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Introduction Endothelin antagonist receptors (ERAs) and phosphodiesterase-5 inhibitors (PDE5i) are beneficial in pulmonary arterial hypertension (PAH) and digital ulcers (DU) and prevent from DU recurrences. Our study aimed to determine the difference in the incidence rate of PAH and scleroderma renal crisis (SRC) in patients with SSc and DU (SSc-DU) under ERAs/PDE5i or without treatment. Methods We conducted a retrospective cohort study including SSc-DU patients from the Spanish Scleroderma Registry (RESCLE). The primary outcome was the incidence rate of PAH and SRC in patients under ERAs/PDE5i or not. Results Some 544 patients out of 1817 (29.9%) in the RESCLE database had DU, 221 (40.6%) under ERAs/PDE5i and 323 (59.4%) not. The incidence rate (95% CI) difference between patients under treatment or not under did not reach statistical significance in PAH [−0.1 (−4.8, 4.69), P = 0.988] or in SRC [0.7 (−2.2, 3.7), P = 0.620]. However, the time from the first DU to the diagnosis of SRC was delayed in treated patients [mean (s.d.) 7.6 (5.8) years vs 2.9 (5.3); P = 0.021]. The dcSSc subset was more prevalent in the treatment group (36 vs 26%; P = 0.018), along with anti-topoisomerase I antibodies (34 vs 18%; P Conclusion There was no difference in the incidence rate of PAH and SRC between groups. However, treatment with ERAs and/or PDE5i appeared to delay the occurrence of SRC.

Primary biliary cirrhosis (PBC) is associated to any systemic autoimmune disease (SAD), in particular systemic sclerosis (SSc). To investigate the prevalence of SAD in a cohort of patients with PBC, specifically the prevalence of SSc and its clinical subtypes, and determining the clinical and biological profile of patients with associated PBC and SSc.Observational study of 62 patients with PBC following a protocol that included an anamnesis and physical examination to detect the presence of SAD as well as a nailfold capillaroscopy and an immunological study with specific SSc autoantibodies. A comparative analysis was conducted between patients with isolated PBC and patients with PBC and an associated SAD.SAD was associated to PBC in 22 patients (35,4%), and SSc was the most frequent illness, identified in 13 cases (21%). Five patients (8%) without previous diagnosis of SAD fulfilled pre-scleroderma criteria, according to LeRoy and Medsger criteria. The presence of anticentromere antibodies (54,5% vs. 5%, P.001) was the unique immunological determination identified more frequently in patients with PBC-SAD. The SSc suggestive capillary pattern was visualized in 11 patients (20,4%), mainly the slow pattern. No factors associated with greater morbi-mortality were identified in the PBC-SAD group.It does exist a subgroup of patients with PBC and clinical-biological features suggestive of an SAD, which advise a protocolized study to detect early the association to an SAD.

Background:Prior literature shows a global increase of cancer risk among patients with systemic sclerosis (SSc). Although breast cancer (BC) is one of the most frequent malignancies in SSc patients, the characteristics of this neoplasm among SSc patients is not well established and it is uncertain whether SSc significantly increases the risk of this cancer.Objectives:Describe the characteristics and risk factors for BC among Spanish patients with SSc.Methods:Ambispective and multicenter study of patients with a diagnosis of SSc according to ACR/EULAR criteria and/or LeRoy classification included in the Spanish Scleroderma Registry (RESCLE) from 2006 to 2018. Characteristics of patients with BC were described and incidence was compared with that of the general population.Results:Among 1930 patients with SSc, 206 (10.7%) had cancer. BC was the most frequent tumor location (47 patients of 206 with cancer [22.8%]), followed by lung cancer (29, 14.1%). The risk of BC was increased in patients with SSc compared to the general population (standardized incidence ratio [SIR] 1.31; 95% CI 1.10-1.54;P= 0.003).The comparison of patients with BC and those without cancer showed that patients with BC had older age at diagnosis of SSc (50.9 vs 45.9 years, respectively;P=0.004), were more frequently diagnosed of interstitial lung disease (ILD) (30/47 [63.8%] vs 694/1714 [40.5];P= 0.002) and pulmonary hypertension (12/24 [50.0%] vs 262/917 [28.6%];P= 0.037), had higher frequency of puffy hands as the first manifestation of SSc (4/45 [8.9%] vs 38/1664 [2.3 %];P= 0.023) and had more frequently primary biliary colangitis (PBC) (7 /46 [15.2%] vs 72 /1708 [4.2%];P= 0.004). Regarding autoimmunity profile, patients with SSc and BC had a significantly higher presence of anti-Ro (11/44 [25.0%] vs 214/1528 [14.0%];P= 0.049) and anti-mitochondrial antibodies (7/28 [25.0%] vs 96/837 [11.5%];P= 0.039). Multivariable regression analysis showed an independent association between the puffy hands (OR = 6.40; 95% CI 1.73-23.60;P= 0.005), diagnosis of PBC (OR = 5.70; 95% CI 2.16-15.07;P= 0.001), presence of ILD (OR = 3.29, 95% CI 1.69-6.39;PP= 0.048) with the presence of BC.Conclusion:BC risk was increased in patients with SSc. The development of ILD, PBC, the presence of anti Ro and puffy hands as the first clinical manifestation of SSc were identified as independent factors associated with the development of BC in our cohort.References:Colaci M et al. Breast cancer in systemic sclerosis: results of a cross-linkage of an Italian Rheumatologic Center and a population-based Cancer Registry and review of the literaure. Autoimmun Rev. 2014;13(2):132-7.Zhang JQ et al. The risk of cancer development in systemic sclerosis: a meta-analysis. Cancer Epidemiol. 2013;37(5):523-7.Disclosure of Interests:Cristina Carbonell: None declared, Antonio-J Chamorro: None declared, Miguel Marcos: None declared, Alfredo Guillén del Castillo: None declared, Dolores Colunga Argüelles Consultant of: Actelion pharmaceuticals, GSK, MSD., Manuel Rubio-Rivas: None declared, Ana Argibay: None declared, Begoña Marí-Alfonso: None declared, Adela Marín Ballvé: None declared, Antoni Castro Consultant of: Actelion pharmaceuticals, GSK, MSD., Ana Belén Madroñero-Vuelta: None declared, Eduardo L. Callejas-Moraga: None declared, Vicent Fonollosa-Pla Consultant of: Actelion pharmaceuticals, GSK, MSD., Carmen Pilar Simeón-Aznar Consultant of: Actelion pharmaceuticals, GSK, MSD., on behalf of RESCLE Investigators, Autoimmune Diseases Study Group (GEAS): None declared

Background Monotherapy with endotelin antagonist receptors (ERA) an phosphodiesterase 5 (PDE5) inhibitors is a first choice treatment for PAH in functional class (FC) II-III, with the same grade of evidence and recommendation than combination therapy. Recently, studies have proven superiority of combination therapy against monotherapy in combined morbi-mortaliy endpoints. Objectives To demonstrate superiority of combination therapy against monotherapy in a single mortality endpoint in SSc-associated PAH. Methods Retrospective cohort study including patients from the Spanish Scleroderma Registry (RESCLE) diagnosed with SSc-associated-PAH by right heart catheterization (RHC). Patients were divided in 3 groups: monotherapy vs. sequential combination therapy (>12 weeks between first and second treatment) vs. upfront combination therapy ( Results Seventy-six patients with PAH out of 1817 participants were included. Thirty-four (45%)were receiving monotherapy [with ERA (22 patients, 29%) or PDE5 inhibitors (12 patients, 16%)], 25 patients (33%) sequential combination therapy and 17 patients (22%) upfront combination therapy. Baseline demographic, clinical and complementary tests were similar among groups. ILD (mainly moderate) was more frequent in both combination groups in 58% vs. 80% vs. 76.4%, without statistical significance. A worse FVC/DLco in the sequential combination group was reported (2.9±1.1 vs. 1.8±0.4 vs.2.3±0.8, global p=0.085 but p=0.043 comparing monotherapy with sequential combination) and also a worse mPAP in both sequential and upfront combination groups(37.2±8.7 mmHg vs. 40.8±8.8 vs. 46±15.9, p=0.026). The treatment regimen prescribed (p=0.017) and FC at baseline (p=0.007) were found predictors of mortality. Sequential combination therapy was found a protective factor [HR=0.11 (95%CI 0.03–0.51), p=0.004] and the upfront combination therapy showed a tendency of protection [HR=0.68 (95%CI 0.23–1.97), p=0.476]. Survival rates from diagnosis of PAH among groups were: 78% vs. 95.8% vs. 94.1% at 1 year, 40.7% vs. 81.5% vs. 51.8% at 3 years and 31.6% vs. 56.5% vs. 34.5% at 5 years (p=0.007). Side effects were not significantly different among groups. Conclusions Combined sequential therapy improves survival in SSc-PAH patients, even wtih moderate ILD. Upfront combination therapy may improve survival, but did not reach statistical significants due to study limitations. Treatment regimen and FC were found as prognostic factors for survival: sequential combination therapy was a protective factor and FC was a risk factor. Disclosure of Interest None declared

Objetive To assess the prevalence and causes of hepatobiliary involvement (HBI) in systemic sclerosis (SSc), to investigate the clinical characteristics and prognosis of SSc patients with HBI (SSc-HBI) and without HBI (SSc-non HBI), and to compare both groups according to the cutaneous SSc subsets. Methods 1572 SSc patients were collected in the RESCLE registry up to January 2015, and all hepatobiliary disturbances were recorded. We investigated the HBI related characteristics and survival from the entire SSc cohort and according to the following cutaneous subsets: diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc), and SSc sine scleroderma (ssSSc). Results Out of 1572, 118 (7.5%) patients had HBI. Primary biliary cholangitis (PBC) was largely the main cause (n = 67, 4.3%), followed by autoimmune hepatitis (n = 19, 1.2%), and anti-mitochondrial negative PBC (n = 6, 0.4%). Other causes of HBI were: secondary liver diseases (n = 11, 0.7%), SSc-related HBI (n = 7, 0.4%), nodular regenerative hyperplasia (n = 3, 0.2%), liver cirrhosis (n = 3, 0.2%), and HBI of unknown origin (n = 2, 0.1%). In multivariate analysis, HBI was independently associated to lesser risk of dcSSc (5.1% vs. 24.4%), and higher frequency of calcinosis (26% vs. 18%), left ventricular diastolic dysfunction (46% vs. 27%), sicca syndrome (51% vs. 29%), and anti-centromere antibodies (ACA, 73% vs. 44%). According to the cutaneous subsets, HBI was associated: (1) in lcSSc, to longer time from SSc onset to diagnosis (10.8±12.5 vs. 7.2±9.3 years), sicca syndrome (54% vs. 33%), and ACA (80% vs. 56%); (2) in ssSSc, to sicca syndrome (44% vs. 19%), and (3) in dcSSc, no associations were found. HBI was the cause of death in 2.3% patients but the cumulative survival according to the presence or absence of HBI showed no differences. Conclusions HBI prevalence in SSc is 7.5% and dcSSc is the least involved subset. PBC is the main cause of HBI. Patients with SSc-HBI exhibited specific clinical and immunologic profile. Survival is similar for SSc patients with HBI.

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analyzed in 2,134 case subjects and 9,125 unaffected individuals from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, p = 1.94 × 10−54, per-allele OR = 1.79; and rs9275592, p = 1.14 × 10−40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, p = 1.23 × 10−10, OR = 1.28; and rs128738, p = 4.60 × 10−9, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis.

Objective Digital ulcers (DU) are the most common vascular complication of systemic sclerosis (SSc). We compared the characteristics between patients with prior or current DU with those never affected and evaluated whether a history of DU may be a predictor of vascular, organ involvement, and/or death in patients with SSc. Methods Data from SSc patients with or without prior or current DU were collected by 19 referral centers in an ongoing registry of Spanish SSc patients, named Registro de ESCLErodermia (RESCLE). Demographics, organ involvement, autoimmunity features, nailfold capillary pattern, survival time, and causes of death were analyzed to identify DU related characteristics and survival of the entire series and according to the following cutaneous subsets—diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc), and SSc sine scleroderma (ssSSc). Results Out of 1326, 552 patients enrolled in the RESCLE registry had prior or current DU, 88% were women, the mean age was 50 ± 16 years, and the mean disease duration from first SSc symptom was 7.6 ± 9.6 years. Many significant differences were observed in the univariate analysis between patients with and without prior/current DU. Multivariate analysis identified that history of prior/current DU in patients with SSc was independently associated to younger age at SSc diagnosis, diffuse cutaneous SSc, peripheral vascular manifestations such Raynaud's phenomenon, telangiectasia, and acro-osteolysis but no other vascular features such as pulmonary arterial hypertension or scleroderma renal crisis. DU was also associated to calcinosis cutis, interstitial lung disease, as well as worse survival. Multivariate analysis performed in the cutaneous subsets showed that prior/current DU were independently associated: (1) in dcSSc, to younger age at SSc diagnosis, presence of telangiectasia and calcinosis and rarely a non-SSc pattern on nailfold capillaroscopy; (2) in lcSSc, to younger age at SSc diagnosis, presence of Raynaud's phenomenon as well as calcinosis cutis, interstitial lung disease, and higher incidence of death from all causes; and (3) in ssSSc, to younger age at first SSc symptom and greater incidence of death from all causes. Conclusions Digital ulcers develop in patients with SSc younger at diagnosis, mainly in patients with dcSSc and lcSSc, and they are associated to other peripheral vascular manifestations such as Raynaud's phenomenon, telangiectasia, and acro-osteolysis but also to calcinosis, and interstitial lung disease. History of DU in SSc leads to worse survival, also noticeable for lcSSc and ssSSc subsets but not for dcSSc patients.

Recent studies have focused attention on the involvement of NLRP1 to confer susceptibility for extended autoimmune/inflammatory disorders, being considered a common risk factor in autoimmunity.1–3 NLRP1 provides a scaffold for the assembly of the inflammasome that activates caspases 1 and 5, required for processing and activation of the proinflammatory cytokines interleukin 1β (IL-1β), IL-18 and IL-33 and promoting inflammation.4 In this study, we examined for the first time whether NLRP1 is associated with giant cell arteritis (GCA), a chronic systemic vasculitis affecting large and medium-sized arteries derived from the aorta, in particular the cranial branches of the carotid artery. GCA is the most common vasculitis in the elderly in Western countries with a female predominance.5 To investigate the possible genetic association of NLRP1 with this disease, we genotyped a single-nucleotide polymorphism (rs8182352), which has been reported to confer risk to the development of autoimmune processes in previous studies,1 ,2 in a total of 3583 individuals, comprising a discovery set from Spain (574 patients diagnosed with biopsy-proven GCA and 2366 healthy controls) and a replication set of subjects from Italy (111 biopsy-proven GCA patients and 532 controls) using a predesigned TaqMan allele discrimination assay. All individuals were of …

The novel antipsychotic olanzapine has structural and pharmacological properties similar to clozapine. Until recently, no haematological toxicity has been reported with olanzapine use and it was expected to be a safer alternative. The authors report a case of agranulocytosis induced by olanzapine and reviewed the 11 cases reported in the literature.

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 (PFDR=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 (PMH=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.

Objective. To investigate whether a functional integrin alpha M (ITGAM) variant is involved in susceptibility to and clinical manifestations of giant cell arteritis (GCA). Methods. A Spanish cohort of 437 white patients with biopsy-proven GCA and 1388 healthy controls were genotyped using the TaqMan allele discrimination technology. Results. No association was observed between ITGAM rs1143679 and GCA (p = 0.80, OR 0.97). Similarly, subphenotype analyses did not yield significant differences between the case subgroups and the control set or between GCA patients with or without the main specific features of GCA. Conclusion. Our results suggest that the ITGAM rs1143679 variant does not play an important role in the pathophysiology of GCA. The Journal of Rheumatology Copyright © 2011. All rights reserved.

Introducción: Descripción de las características epidemiológicas, clínicas, respuesta al tratamiento y complicaciones de una serie de 55 pacientes con arteritis de células gigantes(ACG) confirmada por biopsia en un hospital comarcal. Material y métodos: Estudio retrospectivo de los pacientes diagnosticados de ACG por biopsia de arteria temporal en el periodo comprendido entre 1989 y 2001 en nuestro centro. Resultados: La incidencia anual aproximada calculada en nuestra área sería de 4,1 casos por 100.000 habitantes mayor de 50 años. La edad media al diagnóstico fue de 74 años y un 78,2% eran mujeres. El síntoma más frecuente al diagnóstico fue la cefalea (81,5%), seguido de las manifestaciones sistémicas (74,1%), a más distancia se encontraba la claudicación mandibular (32,7%), trastornos visuales (30,2%), manifestaciones isquémicas (17%). La polimialgia reumática se asoció a ACG en el 49,1%. La palpación de arteria temporal fue anormal en el 76,9% de los pacientes. La dosis media de inicio de tratamiento fue de 69 mg prednisona /dia, con una media de tiempo de reducción a mitad de dosis fue de 3,5 meses. Un 24,1% de los pacientes presentaron un rebrote durante el primer año. Un 38% de los pacientes presentaron complicaciones durante el tratamiento corticoideo. La VSG fue inferior a 50 mm en el 12,7% de los pacientes, existía anemia en el 37,7% y trombocitosis en el 32,1%. En estos últimos se detectó una tendencia a la relación con presencia de alteraciones visuales específicas. Conclusiones: La incidencia de ACG en nuestra área estaría dentro de las zonas de baja incidencia. Los resultados de nuestra serie no difieren de otras descritas previamente en la literatura en cuanto a las manifestaciones clínicas de los pacientes, existe un claro predominio del sexo femenino y se detecta una tendencia a la relación de alteraciones visuales específicas con presencia de trombocitosis.

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

Background CD226 genetic variants have been associated with a number of autoimmune diseases. Objectives The aim of this study was to investigate the potential implication of the CD226 loci in the susceptibility to and main clinical manifestations of giant cell arteritis (GCA). Methods A Spanish Caucasian cohort of 455 patients diagnosed with biopsy-proven GCA and 1414 healthy controls were included in the study. Three CD226 polymorphisms, rs727088, rs34794968 and rs763361, were genotyped using the TaqMan® allelic discrimination technology. PLINK software was used for the statistical analyses. Results No significant association between the CD226 polymorphisms and susceptibility to GCA was found (rs727088: P =0.92, OR=1.01 CI 95% 0.86-1.18; rs34794968: P =0.61, OR=1.04 CI 95% 0.89-1.22; rs763361: P =0.88, OR=0.99 CI 95% 0.84-1.16). Similarly, when patients were stratified according to the specific clinical features of GCA such as polymyalgia rheumatica, visual ischemic manifestations or irreversible occlusive disease, no association was observed either between the case subgroups and the control set or between GCA patients with and without the specific features of the disease. Furthermore, the haplotype analysis revealed no significant association with the disease. Conclusions Our results show that the CD226 gene does not play a relevant role in the susceptibility to GCA and clinical manifestations of this vasculitis. References Hafler JP, Maier LM, Cooper JD, Plagnol V, Hinks A, Simmonds MJ, et al. CD226 Gly307Ser association with multiple autoimmune diseases. Genes Immun. 2009; 10:5-10. Lofgren SE, Delgado-Vega AM, Gallant CJ, Sanchez E, Frostegard J, Truedsson L, et al. A 3’-untranslated region variant is associated with impaired expression of CD226 in T and natural killer T cells and is associated with susceptibility to systemic lupus erythematosus. Arthritis Rheum. 2010; 62:3404-3414. Salvarani C, Cantini F, Boiardi L, Hunder GG. Polymyalgia rheumatica and giant-cell arteritis. N Engl J Med. 2002; 347:261-271. Gonzalez-Gay MA, Vazquez-Rodriguez TR, Lopez-Diaz MJ, Miranda-Filloy JA, Gonzalez-Juanatey C, Martin J, et al. Epidemiology of giant cell arteritis and polymyalgia rheumatica. Arthritis Rheum. 2009; 61:1454-1461. Disclosure of Interest None Declared