RESUMEN
OBJECTIVE: The aim of this study was to examine the impact of smoking on health-related quality of life (HRQoL) among AS patients who were taking biologic DMARDS. METHODS: This is a longitudinal cohort study of AS patients with anti-TNF treatment in the Australian Rheumatology Association Database (2003-11). They were assessed using the 36-item Short Form Health Survey (SF-36), Assessment of Quality of Life (AQoL) and HAQ for spondylitis (HAQ-S) on a biannual basis. Linear mixed models were used to assess the impact of smoking on HRQoL outcomes over the first 2 years of treatment. RESULTS: Four hundred and twenty-two patients [73% male, mean age 44.9 years (s.d. 12.7) provided 1189 assessments for the study. Current smokers (n = 79) were slightly younger, more likely to be male, less likely to use or to have previously used prednisolone and had a slightly shorter disease duration than past smokers (n = 138) or non-smokers (n = 205). After adjusting for smoking, gender, age, education, employment, co-morbidities and medication use, including DMARDs, anti-inflammatories and analgesics, all the HRQoL measures improved significantly over the study period and the improvements were not modified by smoking status (all P-values >0.36). Current smokers tended to have a poorer HRQoL on the SF-36 physical score [-1.93 (95% CI -3.94, 0.09), P = 0.06] and the HAQ-S score [0.10 (95% CI -0.01, 0.20), P = 0.07] compared with non-smokers. CONCLUSION: Among AS patients, active smoking did not diminish or modify the improvements in HRQoL from anti-TNF treatment, even though current smokers compared with non-smokers tended to have poorer scores in some HRQoL measures.
Asunto(s)
Antirreumáticos/uso terapéutico , Factores Biológicos/uso terapéutico , Fumar/efectos adversos , Espondilitis Anquilosante/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adulto , Femenino , Humanos , Estudios Longitudinales , Masculino , Calidad de Vida , Resultado del TratamientoRESUMEN
BACKGROUND: Uricosuric agents have long been used in the treatment of gout but there is little evidence regarding their benefit and safety in this condition. OBJECTIVES: To assess the benefits and harms of uricosuric medications in the treatment of chronic gout. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 4, 2013), Ovid MEDLINE and Ovid EMBASE for studies to the 13 May 2013. We also searched the World Health Organization Clinical Trials Registry, ClinicalTrials.gov and the 2011 to 2012 American College of Rheumatology and European League against Rheumatism abstracts. WE considered black box warnings and searched drug safety databases to identify and describe rare adverse events. SELECTION CRITERIA: We considered all randomised controlled trials (RCTs) or quasi-randomised controlled trials (controlled clinical trials (CCTs)) that compared uricosuric medications (benzbromarone, probenecid or sulphinpyrazone) alone or in combination with another therapy (placebo or other active uric acid-lowering medication, or non-pharmacological treatment) in adults with chronic gout for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the studies for inclusion, extracted data and performed a risk of bias assessment. Main outcomes were frequency of acute gout attacks, serum urate normalisation, study participant withdrawal due to adverse events, total adverse events, pain reduction, function and tophus regression. MAIN RESULTS: The search identified four RCTs and one CCT that evaluated the benefit and safety of uricosurics for gout. One study (65 participants) compared benzbromarone with allopurinol for a duration of four months; one compared benzbromarone with allopurinol (36 participants) for a duration of nine to 24 months; one study (62 participants) compared benzbromarone with probenecid for two months and one study (74 participants) compared benzbromarone with probenecid. One study (37 participants) compared allopurinol with probenecid. No study was completely free from bias.Low-quality evidence from one study (55 participants) comparing benzbromarone with allopurinol indicated uncertain effects in terms of frequency of acute gout attacks (4% with benzbromarone versus 0% with allopurinol; risk ratio (RR) 3.58, 95% confidence interval (CI) 0.15 to 84.13), while moderate-quality evidence from two studies (101 participants; treated for four to nine months) indicated similar proportions of participants achieving serum urate normalisation (73.9% with benzbromarone versus 60% with allopurinol; pooled RR 1.27, 95% CI 0.90 to 1.79). Low-quality evidence indicated uncertain differences in withdrawals due to adverse events (7.1% with benzbromarone versus 6.1% with allopurinol; pooled RR 1.25, 95% CI 0.28 to 5.62), and total adverse events (20% with benzbromarone versus 6.7% with allopurinol; RR 3.00, 95% CI 0.64 to 14.16). The study did not measure pain reduction, function and tophus regression.When comparing benzbromarone with probenecid, there was moderate-quality evidence based on one study (62 participants) that participants taking benzbromarone were more likely to achieve serum urate normalisation after two months (81.5% with benzbromarone versus 57.1% with probenecid; RR 1.43, 95% CI 1.02 to 2.00). This indicated that when compared with probenecid, five participants needed to be treated with benzbromarone in order to have one additional person achieve serum urate normalisation (number needed to treat for an additional beneficial outcome (NNTB) 5). However, the second study reported no difference in the absolute decrease in serum urate between these groups after 12 weeks. Low-quality evidence from two studies (129 participants) indicated uncertain differences between treatments in the frequency of acute gout attacks (6.3% with benzbromarone versus 10.6% with probenecid; pooled RR 0.73, 95% CI 0.09 to 5.83); fewer withdrawals due to adverse events with benzbromarone (2% with benzbromarone versus 17% with probenecid; pooled RR 0.15, 95% CI 0.03 to 0.79, NNTB 7) and fewer total adverse events (21% with benzbromarone versus 47% with probenecid; pooled RR 0.43, 95% CI 0.25 to 0.74; NNTB 4). The studies did not measure pain reduction, function and tophus regression.Low-quality evidence based on one small CCT (37 participants) indicated uncertainty around the difference in the incidence of acute gout attacks between probenecid and allopurinol after 18 to 20 months' treatment (53% with probenecid versus 55% with allopurinol; RR 0.96, 95% CI 0.53 to 1.75). The study did not measure or report the proportion achieving serum urate normalisation, pain reduction, function, tophus regression, withdrawal due to adverse events and total adverse events. AUTHORS' CONCLUSIONS: There was moderate-quality evidence that there is probably no important difference between benzbromarone and allopurinol at achieving serum urate normalisation, but that benzbromarone is probably more successful than probenecid at achieving serum urate normalisation in people with gout. There is some uncertainty around the effect estimates, based on low-quality evidence from only one or two trials, on the number of acute gout attacks, the number of withdrawals due to adverse events or the total number of participants experiencing adverse events when comparing benzbromarone with allopurinol. However, when compared with probenecid, benzbromarone resulted in fewer withdrawals due to adverse events and fewer participants experiencing adverse events. Low-quality evidence from one small study indicated uncertain effects in the incidence of acute gout attacks when comparing probenecid with allopurinol therapy. We downgraded the evidence because of a possible risk of performance and other biases and imprecision.
Asunto(s)
Gota/tratamiento farmacológico , Uricosúricos/uso terapéutico , Adulto , Anciano , Alopurinol/uso terapéutico , Benzbromarona/uso terapéutico , Enfermedad Crónica , Ensayos Clínicos Controlados como Asunto , Femenino , Gota/sangre , Humanos , Masculino , Persona de Mediana Edad , Probenecid/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Ácido Úrico/sangre , Uricosúricos/efectos adversosRESUMEN
BACKGROUND: Allopurinol, a xanthine oxidase inhibitor, is considered one of the most effective urate-lowering drugs and is frequently used in the treatment of chronic gout. OBJECTIVES: To assess the efficacy and safety of allopurinol compared with placebo and other urate-lowering therapies for treating chronic gout. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE on 14 January 2014. We also handsearched the 2011 to 2012 American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) abstracts, trial registers and regulatory agency drug safety databases. SELECTION CRITERIA: All randomised controlled trials (RCTs) or quasi-randomised controlled clinical trials (CCTs) that compared allopurinol with a placebo or an active therapy in adults with chronic gout. DATA COLLECTION AND ANALYSIS: We extracted and analysed data using standard methods for Cochrane reviews. The major outcomes of interest were frequency of acute gout attacks, serum urate normalisation, pain, function, tophus regression, study participant withdrawal due to adverse events (AE) and serious adverse events (SAE). We assessed the quality of the body of evidence for these outcomes using the GRADE approach. MAIN RESULTS: We included 11 trials (4531 participants) that compared allopurinol (various doses) with placebo (two trials); febuxostat (four trials); benzbromarone (two trials); colchicine (one trial); probenecid (one trial); continuous versus intermittent allopurinol (one trial) and different doses of allopurinol (one trial). Only one trial was at low risk of bias in all domains. We deemed allopurinol versus placebo the main comparison, and allopurinol versus febuxostat and versus benzbromarone as the most clinically relevant active comparisons and restricted reporting to these comparisons here.Moderate-quality evidence from one trial (57 participants) indicated allopurinol 300 mg daily probably does not reduce the rate of gout attacks (2/26 with allopurinol versus 3/25 with placebo; risk ratio (RR) 0.64, 95% confidence interval (CI) 0.12 to 3.52) but increases the proportion of participants achieving a target serum urate over 30 days (25/26 with allopurinol versus 0/25 with placebo, RR 49.11, 95% CI 3.15 to 765.58; number needed to treat for an additional beneficial outcome (NNTB) 1). In two studies (453 participants), there was no significant increase in withdrawals due to AE (6% with allopurinol versus 4% with placebo, RR 1.36, 95% CI 0.61 to 3.08) or SAE (2% with allopurinol versus 1% with placebo, RR 1.93, 95% CI 0.48 to 7.80). One trial reported no difference in pain reduction or tophus regression, but did not report outcome data or measures of variance sufficiently and we could not calculate the differences between groups. Neither trial reported function.Low-quality evidence from three trials (1136 participants) indicated there may be no difference in the incidence of acute gout attacks with allopurinol up to 300 mg daily versus febuxostat 80 mg daily over eight to 24 weeks (21% with allopurinol versus 23% with febuxostat, RR 0.89, 95% CI 0.71 to 1.1); however more participants may achieve target serum urate level (four trials; 2618 participants) with febuxostat 80 mg daily versus allopurinol 300 mg daily (38% with allopurinol versus 70% with febuxostat, RR 0.56, 95% CI 0.48 to 0.65, NNTB with febuxostat 4). Two trials reported no difference in tophus regression between allopurinol and febuxostat over a 28- to 52-week period; but as the trialists did not provide variance, we could not calculate the mean difference between groups. The trials did not report pain reduction or function. Moderate-quality evidence from pooled data from three trials (2555 participants) comparing allopurinol up to 300 mg daily versus febuxostat 80 mg daily indicated no difference in the number of withdrawals due to AE (7% with allopurinol versus 8% with febuxostat, RR 0.89, 95% CI 0.62 to 1.26) or SAE (4% with allopurinol versus 4% with febuxostat, RR 1.13, 95% CI 0.71 to 1.82) over a 24- to 52-week period.Low-quality evidence from one trial (65 participants) indicated there may be no difference in the incidence of acute gout attacks with allopurinol up to 600 mg daily compared with benzbromarone up to 200 mg daily over a four-month period (0/30 with allopurinol versus 1/25 with benzbromarone, RR 0.28, 95% CI 0.01 to 6.58). Based on the pooled results of two trials (102 participants), there was moderate-quality evidence of no probable difference in the proportion of participants achieving a target serum urate level with allopurinol versus benzbromarone (58% with allopurinol versus 74% with benzbromarone, RR 0.79, 95% CI 0.56 to 1.11). Low-quality evidence from two studies indicated there may be no difference in the number of participants who withdrew due to AE with allopurinol versus benzbromarone over a four- to nine-month period (6% with allopurinol versus 7% with benzbromarone, pooled RR 0.80, 95% CI 0.18 to 3.58). There were no SAEs. They did not report tophi regression, pain and function.All other comparisons were supported by small, single studies only, limiting conclusions. AUTHORS' CONCLUSIONS: Our review found low- to moderate-quality evidence indicating similar effects on withdrawals due to AEs and SAEs and incidence of acute gout attacks when allopurinol (100 to 600 mg daily) was compared with placebo, benzbromarone (100 to 200 mg daily) or febuxostat (80 mg daily). There was moderate-quality evidence of little or no difference in the proportion of participants achieving target serum urate when allopurinol was compared with benzbromarone. However, allopurinol seemed more successful than placebo and may be less successful than febuxostat (80 mg daily) in achieving a target serum urate level (6 mg/dL or less; 0.36 mmol/L or less) based on moderate- to low-quality evidence. Single studies reported no difference in pain reduction when allopurinol (300 mg daily) was compared with placebo over 10 days, and no difference in tophus regression when allopurinol (200 to 300 mg daily) was compared with febuxostat (80 mg daily). None of the trials reported on function, health-related quality of life or participant global assessment of treatment success, where further research would be useful.
Asunto(s)
Alopurinol/administración & dosificación , Supresores de la Gota/administración & dosificación , Gota/tratamiento farmacológico , Benzbromarona/administración & dosificación , Enfermedad Crónica , Colchicina/administración & dosificación , Febuxostat , Gota/sangre , Humanos , Probenecid/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Tiazoles/administración & dosificación , Ácido Úrico/sangreRESUMEN
OBJECTIVE: To systematically review the evidence on the efficacy, safety, and cost-effectiveness of urate-lowering therapy for gout: xanthine oxidase inhibitors (allopurinol and febuxostat), uricosuric medications (benzbromarone, probenecid and sulfinpyrazone), and uricases (pegloticase and rasburicase). METHODS: A systematic review was performed as part of the 3e (Evidence, Expertise, Exchange) Initiative on Gout. The primary efficacy outcomes were frequency of acute gout attacks, study participant withdrawal due to adverse events, and cost-effectiveness. Serum urate-lowering was a secondary outcome and was the most commonly reported outcome in the included trials. RESULTS: The search identified 17 articles for efficacy, 31 for safety, and 3 for cost-effectiveness. The main outcome described in these studies was serum urate-lowering. Allopurinol, febuxostat, and pegloticase are all effective at lowering serum urate compared to placebo and febuxostat (≥ 80 mg) was more effective at lowering serum urate than allopurinol. Compared to probenecid, benzbromarone was more effective at lowering serum urate. Regarding acute gout attacks, pegloticase and febuxostat (≥ 120 mg) resulted in more acute attacks than placebo. Regarding the primary safety outcome, more withdrawals due to adverse events were seen only when pegloticase was compared to placebo. The two trials of cost-effectiveness were inconclusive. CONCLUSION: There is currently moderate quality data supporting the efficacy and safety of allopurinol, febuxostat, benzbromarone, and probenecid in gout. Pegloticase, while efficacious, is associated with more withdrawals due to adverse events and infusion reactions. There is insufficient evidence currently with respect to the cost-effectiveness or the most optimal sequencing of urate-lowering therapy.
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Gota/tratamiento farmacológico , Ácido Úrico/sangre , Uricosúricos/uso terapéutico , Gota/sangre , Humanos , Resultado del TratamientoRESUMEN
OBJECTIVE: To systematically review the evidence on treatment available to prevent an acute attack of gout when initiating a urate-lowering therapy (ULT) and for how long this treatment should be continued. To also evaluate the evidence on the optimal time to start a ULT after an acute attack of gout. METHODS: A systematic review as part of the 3e (Evidence, Expertise, Exchange) Initiative on Diagnosis and Management of Gout was performed using Medline, Embase, Cochrane Central Register of Controlled Trials (from 1950 to October 2011), and the European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) 2010/2011 meeting abstracts. Two reviewers independently screened titles and abstracts for selection criteria. Included articles were reviewed in detail, and a risk of bias assessment (using the Cochrane tool) was performed. RESULTS: The search identified 8168 articles and 197 abstracts, from which 4 randomized controlled trials were included in the review. Two of these studies compared placebo with colchicine, 1 compared differing durations of colchicine, and 1 compared colchicine with canakinumab. CONCLUSION: Two randomized controlled trials have shown that colchicine prophylaxis for at least 6 months, when starting a ULT, reduces the risk of acute attacks. Canakinumab, although not currently licensed for gout, has been shown to provide prophylaxis superior to colchicine, when starting a ULT. There is no evidence on the optimum time to start a ULT after an acute gout attack.
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Gota/tratamiento farmacológico , Gota/prevención & control , Uricosúricos/uso terapéutico , Esquema de Medicación , Gota/sangre , Humanos , Factores de Tiempo , Resultado del TratamientoRESUMEN
We aimed to develop evidence-based multinational recommendations for the diagnosis and management of gout. Using a formal voting process, a panel of 78 international rheumatologists developed 10 key clinical questions pertinent to the diagnosis and management of gout. Each question was investigated with a systematic literature review. Medline, Embase, Cochrane CENTRAL and abstracts from 2010-2011 European League Against Rheumatism and American College of Rheumatology meetings were searched in each review. Relevant studies were independently reviewed by two individuals for data extraction and synthesis and risk of bias assessment. Using this evidence, rheumatologists from 14 countries (Europe, South America and Australasia) developed national recommendations. After rounds of discussion and voting, multinational recommendations were formulated. Each recommendation was graded according to the level of evidence. Agreement and potential impact on clinical practice were assessed. Combining evidence and clinical expertise, 10 recommendations were produced. One recommendation referred to the diagnosis of gout, two referred to cardiovascular and renal comorbidities, six focused on different aspects of the management of gout (including drug treatment and monitoring), and the last recommendation referred to the management of asymptomatic hyperuricaemia. The level of agreement with the recommendations ranged from 8.1 to 9.2 (mean 8.7) on a 1-10 scale, with 10 representing full agreement. Ten recommendations on the diagnosis and management of gout were established. They are evidence-based and supported by a large panel of rheumatologists from 14 countries, enhancing their utility in clinical practice.
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Gota/diagnóstico , Gota/terapia , Enfermedad Aguda , Biomarcadores/metabolismo , Comorbilidad , Monitoreo de Drogas/métodos , Medicina Basada en la Evidencia/métodos , Humanos , Cooperación Internacional , Estilo de Vida , Guías de Práctica Clínica como Asunto , Uricosúricos/uso terapéuticoRESUMEN
OBJECTIVE: The authors prospectively determined: (1) the specificity and sensitivity of dual energy CT (DECT) for gout; and (2) the interobserver and intraobserver reproducibility for DECT urate volume measurements. METHODS: Forty crystal-proven gout patients (17 tophaceous) and 40 controls with other arthritic conditions prospectively underwent DECT scans of all peripheral joints using a gout protocol that color-codes the composition of tissues. A blinded radiologist identified urate deposition to calculate specificity and sensitivity of DECT for gout. Inter-rater volumetric reproducibility was determined by two independent radiologists on 40 index tophi from the 17 tophaceous gout patients using automated software. RESULTS: The mean age of the 40 gout patients was 62 years, the mean gout duration was 13 years and 87% had a history of urate-lowering therapy (ULT). The specificity and sensitivity of DECT for gout were 0.93 (95% CI, 0.80 to 0.98) and 0.78 (0.62 to 0.89), respectively. When the authors excluded three gout cases with unreadable or incomplete scans, the sensitivity was 0.84 (95% CI, 0.68 to 0.94). The urate volumes of 40 index tophi ranged from 0.06 cm(3) to 18.74 cm(3) with a mean of 2.45 cm(3). Interobserver and intraobserver intraclass correlation coefficients for DECT volume measurements were 1.00 (95% CI, 1.00 to 1.00) and 1.00 (95% CI, 1.00 to 1.00) with corresponding bias estimates (SD) of 0.01 (0.00) cm(3) and 0.01 (0.03) cm(3). CONCLUSIONS: These prospective data indicate high reproducibility of DECT urate volume measures. The specificity was high, but sensitivity was more moderate, potentially due to frequent ULT use in our patients.
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Gota/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Estudios Prospectivos , Sensibilidad y Especificidad , Ácido Úrico/análisisRESUMEN
PURPOSE: To determine the influence of factors such as age, osteoarthritis (OA), and glucocorticoid treatment on total RNA and mRNA regulation in the cornea and how these factors differ between prepupillary and peripheral areas of the cornea. METHODS: Molecular analyses of corneal tissue were performed using rabbits of different age groups and skeletally mature animals that had undergone anterior cruciate ligament (ACL) transection, an established model of knee OA. Systemic glucocorticoids were administered to cohorts of the osteoarthritic and control animals to determine the influence of distal joint disease on the corneal response. Corneal tissue was analyzed for changes in mRNA levels for several relevant genes: collagen I, collagen III, collagen V, decorin core protein, cyclooxygenase-2 (COX-2), glucocorticoid receptor, and the housekeeping gene beta-actin. RESULTS: The corneal tissue was found to have diminishing total RNA with age, which is consistent with previous studies in the literature. Interestingly, in skeletally mature animals, distal joint OA was found to affect corneal mRNA levels for several important structural and inflammatory genes (collagen I, decorin core protein, and COX-2) in a manner that progressed with OA progression. Although systemic glucocorticoid treatment did not alter mRNA levels in the normal cornea, it did counteract the changes observed early after OA induction (3 weeks) while having less of an effect in later, more established arthritis (6 weeks). CONCLUSIONS: This study reveals that distal joint OA can affect mRNA levels for several structural and inflammatory genes of the cornea, changes that seem to be suppressed by systemic glucocorticoid treatment. These findings indicate that OA has associated systemic factors that influence corneal cell metabolism.
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Envejecimiento/fisiología , Córnea/metabolismo , Glucocorticoides/uso terapéutico , Metilprednisolona/análogos & derivados , Osteoartritis de la Rodilla/tratamiento farmacológico , ARN Mensajero/metabolismo , Actinas/genética , Animales , Ciclooxigenasa 2/genética , Decorina , Proteínas de la Matriz Extracelular/genética , Femenino , Colágenos Fibrilares/genética , Metilprednisolona/uso terapéutico , Acetato de Metilprednisolona , Reacción en Cadena de la Polimerasa , Proteoglicanos/genética , Conejos , Receptores de Glucocorticoides/genéticaRESUMEN
OBJECTIVE: Using a rabbit model of inflammatory arthritis, to determine the influence of early disease on expression of specific genes and investigate the influence of intraarticular (IA) and intramuscular (IM) corticosteroids on the regulation of these genes in connective tissues of the rabbit knee. METHODS: Skeletally mature rabbits underwent induction of antigen-induced arthritis or remained untreated as control animals. Four days after disease induction, at an early stage of the disease, animals underwent either IA or IM treatment with glucocorticoids (GC) (5 mg/knee and 10 mg/kg methylprednisolone acetate, respectively). Twenty-four hours following treatment, synovium, menisci, and cartilage of the knee were collected and analyzed for changes in mRNA levels using reverse transcription-polymerase chain reaction for a number of relevant genes: collagen I, collagen II, biglycan, decorin, matrix metalloproteinases-3 and -13 (MMP-3 and MMP-13), cyclooxygenases-1 and -2 (COX-1 and COX-2), tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta), inducible nitric oxide synthase (iNOS), hyaluronan synthase-2 (HAS-2), and the housekeeping gene beta-actin. RESULTS: Early inflammatory arthritis led to an overall upregulation of most genes assessed, but a downregulation of some genes (iNOS, HAS-2, COX-1) in some tissues. While genes such as collagen II, MMP-3, and MMP-13 were uniformly downregulated by GC treatment in both normal and arthritic tissues, other genes such as collagen I, biglycan, and decorin differed in their pattern of response depending on the tissue examined, the route of drug administration, and whether normal or arthritic tissue was studied. CONCLUSION: Early mRNA changes in RA-like disease led to alterations in all tissues examined. The changes were uniquely altered by GC treatment. Route of GC administration influenced outcome.
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Corticoesteroides/farmacología , Artritis/tratamiento farmacológico , Artritis/metabolismo , Tejido Conectivo/metabolismo , Articulación de la Rodilla/metabolismo , ARN Mensajero/metabolismo , Actinas/genética , Actinas/metabolismo , Corticoesteroides/administración & dosificación , Animales , Artritis/patología , Colágeno/genética , Colágeno/metabolismo , Tejido Conectivo/patología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Inyecciones Intraarticulares , Inyecciones Intramusculares , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Articulación de la Rodilla/patología , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Prostaglandina-Endoperóxido Sintasas/genética , Prostaglandina-Endoperóxido Sintasas/metabolismo , Proteoglicanos/genética , Proteoglicanos/metabolismo , Conejos , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The impact and molecular mechanism of action of glucocorticoids in connective tissues is largely unclear, even though widely used, and whether factors such as injury and inflammation modulate this response has not been elucidated. This study describes the role of glucocorticoids in the regulation of mRNA levels for collagens I and III, MMP-13, biglycan, decorin, COX-2 and the glucocorticoid receptor in connective tissues of normal and injured joints in an established rabbit in vivo MCL scar model, and examines the potential mechanism(s) involved. In vitro promoter studies were performed using an MMP-13 promoter-luciferase expression construct in transient transfection assays with a rabbit synovial cell line (HIG-82) to identify sites of glucocorticoid-mediated transcriptional regulation and the promoter elements involved. The in vivo results indicate that scar tissue from different phases of healing (early inflammatory, granulation tissue and neovascular, and later remodelling phases, respectively) displays a different pattern of responsiveness to glucocorticoid treatment than uninjured tissue and that this responsiveness is gene dependent. The most significant impact was seen for genes such as collagen I, collagen III and MMP-13, all of which are involved in connective tissue structure and remodelling. The in vitro studies confirmed the apparent in vivo glucocorticoid-mediated response of MMP-13 mRNA and implicated the AP-1 site of the MMP-13 promoter in this regulation. Immunohistochemistry studies showed increased MMP-13 protein expression, consistent with the mRNA findings, following glucocorticoid treatment in injured tissue but not normal tissues. In conclusion, connective tissue responsiveness to glucocorticoid treatment varies depending on injury and the stage of healing of the tissue, and consequently, glucocorticoid-responsiveness may be modulated differently in states of injury and inflammation.
Asunto(s)
Cicatriz/metabolismo , Colagenasas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Glucocorticoides/farmacología , Ligamento Colateral Medial de la Rodilla/lesiones , Ligamento Colateral Medial de la Rodilla/metabolismo , ARN Mensajero/metabolismo , Análisis de Varianza , Animales , Biglicano , Línea Celular , Colágeno/metabolismo , Colagenasas/genética , Ciclooxigenasa 2/metabolismo , Cartilla de ADN , Decorina , Proteínas de la Matriz Extracelular/metabolismo , Inmunohistoquímica , Luciferasas , Metaloproteinasa 13 de la Matriz , Ligamento Colateral Medial de la Rodilla/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Regiones Promotoras Genéticas/genética , Proteoglicanos/metabolismo , Conejos , Receptores de Glucocorticoides/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
OBJECTIVE: . To determine the effect of glucocorticoid treatment on mRNA levels for matrix molecules and enzymes in knee connective tissues from skeletally mature and skeletally immature rabbits. METHODS: Intraarticular and extraarticular connective tissues of the knee were collected from skeletally mature or immature rabbits at 72 and/or 24 h postinjection of a single intramuscular inoculation of 10 mg/kg methylprednisolone or dexamethasone (skeletally mature rabbits) or 1 mg/kg (skeletally immature rabbits). Total RNA was isolated and mRNA levels for matrix molecules, matrix metalloproteinases (MMP) and their inhibitors, cyclooxygenase-2, transforming growth factor-ss, glucocorticoid receptor, and heat shock protein 90 alpha and beta were assessed by RT-PCR. RESULTS: Glucocorticoid treatment resulted in significant alterations in mRNA levels for a specific subset of genes in a tissue-specific and time-dependent manner in both maturity groups. Most notably, glucocorticoid treatment resulted in significant suppression of mRNA levels for collagens I and III, and MMP-3 and MMP-13. CONCLUSION: mRNA levels for both anabolic genes (collagens) and catabolic genes (MMP) in connective tissues are rapidly affected by systemic glucocorticoid treatment irrespective of skeletal maturity. This glucocorticoid sensitivity of normal tissues may lead to unwanted bystander effects when corticosteroids are used therapeutically, effects that could contribute to a negative influence on the functioning of such tissues.
Asunto(s)
Envejecimiento , Desarrollo Óseo/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Glucocorticoides/farmacología , Ligamentos Articulares/efectos de los fármacos , Rodilla de Cuadrúpedos/efectos de los fármacos , Animales , Desarrollo Óseo/fisiología , Ciclooxigenasa 2 , Cartilla de ADN/química , Dexametasona/farmacología , Femenino , Glucocorticoides/administración & dosificación , Proteínas HSP90 de Choque Térmico/genética , Proteínas HSP90 de Choque Térmico/metabolismo , Inyecciones Intramusculares , Ligamentos Articulares/metabolismo , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Metilprednisolona/farmacología , Prostaglandina-Endoperóxido Sintasas/genética , Prostaglandina-Endoperóxido Sintasas/metabolismo , ARN Mensajero/metabolismo , Conejos , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Rodilla de Cuadrúpedos/metabolismo , Inhibidores Tisulares de Metaloproteinasas/genética , Inhibidores Tisulares de Metaloproteinasas/metabolismo , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Rheumatoid arthritis (RA) is a systemic inflammatory disease that can elicit a variable disease course, can influence a variable number of joints, and can exhibit a variable response to treatment. All of these factors contribute to the degree and extent of damage to joint components, as well as the potential for repair of other injured joint tissues/components. Furthermore, some of the RA treatments/drugs themselves can influence repair and injury responses, as well as the outcome of surgical interventions for advanced disease. However, as treatments and interventions become more sophisticated and successful in patient populations, the opportunity to initiate the repair/replacement of the damaged joint tissues also becomes more of a reality. This review will address the current clinical findings in the literature, and then discuss the issues and opportunities to initiate repair of damaged or injured joint tissues in order to restore joint function. These include growth factors, gene therapy, and bioengineered tissues, alone or in combination to augment endogenous repair or replace tissue damaged beyond such repair capabilities.