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YEAR IN REVIEWGOUT IN 2013

Imaging, genetics and therapy: gout research continues apace Fiona M. McQueen

In 2013, much progress has occurred in gout research. Imaging continues to help elucidate aspects of pathophysiology and now suggests that healing of erosions could occur when urate levels are reduced dramatically. New genetic loci associated with hyperuricaemia have been identified and management strategies for prophylaxis of gout flares continue to evolve.McQueen, F. M. Nat. Rev. Rheumatol. advance online publication 26 November 2013; doi:10.1038/nrrheum.2013.164

During 2013, there have been major advances in gout research. The pathological basis of this disease and response to therapy continue to be investigated using imaging (Figure 1). Explor atory data indicate that gouty erosions have the potential to heal in patients treated with intensive urate-lowering therapy (ULT), leading to tophus regression. This finding provides a rationale for aiming for a very low serum uric acid (SUA) level in situations in which the skeleton shows evidence of erosive change. The genetics of hyperuricaemia have recently been highlighted because of a genome-wide association study (GWAS) that identified multiple new loci of interest, some of which implicate glucose metabolism in systemic urate control—further linking gout with other features of the metabolic syndrome. Advances in management include a focus on prevention of the acute gout flare during initiation of ULT, an important topic considering the plethora of new drugs being developed and the negative effects that flares might have on long-term patient compliance.

Imaging continues to yield information rele vant to gout pathology and holds pro mise

for monitoring responses to ULT.1 Peglo-ticase is an enzymatic form of ULT tar geted to patients with chronic refractory gout,2 and provides a unique in vivo model for examining the effects of profound urate lower ing on the gouty joint. This issue was recently explored by Dalbeth et al.1 in a US–New Zealand collaboration. Serial radio-graphs (hands and feet) were obtained from eight patients with chronic tophaceous gout treated with pegloticase to determine whether intraosseous tophus resolution might allow bone erosions to regress after 12 months. As expected, urate levels were decreased in all patients. Interest ingly, there was indeed a change in the radiographic erosion score over this period (by 7 units; P = 0.008), but joint-space narrowing (JSN) scores did not change. Further reductions were observed in erosion (but not JSN) scores for the five patients who were analysed again by radiography after 24 months.

These findings are consistent with the direct link between tophus deposition and erosion in gout.3 Using ULT to cause disso-lution of an intraosseous tophus could poten-tially lead to a large bony defect that might collapse owing to loss of structural integrity. However, both sclerosis and ‘filling in’ of erosions were observed, indicating initia-tion of repair. By contrast, radiographic JSN, a surrogate measure of cartilage damage, was unchanged after pegloticase. Cartilage has recently been in the imaging spotlight with the description of an ultrasonographic “double contour sign”, thought to indicate deposition of monosodium urate (MSU) crystals in a fine layer over hyaline cartilage.4

Pegloticase would probably also lead to dis-solution of this MSU crystal layer, so does this imply that reparative mechanisms for cartilage are less efficient than for bone, or that cartilage integrity was not much affected (by MSU)? Larger studies are clearly war-ranted, but the overall message from this work is positive—bone damage from tophus deposition in gout might be at least partially reversible. Thus, maintenance of low urate levels in patients with erosive gout, even when flares are no longer occurring, seems to be important.

Contrasting with the very small patient numbers in the previous study, Kottgen et al.5 combined data from >140,000 individuals of European ancestry to identify genetic loci associated with SUA concentrations. Using powerful GWAS methods, 26 SUA-associated single nucleotide polymorphisms (SNPs) were identified, 10 having been already described and 16 being new loci. A weighted genetic score was constructed on the basis of the number of risk alleles identi-fied across loci. Risk scores were associated with gout prevalence, which increased from <1% to 18% across risk score categories in different populations, and with gout inci-dence in other populations in which patients with gout were followed for up to 22 years.

Although the renal urate transporter gene ABCG2 and the glucose transporter 9 gene (GLUT9, also known as SLC2A9), were con-firmed to be associated with SUA levels, none of the genes at the newly identified loci were involved in urate transport. The analysis highlighted links with the inhibins– activins growth factor system and with glucose meta-bolism genes, which is consistent with the association between hyperuricaemia and the later development of type II dia betes mel-litus in men with high cardio vascular risk.6 Therapeutic agents that promote hypoglycae-mia by lowering insulin resistance (such as metformin) tend also to decrease SUA levels, emphasizing the complex links within the metabolic syndrome.5 As part of the GWAS analysis, different ethnic groups were exam-ined and although allele frequencies at the index SNPs varied across groups, associations were of comparable magnitude and in the same direction. Other studies have suggested that the strength of such associations can vary according to ethnicity; New Zealand Maori

Key advances

■ Regression and possible healing of radiographic erosions can occur with aggressive urate-lowering therapy1

■ Genes that modulate glucose metabolism are associated with hyperuricaemia, linking different features of the metabolic syndrome5

■ Effective gout flare prophylaxis using IL-1β blockade can be achieved in many patients initiating urate-lowering therapy8

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YEAR IN REVIEW

and Pacific islanders with gout were shown to have the same risk variants in SLC2A9 as white individuals, but the degree of risk con-ferred was substantially greater in the former group.7 Despite these extensive new data,5 it is worth noting that the variance in SUA level explained by all associations was only 7.0% (5.2% being explained by previously known loci), leaving a sizeable gap between current genetic knowledge and heritability estimates for SUA levels of 40–60%.

The optimal use of novel and conventional ULT remains a crucial issue. In 2013, Mitha et al.8 reported results of the PRESURGE2 study, examining the efficacy of rilonacept for the prevention of gout flare during ULT initiation with allo purinol. Most clinicians are familiar with the common occurrence of gout flare in these circumstances (which can contribute to patient noncompliance), therefore, prevention of flare is an important goal. Rilonacept is a soluble decoy receptor fusion protein that binds IL-1α and IL-1β, preventing activation of cell surface recep-tors. As IL-1β is known to be a major inflam-matory cytokine in gout, a strong scientific rationale exists for this strategy, especially for patients who cannot tolerate other medica-tions used in this setting (NSAIDs and col-chicine).9 Gout flares have been proposed to occur when the SUA level is suddenly

Synovitis: on PDUS

Cartilage: coated by MSU crystals (ultrasonography)

Synovitis and tenosynovitis:

on MRI

Imaging in gout reveals pathology

Bone erosions: Tophi sited within gouty erosions on CT, DECT and ultrasonography

Tophaceous deposits:within joints, tendons and entheses (DECT)

a

c

e

fd

b

g

decreased, resulting in release of ‘naked’ MSU crystals from inside the tophus.10 This step initiates a cascade of events, triggering the innate immune response and leading to IL-1β release, neutro phil activation and acute inflammation. Mitha et al.8 recruited 248 patients with gout who were treated with allopurinol 300 mg daily, titrated upwards to achieve a SUA of <6 mg/dl (~0.36 mmol/l). The participants were randomly assigned to receive weekly subcutaneous injections of placebo, or 80 mg or 160 mg rilonacept. Rilonacept significantly reduced the occur-rence of flares, with >70% of treated patients having none compared with 44% of those receiving placebo (P <0.0001). The number of adverse events was similar for all groups and injection site reactions to rilonacept were mild.

Colchicine is currently considered the standard of care for flare prophylaxis during initiation of ULT.9 Colchicine and NSAIDs should generally be avoided in patients with chronic renal impairment, and inhibi-tors of IL-1β (rilonacept or canakinumab) might have an important niche role here. Unfortunately, information about renal function is lacking in the Mitha et al.8 study and no large trials of IL-1β blockade in patients with renal impairment are available. Benefits would need to be weighed against

risks of potentiating infection, especially in those receiving haemodialysis, and the use of expensive biologic agents always raises pharmacoeconomic issues.

In summary, 2013 has seen gout research proceeding apace on many fronts, ranging from imaging for monitoring the effects of ULT, to state-of-the-art genetics, to the further use of cytokine inhibitors. Moving forward, priori ties for the research agenda include imaging studies using CT and dual-energy CT to further investigate the erosion response to ULT, genetics studies to investi-gate the ‘heritability gap’ referred to earlier and trials of therapeutics for patients with gout who have renal impairment.

Department of Molecular Medicine and Pathology, University of Auckland, PO Box 92019, Auckland 1023, New Zealand. f.mcqueen@auckland.ac.nz

AcknowledgementsThe author wishes to thank R. Stuart (Northern Clinic, Auckland), N. Dalbeth and A. Doyle (University of Auckland), and Q. Reeves (Auckland District Health Board) for their assistance in providing images for Figure 1.

Competing interestsThe author declares no competing interests.

1. Dalbeth, N. et al. Exploratory study of radiographic change in patients with tophaceous gout treated with intensive urate-lowering therapy. Arthritis Care Res. http:// dx.doi.org/10.1002/acr.2205.

2. Becker, M. A. et al. Long-term safety of pegloticase in chronic gout refractory to conventional treatment. Ann. Rheum. Dis. 72, 1469–1474 (2013).

3. Dalbeth, N. et al. Mechanisms of bone erosion in gout: a quantitative analysis using plain radiography and computed tomography. Ann. Rheum. Dis. 68, 1290–1295 (2009).

4. Thiele, R. G. & Schlesinger, N. Diagnosis of gout by ultrasound. Rheumatology 46, 1116–1121 (2007).

5. Kottgen, A. et al. Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat. Genet. 45, 145–154 (2013).

6. Choi, H. K., De Vera, M. A. & Krishnan, E. Gout and the risk of type 2 diabetes among men with a high cardiovascular risk profile. Rheumatology 47, 1567–1570 (2008).

7. Hollis-Moffatt, J. E. et al. Role of the urate transporter SLC2A9 gene in susceptibility to gout in New Zealand Maori, Pacific Island, and Caucasian case–control sample sets. Arthritis Rheum. 60, 3485–3492 (2009).

8. Mitha, E. et al. Rilonacept for gout flare prevention during initiation of uric acid-lowering therapy: results from the PRESURGE2 international, phase 3, randomized, placebo-controlled trial. Rheumatology 52, 1285–1292 (2013).

9. Schlesinger, N. Treatment of chronic gouty arthritis: it is not just about urate-lowering therapy. Semin. Arthritis Rheum. 42, 155–165 (2012).

10. Liu-Bryan, R. & Terkeltaub, R. Evil humors take their toll as innate immunity makes gouty joints TREM-ble. Arthritis Rheum. 54, 383–386 (2006).

Figure 1 | Different imaging modalities reveal all aspects of gout pathology. a | High-resolution CT scan (wrist, axial): large gout erosion plus tophus at 1st metacarpal base (circle). b | DECT (great toe): tophus (red) within erosions (arrows). c | Ultrasonography (1st MTP joint): erosions (arrows). d | DECT (3D reconstruction): tophaceous deposits at MTP joints (circle), Achilles tendon sheath and plantar fascia (arrows). e | Ultrasonography (1st metatarsal head): double contour sign (arrows). f | MRI (wrist; post-contrast axial T1w scan): synovitis at distal radioulnar joint (arrow) and extensor tenosynovitis (arrowheads). g | PDUS (great toe): vascular signal indicating synovitis. Abbreviations: DECT, dual-energy CT; MTP, metatarsophalangeal; PDUS, power Doppler ultrasonography.

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