Development of a Multivariable Improvement Measure for Gout

Naomi Schlesinger; N. Lawrence Edwards; Anthony E. Yeo; Peter E. Lipsky

Disclosures

Arthritis Res Ther. 2020;22(164) 

In This Article

Background

Inflammatory rheumatic diseases are generally multifaceted disorders, and the complex pathology underlying these conditions makes it difficult to assess patient status and the efficacy of therapy with a single representative outcome measure.[1] The lack of a single gold standard for patient monitoring has prompted the development of composite measures for many rheumatic diseases,[2] and there are well-established indices for rheumatoid arthritis,[3,4] psoriatic arthritis,[5–7] systemic lupus erythematosus,[8–10] ankylosing spondylitis,[11] osteoarthritis,[12,13] and fibromyalgia.[14]

Gout is also a multifactorial inflammatory disease. Even though the cause of gout, namely hyperuricemia, is known, patients experience a wide range of symptoms, including severe pain, acute and persistent inflammatory arthritis, tophi, and disability associated with both flares and chronic disease.[15,16] Moreover, the spectrum of disease changes with time.[17,18] It has been recommended that multiple domains should be evaluated when assessing effects of treatment for gout.[19,20] Although assessment of urate-lowering therapy (ULT) for this disease has focused primarily on the ability to lower serum urate (sU) and decrease in the frequency of flares,[21–25] some trials have included additional endpoints to address effects of treatment on pain, arthritis, and disability.[26,27]

The overall goal of ULT is the dissolution of all urate deposits and the prevention of new deposits from occurring. Although it is assumed that this occurs when the sU level is maintained at a level < 6 mg/dL, there is no direct means other than imaging modalities to assess this. Therefore, there is the general recognition that assessment of ULT and other treatments for gout could be facilitated by endpoints that more closely reflected the multidimensional effects of urate deposition. This has prompted multiple groups to propose composite measures aimed at this goal. Over a decade ago, an Outcome Measures in Rheumatology (OMERACT) special interest group proposed core domains for interventional studies in chronic gout that included sU, gout flare recurrence, tophus regression, joint damage imaging, health-related quality of life, musculoskeletal function, patient global assessment (PGA), ability to participate in usual activities, and safety and tolerability.[28] Since that time, there have been multiple discussions regarding the domains most important for inclusion in a composite measure for use in clinical trials of advanced gout.[29] These measures are generally aimed at determining the patient's status at a given point in time rather than providing a change score that captures response to treatment over time. Despite very high interest and intensive deliberation, development and testing of composite measures for either acute or advanced gout has been very limited. A composite index for evaluation of treatments for acute gout has been developed,[30] and a composite Gout Activity Score (GAS) has been shown to be sensitive to change and to have predictive validity with a correlation to the domains of the Gout Impact Scale (GIS);[31,32] however, these composite measures have not been tested in trials of ULT.

The present study used results from two identical randomized controlled trials (RCTs) of pegloticase (NCT00325195, NCT01356498) for development of a composite measure for capturing responses to gout treatment. The construction of the Gout Multivariable Improvement Measure (GMIM) involved evaluation of criteria proposed to define remission in gout and included sU, frequency of flares, tophus reduction, pain evaluation, and PGA.[33] Previous evaluation of patient responses added tender and swollen joints to the list of patient features incorporated.[34] GMIM therefore comprised sU, flares, tophi, PGA, pain, and swollen and tender joint counts (SJC, TJC). Improvement was defined as sU < 6 mg/dL and absence of flares during the preceding 3 months plus 20%, 50%, or 70% improvement in ≥ 3 of the other 5 clinical evaluations.

The aim of this study was to use GMIM to assess the degree of response in patients with chronic refractory gout treated with pegloticase and to validate the composite response measure by comparing its ability to discriminate those with persistent urate lowering from pegloticase treatment with those with transient urate lowering and also those receiving placebo. GMIM was also tested in a group of patients who received placebo in the RCTs and began pegloticase in the open-label extension to evaluate the composite measure in a situation not used to develop the tool. Although based on data from a subset of subjects with advanced gout, the tool may have utility in other settings.

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