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Papers by Enrique Raya

Research paper thumbnail of Identification of the<i>PTPN22</i>functional variant R620W as susceptibility genetic factor for giant cell arteritis

Annals of the Rheumatic Diseases, Aug 14, 2013

Objective To analyse the role of the PTPN22 and CSK genes, previously associated with autoimmunit... more Objective To analyse the role of the PTPN22 and CSK genes, previously associated with autoimmunity, in the predisposition and clinical phenotypes of giant cell arteritis (GCA). Methods Our study population was composed of 911 patients diagnosed with biopsy-proven GCA and 8136 unaffected controls from a Spanish discovery cohort and three additional independent replication cohorts from Germany, Norway and the UK. Two functional PTPN22 polymorphisms (rs2476601/R620W and rs33996649/ R263Q) and two variants of the CSK gene (rs1378942 and rs34933034) were genotyped using predesigned TaqMan assays. Results The analysis of the discovery cohort provided evidence of association of PTPN22 rs2476601/R620W with GCA (P FDR =1.06E-04, OR=1.62, CI 95% 1.29 to 2.04). The association did not appear to follow a specific GCA subphenotype. No statistically significant differences between allele frequencies for the other PTPN22 and CSK genetic variants were evident either in the case/control or in stratified case analysis. To confirm the detected PTPN22 association, three replication cohorts were genotyped, and a consistent association between the PTPN22 rs2476601/R620W variant and GCA was evident in the overall meta-analysis (P MH =2.00E-06, OR=1.51, CI 95% 1.28 to 1.79). Conclusions Our results suggest that the PTPN22 polymorphism rs2476601/R620W plays an important role in the genetic risk to GCA.

Research paper thumbnail of A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis

American Journal of Human Genetics, 2017

If citing, it is advised that you check and use the publisher's definitive version for pagination... more If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections.

Research paper thumbnail of Real-World Persistence and Treatment Patterns in Patients with Psoriatic Arthritis Treated with Anti-IL17 Therapy in Spain: The PerfIL-17 Study

Advances in Therapy

Introduction: Given the growing interest and use of interleukin-17 inhibitors (anti-IL17) for the... more Introduction: Given the growing interest and use of interleukin-17 inhibitors (anti-IL17) for the treatment of psoriatic arthritis (PsA), an observational study has been conducted to characterize the patient profile, treatment patterns, and persistence of ixekizumab or secukinumab in patients with PsA receiving them as first anti-IL17. Methods: This is a multicenter retrospective study, conducted at eight Spanish hospitals where data from adult patients with PsA were collected from electronic medical records. Three cohorts of patients, initiating treatment with an anti-IL17 [secukinumab 150 mg (SECU150), secukinumab 300 mg (SECU300), or ixekizumab (IXE)] between January 2019 and March 2021, were included. Demographic and clinical patient characteristics, treatment patterns, and persistence were analyzed descriptively. Con

Research paper thumbnail of Interleukin 6 gene promoter polymorphism is not associated with ankylosing spondylitis

PubMed, Jun 1, 2000

Objective: To investigate the possible association between the recently described interleukin 6 (... more Objective: To investigate the possible association between the recently described interleukin 6 (IL-6) promoter polymorphisms at position -174, and susceptibility to ankylosing spondylitis (AS). Methods: Ninety-two patients with AS, 157 healthy controls, and an additional group of 52 HLA-B27 positive unrelated individuals were included in this study. The -174 polymorphic site in the promoter region of IL-6 gene was typed by polymerase chain reaction-restriction fragment length polymorphism. Results: No statistically significant differences were observed when IL-6 promoter genotype and allele distribution between patients with AS and healthy controls were compared. Conclusion: Our results suggest the -174 IL-6 polymorphism does not play an important role in susceptibility to AS. Larger studies are needed to provide more conclusive evidence on the role of -174 IL-6 polymorphism in AS.

Research paper thumbnail of The Functional PTPN22 Variant R620W Is Strongly Associated With Giant Cell Artetitis Predisposition

Arthritis & Rheumatism, Oct 31, 2013

Research paper thumbnail of POS0095 Single-Cell Landscape of CD4+ T Lymphocytes Reveals a Potential Role of Cytotoxic Cells in Giant Cell Arteritis

Annals of the Rheumatic Diseases, May 30, 2023

Research paper thumbnail of Protective Role of the Vitamin D Receptor Apai (rs7975232) Polymorphism Against Subclinical Atherosclerosis in Patients with Rheumatoid Arthritis from Northern Spain

Arthritis & Rheumatism, Oct 31, 2015

Research paper thumbnail of SAT0471 Cathepsin K is A Bone Remodelling Marker in Females with Postmenopausal Osteoporosis

Annals of the Rheumatic Diseases, Jun 1, 2014

Background: Cathepsin K is a protease expressed by osteoclasts that plays an important role in os... more Background: Cathepsin K is a protease expressed by osteoclasts that plays an important role in osteoclastic mediated bone resorption. It degrades organic bone matrix, primarily type 1 collagen. Postmenopausal osteoporosis is characterised by an increase in bone resorption that manifests as elevation of bone remodelling makers. This phenomenon starts in the peri-menopausal period. The potential role of cathepsin K levels as markers of bone remodelling in postmenopausal osteoporosis is being evaluated, but there is paucity of data. There is increasing interest in identifying markers able to differentiate the number and activity of osteoclasts to clarify the mechanism of action of current anti-osteoporotic therapies. It is also suggested that such markers might help in the development of more specific novel treatments. Objectives: To evaluate the role of cathepsin K as bone remodelling marker in females with postmenopausal osteoporosis. Methods: Cross sectional study. Two groups were evaluated: postmenopausal females and healthy controls (this group was subdivided into pre and postmenopausal females). Cathepsin K levels in sera were determined by polyclonal antibody ELISA (BI-20432). Data were analysed with STATA10. Differences in cathepsin K levels between groups were determined. A quantile regression model was built to assess cathepsin K leves for the median, first and third quantile according to the variables of interest. A p value of <0.05 was considered as statistically significant. Results: Cathepsin K levels were higher in postmenopausal osteoporotic females than in healthy controls (X 2 =17.54 y 2 g.l, p<0.01) with a clear dose response gradient (p<0.001). Conclusions: Cathepsin K is a bone remodelling marker in females with postmenopausal osteoporosis. There is a dose response gradient on bone mineral density independently of postmenopausal status, which is maximal in females with postmenopausal osteoporosis and minimal in females with normal bone density. References: [1] Dodds RA, James IA, Rieman D et al.: Human osteoclast Cathepsin K is Processed Intracellulary Prior to Attachment and Bone Resorption.

Research paper thumbnail of Biologic therapy in refractory neurobehçet’s disease: a multicentre study of 41 patients and literature review

Rheumatology, Feb 15, 2022

Objectives To assess efficacy and safety of biologic therapy (BT) in neurobehçet’s disease (NBD) ... more Objectives To assess efficacy and safety of biologic therapy (BT) in neurobehçet’s disease (NBD) refractory to glucocorticoids and at least one conventional immunosuppressive drug. Methods Open-label, national, multicentre study. NBD diagnosis was based on the International Consensus Recommendation criteria. Outcome variables were efficacy and safety. Main efficacy outcome was clinical remission. Other outcome variables analysed were glucocorticoid-sparing effect and improvement in laboratory parameters. Results We studied 41 patients [21 women; age 40.6 (10.8) years]. Neurological damage was parenchymal (n = 33, 80.5%) and non-parenchymal (n = 17, 41.5%). First BTs used were infliximab (n = 19), adalimumab (n = 14), golimumab (n = 3), tocilizumab (n = 3) and etanercept (n = 2). After 6 months of BT, neurological remission was complete (n = 23, 56.1%), partial (n = 15, 37.6%) and no response (n = 3, 7.3%). In addition, median (IQR) dose of oral prednisone decreased from 60 (30–60) mg/day at the initial visit to 5 (3.8–10) mg/day after 6 months (P &lt; 0.001). It was also the case for mean erythrocyte sedimentation rate [31.5 (25.6)–15.3 (11.9) mm/1st h, P = 0.011] and median (IQR) C-reactive protein [1.4 (0.2–12.8) to 0.3 (0.1–3) mg/dl, P = 0.001]. After a mean follow-up of 57.5 months, partial or complete neurological remission persisted in 37 patients (90.2%). BT was switched in 22 cases (53.6%) due to inefficacy (n = 16) or adverse events (AEs) (n = 6) and discontinued due to complete prolonged remission (n = 3) or severe AE (n = 1). Serious AEs were observed in two patients under infliximab treatment. Conclusions BT appears to be effective and relatively safe in refractory NBD.

Research paper thumbnail of Machine Learning for the Identification of a Common Signature for Anti–SSA/Ro 60 Antibody Expression Across Autoimmune Diseases

Arthritis & rheumatology, Aug 25, 2022

ObjectiveAnti‐Ro autoantibodies are among the most frequently detected extractable nuclear antige... more ObjectiveAnti‐Ro autoantibodies are among the most frequently detected extractable nuclear antigen autoantibodies, mainly associated with primary Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), and undifferentiated connective tissue disease (UCTD). This study was undertaken to determine if there is a common signature for all patients expressing anti–Ro 60 autoantibodies regardless of their disease phenotype.MethodsUsing high‐throughput multiomics data collected from the cross‐sectional cohort in the PRECISE Systemic Autoimmune Diseases (PRECISESADS) study Innovative Medicines Initiative (IMI) project (genetic, epigenomic, and transcriptomic data, combined with flow cytometry data, multiplexed cytokines, classic serology, and clinical data), we used machine learning to assess the integrated molecular profiling of 520 anti–Ro 60+ patients compared to 511 anti–Ro 60– patients with primary SS, patients with SLE, and patients with UCTD, and 279 healthy controls.ResultsThe selected clinical features for RNA‐Seq, DNA methylation, and genome‐wide association study data allowed for a clear distinction between anti–Ro 60+ and anti–Ro 60– patients. The different features selected using machine learning from the anti–Ro 60+ patients constituted specific signatures when compared to anti–Ro 60– patients and healthy controls. Remarkably, the transcript Z score of 3 genes (ATP10A, MX1, and PARP14), presenting with overexpression associated with hypomethylation and genetic variation and independently identified using the Boruta algorithm, was clearly higher in anti–Ro 60+ patients compared to anti–Ro 60– patients regardless of disease type. Our findings demonstrated that these signatures, enriched in interferon‐stimulated genes, were also found in anti–Ro 60+ patients with rheumatoid arthritis and those with systemic sclerosis and remained stable over time and were not affected by treatment.ConclusionAnti–Ro 60+ patients present with a specific inflammatory signature regardless of their disease type, suggesting that a dual therapeutic approach targeting both Ro‐associated RNAs and anti–Ro 60 autoantibodies should be considered.

Research paper thumbnail of Dose-Dependent Effect of Melatonin on BAT Thermogenesis in Zücker Diabetic Fatty Rat: Future Clinical Implications for Obesity

Antioxidants

Experimental data have revealed that melatonin at high doses reduced obesity and improved metabol... more Experimental data have revealed that melatonin at high doses reduced obesity and improved metabolic outcomes in experimental models of obesity, mainly by enhancing brown adipose tissue (BAT) thermogenesis. A potential dose-response relationship has yet to be performed to translate these promising findings into potential clinical therapy. This study aimed to assess the effects of different doses of melatonin on interscapular BAT (iBAT) thermogenic capacity in Zücker diabetic fatty (ZDF) rats. At 6 wk of age, male ZDF rats were divided into four groups (n = 4 per group): control and those treated with different doses of melatonin (0.1, 1, and 10 mg/kg of body weight) in their drinking water for 6 wk. Body weight (BW) was significantly decreased at doses of 1 and 10 mg/kg of melatonin, but not at 0.1 mg/kg compared with the control, with a similar rate of BW decrease being reached at the dose of 1 mg/kg (by ~11%) and 10 mg/kg (by ~12%). This effect was associated with a dose-dependent ...

Research paper thumbnail of Chemosensory Recognition in Trogonophis

Chemosensory Social Recognition in an amphisbaenian (Trogonophis wiegmanni)<br>

Research paper thumbnail of THU0297 SERIOUS Infections in 134 Patients with Giant Cell Arteritis with Tocilizumab in Clinical Practice. Frequency, Type and Clinical Associations

Annals of the Rheumatic Diseases, 2020

Background:Infections are the most common adverse event of Tocilizumab (TCZ) in Giant Cell Arteri... more Background:Infections are the most common adverse event of Tocilizumab (TCZ) in Giant Cell Arteritis (GCA). In GiACTA study(1),serious infections were observed in 7% (9.6/100 patient-years) of patients who received TCZ weekly. Randomized clinical trials (RCTs) are conducted under highly standardized design excluding some real-world patients. Therefore, adverse events may be underestimated in RCTs. In our series of real-life, serious infections occurred in 11.9% (10.6/100 patient-years)(2).Objectives:In a wide series of GCA of clinical practice treated with TCZ, we assess the frequency, type and predisposing factors of serious infections.Methods:Multicenter study of 134 patients diagnosed with GCA, all of them refractory to conventional therapy, treated with TCZ. Serious infection was considered when a life-threatening infection, fatal, or requiring hospitalization occurred, intravenous antibiotics were required, or the infectious process led to persistent or significant disability.R...

Research paper thumbnail of Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature

Scientific Reports, 2021

Primary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic inf... more Primary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns...

Research paper thumbnail of Association study of ghrelin receptor gene polymorphisms in rheumatoid arthritis

Clinical and experimental rheumatology

Ghrelin is a newly characterised growth hormone (GH) releasing peptide widely distributed that ma... more Ghrelin is a newly characterised growth hormone (GH) releasing peptide widely distributed that may play an important role in the regulation of metabolic balance in inflammatory diseases such as rheumatoid arthritis (RA) by decreasing the pro-inflammatory Th1 responses. In this study we investigated the possible contribution of several polymorphisms in the functional Ghrelin receptor to RA susceptibility. A screening of 3 single nucleotide polymorphisms (SNPs) was performed in a total of 950 RA patients and 990 healthy controls of Spanish Caucasian origin. Genotyping of all 3 SNPs was performed by real-time polymerase chain reaction technology, using the TaqMan 5'-allele discrimination assay. We observed no statistically significant deviation between RA patients and controls for the GHSR SNPs analysed. In addition, we performed a haplotype analysis that did not reveal an association with RA susceptibility. The stratification analysis for the presence of shared epitope (SE), rheum...

Research paper thumbnail of FRI0556 Development of standards of care in spondyloarthritis

Annals of the Rheumatic Diseases, 2013

Background: Systemic Lupus Erythematosus (SLE) is a risk factor for osteoporosis (OP) and ocular ... more Background: Systemic Lupus Erythematosus (SLE) is a risk factor for osteoporosis (OP) and ocular adverse drug reactions (OADR) as cataracts and secondary glaucoma, mainly owing to the chronic treatment with Glucocorticoids (GC). Recommendations and Quality Indicators (QIs) have been developed to guide rheumatologists in the monitoring and treating of these conditions [1, 2, 3, 4]. However it is well known how the adherence to Recommendations and QIs is low in clinical practice. Objectives: To evaluate if the introduction of a clinical chart developed for the routinary assessment of SLE patients, might improve the adherence of rheumatologists to the existing Recommendations for the monitoring of OP and ocular toxicity. Methods: In 2011 a core-set of clinical variables to be regularly evaluated in SLE patients was developed, based on Recommendations and QIs. Patients with a diagnosis of SLE based on the American College of Rheumatology criteria, followed at our Rheumatology Unit, were consecutively enrolled during their regular outpatient visit in 2012 and were evaluated using the SLE dedicated chart. Adherence to Recommendations and QIs was compared with data from the same patients before the introduction of the chart. Results: One hundred and eleven SLE patients were enrolled; 11 of them, with a follow-up (fu) shorter than 2 years were excluded. Therefore, 100 patients, 98 F/2 M, mean age 43,4±11,9 years, disease duration 17,4±7,8 years, mean fu 13,4±7 years, were analyzed. Before the introduction of the SLE-dedicated chart the prevalence of adherence to OP and ocular monitoring were respectively of 19 (19%) and 32 (32%) cases. After the use of the coreset these values changed respectively in 52 (52%) and 66 (66%) cases. The comparison of both these results showed a significant difference, with respective p values of 0,05 and 0,03. Conclusions: These results show how introducing an SLE ad hoc designed core-set might significantly increase the adherence to the OP and ocular monitoring in clinical practice, thus assuring an improvement in the quality of care of SLE patients.

Research paper thumbnail of OP0056 The PTPN22/CSK Signalling Pathway is Involved in Susceptibility to Develop Giant Cell Arteritis

Annals of the Rheumatic Diseases, 2013

Background The PTPN22/CSK signalling represents one of the most relevant pathways in the innate i... more Background The PTPN22/CSK signalling represents one of the most relevant pathways in the innate immunity, and it has been implicated in the susceptibility to develop a wide number of autoimmune diseases. Objectives To analyse the possible role of different single-nucleotide polymorphisms of the PTPN22 and CSK genes in the predisposition and clinical phenotypes of giant cell arteritis (GCA) in a large Caucasian population. Methods Our study population consisted of 623 patients diagnosed with biopsy-proven GCA and 1,729 healthy controls of Spanish Caucasian origin. Two functional PTPN22 polymorphisms (rs24746601, R620W and rs33996649, R263Q) and two variants of the CSK gene (rs1378942 and rs34933034), previously associated with autoimmunity, were genotyped using specifically designed TaqMan® assays. Results A significant association of the PTPN22 non-synonymous change rs2476601 with GCA susceptibility was yielded after the analysis of the allele frequencies (P=1.06E-04, OR= 1.62, CI 95% 1.29-2.04). No statistically significant differences between cases and controls of the rest of SNPs analysed were observed. Similarly, when patients were stratified according to specific clinical features of GCA, such as polymyalgia rheumatica (PMR), visual ischemic manifestations (VIM) or irreversible occlusive disease (IOD), only significant differences were found between the case subgroups and the control set for PTPN22 rs2476601 (P=2.26E-04, OR=1.77 CI 95% 1.30-2.40; P=1.03E-03, OR=1.82 CI 95% 1.27-2.62; P=5.47E-04, OR=2.14 CI 95% 1.38-3.33, respectively). Conclusions Our results clearly suggest that the PTPN22 polymorphism rs2476601 is associated with susceptibility to GCA. Disclosure of Interest None Declared

Research paper thumbnail of Physicians' and Patients' Preferences Over the Attributes of Biological Agents Used In the Treatment of Rheumatic Diseases In Spain: A Conjoint Analysis

Value in Health, 2014

Objectives: Rituximab SC reduces administration times (~5 minutes) compared with the IV route (~4... more Objectives: Rituximab SC reduces administration times (~5 minutes) compared with the IV route (~4 hours). We examined the extent of patient preference for rituximab SC versus IV in the PrefMab and MabCute studies using the Rituximab Administration Satisfaction Questionnaire (RASQ). MethOds: In PrefMab (NCT01724021) patients with untreated CD20+ DLBCL/FL received 1 cycle of IV rituximab (375mg/m 2) followed by either SC rituximab (1400mg, x3) then IV rituximab (x4), or IV rituximab (x3) then SC rituximab (x4), with chemotherapy. In MabCute (NCT01461928) patients with relapsed/refractory CD20+ indolent NHL received induction rituximab IV (375mg/m 2 ; 1 cycle) then rituximab SC (1400mg; cycles 2-8) plus 6-8 chemotherapy cycles. RASQ evaluated preference by assessing patients' perceptions of the impact of administration route and treatment satisfaction. Conceptual validation of RASQ has been conducted and psychometric data will be reported. Results: Median RASQ scores for PrefMab were: convenience IV (n= 211) 58.3 (interquartile range: 41.7-75.0) and SC (n= 207) 83.3 (75.0-91.7); satisfaction: IV (n= 211) 75.0 (62.5-87.5), SC (n= 208) 87.5 (75.0-100.0); impact on daily life: IV (n= 145) 50.0 (41.7-83.3), SC (n= 163) 83.3 (83.3-100.0); physical impact IV (n= 211) 83.3 (66.7-100.0), SC (n= 208) 83.3 (75.0-100.0); psychological impact IV (n= 211) 80.0 (65.0-90.0), SC (n= 208) 88.8 (75.0-95.0). SC administration was preferred by 80.3% and 85.9% of patients with IV or SC as most recent dose, respectively. Results were similar irrespective of treatment sequence. Median RASQ scores for MabCute (n= 92

Research paper thumbnail of Expression Quantitative Trait Locus Analysis in Systemic Sclerosis Identifies New Candidate Genes Associated With Multiple Aspects of Disease Pathology

Arthritis & rheumatology, May 28, 2021

Objective. To identify the genetic variants that affect gene expression (expression quantitative ... more Objective. To identify the genetic variants that affect gene expression (expression quantitative trait loci [eQTLs]) in systemic sclerosis (SSc) and to investigate their role in the pathogenesis of the disease. Methods. We performed an eQTL analysis using whole-blood sequencing data from 333 SSc patients and 524 controls and integrated them with SSc genome-wide association study (GWAS) data. We integrated our findings from expression modeling, differential expression analysis, and transcription factor binding site enrichment with key clinical features of SSc. Results. We detected 49,123 validated cis-eQTLs from 4,539 SSc-associated single-nucleotide polymorphisms (SNPs) (P GWAS < 10 −5). A total of 1,436 genes were within 1 Mb of the 4,539 SSc-associated SNPs. Of those 1,436 genes, 565 were detected as having ≥1 eQTL with an SSc-associated SNP. We developed a strategy to prioritize diseaseassociated genes based on their expression variance explained by SSc eQTLs (r 2 > 0.05). As a result, 233 candidates were identified, 134 (58%) of them associated with hallmarks of SSc and 105 (45%) of them differentially expressed in the blood cells, skin, or lung tissue of SSc patients. Transcription factor binding site analysis revealed enriched motifs of 24 transcription factors (5%) among SSc eQTLs, 5 of which were found to be differentially regulated in the blood cells (ELF1 and MGA), skin (KLF4 and ID4), and lungs (TBX4) of SSc patients. Ten candidate genes (4%) can be targeted by approved medications for immune-mediated diseases, of which only 3 have been tested in clinical trials in patients with SSc. Conclusion. The findings of the present study indicate a new layer to the molecular complexity of SSc, contributing to a better understanding of the pathogenesis of the disease.

Research paper thumbnail of AB0376 Cardiovascular Risk Stratification According to Serum Non-HDL Cholesterol Levels in Patients with Recently Diagnosed Rheumatoid Arthritis

Annals of the Rheumatic Diseases, May 30, 2023

BackgroundIt is estimated that rheumatoid arthritis (RA) increases the risk of cardiovascular dis... more BackgroundIt is estimated that rheumatoid arthritis (RA) increases the risk of cardiovascular disease (CVD) by 50% compared to the general population [1,2]. Non-HDL cholesterol (non-HDL CT) has become an innovative marker of cardiovascular risk (CVR). According to the recommendations of the ESC of 2022 [2], patients with RA start from an intermediate CVR and recommend non-HDL TC levels &lt;130mg/dL.ObjectivesTo evaluate long-term risk of CVD according to nonHDL CT levels in a cohort of patients with recently diagnosed RA who started biological therapy and describe its characteristics.Methods71 patients with RA under biological treatment were reviewed. Demographic, clinical, and analytical data were obtained at the time of diagnosis. To estimate the risk of CVD in the long term, we applied the model developed by Brunner F. J. et al. [3] -Figure 1-. Based on this, the patients were stratified into 5 CVR groups according to the non-HDL CT and grouped into three age ranges. Statistical analysis was carried out using IBM-SPSS Statistics version 26.ResultsThe demographic, clinical, laboratory characteristics and CVR groups are indicated in Table 1. Regarding the mean age according to the CVR group: in the 8 patients of group 1 it was 38.13 ± 15.28 years - 7 with age &lt; 45 years and one &gt; 60 years -, in group 2 it was 42.93 ± 11.76 years - 17 patients &lt; 45 years, 10 between 45 and 59 years and 2 ≥ 60 years -, in the 31 patients of group 3 it was 51.45 ± 11.49 years - 8 &lt; 45 years, 15 between 45-59 years and 8 ≥ 60 years -. In the 2 patients in group 4 it was 52.5 years (45-59) and the patient in group 5 was 36 years old at diagnosis.No significant correlations were found between CRP, ESR, RF, ACPAs levels and presence of radiographic erosions with nonHDL CT values. Significant differences (p value &lt; 0.01) were observed between the youngest individuals (age &lt; 45 years) in groups 1 and 2 with respect to individuals older than 60 years in risk groups 3 or 4. The application of the current model -Figure 1- estimated a mean probability of CVD of 9.7% at 75 years with a reduction to 3.54% after a 50% decrease in non-HDL TC. A single fatal cardiovascular event was recorded in an obese, hypertensive, and diabetic man, classified in risk group 3.ConclusionIn our cohort of patients with new-onset RA, the majority (46%) were classified as CVR group 3 (nonHDL CT 145-184 mg/dL), despite approximately 50% being &lt;45 years of age. Exposure from an early age to a moderate increase in non-HDL CT induces an increase in long-term CVR, not captured by the 10-year CVR estimate. For all this, emphasis should be placed on the establishment of measures to reduce CVR guided by non-HDL CT levels in patients diagnosed with RA.References[1]https://doi.org/10.1136/annrheumdis-2016-209775[2]https://doi.org/10.1016/j.rec.2022.04.003[3]https://doi.org/10.1016/s0140-6736(19)32519-xTable 1.N%DEMOGRAPHICTotal number of patients71SexM1115.5%W6084.5%Median age at diagnosis46,28 ± 12,73CLINICALRadiographic erosions2433.8%Corticosteroid therapy4563.38%LABORATORYRF (+)4766.19%ACPA (+)4664.78%MeanMedianCRP13.35 ± 19.066.74 IQR 15.90ESR25.06 35 ± 16.5620 IQR 17.00Total CT203Non-HDL CT144Colesterol LDL121.5N%CVRPrevious CVD0Statins22.81%Active smoking2129.57%Hypertension1318.30%IMC &gt; 301521.12%Diabetes22.81%CVR group according to nonHDL CT1 (&lt;100 mg/dL)811.3%2 (100-144 mg/dL)2940.8%3 (145-184 mg/dL)3143.7%4 (185-219 mg/dL)22.8%5 (≥ 220 mg/dL)11.4%Figure 1.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Research paper thumbnail of Identification of the<i>PTPN22</i>functional variant R620W as susceptibility genetic factor for giant cell arteritis

Annals of the Rheumatic Diseases, Aug 14, 2013

Objective To analyse the role of the PTPN22 and CSK genes, previously associated with autoimmunit... more Objective To analyse the role of the PTPN22 and CSK genes, previously associated with autoimmunity, in the predisposition and clinical phenotypes of giant cell arteritis (GCA). Methods Our study population was composed of 911 patients diagnosed with biopsy-proven GCA and 8136 unaffected controls from a Spanish discovery cohort and three additional independent replication cohorts from Germany, Norway and the UK. Two functional PTPN22 polymorphisms (rs2476601/R620W and rs33996649/ R263Q) and two variants of the CSK gene (rs1378942 and rs34933034) were genotyped using predesigned TaqMan assays. Results The analysis of the discovery cohort provided evidence of association of PTPN22 rs2476601/R620W with GCA (P FDR =1.06E-04, OR=1.62, CI 95% 1.29 to 2.04). The association did not appear to follow a specific GCA subphenotype. No statistically significant differences between allele frequencies for the other PTPN22 and CSK genetic variants were evident either in the case/control or in stratified case analysis. To confirm the detected PTPN22 association, three replication cohorts were genotyped, and a consistent association between the PTPN22 rs2476601/R620W variant and GCA was evident in the overall meta-analysis (P MH =2.00E-06, OR=1.51, CI 95% 1.28 to 1.79). Conclusions Our results suggest that the PTPN22 polymorphism rs2476601/R620W plays an important role in the genetic risk to GCA.

Research paper thumbnail of A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis

American Journal of Human Genetics, 2017

If citing, it is advised that you check and use the publisher's definitive version for pagination... more If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections.

Research paper thumbnail of Real-World Persistence and Treatment Patterns in Patients with Psoriatic Arthritis Treated with Anti-IL17 Therapy in Spain: The PerfIL-17 Study

Advances in Therapy

Introduction: Given the growing interest and use of interleukin-17 inhibitors (anti-IL17) for the... more Introduction: Given the growing interest and use of interleukin-17 inhibitors (anti-IL17) for the treatment of psoriatic arthritis (PsA), an observational study has been conducted to characterize the patient profile, treatment patterns, and persistence of ixekizumab or secukinumab in patients with PsA receiving them as first anti-IL17. Methods: This is a multicenter retrospective study, conducted at eight Spanish hospitals where data from adult patients with PsA were collected from electronic medical records. Three cohorts of patients, initiating treatment with an anti-IL17 [secukinumab 150 mg (SECU150), secukinumab 300 mg (SECU300), or ixekizumab (IXE)] between January 2019 and March 2021, were included. Demographic and clinical patient characteristics, treatment patterns, and persistence were analyzed descriptively. Con

Research paper thumbnail of Interleukin 6 gene promoter polymorphism is not associated with ankylosing spondylitis

PubMed, Jun 1, 2000

Objective: To investigate the possible association between the recently described interleukin 6 (... more Objective: To investigate the possible association between the recently described interleukin 6 (IL-6) promoter polymorphisms at position -174, and susceptibility to ankylosing spondylitis (AS). Methods: Ninety-two patients with AS, 157 healthy controls, and an additional group of 52 HLA-B27 positive unrelated individuals were included in this study. The -174 polymorphic site in the promoter region of IL-6 gene was typed by polymerase chain reaction-restriction fragment length polymorphism. Results: No statistically significant differences were observed when IL-6 promoter genotype and allele distribution between patients with AS and healthy controls were compared. Conclusion: Our results suggest the -174 IL-6 polymorphism does not play an important role in susceptibility to AS. Larger studies are needed to provide more conclusive evidence on the role of -174 IL-6 polymorphism in AS.

Research paper thumbnail of The Functional PTPN22 Variant R620W Is Strongly Associated With Giant Cell Artetitis Predisposition

Arthritis & Rheumatism, Oct 31, 2013

Research paper thumbnail of POS0095 Single-Cell Landscape of CD4+ T Lymphocytes Reveals a Potential Role of Cytotoxic Cells in Giant Cell Arteritis

Annals of the Rheumatic Diseases, May 30, 2023

Research paper thumbnail of Protective Role of the Vitamin D Receptor Apai (rs7975232) Polymorphism Against Subclinical Atherosclerosis in Patients with Rheumatoid Arthritis from Northern Spain

Arthritis & Rheumatism, Oct 31, 2015

Research paper thumbnail of SAT0471 Cathepsin K is A Bone Remodelling Marker in Females with Postmenopausal Osteoporosis

Annals of the Rheumatic Diseases, Jun 1, 2014

Background: Cathepsin K is a protease expressed by osteoclasts that plays an important role in os... more Background: Cathepsin K is a protease expressed by osteoclasts that plays an important role in osteoclastic mediated bone resorption. It degrades organic bone matrix, primarily type 1 collagen. Postmenopausal osteoporosis is characterised by an increase in bone resorption that manifests as elevation of bone remodelling makers. This phenomenon starts in the peri-menopausal period. The potential role of cathepsin K levels as markers of bone remodelling in postmenopausal osteoporosis is being evaluated, but there is paucity of data. There is increasing interest in identifying markers able to differentiate the number and activity of osteoclasts to clarify the mechanism of action of current anti-osteoporotic therapies. It is also suggested that such markers might help in the development of more specific novel treatments. Objectives: To evaluate the role of cathepsin K as bone remodelling marker in females with postmenopausal osteoporosis. Methods: Cross sectional study. Two groups were evaluated: postmenopausal females and healthy controls (this group was subdivided into pre and postmenopausal females). Cathepsin K levels in sera were determined by polyclonal antibody ELISA (BI-20432). Data were analysed with STATA10. Differences in cathepsin K levels between groups were determined. A quantile regression model was built to assess cathepsin K leves for the median, first and third quantile according to the variables of interest. A p value of <0.05 was considered as statistically significant. Results: Cathepsin K levels were higher in postmenopausal osteoporotic females than in healthy controls (X 2 =17.54 y 2 g.l, p<0.01) with a clear dose response gradient (p<0.001). Conclusions: Cathepsin K is a bone remodelling marker in females with postmenopausal osteoporosis. There is a dose response gradient on bone mineral density independently of postmenopausal status, which is maximal in females with postmenopausal osteoporosis and minimal in females with normal bone density. References: [1] Dodds RA, James IA, Rieman D et al.: Human osteoclast Cathepsin K is Processed Intracellulary Prior to Attachment and Bone Resorption.

Research paper thumbnail of Biologic therapy in refractory neurobehçet’s disease: a multicentre study of 41 patients and literature review

Rheumatology, Feb 15, 2022

Objectives To assess efficacy and safety of biologic therapy (BT) in neurobehçet’s disease (NBD) ... more Objectives To assess efficacy and safety of biologic therapy (BT) in neurobehçet’s disease (NBD) refractory to glucocorticoids and at least one conventional immunosuppressive drug. Methods Open-label, national, multicentre study. NBD diagnosis was based on the International Consensus Recommendation criteria. Outcome variables were efficacy and safety. Main efficacy outcome was clinical remission. Other outcome variables analysed were glucocorticoid-sparing effect and improvement in laboratory parameters. Results We studied 41 patients [21 women; age 40.6 (10.8) years]. Neurological damage was parenchymal (n = 33, 80.5%) and non-parenchymal (n = 17, 41.5%). First BTs used were infliximab (n = 19), adalimumab (n = 14), golimumab (n = 3), tocilizumab (n = 3) and etanercept (n = 2). After 6 months of BT, neurological remission was complete (n = 23, 56.1%), partial (n = 15, 37.6%) and no response (n = 3, 7.3%). In addition, median (IQR) dose of oral prednisone decreased from 60 (30–60) mg/day at the initial visit to 5 (3.8–10) mg/day after 6 months (P &lt; 0.001). It was also the case for mean erythrocyte sedimentation rate [31.5 (25.6)–15.3 (11.9) mm/1st h, P = 0.011] and median (IQR) C-reactive protein [1.4 (0.2–12.8) to 0.3 (0.1–3) mg/dl, P = 0.001]. After a mean follow-up of 57.5 months, partial or complete neurological remission persisted in 37 patients (90.2%). BT was switched in 22 cases (53.6%) due to inefficacy (n = 16) or adverse events (AEs) (n = 6) and discontinued due to complete prolonged remission (n = 3) or severe AE (n = 1). Serious AEs were observed in two patients under infliximab treatment. Conclusions BT appears to be effective and relatively safe in refractory NBD.

Research paper thumbnail of Machine Learning for the Identification of a Common Signature for Anti–SSA/Ro 60 Antibody Expression Across Autoimmune Diseases

Arthritis & rheumatology, Aug 25, 2022

ObjectiveAnti‐Ro autoantibodies are among the most frequently detected extractable nuclear antige... more ObjectiveAnti‐Ro autoantibodies are among the most frequently detected extractable nuclear antigen autoantibodies, mainly associated with primary Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), and undifferentiated connective tissue disease (UCTD). This study was undertaken to determine if there is a common signature for all patients expressing anti–Ro 60 autoantibodies regardless of their disease phenotype.MethodsUsing high‐throughput multiomics data collected from the cross‐sectional cohort in the PRECISE Systemic Autoimmune Diseases (PRECISESADS) study Innovative Medicines Initiative (IMI) project (genetic, epigenomic, and transcriptomic data, combined with flow cytometry data, multiplexed cytokines, classic serology, and clinical data), we used machine learning to assess the integrated molecular profiling of 520 anti–Ro 60+ patients compared to 511 anti–Ro 60– patients with primary SS, patients with SLE, and patients with UCTD, and 279 healthy controls.ResultsThe selected clinical features for RNA‐Seq, DNA methylation, and genome‐wide association study data allowed for a clear distinction between anti–Ro 60+ and anti–Ro 60– patients. The different features selected using machine learning from the anti–Ro 60+ patients constituted specific signatures when compared to anti–Ro 60– patients and healthy controls. Remarkably, the transcript Z score of 3 genes (ATP10A, MX1, and PARP14), presenting with overexpression associated with hypomethylation and genetic variation and independently identified using the Boruta algorithm, was clearly higher in anti–Ro 60+ patients compared to anti–Ro 60– patients regardless of disease type. Our findings demonstrated that these signatures, enriched in interferon‐stimulated genes, were also found in anti–Ro 60+ patients with rheumatoid arthritis and those with systemic sclerosis and remained stable over time and were not affected by treatment.ConclusionAnti–Ro 60+ patients present with a specific inflammatory signature regardless of their disease type, suggesting that a dual therapeutic approach targeting both Ro‐associated RNAs and anti–Ro 60 autoantibodies should be considered.

Research paper thumbnail of Dose-Dependent Effect of Melatonin on BAT Thermogenesis in Zücker Diabetic Fatty Rat: Future Clinical Implications for Obesity

Antioxidants

Experimental data have revealed that melatonin at high doses reduced obesity and improved metabol... more Experimental data have revealed that melatonin at high doses reduced obesity and improved metabolic outcomes in experimental models of obesity, mainly by enhancing brown adipose tissue (BAT) thermogenesis. A potential dose-response relationship has yet to be performed to translate these promising findings into potential clinical therapy. This study aimed to assess the effects of different doses of melatonin on interscapular BAT (iBAT) thermogenic capacity in Zücker diabetic fatty (ZDF) rats. At 6 wk of age, male ZDF rats were divided into four groups (n = 4 per group): control and those treated with different doses of melatonin (0.1, 1, and 10 mg/kg of body weight) in their drinking water for 6 wk. Body weight (BW) was significantly decreased at doses of 1 and 10 mg/kg of melatonin, but not at 0.1 mg/kg compared with the control, with a similar rate of BW decrease being reached at the dose of 1 mg/kg (by ~11%) and 10 mg/kg (by ~12%). This effect was associated with a dose-dependent ...

Research paper thumbnail of Chemosensory Recognition in Trogonophis

Chemosensory Social Recognition in an amphisbaenian (Trogonophis wiegmanni)<br>

Research paper thumbnail of THU0297 SERIOUS Infections in 134 Patients with Giant Cell Arteritis with Tocilizumab in Clinical Practice. Frequency, Type and Clinical Associations

Annals of the Rheumatic Diseases, 2020

Background:Infections are the most common adverse event of Tocilizumab (TCZ) in Giant Cell Arteri... more Background:Infections are the most common adverse event of Tocilizumab (TCZ) in Giant Cell Arteritis (GCA). In GiACTA study(1),serious infections were observed in 7% (9.6/100 patient-years) of patients who received TCZ weekly. Randomized clinical trials (RCTs) are conducted under highly standardized design excluding some real-world patients. Therefore, adverse events may be underestimated in RCTs. In our series of real-life, serious infections occurred in 11.9% (10.6/100 patient-years)(2).Objectives:In a wide series of GCA of clinical practice treated with TCZ, we assess the frequency, type and predisposing factors of serious infections.Methods:Multicenter study of 134 patients diagnosed with GCA, all of them refractory to conventional therapy, treated with TCZ. Serious infection was considered when a life-threatening infection, fatal, or requiring hospitalization occurred, intravenous antibiotics were required, or the infectious process led to persistent or significant disability.R...

Research paper thumbnail of Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature

Scientific Reports, 2021

Primary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic inf... more Primary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns...

Research paper thumbnail of Association study of ghrelin receptor gene polymorphisms in rheumatoid arthritis

Clinical and experimental rheumatology

Ghrelin is a newly characterised growth hormone (GH) releasing peptide widely distributed that ma... more Ghrelin is a newly characterised growth hormone (GH) releasing peptide widely distributed that may play an important role in the regulation of metabolic balance in inflammatory diseases such as rheumatoid arthritis (RA) by decreasing the pro-inflammatory Th1 responses. In this study we investigated the possible contribution of several polymorphisms in the functional Ghrelin receptor to RA susceptibility. A screening of 3 single nucleotide polymorphisms (SNPs) was performed in a total of 950 RA patients and 990 healthy controls of Spanish Caucasian origin. Genotyping of all 3 SNPs was performed by real-time polymerase chain reaction technology, using the TaqMan 5'-allele discrimination assay. We observed no statistically significant deviation between RA patients and controls for the GHSR SNPs analysed. In addition, we performed a haplotype analysis that did not reveal an association with RA susceptibility. The stratification analysis for the presence of shared epitope (SE), rheum...

Research paper thumbnail of FRI0556 Development of standards of care in spondyloarthritis

Annals of the Rheumatic Diseases, 2013

Background: Systemic Lupus Erythematosus (SLE) is a risk factor for osteoporosis (OP) and ocular ... more Background: Systemic Lupus Erythematosus (SLE) is a risk factor for osteoporosis (OP) and ocular adverse drug reactions (OADR) as cataracts and secondary glaucoma, mainly owing to the chronic treatment with Glucocorticoids (GC). Recommendations and Quality Indicators (QIs) have been developed to guide rheumatologists in the monitoring and treating of these conditions [1, 2, 3, 4]. However it is well known how the adherence to Recommendations and QIs is low in clinical practice. Objectives: To evaluate if the introduction of a clinical chart developed for the routinary assessment of SLE patients, might improve the adherence of rheumatologists to the existing Recommendations for the monitoring of OP and ocular toxicity. Methods: In 2011 a core-set of clinical variables to be regularly evaluated in SLE patients was developed, based on Recommendations and QIs. Patients with a diagnosis of SLE based on the American College of Rheumatology criteria, followed at our Rheumatology Unit, were consecutively enrolled during their regular outpatient visit in 2012 and were evaluated using the SLE dedicated chart. Adherence to Recommendations and QIs was compared with data from the same patients before the introduction of the chart. Results: One hundred and eleven SLE patients were enrolled; 11 of them, with a follow-up (fu) shorter than 2 years were excluded. Therefore, 100 patients, 98 F/2 M, mean age 43,4±11,9 years, disease duration 17,4±7,8 years, mean fu 13,4±7 years, were analyzed. Before the introduction of the SLE-dedicated chart the prevalence of adherence to OP and ocular monitoring were respectively of 19 (19%) and 32 (32%) cases. After the use of the coreset these values changed respectively in 52 (52%) and 66 (66%) cases. The comparison of both these results showed a significant difference, with respective p values of 0,05 and 0,03. Conclusions: These results show how introducing an SLE ad hoc designed core-set might significantly increase the adherence to the OP and ocular monitoring in clinical practice, thus assuring an improvement in the quality of care of SLE patients.

Research paper thumbnail of OP0056 The PTPN22/CSK Signalling Pathway is Involved in Susceptibility to Develop Giant Cell Arteritis

Annals of the Rheumatic Diseases, 2013

Background The PTPN22/CSK signalling represents one of the most relevant pathways in the innate i... more Background The PTPN22/CSK signalling represents one of the most relevant pathways in the innate immunity, and it has been implicated in the susceptibility to develop a wide number of autoimmune diseases. Objectives To analyse the possible role of different single-nucleotide polymorphisms of the PTPN22 and CSK genes in the predisposition and clinical phenotypes of giant cell arteritis (GCA) in a large Caucasian population. Methods Our study population consisted of 623 patients diagnosed with biopsy-proven GCA and 1,729 healthy controls of Spanish Caucasian origin. Two functional PTPN22 polymorphisms (rs24746601, R620W and rs33996649, R263Q) and two variants of the CSK gene (rs1378942 and rs34933034), previously associated with autoimmunity, were genotyped using specifically designed TaqMan® assays. Results A significant association of the PTPN22 non-synonymous change rs2476601 with GCA susceptibility was yielded after the analysis of the allele frequencies (P=1.06E-04, OR= 1.62, CI 95% 1.29-2.04). No statistically significant differences between cases and controls of the rest of SNPs analysed were observed. Similarly, when patients were stratified according to specific clinical features of GCA, such as polymyalgia rheumatica (PMR), visual ischemic manifestations (VIM) or irreversible occlusive disease (IOD), only significant differences were found between the case subgroups and the control set for PTPN22 rs2476601 (P=2.26E-04, OR=1.77 CI 95% 1.30-2.40; P=1.03E-03, OR=1.82 CI 95% 1.27-2.62; P=5.47E-04, OR=2.14 CI 95% 1.38-3.33, respectively). Conclusions Our results clearly suggest that the PTPN22 polymorphism rs2476601 is associated with susceptibility to GCA. Disclosure of Interest None Declared

Research paper thumbnail of Physicians' and Patients' Preferences Over the Attributes of Biological Agents Used In the Treatment of Rheumatic Diseases In Spain: A Conjoint Analysis

Value in Health, 2014

Objectives: Rituximab SC reduces administration times (~5 minutes) compared with the IV route (~4... more Objectives: Rituximab SC reduces administration times (~5 minutes) compared with the IV route (~4 hours). We examined the extent of patient preference for rituximab SC versus IV in the PrefMab and MabCute studies using the Rituximab Administration Satisfaction Questionnaire (RASQ). MethOds: In PrefMab (NCT01724021) patients with untreated CD20+ DLBCL/FL received 1 cycle of IV rituximab (375mg/m 2) followed by either SC rituximab (1400mg, x3) then IV rituximab (x4), or IV rituximab (x3) then SC rituximab (x4), with chemotherapy. In MabCute (NCT01461928) patients with relapsed/refractory CD20+ indolent NHL received induction rituximab IV (375mg/m 2 ; 1 cycle) then rituximab SC (1400mg; cycles 2-8) plus 6-8 chemotherapy cycles. RASQ evaluated preference by assessing patients' perceptions of the impact of administration route and treatment satisfaction. Conceptual validation of RASQ has been conducted and psychometric data will be reported. Results: Median RASQ scores for PrefMab were: convenience IV (n= 211) 58.3 (interquartile range: 41.7-75.0) and SC (n= 207) 83.3 (75.0-91.7); satisfaction: IV (n= 211) 75.0 (62.5-87.5), SC (n= 208) 87.5 (75.0-100.0); impact on daily life: IV (n= 145) 50.0 (41.7-83.3), SC (n= 163) 83.3 (83.3-100.0); physical impact IV (n= 211) 83.3 (66.7-100.0), SC (n= 208) 83.3 (75.0-100.0); psychological impact IV (n= 211) 80.0 (65.0-90.0), SC (n= 208) 88.8 (75.0-95.0). SC administration was preferred by 80.3% and 85.9% of patients with IV or SC as most recent dose, respectively. Results were similar irrespective of treatment sequence. Median RASQ scores for MabCute (n= 92

Research paper thumbnail of Expression Quantitative Trait Locus Analysis in Systemic Sclerosis Identifies New Candidate Genes Associated With Multiple Aspects of Disease Pathology

Arthritis & rheumatology, May 28, 2021

Objective. To identify the genetic variants that affect gene expression (expression quantitative ... more Objective. To identify the genetic variants that affect gene expression (expression quantitative trait loci [eQTLs]) in systemic sclerosis (SSc) and to investigate their role in the pathogenesis of the disease. Methods. We performed an eQTL analysis using whole-blood sequencing data from 333 SSc patients and 524 controls and integrated them with SSc genome-wide association study (GWAS) data. We integrated our findings from expression modeling, differential expression analysis, and transcription factor binding site enrichment with key clinical features of SSc. Results. We detected 49,123 validated cis-eQTLs from 4,539 SSc-associated single-nucleotide polymorphisms (SNPs) (P GWAS < 10 −5). A total of 1,436 genes were within 1 Mb of the 4,539 SSc-associated SNPs. Of those 1,436 genes, 565 were detected as having ≥1 eQTL with an SSc-associated SNP. We developed a strategy to prioritize diseaseassociated genes based on their expression variance explained by SSc eQTLs (r 2 > 0.05). As a result, 233 candidates were identified, 134 (58%) of them associated with hallmarks of SSc and 105 (45%) of them differentially expressed in the blood cells, skin, or lung tissue of SSc patients. Transcription factor binding site analysis revealed enriched motifs of 24 transcription factors (5%) among SSc eQTLs, 5 of which were found to be differentially regulated in the blood cells (ELF1 and MGA), skin (KLF4 and ID4), and lungs (TBX4) of SSc patients. Ten candidate genes (4%) can be targeted by approved medications for immune-mediated diseases, of which only 3 have been tested in clinical trials in patients with SSc. Conclusion. The findings of the present study indicate a new layer to the molecular complexity of SSc, contributing to a better understanding of the pathogenesis of the disease.

Research paper thumbnail of AB0376 Cardiovascular Risk Stratification According to Serum Non-HDL Cholesterol Levels in Patients with Recently Diagnosed Rheumatoid Arthritis

Annals of the Rheumatic Diseases, May 30, 2023

BackgroundIt is estimated that rheumatoid arthritis (RA) increases the risk of cardiovascular dis... more BackgroundIt is estimated that rheumatoid arthritis (RA) increases the risk of cardiovascular disease (CVD) by 50% compared to the general population [1,2]. Non-HDL cholesterol (non-HDL CT) has become an innovative marker of cardiovascular risk (CVR). According to the recommendations of the ESC of 2022 [2], patients with RA start from an intermediate CVR and recommend non-HDL TC levels &lt;130mg/dL.ObjectivesTo evaluate long-term risk of CVD according to nonHDL CT levels in a cohort of patients with recently diagnosed RA who started biological therapy and describe its characteristics.Methods71 patients with RA under biological treatment were reviewed. Demographic, clinical, and analytical data were obtained at the time of diagnosis. To estimate the risk of CVD in the long term, we applied the model developed by Brunner F. J. et al. [3] -Figure 1-. Based on this, the patients were stratified into 5 CVR groups according to the non-HDL CT and grouped into three age ranges. Statistical analysis was carried out using IBM-SPSS Statistics version 26.ResultsThe demographic, clinical, laboratory characteristics and CVR groups are indicated in Table 1. Regarding the mean age according to the CVR group: in the 8 patients of group 1 it was 38.13 ± 15.28 years - 7 with age &lt; 45 years and one &gt; 60 years -, in group 2 it was 42.93 ± 11.76 years - 17 patients &lt; 45 years, 10 between 45 and 59 years and 2 ≥ 60 years -, in the 31 patients of group 3 it was 51.45 ± 11.49 years - 8 &lt; 45 years, 15 between 45-59 years and 8 ≥ 60 years -. In the 2 patients in group 4 it was 52.5 years (45-59) and the patient in group 5 was 36 years old at diagnosis.No significant correlations were found between CRP, ESR, RF, ACPAs levels and presence of radiographic erosions with nonHDL CT values. Significant differences (p value &lt; 0.01) were observed between the youngest individuals (age &lt; 45 years) in groups 1 and 2 with respect to individuals older than 60 years in risk groups 3 or 4. The application of the current model -Figure 1- estimated a mean probability of CVD of 9.7% at 75 years with a reduction to 3.54% after a 50% decrease in non-HDL TC. A single fatal cardiovascular event was recorded in an obese, hypertensive, and diabetic man, classified in risk group 3.ConclusionIn our cohort of patients with new-onset RA, the majority (46%) were classified as CVR group 3 (nonHDL CT 145-184 mg/dL), despite approximately 50% being &lt;45 years of age. Exposure from an early age to a moderate increase in non-HDL CT induces an increase in long-term CVR, not captured by the 10-year CVR estimate. For all this, emphasis should be placed on the establishment of measures to reduce CVR guided by non-HDL CT levels in patients diagnosed with RA.References[1]https://doi.org/10.1136/annrheumdis-2016-209775[2]https://doi.org/10.1016/j.rec.2022.04.003[3]https://doi.org/10.1016/s0140-6736(19)32519-xTable 1.N%DEMOGRAPHICTotal number of patients71SexM1115.5%W6084.5%Median age at diagnosis46,28 ± 12,73CLINICALRadiographic erosions2433.8%Corticosteroid therapy4563.38%LABORATORYRF (+)4766.19%ACPA (+)4664.78%MeanMedianCRP13.35 ± 19.066.74 IQR 15.90ESR25.06 35 ± 16.5620 IQR 17.00Total CT203Non-HDL CT144Colesterol LDL121.5N%CVRPrevious CVD0Statins22.81%Active smoking2129.57%Hypertension1318.30%IMC &gt; 301521.12%Diabetes22.81%CVR group according to nonHDL CT1 (&lt;100 mg/dL)811.3%2 (100-144 mg/dL)2940.8%3 (145-184 mg/dL)3143.7%4 (185-219 mg/dL)22.8%5 (≥ 220 mg/dL)11.4%Figure 1.Acknowledgements:NIL.Disclosure of InterestsNone Declared.