits were made, using the Gini index, to divide the population into two branches, until the terminal node. Finally, the model’s performance was assessed using the validation set.Results:Among the 101 patients included in the cohort, 41 (41.6%) were classified as D2M, 59 (58.4%) were male with a mean age of 43 years old. D2M patients were less frequently HLA-B27 positive, had more peripheral manifestations (enthesitis), extra-musculoskeletal manifestations (IBD), comorbidities, and scored higher in composite disease activity indices 6 months after starting a first bDMARD (but did not in baseline indices). Two different CART models were obtained, with a lesser number of patients included in the second model because of the missing values. These 2 models with their cut-off points and the probability of D2M axSpA after each step are shown in Figure 1. The first model (Figure 1, model a) had a pre-test probability of D2M of 44%, and identified BASDAI (cut-off point < 4) after 6 months of therapy with the first bDMARD and age at the beginning of the first bDMARD (cut-off point ≥ 44 years old) as the most relevant factors. The second model (Figure 1, model b) had a pre-test probability of D2M of 47%. It used delta-ASDAS (cut-off point ≥ 1.1) as the variable for the first step, and tender joint count (cut-off point < 1) after 6 months of therapy with the first bDMARD and baseline age (cut-off point ≥ 53) for the second step. After validation, the CART models achieved an AUC of 0.94 (95% CI 0.87-1) and 0.83 (95% CI 0.67-1), respectively, and both of them classified properly 83% of the patients.Conclusion:This study identified two predictive models, which may be applied using everyday information, and could identify D2M-axSpA patients only after the first 6 months of bDMARD therapy. Next step will involve further validation in an external cohort.REFERENCES:[1] Wendling D, Verhoeven F, Prati C. Is the Difficult-to-Treat (D2T) concept applicable to axial spondyloarthritis? Joint Bone Spine. 2023;90(3):105512.Figure 1.CART models predicting D2M-axSpA. The value at each node represents the most frequently expected outcome (D2M in red or GR in green).GR: good responders, D2M: difficult-to-manage, BASDAI: Bath Ankylosing Spondylitis Disease Activity, ASDAS: Ankylosing Spondylitis Disease Activity Score, TJC: tender joint count.Acknowledgements:NIL.Disclosure of Interests:Manuel Juárez: None declared, Diego Benavent Eli Lilly, Janssen and UCB Pharma, Victoria Navarro-Compán Eli Lilly, Janssen, MSD, Novartis, Pfizer and UCB Pharma, AbbVie, Eli Lilly, Galapagos, Moonlake, MSD, Novartis, Pfizer and UCB Pharma, AbbVie and Novartis, Mariana Díaz-Almirón: None declared, Marta Novella-Navarro UCB, Lilly, Galapagos and Janssen, Diana Peiteado: None declared, Alejandro Villalba Janssen, Irene Monjo-Henry Roche, Novartis, UCB and Gedeon Richter, Laura Nuño: None declared, Alejandro Balsa AbbVie, Amgen, Pfizer, Galapagos, Novartis, Gilead, BMS, Nordic, Sanofi, Sandoz, Lilly, UCB and Roche, Chamaida Plasencia-Rodríguez AbbVie, Pfizer, Novartis, Lilly and Roche.

Background:Since the publication of difficult-to-treat rheumatoid arthritis (D2TRA) criteria1, several studies have attempted to establish the most appropriate pharmacological and non-pharmacological strategies for the management of these patients. However, data on the treatment of choice for patients who become D2TRA are still scarce.Objectives:To evaluate the survival of different biologic or targeted synthetic disease modifying antirheumatic drugs (b/tsDMARD) administered after fulfilling the D2TRA criteria. To assess clinical factors related to the survival of these treatments.Methods:This retrospective cohort study included D2TRA patients according to EULAR definition. Sociodemographic characteristics, clinical and serological features and disease activity data were collected at the start of the 1st b/tsDMARD. The DAS28 was also collected at the start of the following treatment after meet D2T classification and at 6 months and patients were followed-up at least for one year. Drug retention of the subsequent line of b/tsDMARD was assessed by Kaplan–Meier plots using the log-rank test. Predictive factors affecting the discontinuation were evaluated using the univariate and multivariate analysis by the Cox proportional hazard model.Results:Of the 122 patients included, 75 maintained active treatment (61.5%) with the subsequent line after D2T compared to 37 patients (38.5%) who discontinued this treatment and required more sucessive lines of b/tsDMARDs. The treatments used after D2T were TNFi (17 patients), anti-IL6R (31 patients), abatacept (27 patients), rituximab (27 patients) and JAKi (20 patients). The mean survival of the treatments was 78.3 ± 7.6 months and the percentage of patients who maintained the treatment after D2T was 29.4% for TNFi, 29.6% for abatacept, 74.2 % for anti-IL6R, 88.9 % for rituximab and 75.0% for JAKi.Significant differences were assessed between different b/tsDMARDs (log-rank p<0.01) (Figure 1). To evaluate these differences, a Cox regression was performed taking each b/tsDMARD as a reference and comparing with the others. The main differences were found between TNFi and abatacept with rituximab, meanwhile, anti-IL6R and JAKi did not show significant differences (Table 1).Table 1.line of DMARDTNFianti-IL6RAbataceptRituximabJAKiTNFi-0.030.65<0.010.03Anti-IL60.03-<0.010.110.98Abatacept0.98<0.01-<0.01<0.01Rituximab<0.010.11<0.01-0.13JAKi0.030.98<0.010.13-DAS28 values 6 months after initiation of the subsequent b/tsDMARD were higher in those patients who discontinued versus those who remained on treatment [4.4 (1.2) vs 3.5 (1.3), p= 0.01]. No significant differences were found in age at diagnosis or at initiation of the 1st b/tsDMARD, neither for previous or concomitant treatments, extra-articular manifestations, erosions or serological status. A multivariate Cox regression model was performed in which the subsequent treatment after D2T [HR=1.26 (95%CI 1.06-1.05)] and higher DAS28 values at 6 months [HR=1.41 (95%CI 1.15-1.72)] were independent risk factors associated with discontinuation of this treatment.Conclusion:Once patients meet D2TRA criteria, the subsequent line of b/tsDMARDs with the best survival is rituximab, followed by JAKi and anti-IL6R being TNFi and abatacept the choices with leass retention rate. Moreover, the DAS28 in the first 6 months of starting the treatment after D2T was an independent risk factor for drug survival.REFERENCES:[1] Nagy G et al. EULAR definition of difficult-to-treat rheumatoid arthritis. Ann Rheum Dis 2021;80:31-5.Figure 1.Survival plot for each line of treatment after fulfilling D2TRA classificationAcknowledgements:NIL.Disclosure of Interests:Marta Novella-Navarro Lilly, UCB, Galapagos and Amgen, Virginia Ruiz: None declared, Natalia López-Juanes: None declared, Chafik Alejandro Chacur: None declared, Irene Monjo-Henry Lilly, UCB, Abbvie, Laura Nuño: None declared, Monica Giselle Kafati Sarmiento: None declared, Diana Peiteado: None declared, Alejandro Villalba: None declared, Elisa Fernández-Fernández: None declared, María Sanz-Jardón: None declared, Raimon Sanmarti: None declared, Chamaida Plasencia-Rodríguez Lilly, UCB, Amgen, Galapagos, Pfizer, Alejandro Balsa Roche, Lilly, Abbvie, Galapagos, UCB, Pfizer.

BackgroundPatients with rheumatic and musculoskeletal diseases (RMDs) require a tailored follow-up, which may be limited by the healthcare resources. Innovative tools that save time need to be implemented effectively in the clinical care of patients with RMDs.ObjectivesTo test the feasibility of a digital solution for real-time monitoring of electronic patient reported outcomes (ePROs) in patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA).MethodsDigireuma was a bicentric 6-month prospective study including patients with RA and SpA, using a digital solution, namely Adhera Rheumatology Digital Program. During follow-up, patients had a hybrid follow-up: face-to-face -baseline and 6 months visits-and digital. In the digital follow-up, patients were asked to report disease specific ePROs on a pre-established basis in the mobile solution- including at least one assessment per week. In addition, flares and incidences with medication were available to be reported at any time. Four rheumatologists monitored these outcomes, and contacted patients when deemed necessary (Figure 1). Assessment measures included patient global assessment (PGA) of disease activity, (self-reported) tender joint count (TJC) and swollen joint count (SJC), Health Assessment Questionnaire (HAQ) and pain visual analogue scale (VAS), for patients with RA; PGA, TJC, SJC, BASDAI, and ASAS-Health Index, for patients with SpA. All measures were delivered every two weeks. Engagement at 3 and 6 months was assessed.ResultsOut of 56 recruited patients, 51 (24/27 (89%) RA, 27/29 (93%) SpA) downloaded and used the mobile solution and 47 (84%) submitted at least one ePROs entry. Median age (IQR) was 47 (13.2) and 40 (16.0) years in the RA and SpA groups, respectively. 20/27 (74%) patients with RA and 14/29 (48%) with SpA were female. In the RA group there were a total of 2156 digital solution accesses (57 per patient) in 6 months, while patients with SpA had a total of 1644 accesses (29 per patient). ePROs measurements outcomes at baseline and 6 months are shown in Table 1. Patients with RA completed a median of 6710 ePROs interactions during follow-up, whereas patients with SpA completed a median of 4315. Regarding alerts, among a total of 52 notifications, 47 were deemed necessary to be contacted (5 cases were assessed directly in a programmed consultation, due to time-proximity). Among all alerts, 45 were flares (31 RA, 14 SpA) and 4 problems with the medication (3 causes were not registered). Of the 47 cases that were contacted, 36 (77%) were managed remotely, 9 (19%) required a face-to-face intervention and in 2 (4%) cases it was not possible to reach patients before consultation. Regarding engagement, at three months 26 patients (55%)- 15 with RA and 11 with SpA- continued submitting data periodically, while at six months 22 patients (47%)- 13 with RA and 9 with SpA- continued submitting any data.ConclusionThis study shows that ePROs can be used to monitor disease activity, flares, and medication issues in patients with RA and SpA, with three out of four alerts being managed remotely. After six months, more than half of the patients showed non-adherence to the monitoring plan/digital solution. The participation of both healthcare professionals and patients is critical for the successful implementation of mobile health in clinical practice, specially to identify long term usage strategies.Figure 1.Digital monitoring in the studyTable 1.Onboarded patient outcomesDAS-28BASDAITJCSJCHAQPtGAVAS painBaseline, Face-to-faceRA2.6 (1.6, 3.6)-1 (0, 3.25)0.5 (0, 2.5)0.13 (0, 0.9)2 (1, 5)4 (2, 5)SpA-2.1 (0.8, 3.8)0 (0, 1)0 (0, 1)-2 (1, 4)2.5 (1, 4)Baseline, DigitalRA--1 (1, 3)1 (1, 2.5)0.2 (0, 0.5)2 (1.8, 3.5)3 (1, 6)SpA-3.3 (1.5, 7)1 (1, 2.75)3 (1.2, 4.75)-1 (1, 2.5)-6 months, Face-to-faceRA1.6 (1.1, 2.9)-0 (0, 2)0 (0, 2)0.13 (0, 0.63)1.5 (0.5, 4)1.35 (0.75, 3)SpA-2.2 (1.2, 4.8)0 (0, 2)0 (0, 0.25)-2 (1, 5)2 (1, 4.25)6 months, DigitalRA--1 (1, 1.8)1 (1, 1.8)0.25(0.1, 0.5)2 (2, 2.8)2 (1, 2)SpA-2.2(1.9, 2.5)2.5(2.2, 2.8)5 (3, 7)-2.5(1.5, 3.3)-AcknowledgementsThis study was funded by an unrestricted grant from Abbvie.Disclosure of InterestsDiego Benavent Speakers bureau: Janssen, Roche, Galapagos., Grant/research support from: Novartis, Abbvie., Luis Fernández-Luque Employee of: Employee of AdheraHealth Inc., María Sanz: None declared, Victoria Navarro-Compán Speakers bureau: AbbVie, Eli Lilly, Janssen, MSD, Novartis, Pfizer, UCB Pharma, Consultant of: AbbVie, Eli Lilly, MSD, Novartis, Pfizer, UCB Pharma, Grant/research support from: AbbVie and Novartis, Marta Novella-Navarro Speakers bureau: Galapagos, UCB, Lilly and Janssen, Grant/research support from: UCB, Lilly and Janssen, Ioannis Bilionis Employee of: Employee of AdheraHealth Inc, Enrique Calvo-Aranda Speakers bureau: Abbvie, LETICIA LOJO: None declared, Alejandro Balsa Speakers bureau: Pfizer, Abbvie, Lilly, Galapagos, BMS, Sandoz, Nordic Pharma, Gebro, Roche, Sanofi, UCB, Consultant of: Pfizer, Abbvie, Lilly, Galapagos, BMS, Nordic Pharma, Sanofi, UCB, Grant/research support from: Pfizer, Abbvie, BMS, Nordic Pharma, Gebro, Roche, UCB, Chamaida Plasencia Speakers bureau: Pfizer, Abbvie, Lilly, Sandoz, Sanofi, Biogen, Roche, Novartis, Grant/research support from: Pfizer and Abbvie.

BackgroundDespite pharmacological options for axial spondyloarthritis (axSpA) have increased recently, still one out of three patients do not achieve the recommended target [1].ObjectivesTo determine patient and disease characteristics in patients with “difficult to treat” (D2T) axSpA in comparison with “good responders” (GR) and to identify predictive factors of D2T-axSpA.MethodsData from an observational prospective cohort recruiting consecutively patients diagnosed of axSpA initiating the first bDMARD from La Paz Hospital between 2004-2019 were analysed. Patients who fulfilled one of the following definitions were included: i) D2T: failure to at least two b/tsDMARDs, ii) GR: patients remaining treated with the first bDMARD for at least 3 years or stopping it due to disease control. Clinical characteristics, laboratory tests, concomitant treatment and disease activity measures prior to starting the first bDMARD and after 6 months were collected. Also, b/tsDMARD courses were registered. Chi-square or Fisher test were used for qualitative variables and unpaired t-student was used for quantitative variables. Univariable and multivariable logistic binary regression analyses were used.ResultsOut of 101 patients included, 41.6% were classified as D2T and 58.4% as GR. When initiating the first bDMARD, compared with GR, D2T patients had statistically significant shorter symptom duration and more frequently enthesitis, inflammatory bowel disease (IBD), concomitant NSAIDs, smoking habit and comorbidities (hypertension, dyslipidemia, depression or anxiety and fibromyalgia), all p<0.05 (Table 1). However, no significant differences were found in age, sex, BMI, subtype of axSpA, dactylitis, peripheral arthritis, uveitis, psoriasis, concomitant csDMARDs, diabetes mellitus or cardiopathy. While no differences were found for disease activity composite measures (ASDAS, BASDAI) and CRP or ESR, D2T patients had greater scores in BASDAI questions for pain and morning stiffness, TJC, PtGA and PhyGA. After 6 months of starting the first bDMARD, the scores for all disease activity measures, including ASDAS, BASDAI, CRP and ESR were significantly higher in D2T patients. Reasons for b/tsDMARDs discontinuation in D2T patients are shown in Figure 1. In multivariable analysis, smoking habit (OR=6.5, p<0.05), HLAB27 negative (OR=5.8, p<0.05), enthesitis (OR=48.1, p<0.01), baseline TJC (OR=1.2, OR<0.05) and baseline PhyGA (OR=1.05, p<0.05) were independently associated with D2T.ConclusionCompared with GR, patients with D2T-axSpA have more frequently poor prognostic factors for therapy response (smoking and HLAB27 negative) and worse response to first bDMARD after 6 months. Further strategies to implement recommendations for not smoking and control of comorbidities should be implemented.Reference[1]Smolen JS, et al. Treating axial spondyloarthritis and peripheral spondyloarthritis, especially psoriatic arthritis, to target: 2017 update of recommendations by an international task force. Ann Rheum Dis. 2018.Table 1.Stratified characteristics. Results are shown as absolute numbers (%) or mean ± standard deviation.GR (n=59)D2T (n=42)p valueSymptom duration until first bDMARD (year)10.5±10.75.5±7.7<0.01Current smoking habit7 (11.9)13 (31)<0.05HLAB27 +48 (82.8)27 (64.3)<0.05Enthesitis35 (59.3)40 (95.2)<0.001IBD2 (3.4)6 (14.3)<0.05ComorbiditiesHypertension15 (25.4)20 (47.6)<0.05Dyslipidemia23 (39)28 (66.7)<0.01Depression or anxiety14 (23.7)23 (54.8)<0.01Fibromyalgia1 (1.7)6 (14.3)<0.05Concomitant NSAIDs43 (81.1)35 (97.2)<0.05BaselineASDAS3.3±13.6±0.90.2BASDAI5.6±2.16.4±1.70.06BASDAI-spinal pain6.4±2.77.5±2.1<0.05BASDAI-stiffness severity5.9±2.87.1±2.5<0.05BASDAI-stiffness duration4.7±2.76.1±2.8<0.05TJC1.1±2.74.4±6.7<0.01PtGA59.9±22.470.4±18.7<0.05PhyGA39.9±19.750±20.2<0.056-monthASDAS1.6±0.92.8±1.1<0.001BASDAI3.3±2.15.4±2<0.001CRP (mg/L)1.7±2.75.9±7.9<0.01Figure 1.Reasons for b/tsDMARD discontinuation in D2T-axSpA.Disclosure of InterestsManuel Juárez: None declared, Diego Benavent Speakers bureau: Janssen, Roche, Galapagos, Grant/research support from: Novartis, Abbvie, Victoria Navarro-Compán Speakers bureau: AbbVie, Eli Lilly, Janssen, MSD, Novartis, Pfizer, UCB Pharma, Consultant of: AbbVie, Eli Lilly, MSD, Novartis, Pfizer, UCB Pharma, Grant/research support from: AbbVie and Novartis, Marta Novella-Navarro Speakers bureau: Galapagos, UCB, Lilly and Janssen, Grant/research support from: UCB, Lilly and Janssen, Diana Peiteado: None declared, Alejandro Villalba: None declared, Irene Monjo Speakers bureau: Roche, Novartis, UCB, Gedeon Richter, Consultant of: Roche, Laura Nuño: None declared, Alejandro Balsa Speakers bureau: Pfizer, Abbvie, Lilly, Galapagos, BMS, Sandoz, Nordic Pharma, Gebro, Roche, Sanofi, UCB, Consultant of: Pfizer, Abbvie, Lilly, Galapagos, BMS, Nordic Pharma, Sanofi, UCB, Grant/research support from: Pfizer, Abbvie, BMS, Nordic Pharma, Gebro, Roche, UCB, Chamaida Plasencia Speakers bureau: Pfizer, Abbvie, Lilly, Sandoz, Sanofi, Biogen, Roche, Novartis, Grant/research support from: Pfizer and Abbvie.

BackgroundObesity has been associated with the response to biologic disease modifying anti-rheumatic drugs (bDMARDs). Obese patients have lower response to anti-TNF drugs than to other cytokine-targeted drugs, such as anti-IL6[1]. IL6 receptor inhibition is effective in the treatment of rheumatoid arthritis (RA), and there are two ways of administration: intravenous (IV) weight-adjusted tocilizumab and subcutaneous (SC) fixed-dose tocilizumab or sarilumab. However, evidence regarding the influence of body mass index (BMI) and these different routes of administration is still scarce.ObjectivesTo analyze the role of BMI in the clinical response to antiIL6 therapy in its different routes of administration in patients with RA. To perform an in-depth analysis of the pathophysiology of obesity by assessing serum adipokine levels and their potential changes according to treatment.MethodsThis study involved 65 patients with RA starting IV tocilizumab at 8mg/kg every 4 weeks or SC antiIL6: tocilizumab 162mg/week or sarilumab 200mg/14days. Demographic and clinical characteristics before antiIL6 initiation (age, sex, smoking habit, age at diagnosis, concomitant and previous treatments and BMI) were collected. Laboratory parameters such as rheumatoid factor and anti-citrullinated peptide antibody were also assessed. Adipokine serum levels (leptin and adiponectin) were measured at baseline and after 6 months (6M) of treatment. Clinical response to treatment was assessed by Clinical Disease Activity Index (CDAI) 6M after initiation of the bDMARD. Differences between variables were assessed using the X2 test and Mann-Whitney test. Correlations between BMI, adipokines and other quantitative variables were assessed using the Pearson or Spearman coefficients. P-values <0.05 were considered statistically significant.ResultsForty seven patients started IV antiIL6 (72.3%) and 18 SC (27.7%). Thirty six (55.4%) achieved low disease activity (LDA)/remission by CDAI: 24 patients from the IV group (51.4%) and 12 (66.7%) from the SC group without significant differences (p=0.19). No differences between BMI or serum adipokine levels were associated with the achievement of LDA/remission when patients were stratified according to the route of antiIL6 administration.Leptin levels in both groups (SC and IV) were very similar at baseline and 6M and regarding changes on adipokine profile between baseline and 6M, we observed a decrease in leptin and an increase in adiponectin levels both in SC and IV (Table 1).Serum adipokine levels (ng/mL)Route of administrationbaseline6 monthspivLeptin18.6 (10.4-30.9)16.9 (7.2-29.2)0.22Adiponectin18310(13250-33890)20610 (12690-33650)0.39scLeptin17.9 (10.1-27.4)16.3 (7.6-30.7)0.22Adiponectin28750 (20570-4394)33350 (24157-49862)0.35BMI showed a significant positive correlation with leptin, overall and stratifying by route of administration, both at baseline and 6M. Adiponectin did not show a significant correlation with BMI.Figure 1.ConclusionObesity and serum adipokines did not show association with the achievement of LDA/remission in patients treated with antiIL6 regardless the route of administration. Furthermore, IV and SC treatments could be used both in obese and normal-weight RA patients expecting the same efficacy.Reference[1]Novella-Navarro et al. Obesity and response to biological therapy in rheumatoid arthritis: the role of body mass index and adipose tissue cytokines. Clin Exp Rheumatol. 2022 Sep;40(9):1726-1732.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Background:Baricitinib (BARI) and tofacitinib (TOFA) are Janus kinase inhibitors (JAKi) approved for treating rheumatoid arthritis (RA). Phase II clinical trials have shown a significant dose-response relationship for JAKi. However, there’s a lack of studies analyzing the correlation between blood drug levels and clinical response in RA [1].Objectives:To evaluate the precision of drug plasma levels in discerning the clinical disease status of RA patients receiving BARI and TOFA.Methods:Multicenter, non-interventional prospective study involving RA patients receiving BARI or TOFA, according to clinical judgment. Patients were enrolled during their first follow-up visit after initiating JAKi treatment (at 12-16 weeks). The primary endpoints was to determine the accuracy of drug plasma levels in discerning clinical disease status based on the Clinical Disease Activity Index (CDAI). BARI and TOFA levels were determined simultaneously by liquid chromatography tandem mass spectrometry (LC-MS/MS)[2]. C max (after 45min of drug administration) and C min (just before drug intake) was analysed in each patient.Results:Fourty-nine patients (84% female, 86% seropositive (RF and/or ACPA), mean age 54 ± 12.9 years and mean RA duration 10±8.4 years) were included: 44 received BARI and 5 TOFA. The mean number of previously administered biological DMARDs was 1.1±1.5. Three patients had received previous treatment with another JAKi. The mean DAS28 and CDAI at JAKi initiation were 4.63±1.25 and 21.6±9.0, respectively. At the 12–16-week visit, 37 patients (75.5%) achieved remission or low disease activity according to CDAI, with a mean DAS28 and CDAI of 2.62±1.25 and 8.0±7.2, respectively (Table 1). Table 2 summarizes the mean drug plasma levels according to CDAI score. Drug plasma levels (both Cmax and Cmin) showed similar results in patients with different disease activity statuts according to CDAI, without significant differences. However, the two patients treated with BARI and high disease activity showed the lower drug levels, although the difference was not significant.Conclusion:In this preliminary study, no clear dose-response relationship was found between plasma JAKi levels and disease activity in RA. However further studies including patients with moderate/high disease activity are needed to assess the potential usefulness of evaluating plasma drug levels as indicator of the clinical status of RA patients undergoing treatment with BARI and TOFA.REFERENCES:[1] Kremer JM, Cohen S, Wilkinson BE, Connell CA, French JL, Gomez-Reino J, et al. A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. Arthritis Rheum 2012;64:970-81.[2] Koller D, Vaitsekhovich V, Mba C, Steegmann JL, Zubiaur P, Abad-Santos F, et al. Effective quantification of 11 tyrosine kinase inhibitors and caffeine in human plasma by validated LC-MS/MS method with potent phospholipids clean-up procedure. Application to therapeutic drug monitoring. Talanta 2020;208:120450.Acknowledgements:NIL.Disclosure of Interests:Beatriz Frade-Sosa received support for attending meetings and/or speaker honoraria from Pfizer, AbbVie, Lilly, BMS, Galápagos, Sandoz and GSK., Chafik Alejandro Chacur: None declared, Jose Inciarte-Mundo Current employee at Astrazeneca., Cristina Valero: None declared, Marta Novella-Navarro: None declared, Helena Borrell Paños: None declared, Águeda Prior-Español: None declared, Eduard Graell: None declared, Pablo Zubiaur: None declared, Gonzalo Villapalos: None declared, Nuria Sapena: None declared, Lola Tobalina: None declared, Antonio Gómez-Centeno: None declared, Lourdes Mateo: None declared, Alejandro Balsa: None declared, Sara Marsal Barril: None declared, Rosario Garcia-Vicuña: None declared, Raimon Sanmarti: None declared.

Methotrexate (MTX) remains the first line of treatment in Rheumatoid Arthritis (RA)1,2. Inhibition of AICAR transformylase by MTX results in augmented release of adenine nucleotides to the extracellular space1; these are rapidly hydrolysed by the combined action of ectonucleotidases CD39 and CD79 rendering the antiinflammatory agent adenosine1. CD39, the rate-limiting enzyme in this cascade, is highly expressed by a subset of human FoxP3+CD4+ regulatory T cells (Treg39+)2-4 and MTX may act synergistically with Tregs in the control of inflammation. To study the expression of CD39 on circulating Treg cells of untreated early Rheumatoid Arthritis (ERA) patients and its relation with the ex vivo effect of MTX. Peripheral blood was drawn from 22 DMARD- and steroid- naïve ERA patients with a disease duration < 24 weeks, 15 longstanding RA patients (LRA, disease duration > 2 years) and 37 age and gender-matched healthy controls (HC). LRA patients were receiving low-dose weekly MTX and were naïve for biologicals. 10 ERA patients who had achieved remission 12 months after initiating MTX donated blood for a second time (ERA-R). The frequency of Treg and Treg cell subsets was assessed by flow cytometry. CD4+CD25+CD127- (total T reg), CD4+CD27+CD127-CD39+ Treg (Treg39+) and CD4+CD25-CD39- responder T (Tresp39-) cells were isolated by Ficoll-Hypaque, followed by sorting. The suppressor potency of Tregs was assessed in cocultures of isolated Tregs with Tresp, established at different Treg/Tresp ratios. Proliferation was determined by CFSE dilution; cytokine secretion was measured by ELISA of culture supernatants. As previously described5, ERA but not LRA patients demonstrated a superior frequency of circulating Treg (CD4+CD25+CD127-FoxP3+) cells. In addition, the proportion of Tregs that expressed CD39 (Treg39+) was significantly increased in ERA but not LRA. Total ERA Tregs were significantly more potent suppressors of proliferation, TNFα and IFNγ secretion when compared with HC or LRA Tregs, and this difference was partially and significantly abrogated in the presence of adenosine deaminase, or the adenosine A2A receptor (A2AR) antagonists DMPX (3,7-dimethyl-1-propargylxanthine) or ZM 241385, but not in the presence of the adenosine A1 receptor antagonist DPCPX (8-cyclopentyl-dipropylxanthine). When MTX was added to the culture medium, the suppressor potency of total Tregs was further enhanced in all 3 groups of patients, and this enhancement was significantly higher in ERA total Treg/Tresp39- cocultures as compared with HC or LRA total Treg/Tresp39- cocultures. The effect of MTX was also partially and significantly abrogated by adenosine deaminase, DMPX or ZM 241385 but not by DPCPX. We then tested the suppressor potency of isolated Treg39+ together with the enhancer effect of MTX on this potency, and observed that there were no longer differences among ERA, LRA and HC; this further suggests that the differences observed in assays using total Tregs can be attributable to the increased Treg39+ proportions present in ERA. The frequency and function of ERA-R Treg cells were not different from HC or LRA Tregs. The suppressor action of CD39+Tregs is mediated at least in part by adenosine trough A2AR ligation, and the superior suppressive potency of total ERA Tregs is associated with their higher proportion of TregCD39+ cells as compared with HC or LRA. In addition, the augmented suppressor effect observed in the presence of MTX is partly mediated by an increased adenosine production acting on A2AR and is more marked in ERA patients reflecting again their higher proportion of Treg39+ cells. This indicates that MTX cooperates with Treg39+ cells in the control of inflammation. [1]Montesinos MC, et al. Arthritis Rheum. 2007. [2]Peres RS, et al. Proc Natl Acad Sci U S A. 2015. [3]Deaglio S, et al. J Exp Med. 2007. [4]Borsellino G, et al. Blood. 2007. [5]Benito-Miguel M, et al. J Immunol. 2009. FIS PI 20/00141; FIS RD16/0012/0012; Fondo Europeo de Desarrollo Regional (FEDER), unrestricted research grant from Gebro Pharma Laura Nuño: None declared, Alejandro Villalva: None declared, Marta Novella-Navarro: None declared, Irene Monjo: None declared, Diana Peiteado: None declared, Sara García-Carazo: None declared, Amaya Puig-Kröger: None declared, Alejandro Balsa Grant/research support from: BMS, Gebro Pharma, Maria-Eugenia Miranda-Carus Grant/research support from: BMS, Gebro Pharma