Overview of Serum Uric Acid Treatment Targets in Gout: Why Less Than 6 mg/dL?

Figures & data

Figure 1. Diagram showing the path from hyperuricemia to structural joint damage. Long-standing hyperuricemia may lead to monosodium urate (MSU) deposits. Hyperuricemia is typically asymptomatic and is often associated with subclinical inflammation and bone erosion. Crystal shedding into the joint can cause Intermittent, acute inflammation and a gout flare-up. Continued crystal deposition can result in chronic manifestation of the disease, including persistent inflammation, increased number of flares, development of tophi, and structural joint damage. Adapted from Adv Ther, ‘A review of uric acid, crystal deposition disease, and gout’, volume 32, 2015, Perez-Ruiz F, et al, Figure 1: ‘Diagram showing the path from hyperuricemia to structural joint damage’ on page 32, with permission of Springer (© 2014) [26].

Figure 2. Five-year cumulative incidence of gout according to sUA level in men in the Normative Aging Study [33]. Reproduced with permission from Roddy E and Doherty M: Arthritis Res Ther 2010;12(6):223. [32].

Table 1. The ACR/EULAR gout classification criteria (reproduced with permission from Neogi et al. [36].

Steps	Categories	Score*
Step 1: Entry criterion (only apply criteria below to those meeting this entry criterion)	At least one episode of swelling, pain, or tenderness in a peripheral joint or bursa
Step 2: Sufficient criterion (if met, can classify as gout without applying criteria below)	Presence of MSU crystals in a symptomatic joint or bursa (i.e., in synovial fluid) or tophus
Step 3: Criteria (to be used if sufficient criterion not met)
Clinical
Pattern of joint/bursa involvement during symptomatic episode(s) ever^†	Ankle or mid-foot (as part of monoarticular or oligoarticular episode without involvement of the first metatarsophalangeal joint	1
	Involvement of the first metatarsophalangeal joint (as part of monoarticular or oligoarticular episode)	2
• Characteristics of symptomatic episode(s) ever
– Erythema overlying affected joint (patient reported or physician observed)	One characteristic	1
– Cannot bear touch or pressure to affected joint	Two characteristics	2
– Great difficulty walking or inability to use affected joint	Three characteristics	3
• Time course of episode(s) ever (presence [ever] of ≥2, irrespective of anti-inflammatory treatment)
– Time to maximal pain <24 h	One typical episode	1
– Resolution of symptoms in ≤14 d	Recurrent typical episodes	2
– Complete resolution (to baseline level) between symptomatic episodes
• Clinical evidence of tophus
– Draining or chalk-like subcutaneous nodule under transparent skin, often with overlying vascularity, located in typical locations: joints, ears, olecranon bursae, finger pads, tendons (e.g. Achilles)	Present	4
Laboratory
• Serum urate^‡: measured by the uricase method. Ideally should be scored at a time when the patient was not receiving urate-lowering therapy and it was >4 weeks from the start of an episode (i.e. during intercritical period); if practicable, retest under those conditions. The highest value irrespective of timing should be scored	<4 mg/dL (<0.24 μmol/L) 6–<8 mg/dL (0.36–<0.48 μmol/L) 8–<10 mg/dL (0.48–<0.60 μmol/L) ≥10 mg/dL (≥0.60 μmol/L)	−4 2 3 4
• Synovial fluid analysis of a symptomatic ever joint or bursa^§	MSU negative	−2
Imaging^#
• Imaging evidence of urate deposition in symptomatic (ever) joint or bursa: ultrasound evidence of double-contour sign^¶ or DECT demonstrating urate deposition**	Present (either modality)	4
• Imaging evidence of gout-related joint damage: conventional radiography of the hands and/or feet demonstrates at least one erosion^††	Present	4

DECT: dual-energy computed tomography; MSU: monosodium urate.

*The higher the score, the greater likelihood of gout. A web-based calculator can be accessed at http://goutclassificationcalculator.auckland.ac.nz, and through the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) websites.

^†Symptomatic episodes are periods of symptoms that include any swelling, pain, and/or tenderness in a peripheral joint or bursa.

^‡If serum urate level is <4 mg/dL (<0.24 mmol/L), subtract 4 points; if serum urate level is ≥4 mg/dL to <6 mg/dL (≥0.24–<0.36 mmol/L), score this item as 0.

^§Should be assessed by a trained observer. If polarizing microscopy of synovial fluid from a symptomatic (ever) joint or bursa by a trained examiner fails to show MSU crystals, subtract 2 points. If synovial fluid was not assessed, score this item as 0.

^#If imaging is not available, score these items as 0.

^¶Hyperechoic irregular enhancement over the surface of the hyaline cartilage that is independent of the insonation angle of the ultrasound beam (note: false-positive double-contour sign [artifact] may appear at the cartilage surface but should disappear with a change in the insonation angle of the probe).

**Presence of color-coded urate at articular or periarticular sites. Images should be acquired using a DECT scanner, with data acquired at 80 kV and 140 kV and analyzed using gout-specific software with a two-material decomposition algorithm that color-codes urate. A positive scan is defined as the presence of color-coded urate at articular or periarticular sites. Nail bed, submillimeter, skin, motion, beam hardening, and vascular artifacts should not be interpreted as DECT evidence of urate deposition.

^††Erosion is defined as a cortical break with sclerotic margin and overhanging edge, excluding distal interphalangeal joints and gull wing appearance.

Figure 3. Dual-energy computed tomography (DECT) images of ankle and foot (a, b) showing MSU crystal deposition in green color (arrows) and corresponding CT images (c, d) showing erosions (arrowheads). Reproduced with permission from Chowalloor PV, et al: Ther Adv Musculoskelet Dis 2014;6(4):131-43. [40].

Figure 4. Solubility of a substance (a solute) is the amount of that substance that will dissolve in a given amount of solvent; or it is a measure of how well one substance dissolves into another. A solute can fully dissolve in a solution that has less than the maximum amount of solute that can be dissolved. A saturated solution contains as much solute as it possibly can dissolve. A supersaturated solution contains more solute than can be dissolved, increasing the potential for crystal formation.

Figure 5. Mean serum urate levels versus velocity of tophi reduction. Reproduced with permission from Perez-Ruiz F, et al: Arthritis Rheum 2002;47(4):356-60. [59].

Figure 6. Baseline ACR recommendations and overall strategy for treating and managing patients with gout. Data from Khanna D, et al: Arthritis Care Res (Hoboken) 2012;64(10):1431-46. [53].

Table 2. Why keep serum uric acid levels <6 mg/dL?

Keeping the levels of sUA <6 mg/dL, which is below the saturation concentration of 6.8 mg/dL, can help:

– Prevent MSU crystal formation

– Prevent inflammation

– Reduce progressive debilitating joint and tissue damage

– Reduce the amount of crystals in the body

– Reduce the likelihood of flares

– Reduce tophus formation

– Prevent gouty arthritis

– Increase dissolution of tophi

Keeping levels of sUA sufficiently below the saturation concentration of 6.8 mg/dL will mitigate fluctuations in sUA levels due to physiologic and natural factors

Halting crystal formation and eliminating existing crystals, together, is the only way to stop signs and symptoms of gout

MSU: monosodium urate; sUA: serum uric acid.

Figure 7. Percentage of patients who required treatment for flares while receiving a maintenance dose of febuxostat to keep sUA levels <6 mg/dL. Reproduced with permission from Schumacher HR, Jr., et al: Rheumatology (Oxford) 2009;48(2):188-94. [64].

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