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 .

Australian and New Zealand national evidence-based recommendations for the investigation and follow-up of undifferentiated peripheral inflammatory arthritis: an integration of systematic literature research and rheumatological expert opinion.

AIM: To develop Australian and New Zealand (ANZ) recommendations for the investigation and follow-up of undifferentiated peripheral inflammatory arthritis (UPIA) using an evidence-based approach. METHODS: Ten questions pertaining to the investigation and follow-up of patients with UPIA in daily rheumatological practice were defined by clinicians using a modified Delphi approach. A systematic literature search was conducted for each of the final questions. The results were presented to a workshop of 54 ANZ rheumatologists in May 2009. Discussions were held to develop consensus statements for each question, based on published evidence and clinical experience/expertise. RESULTS: Ten recommendations were made on diagnostic value of clinical features in the patient's history and examination, predictors of poor prognosis and persistence, synovial fluid analysis, serology, imaging and human leukocyte antigen B27 testing. The lack of specific research to inform recommendations presented a challenge. Dynamic discussion groups outlined individual experience in areas without good quality clinical trial evidence. The median strength of support for the final set of recommendations was 7/10 (interquartile range 6-8), ranging from 6 to 9 for individual statements. CONCLUSION: Ten ANZ recommendations for the investigation and follow-up of UPIA were formulated, based on available evidence and extensive clinical experience. The systematic literature review was of limited value while animated discussion of individual experience, with subsequent information exchange, highlighted the importance of merging clinical expertise with published literature to establish practical recommendations that can improve quality of care in rheumatology.

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 .

Fractional clearance of urate: validation of measurement in spot-urine samples in healthy subjects and gouty patients.

INTRODUCTION: Hyperuricemia is the greatest risk factor for gout and is caused by an overproduction and/or inefficient renal clearance of urate. The fractional renal clearance of urate (FCU, renal clearance of urate/renal clearance of creatinine) has been proposed as a tool to identify subjects who manifest inefficient clearance of urate. The aim of the present studies was to validate the measurement of FCU by using spot-urine samples as a reliable indicator of the efficiency of the kidney to remove urate and to explore its distribution in healthy subjects and gouty patients. METHODS: Timed (spot, 2-hour, 4-hour, 6-hour, 12-hour, and 24-hour) urine collections were used to derive FCU in 12 healthy subjects. FCUs from spot-urine samples were then determined in 13 healthy subjects twice a day, repeated on 3 nonconsecutive days. The effect of allopurinol, probenecid, and the combination on FCU was explored in 11 healthy subjects. FCU was determined in 36 patients with gout being treated with allopurinol. The distribution of FCU was examined in 118 healthy subjects and compared with that from the 36 patients with gout. RESULTS: No substantive or statistically significant differences were observed between the FCUs derived from spot and 24-hour urine collections. Coefficients of variation (CVs) were both 28%. No significant variation in the spot FCU was obtained either within or between days, with mean intrasubject CV of 16.4%. FCU increased with probenecid (P < 0.05), whereas allopurinol did not change the FCU in healthy or gouty subjects. FCUs of patients with gout were lower than the FCUs of healthy subjects (4.8% versus 6.9%; P < 0.0001). CONCLUSIONS: The present studies indicate that the spot-FCU is a convenient, valid, and reliable indicator of the efficiency of the kidney in removing urate from the blood and thus from tissues. Spot-FCU determinations may provide useful correlates in studies investigating molecular mechanisms underpinning the observed range of efficiencies of the kidneys in clearing urate from the blood. TRIAL REGISTRATION: ACTRN12611000743965.

Synovial membrane cytokine expression is predictive of joint damage progression in rheumatoid arthritis: a two-year prospective study (the DAMAGE study cohort).

OBJECTIVE: The primary aim of this prospective 2-year study was to explain the wide variability in joint damage progression in patients with rheumatoid arthritis (RA) from measures of pathologic changes in the synovial membrane. METHODS: Patients underwent clinical measurements and joint damage assessments by magnetic resonance imaging (MRI) and radiography at enrollment and at year 2. Synovial membrane was obtained by knee biopsy and assessed histologically by hematoxylin and eosin staining. Interleukin-1beta (IL-1beta), IL-10, IL-16, IL-17, RANKL, tumor necrosis factor alpha (TNFalpha), and interferon-gamma (IFNgamma) messenger RNA (mRNA) expression was determined by quantitative reverse transcription-polymerase chain reaction. The relationship of synovial measurements to joint damage progression was determined by multivariate analysis. RESULTS: Sixty patients were enrolled. Histologic features had no relationship to damage progression. Multivariate analysis by several different methods consistently demonstrated that synovial membrane mRNA levels of IL-1beta, TNFalpha, IL-17, and IL-10 were predictive of damage progression. IL-17 was synergistic with TNFalpha. TNFalpha and IL-17 effects were most pronounced with shorter disease duration, and IL-1beta effects were most pronounced with longer disease duration. IFNgamma was protective. These factors explained 57% of the MRI joint damage progression over 2 years. CONCLUSION: We have demonstrated for the first time in a prospective study that synovial membrane cytokine mRNA expression is predictive of joint damage progression in RA. The findings for IL-1beta and TNFalpha are consistent with results of previous clinical research, but the protective role of IFNgamma, the differing effects of disease duration, and IL-17-cytokine interactions had only been demonstrated previously by animal and in vitro research. These findings explain some of the variability of joint damage in RA and identify new targets for therapy.

Documenting damage progression in a two-year longitudinal study of rheumatoid arthritis patients with established disease (the DAMAGE study cohort): is there an advantage in the use of magnetic resonance imaging as compared with plain radiography?

OBJECTIVE: In early rheumatoid arthritis (RA), longitudinal studies have demonstrated that magnetic resonance imaging (MRI) is more sensitive than radiography in demonstrating progressive erosive joint damage. The present study evaluated the progression of erosive damage in patients with established RA by using limited field of view MRI and comparing the results with those obtained by radiography. METHODS: MRI and radiographic studies were available from 47 of 60 patients enrolled in a 2-year RA observational study. MRI of the metacarpophalangeal (MCP) joints was performed at baseline and 2 years later, and a single observer scored all of the MR images with the use of an MRI scoring method developed by the Outcome Measures in Rheumatology Clinical Trials MRI RA study group. MR images from 14 patients were reread by the same observer after 1 week to assess intraobserver reliability. Radiographs were obtained at baseline and at 2 years, and were scored by an observer using the Scott modification of the Larsen score. Radiographs from 14 patients were reread after 1 week to assess the intraobserver reliability. The smallest detectable difference (SDD) was calculated for the MRI scores, the total Larsen scores, and the Larsen scores of the dominant-hand MCP joints (MCPs 2-5) for direct comparison with the MRI results. RESULTS: The median disease duration was 5.1 years (range 0.5-29 years). Evidence of erosion progression was identified by MRI in 30 patients (64%). The SDD based on the intraobserver scores was calculated as +/-3.25 units. Using this result, 11 patients (23%) showed evidence of erosion progression on MRI that was greater than the SDD. The SDD for progression based on the intraobserver total Larsen radiographic scores was 0.77 units, and the SDD for the Larsen scores of the dominant-hand MCP joints was 1.55 units. On the basis of these results, radiographic progression was noted in 19 patients (40%) by the total Larsen score and 7 patients (15%) by the dominant-hand MCP Larsen score. The most striking finding was that although MRI and radiograph scores identified a similar group of patients as having progression of joint damage, the radiographs of both hands appeared to be more responsive to change, albeit with the caveat that radiographic progression was most marked outside the dominant-hand MCP joints. CONCLUSION: There was no clear advantage of MRI with a limited field of view as compared with radiographic imaging of both hands in detecting progression of joint damage over 2 years in this group of patients with established RA. The conclusion drawn from this study is not that radiographs are better than MRI or vice versa, but that careful analysis is required to determine the optimal imaging method, or combination of imaging methods, for each study population, depending on the objective and duration of the study.

Accuracy and reliability of arthroscopic estimates of cartilage lesion size in a plastic knee simulation model.

PURPOSE: The goal of the study was to determine the accuracy and reliability of arthroscopic percent area estimates in a plastic knee simulation model. A second goal was to determine the effect of lesion location within the knee and lesion size on accuracy and reliability. TYPE OF STUDY: Cross-sectional study of arthroscopic estimates of cartilage lesion size. METHODS: Three experienced arthroscopists performed 3 sets arthroscopic percent area estimates in 5 different plastic knees. Each knee had lesions drawn on 5 surfaces (patellar, medial and lateral femoral condyle, medial and lateral tibial plateaus). Accuracy and reliability were studied using Bland and Altman limits of agreement (LOA) and intraclass correlation coefficients. RESULTS: There was a strong tendency to overestimate lesion size by over 100% on the femoral and patellar surfaces. Intraobserver and interobserver reliabilities were generally poor. The range for the 95% LOA (+/- 1.96 standard deviation [SD] of the difference scores) between repeated measurements was almost 6 times the size of the lesion itself. Reliability of estimates was poorest for the largest lesions and worse at femoral, lateral tibial, and patellar sites. CONCLUSIONS: Assessments of arthroscopic measurements using LOA found that accuracy and reliability were generally poor, although results were better at the medial tibial plateau and for smaller lesions. In spite of these problems, arthroscopy remains a promising measurement tool because it permits physical assessment of cartilage integrity. This study sets the foundations for improvement in techniques of arthroscopic measurement of cartilage lesion size.