Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study.

BACKGROUND: Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci. METHODS: We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings. FINDINGS: We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10-8; OR 1·19 [95% CI 1·12-1·26]) and VTN (rs704; p=2·75 × 10-9; OR 0·84 [0·79-0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10-8; OR 1·18 [1·12-1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15-3·82]; p=1·73 × 10-13). INTERPRETATION: We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis. FUNDING: Institute of Health Carlos III, Spanish Ministry of Science and Innovation, UK Medical Research Council, and National Institute for Health and Care Research.

Lymphoid interstitial pneumonia in a patient with systemic lupus erythematosus: Case report and literature review.

Lymphoid interstitial pneumonia (LIP) is a rare form of interstitial pulmonary disease, which has been described in association with a wide range of autoimmune disorders. Although the association of this entity with Sjogren's syndrome is well known, only a few cases are reported in relation to systemic lupus erythematosus (SLE). The aim of this paper is to review the cases reported in literature to date, as well as to describe the characteristics of these patients including the new case presented herein. We will be focusing on the case of a 36-year-old female patient diagnosed with SLE on hydroxychloroquine treatment who develops pleuritic chest pain and progressive dyspnea after 3 years of follow-up. The chest CT scan showed pleural thickening and both multiple and bilateral micronodules. A lung biopsy was also performed, revealing an infiltration of lymphocytes, plasma cells, and histiocytes in the alveolar septa suggestive of LIP. After conducting a review of the literature, we identified seven other cases describing SLE in association with LIP. The majority of them were young women, and LIP tends to appear early in the course of the disease, even as a form of initial presentation in some cases. Symptoms included cough, dyspnea, and pleuritic pain, with the exception of one case which was asymptomatic. It is noteworthy that half of the patients were positive for anti-SSA/anti-SSB autoantibodies, and some of them also met criteria for Sjogren's syndrome. Treatment with steroids and other immunosuppressive agents improved symptoms in all of them.

Ocular involvement in adult and paediatric patients with monogenic autoinflammatory diseases: a Spanish multicentre retrospective study.

OBJECTIVES: Ophthalmologic involvement in monogenic autoinflammatory diseases has been explored mainly in paediatric patients. The aim of this study is to characterise ophthalmologic manifestations, therapeutic management and visual outcomes in a Spanish (UVESAI) cohort of adult/paediatric patients with monogenic autoinflammatory diseases. METHODS: Multicentre and retrospective study of patients with monogenic autoinflammatory diseases and ocular involvement. Eye manifestations, structural complications, treatments used and visual outcomes were analysed, and compared with previous studies. RESULTS: Forty-six patients (44/2 adults/children; 21/25 adult/paediatric-onset) with monogenic autoinflammatory diseases [cryopyrin associated periodic syndromes (n=13/28.3%), mainly Muckle-Wells syndrome (MWS) (n=11/24%); familial Mediterranean fever (FMF) (n=12/26%); TNF receptor-associated periodic syndrome (TRAPS); (n=9/20%); Blau syndrome (n=8/17%); hyperimmunoglobulin D syndrome (HIDS) (n=2/4.3%), deficiency of adenosine deaminase-2 and NLRC4-Autoinflammatory disease] (one each) were included. Conjunctivitis (n=26/56.5%) and uveitis (n=23/50%) were the most frequent ocular manifestations. Twelve (26.1%) patients developed structural complications, being cataracts (n=11/24%) and posterior synechiae (n=10/22%) the most frequent. Conjunctivitis predominated in TRAPS, FMF, MWS and HIDS (mainly in adults), and uveitis, in Blau syndrome. Seven (8%) eyes (all with uveitis) presented with impaired visual acuity. Local and systemic treatment led to good visual outcomes in most patients. Compared with previous studies mainly including paediatric patients, less severe ocular involvement was observed in our adult/paediatric cohort. CONCLUSIONS: Conjunctivitis was the most common ocular manifestation in our TRAPS, FMF, MWS and HIDS patients, and uveitis predominated in Blau syndrome. Severe eye complications and poor visual prognosis were associated with uveitis. Adults with monogenic autoinflammatory diseases seem to exhibit a less severe ophthalmologic presentation than paediatric patients.

The complex HLA-E-nonapeptide in Behçet disease.

Introduction: The knowledge of the aetiology of Behçet disease (BD), an immune-mediated vasculitis, is limited. HLA-B, mainly HLA-B51, and HLA-A molecules are associated with disease, but the ultimate cause of this association remains obscure. There is evidence that NK cells participate in the etiopathology of BD. NK cells have activator and inhibitor surface receptors, like the KIR and the NKG2 families. Classical HLA-class I molecules (A, B and C) are keys in the activity control of the NK because they are KIR ligands. Most NKG2 receptors bind HLA-E, which presents only nonapeptides derived from the signal peptide of other class-I molecules. Objective: This study investigates the contribution of the pair HLA-E and ligand, nonapeptide derived from the 3-11 sequence of the signal peptides of class I classical molecules, to the susceptibility to BD. Methods: We analyzed the frequency of the HLA-derivated nonapeptide forms in 466 BD patients and 444 controls and an HLA-E functional dimorphism in a subgroup of patients and controls. Results: In B51 negative patients, the frequency of VMAPRTLLL was lower (70.4% versus 80.0% in controls; P=0.006, Pc=0.04, OR=0.60, 95%CI 0.41-0.86), and the frequency of VMAPRTLVL was higher (81.6% versus 71.4% in controls; P=0.004, Pc=0.03, OR=1.78, 95%CI 1.20-2.63). In homozygosity, VMAPRTLLL is protective, and VMAPRTLVL confers risk. The heterozygous condition is neutral. There were no significant differences in the distribution of the HLA-E dimorphism. Discussion: Our results explain the association of BD with diverse HLA-A molecules, reinforce the hypothesis of the involvement of the NK cells in the disease and do not suggest a significant contribution of the HLA-E polymorphism to disease susceptibility.

Cranial and extracranial giant cell arteritis do not exhibit differences in the IL6 -174 G/C gene polymorphism.

OBJECTIVES: Since interleukin-6 (IL-6) is a pivotal proinflammatory cytokine implicated in the pathogenesis of giant cell arteritis (GCA), we aimed to determine the potential association of the functional IL6 -174 G/C polymorphism with GCA as well as if the single base change variation at the promoter region in the human IL-6 gene may account for differences in the clinical spectrum of GCA between cranial and extracranial large vessel vasculitis (LVV)-GCA. METHODS: The IL6 -174 G/C polymorphism (rs1800795) was genotyped in 191 patients with biopsy-proven GCA who had typical cranial manifestations of the disease, 109 patients with extracranial LVV-GCA, without cranial ischaemic manifestations of GCA, and 877 ethnically matched unaffected controls. A comparative study was carried out between patients with cranial and extracranial LVV-GCA and controls. RESULTS: No significant differences in genotype and allele frequencies of IL6 -174 G/C polymorphism were found between the whole cohort of GCA patients and healthy controls. It was also the case when cranial and extracranial LVV-GCA were compared or when each of these subgroups was compared to controls. Moreover, no significant results in genotype and allele frequencies of IL6 -174 G/C polymorphism were disclosed when the whole cohort of GCA patients were stratified according to the presence of polymyalgia rheumatica, severe ischaemic manifestations, including permanent visual loss and peripheral arteriopathy, and HLA-DRB1*04:01 status. CONCLUSIONS: Our results show that the IL6 -174 G/C polymorphism does not influence the phenotypic expression of GCA.

Cranial and extracranial large-vessel giant cell arteritis share a genetic pattern of interferon-gamma pathway.

OBJECTIVES: Two main different clinical phenotypes of giant cell arteritis (GCA) have been described, the classic cranial pattern and the extracranial large-vessel (LV) pattern. Since interferon gamma (IFNG) has shown to be a pivotal cytokine in the pathophysiology of GCA, our aim was to evaluate for the first time the influence of IFNG and IFNG receptor 1 (IFNGR1) polymorphisms in the different clinical phenotypes of GCA. METHODS: Two IFNG polymorphisms (rs2069718 G/A and rs1861493 A/G) and one polymorphism in IFNGR1 (rs1327474 G/A) were genotyped in 191 patients with biopsy-proven cranial GCA, 109 with extracranial LV-GCA and 490 healthy controls. A comparative study was conducted between patients with cranial and extracranial LV-GCA. RESULTS: No significant differences in genotype, allele, and haplotype frequencies of IFNG polymorphisms were found between GCA patients with the classic cranial pattern and the extracranial LV-GCA pattern. Similar results were found for genotype and allele frequencies of IFNGR1 polymorphism. It was also the case when patients with extracranial LV-GCA were compared with healthy controls. CONCLUSIONS: Our results show that IFNG and IFNGR1 polymorphisms do not influence the clinical phenotype of expression of GCA. Classic cranial GCA and extracranial LV-GCA seem to share a genetic pattern of IFNG pathway.

Clinical course of Covid-19 in a cohort of patients with Behçet disease.

Objective: The implications of Covid-19 in patients with Behçet's disease (BD) are unknown. Patients with BD usually take long-term therapy with therapeutic agents that have been tested in Covid-19 patients. We aimed to assess the prevalence of Covid-19 in a cohort of patients with BD and investigate whether those patients with a long-term treatment with colchicine, tumor necrosis factor inhibitors (TNFi) or glucocorticoids are at reduced or increased prevalence of Covid-19 related clinical outcomes. Methods: A retrospective study was conducted among 244 patients with BD (86.1% females; mean age 43.95 ± 11.11 years). Each participant completed an online questionnaire regarding demographics, medical conditions, dispensed colchicine, TNFi or oral glucocorticoids, Covid-19 infection, clinical symptoms and recovery. Results: The prevalence of Covid-19 infection was 14.75%. Regarding dose of colchicine, the presence of ageusia was lower in patients taking 0.5 mg/day of colchicine compared to those taking 1.5 mg/day (p = 0.021). The prevalence of dyspnea was significantly higher in patients taking TNFi compared with those without therapy (p = 0.032). With regards to oral glucocorticoids, no significant differences were found. Conclusions: The prevalence of Covid-19 among patients with BD seems to be higher than that among the general population in Spain. Continuous TNFi therapy might increase the prevalence of worse clinical outcomes such as dyspnea; oral glucocorticoids and colchicine apparently provided no protection against the Covid-19 related clinical outcomes of patients with BD.

Objetivo: Se desconocen las implicaciones de la Covid-19 en pacientes con enfermedad de Behçet (EB). Los pacientes con EB generalmente tienen tratamiento de larga duración con agentes terapéuticos que se han probado en pacientes con Covid-19. Nuestro objetivo fue evaluar la prevalencia de la Covid-19 en una cohorte de pacientes con EB e investigar si los pacientes con un tratamiento de larga duración con colchicina, inhibidores del factor de necrosis tumoral (TNFi) o glucocorticoides tienen una prevalencia reducida o aumentada en los resultados clínicos de la Covid-19. Métodos: Se realizó un estudio retrospectivo en 244 pacientes con EB (86,1% mujeres; edad media, 43,95 ± 11,11 años). Cada participante completó un cuestionario en línea sobre datos demográficos, afecciones médicas, tratamiento con colchicina, TNFi o glucocorticoides orales, infección por Covid-19, síntomas clínicos y recuperación. Resultados: La prevalencia de la infección por Covid-19 fue del 14,75%. En cuanto a la dosis de colchicina, la presencia de ageusia fue menor en los pacientes que tomaban 0,5 mg/día de colchicina en comparación con los que tomaban 1,5 mg/día (p = 0,021). La prevalencia de disnea fue significativamente mayor en los pacientes que tomaban TNFi en comparación con aquellos sin terapia (p = 0,032). Con respecto a los glucocorticoides orales, no se encontraron diferencias significativas. Conclusiones: La prevalencia de Covid-19 en pacientes con EB parece ser superior a la de la población general en España. La terapia continua con TNFi podría aumentar la prevalencia de peores resultados clínicos como la disnea; los glucocorticoides orales y la colchicina aparentemente no proporcionan protección contra los resultados clínicos relacionados con la Covid-19 en pacientes con EB.

Standardized incidence ratios and risk factors for cancer in patients with systemic sclerosis: Data from the Spanish Scleroderma Registry (RESCLE).

AIM: Patients with systemic sclerosis (SSc) are at increased risk of cancer, a growing cause of non-SSc-related death among these patients. We analyzed the increased cancer risk among Spanish patients with SSc using standardized incidence ratios (SIRs) and identified independent cancer risk factors in this population. MATERIAL AND METHODS: Spanish Scleroderma Registry data were analyzed to determine the demographic characteristics of patients with SSc, and logistic regression was used to identify cancer risk factors. SIRs with 95% confidence intervals (CIs) relative to the general Spanish population were calculated. RESULTS: Of 1930 patients with SSc, 206 had cancer, most commonly breast, lung, hematological, and colorectal cancers. Patients with SSc had increased risks of overall cancer (SIR 1.48, 95% CI 1.36-1.60; P < 0.001), and of lung (SIR 2.22, 95% CI 1.77-2.73; P < 0.001), breast (SIR 1.31, 95% CI 1.10-1.54; P = 0.003), and hematological (SIR 2.03, 95% CI 1.52-2.62; P < 0.001) cancers. Cancer was associated with older age at SSc onset (odds ratio [OR] 1.22, 95% CI 1.01-1.03; P < 0.001), the presence of primary biliary cholangitis (OR 2.35, 95% CI 1.18-4.68; P = 0.015) and forced vital capacity <70% (OR 1.8, 95% CI 1.24-2.70; P = 0.002). The presence of anticentromere antibodies lowered the risk of cancer (OR 0.66, 95% CI 0.45-0.97; P = 0.036). CONCLUSIONS: Spanish patients with SSc had an increased cancer risk compared with the general population. Some characteristics, including specific autoantibodies, may be related to this increased risk.

Vascular endothelial growth factor haplotypes are associated with severe ischaemic complications in giant cell arteritis regardless of the disease phenotype.

OBJECTIVES: To determine whether functional vascular endothelial growth factor (VEGF) polymorphisms influence the expression of the clinical phenotype of giant cell arteritis (GCA). We also evaluated whether VEGF polymorphism is associated with the development of severe ischaemic manifestations in patients with GCA regardless of the clinical phenotype, classic cranial GCA or predominantly extracranial GCA large vessel vasculitis (LVV). METHODS: VEGF rs833061 T/C, rs2010963 G/C and rs3025039 C/T polymorphisms were genotyped in 185 patients with biopsy-proven cranial GCA, 105 with extracranial LVV-GCA and 490 healthy controls. Allelic combinations (haplotypes) of VEGF were carried out. Comparisons were performed between patients with GCA and healthy controls as well as between patients with GCA stratified according to the clinical phenotype and the presence of severe ischaemic manifestations. RESULTS: No significant differences in genotype, allele, and haplotype frequencies of VEGF were found between patients with GCA and healthy controls as well as between GCA patients with the classic cranial pattern and the extracranial LVV-GCA pattern of the disease. However, the VEGF CGC haplotype (OR= 1.63 [1.05-2.53]) and the CGT haplotype (OR= 2.55 [1.10-5.91]) were significantly more frequent in GCA patients with severe ischaemic complications compared to those patients without these complications. CONCLUSIONS: VEGF haplotypes seem to play a role in the development of severe ischaemic manifestations in GCA patients, regardless of the clinical phenotype of expression of the disease.

Clinical course of Covid-19 in a cohort of patients with Behçet disease.

OBJECTIVE: The implications of Covid-19 in patients with Behçet's disease (BD) are unknown. Patients with BD usually take long-term therapy with therapeutic agents that have been tested in Covid-19 patients. We aimed to assess the prevalence of Covid-19 in a cohort of patients with BD and investigate whether those patients with a long-term treatment with colchicine, tumor necrosis factor inhibitors (TNFi) or glucocorticoids are at reduced or increased prevalence of Covid-19 related clinical outcomes. METHODS: A retrospective study was conducted among 244 patients with BD (86.1% females; mean age 43.95±11.11 years). Each participant completed an online questionnaire regarding demographics, medical conditions, dispensed colchicine, TNFi or oral glucocorticoids, Covid-19 infection, clinical symptoms and recovery. RESULTS: The prevalence of Covid-19 infection was 14.75%. Regarding dose of colchicine, the presence of ageusia was lower in patients taking 0.5mg/day of colchicine compared to those taking 1.5mg/day (p=0.021). The prevalence of dyspnea was significantly higher in patients taking TNFi compared with those without therapy (p=0.032). With regards to oral glucocorticoids, no significant differences were found. CONCLUSIONS: The prevalence of Covid-19 among patients with BD seems to be higher than that among the general population in Spain. Continuous TNFi therapy might increase the prevalence of worse clinical outcomes such as dyspnea; oral glucocorticoids and colchicine apparently provided no protection against the Covid-19 related clinical outcomes of patients with BD.

BAFF, APRIL and BAFFR on the pathogenesis of Immunoglobulin-A vasculitis.

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 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.

The presence of both HLA-DRB1*04:01 and HLA-B*15:01 increases the susceptibility to cranial and extracranial giant cell arteritis.

OBJECTIVES: To determine if patients with the predominant extracranial large-vessel-vasculitis (LVV) pattern of giant cell arteritis (GCA) have a distinctive HLA-B association, different from that reported in biopsy-proven cranial GCA patients. In a further step we assessed if the combination of HLA-B and HLA-DRB1 alleles confers an increased risk for GCA susceptibility, either for the cranial and extracranial LVV phenotypes. METHODS: A total of 184 patients with biopsy-proven cranial GCA, 105 with LVV-GCA and 486 healthy controls were included in our study. We compared HLA-B phenotype frequencies between the three groups. RESULTS: HLA-B*15 phenotype was significantly increased in patients with classic cranial GCA compared to controls (14.7% versus 5.8%, respectively; p<0.01; OR [95% CI] =2.81 [1.54-5.11]). It was mainly due to the HLA-B*15:01 allele (12.5% versus 4.0%, respectively; p<0.01; OR [95% CI] =3.51 [1.77-6.99]) and remained statistically significant after Bonferroni correction. Similar HLA-B*15 association was observed in patients with the LVV-GCA (11.4% versus 5.8%, p=0.04, OR [95% CI] =2.11 [1.04-4.30]). This association was also mainly due to the HLA-B*15:01 allele (10.5% versus 4.0%, respectively; p=0.0054; OR [95% CI] =2.88 [1.19-6.59]). Noteworthy, the presence of HLA-B*15:01 together with HLA-DRB1*04:01 led to an increased risk of developing both cranial and extracranial LVV-GCA. CONCLUSIONS: Susceptibility to GCA is strongly related to the HLA region, regardless of the clinical phenotype of expression of the disease.

HLA association with the susceptibility to anti-synthetase syndrome.

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.

Spanish scleroderma risk score (RESCLESCORE) to predict 15-year all-cause mortality in scleroderma patients at the time of diagnosis based on the RESCLE cohort: Derivation and internal validation.

A few scores predicting the short-term risk of mortality in Systemic sclerosis (SSc) have been reported to date. Our study aimed to create a predictive 15-year all-cause mortality score at the time of the diagnosis of SSc. The study was based on the Spanish Scleroderma Registry (RESCLE). The cohort was split up in derivation (DC) and validation cohort (VC). A multivariate analysis to detect variables related to all-cause mortality within the first 15 years from SSc diagnosis was performed, assigning points to the rounded beta values to create the score (RESCLESCORE). 1935 SSc patients were included. The variables in the final model were as follows: age at diagnosis (+2 points > 65 years-old), male gender (+1 point), lcSSc subset (-1 point), mode of onset other than Raynaud's (+1 point), cancer (+1 point) and visceral involvement, such as ILD (+1 point), PAH (+1 point), heart (+1 point) and renal involvement (+2 points). Autoantibodies did not achieve statistical significance in the multivariate analysis. The 3 categories of risk to predict 15-year all-cause mortality at the time of diagnosis were as follows: low risk (5% vs. 7%, p = .189), intermediate risk (26.5% vs. 25.5%, p = .911) and high risk (47.8% vs. 59%, p = .316). The AUC was 0.799 (DC) vs. 0.778 (VC) (p = .530). In conclusion, the RESCLESCORE demonstrated an excellent ability to categorize SSc patients at the time of diagnosis in separate 15-year all-cause mortality risk strata at the time of diagnosis.

A cross-disease meta-GWAS identifies four new susceptibility loci shared between systemic sclerosis and Crohn's disease.

Genome-wide association studies (GWASs) have identified a number of genetic risk loci associated with systemic sclerosis (SSc) and Crohn's disease (CD), some of which confer susceptibility to both diseases. In order to identify new risk loci shared between these two immune-mediated disorders, we performed a cross-disease meta-analysis including GWAS data from 5,734 SSc patients, 4,588 CD patients and 14,568 controls of European origin. We identified 4 new loci shared between SSc and CD, IL12RB2, IRF1/SLC22A5, STAT3 and an intergenic locus at 6p21.31. Pleiotropic variants within these loci showed opposite allelic effects in the two analysed diseases and all of them showed a significant effect on gene expression. In addition, an enrichment in the IL-12 family and type I interferon signaling pathways was observed among the set of SSc-CD common genetic risk loci. In conclusion, through the first cross-disease meta-analysis of SSc and CD, we identified genetic variants with pleiotropic effects on two clinically distinct immune-mediated disorders. The fact that all these pleiotropic SNPs have opposite allelic effects in SSc and CD reveals the complexity of the molecular mechanisms by which polymorphisms affect diseases.

Role of fibroblast growth factor-23 in calcinosis in women with systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is a complex disorder of unknown etiology. The purpose of this study was to evaluate fibroblast growth factor-23 (FGF-23) serum levels in women with SSc compared with healthy controls and to examine a possible association between FGF-23 serum levels with the presence of calcinosis in SSc patients. METHODS: This cross-sectional study was performed in San Cecilio Hospital, Granada (Spain) from November 2017 to May 2019. Sixty-two women with SSc and 62 age and sex matched healthy controls were included in this study. FGF-23 serum concentration was evaluated by indirect enzyme-linked immunosorbent assay (ELISA). RESULTS: There was no significant difference in FGF-23 levels between SSc patients and healthy controls (78.2 ± 60.5 vs. 80.3 ± 56.3 pg/mL, p= 0.662). Regarding the characteristics of the disease, we found a relationship between the values of FGF-23 and the presence of calcinosis. The levels of FGF-23 are higher in patients suffering from calcinosis (p= 0.028). CONCLUSION: We observed the presence of higher levels of serum FGF-23 in SSc female patients with calcinosis. Therefore, FGF-23 could be a possible therapeutic target for future treatments.

FGF23-Klotho axis in patients with rheumatoid arthritis.

OBJECTIVES: We aimed to compare serum Klotho and fibroblast growth factor-23 (FGF-23) levels between rheumatoid arthritis (RA) patients and healthy controls. Possible association between FGF-23 and soluble Klotho with different characteristic of the disease as well as their potential role as surrogate markers of cardiovascular disease (CVD) were studied. METHODS: Sixty-three patients with RA recruited at Vega-Baja Hospital, Orihuela (Spain) from November 2016 to May 2018 and sixty-five age- and sex-matched healthy controls were included in this study. Serum Klotho and FGF-23 were analysed using ELISA. RESULTS: Patients had higher serum levels of Klotho than healthy controls (p˂0.0001). They were positively associated with the presence of anticitrullinated peptide antibody and rheumatic factor (p<0.05). Klotho serum levels were higher in RA patients treated with biologic agents than in those undergoing conventional therapy (p=0.008). However, no association with carotid intima media thickness was found. Although no significant differences in serum FGF-23 levels between patients and controls were found (p=0.43), FGF-23 levels were positively associated with low-density lipoprotein (LDL-c) level (p<0.05) and smoking (p=0.008) in patients with RA. CONCLUSIONS: The increased serum Klotho levels in RA patients, especially in those undergoing biologic therapy, may indicate a potential implication in the pathogenesis of the disease. Although levels of FGF-23 were related to LDL-c levels, the FGF-23-Klotho axis does not seem to be related to subclinical arteriosclerosis in RA.