Tophus measurement as an outcome measure for clinical trials of chronic gout: progress and research priorities

Despite the recognition that tophus regression is an important outcome measure in clinical trials of chronic gout, there is no agreed upon method of tophus measurement. A number of methods have been used in clinical trials of chronic gout, from simple physical measurement techniques to more complex advanced imaging methods. This article summarizes methods of tophus measurement and discusses their properties. Physical measurement using Vernier calipers meets most aspects of the Outcome Measures in Rheumatology (OMERACT) filter. Rigorous testing of the complex methods, particularly with respect to reliability and sensitivity to change, is needed to determine the appropriate use of these methods. Further information is also required regarding which method of physical measurement is best for use in future clinical trials. The need to develop and test a patient-reported outcome measure of tophus burden is also highlighted.     

Computed tomography of the knee joint as an indicator of intraarticular tophi in gout

Objective. To evaluate the utility of computed tomography (CT) of the knee joint for detecting intraarticular tophaceous deposits. Methods. A prospective study of 16 patients with gout affecting the knee was conducted. A condition for inclusion in the study was the presence of needle-shaped crystals with negative birefringence in the knee joint synovial fluid. Conventional radiography and CT were performed in each case. Results. Intraarticular opacities in the capsule and the synovium, consistent with the presence of tophaceous deposits, were found in 5 of the 16 patients (9 knee joints). The mean duration of gout was longer in the patients with intraarticular tophi than in those without tophi, and 2 of the patients with tophi had poor tolerance to antihyperuricemic therapy. Conclusion. Intraarticular opacities considered to represent tophi were observed in approximately one-third of the patients. The presence of tophi correlated with a longer duration of the disease and a poor tolerance to medication. We therefore suggest that CT of the knees could be useful in the assessment and followup of certain patients with gout.     

Risk factors of ultrasound-detected tophi in patients with gout

Clinical Rheumatology - Tophus is a characteristic manifestation of advanced gout, the clinical significance of which is often underestimated. This study aimed to compare the difference of clinical...     

Effect of urate-lowering therapy on the velocity of size reduction of tophi in chronic gout

OBJECTIVE: The optimal serum urate levels necessary for elimination of tissue deposits of monosodium urate in patients with chronic gout is controversial. This observational, prospective study evaluates the relationship between serum urate levels during therapy and the velocity of reduction of tophi in patients with chronic tophaceous gout. METHOD: Sixty-three patients with crystal-confirmed tophaceous gout were treated with allopurinol, benzbromarone, or combined therapy to achieve serum uric acid levels less than the threshold for saturation of urate in tissues. The tophi targeted for evaluation during followup were the largest in diameter found during physical examination. RESULTS: Patients taking benzbromarone alone or combined allopurinol and benzbromarone therapy achieved faster velocity of reduction of tophi than patients taking allopurinol alone. The velocity of tophi reduction was linearly related to the mean serum urate level during therapy. The lower the serum urate levels, the faster the velocity of tophi reduction. CONCLUSION: Serum urate levels should be lowered enough to promote dissolution of urate deposits in patients with tophaceous gout. Allopurinol and benzbromarone are equally effective when optimal serum urate levels are achieved during therapy. Combined therapy may be useful in patients who do not show enough reduction in serum urate levels with single-drug therapy.     

Establishing outcome domains for evaluating treatment of acute and chronic gout

PURPOSE OF REVIEW: Novel therapies for gout have recently been developed which has prompted considerable efforts in defining the relevant outcomes for measurement in intervention trials of gout. This review summarizes the consensus exercises refining domains for measurement and the work of individual groups in assessment of the validity of measurement tools for these domains. RECENT FINDINGS: Recent publications have focused on the consensus exercises and validation studies of measurement tools, particularly in relation to tophus size and imaging. SUMMARY: Consensus on potential outcome domains has been achieved, but measuring these domains requires further validation in observational studies and confirmation of relevance from people with gout. Further work is also required in refining measurements of tophus size and imaging scores. The role of a response criteria measure is also yet to be defined, especially in relation to reduction in flare frequency, or whether composite criteria are necessary.     

Analysis of risk factors for susceptibility of subcutaneous tophi in people with gout

正Objective To discuss the risk factors for susceptibility of subcutaneous tophi with an aim to provide clinical evidence for the prevention and treatment of tophi.Methods A total of 5 321 cases of gout patients whose course of disease was less than 10 years were selected and divided into two groups according to whether a subcutaneous tophus was present.The clinical information was collected and relevant biochemical indices were de-     

Mucociliary clearance as an outcome measure for cystic fibrosis clinical research

Current concepts of cystic fibrosis (CF) pathophysiology link ion transport abnormalities to reduced airway surface liquid (ASL) hydration and impaired mucus clearance. It is likely that correction of the defects that cause ASL dehydration will prevent degradation of mucus clearance, thereby preventing the initiation and/or progression of CF lung disease. A number of novel therapeutic agents aimed at the earliest steps in disease pathogenesis are now under development for the treatment of CF lung disease. Consequently, there is a tremendous need to develop methods that directly assess the effects of these agents on the underlying pathophysiologic process in the target organ. The measurement of mucociliary clearance (MCC) is a highly biologically relevant outcome, but one that is in need of further development. Here, we describe important methodologic aspects of MCC measurement and issues that have limited its use as an outcome measure in the past. Furthermore, we outline the steps that are being carried out now, and will be carried out in the future, to improve the performance of these studies in clinical trials. A systematic approach to optimizing and standardizing the measurement of MCC should greatly advance our ability to assess novel therapies at a relatively early stage of drug development. The resulting data may then be used to select those candidates that should be rapidly advanced into larger clinical trials.     

Validity of a quality of well-being scale as an outcome measure in chronic obstructive pulmonary disease

This paper evaluates the validity of the Quality of Well-being Scale (QWB) as an outcome measure for research on Chronic Obstructive Pulmonary Disease (COPD). The Quality of Well-being Scale was originally designed for use as a general health outcome measure. One criticism of this approach has been that it may not be valid in studies limited to a specific disease or condition. We report correlations between the QWB and a variety of other outcome measures obtained in an experimental trial evaluating the benefits of behavioral programs for COPD patients. The data from the trial suggest that the QWB is substantially correlated with both performance and physiological variables relevant to the health status of COPD patients. An advantage of the QWB is that it can be transformed into well-year units for cost-effectiveness studies. It is concluded that the QWB has many advantages as an outcome measure for specific disease groups.     

Failure of rasburicase therapy in recurrent acute gout with tophi

Rasburicase, a recombinant urate oxidase enzyme, has been used successfully in several cases of chronic tophaceous gout. We report the case of an elderly woman with chronic tophaceous gout who failed rasburicase therapy due to recurrent acute episodes of gout following each rasburicase infusion, despite prophylactic therapy.     

Plain radiographs as an outcome measure in ankylosing spondylitis

Radiographic evidence of sacroiliitis is a prerequisite for classification according to the (modified) New York criteria. Structural damage is also an important endpoint in the assessment of ankylosing spondylitis (AS). However, little research has been done on the development, validation, and application of scoring methods for radiographic changes in AS. Methodological issues that can be addressed concerning radiographic scoring methods are discussed in detail. A short introduction to the available scoring methods is presented.     

Urinary type II collagen neoepitope as an outcome measure for relapsing polychondritis

Herein we describe the case of a man who was diagnosed as having relapsing polychondritis (RP) when he was 18 years of age and was treated over the course of 2 years with numerous immunosuppressive agents, including tumor necrosis factor alpha (TNFalpha) inhibitors. His respiratory symptoms were refractory to treatment. Serum and urine samples were obtained periodically for measurement of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels, anti-type II collagen (anti-CII) antibodies, and urinary type II collagen neoepitope (uTIINE) levels. The uTIINE assay is specific for collagenase cleavage products CII present in urine. ESRs and CRP levels varied widely but were rarely normal. Anti-CII antibody titers were high initially and decreased slowly and steadily for a year following the start of immunosuppressive medication, remaining low throughout the remainder of the patient's monitored disease course. The uTIINE levels were elevated prior to the initiation of TNFalpha inhibitors. Upon initiation of etanercept, they decreased abruptly to normal and stayed nearly normal. The uTIINE levels rose abruptly again upon discontinuation of TNFalpha inhibitor treatment. The dramatic decline in CII degradation, coincident with the administration of the TNFalpha inhibitors, suggested that this treatment dramatically reduced the chondritis. Serum levels of Th1 cytokines (interferon-gamma, interleukin-12 [IL-12], and IL-2) paralleled changes in uTIINE levels, while those of Th2 cytokines (IL-4, IL-5, IL-6, and IL-10) showed little or no association with disease state or uTIINE levels. These results indicate that RP might be a Th1-mediated disease process. Moreover, the uTIINE assay appears to provide an objective measure of the severity of chondritis that could assist clinical decisions regarding adjustments of steroid and other immunosuppressive therapy. This outcome measure merits investigation in a broader spectrum of RP patients.     

Quality of life as an outcome measure in pulmonary diseases

Chronic obstructive pulmonary disease is a serious debilitating condition that is a major cause of death and disability in the modern world. There is no medical or surgical cure for chronic obstructive pulmonary disease and rehabilitation has become an accepted component of disease management and recommended in practice guidelines. Pulmonary rehabilitation programs are designed to restore patients to their highest level of functioning. Traditional physiological measures of lung function are of limited value in the evaluation of outcomes from rehabilitation and rarely capture the benefits of intervention. This review considers quality-of-life outcome measures. There are 2 major approaches to quality-of-life assessment: psychometric and decision theory. The psychometric approach is used to offer a profile summarizing different dimensions of quality of life. The decision theory approach attempts to weight the different dimensions of health in order to provide a single expression of health status. Measures can be classified as either generic or disease targeted. Generic measures can be used with any population, whereas disease-targeted measures are used for patients with a particular diagnosis. Finally, measures can be categorized by their probable uses. Most measures can be used to characterize populations and to study clinical change. However, only generic, decision theory-based measures can be used to evaluate cost-effectiveness. In this article, we review measures for chronic lung diseases in these different categories and identify those more suitable for particular purposes. We devote particular attention to methods designed for use in cost-effectiveness analysis.     

Effect of urate‐lowering therapy on the velocity of size reduction of tophi in chronic gout

Objective

The optimal serum urate levels necessary for elimination of tissue deposits of monosodium urate in patients with chronic gout is controversial. This observational, prospective study evaluates the relationship between serum urate levels during therapy and the velocity of reduction of tophi in patients with chronic tophaceous gout.

Method

Sixty‐three patients with crystal‐confirmed tophaceous gout were treated with allopurinol, benzbromarone, or combined therapy to achieve serum uric acid levels less than the threshold for saturation of urate in tissues. The tophi targeted for evaluation during followup were the largest in diameter found during physical examination.

Results

Patients taking benzbromarone alone or combined allopurinol and benzbromarone therapy achieved faster velocity of reduction of tophi than patients taking allopurinol alone. The velocity of tophi reduction was linearly related to the mean serum urate level during therapy. The lower the serum urate levels, the faster the velocity of tophi reduction.

Conclusion

Serum urate levels should be lowered enough to promote dissolution of urate deposits in patients with tophaceous gout. Allopurinol and benzbromarone are equally effective when optimal serum urate levels are achieved during therapy. Combined therapy may be useful in patients who do not show enough reduction in serum urate levels with single‐drug therapy.

     

Serum urate as a proposed surrogate outcome measure in gout trials: From the OMERACT working group

Serum urate (SU) is the most common primary efficacy outcome in trials of urate-lowering therapies for gout. Despite this, it is not formally considered a validated surrogate outcome. In this paper we will outline the definitions of biomarkers and surrogate outcome measures, respectively as well as the available frameworks and challenges in the assessment of the validity of serum urate as a surrogate in gout (i.e. a reasonable replacement for gout symptoms).     

Comment on six-minute walk test as an outcome measure for the assessment of treatment in intervention trials of chronic heart failure

Olsson et al.¹ outlined in their article that the 6-minutewalk test (6MWT) has not yet been proven to be a robust testfor identification