#113 Gout: Uric acid targets, urate lowering therapy, and random questions

September 10, 2018 | By Matthew Watto, MD

Master the management of gout with tips from expert, Tuhina Neogi MD, PhD, Professor of Medicine at Boston University School of Medicine. Topics include: how to initiate and titrate urate lowering therapy, guidelines controversy over uric acid targets, colchicine & NSAIDS for anti-inflammatory prophylaxis, uricosuric agents, febuxostat, HLA B5801, use of uric acid levels in the acute setting and more random gout facts.

Credits:
Written and produced by: Matthew Watto MD
Hosts: Paul Williams MD, Stuart Brigham MD, Matthew Watto MD
Guest: Tuhina Neogi MD, PhD 

Special thanks to Tony Sidari MD for his input in drafting our questions for Dr Neogi.

Clinical Pearls

1. STOP referring to gout as acute or chronic! It’s all one disease that requires management of flares and management of the underlying etiology. -Dr Neogi
2. Dr Neogi does not initiate allopurinol during gout flares because patient education is challenging at these visits and patients may confuse which medication is for the flare and which is to be continued long term. Bring the patient back 1-2 weeks after a flare.
3. Who needs urate lowering therapy (ULT): Patients with two or more flares in a year  (Grade A); tophus or tophi on exam or imaging (Grade A); CKD stage 2 or worse (Grade C); past urolithiasis (Grade C) – [Khanna et al. ACR 2012 Gout Guidelines]
4. ULT with allopurinol: Start at 100 mg daily (50 mg daily if CKD 4) and titrate up by 100 mg every two weeks up to 300 mg. Monitor serum uric acid level after 4-8 weeks on therapy.
5. Dr Neogi and the American College of Rheumatology recommend monitoring serum urate (uric acid) levels and titrating to level under 6 mg/dL. Without monitoring it is difficult to discern adherence, efficacy and safety of urate lowering therapy (see below for more on the guidelines controversy).
6. Anti-inflammatory prophylaxis is recommended for all patients starting ULT. Options include: NSAIDS (given w/GI prophylaxis “where indicated”), or colchicine for 6 months OR 3 months after serum uric acid level achieved (6 months if patient has evidence of tophi). [Khanna et al. ACR 2012 Gout Guidelines Part 2 ]. Low dose prednisone is also listed in the guideline, but was not discussed on this episode.
7. Septic arthritis can only be ruled out with arthrocentesis. I personally involve rheumatology in cases where I’m considering both gout and septic arthritis in the differential diagnosis. -Dr Watto’s non-expert opinion

In-Depth Show Notes

Urate lower therapy

Bathtub analogy
Dr Neogi’s bathtub analogy explains gout as process whereby the bathtub (i.e. the body and joints) becomes overflowed with water (i.e. urate and uric acid). If the water level gets to high then it spills over and causes an electrical fire to start (i.e. gout flare). To treat gout we can:  

1. Turn off the faucet with urate lowering therapy e.g. allopurinol, febuxostat
2. Dump out the water with a bucket e.g. use pegloticase (uricase) to metabolize uric acid
3. Drain the bathtub using uricosuric agents e.g. probenecid.

Who needs urate lowering therapy (ULT)

Patients should use urate lowering therapy if they have two or more flares in a year  (Grade A); tophus or tophi on exam or imaging (Grade A); CKD stage 2 or worse (Grade C); or past urolithiasis (Grade C).[Khanna et al. ACR 2012 Gout Guidelines Part 1]

Allopurinol for Urate Lowering therapy (ULT)
The initiation of allopurinol during flares is typically avoided since the resulting acute fluctuation in serum urate (uric acid) levels can THEORETICALLY prolong flares. BUT, a recent study found no significant increase in time to symptom resolution with initiation of allopurinol during flares (Hill et al J Clin Rheumatol. 2015)!

As a rule, Dr Neogi does not initiate urate lowering therapy during gout flares since patients are in too much pain to receive effective education and may be confused about which medication is intended for long term treatment of gout.

A few possible regimens for allopurinol initiation and titration are listed below. Titrate the dose once every two weeks and check urate levels after 4-8 weeks of therapy. –Dr Neogi’s expert opinion:

1. If CKD 2-3 start at allopurinol 100 mg once daily then increase to 200 mg at two weeks and 300 mg after four weeks.
2. Alternative regimen for CKD 2-3: Start at 150 mg once daily and increase to 300 mg after two weeks.
3. If CKD 4 start at allopurinol 50 mg po once daily then increase to 100 mg po once daily at week two, 200 mg daily at week four,  and 300 mg at week six.

The uric acid level should fall within 4-8 weeks of ULT with a goal uric acid level under 6 mg/dL for 6-12 months before risk for flares is truly lowered (Dr Neogi).

Probenecid
A cheap, safe and effective 2nd line agent. It works as a uricosuric agent and “drains water from the bathtub”, but has the downside of requiring multiple pills and twice daily dosing. Additionally, patients on probenecid need to remain well hydrated due to increased risk for kidney stone formation. –Dr Neogi

Anti-inflammatory prophylaxis

All patient should take anti-inflammatory prophylaxis when starting ULT. Options include: NSAIDS (given w/GI prophylaxis “where indicated”), or colchicine for six months OR three months after serum uric acid level achieved (six months if patient has evidence of tophi). [Khanna et al. ACR 2012 Gout Guidelines Part 2 ]. The guidelines also list low dose prednisone as an alternative, but was not discussed on this episode.

Chronic colchicine therapy

Chronic colchicine therapy DOES NOT treat the underlying pathophysiology of gout! Patients may experience ongoing monosodium urate (MSU) crystal formation and deposition before eventually developing refractory symptoms with tophaceous disease and joint destruction! –Dr Neogi strongly recommends against this practice

ULT and the ACR versus ACP Guidelines Controversy

The American College of Physicians (ACP) bases their clinical practice guidelines on randomized controlled trial (RCT) evidence. The American College of Rheumatology (ACR) uses the best available evidence to make their guidelines recommendations. This may include observational studies or expert opinion when available RCT data is absent. Recommendations are given a grade based on the level of available evidence.

At normal pH and body temperature the solubility of urate is 6.8 mg/dL (Martillo Curr Rheumatol Rep. 2014 Feb; 16(2): 400.). The ACP did not identify any RCTs showing improved clinical outcomes by targeting a uric acid level less than 6 mg/dL. The ACR has observational data to show that lower serum urate levels promote faster dissolution of tophi. The ACP literature review did not include studies of pegloticase (Sundy et al JAMA. 2011) showing improved outcomes within 6 months on ULT. Long term extension studies of RCTs using oral urate lowering therapies found a benefit from lowering uric acid levels, but these were also discounted (Dr Neogi). The 2012 ACR guidelines recommend a serum urate (uric acid) target of “less than 6 mg/dL and often less than 5 mg/dL” with a Grade C for expert consensus (Khanna et al. ACR 2012 Gout Guidelines Part 1).

Dr Neogi recommends monitoring serum urate (uric acid) levels because blindly prescribing allopurinol makes it difficult to discern clinical failures from undertreatment or patient non-adherence. Here is the 2003 BMJ article discussing the lack of RCT evidence for the use of parachutes (Gordon BMJ 2003).

Your questions from social media answered

Febuxostat

A Cochrane Review of six studies including nearly 4,000 patients shows febuxostat probably increases gout flares during early treatment (Tayar JH et al. Cochrane Database of Systematic Reviews 2012). Dr Neogi speculates that this is caused by its more rapid lowering of serum urate levels. CAUTION! In the recent CARES trial febuxostat was noninferior to allopurinol for major adverse cardiac events, but was associated with increased all-cause and cardiovascular mortality! Febuxostat should be reserved as second or third line, and requires an informed discussion with each patient. –Dr Neogi.

When to refer

Dr Neogi recommends referral to a rheumatologist if: Unable to bring serum uric acid levels to goal, ongoing clinical symptoms despite your best efforts, need for multiple medications to control gout, and the presence of joint deformities or tophaceous disease.

HLA B5801

Dr Neogi notes it is difficult to get insurance coverage and to find labs able to perform this testing. Nevertheless, the 2012 ACR guidelines state, “Prior to initiation of allopurinol, rapid polymerase chain reaction– based HLA–B*5801 screening should be considered as a risk management component in subpopulations where both the HLA– B*5801 allele frequency is elevated and the HLA– B*5801–positive subjects have a very high hazard ratio (“high risk”) for severe allopurinol hypersensitivity reaction (e.g., Koreans with stage 3 or worse CKD and all those of Han Chinese and Thai descent).” (Khanna et al. ACR 2012 Gout Guidelines Part 1).

What about checking uric acid levels during a suspected gout flare?

Dr Neogi notes that a level under 4 mg/dL in a patient not on ULT makes the diagnosis of gout very unlikely. High serum uric acid levels are not diagnostic of gout since over 20 percent of the population has asymptomatic hyperuricemia (Zhu Arthritis Rheumatism 2011). Normal or low uric acid levels can be misleading since inflammation has a uricosuric effect, meaning serum uric acid levels are theoretically lower during gout flares. Here’s an article reviewing multiple trials that checked serum uric acid levels during gout flares (Leiszler et al. J Fam Pract. 2011 October;60(10):618-620). This writer does not find utility in checking levels during a gout flare. -Dr Watto’s non-expert opinion

Goal and Learning Objectives

Listeners will develop a both a practical and evidence based approach to the management of gout. After listening to this episode listeners will…

1. Initiate, monitor and interpret serum uric acid levels when using urate lowering therapy
2. Review areas of uncertainty and controversy related to gout treatment with urate lowering therapies
3. Compare and contrast the available urate lowering therapies
4. Know who and when to refer to rheumatology for gout

Time Stamps

• 00:00 Intro and guest bio
• 01:30 Allopurinol initiation and titration
• 07:10 Uricosuric therapy
• 09:10 Controversy over uric acid targets for gout
• 17:40 Parachutes and randomized controlled trials
• 19:15 Colchicine or NSAIDS for prophylaxis
• 23:20 Who needs febuxostat?
• 26:20 When to refer for gout, HLA B5801, and checking uric acid levels in the acute setting  
• 33:29 Take home points
• 36:15 Outro

Links from the show are included above.

Disclosures: Dr Neogi reports no relevant financial disclosures. The Curbsiders report not relevant financial disclosures.