RESUMEN
OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases, comprising seven categories. Genetic data could potentially be used to help redefine JIA categories and improve the current classification system. The human leucocyte antigen (HLA) region is strongly associated with JIA. Fine-mapping of the region was performed to look for similarities and differences in HLA associations between the JIA categories and define correspondences with adult inflammatory arthritides. METHODS: Dense genotype data from the HLA region, from the Immunochip array for 5043 JIA cases and 14â 390 controls, were used to impute single-nucleotide polymorphisms, HLA classical alleles and amino acids. Bivariate analysis was performed to investigate genetic correlation between the JIA categories. Conditional analysis was used to identify additional effects within the region. Comparison of the findings with those in adult inflammatory arthritic diseases was performed. RESULTS: We identified category-specific associations and have demonstrated for the first time that rheumatoid factor (RF)-negative polyarticular JIA and oligoarticular JIA are genetically similar in their HLA associations. We also observe that each JIA category potentially has an adult counterpart. The RF-positive polyarthritis association at HLA-DRB1 amino acid at position 13 mirrors the association in adult seropositive rheumatoid arthritis (RA). Interestingly, the combined oligoarthritis and RF-negative polyarthritis dataset shares the same association with adult seronegative RA. CONCLUSIONS: The findings suggest the value of using genetic data in helping to classify the categories of this heterogeneous disease. Mapping JIA categories to adult counterparts could enable shared knowledge of disease pathogenesis and aetiology and facilitate transition from paediatric to adult services.
Asunto(s)
Artritis Juvenil/genética , Artritis Reumatoide/genética , Antígenos HLA/genética , Cadenas HLA-DRB1/genética , Complejo Mayor de Histocompatibilidad/genética , Factor Reumatoide/genética , Adulto , Alelos , Aminoácidos , Artritis Juvenil/clasificación , Estudios de Casos y Controles , Niño , Genotipo , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
The latest change in terminology from juvenile rheumatoid arthritis (JRA) to juvenile idiopathic arthritis (JIA), established by the International League of Associations for Rheumatology (ILAR), has resulted in some confusion for OMFS and other treating clinicians. JIA comprises a group of systemic inflammatory diseases that result in the destruction of hard and soft tissues in a single or multiple joints. In a significant number of patients, one or both temporomandibular joints (TMJ) are also involved. TMJ disease may be accompanied by pain, swelling, and limitation of motion, as well as mandibular retrognathism, open bite, and asymmetry. The purpose of this article is to provide a review, for the oral and maxillofacial surgeon, of the terminology, etiopathogenesis, diagnosis, and management of children with JIA.
Asunto(s)
Artritis Juvenil , Trastornos de la Articulación Temporomandibular , Terminología como Asunto , Artralgia/etiología , Artritis Juvenil/diagnóstico , Artritis Juvenil/etiología , Artritis Juvenil/terapia , Manejo de la Enfermedad , Humanos , Mordida Abierta/etiología , Articulación Temporomandibular , Trastornos de la Articulación Temporomandibular/diagnóstico , Trastornos de la Articulación Temporomandibular/etiología , Trastornos de la Articulación Temporomandibular/terapiaRESUMEN
OBJECTIVES: Inhalation of fine particulate matter, including particles with an aerodynamic diameter less than or equal to a 2.5-microm cut point (PM2.5), has been associated with systemic inflammation and the clinical presentation of various cardiopulmonary heath events. The urban area along Utah's Wasatch Mountains has high PM2.5 concentrations during periods of stagnant air conditions. Short-term inhalation exposures may trigger inflammatory events presenting as symptom onset in new patients with juvenile idiopathic arthritis (JIA). This study evaluated potential associations between JIA symptom onset and temporal changes in regional air pollution measured by stagnant air conditions and PM2.5 concentrations. METHODS: A case-crossover design was used to analyze associations of regional ambient PM2.5 concentrations with onset date of 338 JIA cases living on Utah's Wasatch Front. Patients were drawn from the Intermountain States Database of Childhood Rheumatic Diseases (1993-2006). Time trends, seasonality, month, and weekday were controlled for by matching. Selected exposure windows of PM2.5 and stagnant air days were used in the model to determine the effect of short term cumulative exposure on JIA symptom onset. RESULTS: Increased concentrations of PM2.5 and stagnant air conditions in the preceding 14 days were associated with significantly elevated risk of JIA onset in preschool aged children (RR=1.60, 95% CI 1.00-2.54) but not older children. Elevated risk was larger in males and in systemic onset JIA. CONCLUSION: Exposure to stagnant polluted air may be an environmental risk factor for JIA in young children, potentially triggered by pollution-induced pulmonary mediated inflammation.
Asunto(s)
Artritis Juvenil/etiología , Exposición a Riesgos Ambientales/efectos adversos , Material Particulado/efectos adversos , Material Particulado/análisis , Factores de Edad , Niño , Preescolar , Estudios Cruzados , Femenino , Humanos , Lactante , Masculino , Riesgo , Factores Sexuales , UtahRESUMEN
OBJECTIVE: Juvenile idiopathic arthritis (JIA) is a chronic autoimmune arthropathy. Beta 2-adrenergic receptors are a link between the sympathetic nervous system and the immune system. Associations between variants in the gene encoding the beta 2-adrenergic receptor (ADRB2) and autoimmune disorders such as rheumatoid arthritis (RA) have been demonstrated. We aimed to investigate ADRB2 variants for association with JIA. METHODS: Genotypes and haplotypes of two ADRB2 variants (G16R and Q27E) were determined in 348 children with JIA and 448 healthy controls by direct molecular haplotyping using melting-curve analysis of a fluorescently labelled loci-spanning probe. Case-control analysis was performed to investigate whether ADRB2 variants were associated with JIA. RESULTS: No association was found between JIA and alleles, genotypes, or haplotypes of ADRB2. Specifically, the haplotype that demonstrated a strong association with RA (R16/Q27) was not associated with JIA. None of the variants demonstrated association after stratification by JIA subtypes or gender. CONCLUSIONS: Our results indicate that ADRB2 variants are not associated with JIA or any of the major JIA subtypes. These observations suggest that, although they share several clinical and pathological features, JIA and RA have unique genetic associations.
Asunto(s)
Artritis Juvenil/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Receptores Adrenérgicos beta 2/genética , Niño , Femenino , Haplotipos , Humanos , MasculinoRESUMEN
A 73-year-old man presented with fistulizing cutaneous Crohn's disease of the penis and perianal area without involvement of the gastrointestinal tract. The disease failed to respond to topical clobetasol propionate and oral cyclosporin and methotrexate. A combination treatment of minocycline, thalidomide and prednisolone brought the disease under control and induced remission. Surgery with excision and skin grafting were required to produce cure.
Asunto(s)
Antiinflamatorios/administración & dosificación , Enfermedad de Crohn/terapia , Inmunosupresores/administración & dosificación , Enfermedades del Pene/terapia , Trasplante de Piel , Úlcera Cutánea/terapia , Piel/patología , Anciano , Canal Anal/patología , Terapia Combinada , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/diagnóstico , Fístula Cutánea/etiología , Procedimientos Quirúrgicos Dermatologicos , Diagnóstico Diferencial , Quimioterapia Combinada , Humanos , Masculino , Pene/patología , Pene/cirugía , Úlcera Cutánea/complicaciones , Úlcera Cutánea/diagnóstico , Fístula Urinaria/etiologíaRESUMEN
Juvenile rheumatoid arthritis (JRA) is mediated by Th1-immune responses. In children with JRA, synovial T cells express high levels of the Th1-chemokine receptor CC chemokine receptor 5 (CCR5), which has been implicated in susceptibility to rheumatoid arthritis. To test the hypothesis that genetic variation in CCR5 is associated with susceptibility to JRA, we analyzed patterns of variation in the 5'cis-regulatory region of CCR5 in 124 multiplex families from a JRA-affected sibpair registry. After sequencing the upstream region of CCR5, variants were tested for association with JRA by transmission disequilibrium testing. A single nucleotide polymorphism, C-1835T, was significantly undertransmitted to children with early-onset JRA (P<0.01). C-1835T was genotyped in 424 additional simplex and multiplex families. CCR5-1835T allele was undertransmitted in the cohort of all probands with JRA (P<0.02), as well as in those with early-onset (P<0.01) or pauciarticular JRA (P<0.05). Another variant, a 32-bp deletion in the open reading frame of CCR5 (CCR5-Delta32) was also tested in approximately 700 simplex and multiplex families. CCR5-Delta32 was also significantly undertransmitted to probands with early-onset JRA (P<0.05). Both variants are in regions under natural selection, and result in functional consequences. Our results suggest these CCR5 variants are protective against early-onset JRA.
Asunto(s)
Artritis Juvenil/genética , Polimorfismo Genético , Receptores CCR5/genética , Secuencia de Bases , Niño , Preescolar , Estudios de Cohortes , Femenino , Eliminación de Gen , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido SimpleRESUMEN
Rheumatoid arthritis (RA) is characterized by synovial inflammation mediated by T-cells, monocytes and macrophages. The homing of these cells to the inflamed synovium is regulated by chemokine-receptors and their ligands. A 32-basepair deletion (Delta32) in the gene encoding CCR5, a chemokine-receptor, results in a non-functional receptor. A negative association between CCR5-Delta32 and RA has been described, although other studies found no associations. Furthermore, the observation that individuals homozygous for CCR5-Delta32 develop RA has raised questions about the role of CCR5-Delta32. This meta-analysis of all published case-control association studies confirms the negative association between CCR5-Delta32 and RA (Odds Ratio=0.65; 95% confidence intervals=0.55-0.77; P<0.0001), suggesting that CCR5-Delta32 is protective against the development of RA. CCR5 blockade in animal models of RA results in amelioration of arthritis, suggesting that CCR5 blockade could also modify disease in patients with RA.
Asunto(s)
Artritis Reumatoide/genética , Polimorfismo Genético , Receptores CCR5/genética , Estudios de Casos y Controles , Frecuencia de los Genes , Homocigoto , Humanos , Eliminación de SecuenciaRESUMEN
OBJECTIVE: To determine if a polymorphism in the immunoproteasome subunit LMP7 was associated with juvenile rheumatoid arthritis (JRA) and had functional significance. METHODS: The frequency of LMP7QQ+ vs QQ- (QK and KK genotypes) among 207 patients with JRA and 50 controls was determined. JRA subtypes were pauciarticular (53%), polyarticular (33%), and systemic (14%). Onset was before age 6 (early onset) in 60% of patients. The functional significance of the LMP7 polymorphism was determined by comparing incorporation of LMP7Q vs LMP7K into proteasomes. RESULTS: There was an increased frequency of LMP7QQ in patients vs controls (73 vs 56%; p = 0.016), mainly due to the pauciarticular and systemic JRA subtypes (p = 0.037), and more pronounced in early onset disease (77 vs 56%; p = 0.006). The association persisted with stratification for HLA-DR5(11) and -DPB 1 *0201 (p = 0.002 and 0.013). We found no difference in the relative incorporation of LMP7Q and LMP7K into proteasomes. CONCLUSIONS: These results support an association between LMP7QQ homozygosity and JRA, particularly early onset disease. The difference persists with stratification, at least for DR5(11) and DPB1*0201, suggesting that this effect is unlikely to be due to linkage disequilibrium with HLA alleles known to be associated with early onset pauciarticular JRA. Importantly, as there does not appear to be functional significance associated with the LMP7 polymorphism, this may be a marker for another as yet unidentified susceptibility locus.
Asunto(s)
Artritis Juvenil/genética , Artritis Juvenil/inmunología , Cisteína Endopeptidasas/genética , Complejo Mayor de Histocompatibilidad/genética , Complejos Multienzimáticos/genética , Polimorfismo Genético , Proteínas/genética , Niño , Cisteína Endopeptidasas/inmunología , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Antígenos HLA-DR/genética , Antígeno HLA-DR5/genética , Cadenas HLA-DRB1 , Humanos , Masculino , Complejos Multienzimáticos/inmunología , Complejo de la Endopetidasa ProteasomalRESUMEN
Macrophage activation syndrome (MAS), a recognized complication of systemic juvenile rheumatoid arthritis (sJRA), has been associated with significant morbidity and mortality. Dysregulation of macrophage-lymphocyte interactions leading to uncontrolled proliferation of highly activated macrophages and massive release of proinflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha) appears to be central to the pathogenesis of this syndrome. Until now the mainstay of therapy has been corticosteroids and cyclosporin A. We describe a patient with MAS and sJRA successfully treated with the anti-TNF agent etanercept. The outcome in this patient suggests etanercept might be an effective therapeutic agent in MAS.
Asunto(s)
Artritis Juvenil/diagnóstico , Artritis Juvenil/tratamiento farmacológico , Inmunoglobulina G/administración & dosificación , Activación de Macrófagos/efectos de los fármacos , Receptores del Factor de Necrosis Tumoral/administración & dosificación , Antiinflamatorios no Esteroideos/administración & dosificación , Artritis Juvenil/complicaciones , Biopsia con Aguja , Médula Ósea/patología , Niño , Esquema de Medicación , Quimioterapia Combinada , Etanercept , Estudios de Seguimiento , Humanos , Activación de Macrófagos/fisiología , Masculino , Medición de Riesgo , Índice de Severidad de la Enfermedad , Piel/patología , Síndrome , Resultado del TratamientoRESUMEN
Spondyloarthropathies represent complex genetic diseases whose development is influenced by environmental factors. Estimates suggest that three to nine loci may be responsible for the majority of the genetic susceptibility to ankylosing spondylitis. The only susceptibility locus identified to date in multiple populations is HLA-B, where several HLA-B27 alleles (subtypes) are strongly associated with disease. Recent evidence implicates cytochrome P450 2D6 as a second locus, although its influence on overall risk appears small. Despite considerable efforts to define how HLA-B27 contributes to disease, its role remains enigmatic. Increasing evidence suggests it has effects that are unrelated to its physiologic function. The basis for this is unknown but may be a consequence of the unusual tendency of this allele to misfold.
Asunto(s)
Pruebas Genéticas , Antígeno HLA-B27/genética , Espondiloartropatías/epidemiología , Espondiloartropatías/genética , Causalidad , Femenino , Regulación de la Expresión Génica , Antígeno HLA-B27/análisis , Humanos , Incidencia , Masculino , Polimorfismo Genético , Medición de Riesgo , Sensibilidad y EspecificidadRESUMEN
OBJECTIVE: To test for linkage between the HLA region and juvenile rheumatoid arthritis (JRA), with stratification by onset and course types, in a cohort of affected sibling pairs (ASPs). METHODS: Eighty pairs of siblings with JRA who were registered with the Research Registry for JRA ASPs (sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases) were typed for HLA-DR. The observed ratio of sharing of none, one, or both parental DR alleles was compared against the expected ratio of 1:2:1 by goodness-of-fit chi-square tests. A group of 265 unrelated control subjects served as a comparison population for HLA-DR allele frequencies among patients, by Fisher's exact test. RESULTS: Overall, there was excess sharing of 2 DR alleles among ASPs with JRA. The observed ratio of sharing 0, 1, or 2 DR alleles was 8:40:32, instead of the expected ratio of 20:40:20 (P < 0.001). When stratified by JRA onset type, excess allele sharing was demonstrated among ASPs who were concordant for onset type (P = 0.002). This was true for both pauciarticular and polyarticular onset. When stratified by disease course, excess allele sharing was also demonstrated among ASPs who were concordant for disease course (P < 0.001). This was true for both the pauciarticular and the polyarticular course. Among the 32 ASPs who shared two DR alleles, 5 pairs had both DR8 and DR11, which was significantly more frequent (P < 0.0001) than the incidence in the control group (n = 0). CONCLUSION: This study of an independent cohort of multiplex families confirms the previously reported linkage between pauciarticular JRA and the HLA-DR region that was identified using a different analytic method in a cohort of simplex families. Additionally, this study establishes evidence for linkage between polyarticular JRA and the HLA-DR region.
Asunto(s)
Artritis Juvenil , Alelos , Artritis Juvenil/genética , Estudios de Cohortes , Enfermedades en Gemelos/genética , Femenino , Antígenos HLA/genética , Prueba de Histocompatibilidad , Humanos , MasculinoAsunto(s)
Enfermedades Autoinmunes/inmunología , Hipersensibilidad Inmediata/inmunología , Células TH1 , Células Th2 , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/complicaciones , Autoinmunidad/inmunología , Niño , Diabetes Mellitus Tipo 1/etiología , Humanos , Hipersensibilidad Inmediata/sangre , Hipersensibilidad Inmediata/complicaciones , InmunofenotipificaciónRESUMEN
An 11-year-old patient is described who developed osteonecrosis (ON) of the femoral head 4 months after an episode of arthritis of the hip associated with acute rheumatic fever. ON has been reported to occur after transient synovitis. We believe this is the first report of osteonecrosis after acute rheumatic fever and suggest that rheumatic arthritis, like transient synovitis occurring in the hip, might be a predisposing factor for the subsequent development of ON. In a patient with acute rheumatic fever and hip pain, a radiograph should be obtained early to rule out underlying pathology. If hip symptoms persist, ON should be considered, and a bone scan or magnetic resonance imaging examination should be performed.
RESUMEN
OBJECTIVE: To define the onset and duration of effect of the HLA alleles that are associated with disease susceptibility and protection in juvenile rheumatoid arthritis (JRA) and 2 of its subtypes. METHODS: We typed 680 patients with JRA and 254 ethnically matched unrelated controls for HLA class I and II genes. The frequency of each allele was calculated for each of the age-at-onset, onset type, and sex categories and plotted against the allele frequency in the control population. Survival analysis (with onset of disease as the terminating event) was used to calculate the age by which 50% (St0.5) and 80% (St0.2) of the children with particular alleles and combinations of alleles develop disease. This allele-specific survival analysis also allowed for the comparison of the overall survival functions for the various JRA subtype and sex categories. RESULTS: Certain alleles are strongly associated with early susceptibility to pauciarticular JRA, including HLA-A2, DR8, DR5, and DPB1*0201. Fifty percent of the children carrying at least 1 of these alleles had disease onset prior to their third birthday. Among children who carried HLA-A2 and any 2 HLA-DR alleles (DR3, DR5, DR6, or DR8), the median age at the onset of pauciarticular disease was 2.7 years. Combinations of A2 and DPB1*0201 and one DR allele narrowed the window further to a median age at onset of 2.4 years. B27 and DR4 were associated with protection early in life but with increased risk later in childhood, with St0.5 values of 7.3 and 6.6 years, respectively, for pauciarticular JRA and St0.5 values of 10.2 and 10.7 years, respectively, for polyarticular JRA. Sex strongly influenced the age at which many of the alleles have their effect. CONCLUSION: These data define at what age and for how long various HLA alleles influence susceptibility and protection (window-of-effect) in patients with JRA. In addition, these data establish more clearly the boundaries of ages-at-onset for 2 of the subtypes of the disease.
Asunto(s)
Artritis Juvenil/genética , Artritis Juvenil/inmunología , Antígenos HLA/genética , Factores de Edad , Alelos , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Antígeno HLA-B27/genética , Antígeno HLA-DR1/genética , Antígeno HLA-DR4/genética , Antígeno HLA-DR5/genética , Antígeno HLA-DR6/genética , Humanos , Lactante , Recién Nacido , Masculino , Factores de TiempoRESUMEN
Many nonrheumatic diseases of childhood present with musculoskeletal abnormalities. A significant proportion of these disorders have a genetic basis, many involving defects in structural proteins of the connective tissue. Chief among these are collagen mutations resulting in spondyloepiphyseal dysplasias and Ehlers-Danlos syndrome, as well as fibrillin defects associated with Marfan's syndrome. A variety of other chromosomal anomalies are associated with musculoskeletal abnormalities, and may result from as yet unidentified connective tissue defects. In addition, metabolic diseases may result in findings of hyper- or hypomobility, or carpal tunnel syndrome. Helpful clinical clues to identify nonrheumatologic musculoskeletal disease, as well as recent advances in our understanding of the genetic basis of several of these disorders, are reviewed here.
Asunto(s)
Enfermedades Musculoesqueléticas/complicaciones , Enfermedades Musculoesqueléticas/genética , Enfermedades Reumáticas/etiología , Preescolar , Aberraciones Cromosómicas/fisiopatología , Trastornos de los Cromosomas , Colágeno/genética , Colágeno/fisiología , Enfermedades del Colágeno/complicaciones , Enfermedades del Colágeno/genética , Fibrilinas , Factor 3 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/genética , Humanos , Enfermedades Metabólicas/complicaciones , Enfermedades Metabólicas/genética , Proteínas de Microfilamentos/genética , Mutación , Proteínas Proto-Oncogénicas/genéticaRESUMEN
Juvenile rheumatoid arthritis (JRA) is a chronic inflammatory disease primarily affecting the joints but also extra articular tissue. The long-term outcome of JRA has different aspects, which include disease outcome, mortality, iridocyclitis and stature. Several studies, which have addressed these issues, are reviewed in this article. In addition, functional, educational and employment status of patients with JRA are also reviewed. To facilitate better understanding of these various studies, a description of the terminology used in defining disease is provided. Several of the instruments that are available for assessing outcome among patients are described. The role of laboratory and radiological evaluation in predicting outcome is also addressed.