Abstract
The tophus is the cardinal feature of advanced gout. This review summarises recent research into the biology, impact and treatment of tophaceous gout. Microscopically, tophi are chronic foreign body granuloma-like structures containing collections of monosodium urate (MSU) crystals surrounded by inflammatory cells and connective tissue. Extracellular trap formation mediated by neutrophil interactions with MSU crystals may be a central checkpoint in tophus formation. Gouty tophi impact on many aspects of health-related quality of life. Tophi are also implicated in the development of structural joint damage and increased mortality risk in people with gout. Effective treatment of tophaceous gout requires long-term urate-lowering therapy, ideally to achieve a serum urate concentration of <5 mg/dL (300 μmol/L). Recent advances in gout therapeutics have expanded urate-lowering therapy options for patients with severe tophaceous disease to allow faster regression of tophi, improved health-related quality of life and, potentially, improved structural outcomes.
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References
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Palmer DG, Hogg N, Denholm I, Allen CA, Highton J, Hessian PA. Comparison of phenotype expression by mononuclear phagocytes within subcutaneous gouty tophi and rheumatoid nodules. Rheumatol Int. 1987;7(5):187–93.
Dalbeth N, Pool B, Gamble GD, Smith T, Callon KE, McQueen FM, et al. Cellular characterization of the gouty tophus: a quantitative analysis. Arthritis Rheum. 2010;62(5):1549–56.
Lee SJ, Nam KI, Jin HM, Cho YN, Lee SE, Kim TJ, et al. Bone destruction by receptor activator of nuclear factor kappaB ligand-expressing T cells in chronic gouty arthritis. Arthritis Res Ther. 2011;13(5):R164.
Holzinger D, Nippe N, Vogl T, Marketon K, Mysore V, Weinhage T, et al. Myeloid-related proteins 8 and 14 contribute to monosodium urate monohydrate crystal–induced inflammation in gout. Arthritis Rheum. 2014;66(5):1327–39.
Yagnik DR, Evans BJ, Florey O, Mason JC, Landis RC, Haskard DO. Macrophage release of transforming growth factor beta1 during resolution of monosodium urate monohydrate crystal-induced inflammation. Arthritis Rheum. 2004;50(7):2273–80.
Kaneko K, Iwamoto H, Yasuda M, Inazawa K, Yamaoka N, Fukuuchi T, et al. Proteomic analysis to examine the role of matrix proteins in a gouty tophus from a patient with recurrent gout. Nucleosides, Nucleotides Nucleic Acids. 2014;33(4–6):199–207. A comprehensive list of the protein component of the gouty tophus.
Lin AM, Rubin CJ, Khandpur R, Wang JY, Riblett M, Yalavarthi S, et al. Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis. J Immunol. 2011;187(1):490–500.
Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532–5.
Brinkmann V, Zychlinsky A. Neutrophil extracellular traps: is immunity the second function of chromatin? J Cell Biol. 2012;198(5):773–83.
Schauer C, Janko C, Munoz LE, Zhao Y, Kienhofer D, Frey B, et al. Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat Med. 2014;20(5):511–7. Important paper describing the presence of NET-like features in tophus and the degradation of inflammatory mediators by MSU crystal-induced NETs.
Schorn C, Janko C, Krenn V, Zhao Y, Munoz LE, Schett G, et al. Bonding the foe—NETting neutrophils immobilize the pro-inflammatory monosodium urate crystals. Front Immunol. 2012;3:376. Important paper showing that tophi have NET-like features.
Schorn C, Janko C, Latzko M, Chaurio R, Schett G, Herrmann M. Monosodium urate crystals induce extracellular DNA traps in neutrophils, eosinophils, and basophils but not in mononuclear cells. Front Immunol. 2012;3:277. The first study to show that granulocytes form NETs in response to MSU crystals.
Mitroulis I, Kambas K, Chrysanthopoulou A, Skendros P, Apostolidou E, Kourtzelis I, et al. Neutrophil extracellular trap formation is associated with IL-1β and autophagy-related signaling in gout. Plos One. 2011;6(12):e29318.
von Köckritz-Blickwede M, Chow OA, Nizet V. Fetal calf serum contains heat-stable nucleases that degrade neutrophil extracellular traps. Blood. 2009;114(25):5245–6.
Walke V, Ramraje S, Jadhao V. Cytodiagnosis of gouty tophus. CytoJournal. 2013;10:11.
de Parisot A, Ltaief-Boudrigua A, Villani AP, Barrey C, Chapurlat RD, Confavreux CB. Spontaneous odontoid fracture on a tophus responsible for spinal cord compression: a case report. Joint Bone Spine. 2013;80(5):550–1.
Wendling D, Prati C, Hoen B, Godard J, Vidon C, Godfrin-Valnet M, et al. When gout involves the spine: five patients including two inaugural cases. Joint Bone Spine. 2013;80(6):656–9.
Sanmillan Blasco JL, Vidal Sarro N, Marnov A, Acebes Martin JJ. Cervical cord compression due to intradiscal gouty tophus: brief report. Spine. 2012;37(24):E1534–6.
Lui TH. Acute posterior tarsal tunnel syndrome caused by gouty tophus. Foot Ank Spec. 2014. doi:10.1177/1938640014548318.
Rodas G, Pedret C, Catala J, Soler R, Orozco L, Cusi M. Intratendinous gouty tophus mimics patellar tendonitis in an athlete. J Clin Ultrasound. 2013;41(3):178–82.
Gililland JM, Webber NP, Jones KB, Randall RL, Aoki SK. Intratendinous tophaceous gout imitating patellar tendonitis in an athletic man. Orthopedics. 2011;34(3):223.
Yaegashi Y, Nishida J, Oyama K. Gouty tophus of the second metacarpal simulating a malignancy with pathologic fracture. J Hand Surg [Am]. 2013;38(1):208–9.
Ercin E, Gamsizkan M, Avsar S. Intraosseous tophus deposits in the os trigonum. Orthopedics. 2012;35(1):e120–3.
Adamson R, Lacy JM, Cheng AM, Park DR. Tophus causing bronchial obstruction. Am J Respir Crit Care Med. 2013;188(12):e72–3.
Rohani A, Chamanian S, Hosseinzade P, Ramezani J. A case of mitral valve tophus in a patient with severe gout tophaceous arthritis. J Clin Imaging Sci. 2012;2:68.
Varinot J, Cazejust J, Wendum D. A gouty tophus appearing as an atypical liver nodule in a cirrhotic patient. Clin Res Hepatol Gastroenterol. 2011;35(12):855–6.
Green R, Sensarma K, Jain M, Surtees P. An unusual breast lump presenting as a malignancy found to be a mammary gouty tophus. Breast J. 2011;17(5):528–9.
Hench PS. The diagnosis of gout and gouty arthritis. J Lab Clin Med. 1936;22:48–55.
Gutman AB. The past four decades of progress in the knowledge of gout, with an assessment of the present status. Arthritis Rheum. 1973;16(4):431–45.
Dalbeth N, House ME, Horne A, Taylor WJ. Reduced creatinine clearance is associated with early development of subcutaneous tophi in people with gout. BMC Musculoskelet Disord. 2013;14:363.
Lu CC, Wu SK, Chen HY, Chung WS, Lee MC, Yeh CJ. Clinical characteristics of and relationship between metabolic components and renal function among patients with early-onset juvenile tophaceous gout. J Rheumatol. 2014;41(9):1878–83.
Lahaye C, Auge F, Soubrier M, Ceballos-Picot I. New mutation affecting hypoxanthine phosphoribosyltransferase responsible for severe tophaceous gout. J Rheumatol. 2014;41(6):1252–4.
Hollis-Moffatt JE, Gow PJ, Harrison AA, Highton J, Jones PB, Stamp LK, et al. The SLC2A9 nonsynonymous Arg265His variant and gout: evidence for a population-specific effect on severity. Arthritis Res Ther. 2011;13(3):R85.
Dalbeth N, Schauer C, Macdonald P, Perez-Ruiz F, Schumacher HR, Hamburger S, et al. Methods of tophus assessment in clinical trials of chronic gout: a systematic literature review and pictorial reference guide. Ann Rheum Dis. 2011;70(4):597–604. Reference atlas summarising methods of tophus measurement for clinical trials of gout.
Dalbeth N, Aati O, Gao A, House M, Liu Q, Horne A, et al. Assessment of tophus size: a comparison between physical measurement methods and dual-energy computed tomography scanning. J Clin Rheumatol. 2012;18(1):23–7.
Naredo E, Uson J, Jiménez-Palop M, Martínez A, Vicente E, Brito E, et al. Ultrasound-detected musculoskeletal urate crystal deposition: which joints and what findings should be assessed for diagnosing gout? Ann Rheum Dis. 2013;73(8):1522–8. A systematic study defining ultrasound tophus and demonstrating locations of deposition.
Ogdie A, Taylor WJ, Weatherall M, Fransen J, Jansen TL, Neogi T, et al. Imaging modalities for the classification of gout: systematic literature review and meta-analysis. Ann Rheum Dis. 2014. doi:10.1136/annrheumdis-2014-205431. A systematic review and meta-analysis examining both US tophus and DECT for gout diagnosis.
Perez-Ruiz F, Martin I, Canteli B. Ultrasonographic measurement of tophi as an outcome measure for chronic gout. J Rheumatol. 2007;34(9):1888–93.
Choi HK, Al-Arfaj AM, Eftekhari A, Munk PL, Shojania K, Reid G, et al. Dual energy computed tomography in tophaceous gout. Ann Rheum Dis. 2009;68(10):1609–12.
Melzer R, Pauli C, Treumann T, Krauss B. Gout tophus detection-a comparison of dual-energy CT (DECT) and histology. Semin Arthritis Rheum. 2014;43(5):662–5.
Khanna PP, Nuki G, Bardin T, Tausche AK, Forsythe A, Goren A, et al. Tophi and frequent gout flares are associated with impairments to quality of life, productivity, and increased healthcare resource use: results from a cross-sectional survey. Health Quality Life Outcomes. 2012;10:117. A large multi-national study demonstrating that the presence of tophi is associated with poor health-related quality of life.
Aati O, Taylor WJ, Horne A, Dalbeth N. Toward development of a tophus impact questionnaire: a qualitative study exploring the experience of people with tophaceous gout. J Clin Rheumatol. 2014;20(5):251–5.
Aati O, Taylor WJ, Siegert RJ, Horne A, House ME, Tan P, et al. Development of a patient-reported outcome measure of tophus burden: the Tophus Impact Questionnaire (TIQ-20). Ann Rheum Dis. 2014. doi:10.1136/annrheumdis-2014-205671. Description of a new tophus-specific patient reported outcome tool.
Perez-Ruiz F, Martinez-Indart L, Carmona L, Herrero-Beites AM, Pijoan JI, Krishnan E. Tophaceous gout and high level of hyperuricaemia are both associated with increased risk of mortality in patients with gout. Ann Rheum Dis. 2014;73(1):177–82. A longitudinal study demonstrating that the tophaceous disease predicts mortality in people with gout.
McQueen FM, Doyle A, Reeves Q, Gao A, Tsai A, Gamble GD, et al. Bone erosions in patients with chronic gouty arthropathy are associated with tophi but not bone oedema or synovitis: new insights from a 3T MRI study. Rheumatology (Oxford). 2014;53(1):95–103.
Dalbeth N, Milligan A, Doyle A, Clark B, McQueen F. Characterization of new bone formation in gout: a quantitative site-by-site analysis using plain radiography and computed tomography. Arthritis Res Ther. 2012;14(4):R165.
Dalbeth N, Aati O, Kalluru R, Gamble GD, Horne A, Doyle AJ, et al. Relationship between structural joint damage and urate deposition in gout: a plain radiography and dual-energy CT study. Ann Rheum Dis. 2014. doi:10.1136/annrheumdis-2013-204273.
Resnick D. Crystal-induced arthropathy. Gout and pseudogout. JAMA. 1979;242(22):2440–2.
Popovich I, Dalbeth N, Doyle A, Reeves Q, McQueen FM. Exploring cartilage damage in gout using 3-T MRI: distribution and associations with joint inflammation and tophus deposition. Skeletal Radiol. 2014;43(7):917–24.
Chhana A, Callon KE, Dray M, Pool B, Naot D, Gamble GD, et al. Interactions between tenocytes and monosodium urate monohydrate crystals: implications for tendon involvement in gout. Ann Rheum Dis. 2014;73(9):1737–41.
Pineda C, Amezcua-Guerra LM, Solano C, Rodriguez-Henriquez P, Hernandez-Diaz C, Vargas A, et al. Joint and tendon subclinical involvement suggestive of gouty arthritis in asymptomatic hyperuricemia: an ultrasound controlled study. Arthritis Res Ther. 2011;13(1):R4.
Dalbeth N, Kalluru R, Aati O, Horne A, Doyle AJ, McQueen FM. Tendon involvement in the feet of patients with gout: a dual-energy CT study. Ann Rheum Dis. 2013;72(9):1545–8.
Therimadasamy A, Peng YP, Putti TC, Wilder-Smith EP. Carpal tunnel syndrome caused by gouty tophus of the flexor tendons of the fingers: sonographic features. J Clin Ultrasound. 2011;39(8):463–5.
Radice F, Monckeberg JE, Carcuro G. Longitudinal tears of peroneus longus and brevis tendons: a gouty infiltration. J Foot Ankle Surg. 2011;50(6):751–3.
Dalbeth N, Smith T, Nicolson B, Clark B, Callon K, Naot D, et al. Enhanced osteoclastogenesis in patients with tophaceous gout: urate crystals promote osteoclast development through interactions with stromal cells. Arthritis Rheum. 2008;58(6):1854–65.
Choe JY, Lee GH, Kim SK. Radiographic bone damage in chronic gout is negatively associated with the inflammatory cytokines soluble interleukin 6 receptor and osteoprotegerin. J Rheumatol. 2011;38(3):485–91.
Chhana A, Callon KE, Pool B, Naot D, Watson M, Gamble GD, et al. Monosodium urate monohydrate crystals inhibit osteoblast viability and function: implications for development of bone erosion in gout. Ann Rheum Dis. 2011;70(9):1684–91.
Noda M, Camilliere JJ. In vivo stimulation of bone formation by transforming growth factor-β. Endocrinology. 1989;124(6):2991–4.
Chhana A, Callon KE, Pool B, Naot D, Gamble GD, Dray M, et al. The effects of monosodium urate monohydrate crystals on chondrocyte viability and function: implications for development of cartilage damage in gout. J Rheumatol. 2013;40(12):2067–74.
Liu-Bryan R, Pritzker K, Firestein GS, Terkeltaub R. TLR2 signaling in chondrocytes drives calcium pyrophosphate dihydrate and monosodium urate crystal-induced nitric oxide generation. J Immunol. 2005;174(8):5016–23.
Sasaki K, Yamamoto N, Kiyosawa T, Sekido M. The role of collagen arrangement change during tendon healing demonstrated by scanning electron microscopy. J Electron Microsc. 2012;61(5):327–34.
Jones GC, Corps AN, Pennington CJ, Clark IM, Edwards DR, Bradley MM, et al. Expression profiling of metalloproteinases and tissue inhibitors of metalloproteinases in normal and degenerate human Achilles tendon. Arthritis Rheum. 2006;54(3):832–42.
Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, et al. 2012 American college of rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res. 2012;64(10):1431–46. Guidelines from the American College of Rheumatology specifically address the urate-lowering treatment approaches for people with chronic tophaceous gouty arthropathy.
Perez-Ruiz F, Calabozo M, Pijoan JI, Herrero-Beites AM, Ruibal A. Effect of urate-lowering therapy on the velocity of size reduction of tophi in chronic gout. Arthritis Rheum. 2002;47(4):356–60.
Sriranganathan MK, Vinik O, Falzon L, Bombardier C, van der Heijde DM, Edwards CJ. Interventions for tophi in gout: a Cochrane systematic literature review. J Rheumatol Suppl. 2014;92:63–9.
Sundy JS, Baraf HS, Yood RA, Edwards NL, Gutierrez-Urena SR, Treadwell EL, 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. Phase 3 clinical trial of pegloticase demonstrating that fortnightly infusions of pegloticase lead to improvement in many outcomes including tophus regression in patients with severe gout.
Becker MA, Baraf HS, Yood RA, Dillon A, Vazquez-Mellado J, Ottery FD, et al. Long-term safety of pegloticase in chronic gout refractory to conventional treatment. Ann Rheum Dis. 2013;72(9):1469–74.
Baraf HS, Becker MA, Gutierrez-Urena SR, Treadwell EL, Vazquez-Mellado J, Rehrig CD, et al. Tophus burden reduction with pegloticase: results from phase 3 randomized trials and open-label extension in patients with chronic gout refractory to conventional therapy. Arthritis Res Ther. 2013;15(5):R137.
Khanna D, Khanna PP, Fitzgerald JD, Singh MK, Bae S, Neogi T, et al. 2012 American college of rheumatology guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res. 2012;64(10):1447–61.
Kim YS, Park EH, Lee HJ, Koh YG. First metatarsophalangeal joint arthrodesis for the treatment of tophaceous gouty arthritis. Orthopedics. 2014;37(2):e141–7.
Dalbeth N, Aati O, Gamble GD, Horne A, House ME, Roger M, et al. Zoledronate for prevention of bone erosion in tophaceous gout: a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2014;73(6):1044–51. First randomised controlled trial examining structural damage as a primary endpoint in people with tophaceous gout.
Dalbeth N, Doyle AJ, McQueen FM, Sundy J, Baraf HSB. Exploratory study of radiographic change in patients with tophaceous gout treated with intensive urate-lowering therapy. Arthritis Care Res. 2014;66(1):82–5. Small study demonstrating improvement in bone erosion, but not joint space narrowing, over one year of pegloticase treatment in people with tophaceous gout.
Acknowledgments
Ashika Chhana is funded by a University of Auckland Faculty Research Development Fund grant (3704255). Nicola Dalbeth is supported by the Health Research Council of New Zealand.
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Nicola Dalbeth declares the receipt of consulting and speaker fees or grants from the following companies: Takeda, Teijin, Menorini, Ardea, AstraZeneca, Pfizer, Savient, Fonterra and Metabolex.
Ashika Chhana declares no conflict of interest.
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Chhana, A., Dalbeth, N. The Gouty Tophus: a Review. Curr Rheumatol Rep 17, 19 (2015). https://doi.org/10.1007/s11926-014-0492-x
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DOI: https://doi.org/10.1007/s11926-014-0492-x