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The objective of the study is to determine the importance of the mode of onset as prognostic factor in systemic sclerosis (SSc). Data were collected from the Spanish Scleroderma Registry (RESCLE), a nationwide retrospective multicenter database created in 2006. As first symptom, we included Raynaud's phenomenon (RP), cutaneous sclerosis, arthralgia/arthritis, puffy hands, interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), and digestive hypomotility. A total of 1625 patients were recruited. One thousand three hundred forty-two patients (83%) presented with RP as first symptom and 283 patients (17%) did not. Survival from first symptom in those patients with RP mode of onset was higher at any time than those with onset as non-Raynaud's phenomenon: 97 vs. 90% at 5 years, 93 vs. 82% at 10 years, 83 vs. 62% at 20 years, and 71 vs. 50% at 30 years (p < 0.001). In multivariate analysis, factors related to mortality were older age at onset, male gender, dcSSc subset, ILD, PAH, scleroderma renal crisis (SRC), heart involvement, and the mode of onset with non-Raynaud's phenomenon, especially in the form of puffy hands or pulmonary involvement. The mode of onset should be considered an independent prognostic factor in systemic sclerosis and, in particular, patients who initially present with non-Raynaud's phenomenon may be considered of poor prognosis.

Objectives According to the existence of subclinical organ involvement pre-scleroderma should be divided into two subsets: very early and early disease. Pre-scleroderma patients included in the Spanish Scleroderma Registry (RESCLE) Cohort were reclassified into subsets. Differences were evaluated and the risk of progression to definite systemic sclerosis was estimated. Methods The characteristics of very early and early SSc patients were compared. A logistic regression model was used to determine the risk factors of progression. Results 1632 patients were included, 36 (2.2%) in the very early subset and 111 (6.8%) in the early subset. There were no differences in sex, age at disease onset, duration of Raynaud's phenomenon, antinuclear antibodies or capillaroscopic findings. Three (8.3%) very early SSc patients evolved to definite SSc, 2 (5.6%) of them meeting the ACR/EULAR 2013 criteria, unlike 31 (28%) early SSc patients, 20 (24%) of them meeting the criteria ( p = 0.034). Digestive involvement was an independent risk factor of progression (OR 17; 95% CI, 6.1–47.2). Conclusions The classification of early forms of scleroderma identifies patients with different prognostic risk of progression. The evolution to definite SSc is more frequent in early than in very early SSc patients. Digestive involvement is a risk factor of progression. An active assessment of organ damage in preclinical stages allows a correct classification and risk stratification, with implications for monitoring and treatment.

Resumen Fundamento y objetivo La hipertension arterial pulmonar (HAP) es causa importante de morbimortalidad en la esclerosis sistemica (ES). Su evolucion es peor que en la HAP idiopatica, pero el pronostico mejora si se diagnostica precozmente. El objetivo de este trabajo es describir el resultado de un programa de cribado para el diagnostico de hipertension pulmonar (HP) desarrollado en una cohorte de pacientes espanoles con ES. Pacientes y metodo Se realizo cribado de HP mediante ecocardiografia-doppler transtoracica (EDTT) en 184 pacientes con ES. Los pacientes con valor de presion arterial pulmonar sistolica estimada por EDTT > 35 mmHg se evaluaron de forma protocolizada para establecer o no el diagnostico de certeza de HP y su tipo. Resultados Se diagnostico HAP en 25 pacientes (13,6%). Los pacientes con ES difusa y limitada desarrollaron HAP en proporciones semejantes: 9 de 60 (15%) frente a 16 de 100 (16%). No se registraron casos entre pacientes con ES «sine esclerodermia» o «preesclerodermia» (p Conclusiones La prevalencia de HAP en ES resulto elevada y apoya la implantacion de programas de cribado sistematico.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the production of antinuclear autoantibodies. In addition, the involvement of CD4+ T-helper (Th) cells in SLE has become increasingly evident. Although the role of melatonin has been tested in some experimental models of lupus with inconclusive results, there are no studies evaluating the melatonin effect on cells from patients with SLE. Therefore, the aim of this study was to analyse the role of in vitro administered melatonin in the immune response of peripheral leukocytes from treated patients with SLE (n = 20) and age- and sex-matched healthy controls. Melatonin was tested for its effect on the production of key Th1, Th2, Th9, Th17 and innate cytokines. The frequency of T regulatory (Treg) cells and the expression of FOXP3 and BAFF were also explored. Our results are the first to show that melatonin decreased the production of IL-5 and to describe the novel role of melatonin in IL-9 production by human circulating cells. Additionally, we highlighted a two-faceted melatonin effect. Although it acted as a prototypical anti-inflammatory compound, reducing exacerbated Th1 and innate responses in PHA-stimulated cells from healthy subjects, it caused the opposite actions in immune-depressed cells from patients with SLE. Melatonin also increased the number of Treg cells expressing FOXP3 and offset BAFF overexpression in SLE patient cells. These findings open a new field of research in lupus that could lead to the use of melatonin as treatment or cotreatment for SLE.

Aim To determine if there are ethnic differences in the prevalence of antiphospholipid syndrome (APS), clinical presentation and autoantibody profile between Roma and Caucasian patients with systemic lupus erythematosus (SLE). Method A cross-sectional study was conducted including data from Roma and Caucasian SLE patients consecutively attending six hospitals in Spain. Socio-demographic characteristics, prevalence of APS, clinical and analytical features of SLE and APS were compared between ethnic groups. Results Data from 52 Roma and 98 Caucasian SLE patients were included. Roma SLE patients had a higher risk (odds ratio 2.56, 95% CI 1.02–6.39) and prevalence of APS (28.8% vs. 13.3%, P = 0.027). Furthermore, Roma SLE patients had a statistically significant higher prevalence of abortions (23.5% vs. 10.2%, P = 0.049). In relation to other APS diagnostic criteria, Roma SLE patients had a non-statistically significant higher prevalence of fetal deaths (14.3% vs. 5.1%, P = 0.106) and thrombotic events (21.1% vs. 12.2%, P = 0.160). In relation to SLE clinical features, Roma patients had a significantly higher prevalence of arthritis (75% vs. 57.1%, P = 0.034) and non-significant higher prevalence of serositis (44.2% vs. 29.6%, P = 0.104), discoid lesions (11.5% vs. 5.1%, P = 0.191), oral ulcers (46.1% vs. 34.7%, P = 0.218) and livedo reticularis (21.1% vs. 15.3%, P = 0.374). No statistically significant differences were found in the Systemic Lupus International Collaborating Clinics Damage Index or the autoimmune serological profile. Conclusion Prevalence and risk of APS were significantly higher in Roma SLE patients. Furthermore, Roma patients had a significantly higher prevalence of abortions and a non-significant higher prevalence of fetal deaths and thrombotic events.

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.

To investigate the incidence of clinical and immunological characteristics of a large cohort of Spanish patients with scleroderma (SSc) and identifying factors associated with particular organ manifestations assessed by a nationwide cross-sectional analysis.We classified SSc patients in 4 subsets using a modification of LeRoy and Medsger classification that included: "prescleroderma" (pre-SSc), limited cutaneous SSc (lcSSc), diffuse cutaneous SSc (dcSSc), and SSc sine scleroderma (ssSSc). Fourteen Spanish centers participated in patient recruitment. On January 2008, the database included 916 consecutive Spanish SSc patients, 801 women (87.4%) and 115 men (12.6%), all of whom fulfilled the classification criteria proposed by LeRoy and Medsger. Epidemiological, clinical, and laboratory data were collected according to a standard protocol. Mean age at diagnosis was 51.2 ± 15.1 years and mean age at disease onset was 44.9.0 ± 15.8 years. lcSSc was the most frequent subset (61.8%) followed by dcSSc (26.5%), ssSSc (7.5%), and preSSc (4%) subsets. Gender ratios were as follows: dcSSc subset, 200 women and 43 men (4.7:1); lcSSc subset, 503 women and 63 men (ratio 7.9:1), and ssSSc subset, 62 women and 7 men (ratio 8.9:1). Digital ulcers, interstitial lung disease (ILD), musculoeskeletal and esophageal involvement, and scleroderma renal crisis were more frequent in dcSSc than lcSSc and ssSSc subsets. The incidence of pulmonary arterial hypertension assessed by echocardiography was similar in all subsets but mean estimated systolic pulmonary arterial pressure was higher in ssSSc than in lcSSc subset (47.3 ± 23.9 mm Hg vs 39.6 ± 19.2 mm Hg; P0.03). Cardiac involvement was identified more frequently in ssSSc than in dcSSc and lcSSc subsets (49.3% vs 32.5% and 31.1%, respectively; P = 0.015 and P = 0.004 for both comparisons). Acro-osteolysis (8.2% vs 2.4%, P = 0.049), calcinosis (19.8% vs 7.2%, P0.05), and sicca syndrome (37.5% vs 14.5%, P0.0001) were more frequent in lcSSc than in ssSSc subsets. The frequency of clinical manifestations related to the presence of anticentromere antibodies or antitopoisomerase I antibodies was very similar to that identified in patients categorized to lcSSc and dcSSc, respectively. However, in multivariate studies, the ranking of the variables according to their overall explanatory effect on the model showed that the contributory effect of the antibody status was not greater than that of the clinical categorization into lcSSc and dcSSc for the majority of disease manifestations, but, in important manifestations, as ILD, absence of anticentromere antibodies was an independent predictor factor.The classification of SSc into dcSSc, lcSSc, and ssSSc subsets is the one that most closely reflects the natural history of the disease, as they presented clear clinical differences. The immunological profile helps to define important visceral alteration as ILD. Finally, to improve early diagnosis of SSc, patients with preSSc should be considered both to trace the true evolution of the disease and to define which patients could benefit from therapeutic measures able to prevent the appearance of visceral involvements.

A pulmonary hypertension (PH) registry (Spanish Registry of Pulmonary Arterial Hypertension) was undertaken to analyse prevalence, incidence and survival of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) in Spain, and to assess the applicability of recent survival prediction equations. Voluntary reporting of previously diagnosed and incident PAH or CTEPH cases (July 2007-June 2008) was performed. Demographic, functional and haemodynamic variables were evaluated. 866 patients with PAH and 162 with CTEPH were included. PAH associated with toxic oil syndrome and pulmonary veno-occlusive disease were reported for the first time in a PAH registry. Estimated prevalences were as follows: PAH, 16 and CTEPH, 3.2 cases per million adult inhabitants (MAI). Estimated incidences were as follows: PAH, 3.7 and CTEPH, 0.9 cases per MAI per yr. 1-, 3- and 5-yr survival was 87%, 75% and 65%, respectively, with no differences between PAH and CTEPH. Male sex, right atrial pressure and cardiac index were independent predictors of death. Matching between observed survival and that predicted by different equations was closer when the characteristics of the cohorts were similar. Epidemiology and survival of PAH patients in the Spanish registry are similar to recent registries. Characteristics of the population from which survival prediction equations are derived influence their applicability to a different cohort. CTEPH is much less prevalent than PAH, although has a similar survival rate.

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.

A biological marker can be defined as any substance that can be objectively measured and evaluated as an indicator of a normal biological process, a pathogenic process or pharmacological responses to a therapeutic intervention. In pulmonary hypertension (PH), in addition to routine markers (hemodynamic and functional), there are a growing number of biomarkers that allow an increasingly comprehensive approach to knowledge of susceptibility to this disease and to diagnosis, prognosis and treatment response. These markers can be both constitutive (genetic) and disease-related (related to right ventricular failure, such as BMP/NT-proBNP, endothelial dysfunction, such as endothelin-1, or inflammation, such as certain cytokines and chemokines). Novel insights in genomics and proteomics may allow major advances in this field.

Resumen Fundamento y objetivo Comunicamos nuestra experiencia con rituximab mas ciclofosfamida en el tratamiento de pacientes con miopatia inflamatoria idiopatica refractaria. Pacientes y metodo Estudio prospectivo abierto no controlado sobre 17 pacientes. Resultados Evaluacion cumplimentada tras 1, 6 y 12 meses en el 95,2, el 85,7 y el 52,4% de los ciclos, respectivamente. Remision total o parcial tras 1, 6 y 12 meses en el 65, el 100 y el 63,6% de los ciclos evaluados, respectivamente. Deplecion absoluta de linfocitos B en sangre periferica en los 18 casos con datos disponibles, con tendencia a la normalizacion tras 6 a 12 meses. Hubo 5 recaidas; la mediana de tiempo hasta la recaida fue de 11 meses; hubo repeticion del tratamiento en 4 casos. Cuatro pacientes tenian afectacion respiratoria; uno (etiologia multifactorial) no mejoro, pero si los otros 3, con neumopatia intersticial aislada o asociada a debilidad muscular respiratoria. Hubo 5 pacientes con anticuerpos anti-Jo-1 positivos (6 ciclos), con respuesta al tratamiento superponible al resto. Se observaron escasos efectos adversos; solo cabe destacar un caso de meningitis por Corynebacterium, con buena evolucion. Conclusiones El rituximab parece una alternativa valida en el tratamiento de pacientes con polimiositis o dermatomiositis resistentes.

Resumen Fundamento y objetivo La patologia tiroidea (PT) es mas frecuente en pacientes con hipertension arterial pulmonar (HAP) que en la poblacion general. No estan bien establecidas la frecuencia ni la causa de esta asociacion. El objetivo de este trabajo es cuantificar y analizar la incidencia y las caracteristicas de la PT en una cohorte de pacientes con HAP (idiopatica o asociada preferentemente a enfermedades sistemicas) y realizar una revision de la literatura cientifica. Pacientes y metodo Se estudio a 58 pacientes con HAP prospectivamente segun un protocolo preestablecido (incluido cateterismo cardiaco derecho) y se determinaron la tirotropina (TSH), la tiroxina libre (T 4 l) y los anticuerpos antitiroglobulinicos y anticuerpos antiperoxidasa. Se definio la PT como alteracion de la TSH o elevacion de cualquiera de los 2 anticuerpos antitiroideos (AcAT). Se compararon las variables clinicas, biologicas y hemodinamicas entre los grupos con y sin PT. Resultados Habia PT en 30 pacientes (51%): TSH elevada en 21 (36,21%), hipertiroidismo en 2 pacientes (3,45%) y AcAT elevados en 16 de los 54 pacientes (27,59%), 7 de los cuales eran eutiroideos. En el grupo con PT el tiempo de evolucion de la HAP fue mayor (4,62 frente a 2,61 anos; intervalo de confianza [IC] del 95%: 0,63 a 3,38; p=0,005), hubo mas pacientes en clase funcional iv (13 frente a 5, el 43,3 frente al 15,8%; IC del 95%: 0,05 a 11,75; p=0,046), el gasto cardiaco fue menor (IC del 95%: 3,16 a 4,89; p=0,032) y fue mas frecuente el tratamiento con epoprostenol (14 frente a 4, el 46 frente al 14,3%; IC del 95%: 1,46 a 18,85; odds ratio de 5,25; p=0,008) que en el grupo sin PT. Conclusiones La frecuencia de PT en esta cohorte de pacientes con HAP alcanza un 51% y solo se relaciono con mayor tiempo de evolucion de la enfermedad y con peor situacion hemodinamica. Aunque el epoprostenol se utilizo mas en el grupo con PT, no puede establecerse una relacion causal con la PT.

BACKGROUND AND OBJECTIVE: To assess the value of rituximab in systemic autoimmune diseases which are refractory to others treatments. PATIENTS AND METHOD: Prospective study on 12 patients -7 with systemic lupus erythematosus (SLE), 4 with Wegener's granulomatosis (WG), and 1 with overlapping connective disease and autoimmune thrombocytopenia-, controlled in a specialized unit of a tertiary hospital. Four weekly doses of rituximab, 2 biweekly doses of cyclophosphamide, and glucocorticoids were administered to all patients, and other immunosuppressants were also administered as considered necessary in each case. RESULTS: Mean follow up after treatment with rituximab was 12.8 moths for SLE patients and 12.3 for WG patients. In SLE patients, proteinuria was reduced below 1 g daily in 5 cases (83%), with a clear parallel improvement in the urinary sediment. Serositis was resolved in both cases. One patient required 3 treatment cycles to obtain an adequate response and another required a second cycle for relapse. Only one patient with WG had a favorable response. The patient treated for autoimmune thrombocytopenia had a favorable response, with no relapses, and creatine-kinase levels also tended to return to normal. There were 2 serious adverse events (terminal renal failure and serious colitis in a patient with SLE, and death of one patient with WG), that were not adjudicated directly to rituximab. Immunoglobulin levels did not change substantially. There were no infusion reactions or associated infections. CONCLUSIONS: Rituximab was useful in patients with SLE refractory to other immunosuppressants. On the contrary, its efficacy in WG was limited. The response of thrombocytopenia was complete and maintained.

Pulmonary arterial hypertension (PAH) is an important cause of morbimortality in systemic sclerosis (SSc). Evolution is worse than that of subjects with idiopathic PAH, but prognosis improves when PAH is diagnosed early. The aim of this research is to describe results of a screening program for diagnosis of pulmonary hypertension (PH) carried out in a cohort of Spanish patients with SSc.PH screening was performed by transthoracic doppler echocardiography (TTDE) in 184 patients with SSc. Patients with systolic pulmonary arterial pressure estimated by TTDE35 mmHg were evaluated per protocol to confirm diagnosis and type of PH.PAH was diagnosed in 25 patients (13.6%). Patients with diffuse and limited SSc developed PAH in a similar degree, 9/60 (15%) vs. 16/100 (16%), with no cases among patients with SSc "sine scleroderma" or "pre-scleroderma" (P.001). The only clinical or epidemiological data characterizing patients with PAH were older age (mean age 67 years for patients with PAH vs. 56 years for those without PAH, P=.007), limited SSc, a trend toward shorter evolution of the underlying disease (median 8 years for patients with PAH vs. 10 years for those without PAH, P=.73), and a higher frequency of positive anticentromere antibodies (16 patients [64%] with PAH vs. 70 (48,3%) without PAH, P=.19).Prevalence of PAH in SSc was high and supports the implementation of a regular screening program.

Introduction According to genome wide association (GWA) studies as well as candidate gene approaches, Behçet’s disease (BD) is associated with human leukocyte antigen (HLA)-A and HLA-B gene regions. The HLA-B51 has been consistently associated with the disease, but the role of other HLA class I molecules remains controversial. Recently, variants in non-HLA genes have also been associated with BD. The aims of this study were to further investigate the influence of the HLA region in BD and to explore the relationship with non-HLA genes recently described to be associated in other populations. Methods This study included 304 BD patients and 313 ethnically matched controls. HLA-A and HLA-B low resolution typing was carried out by PCR-SSOP Luminex. Eleven tag single nucleotide polymorphisms (SNPs) located outside of the HLA-region, previously described associated with the disease in GWA studies and having a minor allele frequency in Caucasians greater than 0.15 were genotyped using TaqMan assays. Phenotypic and genotypic frequencies were estimated by direct counting and distributions were compared using the χ2 test. Results In addition to HLA-B*51, HLA-B*57 was found as a risk factor in BD, whereas, B*35 was found to be protective. Other HLA-A and B specificities were suggestive of association with the disease as risk (A*02 and A*24) or protective factors (A*03 and B*58). Regarding the non-HLA genes, the three SNPs located in IL23R and one of the SNPs in IL10 were found to be significantly associated with susceptibility to BD in our population. Conclusion Different HLA specificities are associated with Behçet’s disease in addition to B*51. Other non-HLA genes, such as IL23R and IL-10, play a role in the susceptibility to the disease., This work was supported by Fondo de Investigaciones Sanitarias (10/1701), Fondos FEDER, Plan Andaluz de Investigación (CTS-0197 and CTS-180), Red Enfermedades Inflamatorias y Reumáticas RD08/0075/0013 and Consejería de Salud de la Junta de Andalucía (PI0411/2010). LOF is the recipient of a fellowship (FI11/00547).

Peritoneal vasculitis is a rare and severe clinical manifestation of systemic lupus erythematosus. We report a patient who presented with ascites due to peritoneal vasculitis and cutaneous, articular, hematological and renal inflammatory activity. Treatment with glucocorticoids and immunosuppressive drugs was ineffective. In view of the resistance to different therapies, 4 weekly infusions of 375 mg/m2 of rituximab (RTX) were started, in association with cyclophosphamide pulses during the first and the third weeks. With this treatment strategy, the patient reached a complete response which was achieved in later flares of inflammatory activity (the second and third flares were multisystemic and with ascites again, and the fourth flare with nephritis).

Peritoneal vasculitis is a rare and severe clinical manifestation of systemic lupus erythematosus. We report a patient who presented with ascites due to peritoneal vasculitis and cutaneous, articular, hematological and renal inflammatory activity. Treatment with glucocorticoids and immunosuppressive drugs was ineffective. In view of the resistance to different therapies, 4 weekly infusions of 375mg/m2 of rituximab (RTX) were started, in association with cyclophosphamide pulses during the first and the third weeks. With this treatment strategy, the patient reached a complete response which was achieved in later flares of inflammatory activity (the second and third flares were multisystemic and with ascites again, and the fourth flare with nephritis).

A pesar de los avances en el tratamiento de los pacientes con hipertension arterial pulmonar (HAP), su supervivencia sigue estando muy afectada. El imatinib, un antagonista del factor de crecimiento derivado de las plaquetas con accion antiproliferativa, ha sido eficaz en modelos experimentales y en algunos casos comunicados. Se describe el resultado del tratamiento con imatinib en 4 pacientes con HAP en clase funcional IV y refractarios al tratamiento con asociaciones de medicamentos para la HAP. La respuesta final fue favorable solo en uno de los 4 casos, que 5 meses despues de iniciado el tratamiento estaba en clase funcional III y con mejoria significativa de los parametros hemodinamicos. Sin embargo, el paciente fallecio por hepatitis toxica grave en la que el imatinib pudo haber participado. Estos resultados se anaden a la escasa experiencia clinica comunicada (solo otros 4 casos) e indican que debemos mantener la cautela sobre la utilidad del imatinib en el tratamiento de la HAP.

Objective Signal-transducer and activator of transcription protein 3 ( STAT3 ) gene encodes a transducer and transcription factor that plays an important role in many cellular processes such as cell growth, apoptosis and immune response. Several STAT3 genetic variants have been associated to different autoimmune diseases. Our aim was to reveal the possible STAT3 influence in other immune-mediated diseases such as psoriatic arthritis (PsA) and Behcet disease (BD). Methods The STAT3 rs744166 and rs2293152 polymorphisms were genotyped using predesigned TaqMan® assays in a total of 335 PsA patients, 217 BD patients, and 1844 ethnically matched healthy controls of Spanish Caucasian origin. Results A statistically significant association of the STAT3 rs744166 ∗ G allele with PsA was observed ( P -value = 1.36 × 10 −3 , OR 1.35). The detected effect was more evident when the rs744166 ∗ GG homozygote frequencies were compared between PsA patients and controls (genotype P -value = 9.77 × 10 −5 , OR 1.82). In contrast, the allele and genotypic distributions of rs744166 polymorphism showed no significant differences between patients with BD and control subjects (allelic P -value = 0.80, OR 1.03). Additionally, no evidence of association was detected between the rs2293152 genetic variant and both studied diseases. Conclusion Our results suggest for the first time that the STAT3 gene might be involved in PsA but not in Behcet’s disease predisposition.

A biological marker can be defined as any substance that can be objectively measured and evaluated as an indicator of a normal biological process, a pathogenic process or pharmacological responses to a therapeutic intervention. In pulmonary hypertension (PH), in addition to routine markers (hemodynamic and functional), there are a growing number of biomarkers that allow an increasingly comprehensive approach to knowledge of susceptibility to this disease and to diagnosis, prognosis and treatment response. These markers can be both constitutive (genetic) and disease-related (related to right ventricular failure, such as BMP/NT-proBNP, endothelial dysfunction, such as endothelin-1, or inflammation, such as certain cytokines and chemokines). Novel insights in genomics and proteomics may allow major advances in this field.

Behcet disease (BD) is a multifactorial disorder with a highest prevalence among people with Mediterranean or Asian ancestry having association with HLA-B51 and other HLA and non-HLA loci.1–4 Very recently, one genome-wide association study (GWAS) identified the GIMAP locus, which encoded proteins involved in development of the T and B lymphocytes, as associated with the disease in the Asian populations.5 To investigate whether this association is replicated in Europeans, a total of 1086 (326 patients and 760 controls) Spanish individuals of European origin were genotyped after obtaining written informed consent and approval from the local ethical committees of all the institutions involved. Patients fulfilled the 1990 International Study Group classification criteria for Behcet’s disease,6 and the group was composed of 44.5% men with the following clinical features: 100% had oral ulcers, 63.6% genital ulcers, 58.7% uveitis, 48% arthritis, 20.2% vascular, 21.9% neurological and 19.2% gastrointestinal involvement. Regarding HLA association, in addition to B*51 (p

To study severe infectious complications in a cohort of patients with systemic lupus erythematosus (SLE).Retrospective study of 705 patients followed from January 1980 to January 2008. Data are expressed in percentages.The frequency of severe infectious was 38.6%. The etiology was bacterial 54.4%, viric 30.4% and opportunist in 15.2% patients. Involved organs were: Lung 38.2%, kidney 48.9%, central nervous system 43%. 43.75% patients received pulsed ciclofosfamide therapy and 88.6% received glucocorticoids (39.7% pulsed). The mortality was 27.7%.At present, infection is an important cause of mortality in patients with SLE. Early diagnosis of infectious complications is very important in SLE.

We report our experience with rituximab plus cyclophosphamide in the treatment of patients with resistant idiopathic inflammatory myopathies.Open-label uncontrolled prospective study on 17 patients.Evaluation was completed after 1, 6 and 12 months in 95'2, 85'7 y 52'4% of cycles, respectively. Total or partial remission was achieved after 1, 6 and 12 months in 65, 100 y 63'6% of evaluated cycles, respectively. Absolute depletion of B lymphocites from peripheral blood was found in the 18 cases with available data. There were 5 relapses; median of time to relapse: 11 months; treatment was repeated in 4. Four patients (6 cycles) had impaired pulmonary function; one (with a multifactorial etiology) did not improve but the other 3, with interstitial pneumonia associated or not with respiratory muscle weakness, did. Five patients with positive anti-Jo-1 antibodies (6 cycles) displayed similar results. The only adverse event observed was a case of meningitis caused by Corynebacterium, with good results.Rituximab seems a valid alternative for the treatment of patients with resistant polymyositis or dermatomyosytis.

Despite advances in the treatment of patients with pulmonary arterial hypertension (PAH), survival has not improved greatly (is still very affected). Imatinib, an antagonist of platelet-derived growth factor with antiproliferative activity, has been effective in experimental models and clinically in several published reports. We report the results of imatinib therapy in 4 patients with PAH (functional class IV) who were refractory to treatment with drug combinations for this condition. The final outcome was favorable in only 1 of the 4 cases. In this case, the patient was in functional class III and his hemodynamic parameters had improved significantly within 5 months after starting therapy. However, the patient died as a result of severe toxic hepatitis in which imatinib may have played a role. The present report adds to the few already in the literature (4 cases) and suggests that care should continue to be shown when using imatinib to treat PAH.

Thyroid disease (TD) is more prevalent in patients with pulmonary arterial hypertension (PAH) than in the general population. The frequency and the cause of this association are not well established. We aimed to quantify and analyze the incidence and characteristics of TD in a cohort of PAH patients (idiopathic or preferentially associated with systemic diseases) and review the literature.Fifty eight PAH patients were prospectively studied, according to a previously established protocol (that included right heart catheterization); TSH, T(4), and antithyroglobulin and antiperoxidase antibodies were determined. TD was defined as an abnormal TSH level and/or elevated antithyroid antibodies (TAbs). Clinical, biological and hemodynamic variables were compared between patients with and without TD.TD was detected in 30 patients (51%): high TSH levels were observed in 21 (36,21%); hyperthyroidism in 2 (3,45%); and TAbs in 16 of 54 (27,59%), 7 of whom were euthyroid. In the TD group, PAH evolution time was longer (4,62 vs 2,61 years; P=.005, CI 95%, 0,63-3,38), more patients were in functional class IV (13;43,3% vs 5;15,8%, P=.046, CI 95% ,0,05-11,75), cardiac output was lower (P=.032, CI 95%, 3,16-4,89) and epoprostenol treatment was more frequently used (14;46,6% vs 4;14,3%, P=.008, CI 95%, 1,46-18,85; OR=5,25).The frequency of TD detected in this PAH cohort reaches 51% and it was associated with a longer evolution time of PAH and worse hemodynamic situation. Although epoprostenol was used more frequently in TD patients, a causal relationship with TD could not be established.

To assess the value of rituximab in systemic autoimmune diseases which are refractory to others treatments.Prospective study on 12 patients -7 with systemic lupus erythematosus (SLE), 4 with Wegener's granulomatosis (WG), and 1 with overlapping connective disease and autoimmune thrombocytopenia-, controlled in a specialized unit of a tertiary hospital. Four weekly doses of rituximab, 2 biweekly doses of cyclophosphamide, and glucocorticoids were administered to all patients, and other immunosuppressants were also administered as considered necessary in each case.Mean follow up after treatment with rituximab was 12.8 moths for SLE patients and 12.3 for WG patients. In SLE patients, proteinuria was reduced below 1 g daily in 5 cases (83%), with a clear parallel improvement in the urinary sediment. Serositis was resolved in both cases. One patient required 3 treatment cycles to obtain an adequate response and another required a second cycle for relapse. Only one patient with WG had a favorable response. The patient treated for autoimmune thrombocytopenia had a favorable response, with no relapses, and creatine-kinase levels also tended to return to normal. There were 2 serious adverse events (terminal renal failure and serious colitis in a patient with SLE, and death of one patient with WG), that were not adjudicated directly to rituximab. Immunoglobulin levels did not change substantially. There were no infusion reactions or associated infections.Rituximab was useful in patients with SLE refractory to other immunosuppressants. On the contrary, its efficacy in WG was limited. The response of thrombocytopenia was complete and maintained.

Background Behcet9s disease (BD) has been consistently associated with HLA class I molecules, specifically, with HLA-B51. However, the role of others HLA class I molecules remains controversial. The current methods of genotyping permit to deduce the HLA typing of a large number of individuals by imputation by using data obtained from high throughput platforms. This approach has improved the knowledge of the association of HLA with the susceptibility to immune-mediated diseases. Objectives Review of the association of HLA region with BD by comprehensive reanalysis with using a novel imputation method [1,2]. Methods The HLA typings of 1794 individuals (277 patients and 1517 healthy controls) were imputed from SNPs genotyping data obtained by Human Immuno DNA Analysis BeadChip Kit (Immunochip). The statistical analyses were performed with PLINK and R. Results The strongest association signals were observed in the HLA-B region, specifically, rs1050502 represented the highest peak (p=7.73 x 10 -24 , OR=4.029, 95%CI 3.123 to 5.198). According to the analysis performed, the amino-acid positions 97 in the HLA-B and 66 HLA-A molecules are the most relevant for the disease susceptibility. Conclusions HLA-B and HLA-A are associated with the susceptibility to BD References Raychauduri S, Sandor C, Stahl EA, et al. (2012) Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Gen 44,291-296 Jia X, Han B, Onengut-Gumuscu S, et al. (2013) Imputing amino acid polymorphisms in human leukocyte antigens. PloS one 8, e64683 Disclosure of Interest None declared

It is well established that patients with CTDs such as SSc carry a considerable risk of developing pulmonary arterial hypertension (PAH). Such SSc-PAH patients have an even worse prognosis than patients with only one of these two conditions. In view of the high incidence and prevalence of PAH in SSc, and the available treatment options that improve quality of life, exercise capacity and possibly survival, systematic screening has been recommended. The present article reviews current recommendations from PAH guidelines, focusing on studies that used Doppler echocardiography for screening, and describes limitations associated with the procedure. Furthermore, characteristics and parameters used to identify patients at high risk of developing PAH are summarized.