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1.
Ann Rheum Dis ; 2024 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-39168586

RESUMEN

OBJECTIVES: The dynamics of monosodium urate (MSU) crystal changes across a range of serum urate concentrations in people with gout are unknown. This study aimed to systematically examine the relationship between serum urate and changes in dual-energy CT (DECT) urate volume in people with gout and stable serum urate concentrations. METHODS: Individual participant data were analysed from three studies of people with gout. The time periods for the analysis were selected to identify study participants with serial DECT scans of both feet over a 12-month epoch of stable urate-lowering therapy and serum urate concentrations. Data from 251 study participants were analysed using a mixed models analysis of covariance approach according to mean serum urate cut-points and mean serum urate bands. RESULTS: For all mean serum urate cut-points assessed (0.24, 0.30, 0.36, 0.42 and 0.48 mmol/L), reductions in DECT urate volumes were observed below the cut-point. Increased DECT urate volumes were observed at or above the 0.48 mmol/L mean serum urate cut-point. Differences in the change in DECT volume were observed for the 0.42 mmol/L cut-point (p=0.0044) and the 0.48 mmol/L cut-point (p<0.0001). Significantly reduced DECT urate volumes were observed for the mean serum urate bands<0.24 mmol/L and 0.24-0.29 mmol/L and increased DECT urate volume was observed for the mean serum urate band≥0.48 mmol/L. CONCLUSIONS: Over 1 year, MSU crystal dissolution, as measured by DECT, occurs with mean serum urate bands of<0.24 mmol/L and 0.24-0.29 mmol/L while MSU crystal formation occurs with mean serum urate≥0.48 mmol/L.

2.
J Rheumatol ; 2024 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-39089837

RESUMEN

OBJECTIVE: To investigate (1) the effect of colchicine prophylaxis on gout remission when commencing urate-lowering therapy (ULT), and (2) illness perceptions of people in remission using 2 definitions of gout remission. METHODS: Data from a 12-month double-blind placebo-controlled trial of 200 people with gout commencing allopurinol were analyzed. Participants were randomly assigned to prophylaxis with 0.5 mg daily colchicine or placebo for 6 months, followed by 6 months of additional follow-up. Gout remission was assessed using the 2016 preliminary definition or simplified definition without patient-reported outcomes. Illness perceptions were assessed using a gout-specific version of the Brief Illness Perception Questionnaire. RESULTS: In the first 6 months, few participants were in remission according to either the 2016 preliminary definition (3% for colchicine and 4% for placebo) or the simplified definition (7% for colchicine and 12% for placebo). In the second 6 months, after study drug (colchicine or placebo) discontinuation, fewer participants in the colchicine group than in the placebo group were in remission according to the 2016 preliminary definition (4% vs 14%, P = 0.03), and the simplified definition (14% vs 28%, P = 0.02). Participants fulfilling remission using either definition had more favorable perceptions about their gout symptoms and illness concerns, as well as consequences, when using the simplified definition. CONCLUSION: Using either definition, 6 months of colchicine prophylaxis when initiating ULT does not provide an advantage in the fulfillment of gout remission. People fulfilling either definition report fewer symptoms, less concern about their gout, and, when using the simplified definition, are less affected by gout.

3.
Arthritis Care Res (Hoboken) ; 76(10): 1371-1378, 2024 10.
Artículo en Inglés | MEDLINE | ID: mdl-38766703

RESUMEN

OBJECTIVE: The study objective was to determine predictors of gout flare when commencing allopurinol using the "start-low go-slow" dose escalation strategy. METHODS: A post hoc analysis of a 12-month double-blind placebo-controlled noninferiority trial with participants randomized 1:1 to colchicine 0.5 mg daily or placebo for the first six months was undertaken. Multivariate logistic regression models were used to identify independent predictors of gout flares in the first and last six months of the trial. RESULTS: Multivariable analysis revealed a significant association between risk of a gout flare in the first six months and flare in the month before starting allopurinol (odds ratio [OR] 2.65, 95% confidence interval [CI] 1.36-5.17) and allopurinol 100 mg starting dose (OR 3.21, 95% CI 1.41-7.27). The predictors of any gout flares in the last six months of the trial, after stopping colchicine or placebo, were having received colchicine (OR 2.95, 95% CI 1.48-5.86), at least one flare in the month before stopping study drug (OR 5.39, 95% CI 2.21-13.15), and serum urate ≥0.36 mmol/L at month 6 (OR 2.85, 95% CI 1.14-7.12). CONCLUSION: Anti-inflammatory prophylaxis when starting allopurinol using the "start-low go-slow" dose escalation strategy may be best targeted at those who have had a gout flare in the month before starting allopurinol and are commencing allopurinol 100 mg daily. For those with ongoing gout flares during the first six months of starting allopurinol who have not yet achieved serum urate target, a longer period of prophylaxis may be required.


Asunto(s)
Alopurinol , Colchicina , Supresores de la Gota , Gota , Humanos , Alopurinol/administración & dosificación , Alopurinol/uso terapéutico , Gota/tratamiento farmacológico , Gota/sangre , Gota/diagnóstico , Supresores de la Gota/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Método Doble Ciego , Colchicina/administración & dosificación , Anciano , Brote de los Síntomas , Adulto , Factores de Tiempo , Resultado del Tratamiento , Relación Dosis-Respuesta a Droga
4.
Br J Clin Pharmacol ; 90(5): 1268-1279, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38359899

RESUMEN

AIMS: Dose escalation at the initiation of allopurinol therapy can be protracted and resource intensive. Tools to predict the allopurinol doses required to achieve target serum urate concentrations would facilitate the implementation of more efficient dose-escalation strategies. The aim of this research was to develop and externally evaluate allopurinol dosing tools, one for use when the pre-urate-lowering therapy serum urate is known (Easy-Allo1) and one for when it is not known (Easy-Allo2). METHODS: A revised population pharmacokinetic-pharmacodynamic model was developed using data from 653 people with gout. Maintenance doses to achieve the serum urate target of <0.36 mmol L-1 in >80% of individuals were simulated and evaluated against external data. The predicted and observed allopurinol doses were compared using the mean prediction error (MPE) and root mean square error (RMSE). The proportion of Easy-Allo predicted doses within 100 mg of the observed was quantified. RESULTS: Allopurinol doses were predicted by total body weight, baseline urate, ethnicity and creatinine clearance. Easy-Allo1 produced unbiased and suitably precise dose predictions (MPE 2 mg day-1 95% confidence interval [CI] -13-17, RMSE 91%, 90% within 100 mg of the observed dose). Easy-Allo2 was positively biased by about 70 mg day-1 and slightly less precise (MPE 70 mg day-1 95% CI 52-88, RMSE 131%, 71% within 100 mg of the observed dose). CONCLUSIONS: The Easy-Allo tools provide a guide to the allopurinol maintenance dose requirement to achieve the serum urate target of <0.36 mmol L-1 and will aid in the development of novel dose-escalation strategies for allopurinol therapy.


Asunto(s)
Alopurinol , Relación Dosis-Respuesta a Droga , Supresores de la Gota , Gota , Modelos Biológicos , Ácido Úrico , Alopurinol/administración & dosificación , Alopurinol/farmacocinética , Humanos , Gota/tratamiento farmacológico , Gota/sangre , Supresores de la Gota/administración & dosificación , Supresores de la Gota/farmacocinética , Ácido Úrico/sangre , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Cálculo de Dosificación de Drogas , Simulación por Computador
5.
Artículo en Inglés | MEDLINE | ID: mdl-37688559

RESUMEN

OBJECTIVES: In 2015, the 20-item Tophus Impact Questionnaire (TIQ-20) was developed as a tophus-specific patient reported outcome measure. The aim of this study was to determine whether TIQ-20 scores change during urate-lowering therapy. METHODS: We analysed data from a two-year clinical trial of allopurinol dose escalation using a treat-to-target serum urate approach. For participants with tophaceous gout, the longest diameter of up to three index tophi was measured using Vernier calipers and the TIQ-20 was recorded at study visits. Participants at the one site were invited into a dual energy CT (DECT) sub-study. Participants were included in this analysis if they had tophaceous gout and TIQ-20 scores available at baseline, Year 1, and Year 2 (n = 58, 39 with DECT data). Data were analysed using mixed model approach to repeated measures. RESULTS: Improvements were observed in all tophus measures over the two-year period. The mean (SD) TIQ-20 scores reduced over two years from 3.59 (1.77)-2.46 (1.73), P< 0.0001, and the mean (95%CI) TIQ-20 change over the two years was -1.13 (-1.54, -0.71). Effect size (Cohen's d) for the change in the sum of the index tophi diameter over two years was 0.68, for DECT urate volume was 0.50, and for the TIQ-20 was 0.71. CONCLUSION: For people with tophaceous gout treated with allopurinol using a treat to target serum urate approach, improvements in TIQ-20 occur, as well as improvements in physical and imaging tophus measures. These findings demonstrate that the TIQ-20 is a responsive patient-reported instrument of tophus impact.

6.
Ann Rheum Dis ; 82(12): 1626-1634, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37652661

RESUMEN

OBJECTIVES: To determine whether placebo is non-inferior to low-dose colchicine for reducing gout flares during the first 6 months of allopurinol using the 'start-low go-slow' dose approach. METHODS: A 12-month double-blind, placebo-controlled non-inferiority trial was undertaken. Adults with at least one gout flare in the preceding 6 months, fulfilling the American College of Rheumatology (ACR) recommendations for starting urate-lowering therapy and serum urate ≥0.36 mmol/L were recruited. Participants were randomised 1:1 to colchicine 0.5 mg daily or placebo for the first 6 months. All participants commenced allopurinol, increasing monthly to achieve target urate <0.36 mmol/L. The primary efficacy outcome was the mean number of gout flares/month between 0 and 6 months, with a prespecified non-inferiority margin of 0.12 gout flares/month. The primary safety outcome was adverse events over the first 6 months. RESULTS: Two hundred participants were randomised. The mean (95% CI) number of gout flares/month between baseline and month 6 was 0.61 (0.47 to 0.74) in the placebo group compared with 0.35 (0.22 to 0.49) in the colchicine group, mean difference 0.25 (0.07 to 0.44), non-inferiority p=0.92. There was no difference in the mean number of gout flares/month between randomised groups over the 12-month period (p=0.68). There were 11 serious adverse events in 7 participants receiving colchicine and 3 in 2 receiving placebo. CONCLUSIONS: Placebo is not non-inferior to colchicine in prevention of gout flares in the first 6 months of starting allopurinol using the 'start-low go-slow' strategy. After stopping colchicine, gout flares rise with no difference in the mean number of gout flares/month between groups over a 12-month period. TRIAL REGISTRATION NUMBER: ACTRN 12618001179224.


Asunto(s)
Gota , Adulto , Humanos , Gota/tratamiento farmacológico , Alopurinol/uso terapéutico , Colchicina/uso terapéutico , Supresores de la Gota/uso terapéutico , Ácido Úrico , Brote de los Síntomas , Resultado del Tratamiento
7.
Arthritis Care Res (Hoboken) ; 75(9): 1949-1954, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-36594401

RESUMEN

OBJECTIVE: The gouty tophus is an organized structure composed of monosodium urate (MSU) crystals and chronic inflammatory soft tissue. This dual-energy computed tomography (DECT) study aimed to determine whether the composition of the tophus changes during urate-lowering therapy. METHODS: Serial DECT scans from 32 people with gout were obtained over 2 years of allopurinol therapy, dose-escalated to serum urate of <0.36 mmoles/liter. Up to 5 index tophi were selected for each patient, with 103 separate tophi included in the analysis. Using manual outlining methods of conventional CT and DECT scans, the same index tophi were serially measured for total tophus volume and urate volume. For each tophus, the soft tissue volume was then calculated by subtracting the urate volume from the total tophus volume. RESULTS: The mean ± SD serum urate reduced from 0.43 ± 0.03 mmoles/liter at baseline to 0.31 ± 0.02 mmoles/liter at year 2. The mean ± SD total tophus volume reduced over the 2-year period from 5.17 ± 5.55 cm3 to 2.61 ± 2.73 cm3 (P < 0.0001). Greater reductions in tophus urate volumes than tophus soft tissue volumes were observed; the tophus urate volume decreased by 70.6%, and tophus soft tissue volume decreased by 37.8% (P < 0.0001). The mean tophus urate:soft tissue ratio reduced from 0.15 at baseline to 0.05 at year 2 (P < 0.001). CONCLUSION: The composition of the tophus is dynamic and changes during urate-lowering therapy for gout management. The soft tissue component of the tophus is slower to respond and may persist without measurable MSU crystal deposition.


Asunto(s)
Gota , Ácido Úrico , Humanos , Tomografía Computarizada por Rayos X/métodos , Gota/diagnóstico por imagen , Gota/tratamiento farmacológico , Alopurinol/uso terapéutico , Supresores de la Gota/uso terapéutico
8.
J Rheumatol ; 49(12): 1372-1378, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35777814

RESUMEN

OBJECTIVE: To determine the long-term use of and adherence to urate-lowering therapy (ULT), serum urate (SU) control, and self-reported flares in participants from a randomized controlled trial of allopurinol dose escalation, in order to achieve target SU concentration (< 0.36 mmol/L) in people with gout. METHODS: For surviving study participants, ULT dispensing and SU testing within the preceding 12 months was obtained by medical record review. A phone interview was conducted to determine self-reported flares and adherence. RESULTS: Over a mean follow-up of 6.5 (SD 2.5) years since enrollment, 60 out of 183 (33%) participants had died. Review of the 119 surviving participants showed that 98 (82%) were receiving allopurinol, 5 (4%) were receiving febuxostat, and 10 (8%) were not receiving ULT; for the remaining 6 (5.0%), ULT use could not be determined. In those receiving allopurinol, the mean dose was 28.1 (range -600 to 500) mg/day lower than at the last study visit; 49% were receiving the same dose, 18% were on a higher dose, and 33% were on a lower dose than at the last study visit. SU values were available for 86 of the 119 (72%) participants; 50 out of 86 (58%) participants had an SU concentration of < 0.36 mmol/L. Of the 89 participants who participated in the phone interview, 19 (21%) reported a gout flare in the preceding 12 months and 79 (89%) were receiving allopurinol; 71 (90%) of those receiving allopurinol reported 90% or greater adherence. CONCLUSION: Most of the surviving participants in the allopurinol dose escalation study had good real-world persistence with allopurinol, remained at target SU, and had a low number of self-reported flares.


Asunto(s)
Alopurinol , Gota , Humanos , Alopurinol/uso terapéutico , Gota/tratamiento farmacológico , Ácido Úrico , Supresores de la Gota/uso terapéutico , Estudios de Seguimiento , Resultado del Tratamiento , Brote de los Síntomas
9.
BMC Rheumatol ; 6(1): 31, 2022 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-35672866

RESUMEN

OBJECTIVES: To determine the effect of omega-three supplementation with fish oil on serum urate, weight and body mass index (BMI) in people with gout. METHODS: A pilot 6-month, randomized, open-label clinical trial was undertaken in people with gout with serum urate ≥ 0.36 mmol/l. Forty participants were randomized to receive 6.2 g omega-3 fish oil daily or no fish oil for 24 weeks. Blood was obtained monthly for serum urate and red cell EPA (20:5n-3) DHA (22:6n-3) were measured using a blood spot collection system. RESULTS: There was no statistically significant difference in the mean (SEM) decrease in serum urate between baseline and week 24 between randomized groups: fish oil - 0.021 (0.02) mmol/l versus control - 0.006 (0.02) mmol/l. There was no significant difference in change in weight or BMI between baseline and week 24 between randomized groups. There was a statistically significant correlation between red cell omega-three concentrations and the total number of flares per participant between week 12 and week 24; total omega-three r = - 0.75 (p ≤ 0.001), EPA r = - 0.75 (p ≤ 0.001) and DHA r = -0.76 (p ≤ 0.001). In the omega-three fish oil group four participants reported gastrointestinal adverse effects definitely or probably related to the omega-three supplementation. CONCLUSIONS: The lack of untoward effect of omega three fish oil supplementation on serum urate and BMI together with the relationship between higher omega-three concentrations and lower gout flares supports the development of further adequately powered clinical trials to determine the role of omega-three supplements as prophylaxis against gout flares in people starting urate lowering therapy. Clinical trial registration ACTRN12617000539336p Registered 13/04/2017.

10.
Rheumatology (Oxford) ; 59(9): 2374-2380, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-31891407

RESUMEN

OBJECTIVES: Cherry concentrate has been suggested to reduce serum urate (SU) and gout flares. The aims of this study were to determine the magnitude of the effect of tart cherry concentrate on SU in people with gout, the most effective dose of tart cherry concentrate for lowering SU, and adverse effects. METHODS: Fifty people with gout and SU > 0.36 mmol/l were recruited. Half were on allopurinol and half were on no urate-lowering therapy. Participants were randomized to receive tart cherry juice concentrate: placebo, 7.5 ml, 15 ml, 22.5 ml or 30 ml twice daily for 28 days. Blood samples were taken at baseline, then at 1, 3 and 5 h post cherry and then on days 1, 3, 7, 14, 21 and 28. The area under the curve for SU was calculated over the 28-day study period. RESULTS: Cherry concentrate dose had no significant effect on reduction in SU area under the curve, urine urate excretion, change in urinary anthocyanin between day 0 and day 28, or frequency of gout flares over the 28-day study period (P = 0.76). There were 24 reported adverse events, with only one (hyperglycaemia) considered possibly to be related to cherry concentrate. Allopurinol use did not modify the effect of cherry on SU or urine urate excretion. CONCLUSION: Tart cherry concentrate had no effect on SU or urine urate excretion. If there is an effect of cherry concentrate on gout flares over a longer time period, it is not likely to be mediated by reduction in SU. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR), https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368887, ANZCTR 12615000741583).


Asunto(s)
Supresores de la Gota/uso terapéutico , Gota/tratamiento farmacológico , Fitoterapia , Extractos Vegetales/uso terapéutico , Prunus avium , Ácido Úrico/sangre , Adulto , Anciano , Alopurinol/uso terapéutico , Femenino , Gota/sangre , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento
11.
Clin Transl Sci ; 13(1): 110-115, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31444839

RESUMEN

The aims of this study were to determine factors that predict serum urate (SU) lowering response to allopurinol and the conversion of allopurinol to oxypurinol, and to determine a minimum therapeutic oxypurinol concentration. Data from 129 participants in a 24-month open, randomized, controlled, parallel-group, comparative clinical trial were analyzed. Allopurinol dose, SU, and plasma oxypurinol concentrations were available at multiple time points. The slope for the association between allopurinol dose and SU was calculated as a measure of sensitivity to allopurinol. The slope for the association between allopurinol dose and oxypurinol was calculated as a measure of allopurinol metabolism. Receiver operating characteristic (ROC) curves were used to identify a minimum oxypurinol concentration predictive of SU < 6 mg/dL. There was a wide range of SU concentrations for each allopurinol dose. The relationship between sensitivity to allopurinol and allopurinol metabolism for each 100 mg allopurinol dose increase varied between individuals. Body mass index (P = 0.023), creatinine clearance (CrCL; P = 0.037), ABCG2 Q141K (P = 0.019), and SU (P = 0.004) were associated with sensitivity to allopurinol. The minimum oxypurinol concentration for achieving the urate target was found to be about 104 µmol/L, but predictive accuracy was poor (ROC curve area under the curve (AUC) 0.65). The minimum therapeutic oxypurinol concentration was found to increase with decreasing renal function. Although there is a positive relationship between change in oxypurinol and change in SU concentration, a minimum therapeutic oxypurinol is dependent on CrCL and cannot reliably predict SU target. Other variables, including ABCG2 Q141K genotype, impact on sensitivity to allopurinol (ACTRN12611000845932).


Asunto(s)
Alopurinol/administración & dosificación , Supresores de la Gota/administración & dosificación , Gota/tratamiento farmacológico , Oxipurinol/sangre , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Anciano , Alopurinol/farmacocinética , Índice de Masa Corporal , Creatinina/sangre , Creatinina/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Gota/sangre , Gota/diagnóstico , Gota/genética , Supresores de la Gota/farmacocinética , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Oxipurinol/metabolismo , Curva ROC , Eliminación Renal , Resultado del Tratamiento , Ácido Úrico/sangre
12.
Arthritis Rheumatol ; 71(10): 1733-1738, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31162825

RESUMEN

OBJECTIVE: To determine whether gout and serum urate (SU) levels are associated with increased risk of death, time to first readmission for any cardiovascular event, or incident heart failure in individuals with cardiovascular disease. METHODS: Individuals presenting with an acute coronary syndrome (ACS) were enrolled in the Coronary Disease Cohort Study. Clinical data were collected from the medical records at the index hospital admission, and clinical, echocardiographic, and biochemical data were collected postdischarge. Gout was defined by self-report, use of urate-lowering therapy, or use of colchicine with evidence of gout on review of the medical record. The primary end points were all-cause mortality, time to readmission for a cardiac ischemic event, and time to readmission for heart failure. RESULTS: Data from 1,514 participants were available. During the follow-up period, 53 of 160 participants with gout (33.1%) and 298 of 1,354 participants without gout (22.0%) died. After adjustment for other factors known to be associated with mortality, there was no gout-specific increase in risk of mortality (adjusted hazard ratio 0.98 [95% confidence interval 0.69-1.38]). Time to readmission for heart failure was significantly briefer in those with, compared to those without, gout (adjusted hazard ratio 1.42 [95% confidence interval 1.02-1.97]). Irrespective of whether a participant had gout or not, as SU level increased, there was an increased risk of death and readmission for either a cardiovascular event or heart failure. CONCLUSION: Survival post-ACS is similar with and without the presence of gout. People with gout are at an increased risk of readmission for heart failure and have longer hospital stays. Risk of these events increases in parallel with increases in SU levels.


Asunto(s)
Gota/epidemiología , Insuficiencia Cardíaca/epidemiología , Hospitalización/estadística & datos numéricos , Hiperuricemia/epidemiología , Mortalidad , Ácido Úrico/sangre , Síndrome Coronario Agudo/epidemiología , Anciano , Anciano de 80 o más Años , Enfermedades Cardiovasculares/epidemiología , Enfermedad de la Arteria Coronaria/epidemiología , Femenino , Estudios de Seguimiento , Gota/sangre , Humanos , Hiperuricemia/sangre , Masculino , Persona de Mediana Edad , Nueva Zelanda/epidemiología , Modelos de Riesgos Proporcionales
13.
Arthritis Rheumatol ; 71(10): 1739-1746, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31081595

RESUMEN

OBJECTIVE: To examine whether allopurinol dose escalation to achieve serum urate (SU) target can influence bone erosion or monosodium urate (MSU) crystal deposition, as measured by dual-energy computed tomography (DECT) in patients with gout. METHODS: We conducted an imaging study of a 2-year randomized clinical trial that compared immediate allopurinol dose escalation to SU target with conventional dosing for 1 year followed by dose escalation to target, in gout patients who were receiving allopurinol and who had an SU level of ≥0.36 mmoles/liter. DECT scans of feet and radiographs of hands and feet were obtained at baseline, year 1, and year 2 visits. DECT scans were scored for bone erosion and urate volume. RESULTS: Paired imaging data were available for 87 patients (42 in the dose-escalation group and 45 in the control group). At year 2, the progression in the CT erosion score was higher in the control group than in the dose-escalation group (+7.8% versus +1.4%; P = 0.015). Changes in plain radiography erosion or narrowing scores did not differ between groups. Reductions in DECT urate volume were observed in both groups. At year 2, patients in the control group who had an SU level of <0.36 mmoles/liter and patients in the dose-escalation group had reduced DECT urate volume (-27.6 to -28.3%), whereas reduction in DECT urate volume was not observed in control group patients with an SU level of ≥0.36 mmoles/liter (+1.5%) (P = 0.023). CONCLUSION: These findings provide evidence that long-term urate-lowering therapy using a treat-to-SU-target strategy can influence structural damage and reduce urate crystal deposition in gout.


Asunto(s)
Alopurinol/administración & dosificación , Resorción Ósea/diagnóstico por imagen , Articulaciones del Pie/diagnóstico por imagen , Supresores de la Gota/administración & dosificación , Gota/tratamiento farmacológico , Articulaciones de la Mano/diagnóstico por imagen , Ácido Úrico/metabolismo , Anciano , Relación Dosis-Respuesta a Droga , Femenino , Huesos del Pie/diagnóstico por imagen , Gota/diagnóstico por imagen , Gota/metabolismo , Huesos de la Mano/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Rayos X , Resultado del Tratamiento
14.
J Clin Rheumatol ; 25(7): 284-287, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-30001258

RESUMEN

BACKGROUND/OBJECTIVE: The aim of this study was to determine whether reducing the dose of supplemental folic acid used in conjunction with methotrexate (MTX) therapy in people with active rheumatoid arthritis (RA) improved disease control and/or increased MTX-related adverse effects. METHODS: A randomized double-blind randomized controlled trial comparing 5 mg/wk and 0.8 mg/wk folic acid was undertaken. Rheumatoid arthritis patients on MTX for 3 months or more at a stable dose for 1 month or more were recruited. All participants had DAS28 of 3.2 or greater or required a change in therapy determined by the treating clinician. Disease activity, full blood count, liver function tests, red blood cell (RBC) folate, and RBC MTX polyglutamates were assessed at weeks 0, 4, 8, 16, and 24 along with reports of adverse events. RESULTS: Forty participants were recruited. The mean (SD) change in RBC folate between week 0 and 24 was +87.9 (57.4) nmol/L in the high-dose group and -113.3 (65.7) nmol/L in the low-dose group (p < 0.05). There was no significant difference in the change in DAS28 between the high- and low-dose groups at 24 weeks (-0.13 [95% confidence interval, -0.69 to 0.43] vs -0.25 [-0.87 to 0.37], respectively [p = 0.78]). There was no significant difference in MTX-related adverse effects between the 2 groups. CONCLUSIONS: A reduction in RBC folate secondary to reduction in folic acid dose was not associated with a change in RA disease activity or MTX-related adverse effects. The prevention of MTX-related adverse effects remains the primary reason for coprescribing folic acid with MTX. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR12610000739011).


Asunto(s)
Artritis Reumatoide , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Ácido Fólico/administración & dosificación , Metotrexato , Adulto , Antirreumáticos/administración & dosificación , Antirreumáticos/efectos adversos , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Monitoreo de Drogas/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Femenino , Humanos , Masculino , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Gravedad del Paciente , Proyectos Piloto , Resultado del Tratamiento , Complejo Vitamínico B/administración & dosificación
15.
Arthritis Res Ther ; 20(1): 255, 2018 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-30446002

RESUMEN

OBJECTIVE: Allopurinol dosing has frequently been limited based on creatinine clearance (CrCL), resulting in failure to achieve target serum urate (SU). The aim of this analysis was to determine how many milligrams of allopurinol above the recommended CrCL-based dose (R+) are required to achieve target SU and to investigate the factors that influence R+. METHODS: We analysed data from participants in a 24-month open, randomized, controlled, parallel-group, comparative clinical trial. Data obtained during the 12-month dose escalation (DE) phase of the study (year 1 for DE/DE and year 2 for control/DE) were combined. R+ dose was defined as the number of milligrams of allopurinol above the CrCL-based dose at the final visit. RESULTS: Of the 132 participants, R+ allopurinol dose at the final visit was ≤ 100 mg/day in 38 (28.8%), 101-200 mg/day in 46 (34.8%) and > 200 mg/day in 48 participants (37.1%). There was no significant difference between the R+ groups in the number of participants achieving target SU. There was an increase in plasma oxypurinol and a larger percentage and absolute change in SU as R+ increased. Multivariate analysis revealed CrCL, weight, baseline SU and allopurinol dose, were significantly positively associated with allopurinol dose at 12 months. There were no significant differences across R+ groups in renal or liver function adverse events, although there were numerically more serious adverse events in the higher R+ groups. CONCLUSION: A wide range of R+ doses are required to achieve target SU. Four easily obtained clinical variables (baseline SU, CrCL, weight, and allopurinol dose) may be helpful to predict allopurinol dose. TRIAL REGISTRATION: ANZCTR, ACTRN12611000845932 . Registered on 10 August 2011.


Asunto(s)
Alopurinol/administración & dosificación , Creatinina/sangre , Supresores de la Gota/administración & dosificación , Gota/sangre , Tasa de Depuración Metabólica/efectos de los fármacos , Ácido Úrico/sangre , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Sistemas de Liberación de Medicamentos/métodos , Femenino , Gota/tratamiento farmacológico , Humanos , Masculino , Tasa de Depuración Metabólica/fisiología , Persona de Mediana Edad , Ácido Úrico/antagonistas & inhibidores
16.
Rheumatology (Oxford) ; 57(12): 2183-2189, 2018 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-30107437

RESUMEN

Objectives: To determine factors that predict inadequate serum urate (SU) lowering response in a randomized controlled trial of allopurinol dose escalation (DE) in gout. Methods: Participants undergoing allopurinol DE were classified as: complete response (CR)-reached target SU at month 9 and 12 of the DE phase or if still dose escalating at month 9 reached target SU by month 12; partial response (PR)-reached target at some stage but not fulfilling criteria for CR; or inadequate response (IR)-did not reach target SU at any time. Results: IR was uncommon, occurring in 13/150 (8.7%), compared with 82 (54.7%) CR, and 55 (36.6%) PR. Mean (s.e.m.) SU was higher at the end of the 12-month DE in IR compared with both CR and PR groups; 7.6 (0.31) vs 5.01 (0.06) and 5.97 (0.17) mg/dl respectively (P < 0.001). In univariate analysis, compete responders tended to be older, be receiving less allopurinol, have longer gout duration and were more likely to be New Zealand (NZ) European ethnicity, compared with IR+PR. Using multi-variate logistic regression analysis, only longer duration of gout and NZ European ethnicity remained significant independent predictors of CR. Baseline SU ⩾ 8 mg/dl had a sensitivity of 69.2% and specificity of 85.1% in predicting IR. The odds ratio for an IR if baseline SU was ⩾8 mg/dl was 11.7 (95% CI 3.3, 41.2). Conclusion: A minority of people with gout never reach target SU when allopurinol dose is increased in a treat-to-target manner. Approximately one-third of those with SU ⩾ 8mg/dl despite allopurinol ⩾300mg/d have an IR to DE. Trial registration: Australian New Zealand Clinical Trails Registry, https://www.anzctr.org.au, ACTRN12611000845932.


Asunto(s)
Alopurinol/administración & dosificación , Supresores de la Gota/administración & dosificación , Gota/sangre , Gota/tratamiento farmacológico , Ácido Úrico/sangre , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento
17.
Br J Clin Pharmacol ; 84(5): 937-943, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29341237

RESUMEN

AIM: This research aims to evaluate the predictive performance of a published allopurinol dosing tool. METHODS: Allopurinol dose predictions were compared to the actual dose required to achieve serum urate (SU) <0.36 mmol l-1 using mean prediction error. The influence of patient factors on dose predictions was explored using multilinear regression. RESULTS: Allopurinol doses were overpredicted by the dosing tool; however, this was minimal in patients without diuretic therapy (MPE 63 mg day-1 , 95% CI 40-87) compared to those receiving diuretics (MPE 295 mg day-1 , 95% CI 260-330, P < 0.0001). ABCG2 genotype (rs2231142, G>T) had an important impact on the dose predictions (MPE 201, 107, 15 mg day-1 for GG, GT and TT, respectively, P < 0.0001). Diuretic use and ABCG2 genotype explained 53% of the variability in prediction error (R2  = 0.53, P = 0.0004). CONCLUSIONS: The dosing tool produced acceptable maintenance dose predictions for patients not taking diuretics. Inclusion of ABCG2 genotype and a revised adjustment for diuretics would further improve the performance of the dosing tool.


Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Alopurinol/uso terapéutico , Técnicas de Apoyo para la Decisión , Diuréticos/efectos adversos , Proteínas de Neoplasias/genética , Adulto , Anciano , Anciano de 80 o más Años , Interacciones Farmacológicas , Femenino , Genotipo , Supresores de la Gota/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Ensayos Clínicos Controlados Aleatorios como Asunto , Ácido Úrico/sangre , Adulto Joven
18.
Calcif Tissue Int ; 102(1): 73-84, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29018897

RESUMEN

INTRODUCTION: Numerous observational studies have reported that serum urate concentration positively correlates with bone density and reduced risk of fractures. The aim of this study was to examine whether soluble urate directly influences bone remodelling. METHODS: In laboratory studies, the in vitro effects of soluble urate were examined in osteoclast, osteoblast and osteocyte assays at a range of urate concentrations consistent with those typically observed in humans (up to 0.70 mmol/L). The clinical relevance of the in vitro assay findings was assessed using serial procollagen-1 N-terminal propeptide (P1NP) and Month 12 bone density data from a randomised controlled trial of allopurinol dose escalation in people with gout. RESULTS: Addition of urate in the RAW264.7 cell osteoclastogenesis assay led to small increases in osteoclast formation (ANOVA p = 0.018), but no significant difference in bone resorption. No significant effects on osteoclast number or activity were observed in primary cell osteoclastogenesis or resorption assays. Addition of urate did not alter viability or function in MC3T3-E1 pre-osteoblast, primary human osteoblast, or MLO-Y4 osteocyte assays. In the clinical trial analysis, reducing serum urate over a 12 month period by allopurinol dose escalation did not lead to significant changes in P1NP or differences in bone mineral density. CONCLUSION: Addition of soluble urate at physiological concentrations does not influence bone remodelling in vitro. These data, together with clinical trial data showing no effect of urate-lowering on P1NP or bone density, do not support a direct role for urate in influencing bone remodelling.


Asunto(s)
Remodelación Ósea/efectos de los fármacos , Osteoclastos/efectos de los fármacos , Osteocitos/efectos de los fármacos , Ácido Úrico/farmacología , Remodelación Ósea/fisiología , Resorción Ósea/metabolismo , Huesos/efectos de los fármacos , Huesos/metabolismo , Diferenciación Celular/efectos de los fármacos , Humanos , Osteoclastos/metabolismo , Osteocitos/metabolismo , Osteogénesis/efectos de los fármacos
19.
Arthritis Res Ther ; 19(1): 283, 2017 12 21.
Artículo en Inglés | MEDLINE | ID: mdl-29268756

RESUMEN

BACKGROUND: The use of allopurinol in people with chronic kidney disease (CKD) remains one of the most controversial areas in gout management. The aim of this study was to determine the effect of baseline kidney function on safety and efficacy of allopurinol dose escalation to achieve serum urate (SU) <6 mg/dl. METHODS: We undertook a post hoc analysis of a 24-month allopurinol dose escalation treat-to-target SU randomized controlled trial, in which 183 people with gout were randomized to continue current dose allopurinol for 12 months and then enter the dose escalation phase or to begin allopurinol dose escalation immediately. Allopurinol was increased monthly until SU was <6 mg/dl. The effect of baseline kidney function on urate lowering and adverse effects was investigated. RESULTS: Irrespective of randomization, there was no difference in the percentage of those with creatinine clearance (CrCL) <30 ml/min who achieved SU <6 mg/dl at the final visit compared to those with CrCL ≥30 to <60 ml/min and those with CrCL ≥60 ml/min, with percentages of 64.3% vs. 76.4% vs. 75.0%, respectively (p = 0.65). The mean allopurinol dose at month 24 was significantly lower in those with CrCL <30 ml/min as compared to those with CrCL ≥30 to <60 ml/min or CrCL ≥60 ml/min (mean (SD) 250 (43), 365 (22), and 460 (19) mg/day, respectively (p < 0.001)). Adverse events were similar among groups. CONCLUSIONS: Allopurinol is effective at lowering urate even though and accepting that there were small numbers of participants with CrCL <30 ml/min, these data indicate that allopurinol dose escalation to target SU is safe in people with severe CKD. The dose required to achieve target urate is higher in those with better kidney function. TRIAL REGISTRATION: Australian and New Zealand Clinical trials Registry, ACTRN12611000845932 . Registered on 10 August 2011.


Asunto(s)
Alopurinol/administración & dosificación , Supresores de la Gota/administración & dosificación , Gota/complicaciones , Gota/tratamiento farmacológico , Insuficiencia Renal Crónica/complicaciones , Adulto , Anciano , Alopurinol/efectos adversos , Creatinina/sangre , Relación Dosis-Respuesta a Droga , Femenino , Supresores de la Gota/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Ácido Úrico/sangre
20.
Ann Rheum Dis ; 76(12): 2065-2070, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28830881

RESUMEN

OBJECTIVES: To determine the long-term safety and efficacy of allopurinol dose escalation (DE) to achieve target serum urate (SU) in gout. METHODS: People, including those with chronic kidney disease, who completed the first 12 months of a randomised controlled trial continued into a 12-month extension study. Participants randomised to continue current dose for the first 12 months began allopurinol DE at month 12 if SU was ≥6 mg/dL (control/DE). Immediate DE participants who achieved target SU maintained allopurinol dose (DE/DE). The primary endpoints were reduction in SU and adverse events (AEs) at month 24. RESULTS: The mean (SE) change in SU from month 12 to 24 was -1.1 (0.2) mg/dL in control/DE and 0.1 (0.2) mg/dL in DE/DE group (p<0.001). There was a significant reduction in the percentage of individuals having a gout flare in the month prior to months 12 and 24 compared with baseline in both groups and in mean tophus size over 24 months, but no difference between randomised groups. There were similar numbers of AEs and serious adverse events between groups. CONCLUSIONS: The majority of people with gout tolerate higher than creatinine clearance-based allopurinol dose and achieve and maintain target SU. Slow allopurinol DE may be appropriate in clinical practice even in those with kidney impairment. TRIAL REGISTRATION NUMBER: ACTRN12611000845932.


Asunto(s)
Alopurinol/administración & dosificación , Supresores de la Gota/administración & dosificación , Gota/sangre , Gota/tratamiento farmacológico , Ácido Úrico/sangre , Anciano , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Tiempo , Resultado del Tratamiento
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