RESUMEN

Bruton's tyrosine kinase (BTK) is a target for treatment of hematologic malignancies and autoimmune diseases. TAK-020 is a highly selective covalent BTK inhibitor that inhibits both B cell receptor and fragment crystallizable receptor signaling. We assessed the safety/tolerability and pharmacokinetics/pharmacodynamics (PDs) of TAK-020 in healthy subjects. Each cohort of the single-rising dose (n = 72; 9 cohorts) and the multiple-rising dose (n = 48; 6 cohorts) portions of the study comprised six TAK-020-treated and two placebo-treated, subjects aged 18-55 years (inclusive). The PD effects were assessed by measuring BTK occupancy and the inhibition of fragment crystallizable epsilon receptor 1 (FcεRI)-mediated activation of basophils. Overall, treatment-emergent adverse events (TEAEs) were similar to placebo; there were no serious TEAEs or no TEAEs leading to discontinuation. TAK-020 was rapidly absorbed (median time to maximum plasma concentration (Tmax ) 45-60 minutes) with a half-life of ~ 3-9 hours at doses ≥ 2.5 mg. TAK-020 exposure was generally dose proportional for single doses ≤ 70 mg and after multiple doses of ≤ 60 mg once daily. Target occupancy was dose dependent, with doses ≥ 2.5 mg yielding maximum and sustained occupancy > 70% for > 96 hours. Single doses ≥ 4.4 mg reduced FcεRI-mediated activation of basophils by > 80% and comparable inhibition was observed with daily dosing ≥3.75 mg for 9 days. Inhibition persisted for 24-72 hours postdose and the duration generally increased with dose. TAK-020 was generally well-tolerated in healthy subjects after single and multiple doses and demonstrated target engagement and pathway modulation. The PD effects outlasted drug exposures, as expected for covalent inhibition of BTK.

Asunto(s)

Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Basófilos/efectos de los fármacos , Inhibidores de Proteínas Quinasas/efectos adversos , Administración Oral , Adolescente , Adulto , Agammaglobulinemia Tirosina Quinasa/metabolismo , Basófilos/inmunología , Basófilos/metabolismo , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Miastenia Gravis/tratamiento farmacológico , Miastenia Gravis/inmunología , Placebos/administración & dosificación , Placebos/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/inmunología , Adulto Joven

RESUMEN

AIMS: This investigation characterised tolerability, pharmacokinetics and pharmacodynamics of the anti-CD38 antibody TAK-079. METHODS: A randomised, double-blind, placebo-controlled trial of a single intravenous (i.v.) infusion or subcutaneous (s.c.) injection of TAK-079 at escalating doses in healthy subjects (n = 74), who were followed for 92 days postexposure. RESULTS: TAK-079 was well tolerated. All adverse events were mild or moderate. There were no withdrawals, infusion, or injection site reactions over the tested i.v. and s.c. doses up to 0.06 and 0.6 mg kg-1 , respectively. At higher doses, transient cytokine level increases, following i.v. administration, coincided with reduction in CD38-expressing cells; clinical symptoms included mild pyrexia, headache, and postural hypotension. Following an i.v. infusion of 0.06 mg kg-1 TAK-079, maximum observed serum concentration (Cmax ) was 100.4 (%CV: 52) ng mL-1 , time to Cmax was the end of infusion and natural killer (NK_ cells were reduced 93.8 (±8.5) % from baseline levels. Following a s.c. injection of 0.6 mg kg-1 TAK-079, Cmax was 23.0 (%CV: 67) ng mL-1 with time to Cmax of 24 (range 7.98-96.02) hours, and plasmablasts were subsequently reduced 93.4 (±8.8) % from predose levels. Serum immunoglobulin (Ig)M, IgA and IgG levels were reduced by 15-60% and had not returned to baseline levels within 78 days after administration at ≥0.3 mg kg-1 s.c. Reductions in NK cells at 0.6 mg kg-1 s.c. were approximately 2-3 times more durable than at 0.06 mg kg-1 i.v. CONCLUSIONS: TAK-079 was well tolerated and s.c. administration elicited more durable reductions in plasmablasts and NK cells. This plasmacytolytic profile could be useful for treating disorders caused by plasma or NK cells, malignant counterparts, and/or pathogenic antibodies.

Asunto(s)

Anticuerpos Monoclonales , Antineoplásicos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Voluntarios Sanos , Humanos , Células Asesinas Naturales

RESUMEN

Ectoenzyme CD38 is increased on lymphocytes in response to an antigenic challenge and it is hypothesized that targeting these activated lymphocytes could ameliorate pathologic activities in autoimmune diseases. The cynomolgus monkey is an appropriate model for assessing potential effects of targeting CD38 in humans because these species exhibit similar expression profiles. TAK-079 is a human monoclonal antibody (IgG1 λ ) that binds to CD38 and lyses bound cells by complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. TAK-079 binds to monkey CD38 with an affinity at EC50 4.5 nM, and the potential activity of TAK-079 was investigated in a monkey collagen-induced arthritis model of autoimmune disease. Prophylactic administration of TAK-079 (3 mg/kg i.v. weekly) was well tolerated and prevented arthritis development compared with vehicle-treated control animals, which exhibited progressive disease with radiographic damage and worsening clinical scores over the study course. Therapeutic treatment of arthritic monkeys with TAK-079 (3 mg/kg i.v. weekly) was also well tolerated and reduced disease progression and symptoms. Arthritis scores and joint swelling were significantly lower than the vehicle control, accompanied by decreases in blood levels of C-reactive protein, alkaline phosphatase, and natural killer, B, and T cells. Histopathology, morphometry, and radiology revealed significantly less joint damage in animals exposed prophylactically to TAK-079 treatment compared with vehicle-treated animals and significantly less damage in animals treated therapeutically with TAK-079 or dexamethasone (0.1 mg/kg oral gavage daily), illustrating potential disease-modifying activity. In conclusion, these data indicate that depletion of CD38-expressing cells could be a therapeutic mechanism for treating autoimmune diseases. SIGNIFICANCE STATEMENT: This study demonstrates that targeting CD38-expressing leukocytes with a cytolytic antibody can ameliorate autoimmune disease in cynomolgus monkeys. The study gives a unique perspective into this therapeutic strategy because the three other anti-CD38 cytolytic antibodies in clinical development (daratumumab, isatuximab, and MOR202) cannot be tested in similar models because they do not crossreact with CD38 expressed by new world primates.

Asunto(s)

ADP-Ribosil Ciclasa 1/metabolismo , Anticuerpos Monoclonales/inmunología , Artritis Experimental/inmunología , Linfocitos B/metabolismo , Regulación de la Expresión Génica/inmunología , Células Asesinas Naturales/metabolismo , Linfocitos T/metabolismo , ADP-Ribosil Ciclasa 1/inmunología , Animales , Artritis Experimental/metabolismo , Artritis Experimental/patología , Linfocitos B/inmunología , Células CHO , Cricetulus , Progresión de la Enfermedad , Células Asesinas Naturales/inmunología , Macaca fascicularis , Linfocitos T/inmunología

RESUMEN

BACKGROUND: Hyperuricemia is associated with hypertension, with elevated serum uric acid levels postulated to have a causal role in the development of hypertension. Consequently, serum uric acid reduction may help lower blood pressure (BP). A Phase 2, double-blind, placebo-controlled trial was conducted to assess the potential BP-lowering effects of the xanthine oxidase inhibitor febuxostat in subjects with hypertension and hyperuricemia (serum uric acid ≥0.42 mmol/L [≥7.0 mg/dL]). METHODS AND RESULTS: Subjects (n=121) were randomized 1:1 to febuxostat 80 mg once daily or to placebo. The primary end point was change from baseline to Week 6 in 24-hour mean ambulatory systolic BP (SBP). Additional end points included the following: change from baseline to Week 3 in 24-hour mean SBP and changes from baseline to Weeks 3 and 6 in 24-hour mean ambulatory diastolic BP, serum uric acid, mean daytime and nighttime ambulatory SBP/diastolic BP, and clinic SBP/diastolic BP. For the overall study population, there were no significant differences between febuxostat and placebo for changes from baseline to Weeks 3 or 6 in ambulatory, daytime or nighttime, or clinic SBP or diastolic BP. However, in a preplanned subgroup analysis, there was a significant decrease in SBP from baseline to Week 6 in subjects with normal renal function (estimated glomerular filtration rate ≥90 mL/min) treated with febuxostat versus placebo; least squares mean difference, -6.7; 95% confidence interval -13.3 to -0.0; P=0.049. CONCLUSIONS: This study suggests that febuxostat may lower BP in hyperuricemic patients with hypertension and normal renal function; further studies should be conducted to confirm this finding. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01496469.

Asunto(s)

Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Inhibidores Enzimáticos/uso terapéutico , Febuxostat/uso terapéutico , Hipertensión/tratamiento farmacológico , Hiperuricemia/tratamiento farmacológico , Ácido Úrico/sangre , Xantina Oxidasa/antagonistas & inhibidores , Adulto , Anciano , Antihipertensivos/efectos adversos , Biomarcadores/sangre , Monitoreo Ambulatorio de la Presión Arterial , Método Doble Ciego , Inhibidores Enzimáticos/efectos adversos , Febuxostat/efectos adversos , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/diagnóstico , Hipertensión/fisiopatología , Hiperuricemia/sangre , Hiperuricemia/complicaciones , Hiperuricemia/diagnóstico , Masculino , Persona de Mediana Edad , América del Norte , Prueba de Estudio Conceptual , Estudios Prospectivos , Factores de Tiempo , Resultado del Tratamiento , Xantina Oxidasa/metabolismo

RESUMEN

BACKGROUND AND OBJECTIVES: Higher urinary uric acid excretion is a suspected risk factor for calcium oxalate stone formation. Febuxostat, a xanthine oxidoreductase inhibitor, is effective in lowering serum urate concentration and urinary uric acid excretion in healthy volunteers and people with gout. This work studied whether febuxostat, compared with allopurinol and placebo, would reduce 24-hour urinary uric acid excretion and prevent stone growth or new stone formation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this 6-month, double-blind, multicenter, randomized controlled trial, hyperuricosuric participants with a recent history of calcium stones and one or more radio-opaque calcium stone ≥ 3 mm (as seen by multidetector computed tomography) received daily febuxostat at 80 mg, allopurinol at 300 mg, or placebo. The primary end point was percent change from baseline to month 6 in 24-hour urinary uric acid. Secondary end points included percent change from baseline to month 6 in size of index stone and change from baseline in the mean number of stones and 24-hour creatinine clearance. RESULTS: Of 99 enrolled participants, 86 participants completed the study. Febuxostat led to significantly greater reduction in 24-hour urinary uric acid (-58.6%) than either allopurinol (-36.4%; P=0.003) or placebo (-12.7%; P<0.001). Percent change from baseline in the size of the largest calcium stone was not different with febuxostat compared with allopurinol or placebo. There was no change in stone size, stone number, or renal function. No new safety concerns were noted for either drug. CONCLUSIONS: Febuxostat (80 mg) lowered 24-hour urinary uric acid significantly more than allopurinol (300 mg) in stone formers with higher urinary uric acid excretion after 6 months of treatment. There was no change in stone size or number over the 6-month period.

Asunto(s)

Alopurinol/uso terapéutico , Oxalato de Calcio/metabolismo , Inhibidores Enzimáticos/uso terapéutico , Tiazoles/uso terapéutico , Ácido Úrico/orina , Cálculos Urinarios/tratamiento farmacológico , Xantina Oxidasa/antagonistas & inhibidores , Adulto , Alopurinol/efectos adversos , Biomarcadores/orina , Método Doble Ciego , Inhibidores Enzimáticos/efectos adversos , Febuxostat , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tomografía Computarizada Multidetector , Tiazoles/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos , Cálculos Urinarios/diagnóstico por imagen , Cálculos Urinarios/orina , Xantina Oxidasa/metabolismo

RESUMEN

AIMS: To determine the effect of febuxostat on cytochrome P450 2C8 (CYP2C8) activity using rosiglitazone as a CYP2C8 substrate. METHODS: Healthy subjects received febuxostat 120 mg daily (regimen A) or matching placebo (regimen B) for 9 days along with a single oral dose of rosiglitazone 4 mg on day 5 in a double-blind, randomized, cross-over fashion (≥7 day washout between periods). Plasma samples for analysis of the impact of febuxostat on the pharmacokinetics (PK) of rosiglitazone and its metabolite, N-desmethylrosiglitazone, were collected for 120 h after co-administration. RESULTS: Of the 39 subjects enrolled, 36 completed the study and were included in the PK analyses. Rosiglitazone PK parameters were comparable between regimens A and B. Median time to maximal plasma concentration, mean maximal plasma concentration (C(max)), area under the concentration-time curve (AUC) from time zero to the last quantifiable concentration (AUC(0-tlqc)), AUC from time zero to infinity (AUC(0-∞)), and terminal elimination half-life for regimen A were 0.50 h, 308.6 ng ml⁻¹, 1594.9 ng h ml⁻¹, 1616.0 ng h ml⁻¹ and 4.1 h, respectively, and for regimen B they were 0.50 h, 327.6 ng ml⁻¹, 1564.5 ng h ml⁻¹, 1584.2 ng h ml⁻¹ and 4.0 h, respectively. Point estimates for the ratio of regimen A to regimen B (90% confidence intervals) for rosiglitazone C(max) , AUC(0-tlqc) and AUC(0-∞) central values were 0.94 (0.89-1.00), 1.02 (1.00-1.04) and 1.02 (1.00-1.04), respectively. CONCLUSIONS: Co-administration of febuxostat had no effect on rosiglitazone or N-desmethylrosiglitazone PK parameters, suggesting that febuxostat can be given safely with drugs metabolized through CYP2C8.

Asunto(s)

Hidrocarburo de Aril Hidroxilasas/metabolismo , Supresores de la Gota/administración & dosificación , Hipoglucemiantes/farmacocinética , Tiazoles/administración & dosificación , Tiazolidinedionas/farmacocinética , Administración Oral , Adolescente , Adulto , Análisis de Varianza , Área Bajo la Curva , Disponibilidad Biológica , Biotransformación , Estudios Cruzados , Citocromo P-450 CYP2C8 , Método Doble Ciego , Interacciones Farmacológicas , Febuxostat , Femenino , Supresores de la Gota/efectos adversos , Semivida , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/sangre , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Modelos Biológicos , Rosiglitazona , Especificidad por Sustrato , Tiazoles/efectos adversos , Tiazolidinedionas/administración & dosificación , Tiazolidinedionas/efectos adversos , Tiazolidinedionas/sangre , Adulto Joven

RESUMEN

OBJECTIVE: To assess the health related quality of life of patients with primary Sjögren's Syndrome (PSS) in a large US sample. METHODS: Questionnaires were mailed to 547 patients with a confirmed diagnosis of PSS (PhysR-PSS) and all active members of the Sjögren's Syndrome Foundation USA (SSF-PSS), half of whom identified a friend without PSS to also complete the survey. RESULTS: 277 PhysR-PSS patients were compared to 606 controls. The mean age was 62 years in the PhysR-PSS group and 61 years in the control group. 90% in both groups were women. Time from first symptom to diagnosis of PSS was a mean of 7 years. Sicca related morbidity, fatigue severity, depression and pain (assessed by validated questionnaires, PROFAD-SSI, FACIT-F, CES-D, BPI) were significantly greater, and all eight SF-36 domains were significantly diminished, in patients compared to controls. Somatic fatigue was the dominant predictor of physical function and of general health. Depression was the dominant predictor of emotional well being. Health care utilization was higher in patients than controls, including out of pocket dental expenses (mean: PhysR-PSS = $1473.3, controls = $503.6), dental visits (mean: PhysR-PSS = 4.0, controls = 2.3), current treatments (mean: PhysR-PSS = 6.6, controls = 2.5), and hospitalizations (53% PhysR-PSS, vs. 40% controls). CONCLUSION: Diminished health quality and excess health costs are prevalent among PSS patients. Health experiences and functional impact of PSS is similar among US and European patients. Delayed diagnosis, sicca related morbidity, fatigue, pain and depression are substantial suggesting unmet health needs and the importance of earlier recognition of PSS.

Asunto(s)

Calidad de Vida , Síndrome de Sjögren , Adulto , Anciano , Análisis de Varianza , Atención Odontológica/economía , Atención Odontológica/estadística & datos numéricos , Depresión/etiología , Síndrome de Fatiga Crónica/etiología , Femenino , Servicios de Salud/estadística & datos numéricos , Encuestas Epidemiológicas , Humanos , Modelos Lineales , Persona de Mediana Edad , Dolor/etiología , Índice de Severidad de la Enfermedad , Síndrome de Sjögren/complicaciones , Síndrome de Sjögren/psicología , Trastornos Somatomorfos/etiología , Encuestas y Cuestionarios , Estados Unidos

RESUMEN

BACKGROUND: In small studies, investigators have described oral features and their sequelae in primary Sjögren syndrome (PSS), but they have not provided a full picture of the aspects and implications of oral involvement. The authors describe what is, to their knowledge, the first large-scale evaluation to do so. In addition, they report data regarding utilization and cost of dental care among patients with PSS. METHODS: The authors surveyed patients with primary Sjögren syndrome as identified by their physicians (PhysR-PSS), patient-members of the Sjögren's Syndrome Foundation (SSF-PSS) and control subjects who did not have PSS. They made comparisons between the three groups. RESULTS: Subjects were 277 patients with PhysR-PSS, 1,225 patients with SSF-PSS and 606 control subjects. More than 96 percent of those in the patient groups experienced oral problems. An oral complaint was the initial symptom in more than one-half of the patients. Xerostomia-associated signs and symptoms were common and severe, as evidenced by scores on an inventory of sicca symptoms. These patients' rate of dental care utilization was high, and the care was costly. CONCLUSIONS: Oral and dental disease in PSS is extensive and persistent and represents a significant burden of illness. CLINICAL IMPLICATIONS: Oral symptoms and signs are common in patients with PSS. Early recognition of the significance of these findings by oral specialists could accelerate diagnosis and minimize oral morbidities.

Asunto(s)

Estado de Salud , Enfermedades de la Boca/complicaciones , Salud Bucal , Síndrome de Sjögren/fisiopatología , Anciano , Análisis de Varianza , Estudios de Casos y Controles , Estudios de Cohortes , Costo de Enfermedad , Estudios Transversales , Atención Dental para Enfermos Crónicos , Encuestas de Salud Bucal , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Valores de Referencia , Síndrome de Sjögren/complicaciones , Síndrome de Sjögren/psicología , Xerostomía/complicaciones

Asunto(s)

Artritis Reumatoide/genética , Predisposición Genética a la Enfermedad , Polimorfismo Genético , Proteínas Tirosina Fosfatasas/genética , Población Blanca/genética , Artritis Reumatoide/etnología , Artritis Reumatoide/inmunología , Femenino , Frecuencia de los Genes , Humanos , Masculino , Nueva Zelanda/epidemiología , Proteína Tirosina Fosfatasa no Receptora Tipo 22

Asunto(s)

Gota/complicaciones , Artropatías/etiología , Úlcera Cutánea/etiología , Gota/patología , Humanos , Artropatías/patología , Masculino , Persona de Mediana Edad , Nariz/patología , Polinesia , Úlcera Cutánea/patología , Articulación del Dedo del Pie/patología

RESUMEN

The product of the deleted in colorectal carcinoma (DCC) gene has a role in apoptosis and is a positional candidate for IDDM6, the putative chromosome 18q12-q23 autoimmune disease locus. We hypothesised that a nonconservative substitution (DCC 201 R --> G; nucleotide (nt) 601 C --> G), located in an extracellular immunoglobulin-like domain of DCC, is an aetiological determinant of autoimmunity. We tested this hypothesis by genetically testing the nt 601 C --> G polymorphism for association with three autoimmune phenotypes in a large population-based case-control study. There was no evidence for association of DCC nt 601 C --> G with autoimmune disease in cohorts comprising 2253 subjects with rheumatoid arthritis, type I diabetes and Graves' disease, and 2225 control subjects, from New Zealand and the United Kingdom. Furthermore, using the transmission disequilibrium test, there was no significant evidence for biased transmission of the nt 601 C --> G polymorphism to probands within a 382 family type I diabetes affected sibpair cohort from the United Kingdom. Thus, the DCC 201 R --> G polymorphism does not appreciably influence risk of developing the autoimmune diseases tested.

Asunto(s)

Enfermedades Autoinmunes/genética , Neoplasias Colorrectales/genética , Genes DCC , Polimorfismo Genético , Adulto , Edad de Inicio , Estudios de Casos y Controles , Niño , Preescolar , Genética de Población , Haplotipos , Heterocigoto , Humanos , Repeticiones de Microsatélite

RESUMEN

OBJECTIVE: Magnetic resonance imaging (MRI) is capable of revealing synovitis and tendinitis in early rheumatoid arthritis (RA), as well as bone edema and erosion. These features are visible before radiographic joint damage occurs. We sought to examine whether MRI of one body region (the wrist) can be used to predict whole-body radiography scores reflecting joint damage at 6 years. METHODS: We conducted a 6-year prospective study of a cohort of patients who fulfilled the criteria for RA at presentation, using clinical parameters, radiographs, and MRI scans of the dominant wrist. Of the 42 patients enrolled at baseline, full MRI, radiographic, and clinical data were available for 31 at 6-year followup. MRI scans were scored by 2 radiologists, using a validated scoring system. Radiographs of the hands and feet were graded using the modified Sharp scoring method. MRI and radiography scores obtained at baseline and 6 years were compared, and baseline MRI scores were examined for their ability to predict radiographic outcome at 6 years. RESULTS: At 6 years, the total Sharp score correlated significantly with the total MRI score and the MRI erosion score (r = 0.81, P < 0.0001 and r = 0.79, P < 0.0001, respectively). The 6-year Sharp score also correlated with the baseline total MRI and MRI erosion scores (r = 0.56, P < 0.0001 and r = 0.33, P = 0.03, respectively). MRI synovitis and bone edema scores remained constant for the group as a whole over 6 years, but bone erosion scores progressed (P = 0.0001), consistent with radiographic deterioration. Erosions on 6-year MRI scans were frequently preceded by MRI bone edema at baseline (odds ratio 6.5, 95% confidence interval 2.78-18.1). Regression models indicated that the baseline MRI bone edema score was predictive of the 6-year total Sharp score (P = 0.01), as was the C-reactive protein (CRP) level (P = 0.0002). Neither shared epitope status nor swollen or tender joint counts predicted radiographic outcome in this cohort. A model incorporating baseline MRI scores for erosion, bone edema, synovitis, and tendinitis plus the CRP level and the erythrocyte sedimentation rate explained 59% of the variance in the 6-year total Sharp score (R(2) = 0.59, adjusted R(2) = 0.44). CONCLUSION: MRI scans performed at the first presentation of RA can be used to help predict future radiographic damage, allowing disease-modifying therapy to be targeted to patients with aggressive disease.

Asunto(s)

Artritis Reumatoide/diagnóstico por imagen , Huesos del Carpo/diagnóstico por imagen , Edema/diagnóstico por imagen , Imagen por Resonancia Magnética , Articulación de la Muñeca/diagnóstico por imagen , Artritis Reumatoide/patología , Artritis Reumatoide/cirugía , Artrografía/normas , Artrografía/estadística & datos numéricos , Huesos del Carpo/patología , Progresión de la Enfermedad , Edema/patología , Epítopos , Pie , Mano , Humanos , Imagen por Resonancia Magnética/normas , Imagen por Resonancia Magnética/estadística & datos numéricos , Variaciones Dependientes del Observador , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Inducción de Remisión , Reproducibilidad de los Resultados , Sinovitis/diagnóstico por imagen , Sinovitis/patología , Articulación de la Muñeca/patología