RESUMEN
Genetic biomarkers could be useful for orienting treatment of patients with rheumatoid arthritis (RA), but none has been convincingly validated yet. Putative biomarkers include 14 single nucleotide polymorphisms that have shown association with response to TNF inhibitors (TNFi) in candidate gene studies and that we assayed here in 755 RA patients. Three of them, in the PTPRC, IL10 and CHUK genes, were significantly associated with response to TNFi. The most significant result was obtained with rs10919563 in PTPRC, which is a confirmed RA susceptibility locus. Its RA risk allele was associated with improved response (B=0.33, P=0.006). This is the second independent replication of this biomarker (P=9.08 × 10(-8) in the combined 3003 RA patients). In this way, PTPRC has become the most replicated genetic biomarker of response to TNFi. In addition, the positive but weaker replication of IL10 and CHUK should stimulate further validation studies.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Quinasa I-kappa B/genética , Interleucina-10/genética , Antígenos Comunes de Leucocito/genética , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adalimumab/uso terapéutico , Artritis Reumatoide/genética , Femenino , Estudios de Asociación Genética , Marcadores Genéticos , Humanos , Infliximab/uso terapéutico , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , RiesgoRESUMEN
OBJECTIVE: Methotrexate (MTX) is the first-choice drug for the treatment of rheumatoid arthritis (RA) patients. However, 30% of RA patients discontinue therapy within 1 year, usually because of adverse effects. Previous studies have reported conflicting results on the association of polymorphisms in the MTHFR gene with the toxicity of MTX in RA. The aim of this study was to assess the involvement of the C677T and A1298C polymorphisms in the MTHFR gene in the toxicity of MTX in a Spanish RA population. METHODS: The study included retrospectively 468 Spanish RA patients treated with MTX. Single nucleotide polymorphism (SNP) genotyping was performed using the oligonucleotide microarray technique. Allele and genotype association analyses with regard to MTX toxicity and a haplotype association test were also performed. RESULTS: Eighty-four out of the 468 patients (18%) had to discontinue therapy due to adverse effects or MTX toxicity. The C677T polymorphism (rs1801133) was associated with increased MTX toxicity [odds ratio (OR) 1.42, 95% confidence interval (CI) 1.01-1.98, p = 0.0428], and the strongest association was shown in the recessive model (OR 1.95, 95% CI 1.08-3.53, p = 0.0246). The A1298C polymorphism (rs1801131) was not associated with increased MTX toxicity (OR 0.94, 95% CI 0.65-1.38, p = 0.761). A borderline significant risk haplotype was found: 677T-1298A (OR 1.40, 95% CI 1.00-1.96, p = 0.0518). CONCLUSION: These results demonstrate that the C677T polymorphism in the MTHFR gene is associated with MTX toxicity in a Spanish RA population.
Asunto(s)
Antirreumáticos/efectos adversos , Artritis Reumatoide/tratamiento farmacológico , Metotrexato/efectos adversos , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Artritis Reumatoide/enzimología , Artritis Reumatoide/genética , Estudios de Cohortes , Femenino , Genotipo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , EspañaRESUMEN
OBJECTIVE: To examine genetic association between rheumatoid arthritis (RA) and known polymorphisms in core genes of the nuclear factor (NF)kappaB pathway, the major intracellular pathway in RA pathogenesis. METHODS: Discovery and replication sample sets of Spanish patients with RA and controls were studied. A total of 181 single nucleotide polymorphisms (SNPs) uniformly spaced along the genomic sequences of 17 core genes of the NFkappaB pathway (REL, RELA, RELB, NFKB1, NFKB2, NFKBIA, NFKBIB, NFKBIE, IKBKA, IKBKB, IKBKE, IKBKAP, KBRAS1, KBRAS2, MAP3K1, MAP3K14, TAX1BP1) were studied by mass spectrometry analysis complemented with 5'-nuclease fluorescence assays in the discovery set, 458 patients with RA and 657 controls. SNPs showing nominal significant differences were further investigated in the replication set of 1189 patients with RA and 1092 controls. RESULTS: No clear reproducible association was found, although 12 SNPs in IKBKB, IKBKE and REL genes showed significant association in the discovery set. Interestingly, two of the SNPs in the IKBKE gene, weakly associated in the discovery phase, showed a trend to significant association in the replication phase. Pooling both sample sets together, the association with these two SNPs was significant. CONCLUSION: We did not find any major effect among the explored members of the NFkappaB pathway in RA susceptibility. However, it is possible that variation in the IKBKE gene could have a small effect that requires replication in additional studies.
Asunto(s)
Artritis Reumatoide/genética , FN-kappa B/genética , Polimorfismo de Nucleótido Simple , Adulto , Estudios de Casos y Controles , Susceptibilidad a Enfermedades , Femenino , Frecuencia de los Genes , Variación Genética , Haplotipos , Humanos , Quinasa I-kappa B/genética , Funciones de Verosimilitud , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
Catastrophic antiphospholipid syndrome (CAPS) is a rare complication of antiphospholipid syndrome. It is a disseminated severe vascular pathology which presents with multi-organic dysfunction that progresses rapidly. Prognosis ends up being fatal in half of the cases. It may appear during pregnancy, surgery, infection, or after suspension of anticoagulation therapy. We studied two female patients with CAPS who survived after treatment with anticoagulation therapy and intravenous corticosteroids. The evolution of our two patients, after 17 months of follow-up under oral anticoagulant treatment was favourable and they are currently asymptomatic. In these patients the early diagnosis and treatment were essential to enhance their possibilities of survival.
Asunto(s)
Anticoagulantes/uso terapéutico , Síndrome Antifosfolípido/tratamiento farmacológico , Síndrome Antifosfolípido/fisiopatología , Índice de Severidad de la Enfermedad , Adulto , Femenino , Humanos , Insuficiencia Multiorgánica/prevención & control , PronósticoAsunto(s)
Autoanticuerpos/inmunología , Peroxidasa/inmunología , Poliarteritis Nudosa/inmunología , Fibrosis Pulmonar/inmunología , Esclerodermia Sistémica/inmunología , Anciano , Resultado Fatal , Femenino , Humanos , Persona de Mediana Edad , Poliarteritis Nudosa/complicaciones , Poliarteritis Nudosa/patología , Fibrosis Pulmonar/complicaciones , Fibrosis Pulmonar/patología , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/patologíaRESUMEN
BASIS: A significant proportion of our patients has described to have problems from tolerance to Dolquine, a new presentation of hydroxychloroquine recently marketed in Spain, compared to Plaquenil. The objective was to know the tolerability and the adverse effects of this new presentation. PATIENTS AND METHOD: A cross-sectional multicenter study on 133 patients treated with Dolquine was conducted. RESULTS: Of the 133 patients (87% women; average age [AA]: 32.9 [15.4] years) who received Dolquine during an average period of 6.7 (1.4) months, 32 patients (24%) described to have more problems with this drug in comparison with other antimalarial. The adverse effects experienced were: bitter taste (62.4%), difficulty in swallowing the tablet (13.5%), dyspepsia (9.8%), nausea (7.5%), vomiting (1.5%), pruritus (1.5%), diarrhea (0.7%), and instability feeling (0.7%). The presence of gastrointestinal adverse effects was not related to the consumption of gastroerosive drugs, gastric protectors, or a high number of drugs. The attrition rate was 9.8%. Conclusions. Dolquine induces lower tolerance and more gastrointestinal adverse effects than Plaquenil, pointing out its bitter taste and the difficulty in swallowing it. Despite this higher intolerance there was not an increase in the attition rate from the antimalarial treatment in comparison to other series.
Asunto(s)
Publicidad , Antimaláricos/efectos adversos , Hidroxicloroquina/efectos adversos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/inmunología , Adulto , Antimaláricos/uso terapéutico , Enfermedades Autoinmunes/inmunología , Femenino , Humanos , Hidroxicloroquina/uso terapéutico , Masculino , EspañaRESUMEN
OBJECTIVE: To investigate the association of the poly(ADP-ribose) polymerase 1 (PARP-1) gene promoter polymorphism with rheumatoid arthritis (RA) predisposition. METHODS: An association study with 213 Spanish RA patients and 242 healthy subjects was carried out to investigate the association of all known PARP-1 gene promoter polymorphisms, i.e., a CA microsatellite repeat, a poly(A)(n), and 3 single point mutations (C410T, C1362T, and G1672A), with disease susceptibility. Additionally, we analyzed the distribution of PARP-1 polymorphisms in 58 Spanish families with 1 or more affected members. RESULTS: Upon complete genotyping of the panel of 455 samples, strong linkage disequilibrium was observed among the 5 PARP-1 polymorphisms. Only 2 PARP-1 haplotypes were detected: haplotype A (410T-[A](10)-[CA](10-12)-1362C, which includes short PARP-1 CA alleles) and haplotype B (410C-[A](11)-[CA](13-20)-1362T, always paired with long PARP-1 CA variants). Regarding the G1672A variation, although linkage disequilibrium was detected, it did not seem to be part of the conserved haplotypes described. Haplotype B was statistically overrepresented in the RA patient group compared with the healthy subjects (odds ratio 1.42, 95% confidence interval 1.06-1.91, P = 0.019). In addition, a significant dose effect of PARP-1 haplotype carriage on disease predisposition was observed. Of note, within haplotype B, the PARP-1 CA 97-bp allele was found to be the RA-predisposing marker (odds ratio 2.17, 95% confidence interval 1.27-3.72, P = 0.003, corrected P < 0.05). CONCLUSION: Our results demonstrate the existence of 2 unique PARP-1 haplotypes in the Spanish population and provide the first evidence that PARP-1 haplotypes play a role in susceptibility to RA.
Asunto(s)
Artritis Reumatoide/enzimología , Artritis Reumatoide/genética , Predisposición Genética a la Enfermedad/genética , Haplotipos , Poli(ADP-Ribosa) Polimerasas/genética , Regiones Promotoras Genéticas/genética , Artritis Reumatoide/epidemiología , Cartilla de ADN/química , Femenino , Frecuencia de los Genes , Humanos , Masculino , Repeticiones de Microsatélite , Epidemiología Molecular , Polimorfismo Genético , España/epidemiologíaRESUMEN
An association study and a linkage analysis were carried out in parallel in order to investigate the association of the inducible nitric oxide synthase (NOS2) gene promoter polymorphism with rheumatoid arthritis (RA) predisposition and/or outcome including a -954G-C mutation, a di-allelic (TAAA)(n) marker and the highly polymorphic (CCTTT). The -954G-C point mutation occurred non-polymorphic and the di-allelic (TAAA)(n) marker was not associated with RA predisposition. The (CCTTT)(n)locus showed a trend for RA association in the case-control study, however, stratification data by Class II status did not yield significant effect and overall, the family study showed no significant association nor linkage for any of the markers under study using TDT and non-parametric linkage respectively. Finally, no influence was detected regarding any of the clinical parameters tested. After evaluating for the first time the influence of NOS2 promoter polymorphism in RA, it seems to have no major effect on disease susceptibility and/or outcome.
Asunto(s)
Artritis Reumatoide/enzimología , Artritis Reumatoide/genética , Óxido Nítrico Sintasa/genética , Polimorfismo Genético , Regiones Promotoras Genéticas , Alelos , Estudios de Casos y Controles , Ligamiento Genético , Humanos , Repeticiones de Microsatélite , Óxido Nítrico Sintasa de Tipo II , Mutación PuntualRESUMEN
OBJECTIVES: We investigated the association between HLA class II haplotypes and antiphospholipid syndrome (APS). METHODS: HLA DRB1, DQB1 and DQA1 genotypes were determined by the polymerase chain reaction using sequence-specific primers in 83 Caucasoid British patients with APS. The genotype frequencies were compared between subgroups of patients and 177 healthy controls. RESULTS: DQB1*0604/5/6/7/9-DQA1*0102-DRB1*1302 and DQB1*0303-DQA1*0201-DRB1*0701 haplotypes showed significantly positive correlations with APS [P=0.0087 and P=0.0012, respectively]. The association of the former was enhanced in primary APS patients with anti-beta 2-glycoprotein I antibodies (anti-beta 2GPI) [odds ratio 6.2, 95% confidence interval (2.2-17.6), P=0.0014, corrected P=0.042]. CONCLUSIONS: These alleles and haplotypes might affect anti-ss2GPI production and APS development in different and heterogeneous fashion.
Asunto(s)
Síndrome Antifosfolípido/genética , Antígenos de Histocompatibilidad Clase II/genética , Polimorfismo Genético , Población Blanca/genética , Adolescente , Adulto , Anciano , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Antígenos HLA-DQ/genética , Cadenas alfa de HLA-DQ , Cadenas beta de HLA-DQ , Antígenos HLA-DR/genética , Cadenas HLA-DRB1 , Haplotipos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: To investigate a possible association of Fcgamma receptor IIIA (FcgammaRIIIA) gene polymorphism at position 158 with susceptibility to, and the outcome of, rheumatoid arthritis (RA). METHODS: One hundred seventeen RA patients and 142 unrelated healthy control subjects from the same geographic area were studied. Genotyping for FcgammaRIIIA-158V/F was performed by a method based on polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis using amplification-created restriction sites. HLA-DRB1 typing by PCR-sequence-specific oligonucleotide hybridization (reverse hybridization) was also performed. RESULTS: Allele and genotype distributions in healthy controls were similar to those reported in other populations. The overall distribution of genotypes in the patients was significantly different from that in the controls (P = 0.023, by chi-square test from 3 x 2 contingency table). An overrepresentation of the FcgammaRIIIA-158FF genotype in the patients was observed (for 158FF versus non-158FF P = 0.01, odds ratio [OR] 1.98, 95% confidence interval [95% CI] 1.16-3.4). However, the FcgammaRIIIA-158VF genotype was increased in controls (for 158VF versus non-158VF P = 0.021, OR 0.54, 95% CI 0.32-0.92). No associations were found with any of a series of clinical parameters. Analysis of FcgammaRIIIA-158FF along with shared epitope showed that the presence of both factors increased the susceptibility to RA (P = 0.0009, OR 3.6, 95% CI 1.63-8.01); however, they probably do not interact to produce this effect. CONCLUSION: These results indicate that the FcgammaRIIIA-158 genotypes confer differential susceptibility to RA in our study population. Further studies to elucidate the role of this polymorphism in the pathogenesis of RA and other autoimmune diseases are warranted.
Asunto(s)
Artritis Reumatoide/genética , Predisposición Genética a la Enfermedad/genética , Receptores de IgG/genética , Adulto , Femenino , Frecuencia de los Genes , Genotipo , Homocigoto , Humanos , Persona de Mediana EdadRESUMEN
OBJECTIVE: Antiphospholipid antibodies (aPL) are thrombophilic risk markers in patients with systemic lupus erythematosus (SLE) or primary antiphospholipid syndrome (APS). The risk factors for recurrent venous or arterial thrombosis and indications for longterm anticoagulation therapy are debated. We hypothesized that carrying a second thrombophilic defect, factor V Leiden mutation, would increase the risk for thrombosis in patients with aPL. METHODS: Seventy-five patients with primary APS and 83 with SLE and aPL with or without thrombosis followed at 2 university hospitals were studied. Factor V mutation rate was analyzed in patients and in 200 healthy blood donors by polymerase chain reaction analysis. RESULTS: The prevalence of factor V Leiden mutation in patients with SLE and aPL or primary APS was similar to controls. Patients with deep vein thrombosis or arterial thrombosis did not have a significantly increased rate of factor V mutation compared to controls or to patients with aPL without thrombosis. CONCLUSION: Factor V Leiden mutation is not significantly associated with vein thrombosis in patients with aPL. However, due to the sample size we cannot rule out synergy between both factor V Leiden and aPL. A trend toward increased risk for thrombosis was detected in patients with the mutation and this should be analyzed in a larger study.
Asunto(s)
Anticuerpos Antifosfolípidos/inmunología , Factor V/genética , Mutación Puntual/genética , Trombosis de la Vena , Adulto , Síndrome Antifosfolípido/complicaciones , Síndrome Antifosfolípido/epidemiología , Síndrome Antifosfolípido/inmunología , Arteriopatías Oclusivas/epidemiología , Arteriopatías Oclusivas/genética , Arteriopatías Oclusivas/inmunología , Femenino , Humanos , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/epidemiología , Lupus Eritematoso Sistémico/inmunología , Masculino , Recurrencia , Factores de Riesgo , España/epidemiología , Trombosis de la Vena/epidemiología , Trombosis de la Vena/genética , Trombosis de la Vena/inmunologíaRESUMEN
A role for Fcgamma receptor in the pathophysiology of thrombosis in APS has been hypothesized. The polymorphism of this receptor, FcgammaRIIA H/R131, is associated with the binding affinity for human IgG2 (i.e. FcgammaRIIA-H131 isoform has a higher affinity than FcgammaRIIA-R131). Since anti-beta2 glycoprotein I antibodies (anti beta2GPI), which play a major pathogenic role in APS, show IgG2 dominant distribution, we investigated the prevalence of receptor isoforms in patients with antiphospholipid antibodies (aPL) by a PCR-RFLP method. We studied 100 Caucasian patients with aPL (57 primary APS, 32 secondary APS to SLE and 11 other diseases with aPL) and 41 healthy controls. H131/H131, H131/R131 and R131/R131 genotypes were found in 21 (21%), 50 (50%) and 29 (29%) in the patient group, and 9 (22%), 23 (56%) and 9 (22%) in control group, respectively. Thus there was no statistically significant difference in the prevalence of each genotype in these groups. None of the clinical manifestations of primary APS (arterial/venous thrombosis, recurrent pregnancy loss and thrombocytopenia) was significantly correlated with any FcgammaRIIA genotype. In conclusion, FcgammaRIIA polymorphism did not correlate with the manifestations of APS, and FcgammaRIIA genotype is not a genetic marker of APS.
Asunto(s)
Anticuerpos Antifosfolípidos/sangre , Anticuerpos Antifosfolípidos/genética , Anticuerpos Antifosfolípidos/inmunología , Antígenos CD/genética , Polimorfismo Genético , Receptores de IgG/genética , Adolescente , Adulto , Anciano , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , EmbarazoRESUMEN
A multicentre, double-blind, randomised, parallel group study was undertaken to investigate the efficacy and safety of aceclofenac (123 patients, 100 mg twice daily) in comparison to piroxicam (117 patients, 20 mg once daily and placebo once daily) in patients with osteoarthritis of the knee. The treatment period of two months was preceded by a washout period of one week duration. On completion of the study, patients in both aceclofenac and piroxicam-treated groups exhibited significant improvement in pain intensity and functional capacity of the affected knee, as represented by the Osteoarthritis Severity Index (OSI) (p < 0.0001 and p < 0.001 respectively). This was further substantiated following the patient's assessment of pain intensity using the Visual Analogue Scale (VAS), in which significant improvements were demonstrated at all time points for each treatment group (p < 0.001). Although both treatment groups showed a significant improvement in all investigator's clinical assessments (functional exploration of the knee, knee flexion and extension (EXT)), there were no significant differences between the groups. There was, however, a more rapid improvement in knee flexion in the aceclofenac group after 15 days of treatment. Both aceclofenac and piroxicam were well tolerated by patients, the most commonly reported adverse events being gastrointestinal, although their incidence was low. Only 24 patients on aceclofenac, as opposed to 33 on piroxicam complained of dyspepsia, epigastralgia and pyrosis. While 7 patients in each group were withdrawn because of adverse events, only one patient with piroxicam was withdrawn because of severe upper gastrointestinal bleeding. Twice as many reports of fecal blood loss were made in the piroxicam group in comparison to the aceclofenac group. In summary, this study confirms the therapeutic efficacy of aceclofenac and suggests that it is a well-tolerated alternative NSAID to piroxicam in the treatment of osteoarthritis.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Diclofenaco/análogos & derivados , Osteoartritis/tratamiento farmacológico , Piroxicam/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Diclofenaco/uso terapéutico , Método Doble Ciego , Evaluación de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dimensión del DolorRESUMEN
In the spring of 1993, an epidemic of infection with human parvovirus B19 occurred in Cadiz, Spain. Evaluation of the 43 patients in whom this diagnosis was confirmed revealed four groups of predominant manifestations: (1) hematologic manifestations in six cases (13.9%), including four of aplastic crisis and two of pancytopenia; (2) dermatologic manifestations in 23 cases (53.4%), including 10 of erythema infectiosum and one of erythema multiforme ampullosum; (3) arthralgias/arthritis in nine cases (20.9%), including two with a chronic course; and (4) infection during pregnancy in three cases (7.0%), including two that ended in abortion. Of the 43 patients, 37.2% presented with fever and adenopathies, and these were the only manifestations in two cases. The appearance of clinical disease correlated with modifications in isotype and serum level of specific antibodies to parvovirus B19; the disappearance of IgM antibodies coincided with the resolution of clinical manifestations. Although their presence did not correlate with the course of the disease, the detection of circulating immune complexes in 81.6% of cases supports the possibility that some manifestations were immune mediated.