Objective In 2020, the Spanish Society of Rheumatology (SER) and the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) published joint recommendations on the management of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Since then, new evidence has emerged supporting an update focused on treatment. Methods A systematic literature review was conducted covering the period from October 2020 to October 2025. Results L-6 and JAK inhibitors (JAKi) show efficacy comparable to rituximab (RTX) and abatacept (ABA) in controlling joint disease, preserving pulmonary function, limiting radiological progression, and reducing RA-ILD-related mortality, without a significant increase in serious respiratory events. ABA has not demonstrated a lower risk of severe or opportunistic infections; therefore, these four options (ABA, RTX, anti-IL6, and JAKi) may be used interchangeably in RA-ILD patients requiring treatment intensification. In those with a progressive fibrosing phenotype and intolerance to nintedanib, pirfenidone may be considered. Conclusions Recent evidence has expanded the therapeutic options available for RA-ILD.

Objetivo En 2020, la SER y la Sociedad Española de Neumología y Cirugía Torácica (SEPAR) publicaron recomendaciones conjuntas sobre el manejo de la enfermedad pulmonar intersticial difusa asociada a la artritis reumatoide (EPID-AR). Desde entonces ha surgido nueva evidencia que justifica una actualización centrada en su tratamiento. Métodos Se realizó una revisión sistemática de la literatura entre octubre de 2020 y octubre de 2025. Resultados Los inhibidores de IL-6 y de JAK (JAKi) muestran eficacia comparable a rituximab (RTX) y abatacept (ABA) en el control articular, la estabilización funcional, la progresión radiológica y la mortalidad asociada a la EPID, sin aumento significativo de eventos respiratorios graves. No se ha demostrado que ABA reduzca el riesgo de infecciones graves u oportunistas, por lo que las cuatro opciones pueden emplearse indistintamente en pacientes con EPID-AR que requieran intensificar el tratamiento. En casos con fenotipo fibrótico progresivo e intolerancia a nintedanib puede considerarse pirfenidona. Conclusiones La evidencia reciente amplía las opciones terapéuticas disponibles para la EPID-AR.

Objectives: Nailfold capillaroscopy (CP) is used in the study of Raynaud's phenomenon (RPh). Many people have cardiovascular risk factors (CVRF): tobacco (TOB), diabetes (DM), alcohol (ALC), dyslipidaemia (DL), arterial hypertension (HT), and obesity (OBE). The objective of the work was to investigate whether CVRF produce capillaroscopic alterations, which could influence their final interpretation. Methods: Multicentre descriptive retrospective study of patients referred to CP consultation for RPh or suspected connective tissue disease in two Madrid hospitals between 2015 and 2018. 200x videocapillaroscopy (Dinolite (R)) was used. Analytical, clinical, therapeutic variables, CVRF, and capillaroscopic alterations (tortuosities, ramifica tions, dilations, giant capillaries, decreased density, and haemorrhages) were collected. For the statistical study, parametric and non-parametric tests were used (statistical significance at P<.05). Results: Three hundred forty medical records were reviewed, 286 (84.1%), mean age of 52.36 +/- 16.97 years; 270 had RPh (79.4%) and 212 (62.4%) CVRF: 108 TOB (31.8%), 108 DL (31.8%), 62 HT (18.2%), 20 DM (5.8%), 8 ALC (2.4%). Three groups were formed: 155 primary RPh (45.6%), 123 with connective tissue disease (36.2%) and 62 with other osteoarticular diseases (18.2%). The statistical study showed an association between all capillaroscopic alterations and CVRF (P<.001), as well as between: decreased density with HT (p = 0.006); tortuosities with HT (P<.001) and hypercholesterolaemia (P=.006); Dilations, ramifications, haemorrhages with HT (P<.001, P=.019, and P=.008) and TOB (P<.001, P=.019, and P=.002); giant capillaries with TOB (P=.034). Conclusions: This work shows the association between capillaroscopic alterations and CVRF, which should be considered for correct CP interpretation.

BACKGROUND:While risk factors for difficult-to-treat rheumatoid arthritis (D2TRA) have been studied in recent years, no studies have determined if there are differences between early and late developers of D2TRA. This study investigates whether patients can be classified by time to D2TRA development and examines risk factors for earlier onset. PATIENTS AND METHODS:Observational study involving D2TRA patients whose reason for switching b/tsDMARD therapy was inefficacy (D2TRA-Inneficacy). Demographic data, comorbidities and disease characteristics, acute phase reactants and Disease Activity Score-28 [DAS28-ESR]) at baseline and 6 months after initiation of the first b/tsDMARD, and duration of each treatment were recorded. Using LASSO (Least Absolute Shrinkage and Selection Operator) Cox-regression feature-selection strategy, we identified those factors influencing the time to D2TRA-Inneficacy. DBSCAN clustering was conducted to identify subgroups based on time to D2TRA. Finally, we used ROC and Precision-Recall curves in tandem with the Youden index to establish a cutoff point for differentiating early and late-D2TRA. RESULTS:Of the 131 patients with D2TRA, 96 (72.7%) were classified as D2TRA-inefficacy. The variables presence of anxiety-depressive syndrome (ADS) at first b/tsDMARD, CRP at 6 months after starting the first b/tsDMARD and age at disease diagnosis were selected based on their contracted scores from the LASSO Cox-regression model, following the criterion of minimizing the cross-validated error. DBSCAN clustering based on selected variables identified three clusters. These clusters, differentiated by time to D2TRA, classified patients into early and late D2TRA groups. Finally, an optimal cut-off point of 44.5 months was determined using the Youden index to distinguish between the two groups. CONCLUSION:In our cohort, the cut-off time for defining early developers of D2TRA-inefficacy was 44.5 months. The presence of ADS diagnosis, a higher CRP 6 months after the first b/tsDMARD, and being older at diagnosis were predictors of early development of D2TRA.

Objetivos La capilaroscopia periungueal (CP) es una herramienta utilizada en el estudio del fenómeno de Raynaud (FRy). Muchas personas presentan factores de riesgo cardiovascular (FRCV): tabaco (TAB), diabetes (DM), alcohol (ALC), dislipemia (DL), hipertensión arterial (HTA) y obesidad (OBE). El objetivo del trabajo fue estudiar si los si los FRCV producen alteraciones capilaroscópicas, pudiendo influir en su interpretación final. Métodos Estudio retrospectivo descriptivo multicéntrico de pacientes derivados a consulta de CP por FRy o sospecha conectivopatía, en 2 hospitales madrileños entre 2015 y 2018. Se usó videocapilaroscopio ×200 (Dinolite®). Se recogieron variables analíticas, clínicas, terapéuticas, FRCV, y alteraciones capilaroscópicas (tortuosidades, ramificaciones, dilataciones, megacapilares, disminución densidad y hemorragias). Para el estudio estadístico se emplearon test paramétricos y no paramétricos; se obtuvo una significación estadística de p<0,05. Resultados Se revisaron 340 historias clínicas, 286 mujeres (84,1%), edad media 52,36±16,97 años; 270 presentaban FRy (79,4%) y 212 (62,4%) FRCV: 108 TAB (31,8%), 108 DL (31,8%), 62 HTA (18,2%), 20 DM (5,8%) y 8 ALC (2,4%). Se formaron 3 grupos: 155 FRy primario (45,6%), 123 con conectivopatías (36,2%) y 62 con otras afecciones osteoarticulares (18,2%). El estudio estadístico mostró asociación entre todas las alteraciones capilaroscópicas y FRCV (p<0,001), como también entre: disminución de densidad capilar y HTA (p=0,006); tortuosidades y HTA (p<0,001) e hipercolesterolemia (p=0,006); dilataciones, ramificaciones, hemorragias y HTA (p<0,001, p=0,019, p=0,008, p=0,006) y TAB (p<0,001, p=0,019 y p=0,002); megacapilares y TAB (p=0,034). Conclusiones Este trabajo evidencia una asociación entre alteraciones capilaroscópicas y FRCV que debería ser considerada para su correcta interpretación.

Objectives To investigate the appearance of anti-drug antibodies (ADA) against infliximab (IFX) determined by drug-sensitive and drug-tolerant assays and their relationship with drug levels and drug survival.Methods This longitudinal observational study included 45 patients with RA and 61 with SpA. Serum samples were obtained at weeks 2, 6, 12, 24 and 52. Serum IFX levels were measured by a capture ELISA and ADA by an in-house drug-sensitive two-site (bridging) ELISA (bELISA) and a commercially available drug-tolerant ELISA (IDK, Immundiagnostik, Germany).Results ADA were detected earlier by IDK than by bELISA. Once ADA appeared, positivity persisted throughout the study period. Patients who were bELISA ADA+ had higher IDK ADA levels (than bELISA ADA- patients). Circulating IFX levels were detected in all patients except those found to be bELISA ADA+. Serum IFX levels were lower in IDK ADA+ than in IDK ADA- patients. Most patients (64%) discontinued due to inefficacy. The early onset of immunogenicity was related to IFX survival. In both RA and SpA, the median survival (years) was shorter in patients with earlier development of ADA (IDK+ before or at week 24) than those who became IDK+ later (after week 24) or never developed ADA.Conclusion A drug-tolerant assay detects ADA during IFX therapy earlier and more frequently than a drug-sensitive assay. The onset of immunogenicity detected by drug-tolerant assays is related to the subsequent detection of ADA by drug-sensitive assays and drug survival.

OBJECTIVES:GCA is a large/medium-vessel granulomatous vasculitis, and the Programmed Cell Death 1/Programmed Cell Death-ligand-1 (PD-1/PD-L1) coinhibitory pathway seems to be implicated in its pathogenesis. CD4 T cells expressing high PD-1 levels, CD4+CXCR5-PD-1hi peripheral helper (Tph) and CD4+CXCR5+PD-1hi follicular helper T cells (Tfh) are key mediators of autoimmunity. Their frequencies are elevated in the peripheral blood of subjects with several autoimmune conditions but have not been investigated in GCA. Our objective was to study the frequency of circulating Tph (cTph) and Tfh (cTfh) in patients with newly diagnosed GCA (nGCA). METHODS:Prospective, non-interventional study on consecutive patients referred to our US GCA fast-track clinic over a period of 24 months. Peripheral blood was drawn immediately upon initial diagnosis. For each patient, an age- and gender-matched healthy control (HC) was included. Peripheral blood mononuclear cells isolated by Ficoll-Hypaque were examined by cytometry. Patients were subsequently treated with standard therapy according to the updated 2018 EULAR recommendations. RESULTS:Sixty-five nGCA patients were included. As compared with HC, nGCA patients presented at baseline with an increased frequency of cTph and cTfh cells. Among the 46 patients who could be followed up for 12 months, 19 experienced a relapse. The baseline frequency of cTph and cTfh cells had been significantly lower in patients who relapsed as compared with those who did not. A cTph cell frequency <1.0 predicted relapse with a sensitivity of 90% and specificity of 93%. CONCLUSION:nGCA patients demonstrate increased baseline cTph and cTfh cell frequencies. Lower baseline proportions of cTph and cTfh cells associate with relapse.

OBJECTIVES:A subset of human circulating FoxP3+ regulatory T cells expresses CD39 (cTreg39+) and hydrolyses pro-inflammatory adenine nucleotides released at inflammatory foci, releasing the anti-inflammatory agent adenosine. Methotrexate (MTX), inhibiting 5-aminoimidazole-4-carboxamide ribonucleotide transformylase, enhances the extrusion of adenine nucleotides and may help Treg39+ cells control inflammation. Therefore, we examined the relation of cTreg39+ cells with the effect of MTX in early rheumatoid arthritis (eRA). METHODS:Freshly isolated peripheral blood lymphocytes from 98 untreated eRA patients and 98 healthy controls (HC) were examined by cytometry. Twelve months (12 m) after initiating MTX, 82 patients were clinically re-evaluated and cytometry was repeated in 40 of them. The effect of MTX on Treg cell potency was assessed in Treg/Tresp cocultures. RESULTS:The baseline (0 m) cTreg39+ cell frequency was elevated in eRA above HC levels. Patients who reached low disease activity at 12 months (12 m-LDA, DAS28-ESR ≤ 3.2, n = 51) had presented with a significantly higher 0 m cTreg39+ frequency vs those who did not (n = 31). The 0 m cTreg39+ cutoff for attaining 12 m-LDA was 42.0% (sensitivity = 90.4%, specificity = 96.8%). At 12 m, the cTreg39+ frequency was no longer elevated but its association with disease activity remained: it was still significantly higher in patients who had reached LDA vs those who had not. In vitro, MTX augmented the Treg39+ cell potency but had no effect on Treg39- cells. CONCLUSION:MTX cooperates with Treg39+ cells and the baseline cTreg39+ frequency predicts the response to MTX in eRA. In addition, the transiently elevated baseline cTreg39+ frequency in eRA may provide a slot for prompt MTX initiation.

Rheumatoid arthritis (RA) and axial spondyloarthritis (axSpA) are the most common rheumatic diseases (RDs). They are characterised by chronic inflammation of the joints and musculoskeletal components. Adipose tissue releases adipokines that regulate numerous biological processes, including inflammation, thus stabilising the relationship between RDs and adipokines, such as adiponectin and leptin. The correlation between these adipokines and RA highlights a possible role of other adipokines in RDs. Therefore, we decided to analyse the role of the adipokine adipsin in the context of RDs. Adipsin levels were measured in serum from 233 patients (66 early-RA, 98 established-RA, and 69 axSpA) and 88 healthy controls (HCs). Associations between adipsin and clinical or demographic variables were assessed using univariate and multivariate regression models. The diagnostic utility of adipsin was evaluated using ROC curve analysis. Our study revealed that adipsin concentrations were significantly higher in both early-RA and established-RA patients than in axSpa and in HCs. No significant differences were found between axSpA and HCs. In early-RA, female sex and prednisone use were independently associated with higher adipsin levels. In established-RA, age and disease duration showed a positive association with adipsin concentrations. In axSpA, disease duration and CRP correlated with adipsin levels, but no consistent associations were observed for BMI or HLA-B27 status. ROC analysis revealed good discriminatory capacity of adipsin to differentiate early-RA from HCs (AUC = 0.82; optimal cut-off: 1.325 µg/mL). We provide evidence supporting the involvement of adipsin in the pathophysiology of RA and highlight its value as a new potential biomarker.

Introduction and objectives The SUMAR project aimed to establish a consensus on the concept of remission in patients with rheumatoid arthritis (RA) that takes into account the different perspectives of patients, health care professionals and health care managers. Materials and methods The scientific committee comprised a rheumatologist who acted as a national coordinator, 4 rheumatologists, 1 primary care physician, 1 nurse, 2 hospital pharmacists, 2 health care managers and 1 member of a patient advocacy group. The study was undertaken from 2020 to 2021 in three phases: (1) analysis of several perspectives on remission in RA with the participation of 275 patients, 160 rheumatologists and 31 health care managers; (2) an integrative definition of remission, which included two multidisciplinary workshops with 11 and 12 participants; and (3) extension and dissemination with up to 200 participants in 7 regional multidisciplinary meetings. Results The concept of remission in the different settings and by the different stakeholders was heterogeneous. It was agreed that, in addition to inflammatory activity, remission should include pain and functionality as well as the duration of remission. For the participants, the definition of remission varied depending on the clinical scenario, without or with structural damage, seeking to “normalize” the outcomes in the former and avoid progression in the latter. The implementation of the concept of comprehensive remission was considered less feasible, and the main barriers to implementation were the lack of time for consultation and the variability in information technology systems across the different autonomous communities. Discussion and conclusions This definition of remission is not only based on the concept of the presence or absence of inflammatory activity based on existing indexes, but also includes variables directly reported by the patient that are related to their health and quality of life.

BACKGROUND AND OBJECTIVE:The SUMAR project established a definition for remission that includes the patient's perspective (global assessment of pain and HAQ) in the definition of remission in rheumatoid arthritis (RA). This new definition needs to be assessed on clinical practice. The main objective of the RA-Remission study is to estimate the proportion of patients in sustained remission according to SUMAR definition through 2-year follow-up, among patients in SUMAR remission at baseline. This manuscript describes the objectives and methodology of the study. MATERIALS AND METHODS:This is a longitudinal, prospective, observational and multicentre study, involving 10 centres. Patients with RA who have achieved clinical remission in accordance to their attending rheumatologist clinical judgement within the last 6 months will be included. Follow-up visits will take place at 3, 6, 12, 12, 18 and 24 months. Ultrasound assessment of the power Doppler (PD) signal for 30 joints and 6 tendon regions will be performed at each participating centre by an expert blinded to all other study findings. Definitions of remission according to SUMAR, PD and activity indices will be used. Sustained remission will be considered for each of the definitions when the patient in remission at the baseline visit maintains it during all follow-up visits. To estimate the proportion of patients maintaining remission at two years with an accuracy of at least 6%, 180 patients will need to be recruited. DISCUSSION AND CONCLUSIONS:The main strength of the design is the use of ultrasound assessment as the gold standard for assessing inflammatory activity.

Background: Obesity is a frequent comorbidity in rheumatoid arthritis (RA). This condition may lead these patients to have poorer disease control and a worse response to some of the available treatments. Objectives: We aim to analyze the role of body mass index (BMI) in the clinical response to Janus kinase inhibitors (JAKis) in patients with RA. We aim to perform an in-depth analysis of the pathophysiology of obesity by assessing serum adipokine levels, their potential influence in disease activity and their changes with treatment. Methods: This study involved 81 patients with RA treated with JAKis from Hospital La Paz and Hospital Reina Sofía. Patients were classified according to their BMI as normal weight and overweight/obesity. The clinical response to treatment was assessed by the Clinical Disease Activity Index (CDAI) and Disease Activity Score-28 (DAS28) 6 months after the initiation of JAKis. Serum adipokines (leptin and adiponectin) were determined using a commercial immunoassay kit in samples obtained before the initiation of JAKis and after 6 months of treatment. Results: Leptin levels showed a significant positive correlation with BMI at baseline (r = 0.59, p < 0.01) and at 6 months (r = 0.56, p < 0.01) in the whole cohort, but no correlation was found between BMI and adiponectin. No correlation between disease activity and BMI was found in the whole cohort at baseline and at 6 months measured by both the CDAI and DAS28. Fifty patients (61.7%) achieved low disease activity (LDA)/remission at 6 months, regardless their BMI, and no differences in serum adipokine levels were observed at baseline and at 6 months in patients who achieved LDA vs. no-LDA. Conclusions: In this study, we did not find an association between obesity and the extent of LDA in patients treated with JAKis; therefore, this mechanism of action could be suitable for overweight/obese patients with RA.