In a study published in this issue of The Journal of Rheumatology, Mulqueen et al1 examined whether the relative reduction in urate crystals in joints or tendons differed in people with gout on urate-lowering therapy (ULT) with the treat-to-target (T2T) principle. T2T requires uptitration of the ULT dose with a goal of lowering serum urate to < 6 or < 5 mg/dL, depending on the clinical situation, with frequent serum urate monitoring at ULT initiation.2
They used data from 2 clinical trials of oral ULT of T2T, with the first dual-energy computed tomography (DECT) showing total volume of ≥ 0.5 cm3, a subsequent DECT showing reduced total volume, and urate deposit visible in at least 1 joint and 1 tendon on the first scan.1 Up to 3 index urate deposits in joints and in tendons were selected for each participant. The reduction in the DECT urate volume in the joint deposits was similar to that in the tendon deposits at 1 year follow-up in people with gout getting ULT with T2T.1 There was no significant difference in the urate deposit reduction in joints vs tendons.1 The study results are in some contrast to previous ultrasound studies reporting that gout lesions in the joints may reduce more rapidly than in tendons in people with gout using oral ULT.3,4 A previous case series report showed slower resolution in tendons vs joints on DECT following intravenous pegloticase therapy (intravenous ULT).5
So how does the study by Mulqueen et al1 clarify this issue? Key strengths and limitations of the study must be considered first. Strengths include data from 2 gout trials for oral ULT—the most commonly used treatment for gout—the use of 1-year DECT images using a standard protocol, and a single trained reader for the study.1 The limitations include the study of only patients who had a reduction in urate volume, the omission of year 2 DECT data, and a single observer.
There are additional considerations. There is a known discrepancy in the accuracy of ultrasound vs DECT for urate deposit assessment.6,7 Interestingly, there was a recent multicenter study that prospectively collected both DECT and ultrasound data in gout patients treated with ULT who underwent clinical evaluations and imaging studies at baseline, with 6-, 12-, and 24-month follow-ups.8 The absolute and relative changes in index tophus (the largest tophus for certified ultrasound) for volume was measured with both ultrasound and DECT. There was a complete tophus resolution on DECT at 12 months with a T2T serum urate approach, but not on ultrasound imaging, which provided a great variability of volumetric assessment throughout the follow-up. The authors interpreted these data as DECT being more accurate for serial urate/tophus measurements.8 The correlation between relative change in the ultrasound double contour sign count and the overall DECT volume of urate deposition was weak at all timepoints.8 The complete resolution of urate tophi on DECT is an impressive notable finding achieved in patients within 12 months of T2T with ULT.
How do the results of the study inform us?
A key important message from the study1 is that when patients undergo T2T serum urate strategy for gout treatment, there is not only a reduction in serum urate but also resolution of urate deposits in both joints and tendons within 1 year of treatment.1 This is further proof of reversal of pathophysiology of a chronic disease demonstrated with a sensitive and valid imaging modality (DECT) that correlates with a valid disease biomarker (serum urate), in the context of specific treatment strategies such as T2T with oral ULT in adequate doses. Such a clear link from disease pathophysiology to clinical features to treatment to reversal of pathologic features on a valid imaging modality is uncommon or rare in chronic medical conditions. Gout offers an opportunity for such a clear pathophysiological, biochemical, and imaging correlation for improvement and resolution of reversible change from a chronic disease, when patients are treated adequately with T2T serum urate. The T2T principle is well accepted in the management of rheumatoid arthritis, psoriatic arthritis, radiographic axial spondyloarthritis, and systemic lupus erythematosus.9
Most guideline panels and practicing rheumatologists follow T2T in gout.2 Whether we should aim for T2T or treat-to-dissolve (a step further) is an interesting debate.10,11 A different controversy started when the American College of Physicians (ACP) gout treatment guideline,12 which contrasts with every other gout treatment guideline published prior and since,13 brought up a new concept of treat-to-control symptoms in gout, namely, to treat just the symptoms (eg, flares) and not the underlying chronic disease (gout). The ACP guideline excluded from their systematic review randomized trials of pegloticase (the most effective ULT to date), and pivotal febuxostat trials and observational studies of ULT that provide moderate- to high-quality evidence that the T2T principle leads to fewer flares, better quality of life, and lower treatment costs. A nurse-led program in the United Kingdom that achieved a tremendously higher proportion of people with gout achieving T2T in the nurse-led arm compared to primary care provider management, reported a lower rate of gout flares, better quality of life, and cost savings.14 The nurse-led arm had a higher allopurinol dose and 3-times higher rate of T2T (95%, vs 30% with serum urate < 6 mg/100 mL).14
How do the results of the study inform the patient?
Patients with gout have a high rate of nonadherence to oral ULT.15,16 Many reduce the daily ULT dose for fear of potential side effects; lack of knowledge; lack of trust; or recommendations from friends, family, or providers.17 The T2T principle has the premise that patients should take an optimal ULT dose to get optimal benefit, namely, to reduce or eliminate frequent painful, disabling gout flares and improve quality of life. The reduction of urate tophaceous deposit in joints and tendons with T2T is an additional benefit to the patient.
This study in concert with other studies of tophus reduction/resolution confirms that we can achieve not only a reduction but also possible resolution of tophaceous deposits with a T2T strategy, usually within 1 to 2 years of ULT treatment. This new knowledge should help patients make better shared decision-making treatment decisions with their providers. An increasing proportion of patients might choose a higher, more optimal ULT dose that decreases gout flares, joint pain, and swelling, and resolves urate tophi. An alternate approach would be to follow the ACP guidance of treating to only control symptoms with antiinflammatory drugs. That approach, in my opinion, will lead to suboptimal treatment of the underlying pathology in gout, with significant joint pain, reduced function and quality of life, as well as development of gouty tophi over time. Untreated systemic inflammation due to suboptimal gout treatment can increase the risk of acute cardiovascular events18 and other chronic conditions where systemic inflammation is a risk factor.
What are the next steps for us?
We must perform high-quality adequately powered trials and observational studies, and mechanistic studies, such as that by Mulqueen et al,1 to address specific aspects of gout treatment. Longer-term follow-up in mechanistic studies, replication of results by multiple groups (as demonstrated for tophi resolution with T2T oral ULT1,8), and a better linking of disease improvements with patient-reported outcomes are needed to advance the management of gout.
Footnotes
See Joint and tendon urate, page 194
FUNDING
JAS is supported in part by research grants from the Patient-Centered Outcomes Research Institute (PCORI; SDM-2017C2-8224; CER-2020C1-19193); the National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS; 1R01AR082839-01A1); the resources and the use of facilities at the VA Medical Center in Houston, Texas; and the Center for Innovations in Quality, Effectiveness and Safety (#CIN 13-413), Houston, Texas, USA.
COMPETING INTERESTS
JAS has received consultant fees from ROMTech, Atheneum Books, Clearview Healthcare Partners, Yale, Hulio, Horizon/DINORA, ANI/Exeltis, Frictionless Solutions, Schipher, Crealta/Horizon, Medisys, Fidia, PK Med, Two laboratories Inc., Adept Field Solutions, Clinical Care Options, Putnam Associates, Focus Forward, Navigant Consulting, Spherix, Mediterr Q Life Science, UBM, LLC, Trio Health, Medscape, WebMD, and Practice Point Communications; the National Institutes of Health; and the American College of Rheumatology. JAS has received institutional research support from Zimmer Biomet Holdings. JAS received food and beverage payments from Intuitive Surgical/Philips Electronics North America. JAS owns stock options in Atyr, Atai Life Sciences, Kintara, Intelligent Biosolutions, Acumen, TPT Global Tech, Vaxart, Atyu BioPharma, Adaptimmune Therapeutics, GeoVax Labs, Pieris, Enzolytics, Seres Therapeutics, Tonix, Aebona, and Charlotte’s Web Holdings, Inc. JAS previously owned stock options in Amarin, Viking, and Moderna. JAS was on the speaker’s bureau of Simply Speaking. JAS was a member of the executive of Outcome Measures in Rheumatology (OMERACT), an organization that develops outcome measures in rheumatology and receives arms-length funding from 8 companies. JAS previously served on the FDA Arthritis Advisory Committee. JAS previously served in the following committees: member, the American College of Rheumatology’s (ACR) Annual Meeting Planning Committee and Quality of Care Committees; Chair of the ACR Meet-the-Professor, Workshop and Study Group Subcommittee; and co-chair of the ACR Criteria and Response Criteria subcommittee.
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