Improvement in hepatic fibrosis estimated by Fibrosis-4 index in pegloticase treated chronic refractory gout patients.

OBJECTIVES: To determine whether lowering serum urate (SU) affects the course of non-alcoholic fatty liver disease (NAFLD). METHODS: Retrospective data analysis from chronic refractory gout patients who participated in two 6-month pegloticase randomised clinical trials compared patients who received pegloticase biweekly to those who received placebo. Patients with persistent urate-lowering to <1 mg/dL in response to biweekly pegloticase (responders, n=36) were compared to those who received placebo (n=43). NAFLD was assessed using the Fibrosis-4 (Fib-4) index. Comparisons between groups were carried out using 2 sample Wilcoxon tests or regression analysis. RESULTS: At baseline the mean (standard deviation [SD]) Fib-4 values were 1.40 (0.86) in pegloticase responders, and 1.04 (0.53) in patients receiving placebo. Patients receiving placebo exhibited a change of 0.26 (0.41) in Fib-4 score over 6 months vs 0.13 (0.62) for pegloticase responders (p=0.048). When only patients with a Fib-4 value >1.3 were considered (n=27), a significant difference in the change in the Fib-4 values between pegloticase responders vs. placebo was observed (-0.15 [0.67] vs. 0.7 [0.42], p=0.04). The correlation between the SU area under the curve (AUC) over the 6-month trial period and the change in Fib-4 value was R=0.33 (p=0.0004). Multivariable analysis indicated SU AUC was the only significant contributor to the change in Fib-4 values (p=0.018). CONCLUSIONS: Persistent lowering of SU significantly reduced Fib-4 scores, implying a possible effect on NAFLD progression. These results support the consideration of a complete analysis of the impact of profound urate-lowering on NAFLD as measured by the Fib-4 index.

Pegloticase causes prolonged improvement in multiple disease parameters in patients with chronic refractory gout who maintain low serum urate levels.

OBJECTIVES: To assess the benefit of long-term urate-lowering with pegloticase. METHODS: The results from two, 6-month, randomised controlled trials (RCTs) and their 30-month open-label extension (OLE) were analysed. Efficacy was assessed in urate responders (patients with plasma urate <6.0 mg/dL for ≥80% of assessments around the 3- and 6-month time periods) to the approved regimen (8 mg every 2 weeks [q2w]) and responders to q4w treatment. Assessments included serum urate (sU), Patient Global Assessment (PtGA), tender and swollen joints (TJC and SJC), pain, Health Assessment Questionnaire Disability Index, bodily pain, the Arthritis-Specific Health Index, and reduction of target tophi. RESULTS: 34 responders to pegloticase in the RCTs were followed throughout the 2.5 years of the OLE. Of these, 20 received 8 mg pegloticase q2w and 14 q4w. The results for patients who received pegloticase q2w indicated significant improvements between RCT baseline and the final OLE evaluation for sU (p<0.0001), PtGA (p<0.0001), TJC (p=0.0001), and SJC (p=0.0014); 61.5%, had complete target tophus resolution. The results for patients treated monthly indicated significant improvements between RCT baseline and the final OLE evaluation for sU (p<0.001), PGA (p=0.0003), TJC (p=0.008), and SJC (p<0.0001);100% had complete target tophus resolution. CONCLUSIONS: There were significant sustained clinical benefits with long-term pegloticase treatment in patients with chronic refractory gout achieving a urate-lowering effect during the first 6 months of therapy and followed for up to 30 additional months.

Post-hoc analysis of pegloticase pivotal trials in chronic refractory gout: relationship between fluctuations in plasma urate levels and acute flares.

OBJECTIVES: To determine factors associated with gout flares in subjects treated with pegloticase. METHODS: Gout flares from two randomised controlled trials comparing pegloticase (8 mg every 2 weeks [q2] or monthly [q4]) versus placebo were analysed. Responders had persistent urate lowering (<6mg/dL) whereas, non-responders had transient urate lowering during the 6-month RCTs. Gout flares (self-reported) were defined as acute joint pain and swelling requiring treatment. Gout flare prophylaxis (colchicine, 0.6 mg once or twice daily, or a non-steroidal anti-inflammatory drug) was initiated 1 week before the first infusion and continued throughout the study. Plasma urate at the time of flare and the change in urate preceding a flare were analysed. RESULTS: Mean flare rates increased with pegloticase versus placebo during the first 3 months followed by marked reductions during months 4-6. The increase in flares with pegloticase during the first 3 months was most evident (p=0.0006) and the decrease during the second 3 months was least marked (p=0.0006) in subjects receiving monthly pegloticase. Fluctuation in urate levels was highest in monthly responders (p=0.002) and was associated with flare occurrence. Multivariate linear regression analysis indicated the only variables significantly associated with flares were treatment group and absolute change in plasma urate before flares. CONCLUSIONS: Pegloticase treatment increased flares during the first 3 months of treatment in all groups when plasma urate was significantly lowered and was followed by a decline in months 4-6 in patients maintaining a low plasma urate. Flares associated with pegloticase treatment were associated with decreases and fluctuations in plasma urate levels.

Measuring oral health during pregnancy: sensitivity and specificity of a maternal oral screening (MOS) tool.

BACKGROUND: Midwives can play a key role in promoting the oral health of pregnant women and assessing their oral health status. A maternal oral assessment tool (MOS) was developed and pilot tested by the study investigators to assist midwives in this role and the results were promising. The aim of this study was to undertake further sensitivity and specificity assessment of the MOS tool using two-comparison approaches- the longer oral health screening tool known as the Oral Health Impact Profile (OHIP-14) and an oral assessment by trained study dentists. METHODS: Pregnant women were recruited for this study as part of a larger randomised controlled trial of a Midwifery Initiated Oral Health (MIOH) program. Pregnant women completed the MOS and OHIP-14 as part of their initial assessment undertaken by 38 trained and accredited midwives. A dental assessment was conducted for all women in the intervention group using three trained study dentists with high inter rater reliability. RESULTS: Two hundred and eleven pregnant women participated in the validation of the MOS tool. Results from both approaches found the MOS tool to have high sensitivity, correctly identifying 88-94 % of women at risk of poor dental health, and low specificity (14-21 %). CONCLUSIONS: This study has shown that the MOS tool can be successfully implemented by midwives during a woman's first antenatal visit and can identify up to 94 % of women at risk of poor oral health and needing a dental referral. The tool has the potential to be transferable to other antenatal care providers and could be incorporated into hospital obstetric database systems. TRIAL REGISTRATION NUMBER: ACTRN12612001271897 , 6th Dec 2012, retrospectively registered.

The midwifery initiated oral health-dental service protocol: an intervention to improve oral health outcomes for pregnant women.

BACKGROUND: Evidence is emerging that women's poor oral health and health practices during pregnancy are associated with poor oral health in their children and potentially an increased risk of pre-term or low-birth weight infants. METHODS/DESIGN: The Midwifery Initiated Oral Health-Dental Service (MIOH-DS) trial is a three arm multicentre randomised controlled trial which will recruit women from three metropolitan hospitals aimed at improving women's oral health and service access and indirectly reducing perinatal morbidity. All three arms of the trial will deliver oral health promotion material, although a midwife oral assessment and referral to private/public/health fund dental services pathway (Intervention Group 1) and the midwife oral assessment and referral to local free public dental services pathway (Intervention Group 2) will be compared to the control group of oral health promotional material only. Midwives will undergo specific oral health education and competency testing to undertake this novel intervention. DISCUSSION: This efficacy trial will promote a new partnership between midwives and dentists focused on enhancing the oral health of women and their infants. Should the intervention be found effective, this intervention, with existing on-line educational program for midwives, can be easily transferred into practice for large metropolitan health services within and beyond Australia. Further cost-benefit analysis is proposed to inform national health policy. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612001271897.

How do dental and prenatal care practitioners perceive dental care during pregnancy? Current evidence and implications.

BACKGROUND: Poor maternal oral health may be associated with adverse pregnancy and infant outcomes. However, women seldom seek dental care during pregnancy, and misconceptions by prenatal care practitioners about oral health care during pregnancy may contribute to the problem. The aim of this study was to review current knowledge, attitudes, and behavior of dental and prenatal care practitioners about oral health care during pregnancy. METHODS: This review examined all studies published in English that explored the knowledge, attitude, behavior, and barriers faced by dentists, general practitioners, midwives, and obstetricians/gynecologists with respect to oral health care during pregnancy. RESULTS: Despite acknowledging the importance of maternal oral health, many dentists are uncertain about the safety of dental procedures and are hesitant in treating pregnant women. General practitioners and midwives are poorly informed about the impact of poor maternal oral health and rarely initiate this topic during prenatal care. Many general practitioners also believe that dental procedures are unsafe during pregnancy. Obstetricians/gynecologists are well informed about perinatal oral health and are supportive of dental procedures, but because of lack of training in this area and competing health demands they seldom focus on oral health care during their prenatal care. CONCLUSION: No real consensus exists among dentists and prenatal care practitioners with respect to oral health care during pregnancy. This issue poses a significant deterrent for pregnant women seeking dental care. Practice guidelines in perinatal oral health are needed for health professionals to emphasize this important aspect of prenatal care.

Low incidence of complications from endoscopic gastric variceal obturation with butyl cyanoacrylate.

BACKGROUND & AIMS: Endoscopic variceal obturation with tissue adhesive is used to control gastric variceal bleeding. We investigated the prevalence of serious complications from this therapy. METHODS: We performed a retrospective analysis of complications that occurred in 753 patients with gastric variceal hemorrhages who were hospitalized in 2 tertiary referral hospitals. All patients received N-butyl-2-cyanoacrylate as therapy for endoscopic variceal obturation. RESULTS: Complications occurred in 51 patients. Thirty-three patients experienced rebleeding because of early-onset (within 3 months) extrusion of the N-butyl-2-cyanoacrylate glue cast (4.4%), 10 patients developed sepsis (1.3%), and 5 patients developed distant embolisms (0.7%; 1 pulmonary, 1 brain, and 3 splenic). One patient had major gastric variceal bleeding after endoscopic variceal obturation (0.1%), 1 developed a large gastric ulcer (0.1%), and 1 had mesentery hematoma, hemoperitoneum, and infection in the abdominal cavity (0.1%). The complication-related mortality was 0.53% (3 deaths from sepsis and 1 death from rebleeding after early-onset glue cast extrusion). CONCLUSIONS: The occurrence of complications after endoscopic variceal obturation with N-butyl-2-cyanoacrylate in gastric varices treatment is rare.

Dissociation Between Clinical Benefit and Persistent Urate Lowering in Patients with Chronic Refractory Gout Treated with Pegloticase.

OBJECTIVE: To assess clinical benefit in patients with chronic refractory gout who did not meet the protocol-defined criteria of responders to pegloticase. METHODS: This analysis used results from 2 randomized controlled trials (ClinicalTrials.gov: NCT00325195, NCT01356498) to assess the clinical efficacy in responders and nonresponders to treatment (8 mg of pegloticase every 2 weeks). Serum urate was measured before each infusion and the following were recorded: assessment of gout flares, tophus reduction, patient's global assessment (PtGA), tender and swollen joints (TJC and SJC), pain using a 100-mm visual analog scale, and a variety of patient-reported outcomes [Medical Outcomes Study Short Form-36 questionnaire physical component summary score and arthritis-specific health index (ASHI) score]. RESULTS: The analysis included 36 persistent urate responders, 49 nonresponders, and 43 patients who received placebo. Results for both responders and nonresponders indicated significant reduction in tophi and improvements from baseline in PtGA, TJC, SJC, pain, and ASHI. No significant improvements were observed in the patients who received placebo. CONCLUSION: Chronic refractory gout patients not achieving protocol-defined persistent urate lowering still achieve significant clinical benefits with pegloticase treatment, suggesting that transient reduction in serum urate may result in sustained clinical benefit.

Development of a multivariable improvement measure for gout.

BACKGROUND: Gout is a heterogeneous inflammatory disease with numerous clinical manifestations. A composite means to assess the impact of therapy on numerous aspects of gout could be useful. METHODS: Results from patients treated with pegloticase or placebo in two randomized clinical trials and their open-label extension were assessed using a novel evidence-based Gout Multivariable Improvement Measure (GMIM) derived from previously reported criteria for remission and complete response. Improvement was defined as serum urate (sU) < 6 mg/dL and absence of flares during the preceding 3 months plus 20, 50, and 70% improvement in tophus size, patient global assessment, pain, and swollen and tender joints. RESULTS: Patients treated with pegloticase manifested a significantly greater GMIM20, 50, and 70 response vs those treated with placebo (GMIM20 at 6 months 37.1% vs 0%, respectively). Higher response rates were significantly more frequent in subjects with persistent urate lowering (GMIM 58.1% at 6 months) in response to pegloticase versus those with only transient urate lowering (GMIM 7.1% at 6 months). However, when the requirement for a decrease in sU to < 6 mg/dL was omitted, a substantial percentage of subjects with transient urate lowering met the GMIM clinical criteria. A sensitivity analysis indicated that gout flares contributed minimally to the model. The response measured by GMIM persisted into the open-level extension for as long as 2 years. Finally, subjects who received placebo in the randomized control trials, but pegloticase in the open-label extension, manifested GMIM responses comparable to that noted with pegloticase-treated subjects in the randomized controlled trials. CONCLUSIONS: GMIM captures changes in disease activity in response to treatment with pegloticase and may serve as an evidence-based tool for assessment of responses to other urate-lowering therapies in gout patients.

Pegloticase Treatment Significantly Decreases Blood Pressure in Patients With Chronic Gout.

Serum urate is correlated with blood pressure (BP), and lowering urate may decrease BP, but a consistent effect has not been observed. Here, we evaluated whether pegloticase, a recombinant uricase conjugated to polyethylene glycol, which can lead to persistently low serum urate levels (<1 mg/dL), can modulate BP in subjects with chronic refractory gout. This post hoc analysis used results from two 6-month randomized clinical trials in which subjects were treated with 8 mg pegloticase every 2 or 4 weeks (q2w or q4w) or placebo. Responders in this study were defined as those individuals in whom a persistently low urate level (<6 mg/dL and usually <1 mg/dL) was maintained. Serial sitting BP was measured in 173 subjects, and estimated glomerular filtration rate was determined at baseline and after 3 and 6 months. Significant reductions in mean arterial pressure (MAP) from baseline to 6 months were noted in q2w responders ( P=0.0028), whereas reductions in MAP in other groups were not significant. Significant decreases in both systolic and diastolic BP paralleled the change in MAP. Of the 62% of q2w responders exhibiting persistent decreases in MAP, there were no significant differences in baseline age, sex, race, weight, body mass index, history of hypertension, hyperlipidemia, history of coronary artery disease, gout duration, MAP, serum urate, estimated glomerular filtration rate or urinary uric acid/creatinine ratio compared with those who did not lower MAP. No significant changes in estimated glomerular filtration rate occurred in any of the groups during the study. Responders to biweekly pegloticase who maintained a persistently lower serum urate level throughout the trial experienced significant reductions in both systolic and diastolic BP that were independent of changes in renal function. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00325195.

Tophus resolution in patients with chronic refractory gout who have persistent urate-lowering responses to pegloticase.

BACKGROUND: Pegloticase is a recombinant mammalian uricase conjugated to polyethylene glycol approved in the United States for treatment of chronic refractory gout. It can profoundly decrease serum urate to < 1 mg/dl. In patients receiving pegloticase who did not generate high-titer antidrug antibodies (responders), the serum urate remained low for the duration of therapy, 6 months in the phase III clinical trials plus the open-label extension. The objective of this study was to assess the velocity of tophus resolution in subjects treated with pegloticase. METHODS: Data from two randomized controlled trials of pegloticase in chronic refractory gout were analyzed. Tophi were assessed by computer-assisted measurements of standardized digital photographs. Subjects were designated as responders and nonresponders based on maintenance of serum urate < 6 mg/dl at months 3 and 6 of treatment. The projected time of complete resolution of all tophi was determined by linear regression analysis. RESULTS: The mean total tophus area at baseline was 585.8 mm2 for responders, 661.5 mm2 for nonresponders, and 674.4 mm2 for placebo-treated patients. Complete resolution at 6 months of at least one tophus was achieved by 69.6% of 23 responders, 27.9% of 43 nonresponders, and 14.3% of 21 patients who received placebo. Complete resolution of all photographed tophi was achieved by 34.8% of biochemical responders, 11.6% of nonresponders, and 0% of placebo-treated patients. The mean velocity of resolution of all tophi was 60.1 mm2/month in responders with a mean projected time of complete resolution of 9.9 months (4.6-32.6 months). There was a significant inverse correlation between serum urate AUC and tophus resolution velocity (r = - 0.40, P = 0.0002), although considerable heterogeneity in the velocity of resolution was noted. The only patient characteristic that correlated with the velocity of tophus resolution was the baseline tophus area. CONCLUSIONS: Pegloticase treatment caused a rapid resolution of tophi in responders that correlated with the serum urate lowering associated with this therapy.

Evaluation of a midwifery initiated oral health-dental service program to improve oral health and birth outcomes for pregnant women: A multi-centre randomised controlled trial.

BACKGROUND: Oral health care during pregnancy is important for the health of the mother and child. However, pregnant women have limited knowledge about maternal oral health and seldom seek dental care. Further, due to limited training antenatal care providers like midwives rarely discuss oral health with pregnant women. The Midwifery-Initiated Oral Health Dental Service program was developed to address current gaps in oral promotional interventions during pregnancy. OBJECTIVES: To assess the effectiveness of a Midwifery-Initiated Oral Health Dental Service program in improving uptake of dental services, oral health knowledge, quality of oral health, oral health status and birth outcomes of pregnant women. DESIGN: Multi-centre randomised controlled trial. SETTING: Three large metropolitan public hospitals in Sydney, Australia. PARTICIPANTS: Pregnant women attending their first antenatal appointment who were at least 18 years old and had a single low risk pregnancy between 12 and 20 weeks gestation. METHODS: 638 pregnant women were allocated to three groups using block randomisation (n = 211) control group, intervention group 1 (n = 215), intervention group 2 (n = 212) and followed up till birth. Study investigators and data collectors were blinded to group allocation. Intervention group 1 received a midwifery intervention from trained midwives involving oral health education, screening and referrals to existing dental pathways. Intervention group 2 received the midwifery intervention and a dental intervention involving assessment/treatment from cost free local dental services. The control group received oral health information at recruitment. Primary outcome was uptake of dental services. Secondary outcomes included oral health knowledge, quality of oral health, oral health status and birth outcomes. RESULTS: Substantial improvements in the use of dental services (20.2% Control Group; 28.3% Intervention group 1; 87.2% Intervention group 2; Odds Ratio Intervention group 2 vs Control Group = 29.72, 95% CI 15.02-58.53, p < 0.001), women's oral health knowledge (p = 0.03); quality of oral health (p < 0.001) and oral health outcomes (sulcus bleeding, dental plaque, clinical attachment loss, decayed/filled teeth- p < 0.001) were found in Intervention group 2. No difference in the rate of preterm or low-birth weight was found. CONCLUSIONS: The Midwifery-Initiated Oral Health Dental Service program (Intervention group 2) improved the uptake of dental services and oral health of pregnant women and is recommended during antenatal care. A cause and effect relationship between this intervention and improved birth outcomes was not supported.

Frequency, distribution and immunologic nature of infusion reactions in subjects receiving pegloticase for chronic refractory gout.

BACKGROUND: To assess frequency and distribution of infusion reactions (IRs) in responders and nonresponders in randomized clinical trials (RCTs) of intravenous pegloticase and the utility of the National Institute of Allergy and Infectious Disease/Food and Allergy and Anaphylaxis Network (NIAID/FAAN) criteria for identifying anaphylaxis in subjects experiencing IRs. METHODS: IRs from two RCTs of pegloticase were evaluated and categorized as anaphylaxis, hypersensitivity, or other. Serum levels of tryptase and total hemolytic complement (CH50) were evaluated at the time of all IRs. Frequency of IRs by each category was evaluated in all subjects, responders or nonresponders to pegloticase. RESULTS: There were 113 IRs in 1695 infusions. Of the 113 IRs, 6 met criteria for anaphylaxis, 53 had one feature of anaphylaxis and were designated as "hypersensitivity", and 54 had no features and were designated "other". In subjects receiving pegloticase every 2 weeks (Q2w), a total of 852 infusions were administered and the IR frequency was 0.5% in responders and 9.7% in nonresponders. In subjects receiving pegloticase every 4 weeks (Q4w), a total of 846 infusions were given and the IR frequency was 2.6% in responders and 12.2% in nonresponders. There were no differences among the three categories of IRs with regard to clinical course or biochemical evidence of immune activation determined by CH50 or tryptase levels. CONCLUSION: IRs mostly occurred in nonresponders. NIAID/FAAN criteria for anaphylaxis did not identify pegloticase-related IRs as having a higher frequency of immune activation or a more severe course. The results are consistent with the conclusion that discontinuance of pegloticase if uric acid rises to >6 mg/dL will decrease the frequency of IRs.

The evaluation of an oral health education program for midwives in Australia.

BACKGROUND: Antenatal care providers are now recommended to promote oral health during pregnancy and provide dental referrals. However, midwives in Australia are not trained to undertake this role. To address this shortcoming, an online evidence based midwifery initiated oral health (MIOH) education program was systematically developed as a professional development activity. AIM: This study aimed to evaluate the effectiveness of the program in improving the oral health knowledge of midwives and assess their confidence to promote maternal oral health post training. METHODS: The program was evaluated using a pre-post test design involving 50 midwives purposively recruited from two states in Australia. The pre-post questionnaire contained 24 knowledge items previously pilot tested as well as items exploring confidence in promoting oral health and perceptions of the program. FINDINGS: The results showed a significant improvement in the oral health knowledge (↑21.5%, p<0.001) of midwives after completion of the program. The greatest improvement in knowledge occurred in key areas vital in promoting maternal oral health namely the high prevalence of dental problems and its impact on birth and infant outcomes. The majority also reported being confident in introducing oral health into antenatal care (82%) and referring women to dental services (77.6%) after undertaking the education program. CONCLUSION: The MIOH education program is a useful resource to equip midwives with the necessary knowledge and skills to promote oral health during pregnancy. The program is accessible and acceptable to midwives and can potentially be transferable to other antenatal care providers.