Gout: new therapeutic strategies

DOI: https://doi.org/10.29296/25877305-2021-06-04
Download full text PDF
Issue: 
6
Year: 
2021

N. Kunitskaya, MD I.I. Mechnikov North-Western State Medical University, Ministry of Health of
Russia, Saint Petersburg

Long-term urate deposition is now known to require treatment that is not limited to acute episodes, but is also aimed at modulating the activity of key enzymes involved in the metabolism and excretion of urates, including xanthine oxidoreductase (XOR) and URAT1. This review presents the latest data on the efficacy of XOR inhibitors and uricosuric compounds in reducing the level of uric acid (UA) in both the systemic circulation and peripheral tissues. Emphasis is placed on the effect of novel XOR inhibitors on UA metabolism. The decrease of UA levels via XOR inhibition is associated with the reduction of oxidative stress that leads to endothelial dysfunction, thereby contributing to the development of diabetes, hypertension, atherosclerosis, and chronic heart failure. Thus, prevention of the accumulation of oxygen radicals generated by XOR is becoming a new area in the treatment of both hyperuricemia and gout.
Keywords: 
gout
hyperuricemia
oxidative stress
xanthine oxidase inhibitors
anakinra
canakinumab
febuxostat
lesinurad
rilonacept
levotofizopam
pegloticase

It appears your Web browser is not configured to display PDF files. Download adobe Acrobat или click here to download the PDF file.

References: 
  1. So A. IL1 inhibition in gout – where are we a decade on? Arthritis Res Ther. 2019; 21 (1): 233. DOI: 10.1186/s13075-019-2027-3
  2. Bardin T., Dalbeth N., Terkeltaub R. et al. Clinical response of tophus and flares to extended use of lesinurad in combination with a xanthine oxidase inhibitor in patients with gout [abstract]. Arthritis Rheumatol. 2016; 68 (suppl. 10).
  3. Bardin T., Keenan R.T., Khanna P.P. et al. Lesinuradin combination with allopurinol: a randomised, double-blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational CLEAR2 study). Ann Rheum Dis. 2017; 76 (5): 811–20. DOI: 10.1136/annrheumdis-2016-209213
  4. Berry C.E., Hare J.M. Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications. J Physiol Lond. 2004; 555 (Pt. 3): 589–606. DOI: 10.1113/jphysiol.2003.055913
  5. McWherter Ch., Choi1 Y.-J., Serrano R.L. et al. Arhalofenate acid inhibits monosodium urate crystal-induced inflammatory responses through activation of AMP activated protein kinase (AMPK) signaling. Arthritis Res Ther. 2018; 20 (1): 204. DOI: 10.1186/s13075-018-1699-4
  6. Cronstein B.N., Sunkureddi P. Mechanistic aspects of inflammation and clinical management of inflammation in acute gouty arthritis. J Clin Rheumatol. 2013; 19 (1): 19–29. DOI: 10.1097/RHU.0b013e31827d8790
  7. Cronstein B.N., Molad Y., Reibman J. et al., Colchicine alters the quantitative and qualitative display of selectins on endothelial cells and neutrophils. J Clin Invest. 1995; 96 (2): 994–1002. DOI: 10.1172/JCI118147
  8. Crittenden D.B., Pillinger M.H. New therapies for gout. Annu Rev Med. 2013; 64: 325–37. DOI: 10.1146/annurev-med-080911-105830
  9. Marotto D., De Santis A., Chessa D. et al. A Beacon in the Dark: Canakinumab. A New Therapeutic Perspective in Chronic Tophaceous Gout. Rheumatol Ther. 2018; 5: 303–10. DOI: 10.1007/s40744-018-0104-8
  10. Dalbeth N., Jones G., Terkeltaub R. et al. Lesinurad, a selective uric acid reabsorption inhibitor, in combination with febuxostat in patients with tophaceous gout: findings of a phase III clinical trial. Arthritis Rheumatol. 2017; 69 (9): 1903–13. DOI: 10.1002/art.40159
  11. Doehner W., Anker S.D. Xanthine oxidase inhibition for chronic heart failure: is allopurinol the next therapeutic advance in heart failure? Heart. 2005; 91: 707–9. DOI: 10.1136/hrt.2004.057190
  12. Fleischmann R., Shen Z., Yeh L.T. et al. Lesinurad (RDEA594), a novel uricosuric agent, in combination with febuxostat shows significant additive urate lowering effects in gout patients with 100% response achieved for all combination dose regimens. Ann Rheum Dis. 2011; 70: 188 (abstract).
  13. Grassi D., Ferri L., Desideri G. et al. Chronic hyperuricemia, uric acid deposit and cardiovascular risk. Curr Pharm Des. 2013; 19: 2432–8. DOI: 10.2174/1381612811319130011
  14. Gustafsson D., Unwin R. The pathophysiology of hyperuricaemia and its possible relationship to cardiovascular disease, morbidity and mortality. BMC Nephrol. 2013; 14: 164. DOI: 10.1186/1471-2369-14-164
  15. Hande K.R., Noone R.M., Stone W.J. Severe allopurinol toxicity: description and guidelines for prevention in patients with renal insufficiency. Am J Med. 1984; 76: 47–56. DOI: 10.1016/0002-9343(84)90743-5
  16. Harrison R. Structure and function of xanthine oxidoreductase: where are we now? Free Radic Biol Med. 2002; 33: 774–97. DOI: 10.1016/s0891-5849(02)00956-5
  17. Harrison R. Physiological roles of xanthine oxidoreductase. Drug Metab Rev. 2004; 36: 363–75. DOI: 10.1081/dmr-120037569
  18. Harzand A., Tamariz L., Hare J.M. Uric acid, heart failure survival, and the impact of xanthine oxidase inhibition. Congest Heart Fail. 2012; 18 (3): 179–82. DOI: 10.1111/j.1751-7133.2011.00262.x
  19. Jian-Ming L., Yao Q., Chen C. 3,4-Dihydroxy-5-nitrobenzaldehyde (DHNB) is a potent inhibitor of xanthine oxidase: a potential therapeutic agent for treatment of hyperuricemia and gout. Biochem Pharmacol. 2013; 86: 1328–37. DOI: 10.1016/j.bcp.2013.08.011
  20. Jones G., Panova E., Day R. Guideline development for the management of gout: role of combination therapy with a focus on lesinurad. Drug Des Devel Ther. 2017; 11: 3077–81. DOI: 10.2147/DDDT.S97959
  21. Stamp L.K., Merriman T.R., Singh J.A. Expert opinion on emerging urate-lowering therapies. Expert Opin Emerg Drugs. 2018; 23 (3): 201–9. DOI: 10.1080/14728214.2018.1527899
  22. Kotz J. The gout pipeline crystallizes. Nat Rev Drug Discov. 2012; 11: 425–6. DOI: 10.1038/nrd3748
  23. Mandell B.F., Edwards N.L., Sundy J.S. et al. Preventing and treating acute gout attacks across the clinical spectrum: a roundtable discussion. Cleve Clin J Med. 2010; 77: S2–S25. DOI: 10.3949/ccjm.77.s2.01
  24. Pacher P., Nivorozhkin A., Csaba S. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev. 2006; 58: 87–114. DOI: 10.1124/pr.58.1.6
  25. Panus P.C., Wright S.A., Chumley P.H. et al. The contribution of vascular endothelial xanthine dehydrogenase/oxidase to oxygen-mediated cell injury. Arch Biochem Biophys. 1992; 294: 695–702. DOI: 10.1016/0003-9861(92)90743-g
  26. Pascart T., Richette P. Investigational drugs for hyperuricemia, an update on recent developments. Expert Opin Investig Drugs. 2018; 27 (5): 437–44. DOI: 10.1080/13543784.2018.1471133
  27. Pascart T., Richette P. Current and future therapies for gout. Expert Opin Pharmacother. 2017; 18 (12): 1201–11. DOI: 10.1080/14656566.2017.1351945
  28. Perez-Ruiz F., Sundy J.S., Miner J.N. et al,; RDEA594-203 Study Group. Lesinurad in combination with allopurinol: results of a phase 2, randomised, double-blind study in patients with gout with an inadequate response to allopurinol. Ann Rheum Dis. 2016; 75 (6): 1074–80. DOI: 10.1136/annrheumdis-2015-207919
  29. Rajesh M., Mukhopadhyay P., Bátkai S. et al. Xanthine oxidase inhibitor allopurinol attenuates the development of diabetic cardiomyopathy. J Cell Mol Med. 2009; 13: 2330–41. DOI: 10.1111/j.1582-4934.2008.00564.x
  30. Robinson P.C., Dalbeth N. Febuxostat for the treatment of hyperuricaemia in gout. Expert Opin Pharmacother. 2018; 19 (11): 1289–99. DOI: 10.1080/14656566.2018.1498842
  31. Saag K.G., Fitz-Patrick D., Kopicko J. et al. Lesinurad combined with allopurinol: a randomized, double-blind, placebo-controlled study in gout patients with an inadequate response to standard-of-care allopurinol (a US-based study). Arthritis Rheumatol. 2017; 69 (1): 203–12. DOI: 10.1002/art.39840
  32. Saag K., Becker M.A., Storgard C. et al. Examination of Serum Uric Acid (sUA) lowering and safety with extended lesinurad + allopurinol treatment in subjects with gout [abstract]. Arthritis Rheumatol. 2016; 68 (suppl. 10).
  33. Saavedra W.F., Paolocci N., John M.E. St. et al. Imbalance between xanthine oxidase and nitric oxide synthase signaling pathways underlies mechanoenergetic uncoupling in the failing heart. Circ Res. 2002; 90: 297–304. DOI: 10.1161/hh0302.104531
  34. Sabán-Ruiz J., Alonso-Pacho A., Fabregate-Fuente M. et al. Xanthine oxidase inhibitor febuxostat as a novel agent postulated to act against vascular inflammation. Antiinflamm Antiallergy Agents Med Chem. 2013; 12: 94–9. DOI: 10.2174/1871523011312010011
  35. Stamp L.K., O’Donnell J.L., Zhang M. et al. Using allopurinol above the dose based on creatinine clearance is effective and safe in patients with chronic gout, including those with renal impairment. Arthritis Rheum. 2011; 63: 412–21. DOI: 10.1002/art.30119
  36. Suresh E., Das P. Recent advances in management of gout. Q J Med. 2012; 105: 407–17. DOI: 10.1093/qjmed/hcr242
  37. Kishimoto T.K. Development of ImmTOR Tolerogenic Nanoparticles for the mitigation of anti-drug antibodies. Front Immunol. 2020; 11: 969. DOI: 10.3389/fimmu.2020.00969
  38. Terkeltaub R.A., Furst D.E., Bennett K. et al. High versus low dosing of oral colchicine for early acute gout flare: twenty-four-outcome of the first multicenter, randomised, double-blind, placebo-controlled, parallel group, dose comparison colchicine study. Arthritis Rheum. 2010; 62: 1060–8. DOI: 10.1002/art.27327
  39. Wilbur K., Makowsky M. Colchicine myotoxicity: case reports and literature review. Pharmacotherapy. 2004; 24: 1784–92. DOI: 10.1592/phco.24.17.1784.52334
  40. Xu X., Hu X., Lu Z. et al. Xanthine oxidase inhibition with febuxostat attenuates systolic overload-induced left ventricular hypertrophy and dysfunction in mice. J Card Fail. 2008; 14: 746–53. DOI: 10.1016/j.cardfail.2008.06.006
  41. Zurampic (lesinurad) tablets. FDA Full Prescribing Information. URL: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207988lbl.pdf