Precision medicine approach in gout is not so easy as ABCG2

Professor Robert Terkeltaub

Precision medicine in gout has a way to go despite “impressive” guidelines from groups such as ACR, an expert says.

Speaking at ACR Convergence 2020, Professor Robert Terkeltaub said the guidelines – published earlier this year – provided a broad group of recommendations and new evidence supporting the benefit of urate lowering therapy (ULT) and a treat-to-target (TTT) approach.

These included detailed recommendations on ULT indications, titration, serum urate target, ULT agent switching, contraindications and more.

“And this involves recognising that, with allopurinol or febuxostat as primary examples, that they are sufficient for urate lowering therapy in most individuals,” he said.

However Professor Terkeltaub, from the University of California San Diego and Veterans Administration Medical Center, said there were still many gaps in gout management.

For example:

  • Was ULT truly sufficient for erosions or can they be targeted better?
  • Can we target synovitis faster and limit joint damage?
  • How to refine the serum urate target e.g how low, how quick?
  • Can we impact the whole patient including their cardiovascular disease, renal disease, hepatic disease such as NASH?
  • How to precisely treat hyperuricemia in gout with stage IV CKD?
  • The use of uricoserics as monotherapy or in combination with xanthine oxidase inhibitors
  • Immune modulation /suppression in addition to recombinant uricase therapy to gain better outcomes in severe polyarticular tophaceous gout.

In particular, Professor Terkeltaub highlighted the increasing role of pharmacogenomics in ULT.

“The bottom line … is that urate excretion mediated by the high capacity urate transporter ABCG2 is a substantial new precision medical/pharmacogenomic consideration,” he said.

Gout was no longer only considered a disease of renal uric acid underexcretion or uric acid overproduction or a combination of both, but also renal uric acid overload due to ABCG2 functional deficiency with extra-renal underexcretion.

He said defective ABCG2 variants had been linked to early onset and tophaceous gout.

“So ABCG2 has emerged as an important player in urate homeostasis and regulating serum urate levels. ABCG2 variance is common in the ‘new genetics’ of gout susceptibility that has emerged over the last decade through beautiful genome-wide association studies.”

He said the ABCG2 Q141K variant, which causes misfolding, enhanced proteasomal degradation and functional deficiency and was strongly linked to allopurinol drug resistance, was common and had the highest impact.

The allele frequency was about 10% in Caucasians but much higher in other populations such as 19-20% in Mexican-Americans and Native Americans, up to 30% in East Asian populations, and about 50% in Han Chinese and Japanese people with gout.

And there was possible “double whammy” in, for example, East Asian populations which also had an overlap with a relatively high frequency of HLA-B*5801 and allopurinol hypersensitivity syndrome risk.

“So we’ve got to look more carefully and deeply at these issues of pharmacogenomics of ABCG2 … at some point ABCG2 may play a role in how we manage gout patients.”

Professor Terkeltaub said there were other gaps in knowledge which could impact on the application of precision medicine in the clinic.

“We have comorbidities that can act on uric acid balance, uric crystal deposition and can affect inflammatory processes.”

“We have exposures which can do the same. We have some where we haven’t even begun to scratch the surface, including the microbiome, and we have some we know very well such as diet and alcohol and other medications which we use – many for comorbidities – which will raise or lower uric acid.”

Signally and transcriptional pathways which mediate innate and adaptive immunity or inflammation were other factors which act on the elements of gout such as dysregulated uric acid balance, urate crystal deposition and arthritis.

“Additional considerations include the evolving evidence for therapeutic effects of ULT, colchicine, or IL-1 inhibition on potentially co-morbid states in gout including NASH, CAD, hypertension, type 2 diabetic kidney disease proteinuria, and more recently COVID-19 where colchicine is at least being explored.”

He said that precision therapy in gout needs to include prescribing with specific comorbidities in mind.

“Intensive urate lowering beyond treat-to-target with a combination of verinurad and febuxostat has been shown to have a clinically significant impact by decreasing albuminuria in T2D,” he added.

Xanthine oxidase inhibitors had underappreciated anti-inflammatory effects for example in comorbidities such as NASH, he said, and evidence for cardioprotection by colchicine was also maturing.

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