Routine invasive strategy in acute coronary syndrome patients with renal dysfunction. Results of the ARIAM-SEMICYUC registry. / Estrategia invasiva de rutina en el síndrome coronario agudo sin elevación del segmento ST con disfunción renal. Resultados del registro ARIAM-SEMICYUC.

OBJECTIVE: To evaluate the use and effectiveness of a routine invasive strategy (RIS) in patients with acute coronary syndrome without persistent ST-segment elevation with renal dysfunction in the real world scenario. METHODS: A retrospective cohort study based on the ARIAM-SEMICYUC Registry (2011-2014) was carried out. Renal dysfunction was defined as GFR (Cockroft-Gault)<60ml/min (moderate dysfunction) or<30ml/min (severe dysfunction). Patients in which early angiography (<72h) was performed due to cardiogenic shock or recurrent myocardial ischemia were excluded. The primary endpoint was hospital mortality. Confounding factors were controlled using propensity score analysis. RESULTS: A total of 4,279 patients were analyzed, of which 26% had moderate renal dysfunction and 5% severe dysfunction. Patients with renal dysfunction had greater severity and comorbidity, higher hospital mortality (8.6 vs. 1.8%), and lesser use of the RIS (40 vs. 52%). The adjusted OR for mortality in patients without/with renal dysfunction were 0.38 (95% confidence interval [95%CI] 0.17 to 0.81) and 0.52 (95%CI 0.32 to 0.87), respectively (interaction P-value=.4779). The impact (adjusted risk difference) of RIS was higher in the group with renal dysfunction (-5.1%, 95%CI -8.1 to -2.1 vs. -1.6%, 95%CI -2.6 to -0.6; interaction P-value=.0335). No significant interaction was detected for the other endpoints considered (ICU mortality, 30-day mortality, myocardial infarction, acute renal failure or moderate/severe bleeding). CONCLUSIONS: The results suggest that the effectiveness of IRS is similar in patients with normal or abnormal renal function, and alert to the under-utilization of this strategy in such patients.

Registry of the Spanish Network for Systemic Sclerosis: Survival, Prognostic Factors, and Causes of Death.

Systemic sclerosis (SSc) is a rare, multisystem disease showing a large individual variability in disease progression and prognosis. In the present study, we assess survival, causes of death, and risk factors of mortality in a large series of Spanish SSc patients. Consecutive SSc patients fulfilling criteria of the classification by LeRoy were recruited in the survey. Kaplan-Meier and Cox proportional-hazards models were used to analyze survival and to identify predictors of mortality. Among 879 consecutive patients, 138 (15.7%) deaths were registered. Seventy-six out of 138 (55%) deceased patients were due to causes attributed to SSc, and pulmonary hypertension (PH) was the leading cause in 23 (16.6%) patients. Survival rates were 96%, 93%, 83%, and 73% at 5, 10, 20, and 30 years after the first symptom, respectively. Survival rates for diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc were 91%, 86%, 64%, and 39%; and 97%, 95%, 85%, and 81% at 5, 10, 20, and 30 years, respectively (log-rank: 67.63, P < 0.0001). The dcSSc subset, male sex, age at disease onset older than 65 years, digital ulcers, interstitial lung disease (ILD), PH, heart involvement, scleroderma renal crisis (SRC), presence of antitopoisomerase I and absence of anticentromere antibodies, and active capillaroscopic pattern showed reduced survival rate. In a multivariate analysis, older age at disease onset, dcSSc, ILD, PH, and SRC were independent risk factors for mortality. In the present study involving a large cohort of SSc patients, a high prevalence of disease-related causes of death was demonstrated. Older age at disease onset, dcSSc, ILD, PH, and SRC were identified as independent prognostic factors.

Association study of IRAK-M and SIGIRR genes with SLE in a large European-descent population.

OBJECTIVE: The aim of this study was to evaluate the relevance of genetic variants of interleukin receptor-associated kinase-M (IRAK-M) (rs11465955, rs1624395, rs1152888 and rs1370128) and single immunoglobulin IL1-1R-related molecule (SIGIRR) (rs3210908) genes in systemic lupus erythematosus (SLE) in four independent European-descent populations. METHODS: Our study population consisted of a total of 2033 SLE patients and 2357 healthy controls from Spain, Germany, Italy and Argentina. The genotyping was performed using a polymerase chain reaction (PCR) system with pre-developed TaqMan allelic discrimination assay. Genetic association between the genotyped markers was determined by PLINK v1.07. RESULTS: After a meta-analysis including these four populations, a trend of association between rs11465955 (P(meta) (-analysis) = 0.06), rs1370128 (P(meta) (-analysis) = 0.07) and rs1624395 (P(meta) (-analysis) = 0.06) polymorphisms was found. However, these differences did not reach statistical significance. In addition, we did not find any association between SLE and the rs1152888 IRAK-M (P(meta) (-analysis) = 0.13) and the rs3210908 SIGIRR (P(meta) (-analysis) = 0.40) polymorphisms after the meta-analysis. No evidence of association with IRAK-M haplotypes was found. CONCLUSION: These results suggest that the tested variations of IRAK-M and SIGIRR genes do not confer a relevant role in the susceptibility to SLE in European-descent populations.

Off-label use of rituximab in 196 patients with severe, refractory systemic autoimmune diseases.

OBJECTIVES: To analyse the safety and efficacy of the off-label use of rituximab in patients with severe, refractory systemic autoimmune diseases. METHODS: In 2006, the Study Group on Autoimmune Diseases of the Spanish Society of Internal Medicine created the BIOGEAS project, a multicenter study devoted to collecting data on the use of biological agents in adult patients with systemic autoimmune diseases refractory to standard therapies (failure of at least two immunosuppressive agents). RESULTS: One hundred and ninety-six patients with systemic autoimmune diseases treated with rituximab have been included in the Registry (158 women and 38 men, mean age 43 years). Systemic autoimmune diseases included systemic lupus erythematosus (107 cases), inflammatory myopathies (20 cases), ANCA-related vasculitides (19 cases), Sjögren's syndrome (15 cases) and other diseases (35 cases). A therapeutic response was evaluable in 194 cases: 99 (51%) achieved a complete response, 51 (26%) a partial response and 44 (23%) were classified as non-responders. After a mean follow-up of 27.56+/-1.32 months, 44 (29%) out of the 150 responders patients relapsed. There were 40 adverse events reported in 33 (16%) of the 196 patients. The most frequent adverse events were infections, with 24 episodes being described in 19 patients. Thirteen (7%) patients died, mainly due to disease progression (7 cases) and infection (3 cases). CONCLUSIONS: Although not yet licensed for this use, rituximab is currently used to treat severe, refractory systemic autoimmune diseases, with the most favourable results being observed in Sjögren's syndrome, inflammatory myopathies, systemic lupus erythematosus and cryoglobulinemia.

Failure of intravenous immunoglobulin to prevent congenital heart block: Findings of a multicenter, prospective, observational study.

OBJECTIVE: Congenital heart block (CHB) is presumed to be caused by transplacental passage of maternal immunoglobulin against Ro and La ribonucleoproteins. The recurrence rate in subsequent pregnancies following the birth of a child with CHB is approximately 19%. The purpose of this study was to determine whether intravenous immunoglobulin (IVIG) therapy could prevent the development of CHB in the fetuses of high-risk pregnant women. METHODS: A total of 24 pregnancies in 22 women who had a previous pregnancy in which CHB developed, were over the age of 18 years, were <12 weeks pregnant, and had anti-Ro, anti-La, or both antibodies were monitored in this multicenter, prospective, observational study. Fifteen patients received infusions of IVIG. The 9 pregnancies in the remaining 7 patients served as controls. IVIG was administered at a dose of 400 mg/kg at weeks 12, 15, 18, 21, and 24 of pregnancy. Echocardiograms were performed at least every 3 weeks from week 15 to week 30 of gestation. Electrocardiograms were obtained at birth. The outcome measure was the development of third-degree CHB detected by fetal echocardiogram. RESULTS: CHB developed in 3 babies among the 15 pregnancies in the treatment group (20%) and in 1 baby among the 9 pregnancies in the control group (11%). CHB was detected at weeks 18, 23, and 26, respectively, in the 3 babies in the treated group and at week 19 in the baby in the control group. Three of the affected pregnancies ended in termination; 2 for reasons related to the fetal disease and 1 for reasons related to both maternal (severe pulmonary hypertension) and fetal disease (at 21 weeks of gestation). CONCLUSION: IVIG at the dose and frequency used in this study was not effective as prophylactic therapy for CHB in high-risk mothers.

Investigation of TLR5 and TLR7 as candidate genes for susceptibility to systemic lupus erythematosus.

OBJECTIVES: The aim of this study was to evaluate the relevance of genetic variants of TLR5 (rs5744168) and TLR7 (rs179008) gene in systemic lupus erythematosus (SLE) in a Spanish population. MATERIAL AND METHODS: Our study population consisted of 752 SLE patients and 1107 healthy controls. All individual were of Spanish Caucasian origin. The TLR5 and TLR7 polymorphisms were genotyped using a PCR system with pre-developed TaqMan allelic discrimination assay. RESULTS: No statistically significant differences were observed when the allele and genotype distribution of TLR5 rs5744168 and TLR7 rs179008 polymorphisms was compared between SLE patients and healthy controls. A significant increase frequency in the CC genotype of the TLR5 rs5744168 polymorphism among SLE patients without nephritis was found (93% vs. 87% in SLE patients with nephritis, p=0.03, OR=2.11 95%CI 0.93-3.51). However, this difference did not reach statistical significance in the allele frequencies (p=0.08). CONCLUSION: These results suggest that the tested variations of TLR5 and TLR7 genes do not confer a relevant role in the susceptibility or severity to SLE in the Spanish population.

The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype.

The aim of this study was to investigate the possible role of STAT4 gene in the genetic predisposition to systemic sclerosis (SSc) susceptibility or clinical phenotype. A total of 1317 SSc patients [896 with limited cutaneous SSc (lcSSc) and 421 with diffuse cutaneous SSc (dcSSc)] and 3113 healthy controls, from an initial case-control set of Spanish Caucasian ancestry and five independent cohorts of European ancestry (The Netherlands, Germany, Sweden, Italy and USA), were included in the study. The rs7574865 polymorphism was selected as STAT4 genetic marker. We observed that the rs7574865 T allele was significantly associated with susceptibility to lcSSc in the Spanish population [P = 1.9 x 10(-5) odds ratio (OR) 1.61 95% confidence intervals (CI) 1.29-1.99], but not with dcSSc (P = 0.41 OR 0.84 95% CI 0.59-1.21). Additionally, a dosage effect was observed showing individuals with rs7574865 TT genotype higher risk for lcSSc (OR 3.34, P = 1.02 x 10(-7) 95% CI 2.11-5.31). The association of the rs7574865 T allele with lcSSc was confirmed in all the replication cohorts with different effect sizes (OR ranging between 1.15 and 1.86), as well as the lack of association of STAT4 with dcSSc. A meta-analysis to test the overall effect of the rs7574865 polymorphism showed a strong risk effect of the T allele for lcSSc susceptibility (pooled OR 1.54 95% CI 1.36-1.74; P < 0.0001). Our data show a strong and reproducible association of the STAT4 gene with the genetic predisposition to lcSSc suggesting that this gene seems to be one of the genetic markers influencing SSc phenotype.

No evidence for genetic association of interferon regulatory factor 3 in systemic lupus erythematosus.

The aim of this study was to determine the potential role of three IRF3 gene polymorphisms (rs2304204, rs7251 and rs2304207) with systemic lupus erythematosus (SLE). Our study population consisted of 610 patients with SLE and 730 healthy controls. All individual were of Spanish Caucasian origin. The IRF3 polymorphisms were genotyped using a PCR system with pre-developed TaqMan allelic discrimination assay. No statistically significant differences were found when allele and genotype distribution of rs2304204, rs7251 and rs2304207 polymorphisms were compared between patients with SLE and controls [overall P values: rs7251, P = 0.06; rs2304204, P = 0.26 and rs2304207, P = 0.36, by chi-squared test on a 3 x 2 contingency table. Overall allelic P values: rs7251, P = 0.8, OR (95%CI) = 1.03 (0.87-1.22); rs2304204, P = 0.2, OR (95%CI) = 1.12 (0.93-1.34) and rs2304207, P = 0.8, OR (95%CI) = 1.02 (0.82-1.26)]. In addition, no evidence of association with haplotypes and clinical features of SLE was found. Our data suggest that the IRF3 polymorphisms do not appear to play a major role in the susceptibility or severity of SLE in a Spanish population.

The interleukin 23 receptor gene does not confer risk to systemic sclerosis and is not associated with systemic sclerosis disease phenotype.

OBJECTIVES: Multiple studies indicate the role of the interleukin (IL)-17/IL-23 axis in autoimmune diseases, including systemic sclerosis (SSc). The aim of the current study was to investigate the possible implication of the IL23R gene in SSc susceptibility and/or clinical phenotype. METHODS: An initial case-control study in 143 Dutch patients with SSc and geographically matched healthy individuals (n = 246) was carried out and followed by a replication study in a cohort of 365 Spanish patients with SSc and 515 healthy individuals. Seven single nucleotide polymorphisms (SNPs) spanning the IL23R gene were selected and genotyped using a Taqman assay. RESULTS: Using a Dutch cohort of patients with SSc and controls we observed an association between two (rs11209032, rs1495965) of the seven tested SNPs and disease susceptibility (allelic p values: p = 0.02 and p = 0.01 respectively). However, a replication study in an independent Spanish cohort did not confirm these findings and reveal no association of any of the IL23R-tested SNP with disease susceptibility or clinical phenotype. Similarly, a meta-analysis considering both populations did not reveal any significant association. In addition, no association was observed between IL23R genetic variants and SSc clinical phenotypes. CONCLUSIONS: Our results suggest that the IL23R gene is not associated with SSc susceptibility or clinical phenotype.

A large multicentre analysis of CTGF -945 promoter polymorphism does not confirm association with systemic sclerosis susceptibility or phenotype.

OBJECTIVE: To conduct a replication study to investigate whether the -945 CTGF genetic variant is associated with systemic sclerosis (SSc) susceptibility or specific SSc phenotype. METHODS: The study population comprised 1180 patients with SSc and 1784 healthy controls from seven independent case-control sets of European ancestry (Spanish, French, Dutch, German, British, Swedish and North American). The -945 CTGF genetic variant was genotyped using a Taqman 5' allelic discrimination assay. RESULTS: An independent association study showed in all the case-control cohorts no association of the CTGF -945 polymorphism with SSc susceptibility. These findings were confirmed by a meta-analysis giving a pooled OR = 1.12 (95% CI 0.99 to 1.25), p = 0.06. Investigation of the possible contribution of the -945 CTGF genetic variant to SSc phenotype showed that stratification according to SSc subtypes (limited or diffuse), selective autoantibodies (anti-topoisomerase I or anticentromere) or pulmonary involvement reached no statistically significant skewing. CONCLUSION: The results do not confirm previous findings and suggest that the CTGF -945 promoter polymorphism does not play a major role in SSc susceptibility or clinical phenotype.

Screening for PAH in patients with systemic sclerosis: focus on Doppler echocardiography.

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.

Diagnóstico y tratamiento de la hipertensión pulmonar / Diagnosis and treatment of pulmonary hypertension

La hipertensión arterial pulmonar es un proceso idiopático o puede estar asociado a otras circunstancias como enfermedades del tejido conectivo, cardiopatías congénitas, hipertensión portal, exposición a inhibidores del apetito u otras drogas, o a agentes infecciosos como en el virus de la inmunodeficiencia humana (VIH). En la mayor parte de los pacientes se llega al diagnóstico como resultado de la valoración de sus síntomas, mientras que otros son diagnosticados fortuitamente o durante la revisión sistemática de individuos asintomáticos pertenecientes a grupos de riesgo. Se revisan los métodos de valoración útiles para el diagnóstico de la hipertensión arterial pulmonar. Un algoritmo diagnóstico puede servir de guía en dicha evaluación, aunque puede ser modificado de acuerdo con circunstancias clínicas específicas. El número de opciones terapéuticas se ha incrementado en los últimos años. Se revisa la utilización de los bloqueadores de los canales de calcio, prostaciclina y análogos, antagonistas de los receptores de la endotelina, inhibidores de la fosfodiesterasa-5 y del tratamiento combinado y se proporcionan recomendaciones específicas acerca del tratamiento actual

Pulmonary arterial hypertension is an idiopathic process or can be associated with another circumstances (connective tissue diseases, congenital heart disease, portal hypertension, exposure to appetite suppressants or anoher drugs or infectious agents such as HIV). Most patients are diagnosed as the result of an evaluation of symptoms, whereas others are diagnosed incidentally or during screening of asymptomatic populations at risk. We reviews systematic screening for the approach to diagnosing pulmonary arterial hypertension. A diagnostic algorithm can guide the evaluation but it can be modified according to specific clinical circumstances. The number of therapeutic options has increased.in the last years. We reviews the use of calcium-channel blockers, prostacyclin (and analogues), endothelin-receptor antagonists, and phosphodiesterase-5 inhibitors, and the use of combination therapy, and provides specific recommendations about the actual treatment (AU)

[Ocular toxocariasis. A case report]. / Toxocariasis ocular. A propósito de un caso.

CASE REPORT: We present the case of a seven-year-old male with ocular toxocariasis. The fundus of the eye showed a vitritis, as a result of which the retina could not be seen. Following treatment with systemic corticosteroids the condition evolved favorably. However, due to a papillary and peripheral granuloma that raised the macula, a vitrectomy was performed which stabilized the process. DISCUSSION: Ocular toxocariasis is not common in developed countries. The diagnosis is based on funduscopic aspects, serology and IgG positivity of the vitreous. In relation to treatment, as the use of anthelminthics therapy is controversial, the use of corticosteroids and vitrectomy is recommended.

Toxocariasis ocular. A propósito de un caso / Ocular toxocariasis. A case report

Caso clínico: Paciente de 7 años diagnosticado de toxocariasis ocular. El fondo de ojo mostraba una vitritis que no permitía ver la retina. Se instauró tratamiento con corticoides, evolucionando favorablemente, pero existía un granuloma papilar y periférico que levantaba la mácula por lo que se realizó una vitrectomía consiguiéndose la estabilización del proceso. Discusión: La Toxocariasis ocular es rara en los países desarrollados. El diagnóstico está basado en el aspecto oftalmoscópico, la serología y la Ig G + en vítreo. En cuanto al tratamiento sigue siendo controvertido el uso de antihelmínticos y aceptado el uso de corticoides y la vitrectomía

Case report: We present the case of a seven-yearold male with ocular toxocariasis. The fundus of the eye showed a vitritis, as a result of which the retina could not be seen. Following treatment with systemic corticosteroids the condition evolved favorably. However, due to a papillary and peripheral granuloma that raised the macula, a vitrectomy was performed which stabilized the process. Discussion: Ocular toxocariasis is not common in developed countries. The diagnosis is based on funduscopic aspects, serology and IgG positivity of the vitreous. In relation to treatment, as the use of anthelminthics therapy is controversial, the use of corticosteroids and vitrectomy is recommended

Study of a functional polymorphism in the p53 gene in systemic lupus erythematosus: lack of replication in a Spanish population.

The aim of this study was to assess the possible association between the p53 suppressor gene codon 72 polymorphism and systemic lupus erythematosus (SLE). Our study population consisted of 513 SLE patients and 567 healthy controls. All the individuals were of Spanish Caucasian origin. Genotyping of the p53 codon 72 polymorphism was performed by allele-specific PCR. No statistically significant differences were observed between SLE patients and healthy controls when p53 codon 72 genotype and allele frequencies were compared. In addition, no evidence for association with clinical subfeatures of SLE was found. In conclusion, the p53 codon 72 polymorphism associated with SLE in a Korean population does not appear to play a major role in the susceptibility or severity of SLE in the Spanish population.

Enfermedad de Vogt-Koyanagi-Harada. Características de un grupo de pacientes andaluces / Vogt-Koyanagi-Harada disease. Characteristics of a series of patients

Objetivo. Describir las características de una serie de pacientes diagnosticados de enfermedad de Vogt-Koyanagi-Harada (EVKH) seguidos en una Unidad de Uveítis (multidisciplinaria, formada por oftalmólogos e internistas) en nuestro medio. Pacientes y método. Estudio retrospectivo descriptivo de 11 pacientes con EVKH (5 varones y 6 mujeres; edad media al diagnóstico: 32,6 años) seguidos entre 1980 y 2003. Resultados. Todos sufrieron panuveítis y/o desprendimiento exudativo de retina. Aparecieron alteraciones extraoculares en todos: neurológicas en el 63,7% (meningitis aséptica y/o síntomas focales), dermatológicas en el 81,8% (vitíligo, canicie, poliosis, alopecia), hipoacusia neurosensorial (el 50% de pacientes con audiometría) y síntomas generales en el 25%. Todos recibieron glucocorticoides sistémicos. Se añadió ciclosporina en 5 pacientes (45,4%) con inflamación de polo posterior y azatioprina en 2 por inflamación anterior. La agudeza visual final fue > 0,5 en el 81,8% de los casos, pero 2 tuvieron mala evolución (uno, con catarata y queratopatía en banda en ojo izquierdo y deterioro visual grave, precisó vitrectomía derecha y en otro se desarrolló hipotensión ocular grave). Aparecieron complicaciones en otros 2 pacientes: catarata y glaucoma en uno y sinequias iridianas sin glaucoma en otro. Conclusiones. Encontramos menor frecuencia de desprendimiento exudativo de retina y mayor de alteraciones dermatológicas que lo comunicado. Un porcentaje importante de casos precisó inmunosupresores. La agudeza visual final fue buena en la mayoría de los pacientes (AU)

Background. To describe the characteristics of a series of patients diagnosed of Vogt-Koyanagi-Harada disease (VKHD) and controlled by an Uveitis Unit (composed of ophthalmologistsand internists) in our population. Patients and method. Retrospective descriptive study of 11 patients with VKHD (5 males and 6 women; median age at diagnosis 32.6 years old) followed-up between 1980 and 2003. Results. All patients suffered panuveitis and/or exudative retinal detachment. Extraocular signs were present in all cases: neurological in 63.7% (aseptic meningitis and/or focal symptoms), cutaneous in 81.8% (vitiligo, whiteness, poliosis, alopecia), neurosensorial hypoacusis (50% of patients with audiometry), and general symptoms in 25%. They all received systemic corticosteroids. Cyclosporine was added in 5 patients (45.4%) with posterior uveitis, and azathioprine in 2 of them for iridocyclitis. The final visual acuity was 0.5 or better in 81.8% of cases, but 2 patients had an unfavourable evolution (one, who had cataract and band keratopathy in the left eye and severe visual worsening, needed right vitrectomy, and the other suffered severe ocular hypotension). Complications developed in 2 other patients: cataract and glaucoma in one, and synechiae without glaucoma in the other. Conclusions. We found less frequency of exudative retinal detachment and greater frequency of cutaneous signs than the communicated. A significant percentage of cases needed immunosuppressive agents. Final visual acuity was good in the majority of patients (AU)