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Background The purpose of this study was to learn about the clinical practice of specialists who care for patients with giant cell arteritis, to verify whether they follow the diagnosis and treatment recommendations for this disease, and to identify areas for improvement. Methods A cross-sectional survey on clinical practice in 2019. The survey was completed by 167 physicians (64% rheumatologists, 27% internal medicine specialists, and 9% other specialists) who attended a course on updating giant cell arteritis treatment. We compared the clinical practice collected in the study with the latest recommendations approved by the European League Against Rheumatism (EULAR). Results The physicians surveyed cared for a median of 10 patients (interquartile range 6–30) with giant cell arteritis during their practice. As a diagnostic method, respondents used temporal artery biopsy (84%), temporal artery ultrasound (61%) or other imaging techniques (37%). As first-line therapy, respondents used high-dose glucocorticoids (at least 40 mg of prednisone, or equivalent, per day) (84%), glucocorticoids with methotrexate (7%) and glucocorticoids with tocilizumab (5%). The most frequent drugs used for relapse were methotrexate (37%) and tocilizumab (58%). Conclusion Our results indicate that the medical specialists surveyed follow the recent EULAR recommendations for giant cell arteritis diagnosis and therapy.

Aims To assess differences in estimated cardiovascular disease (CVD) risk among rheumatoid arthritis (RA) patients from different world regions and to evaluate the management and goal attainment of lipids and blood pressure (BP). Methods and results The survey of CVD risk factors in patients with RA was conducted in 14 503 patients from 19 countries during 2014–19. The treatment goal for BP was Conclusion We revealed considerable geographical differences in estimated CVD risk and preventive treatment. Low goal attainment for LLT was observed, and only half the patients obtained BP goal. Despite a high focus on the increased CVD risk in RA patients over the last decade, there is still substantial potential for improvement in CVD preventive measures.

We aimed to develop recommendations for the management of methotrexate (MTX) when considering the combination with biological (b) or targeted synthetic (ts) disease modifying drugs (DMARDs) in rheumatoid arthritis (RA). Methods: Eleven experts on RA were selected. Two coordinators formulated 13 questions about the combination therapy of MTX with bDMARDs or tsDMARDs. A systematic review was conducted to answer the questions. Inclusion and exclusion criteria were established as well as the search strategies (Medline, Embase and the Cochrane Library were searched up to January 2019). Two reviewers selected the articles and collected data. Simultaneously, EULAR and ACR meeting abstracts were evaluated. Based on this evidence, the coordinators proposed preliminary recommendations that the experts discussed and voted in a nominal group meeting. The level of evidence and grade of recommendation was established using the Oxford Center for Evidence Based Medicine and the level of agreement with a Delphi. Agreement was established if at least 80% of the experts voted ‘yes’ (yes/no). Results: The systematic review retrieved 513 citations of which 61 were finally included. A total of 10 recommendations were generated, voted and accepted. The level of agreement was very high in all of them and it was achieved in the first Delphi round. Final recommendations cover aspects such as the optimal MTX dosage, tapering strategy or patients’ risk management. Conclusions: This document is intended to help clinicians solve usual clinical questions and facilitate decision making when treating RA patients with MTX in combination with bDMARDs or tsDMARDs, Desarrollar recomendaciones sobre el uso de metotrexato (MTX) en combinación con medicamentos modificadores de la enfermedad (DMARD) biológicos (b) o sintéticos específicos (ts) en la artritis reumatoide (AR). Se seleccionaron 11 expertos en AR. Dos coordinadores formularon 13 preguntas sobre la terapia combinada de MTX con bDMARD o tsDMARD. Se realizó una revisión sistemática para responder las preguntas. Se establecieron criterios de inclusión y exclusión, así como las estrategias de búsqueda (se realizaron búsquedas en Medline, Embase y la Biblioteca Cochrane hasta enero de 2019). Dos revisores seleccionaron los artículos y recopilaron datos. Simultáneamente, se evaluaron los resúmenes de las reuniones EULAR y ACR. Con base en esta evidencia, los coordinadores propusieron recomendaciones preliminares que los expertos discutieron y votaron en una reunión de grupo nominal. El nivel de evidencia y el grado de recomendación se establecieron utilizando el Centro de Oxford para Medicina Basada en Evidencia y el nivel de acuerdo con un Delphi. El acuerdo se estableció si al menos el 80% de los expertos votaron «sí» (sí/no). La revisión sistemática recuperó 513 citas, de las cuales finalmente se incluyeron 61. Se generaron, votaron y aceptaron un total de 10 recomendaciones. El nivel de acuerdo fue muy alto en todas ellas y se logró en la primera ronda de Delphi. Las recomendaciones finales cubren aspectos como la dosis óptima de MTX, la estrategia de reducción o la gestión del riesgo de los pacientes. Este documento está destinado a ayudar a los médicos a resolver preguntas clínicas habituales y facilitar la toma de decisiones al tratar a pacientes con AR con MTX, en combinación con bDMARD o tsDMARD

Background The incidence of sarcoidosis varies widely worldwide. The aim of this study was to estimate the incidence of sarcoidosis in a population-based cohort from northern Spain. Methods Patients diagnosed with sarcoidosis at Marques de Valdecilla University Hospital, corresponding to the central Cantabria that encompasses Santander city and the surroundings, between January 1999 and December 2019were assessed. The diagnosis of sarcoidosis was established according to ATS/ERS/WASOG criteria as follows: compatible clinical and radiological presentation, histopathologic confirmation, and exclusion of other granulomatous diseases. Demographic and clinical data were collected. The incidence of sarcoidosis between 1999-2019 was estimated by sex, age, and year of diagnosis. Results A total of 234 patients were included, with a male/female ratio of 0.81. The mean age of the cohort at diagnosis was 48.43 ± 14.83 years and 129 (55.1%) were women. Incidence during the period of study was 3.58 per 100,000 populations (95% confidence interval: 3.13 – 4.07). No gender predominance was observed. An increase in age at diagnosis over time was found in the linear regression analysis. Thoracic affection was found in 180 patients (76.9%). Most common extra-thoracic areas affected were skin (34.2%), joints (30.8%) and eyes (15.4%). Conclusions The incidence of sarcoidosis estimated in this study was similar to that of other Mediterranean countries. No gender predominance was observed. Consistent with previous studies, male presented an incidence peak 10 years earlier than female. A second peak between ages 60-69 years was identified in both sexes.

We are indebted to the patients and healthy controls for their essential collaboration to this study. We also thank the National DNA Bank Repository (Salamanca) for supplying part of the control samples. This study was supported by European Union FEDER funds and `Fondo de Investigaciones Sanitarias (Grant PI18/00042) from 'Instituto de Salud Carlos III' (ISCIII, Health Ministry, Spain). DP-P is a recipient of a Rio Hortega programme fellowship from the ISCIII, co-funded by the European Social Fund (ESF, `Investing in your future) (Grant Number CM20/00006). SR-M is supported by funds of the RETICS Program (RD16/0012/0009) (ISCIII, co-funded by the European Regional Development Fund (ERDF)). VP-C is supported by a pre-doctoral grant from IDIVAL (PREVAL 18/01). BA-M is a recipient of a `Lopez Albo Post-Residency Programme funded by Servicio Cantabro de Salud. LL-G is supported by funds from IDIVAL (INNVAL20/06). OG is staff personnel of Xunta de Galicia (Servizo Galego de Saude (SERGAS)) through a research-staff stabilization contract (ISCIII/SERGAS) and his work is funded by ISCIII and the European Union FEDER fund (Grant Numbers RD16/0012/0014 (RIER) and PI17/00409). He is beneficiary of project funds from the Research Executive Agency (REA) of the European Union in the framework of MSCA-RISE Action of the H2020 Programme, project 734899-Olive-Net. RL-M is a recipient of a Miguel Servet type I programme fellowship from the ISCIII, co-funded by ESF (`Investing in your future) (Grant Number CP16/00033)., Cytokines signalling pathway genes are crucial factors of the genetic network underlying the pathogenesis of Immunoglobulin-A vasculitis (IgAV), an inflammatory vascular condition. An influence of the interleukin (IL)33- IL1 receptor like (IL1RL)1 signalling pathway on the increased risk of several immune-mediated diseases has been described. Accordingly, we assessed whether the IL33-IL1RL1 pathway represents a novel genetic risk factor for IgAV. Three tag polymorphisms within IL33 (rs3939286, rs7025417 and rs7044343) and three within IL1RL1 (rs2310173, rs13015714 and rs2058660), that also were previously associated with several inflammatory diseases, were genotyped in 380 Caucasian IgAV patients and 845 matched healthy controls. No genotypes or alleles differences were observed between IgAV patients and controls when IL33 and IL1RL1 variants were analysed independently. Likewise, no statistically significant differences were found in IL33 or IL1RL1 genotype and allele frequencies when IgAV patients were stratified according to the age at disease onset or to the presence/absence of gastrointestinal (GI) or renal manifestations. Similar results were disclosed when IL33 and IL1RL1 haplotypes were compared between IgAV patients and controls and between, European Commission, 'Instituto de Salud Carlos III' (ISCIII, Health Ministry, Spain) PI18/00042 Instituto de Salud Carlos III, European Social Fund (ESF) CM20/00006, RETICS Program (ISCIII) RD16/0012/0009, European Commission IDIVAL 18/01 INNVAL20/06, Servicio Cantabro de Salud, European Union FEDER fund RD16/0012/0014 PI17/00409, European Commission 734899 CP16/00033

To analyze the prevalence of metabolic syndrome (MetS) in patients with psoriatic arthritis (PsA) in a systematic literature review (SLR) and in the Spanish CArdiovascular in RheuMAtology (CARMA) cohort.A SLR and a subanalysis of the CARMA cohort were performed. In the SLR, PubMed, EMBASE, the Cochrane Library, and ClinicalTrials.gov up to March 2019 were searched. Systematic literature reviews, clinical trials, and observational studies that analyzed the prevalence or frequency of MetS in PsA were analyzed. Two reviewers selected the articles, assessed the quality of the studies, and collected data, independently. In addition, data on sociodemographic characteristics and MetS in patients with PsA from the CARMA cohort were collected and analyzed. Comparative descriptive analysis was performed.The SLR included 18 articles, of moderate to high quality, with PsA patients of both sexes, with mean ages between 42 and 59 years. The rate of MetS varied from 23.5% to 62.9%. The most commonly used classification method was that of the National Cholesterol Education Program. Additionally, 724 PsA patients from the CARMA cohort were analyzed; 327 (45.4%) were women, 157 (21.8%) smokers, with a mean age of 51 years and a mean PsA disease duration of 9 years. Hypertension was the most common abnormal finding (66.8%), followed by hyperglycemia (42.6%) and hypertriglyceridemia (30.6%). Notably, 222 patients (30.6%) had MetS.The prevalence of MetS in PsA varies, depending on the definition. Whereas 23.5% to 62.9% of PsA patients have MetS, in the CARMA cohort almost a third of patients with PsA have MetS.

Introduction: Recent studies suggest a role of adipokines in the pathogenesis of hidradenitis suppurativa (HS). Omentin-1 and apelin are two recently identified adipokines that have been involved in the regulation of metabolic and inflammatory responses. Aim: To investigate serum omentin-1 and apelin levels in patients with HS and to assess their associations with metabolic parameters, disease severity and HS risk. Material and methods: This case-control study included 139 non-diabetic individuals (78 HS patients and 61 ageand sex-matched controls). Serum concentrations of omentin-1 and apelin and the homeostasis model assessment of insulin resistance (HOMA-IR) were measured in all participants. Results: Serum omentin-1 concentrations were significantly higher in HS patients compared to controls, whereas apelin serum levels did not significantly differ between both groups. These differences in omentin-1 concentrations remained significant even after adjusting for age, sex, and body mass index (BMI). The results of logistic regression analysis showed that increased omentin-1 plasma levels were an independent risk factor for HS. However, we found no association between serum levels of both omentin-1 and apelin with HS severity. Conclusions: Our results show that patients with HS have raised omentin-1 serum levels, which are associated with HS risk.

We are indebted to the patients and healthy controls for their essential collaboration to this study. We also thank the National DNA Bank Repository (Salamanca) for supplying part of the control samples. This study was supported by European Union FEDER funds and `Fondo de Investigaciones Sanitarias´ (grant PI18/00042) from ‘Instituto de Salud Carlos III’ (ISCIII, Health Ministry, Spain). DP-P is a recipient of a Río Hortega programme fellowship from the ISCIII, co-funded by the European Social Fund (ESF, `Investing in your future´) (grant number CM20/00006). SR-M is supported by funds of the RETICS Program (RD16/0012/0009) (ISCIII, co-funded by the European Regional Development Fund (ERDF)). VP-C is supported by a pre-doctoral grant from IDIVAL (PREVAL 18/01). BA-M is a recipient of a `López Albo´ Post-Residency Programme funded by Servicio Cántabro de Salud. LL-G is supported by funds from IDIVAL (INNVAL20/06). OG is staff personnel of Xunta de Galicia (Servizo Galego de Saude (SERGAS)) through a research-staff stabilization contract (ISCIII/SERGAS) and his work is funded by ISCIII and the European Union FEDER fund (grant numbers RD16/0012/0014 (RIER) and PI17/00409). He is beneficiary of project funds from the Research Executive Agency (REA) of the European Union in the framework of MSCA-RISE Action of the H2020 Programme, project 734899—Olive-Net. RL-M is a recipient of a Miguel Servet type I programme fellowship from the ISCIII, co-funded by ESF (`Investing in your future´) (grant number CP16/00033)., Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1038/ s41598- 021- 91055-z, BAFF, APRIL and BAFF-R are key proteins involved in the development of B-lymphocytes and autoimmunity. Additionally, BAFF, APRIL and BAFFR polymorphisms were associated with immunemediated conditions, being BAFF GCTGT>A a shared insertion-deletion genetic variant for several autoimmune diseases. Accordingly, we assessed whether BAFF, APRIL and BAFFR represent novel genetic risk factors for Immunoglobulin-A vasculitis (IgAV), a predominantly B-lymphocyte inflammatory condition. BAFF rs374039502, which colocalizes with BAFF GCTGT>A, and two tag variants within APRIL (rs11552708 and rs6608) and BAFFR (rs7290134 and rs77874543) were genotyped in 386 Caucasian IgAV patients and 806 matched healthy controls. No genotypes or alleles differences were observed between IgAV patients and controls when BAFF, APRIL and BAFFR variants were analysed independently. Likewise, no statistically significant differences were found in the genotype and allele frequencies of BAFF, APRIL or BAFFR when IgAV patients were stratified according to the age at disease onset or to the presence/absence of gastrointestinal (GI) or renal manifestations. Similar results were disclosed when APRIL and BAFFR haplotypes were compared between IgAV patients and controls and between IgAV patients stratified according to the clinical characteristics mentioned above. Our results suggest that BAFF, APRIL and BAFFR do not contribute to the genetic network underlying IgAV., European Union FEDER fund RD16/0012/0014, H2020 Programme 734899, Health Ministry, Servicio Cántabro de Salud, Servizo Galego de Saude, European Commission PI18/00042 EC, Research Executive Agency REA, Instituto de Salud Carlos III CP16/00033,PI17/00409 ISCIII, European Social Fund CM20/00006,RD16/0012/0009 ESF, European Regional Development Fund ERDF, Instituto de Investigación Marqués de Valdecilla PREVAL 18/01 IDIVAL, Servicio Gallego de Salud SERGAS

Background Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized fibro-inflammatory pathology that has been reported to affect principally the retroperitoneum, hepatobiliary system, salivary glands, orbital structures or lymph nodes. However, IgG4-RD with laryngeal involvement is a very rare entity. Our aims were to describe a case of subglottic stenosis as first and only manifestation of IgG4-RD and review the literature. A patient with IgG4-RD affecting the larynx that presented as subglottic stenosis is described. A MEDLINE database search of IgG4-RD cases with laryngopharyngeal manifestations was also conducted. A 30-year-old Caucasian woman was referred to a tertiary care hospital for dyspnea on exertion, which had been increasing for the last 4 months. Medical and surgical procedures revealed a subglottic stenosis, with a histological finding of IgG4 positive plasma cell infiltration. There was no evidence of other organ involvement. She was successfully treated with oral glucocorticoids and rituximab infusions. Glucocorticoids were rapidly tapered and the rituximab regimen was optimized, with no evidence of relapses. In the literature review, we found a total of 12 reported cases with laryngopharyngeal involvement, two of them with subglottic stenosis. IgG4-RD of the larynx is rare but should be considered after excluding more common disorders.

Objective.Tofacitinib (TOF) is the first Janus kinase (JAK) inhibitor approved for psoriatic arthritis (PsA). It has shown efficacy in patients refractory to anti–tumor necrosis factor-α in randomized controlled trials (RCTs). Our aim was to assess efficacy and safety of TOF in clinical practice.Methods.This was an observational, open-label multicenter study of PsA patients treated with TOF due to inefficacy or adverse events of previous therapies. Outcome variables were efficacy, corticosteroid dose-sparing effect, retention rate, and safety. A comparative study of clinical features between our cohort of patients and those from the OPAL Beyond trial was performed.Results.There were 87 patients (28 women/59 men), with a mean age of 52.8 ± 11.4 years. All patients were refractory to biologic disease-modifying antirheumatic drugs (DMARDs) and/or to conventional synthetic DMARDs plus apremilast. TOF was started at 5 mg twice daily after a mean follow-up of 12.3 ± 9.3 years from PsA diagnosis. At first month, Disease Activity Score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) decreased from median 4.8 (IQR 4.1–5.4) to 3.7 (IQR 2.8–4.7,P< 0.01), Disease Activity Index for Psoriatic Arthritis from median 28 (IQR 18.4–34.1) to 15.5 (IQR 10.1–25.7,P< 0.01), and C-reactive protein from median 1.9 (IQR 0.3–5.0) to 0.5 (IQR 0.1–2.2) mg/dL (P< 0.01). Also, TOF led to a significant reduction in prednisone dose. Mild adverse effects were reported in 21 patients (24.13%), mainly gastrointestinal symptoms. TOF retention rate at Month 6 was 77% (95% CI 65.2–86.3). Patients in clinical practice were older with longer disease duration and received biologic agents more commonly than those in the OPAL Beyond trial.Conclusion.Data from clinical practice confirm that TOF seems to be effective, rapid, and relatively safe in refractory PsA despite clinical differences with patients in RCTs.

Objective To assess the efficacy and safety of abatacept (ABA) in monotherapy (ABAMONO) vs combined ABA [ABA plus MTX (ABAMTX) or ABA plus non-MTX conventional synthetic DMARDs (csDMARDs) (ABANON-MTX)] in RA patients with interstitial lung disease (ILD) (RA-ILD). Methods This was a restrospective multicentre study of RA-ILD Caucasian patients treated with ABA. We analysed in the three groups (ABAMONO, ABAMTX, ABANON-MTX) the following outcome variables: (i) dyspnoea; (ii) forced vital capacity (FVC) and diffusion capacity of the lung for the carbon monoxide (DLCO); (iii) chest high-resolution CT (HRCT); (iv) DAS28-ESR; (v) CS-sparing effect; and (vi) ABA retention and side-effects. Differences between basal and final follow-up were evaluated. Multivariable linear regression was used to assess the differences between the three groups. Results We studied 263 RA-ILD patients (mean ± s.d. age 64.6 ± 10 years) [ABAMONO (n = 111), ABAMTX (n = 46) and ABANON-MTX (n = 106)]. At baseline, ABAMONO patients were older (67 ± 10 years) and took higher prednisone dose [10 (interquartile range 5–15) mg/day]. At that time, there were no statistically significant differences in sex, seropositivity, ILD patterns, FVC and DLCO, or disease duration. Following treatment, in all groups, most patients experienced stabilization or improvement in FVC, DLCO, dyspnoea and chest HRCT as well as improvement in DAS28-ESR. A statistically significant difference between basal and final follow-up was only found in CS-sparing effect in the group on combined ABA (ABAMTX or ABANON-MTX). However, in the multivariable analysis, there were no differences in any outcome variables between the three groups. Conclusion In Caucasian individuals with RA-ILD, ABA in monotherapy or combined with MTX or with other conventional-DMARDs seems to be equally effective and safe. However, a CS-sparing effect is only observed with combined ABA.

Giant cell arteritis (GCA) is characterized by granulomatous inflammation of large and medium-sized vessels. It is the most common vasculitis among elderly people in Europe and North America. GCA usually presents with ischemic cranial manifestations such as headache, scalp tenderness, visual manifestations, and claudication of the tongue and jaw. Thickness and tenderness of temporal arteries are the most recognizable signs of GCA on physical examination. Laboratory tests usually show raised acute phase reactants. Skin manifestations are uncommon in GCA and are rarely found as a presenting symptom of GCA. Necrosis of the scalp and tongue is the most common ischemic cutaneous manifestation of GCA. Although infrequent, when present it reflects severe affection and poor prognosis of GCA. Panniculitis-like lesions have been reported in the setting of GCA, with nodules being the most common finding. Other entities, such as generalized granuloma annulare or basal cell carcinoma have been occasionally described in GCA patients. Prompt recognition and initiation of therapy are crucial to prevent serious complications of GCA. When high suspicion of GCA exists, immediate administration of glucocorticoids is recommended. It is advisable to refer the patient to a specialist GCA team for further multidisciplinary assessment. Funding: This line of research on vasculitis was partially supported by RETICS Programs, RD08/0075 (RIER), RD12/0009/ 0013 and RD16/0012 from “Instituto de Salud Carlos III” (ISCIII) (Spain).

Objective To investigate if the Systematic Coronary Risk Evaluation (SCORE) and the QRISK3 algorithms as well as the carotid ultrasound are useful predictors of cardiovascular (CV) events and death in a prospectively defined population-based rheumatoid arthritis (RA) inception cohort. Methods A set of 327 consecutive RA patients without history of diabetes, chronic kidney disease or CV events were studied by carotid ultrasound between 2012 and 2013. At that time, CV risk was calculated according to the modified EULAR systematic coronary risk evaluation (mSCORE) for RA. A five-year prospective follow-up study was conducted by survival analysis models. The EULAR mSCORE based on the 2015/2016 updated EULAR recommendations and the QRISK3 algorithms were retrospectively tested using baseline data. Results After 1,984.25 patient-years of follow-up, 23 had died and 27 had experienced CV events. Linearized mortality rate was 1.16/100 patient-years (95% confidence interval [CI]: 0.74--1.73). Adjusting for age, gender and disease duration, a model with carotid plaques (Hazard ratio [HR]: 6.10 [95% CI:0.74--50.0]; p = 0.09) and another model with carotid plaques and QRISK3 (HR for carotid plaques: 6.12 [95% CI: 0.74--50.5]; p = 0.09 and HR for each 1% in QRISK3: 1.03 [95% CI: 0.99--1.07], p = 0.11, respectively were the best predictors of death whereas a model with carotid plaques (HR: 5.25 [95% CI:1.41--19.50]; p = 0.01) and another model with carotid plaques and QRISK3 (HR for carotid plaques: 5.13 [95% CI: 1.36--19.3]; p = 0.02 and HR for each 1% in QRISK3: 1.03 [95% CI: 0.99--1.07], p = 0.12, respectively, were the best predictors of CV events. In contrast, the mSCORE was a weaker predictor of the risk of death or CV events. Conclusions The presence of carotid plaques predicts the development of CV events and death in patients with RA. The predictable capacity of carotid plaques and QRISK3 is higher than that of mSCORE in RA patients.

Objective Because carotid plaques predict the development of cardiovascular events in RA, we aimed to assess if the combined use of the systematic coronary risk evaluation (SCORE) and the QRISK3 algorithms allows for the identification of RA patients with carotid plaques in a defined population-based RA inception cohort. Methods A set of consecutive RA patients without a history of diabetes, chronic kidney disease or cardiovascular events were studied by carotid US between 2012 and 2019. Modified SCORE (mSCORE) for RA based on the 2015/2016 updated EULAR recommendations and QRISK3 algorithms were retrospectively tested using baseline data obtained at the time of the carotid US assessment. Results A total of 466 (54%) of 865 patients had carotid plaques. Using dichotomized QRISK3 and EULAR mSCORE, 73.2% (95% CI: 68.4.8, 77.6) of patients with QRISK ≥ 10% and EULAR mSCORE Conclusions . The combined use of QRISK3 and EULAR mSCORE allows for the identification of most RA patients at high risk of carotid plaques.

Background Diabetes is common in patients with rheumatoid arthritis (RA). Interleukin (IL)-6 is implicated in both the pathogenesis of RA and in glucose homeostasis; this post hoc analysis investigated the effects of IL-6 receptor vs. tumour necrosis factor inhibition on glycosylated haemoglobin (HbA1c) in patients with RA with or without diabetes. Methods Data were from two placebo-controlled phase III studies of subcutaneous sarilumab 150/200 mg q2w + methotrexate or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and a phase III monotherapy study of sarilumab 200 mg q2w vs. adalimumab 40 mg q2w. Patients with diabetes were identified by medical history or use of antidiabetic medication (patients with HbA1c ≥ 9% were excluded from all three studies). HbA1c was measured at baseline and weeks 12/24. Safety and efficacy were assessed in RA patients with or without diabetes. Results Patients with diabetes (n = 184) were older, weighed more and exhibited higher RA disease activity than patients without diabetes (n = 1928). Regardless of diabetes status, in patients on background csDMARDs, least squares (LS) mean difference (95% CI) in change from baseline in HbA1c for sarilumab 150 mg/200 mg vs. placebo at week 24 was − 0.28 (− 0.40, − 0.16; nominal p p p = 0.0043). Greater reduction in HbA1c than placebo or adalimumab was observed at week 24 with sarilumab in patients with diabetes and/or baseline HbA1c ≥ 7%. There was no correlation between baseline/change from baseline in HbA1c and baseline/change from baseline in C-reactive protein, 28-joint Disease Activity Score, or haemoglobin, nor between HbA1c change from baseline and baseline glucocorticoid use. Medical history of diabetes or use of diabetes treatments had limited impact on safety and efficacy of sarilumab and was consistent with overall phase III findings in patients with RA. Conclusions In post hoc analyses, sarilumab was associated with a greater reduction in HbA1c than csDMARDs or adalimumab, independent of sarilumab anti-inflammatory effects. Prospective studies are required to further assess these preliminary findings. Trial registration ClinTrials.gov NCT01061736: date of registration February 03, 2010; ClinTrials.gov NCT01709578: date of registration October 18, 2012; ClinTrials.gov NCT02332590: date of registration January 07, 2015.

Purpose We assessed the efficacy and safety of biologic therapy in severe and refractory Peripheral Ulcerative Keratitis (PUK). Design Open-label multicenter study of biologic-treated patients with severe PUK refractory to conventional immunosuppressive drugs. Subjects We studied 34 patients (44 affected eyes) (24 women/10 men; mean age, 55.26±17.4 years). PUK was associated with a well-defined condition in 29 of them (rheumatoid arthritis [n = 20], psoriatic arthritis [n = 2], inflammatory bowel disease [n = 2], Behcet disease [n = 1], granulomatosis with polyangiitis [n = 1], microscopic polyangiitis [n = 1], systemic lupus erythematosus [n = 1] and axial spondyloarthritis [n = 1]). Besides topical and oral systemic glucocorticoids, patients had received: methylprednisolone pulses [n = 9], and conventional immunosuppressive drugs, mainly methotrexate [n = 18], and leflunomide [n = 7]. Eleven patients had required ocular surgery prior to biologic therapy. Methods Following biologic therapy, baseline main outcomes were compared with those found at 1st week, 1st and 6th months and 1st year. Main outcome measures Efficacy and safety of biologic therapy. Efficacy was analyzed by the assessment of corneal inflammation (corneal thinning, central keratolysis and ocular perforation); other causes of ocular surface inflammation (scleritis, episcleritis); intraocular inflammation (uveitis); visual acuity and glucocorticoid sparing effect. Results The first biologic agents used were anti-TNFα drugs (n = 25); adalimumab (n = 16), infliximab (n = 8), etanercept (n = 1), and non-TNFα agents (n = 9); rituximab (n = 7), tocilizumab (n = 1) belimumab (n = 1) and abatacept (n = 1). During the follow-up, switching to a second biologic agent was required in 12 of the 25 (48%) patients treated with anti-TNFα drugs. However, no switching was required in those undergoing biologic therapy different from anti-TNFα agents. The main outcome variables showed a rapid and maintained improvement after a mean follow-up of 23.7 ± 20 months. Major adverse effects were tachyphylaxis, relapsing respiratory infections, supraventricular tachycardia, pulmonary tuberculosis and death, one each. Conclusions Biologic therapy is effective and relatively safe in patients with severe and refractory PUK. Non-anti-TNFα agents appear to be effective in these patients.

In the past two decades, we have witnessed significant advances in the management of autoimmune diseases. The widespread use of biologic therapies in patients with severe or refractory autoimmune d...

Patients with rheumatoid arthritis (RA) have a higher incidence of subclinical atherosclerosis and cardiovascular (CV) disease. It is postulated that the appearance of accelerated atherosclerosis in these patients is a consequence of the inflammation present in the disease. In this study, we aim to determine if baseline disease activity in patients with RA predicts the future development of carotid plaque. A set of consecutive RA patients without a history of CV events, cancer or chronic kidney disease, who did not show carotid plaque in a carotid ultrasound assessment, were prospectively followed up for at least 5 years. At the time of recruitment, CV risk factors and disease-related data, including disease activity scores, were assessed. At the end of the follow-up, a carotid ultrasound was repeated and patients were divided into two groups, those who developed carotid plaque, and those who did not. A multivariable regression analysis was performed to define the predictors for the development of carotid plaque. One hundred and sixty patients with RA were followed up for an average of 6 ± 1 years. After this time, 66 (41%) of the patients had developed carotid plaque, and 94 (59%) did not. Patients with carotid plaque were significantly older (47 ± 13 vs. 55 ± 9 years, p &lt, 0.001) at baseline, were more frequently diabetic (0% vs. 6%, p = 0.028), and had higher total cholesterol (197 ± 36 vs. 214 ± 40 mg/dL, p = 0.004) and LDL cholesterol (114 ± 35 vs. 126 ± 35 mg/dL, p = 0.037) at the beginning of the study. After multivariable adjustment, patients who were in the moderate and high disease activity (DAS28-CRP) categories displayed a higher odds ratio for the appearance of carotid plaque (OR 2.26 [95% CI 1.02–5.00], p = 0.044) compared to those in the DAS-28-CRP remission category. Remarkably, when patients were divided in patients within the low-risk SCORE category, and patients included in the remaining SCORE categories (moderate, high and very high), the relation between DAS28-CRP and the development of carotid plaque was only significant in the low-risk SCORE category. In conclusion, disease activity predicts the future development of subclinical atherosclerosis in patients with RA.

Intervertebral disc (IVD) degeneration is a common finding on spine imaging that increases in prevalence with age. IVD degeneration is a frequent cause of low back pain, which is a leading cause of disability. The process of IVD degeneration consists of gradual structural change accompanied by severe alterations in metabolic homeostasis. IVD degeneration, like osteoarthritis, is a common comorbidity in patients with obesity and type 2 diabetes mellitus, two metabolic syndrome pathological conditions in which adipokines are important promoters of low-grade inflammation, extracellular matrix degradation and fibrosis. Impairment in white adipose tissue function, due to the abnormal fat accumulation in obesity, is characterized by increased production of specific pro-inflammatory proteins such as adipokines by white adipose tissue and of cytokines such as TNF by immune cells of the stromal compartment. Investigations into the immunometabolic alterations in obesity and type 2 diabetes mellitus and their interconnections with IVD degeneration provide insights into how adipokines might affect the pathogenesis of IVD degeneration and impair IVD function and repair. Toll-like receptor-mediated signalling has also been implicated as a promoter of the inflammatory response in the metabolic alterations associated with IVD and is thus thought to have a role in IVD degeneration. Pathological starvation, obesity and adipokine dysregulation can result in immunometabolic alterations, which could be targeted for the development of new therapeutics.

Background: Interstitial lung diseases (ILD) lead to an increase in the patient’s morbidity and mortality. According to the etiology, ILD can be divided in disorders with either an unknown or known possible cause such as an underlying connective tissue disease (CTD) [1]. A specific T cell subset termed angiogenic T cells (TAng), that promote endothelial repair and revascularization, has been involved in the pathogenesis of CTD [2]. Nevertheless, little is known about their role in ILD. Objective: To assess the potential role of TAng in ILD. Methods: Peripheral venous blood was collected from 61 patients with ILD (composed of 21 with idiopathic pulmonary fibrosis (IPF) and 40 with CTD-ILD+), 44 CTD-ILD- patients and 20 healthy controls (HC). Quantification of TAng was performed by flow cytometry. TAng were considered as triple-positive for CD3, CD31 and CXCR4. Results: Patients with ILD exhibited a significantly lower TAng frequency than CTD-ILD- patients and HC (mean ± standard deviation: 11.98 ± 4.75 versus 16.24 ± 5.03 and 11.98 ± 4.75 versus 16.50 ± 4.83, respectively, p Conclusion: Our results disclose a decrease of TAng frequency related to the presence of ILD. References: [1] J Clin Med 2020;9(6):1606; [2] Ann Rheum Dis 2015 74(5):921-7. Personal funds, VP-C: PREVAL18/01 (IDIVAL); SR-M: RD16/0012/0009 (ISCIII-ERDF); LL-G: INNVAL20/06 (IDIVAL); RP-F: START PROJECT (FOREUM); RL-M: Miguel Servet type I CP16/00033 (ISCIII-ESF).

Hidradenitis suppurativa (HS) is a chronic inflammatory disease associated with insulin resistance (IR), metabolic syndrome and increased cardiovascular risk. Adipokines are biologically active, pleotropic molecules which have been involved in the development of IR and in the pathogenesis of several chronic inflammatory conditions. The aim of the present study was to analyze serum concentrations of adiponectin, leptin, resistin and visfatin in patients with HS, and investigate their possible associations with IR, HS risk and disease severity. This case-control study enrolled 137 non-diabetic individuals (76 HS-patients and 61 age and sex-matched controls). Serum concentrations of adiponectin, leptin, resistin and visfatin, and the homeostasis model assessment of IR (HOMA-IR) were measured in all the participants. Serum adiponectin concentrations were found to be significantly lower, and leptin, resistin and visfatin levels were significantly higher in HS-patients than in controls. These differences remained significant even after adjusting for age, sex and body mass index, except for leptin. In a multivariate regression analysis, HOMA-IR was inversely correlated with adiponectin and positively associated with resistin levels. Furthermore, serum levels of resistin and visfatin were independently associated with HS risk. However, we found no association between serum levels of adipokines and HS severity. Our results suggest that reduced adiponectin and increased resistin serum levels may be surrogate biomarkers for IR in patients with HS. Moreover, resistin and visfatin might be independent risk factors for the development of HS.

Objective To assess the frequency of cardiovascular and venous thromboembolic events in clinical studies of baricitinib, an oral, selective JAK1 and JAK2 inhibitor approved in more than 50 countries for the treatment of moderately‐to‐severely active rheumatoid arthritis (RA). Methods Data were pooled from 9 RA studies. Placebo comparison up to 24 weeks included data from 6 studies. Randomized dose comparison between baricitinib doses of 2 mg and 4 mg used data from 4 studies and from the associated long‐term extension study. The data analysis set designated “All‐bari‐RA” included all baricitinib exposures at any dose. Results Overall, 3,492 RA patients received baricitinib (7,860 patient‐years of exposure). No imbalance compared to the placebo group was seen in the incidence of major adverse cardiovascular events (MACE) (incidence rates [IRs] of 0.5 per 100 patient‐years for placebo and 0.8 per 100 patient‐years for 4 mg baricitinib), arterial thrombotic events (ATE) (IRs of 0.5 per 100 patient‐years for placebo and 0.5 per 100 patient‐years for 4 mg baricitinib), or congestive heart failure (CHF) broad term (IRs of 4.3 per 100 patient‐years for placebo and 2.4 per 100 patient‐years for 4 mg baricitinib). Deep vein thrombosis (DVT)/pulmonary embolism (PE) were reported in 0 of 1,070 patients treated with placebo and 6 of 997 patients treated with 4 mg baricitinib during the placebo‐controlled period; these events were serious in 2 of 6 patients, while all 6 had risk factors and 1 patient developed DVT/PE after discontinuation of the study drug. In the 2 mg–4 mg‐extended data analysis set, IRs of DVT/PE were comparable between the doses across event types (IRs of 0.5 per 100 patient‐years in those receiving 2 mg baricitinib and 0.6 per 100 patient‐years in those receiving 4 mg baricitinib). In the All‐bari‐RA data analysis set, the rates were stable over time, with an IR of DVT/PE of 0.5 per 100 patient‐years. Conclusions In RA clinical trials, no association was found between baricitinib treatment and the incidence of MACE, ATE, or CHF. With regard to incidence of DVT/PE, 6 events occurred in patients treated with 4 mg baricitinib, but no cases of DVT/PE were reported in the placebo group. During longer‐term evaluation, the incidence of DVT/PE was similar between the baricitinib dose groups, with consistent IR values over time, and this was similar to the rates previously reported in patients with RA.

BAFF, APRIL and BAFF-R are key proteins involved in the development of B-lymphocytes and autoimmunity. Additionally, BAFF, APRIL and BAFFR polymorphisms were associated with immune-mediated conditions, being BAFF GCTGTA a shared insertion-deletion genetic variant for several autoimmune diseases. Accordingly, we assessed whether BAFF, APRIL and BAFFR represent novel genetic risk factors for Immunoglobulin-A vasculitis (IgAV), a predominantly B-lymphocyte inflammatory condition. BAFF rs374039502, which colocalizes with BAFF GCTGTA, and two tag variants within APRIL (rs11552708 and rs6608) and BAFFR (rs7290134 and rs77874543) were genotyped in 386 Caucasian IgAV patients and 806 matched healthy controls. No genotypes or alleles differences were observed between IgAV patients and controls when BAFF, APRIL and BAFFR variants were analysed independently. Likewise, no statistically significant differences were found in the genotype and allele frequencies of BAFF, APRIL or BAFFR when IgAV patients were stratified according to the age at disease onset or to the presence/absence of gastrointestinal (GI) or renal manifestations. Similar results were disclosed when APRIL and BAFFR haplotypes were compared between IgAV patients and controls and between IgAV patients stratified according to the clinical characteristics mentioned above. Our results suggest that BAFF, APRIL and BAFFR do not contribute to the genetic network underlying IgAV.

Early recognition of giant cell arteritis (GCA) is crucial to avoid the development of ischemic vascular complications, such as blindness. The classic approach to making the diagnosis of GCA is based on a positive temporal artery biopsy, which is among the criteria proposed by the American College of Rheumatology (ACR) in 1990 to classify a patient as having GCA. However, imaging techniques, particularly ultrasound (US) of the temporal arteries, are increasingly being considered as an alternative for the diagnosis of GCA. Recent recommendations from the European League Against Rheumatism (EULAR) for the use of imaging techniques for large vessel vasculitis (LVV) included US as the first imaging option for the diagnosis of GCA. Furthermore, although the ACR classification criteria are useful in identifying patients with the classic cranial pattern of GCA, they are often inadequate in identifying GCA patients who have the extracranial phenotype of LVV. In this sense, the advent of other imaging techniques, such as magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET)/CT, has made it possible to detect the presence of extracranial involvement of the LVV in patients with GCA presenting as refractory rheumatic polymyalgia without cranial ischemic manifestations. Imaging techniques have been the key elements in redefining the diagnostic work-up of GCA. US is currently considered the main imaging modality to improve the early diagnosis of GCA.

The discovery of antifibrotic agents have resulted in advances in the therapeutic management of idiopathic pulmonary fibrosis (IPF). Currently, nintedanib and pirfenidone have become the basis of IPF therapy based on the results of large randomized clinical trials showing their safety and efficacy in reducing disease advancement. However, the goal of completely halting disease progress has not been reached yet. Administering nintedanib with add-on pirfenidone is supposed to enhance the therapeutic benefit by simultaneously acting on two different pathogenic pathways. All this becomes more important in the context of the ongoing global pandemic of coronavirus disease 2019 (COVID-19) because of the fibrotic consequences following SARS-CoV-2 infection in some patients. However, little information is available about their drug–drug interaction, which is important mainly in polymedicated patients. The aim of this review is to describe the current management of progressive fibrosing interstitial lung diseases (PF-ILDs) in general and of IPF in particular, focusing on the pharmacokinetic drug-drug interactions between these two drugs and their relationship with other medications in patients with IPF.

Background. Insulin resistance (IR) has been linked to inflammatory states. The aim of this study was to determine whether IR is increased in a cohort of inflammatory bowel disease (IBD) patients with low disease activity. We additionally intended to establish which factors were the determinants of IR in this population, including the presence of nonalcoholic fatty liver disease (NAFLD). Methods. Cross-sectional study encompassing 151 IBD patients and 174 non-diabetic controls. Insulin and C-peptide serum levels and IR and beta cell function (%B) indices based on homoeostatic model assessment (HOMA2) were assessed in patients and controls. Liver stiffness as measured by transient elastography, and the presence of NAFLD detected via ultrasound were additionally assessed. A multivariable regression analysis was performed to evaluate the differences in IR indexes between patients and controls, and to determine which predictor factors were associated with IR in IBD patients. Results. Neither HOMA2-IR (beta coef. −0.26 {95%CI −0.64–0.13}, p = 0.19) nor HOMA2-%B (beta coef. 15 {95%CI −14–44}, p = 0.31) indexes differed between patients and controls after fully multivariable analysis. Among classic IR risk factors, obesity, abdominal circumference, and triglycerides significantly and positively correlated with IR indexes in IBD patients. However, most features related to IBD, such as disease patterns, disease activity, and inflammatory markers, were not associated with IR. The presence of NAFLD was independently and significantly associated with beta cell dysfunction in patients with IBD (HOMA2—B grade 4, 251 ± 40 vs. grade 1, 107 ± 37, p = &lt, 0.001). Conclusions. IR is not increased in IBD patients with low disease activity compared to controls. However, the presence of NAFLD favors the development of IR in patients with IBD.

OBJECTIVE: Clinical heterogeneity, a hallmark of systemic autoimmune diseases, impedes early diagnosis and effective treatment, issues that may be addressed if patients could be classified into groups defined by molecular pattern. This study was undertaken to identify molecular clusters for reclassifying systemic autoimmune diseases independently of clinical diagnosis. METHODS: Unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data on 955 patients with 7 systemic autoimmune diseases and 267 healthy controls was undertaken. In addition, an inception cohort was prospectively followed up for 6 or 14 months to validate the results and analyze whether or not cluster assignment changed over time. RESULTS: Four clusters were identified and validated. Three were pathologic, representing "inflammatory," "lymphoid," and "interferon" patterns. Each included all diagnoses and was defined by genetic, clinical, serologic, and cellular features. A fourth cluster with no specific molecular pattern was associated with low disease activity and included healthy controls. A longitudinal and independent inception cohort showed a relapse-remission pattern, where patients remained in their pathologic cluster, moving only to the healthy one, thus showing that the molecular clusters remained stable over time and that single pathogenic molecular signatures characterized each individual patient. CONCLUSION: Patients with systemic autoimmune diseases can be jointly stratified into 3 stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of nonresponse to therapy, marking a paradigm shift in our view of systemic autoimmune diseases. ispartof: ARTHRITIS & RHEUMATOLOGY vol:73 issue:6 pages:1073-1085 ispartof: location:United States status: published

The addition of carotid ultrasound into cardiovascular (CV) risk scores has been found to be effective in identifying patients with chronic inflammatory diseases at high-CV risk. We aimed to determine if its use would facilitate the reclassification of patients with inflammatory bowel disease (IBD) into the very high-CV-risk category and whether this may be related to disease features. In this cross-sectional study encompassing 186 IBD patients and 175 controls, Systematic Coronary Risk Evaluation (SCORE), disease activity measurements, and the presence of carotid plaques by ultrasonography were assessed. Reclassification was compared between patients and controls. A multivariable regression analysis was performed to evaluate if the risk of reclassification could be explained by disease-related features and to assess the influence of traditional CV risk factors on this reclassification. After evaluation of carotid ultrasound, a significantly higher frequency of reclassification was found in patients with IBD compared to controls (35% vs. 24%, p = 0.030). When this analysis was performed only on subjects included in the SCORE low-CV-risk category, 21% IBD patients compared to 11% controls (p = 0.034) were reclassified into the very high-CV-risk category. Disease-related data, including disease activity, were not associated with reclassification after fully multivariable regression analysis. Traditional CV risk factors showed a similar influence over reclassification in patients and controls. However, LDL-cholesterol disclosed a higher effect in controls compared to patients (beta coef. 1.03 (95%CI 1.02-1.04) vs. 1.01 (95%CI 1.00-1.02), interaction p = 0.035) after adjustment for confounders. In conclusion, carotid plaque assessment is useful to identify high-CV risk IBD patients. Funding: This work was supported by a grant to I.F-A. from the Spanish Ministry of Health, Subdirección General de Evaluación y Fomento de la Investigación, Plan Estatal de Investigación Científica y Técnica y de Innovación 2013–2016 and by Fondo Europeo de Desarrollo Regional—FEDER—(Fondo de Investigaciones Sanitarias, FIS PI14/00394, PI17/00083).

Objectives Combining of genomic data of different pathologies as a single phenotype has emerged as a useful strategy to identify genetic risk loci shared among immune-mediated diseases. Our study aimed to increase our knowledge of the genetic contribution to Kawasaki disease (KD) and IgA vasculitis (IgAV) by performing the first comprehensive large-scale analysis on the genetic overlap between them. Methods A total of 1190 vasculitis patients and 11 302 healthy controls were analysed. First, in the discovery phase, genome-wide data of 405 KD patients and 6252 controls and 215 IgAV patients and 1324 controls, all of European origin, were combined using an inverse variance meta-analysis. Second, the top associated polymorphisms were selected for replication in additional independent cohorts (570 cases and 3726 controls). Polymorphisms with P-values ≤5 × 10−8 in the global IgAV–KD meta-analysis were considered as shared genetic risk loci. Results A genetic variant, rs3743841, located in an intron of the NAGPA gene, reached genome-wide significance in the cross-disease meta-analysis (P = 8.06 × 10−10). Additionally, when IgAV was individually analysed, a strong association between rs3743841 and this vasculitis was also evident [P = 1.25 × 10−7; odds ratio = 1.47 (95% CI 1.27, 1.69)]. In silico functional annotation showed that this polymorphism acts as a regulatory variant modulating the expression levels of the NAGPA and SEC14L5 genes. Conclusion We identified a new risk locus with pleiotropic effects on the two childhood vasculitides analysed. This locus represents the strongest non-HLA signal described for IgAV to date.

Polymyalgia rheumatica (PMR) is a common inflammatory disease found in people older than 50 years of Northern European descent. It is characterized by pain and stiffness in the shoulders, arms, hips, and neck. Relapses are common in patients with PMR.This review describes when and how relapses occur in patients with PMR. Potential predisposing factors associated with relapses and management are also discussed. An extensive literature search on the PubMed database was conducted for publications on 'polymyalgia rheumatica' AND 'relapses' AND 'risk factors'.Relapses are common in PMR being observed in approximately half of the patients. They often occur when the dose of prednisone is below 5-7.5 mg/day. The speed of glucocorticoid tapering is considered to be the main factor influencing the development of relapses in isolated PMRs. In addition, a genetic component may favor the presence of relapses in isolated PMRs. HLA-DRB1*0401 alleles were associated with an increased risk of relapse. An implication of the IL-6 promoter -174 G/C polymorphism and the GG241 ICAM-1 genotype was also reported. With regard to serological biomarkers, elevated levels of angiopoietin-2 were associated with an unfavorable course of PMR. Methotrexate and anti-IL6 receptor antibody tocilizumab may be required in PMR patients with multiple relapses.

Objectives To investigate how markers of beta-cell secretion (proinsulin-processing metabolites) are expressed in SLE patients and their potential relation to features associated with the disease such as activity or damage. Methods One hundred and forty-four SLE patients and 69 nondiabetic sex- and age-matched controls were assessed. Beta-cell secretion molecules, as measured by insulin, split and intact proinsulins, and C-peptide levels were analysed in both groups. Multiple regression analysis was performed to compare proinsulin propeptides between groups and to explore the interrelations with SLE features. Analyses were adjusted for glucocorticoid intake and for insulin resistance classic risk factors. Results Fully multivariable analysis demonstrated that regardless of glucocorticoid use, SLE patients exhibited higher levels of split proinsulin. Likewise, the split proinsulin-to-insulin ratio was upregulated in patients with SLE undergoing glucocorticoid therapy [beta coeficient 0.19 (95% Confidence Interval 0.07, 0.30), P = 0.002] or not [beta coef. 0.09 (95% CI: 0.01, 0.17), P = 0.025]. Similar results were found for the intact proinsulin-to-insulin ratio, although differences were only statistically significant for patients taking glucocorticoids [beta coef. 0.08 (95% CI: 0.03, 0.12), P = 0.001]. SLE damage score was associated with higher serum levels of intact [beta coef. 0.51 (95% CI 0.17, 0.86) pmol/l, P = 0.004] and split proinsulins [beta coef. 1.65 (95% CI 0.24, 3.06) pmol/l, P = 0.022] after multivariable analysis, including disease duration and prednisone use. Conclusion Among patients with SLE, proinsulin-processing metabolites, a marker of beta-cell disruption, are upregulated compared with matched controls. This disproportionate hyperproinsulinemia can be explained by the damage produced by the disease and occurs independently of prednisone use.

Anti-neutrophil cytoplasmic antibodies (ANCA), mainly anti-myeloperoxidase (MPO) antibodies, have been frequently identified in patients with idiopathic pulmonary fibrosis (IPF). However, their role remains unclear, and only 7–23% of these patients develops clinically overt vasculitis. We aimed to investigate the clinical, serological, and radiological features and prognosis of anti-MPO-positive interstitial lung disease (ILD) patients. Fifty-eight consecutive patients firstly referred for idiopathic interstitial pneumonia and showing serological positivity of anti-MPO antibodies were retrospectively enrolled. For each patient, clinical data, lung function testing, chest high-resolution computed tomography (HRCT) pattern, and survival were recorded. Thirteen patients developed a rheumatic disease during a median follow-up of 39 months. Usual interstitial pneumonia (UIP) was the most frequent ILD pattern, significantly influencing the patients’ survival. In fact, while the 52-week survival of the overall population was 71.4 ± 7.5%, significantly higher than IPF, survivals of anti-MPO patients with UIP pattern and IPF were similar. Forced vital capacity and diffusion lung capacity for CO significantly declined in 37.7 and 41.5% of cases, respectively, while disease progression at chest HRCT was observed in 45.2%. A careful clinical history and evaluation should always be performed in ILD patients with anti-MPO antibodies to quickly identify patients who are developing a systemic rheumatic disease.

Objective To investigate the human leukocyte antigen (HLA) association with anti-synthetase syndrome (ASSD). Methods We conducted the largest immunogenetic HLA-DRB1 and HLA-B study to date in a homogeneous cohort of 168 Caucasian patients with ASSD and 486 ethnically matched healthy controls by sequencing-based-typing. Results A statistically significant increase of HLA-DRB1*03:01 and HLA-B*08:01 alleles in patients with ASSD compared to healthy controls was disclosed (26.2% versus 12.2%, P = 1.56E–09, odds ratio–OR [95% confidence interval–CI] = 2.54 [1.84–3.50] and 21.4% versus 5.5%, P = 18.95E–18, OR [95% CI] = 4.73 [3.18–7.05]; respectively). Additionally, HLA-DRB1*07:01 allele was significantly decreased in patients with ASSD compared to controls (9.2% versus 17.5%, P = 0.0003, OR [95% CI] = 0.48 [0.31–0.72]). Moreover, a statistically significant increase of HLA-DRB1*03:01 allele in anti-Jo-1 positive compared to anti-Jo-1 negative patients with ASSD was observed (31.8% versus 15.5%, P = 0.001, OR [95% CI] = 2.54 [1.39–4.81]). Similar findings were observed when HLA carrier frequencies were assessed. The HLA-DRB1*03:01 association with anti-Jo-1 was unrelated to smoking history. No HLA differences in patients with ASSD stratified according to the presence/absence of the most representative non-anti-Jo-1 anti-synthetase autoantibodies (anti-PL-12 and anti-PL-7), arthritis, myositis or interstitial lung disease were observed. Conclusions Our results support the association of the HLA complex with the susceptibility to ASSD.

Background: Previous studies have shown that risk chart algorithms, such as the Systematic Coronary Risk Assessment (SCORE), often underestimate the actual cardiovascular (CV) risk of patients with rheumatoid arthritis (RA). In contrast, carotid ultrasound was found to be useful to identify RA patients at high CV. In the present study, we aimed to determine if specific disease features influence the CV risk reclassification of RA patients assessed by SCORE risk charts and carotid ultrasound. Methods: 1279 RA patients without previous CV events, diabetes, or chronic kidney disease were studied. Disease characteristics including disease activity scores, CV comorbidity, SCORE calculation, and the presence of carotid plaque by carotid ultrasound were assessed. A multivariable regression analysis was performed to evaluate if the reclassification into very high CV risk category was independently associated with specific features of the disease including disease activity. Additionally, a prediction model for reclassification was constructed in RA patients. Results: After carotid ultrasound assessments, 54% of the patients had carotid plaque and consequently fulfilled definition for very high CV risk. Disease activity was statistically significantly associated with reclassification after fully multivariable analysis. A predictive model containing the presence of dyslipidemia and hypertension, an age exceeding 54 years, and a DAS28-ESR score equal or higher than 2.6 yielded the highest discrimination for reclassification. Conclusion: Reclassification into very high CV risk after carotid ultrasound assessment occurs in more than the half of patients with RA. This reclassification can be independently explained by the activity of the disease. Funding: This work was supported by a grant to I.F-A. from the Spanish Ministry of Health, Subdirección General de Evaluación y Fomento de la Investigación, Plan Estatal de Investigación Científica y Técnica y de Innovación 2013–2016, and by Fondo Europeo de Desarrollo Regional — FEDER (Fondo de Investigaciones Sanitarias, FIS PI14/00394, PI17/00083). Prof. González-Gay’s research is supported by the Instituto de Salud Carlos III (ISCIII) (Fondo de Investigación Sanitaria grants PI06/0024, PI09/00748, PI12/00060, PI15/00525, PI18/00043) and the ISCIII RETICS programs (RD12/0009 and RD16/0012).

INTRODUCTION: Interstitial lung disease (ILD) represents one of the most frequent extra-articular manifestations of rheumatoid arthritis (RA) with a deep impact on both quality of life and overall prognosis. A literature search was performed trough some electronic databases, including PubMed, Embase, Scopus, and Web of Science. Areas covered: Many retrospective studies investigated the possible risk factors for RA-ILD, aiming to early identify patients at risk. Among them, male sex, smoking habit, positivity of anti-citrullinated peptide antibodies have been associated to RA-ILD, such as some genetic haplotypes. Histologic and radiologic patterns detected in idiopathic interstitial pneumonias (IIP) have also been observed in RA; among them, usual interstitial pneumonia is the most frequently observed, followed by nonspecific interstitial pneumonia. Since lung involvement can represent the RA onset, an early differential diagnosis with IIP can be difficult or sometimes impossible. High resolution computed tomography represents the gold standard for ILD diagnosis, while multidisciplinary discussion should be required to assess disease staging, severity and progression. Expert opinion: Management of RA-ILD patients are challenging due to the lacking of evidence-based data regarding both assessment and treatment. Moreover, the high variability of clinical presentation and evolution makes difficult to establish the correct therapeutic strategy. Currently, multidisciplinary approach, including at least rheumatologists, pulmonologists, and radiologists, is desirable to define therapy and follow-up strategies.

Arteritis de Takayasu; Tocilizumab; Teràpia biològica Arteritis de Takayasu; Tocilizumab; Terapia biológica Takayasu’s arteritis; Tocilizumab; Biological therapy Objective: To assess the efficacy and safety of tocilizumab (TCZ) in Caucasian patients with refractory Takayasu’s arteritis (TAK) in clinical practice. Methods: A multicenter study of Caucasian patients with refractory TAK who received TCZ. The outcome variables were remission, glucocorticoid-sparing effect, improvement in imaging techniques, and adverse events. A comparative study between patients who received TCZ as monotherapy (TCZMONO) and combined with conventional disease modifying anti-rheumatic drugs (cDMARDs) (TCZCOMBO) was performed. Results: The study comprised 54 patients (46 women/8 men) with a median [interquartile range (IQR)] age of 42.0 (32.5–50.5) years. TCZ was started after a median (IQR) of 12.0 (3.0–31.5) months since TAK diagnosis. Remission was achieved in 12/54 (22.2%), 19/49 (38.8%), 23/44 (52.3%), and 27/36 (75%) patients at 1, 3, 6, and 12 months, respectively. The prednisone dose was reduced from 30.0 mg/day (12.5–50.0) to 5.0 (0.0–5.6) mg/day at 12 months. An improvement in imaging findings was reported in 28 (73.7%) patients after a median (IQR) of 9.0 (6.0–14.0) months. Twenty-three (42.6%) patients were on TCZMONO and 31 (57.4%) on TCZCOMBO: MTX (n = 28), cyclosporine A (n = 2), azathioprine (n = 1). Patients on TCZCOMBO were younger [38.0 (27.0–46.0) versus 45.0 (38.0–57.0)] years; difference (diff) [95% confidence interval (CI) = -7.0 (-17.9, -0.56] with a trend to longer TAK duration [21.0 (6.0–38.0) versus 6.0 (1.0–23.0)] months; diff 95% CI = 15 (-8.9, 35.5), and higher c-reactive protein [2.4 (0.7–5.6) versus 1.3 (0.3–3.3)] mg/dl; diff 95% CI = 1.1 (-0.26, 2.99). Despite these differences, similar outcomes were observed in both groups (log rank p = 0.862). Relevant adverse events were reported in six (11.1%) patients, but only three developed severe events that required TCZ withdrawal. Conclusion: TCZ in monotherapy, or combined with cDMARDs, is effective and safe in patients with refractory TAK of Caucasian origin. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was partially supported by RETICS Programs, RD08/0075 (RIER), RD12/0009/0013 and RD16/0012 from “Instituto de Salud Carlos III” (ISCIII) (Spain). However, this research did not receive any specific grant from funding agencies in the commercial or not-for-profit sectors.

Objective: Cholesterol efflux capacity (CEC) is the ability of high-density lipoprotein (HDL) cholesterol to accept cholesterol from macrophages. Lipid profiles and CEC appear to be altered in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) due to disease activity and inflammation. CEC has been linked to cardiovascular events in the general population and to subclinical atherosclerosis in SLE and RA patients. The aim of this study was to establish whether CEC varies between patients with SLE and those with RA. Methods: The study encompassed 460 individuals (195 SLE patients and 265 patients with RA). CEC (using an in vitro assay) and concentrations of lipoprotein serum were assessed in both populations. A multivariable regression analysis was performed to study whether CEC differs between SLE patients and RA patients. Results: Comparison of lipid patterns revealed that patients with RA have lower HDL cholesterol and higher apolipoprotein B serum levels than SLE patients. CEC was downregulated in SLE patients compared to patients with RA (β -12 [95% confidence interval -13, -10], P < 0.001). It occurred independently of traditional cardiovascular risk factors, statin use, disease-related data, and other variations in the lipid profile related to the diseases. Conclusion: Patients with RA have a more proatherogenic lipid pattern compared to those with SLE. However, CEC seems to be more damaged in SLE patients than in RA patients. Sin financiación 5.178 JCR (2021) Q2, 12/34 Rheumatology 1.566 SJR (2021) Q1, 7/61 Rheumatology No data IDR 2021 UEC

Endothelial progenitor cells (EPC), which are key effectors in the physiologic vascular network, have been described as relevant players in autoimmune diseases. We previously showed that EPC frequency may help to identify the presence of interstitial lung disease (ILD) in rheumatoid arthritis patients. Given that ILD constitutes the main cause of mortality in systemic sclerosis (SSc) patients, we aimed to determine the EPC contribution to the pathogenic processes of vasculopathy and lung fibrosis in SSc-ILD+. EPC quantification was performed by flow cytometry on blood from 83 individuals: 21 SSc-ILD+ patients and subjects from comparative groups (20 SSc-ILD− and 21 idiopathic pulmonary fibrosis (IPF) patients and 21 healthy controls (HC)). EPC were considered as CD34+, CD45low, CD309+, and CD133+. A significant increase in EPC frequency was found in SSc-ILD+ patients when compared to HC (p &lt, 0.001). SSc-ILD+ patients exhibited a higher EPC frequency than SSc-ILD− patients (p = 0.012), whereas it was markedly reduced compared to IPF patients (p &lt, 0.001). EPC frequency was higher in males (p = 0.04) and negatively correlated to SSc duration (p = 0.04) in SSc-ILD+ patients. Our results indicate a role of EPC in the processes of vasculopathy and lung fibrosis in SSc-ILD+. EPC frequency may be considered as a biomarker of ILD in SSc patients.

Background. Cardiovascular (CV) disease risk prediction models developed for use in the general population have suboptimal performance in patients with rheumatoid arthritis (RA). Vascular age (VA) is a new concept that has been proposed as a measure of CV &lsquo, relative&rsquo, risk instead of the &lsquo, absolute&rsquo, risk that current prediction models provide. In the present study we aim to study the performance of vascular age (VA) in the assessment of CV risk in patients with RA. We additionally aimed to analyze its relation with subclinical atherosclerosis as measured through carotid plaque ultrasound. Methods. A total of 1173 non-diabetic RA patients without previous CV events were included. Disease characteristics, SCORE, VA determined on SCORE and on carotid intima media thickness (cIMT), and the presence of plaque through carotid ultrasound were assessed. The interrelations of VA with SCORE, and its associations with subclinical carotid atherosclerosis were studied. Results. On average, RA patients had both a SCORE determined VA (4.7 years) and a cIMT-based VA (2.4 years) significantly higher than the chronological age. When these differences were analyzed in different age intervals, while VA based on SCORE was significantly higher compared to chronological age in all age ranges, VA determined on cIMT was significantly elevated only in RA patients younger than 60 years. The area under the curve analysis for the association of SCORE and VA with the presence of carotid plaque disclosed no differences between both parameters. VA was associated with the presence of carotid plaque after multivariable regression analysis in patients younger than 60 years old. Conclusion. VA is significantly higher than chronological age in patients with RA. The performance of VA in its relation to carotid plaque is similar to that of the SCORE.

Objective To compare the efficacy and safety of TCZ in monotherapy (TCZMONO) vs. combined with conventional immunosuppressive drugs (TCZCOMBO) in Giant Cell Arteritis (GCA) in a clinical practice scenario. Methods Multicenter study of 134 patients with refractory GCA. Patients on TCZMONO (n = 82) were compared with those on TCZCOMBO (n = 52). Drugs were methotrexate (MTX) (n = 48), azathioprine (n = 3), and leflunomide (n = 1). The main outcomes were: prolonged remission (normalization of clinical and laboratory parameters for at least 6 months) and the number of relapses. Results Patients on TCZCOMBO were younger (68.8 ± 8.0 vs 71.2 ± 9.0 years; p = 0.04), with a trend to a longer GCA duration (median [IQR],18.5 [6.25–34.0] vs. 13.0 [7.75–33.5] months; p = 0.333), higher C-reactive protein (CRP) levels (2.1[1–4.7] vs 1.2 [0.2–2.4] mg/dL; p = 0.003), and more prevalence of extra-cranial large-vessel vasculitis (LVV) (57% vs. 34.1%; p = 0.007). In both groups, rapid and sustained improvement was observed. Despite the longer GCA duration, and the higher CRP levels and prevalence of LVV in the TCZCOMBO, the improvement was similar in both groups at 12 months. Moreover, in the TCZCOMBO group, prolonged remission was significantly higher at 12-month. Relapses and serious adverse events were similar in both groups. Conclusion In clinical practice, TCZ in monotherapy or combined with conventional immunosuppressive agents is effective and safe in patients with GCA. Nevertheless, the addition of immunosuppressive drugs, usually MTX, seems to allow a higher rate of prolonged remission, even in patients with a longer GCA duration, more extra-cranial LVV involvement, and higher acute-phase reactants.

Objective. Previously, only the HLA-DRB1 alleles have been assessed in rheumatoid arthritis (RA). The aim of the present study was to identify the key major histocompatibility complex (MHC) susceptibility factors showing a significant association with anti-carbamylated protein antibody-positive (anti-CarP+) RA. Methods. Analyses were restricted to RA patients who were anti-cyclic citrullinated peptide antibody negative (anti-CCP), because the anti-CCP status dominated the results otherwise. Therefore, we studied samples from 1,821 anti-CCP- RA patients and 6,821 population controls from Spain, Sweden, and the Netherlands. The genotypes for similar to 8,000 MHC biallelic variants were assessed by dense genotyping and imputation. Their association with the anti-CarP status in RA patients was tested with logistic regression and combined with inverse-variance meta-analysis. Significance of the associations was assessed according to a study-specific threshold of P < 2.0 x 10(-5). Results. The HLA-B*08 allele and its correlated amino acid variant Asp-9 showed a significant association with anti-CarP+/anti-CCP- RA (P < 3.78 x 10(-7); I-2 = 0). This association was specific when assessed relative to 3 comparator groups: population controls, anti-CarP-/anti-CCP- RA patients, and anti-CCP- RA patients who were positive for other anti-citrullinated protein antibodies. Based on these findings, anti-CarP+/anti-CCP- RA patients could be separated from other antibody-defined subsets of RA patients in whom an association with the HLA-B*08 allele has been previously demonstrated. No other MHC variant remained associated with anti-CarP+/anti-CCP- RA after accounting for the presence of the HLA-B*08 allele. Specifically, the reported association of HLA-DRB1*03 was observed at a level comparable to that reported previously, but it was attributable to linkage disequilibrium. Conclusion. These results identify HLA-B*08 carrying Asp-9 as the MHC locus showing the strongest association with anti-CarP+/anti-CCP- RA. This knowledge may help clarify the role of the HLA in susceptibility to specific subsets of RA, by shaping the spectrum of RA autoantibodies.

The link between chronic inflammation and atherosclerosis is well known. More specifically, we know there is a direct association between chronic inflammatory joint diseases (IJD) such as rheumatoi...