Population pharmacokinetic modelling of febuxostat in healthy subjects and people with gout.

AIMS: To investigate and characterise the pharmacokinetics of febuxostat and the effect of the covariates of renal function and body size descriptors on the pharmacokinetics of the drug. METHODS: Blood samples (n = 239) were collected using sparse and rich sampling strategies from healthy (n = 9) and gouty (n = 29) subjects. Febuxostat plasma concentrations were measured by a validated high-performance liquid chromatography method. Population pharmacokinetic analysis was performed using NONMEM. A common variability on bioavailability (FVAR) approach was used to test the effect of fed status on absorption parameters. Covariates were modelled using a power model. RESULTS: The time course of the plasma concentrations of febuxostat is best described by a two-compartment model. In the final model, the population mean for apparent clearance (CL/F), apparent central volume of distribution (Vc/F), apparent peripheral volume of distribution (Vp/F), absorption rate constant (ka) and apparent intercompartmental clearance (Q/F) were 6.91 l h-1 , 32.8 l, 19.4 l, 3.6 h-1 and 1.25 l h-1 , respectively. The population parmater variability (coefficient of variation) for CL/F, Vc/F and Vp/F were 13.6, 22 and 19.5%, respectively. Food reduced the relative biovailability and ka by 67% and 87%, respectively. Renal function, as assessed by creatinine clearance, was a significant covariate for CL/F while body mass index was a significant covariate for Vc/F. CONCLUSIONS: Renal function and body mass index were significant covariates. Further work is warranted to investigate the clinical relevance of these results, notably as renal impairment and obesity are common occurrences in people with gout.

Systematic review and meta-analysis on prevalence of metabolic syndrome in psoriatic arthritis, rheumatoid arthritis and psoriasis.

BACKGROUND: Psoriatic arthritis (PsA), rheumatoid arthritis (RA) and psoriasis (PsO) are associated with systemic inflammation and increased cardiovascular mortality and morbidity. Metabolic syndrome (MetS) is associated with systemic inflammation, and conditions associated with MetS, such as obesity, are associated with difficulty in attaining minimal disease activity (MDA) in individuals with inflammatory arthritis. This systematic review aims to determine whether there is an increased prevalence of MetS in PsA populations compared with PsO and RA populations. METHODS: A systematic review was conducted to assess the prevalence of MetS in PsA, PsO, and RA populations following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. The quality of the studies reviewed was assessed using the Joanna Briggs Institute Checklist for Prevalence Studies. RESULTS: The pooled prevalence of MetS in PsA populations was 0.46 ± 0.06 (95% CI 0.40-0.51). In comparison, the prevalence of MetS in PsO and RA populations was 0.34 ± 0.03 (95% CI 0.32-0.37) and 0.31 ± 0.04 (95% CI 0.27-0.35), respectively. Patients with PsA were 1.62 ± 0.036 (95% CI 1.50-1.74) and 1.66 ± 0.038 (95% CI 1.54-1.79) times more likely to have MetS compared with PsO and RA populations. CONCLUSION: The prevalence of MetS is significantly increased in PsA populations compared with PsO and RA populations. Further studies should be performed using a standardized definition of MetS in PsA, RA, and PsO populations to determine whether addressing the metabolic components in MetS offers any therapeutic benefits and in terms of attaining MDA and improving cardiovascular health.

Updated APLAR consensus statements on care for patients with rheumatic diseases during the COVID-19 pandemic.

AIM: To update previous guidance of the Asia Pacific League of Associations for Rheumatology (APLAR) on the management of patients with rheumatic and musculoskeletal diseases (RMD) during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: Research questions were formulated focusing on diagnosis and treatment of adult patients with RMD within the context of the pandemic, including the management of RMD in patients who developed COVID-19. MEDLINE was searched for eligible studies to address the questions, and the APLAR COVID-19 task force convened 2 meetings through video conferencing to discuss its findings and integrate best available evidence with expert opinion. Consensus statements were finalized using the modified Delphi process. RESULTS: Agreement was obtained around key aspects of screening for or diagnosis of COVID-19; management of patients with RMD without confirmed COVID-19; and management of patients with RMD with confirmed COVID-19. The task force achieved consensus on 25 statements covering the potential risk of acquiring COVID-19 in RMD patients, advice on RMD medication adjustment and continuation, the roles of telemedicine and vaccination, and the impact of the pandemic on quality of life and on treatment adherence. CONCLUSIONS: Available evidence primarily from descriptive research supported new recommendations for aspects of RMD care not covered in the previous document, particularly with regard to risk factors for complicated COVID-19 in RMD patients, modifications to RMD treatment regimens in the context of the pandemic, and COVID-19 vaccination in patients with RMD.

Elevating the role of carers in rheumatoid arthritis management in the Asia-Pacific region.

AIM: Carers may offer valuable insight into the true health status of patients with rheumatoid arthritis (RA). This multinational, multi-stakeholder, exploratory study in Australia, China and Japan aimed to enrich our understanding of the role and potential impact of carers on RA management. METHOD: This study used a 2-phase sequential mixed methods approach involving 3 key stakeholder groups: rheumatologists, RA patients and carers. The first phase involved an in-depth qualitative exploratory survey (n = 30), which informed the development of the subsequent quantitative validation survey (n = 908). In both phases, patients and carers provided self-assessments of disease and support parameters. RESULTS: In the qualitative phase, patients usually understated the amount of physical support required, compared to carers. Rheumatologists underestimated the amount of physical and emotional care required, compared to carers and patients; however, in the quantitative phase, rheumatologists overestimated the level of support provided by carers. Levels of support provided by carers increased as disease severity increased. Active participation of carers in clinical consultations and treatment decision-making was deemed important by 55% of all patients and 82% of all carers. All stakeholders believed carers' insights into the physical and emotional conditions of patients were useful and should be considered in clinical decision-making. Over 95% of rheumatologists reported soliciting input from the carer. CONCLUSION: Carers provide valuable input that can give clinicians greater insight into the patients' physical and emotional states, and treatment adherence. Development of standardized carer-reported outcomes that correlate with patient-reported outcomes and clinical parameters will ensure clinical meaningfulness and external validity.

A pharmacokinetic-pharmacodynamic study of a single dose of febuxostat in healthy subjects.

AIMS: To examine the pharmacokinetic-phamacodynamic (PK-PD) relationships of plasma febuxostat and serum urate and the effect of a single dose of the drug on renal excretion and fractional clearance of urate (FCU). METHODS: Blood and urine samples were collected at baseline and up to 145 hours following administration of febuxostat (80 mg) to healthy subjects (n = 9). Plasma febuxostat and serum and urinary urate and creatinine concentrations were determined. Febuxostat pharmacokinetics were estimated using a two-compartment model with first-order absorption. An Emax PK-PD model was fitted to mean febuxostat and urate concentrations. Urinary urate excretion and FCU were calculated pre- and post-dose. RESULTS: Maximum mean plasma concentration of febuxostat (2.7 mg L-1 ) was observed 1.2 hours after dosage. Febuxostat initial and terminal half-lives were 2.0 ± 1.0 and 14.0 ± 4.7 hours (mean ± SD), respectively. The majority (81%) of the drug was eliminated in the 9 hours after dosing. Serum urate declined slowly achieving mean nadir (0.20 mmol L-1 ) at 24 hours. The IC50 (plasma febuxostat concentration that inhibits urate production by 50%) was 0.11 ± 0.09 mg L-1 (mean ± SD). Urinary urate excretion changed in parallel with serum urate. There was no systematic or significant change in FCU from baseline. CONCLUSION: The PK-PD model could potentially be used to individualise febuxostat treatment and improve clinical outcomes. A single dose of febuxostat does not affect the efficiency of the kidney to excrete urate. Further investigations are required to confirm the present results following multiple dosing with febuxostat.

Determination of febuxostat in human plasma by high performance liquid chromatography (HPLC) with fluorescence-detection.

Febuxostat prevents gout attacks by lowering serum urate. Aspects of the pharmacokinetic-pharmacodynamic relationship of febuxostat concentrations to urate in gout patients need further elucidation. In order to undertake these studies, the assay methodology for febuxostat has been enhanced and validated to meet FDA standards. An HPLC method with fluorescence-detection has been modified to increase sensitivity, reduce complexity, shorten the sample preparation process and improve the inter-day coefficient of variation of the lowest quality control sample (0.03 µg/L). Protein in plasma samples (200 µL) is now precipitated with acetonitrile (400 µL) containing the internal standard (2-naphthoic acid). The supernatant is analysed at excitation and emission wavelengths of 320 and 380 nm, respectively as in the previous method. A Luna C18 column (Phenomenex, Australia) at 40 °C with mobile phase of glacial acetic acid (0.032%) in acetonitrile:water (60:40, v:v), an injection volume of 10 µL and a flow rate of 1.5 mL/min is employed. Analysis time is 8 min. Calibration curves in drug-free plasma range from 0.005 to 10.00 µg/mL. Data points are fitted using linear regression with a weighting factor of 1/concentration. The inter-day accuracy and imprecision of the quality control samples (0.0075, 0.015, 3.00 and 9.80 µg/mL) is 90-115% and ≤ 14.5%, respectively.

Systematic review of depression and anxiety in psoriatic arthritis.

AIM: To investigate the point prevalence of depression and anxiety in psoriatic arthritis and putative reductions in these comorbidities with the treatment of psoriatic arthritis. METHOD: We performed a systematic review in accordance with PRISMA guidelines examining point prevalence of depression and anxiety in psoriatic arthritis as well as effects of treatment for psoriatic arthritis on these psychiatric comorbidities. MEDLINE, EMBASE, EBM Reviews and Cochrane, and PsycINFO were searched from inception to October 2017. Quality of studies was assessed using the Joanna Briggs Institute Checklist for Prevalence Studies. Study and population characteristics were extracted and entered into an electronic database for subsequent descriptive and meta-analysis of point prevalence. RESULT: Three studies matched inclusion criteria with significant statistical heterogeneity. The prevalence of depression ranged between 9%-22% and anxiety between 15%-30% in patients with psoriatic arthritis. One study matched inclusion criteria for treatment effect analysis, albeit with a high risk of bias and illustrated a benefit of etanercept on the prevalence of depression (9% vs 16%) and anxiety (14% vs 30%) after 24 weeks of treatment. CONCLUSION: This is the first systematic review of point prevalence of depression and anxiety in patients with psoriatic arthritis. There is a moderate point prevalence of both depression and anxiety in patients with psoriatic arthritis, which is similar or slightly higher than the general population and comparable to that seen in other rheumatic diseases. The effects of treatment for psoriatic arthritis on comorbid depression and anxiety remain unclear.

Effectiveness of an electronic patient-centred self-management tool for gout sufferers: a cluster randomised controlled trial protocol.

INTRODUCTION: Gout is increasing despite effective therapies to lower serum urate concentrations to 0.36 mmol/L or less, which, if sustained, significantly reduces acute attacks of gout. Adherence to urate-lowering therapy (ULT) is poor, with rates of less than 50% 1 year after initiation of ULT. Attempts to increase adherence in gout patients have been disappointing. We aim to evaluate the effectiveness of use of a personal, self-management, 'smartphone' application (app) to achieve target serum urate concentrations in people with gout. We hypothesise that personalised feedback of serum urate concentrations will improve adherence to ULT. METHODS AND ANALYSIS: Setting and designPrimary care. A prospective, cluster randomised (by general practitioner (GP) practices), controlled trial. PARTICIPANTS: GP practices will be randomised to either intervention or control clusters with their patients allocated to the same cluster. INTERVENTION: The intervention group will have access to the Healthy.me app tailored for the self-management of gout. The control group patients will have access to the same app modified to remove all functions except the Gout Attack Diary. PRIMARY AND SECONDARY OUTCOMES: The proportion of patients whose serum urate concentrations are less than or equal to 0.36 mmol/L after 6 months. Secondary outcomes will be proportions of patients achieving target urate concentrations at 12 months, ULT adherence rates, serum urate concentrations at 6 and 12 months, rates of attacks of gout, quality of life estimations and process and economic evaluations. The study is designed to detect a ≥30% improvement in the intervention group above the expected 50% achievement of target serum urate at 6 months in the control group: power 0.80, significance level 0.05, assumed 'dropout' rate 20%. ETHICS AND DISSEMINATION: This study has been approved by the University of New South Wales Human Research Ethics Committee. Study findings will be disseminated in international conferences and peer-reviewed journal. TRIAL REGISTRATION NUMBER: ACTRN12616000455460.

Individualising the dose of allopurinol in patients with gout.

AIMS: The aims of the study were to: 1) determine if a plasma oxypurinol concentration-response relationship or an allopurinol dose-response relationship best predicts the dose requirements of allopurinol in the treatment of gout; and 2) to construct a nomogram for calculating the optimum maintenance dose of allopurinol to achieve target serum urate (SU) concentrations. METHODS: A nonlinear regression analysis was used to examine the plasma oxypurinol concentration- and allopurinol dose-response relationships with serum urate. In 81 patients (205 samples), creatinine clearance (CLCR ), concomitant diuretic use and SU concentrations before (UP ) and during (UT ) treatment were monitored across a range of allopurinol doses (D, 50-700 mg daily). Plasma concentrations of oxypurinol (C) were measured in 47 patients (98 samples). Models (n = 47 patients) and predictions from each relationship were compared using F-tests, r2 values and paired t-tests. The best model was used to construct a nomogram. RESULTS: The final plasma oxypurinol concentration-response relationship (UT = UP - C*(UP - UR )/(ID50 + C), r2  = 0.64) and allopurinol dose-response relationship (UT = UP - D* (UP - UR )/(ID50 + D), r2  = 0.60) did not include CLCR or diuretic use as covariates. There was no difference (P = 0.87) between the predicted SU concentrations derived from the oxypurinol concentration- and allopurinol dose-response relationships. The nomogram constructed using the allopurinol dose-response relationship for all recruited patients (n = 81 patients) required pretreatment SU as the predictor of allopurinol maintenance dose. CONCLUSIONS: Plasma oxypurinol concentrations, CLCR and diuretic status are not required to predict the maintenance dose of allopurinol. Using the nomogram, the maintenance dose of allopurinol estimated to reach target concentrations can be predicted from UP .

Clinical Pharmacokinetics and Pharmacodynamics of Febuxostat.

Febuxostat is a xanthine oxidoreductase inhibitor that has been developed to treat chronic gout. In healthy subjects, the pharmacokinetic parameters of febuxostat after multiple oral dose administration include an oral availability of about 85 %, an apparent oral clearance (CL/F) of 10.5 ± 3.4 L/h and an apparent volume of distribution at steady state (V ss/F) of 48 ± 23 L. The time course of plasma concentrations follows a two-compartment model. The initial half-life (t ½) is approximately 2 h and the terminal t ½ determined at daily doses of 40 mg or more is 9.4 ± 4.9 h. Febuxostat is administered once daily. The maximum (peak) plasma concentrations are approximately 100-fold greater than the trough concentrations. Consequently, there is no significant accumulation of the drug during multiple dose administration. There are few data on the pharmacokinetics of febuxostat in patients with gout. While the pharmacokinetic parameters are not affected by mild to moderate hepatic impairment, there is no consensus on whether renal impairment has any effect on the pharmacokinetics of febuxostat. Febuxostat is extensively metabolised by oxidation (approximately 35 %) and acyl glucuronidation (up to 40 %); febuxostat acyl glucuronides are cleared by the kidney. In healthy subjects treated with multiple doses of febuxostat 10-240 mg, the concentrations of serum urate are reduced by a maximum of about 80 %. The percentage reduction in the concentrations of serum urate is slightly less in gouty patients than in healthy subjects.

The global challenges and opportunities in the practice of rheumatology: white paper by the World Forum on Rheumatic and Musculoskeletal Diseases.

Rheumatic and musculoskeletal diseases (RMDs) represent a multitude of degenerative, inflammatory and auto-immune conditions affecting millions of people worldwide. Persons with these diseases may potentially experience severe chronic pain, joint damage, increasing disability and even death. With an increasingly ageing population, the prevalence and burden of RMDs are predicted to increase, placing greater demands on the global practice of rheumatology and related healthcare budgets. Effective treatment of RMDs currently faces a number of challenges in both the developed and developing world, and individual countries may face more specific local challenges. However, limited understanding of the burden of RMDs amongst public health professionals and policy-makers means that these diseases are often not considered a public health priority. The objective of this review is to increase awareness of the RMDs and to identify opportunities to address RMD challenges on both a local and global scale. On 26 September 2014, rheumatology experts from five different continents met at the World Forum on Rheumatic and Musculoskeletal Diseases (WFRMD) to discuss and identify some key challenges for the RMDs community today. The outcomes are presented in this review, focusing on access to rheumatology services, diagnostics and therapies, rheumatology education and training and on clinical trials, as well as investigator-initiated and epidemiological research. The long-term vision of the WFRMD is to increase perception of the RMDs as a major burden to society and to explore potential opportunities to improve global and local RMD care.

"They just scraped off the calluses": a mixed methods exploration of foot care access and provision for people with rheumatoid arthritis in south-western Sydney, Australia.

BACKGROUND: There is little indication that foot health services in Australia are meeting modern day recommendations for Rheumatoid Arthritis (RA) patients. The overall objective of this study was to explore the current state of foot health services for patients with RA with an emphasis on identifying barriers to the receipt of appropriate foot care in South-West Sydney, New South Wales, Australia. METHODS: A mixed (quantitative and qualitative) approach was adopted. Indications for appropriate access to foot care were determined by comparing the foot health, disease and socio-demographic characteristics of patients with unmet foot care demands, foot care users and patients with no demands for foot care. Perceptions of provision of, and access to, foot care were explored by conducting telephone-based interviews using an interpretative phenomenology approach with thematic analysis. RESULTS: Twenty-nine participants took part in the cross-sectional quantitative research study design, and 12 participants took part in the interpretative phenomenological approach (qualitative study). Foot care access appeared to be driven predominantly by the presence of rearfoot deformity, which was significantly worse amongst participants in the foot care user group (p = 0.02). Five main themes emerged from the qualitative data: 1) impact of disease-related foot symptoms, 2) footwear difficulties, 3) medical/rheumatology encounters, 4) foot and podiatry care access and experiences, and 5) financial hardship. CONCLUSIONS: Foot care provision does not appear to be driven by appropriate foot health characteristics such as foot pain or foot-related disability. There may be significant shortfalls in footwear and foot care access and provision in Greater Western Sydney. Several barriers to adequate foot care access and provision were identified and further efforts are required to improve access to and the quality of foot care for people who have RA. Integration of podiatry services within rheumatology centres could resolve unmet needs of people with RA by permitting rapid access to expert-led multidisciplinary foot care for people with RA.

Provision of foot health services for people with rheumatoid arthritis in New South Wales: a web-based survey of local podiatrists.

BACKGROUND: It is unclear if podiatric foot care for people with rheumatoid arthritis (RA) in New South Wales (NSW) meets current clinical recommendations. The objective of this study was to survey podiatrists' perceptions of the nature of podiatric foot care provision for people who have RA in NSW. METHODS: An anonymous, cross-sectional survey with a web-based questionnaire was conducted. The survey questionnaire was developed according to clinical experience and current foot care recommendations. State registered podiatrists practising in the state of NSW were invited to participate. The survey link was distributed initially via email to members of the Australian Podiatry Association (NSW), and distributed further through snowballing techniques using professional networks. Data was analysed to assess significant associations between adherence to clinical practice guidelines, and private/public podiatry practices. RESULTS: 86 podiatrists participated in the survey (78% from private practice, 22% from public practice). Respondents largely did not adhere to formal guidelines to manage their patients (88%). Only one respondent offered a dedicated service for patients with RA. Respondents indicated that the primary mode of accessing podiatry was by self-referral (68%). Significant variation was observed regarding access to disease and foot specific assessments and treatment strategies. Assessment methods such as administration of patient reported outcome measures, vascular and neurological assessments were not conducted by all respondents. Similarly, routine foot care strategies such as prescription of foot orthoses, foot health advice and footwear were not employed by all respondents. CONCLUSIONS: The results identified issues in foot care provision which should be explored through further research. Foot care provision in NSW does not appear to meet the current recommended standards for the management of foot problems in people who have RA. Improvements to foot care could be undertaken in terms of providing better access to examination techniques and treatment strategies that are recommended by evidence based treatment paradigms.

Understanding the dose-response relationship of allopurinol: predicting the optimal dosage.

AIMS: The aim of the study was to identify and quantify factors that control the plasma concentrations of urate during allopurinol treatment and to predict optimal doses of allopurinol. METHODS: Plasma concentrations of urate and creatinine (112 samples, 46 patients) before and during treatment with various doses of allopurinol (50-600 mg daily) were monitored. Non-linear and multiple linear regression equations were used to examine the relationships between allopurinol dose (D), creatinine clearance (CLcr) and plasma concentrations of urate before (UP) and during treatment with allopurinol (UT). RESULTS: Plasma concentrations of urate achieved during allopurinol therapy were dependent on the daily dose of allopurinol and the plasma concentration of urate pre-treatment. The non-linear equation: UT = (1 - D/(ID50 + D)) × (UP - UR) + UR , fitted the data well (r(2) = 0.74, P < 0.0001). The parameters and their best fit values were: daily dose of allopurinol reducing the inhibitable plasma urate by 50% (ID50 = 226 mg, 95% CI 167, 303 mg), apparent resistant plasma urate (UR = 0.20 mmol l(-1), 95 % CI 0.14, 0.25 mmol l(-1)). Incorporation of CLcr did not significantly improve the fit (P = 0.09). CONCLUSIONS: A high baseline plasma urate concentration requires a high dose of allopurinol to reduce plasma urate below recommended concentrations. This dose is dependent on only the pre-treatment plasma urate concentration and is not influenced by CLcr .