2020 ACR Gout Guidelines for Allopurinol Have Changed!

2020 ACR Gout Guidelines for Allopurinol Have Changed! Posted By:
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Gout is the most common type of inflammatory arthritis in both men and women in the United States. Allopurinol is commonly used to manage hyperuricemia in its overall management; however, a rare, life-threatening cutaneous reaction can occur with allopurinol: allopurinol hypersensitivity syndrome (AHS). The reaction can be one of several overlapping syndromes such as Stevens-Johnson, toxic epidermolysis, or drug reaction with eosinophilia and systemic symptoms, and is sometimes referred to as severe cutaneous adverse reaction. The severity of AHS can range from requiring hospitalization to leading to death.

These reactions occur rarely; AHS incidence has been reported to be 0.69 (95% CI: 0.52-0.92) per 1000 person-years. The Agency for Healthcare Research and Quality is looking for ways to predict and minimize these rare reactions.

Several risk factors for development of AHS have been identified:

Commencement of allopurinol therapy

  • Mean time to side effect was 3 weeks; 90% of cases occurred within the first 8 to 9 weeks

Genetic predisposition

  • HLA*B-5801: Genetic marker identified as a risk factor
  • Most common in East Asian populations, including those of Han Chinese (13.3%-20.4%), Korean (12.2%), and Thai (8.1%) descent
  • Less common in those of Japanese (0.6%) and European descent (1.5-5.2%), as well as in African Americans (3.8%) and in whites and Latinos (0.7% each)
  • In a Korean study of patients with chronic kidney disease (CKD), HLA*B-5801 genotyping was found to be cost effective in preventing AHS; prices range from ~$63 to ~$75 USD
  • 2020 American College of Rheumatology (ACR) Guideline for the Management of Gout "conditionally recommends" genotyping in these Asian groups and African American populations based on a 3-fold higher risk of developing AHS over the general population, though they "recommend against" universal genotyping of HLA*B-5801 except in those ethnic and racial backgrounds mentioned.

Dose concentration and clearance factors

  • AHS development influenced by age, BMI, creatinine clearance, and concomitant medications
  • Concurrent use of diuretics (furosemide) plays a role in the severity of dermal reaction

In the 2020 ACR Guideline for the Management of Gout, the "strongly recommended" approach to initiating allopurinol is low and slow, starting doses at ≤100 mg/day or ≤50 mg/day with CKD stages 3/4 and titrating to serum urate levels of ≤6 mg/dL while increasing the dose incrementally every 2 to 5 weeks. Starting allopurinol at higher doses (200 mg-400 mg) has been associated with increased risk of AHS. To determine the appropriate starting dose, check creatinine clearance and have a target serum uric acid level in mind. While titrating the dose, monitor uric acid levels and estimated glomerular filtration rate.

Educating patients about the development of any rash is critical when first prescribing allopurinol, as discontinuing the medication early can lessen the severity of the reaction. It should be noted that there is no treatment other than supportive care. For those who cannot tolerate allopurinol or have one or more risk factors for developing AHS, the ACR "conditionally recommends" going to a second xanthine oxidase inhibitor (XOI) rather than adding or switching to a uricosuric in patients who have two or more gout attacks per year, are not at goal of ≤6 mg/dL, or have non-resolving subcutaneous tophi. Lastly, for those who have had an allergic response to allopurinol and who cannot switch to an alternate XOI inhibitor, allopurinol desensitization is "conditionally recommended."

With all these caveats it should be reiterated that AHS is rare and most patients tolerate initiation and titration of allopurinol in the management of hyperuricemia and gout.

References
  • Cristallo A, Schroeder J, Citterio A, et al. A study of HLA class I and class II 4-digit allele level in Stevens Johnson syndrome and toxic epidermal necrolysis. Int J Immunogenet. 2011;38:303-9.
  • European Medicines Agency. Adenuric: procedural steps taken and scientific information after the authorization. www.ema.europa.eu/en/documents/procedural-steps-after/adenuric-epar-procedural-steps-taken-scientific-information-after-authorisation_en.pdf. Accessed July 2, 2020.
  • FitzGerald JD, Dalbeth N, Mikuls T et al. 2020 American College of Rheumatology Guideline for the Management of Gout, Arthritis Care & Research. Arth Care & Res. 2020;72:744-760.
  • Hung S, Chung W, Liou L et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci USA. 2005;102:4134-4139.
  • Kaniwa N, Saito Y, Aihara M et al. HLA-B locus in Japanese patients with anti-epileptics and allopurinol related Stevens Johnson syndrome and toxic epidermal necrolysis. Pharmacogenomics. 2008;9:1617-1622.
  • Keller SF, Lu N, Blumenthal KG, Rai SK, Yokose C, Choi JW, et al. Racial/ethnic variation and risk factors for allopurinol-associated severe cutaneous adverse reactions: a cohort study. Ann Rheum Dis. 2018;77:1187-1193.
  • Kim S, Newcomb C, Margolis D, Roy J, Hennessy S. Severe cutaneous reactions requiring hospitalization in allopurinol initiators: A population-based cohort study. Arthritis Care Res. 2013;65:578-584.
  • Lonjou C, Borot N, Sekula P et al. A European study of HLA-B in Stevens Johnson syndrome and toxic epidermal necrolysis related to five high risk drugs. Pharmacogenet Genomics. 2008;18:99-107.
  • Ramasamy S, Korb-Wells C, Kannangara D et al. Allopurinol hypersensitivity: a systematic review of all published cases, 1950_2012. Drug Saf. 2013;36:953-980.
  • Shekelle PG, FitzGerald J, Newberry SJ, et al. Management of gout. Agency for Healthcare Research and Quality (US). Rockville, MD;2016.
  • Stamp LK, Taylor WJ, Jones PB, Dockerty JL, Drake J, Frampton C, et al. Starting dose is a risk factor for allopurinol hypersensitivity syndrome: a proposed safe starting dose of allopurinol. Arthritis Rheum. 2012;64:2529-2536.
  • Tassaneeyakul W, Jantararoungtong T, Chen P et al. Strong association between HLA-B*5801 and allopurinol induced Stevens Johnson syndrome and toxic epidermal necrolysis in a Thai population. Pharmacogenet Genomics. 2009;19:704-709.

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Filed under: Rheumatology

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