New updates in the management of gout
With the advances in the diagnosis and management of gout; the novel urate-lowering therapies, new imaging modalities, and a deeper understanding of the pathogenesis of gout raise the possibility of better gout care and improved patient outcomes and adequate lowering of serum uric acid with minimal effects on renal tissues.
Overview of Gout
Gout is a disease caused by an elevated uric acid in the blood resulting in a variety of conditions.it is mainly a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot, and swollen joint. Gouty arthritis is due to excess accumulation of uric acid in the blood. It is much more common in men than women.
Here, we review some recent advances in gout, including introduction of novel therapeutics, and the development of new gout classification and management guidelines.1
New gout classification: The American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2015 gout classification criteria (Table 1) have recently been published. They propose a three-step process for making the diagnosis of gout:2
- Step 1 – Entry criterion is at least one episode of swelling or tenderness in a peripheral joint or bursa.
- Step 2 – Sufficient clinical criteria (if met, can classify as gout; then step 3 is not necessary) presence of MSU crystals in a symptomatic joint or bursa or the presence of tophus.
- Step 3 – If Step 2 does not confirm the diagnosis, then use the given scoring system in Table below. A score of >8 is sufficient for the diagnosis of gout.
- In acute attacks, the rapid development of severe pain, swelling and tenderness that reaches its maximum within just 6 – 12 hours, especially with overlying erythema, is highly suggestive of crystal inflammation though not specific for gout.
- For typical presentations of gout (such as recurrent podagra with hyperuricemia) a clinical diagnosis alone is reasonably accurate but not definitive without crystal confirmation.
- Demonstrations of MSU crystals in synovial fluid or tophus aspirates permits a definitive diagnosis of gout.
- A routine search for MSU crystals is recommended in all synovial samples obtained from undiagnosed inflamed joints.
- Identification of MSU crystals from asymptomatic joints allows definite diagnosis in inter-critical periods.
- Gout and sepsis may coexist, so when septic arthritis is suspected, gram stain and culture of synovial fluid should still perform even if MSU crystals are identified.
- While being the most important risk factor for gout, serum uric acid levels do not confirm or exclude gout as many people with hyperuricemia do not develop gout and during acute attacks serum levels may be normal.
- Renal uric acid excretion should be determined in selected gout patients, especially those with a family history of young onset gout, onset of young underage 25 years or with renal calculi.
- Although radiographs maybe useful for different diagnosis and may show typical features in chronic gout, they are mot useful in confirming the diagnosis of early or acute gout.
- Risk factors for gout and associated morbidity should be assessed, including features of the metabolic syndrome (obesity, hyperglycemia, hyperlipidemia, hypertension).
Urate crystals (monosodium urate -MSU): Needle-like morphology and strong negative birefringence of MSU-crystal under compensated polarized light microscopy. A. Needle-shaped MSU crystals appear yellow when the crystal is parallel to the direction of the polarizer (black arrow) or B. Blue when the crystal is perpendicular to the polarizer (black arrow).3
Patients with gout that is well-controlled with urate-lowering medicines should have annual assessments of: Serum urate; Renal function; HbA1c; Blood pressure.5
Gout in special populations can present with atypical features:Gout in women (more likely to present with advanced disease, with tophi within Heberden’s nodes of osteoarthritis, frequently flare in the context of diuretic use);Early-onset gout (onset before age 25, strong family history of gout and/or nephrolithiasis, and may be associated with genetic or enzymatic diseases of purine metabolism);Transplantation gout (related to cyclosporine or tacrolimus use).6
New medications for gout management
- Febuxostat: Febuxostat is a non-purine analogue, which is structurally different from allopurinol that inhibits xanthine oxidase; there have been no reports of cross-reactive toxicities. In the CONFIRMS trial, 40 mg of febuxostat had similar effectiveness as 300 mg allopurinol, but 80 mg dose of febuxostat outperformed allopurinol. Unlike with allopurinol, there currently is no recommendation for dose reduction in mild to moderate renal impairment.7
- Uricosuric agents: Uricosuric agents can be added on, or used as second-line therapy: probenecid is used occasionally, but is contraindicated in low GFR states, history of kidney stones, or a state of uric acid overproduction is established. Lesinurad (Zurampic) is a uricosuric agent labeled for the treatment of hyperuricemia that is associated with gout. It should be used in patients who are already taking appropriate doses of a xanthine oxidase inhibitor such as allopurinol, but who have not yet reached target levels of serum uric acid. In the majority of patients with gout, hyperuricemia is caused by inefficient renal excretion of uric acid.8 Lesinurad is a selective uric acid reabsorption inhibitor that inhibits the URAT1; thus, increases uric acid excretion. Lesinurad also inhibits organic anion transporter (OAT4), an URAT1 involved in diuretic-induced hyperuricemia.9 The FDA has approved a new fixed-dose combination treatment for hyperuricemia in patients with uncontrolled gout. once-daily combination of lesinurad (Zurampic, AstraZeneca) and allopurinol designed to achieve target serum uric acid (serum UA) levels in patients who cannot do so with allopurinol alone. The most common adverse events included headache, influenza, higher levels of blood creatinine, and heartburn.10
Pegloticase11: Pegloticase is an infusible uric acid-lowering medication recombinant uricase, which was FDA-approved in 2010 for use in recalcitrant gout or patients who have large, refractory tophaceous deposits. Humans have a mutational inactivation of the urate oxidase (uricase) gene, in contrast to non-primate mammals. Pegloticase is a mammalian recombinant uricase conjugated to monomethoxypolyethylene glycol (PEG).The “PEGylation” of the uricase enzyme prolongs its half-life, and reduces immunogenicity. Pegloticase is given intravenously, resulting in rapid dissolution of MSU. It may rapidly resolve tophi and control chronic synovitis in patients with severe chronic refractory gout, Serum UA level should be measured prior to each infusion. If serum UA has risen to greater than 6 mg/dL after an initial decline, pegloticase should be discontinued.12
Better control of hyperuricemia has been achieved with the new gout medications.
1 . Kuo CF, Grainge MJ, Zhang W, et al. : Global epidemiology of gout: prevalence, incidence and risk factors. Nat Rev Rheumatol. 2015;11(11):649–62. 10.1038/nrrheum.2015.91
2. Neogi T, Jansen TL, Dalbeth N, et al. 2015 Gout Classification Criteria. Arthritis Rheumatol 2015;67(10):25572568.
3. Chen LX, Schumacher HR (October 2008). “Gout: an evidence-based review”. J Clin Rheumatol. 14 (5 Suppl): S55–62. doi:10.1097/RHU.0b013e3181896921.
4. Beyl Jr, R. N.; Hughes, L; Morgan, S (2016). “Update on Importance of Diet in Gout”. The American Journal of Medicine. 129 (11): 1153–1158
5. doi:10.1016/j.amjmed.2016.06.040. PMID 27452679. Stein, John J. Cush, Arthur Kavanaugh, C. Michael (2005). Rheumatology : diagnosis and therapeutics (2nd ed.). Philadelphia: Lippincott, Williams & Wilkins. p. 192.
6. Qaseem, A; Harris, RP; Forciea, MA; Clinical Guidelines Committee of the American College of, Physicians. (3 January 2017). “Management of Acute and Recurrent Gout: A Clinical Practice Guideline From the American College of Physicians”.
7. Hui M, Carr A, Cameron S, et al. The British Society for Rheumatology Guideline for the Management of Gout. Rheumatology 2017;56:1246.
8. Molecular analysis of the SLC22A12 (URAT1) gene in patients with primary gout. Vázquez-Mellado J, Jiménez-Vaca AL, Cuevas-Covarrubias S, Alvarado-Romano V, Pozo-Molina G, BurgosVargas R.Rheumatology (Oxford). 2007 Feb; 46(2):215-9. 9
9. Managing hypertensive patients with gout who take thiazide.Handler J.J Clin Hypertens (Greenwich). 2010 Sep; 12(9):731-5
10. Ironwood Pharmaceuticals announces FDA approval of Duzallo (lesinurad and allopurinol) for the treatment of hyperuricemia in patients with uncontrolled gout [news release]. Massachusetts. Ironwood Pharmaceuticals’ website. http://news.ironwoodpharma.com/phoenix.zhtml?c=228069&p=irol-newsArticle&ID=2294774. Accessed August 21, 2017.
11. Guttmann A, Krasnokutsky S, Pillinger MH, Berhanu A. Pegloticase in gout treatment – safety issues, latest evidence and clinical considerations. Ther Adv Drug Saf 2017; 8: 379-88. PubMed Citation (Careful review of the clinical features and epidemiology of gout and efficacy and safety of pegloticase, common side effects being a flare of gout [71-85%], infusion reactions [26-42%], headache [9-11%], nausea [7-12%] and cardiovascular events [2-7%]; no mention of ALT elevations or hepatotoxicity).
12. Sundy JS, Baraf HSB, Yood RA, et al.Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA. 2011;306(7):711-20.