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Nonhealing Ulcers in Patients with Tophaceous Gout: A Systematic Review

Lam, Gretl BA; Ross, Frank L. MD; Chiu, Ernest S. MD

Advances in Skin & Wound Care: May 2017 - Volume 30 - Issue 5 - p 230–237
doi: 10.1097/01.ASW.0000515456.65405.56
Features: Clinical Management Extra

GENERAL PURPOSE: To provide information from a review of the literature about chronic ulcers associated with tophaceous gout.

TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care.

LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant should be better able to:

1. Identify the pathophysiology of tophaceous gout, its presentation, phases, and common comorbidities.

2. Evaluate the findings in this review regarding effectiveness of interventions for chronic tophaceous ulcers.

ABSTRACT: OBJECTIVE: Treating chronic ulcers associated with tophaceous gout is an uncommon but important clinical challenge. However, treatments vary greatly from topical therapies, to debridements, to free flap wound coverage. To the authors’ knowledge, this is the first study to assemble and compare these different approaches in order to guide effective treatment.

DATA SOURCES:An electronic search of MEDLINE (PubMed) was conducted. Search terms included (gout and ulcer) not “peptic ulcer,” and (gout, chronic wound) or (gout, nonhealing wound).

STUDY SELECTION: Studies that discussed the presentation, characterization, or treatment of gout-associated wounds were included. The literature search yielded 9 case reports and case series; there were no randomized controlled studies or reviews.

DATA EXTRACTION: Patient and wound characteristics, treatment approaches, and outcomes were noted.

DATA SYNTHESIS: The 82% of 22 patients were male, aged 36 to 95 years. Three patients had not been previously diagnosed with gout, whereas others had received a diagnosis 2 to 35 years prior to presentation with an ulcer. Many patients had comorbidities including diabetes and peripheral vascular disease. Most of the 43 total ulcers occurred on the feet. Treatments included topical 3% citric acid in petroleum jelly, allogeneic culture dermal substitute, silver-containing dressing and heterologous lyophilized collagen, debridements, and free flap coverage.

CONCLUSIONS: Chronic tophaceous wounds are a worldwide problem. Although physicians report some successes with different treatments, controlled studies are needed to determine the most effective approach and to identify risk factors and preventive strategies.

Gretl Lam, BA • Fourth-year Medical Student (graduates to MD in May 2017) • New York University School of Medicine • New York, New York

Frank L. Ross, MD • Associate Professor • Department of Surgery • New York University School of Medicine • New York, New York • Associate Director • Helen L. and Martin S. Kimmel Hyperbaric and Advanced Wound Healing Center • New York, New York

Ernest S. Chiu, MD • Associate Professor • Department of Surgery • New York University School of Medicine • New York, New York • Director • Helen L. and Martin S. Kimmel Hyperbaric and Advanced Wound Healing Center • New York, New York

All authors, faculty, staff, and planners, including spouses/partners (if any), in any position to control the content of this CME activity have disclosed that they have no financial relationships with, or financial interests in, any commercial companies pertaining to this educational activity.

To earn CME credit, you must read the CME article and complete the quiz online, answering at least 14 of the 19 questions correctly.

This continuing educational activity will expire for physicians on May 31, 2018, and for nurses on May 31, 2019.

All tests are now online only; take the test at http://cme.lww.com for physicians and www.nursingcenter.com for nurses. Complete CE/CME information is on the last page of this article.

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INTRODUCTION

Gout affects more than 8 million Americans (4% of US adults) and has a similarly high prevalence worldwide.1,2 It is the most common type of inflammatory arthropathy and is caused by deposition of monosodium urate crystals in synovial fluid and other tissues.3,4 Hyperuricemia, defined as a serum urate of 6.8 mg/dL (405 µmol/L) or more, is associated with the development of gout, because this level is the limit of urate solubility at physiologic temperature and pH.3,4

There are 2 clinical phases of gout. In the first phase, crystal deposition triggers an acute inflammatory response, resulting in acute attacks that typically resolve spontaneously after 7 to 10 days, with no symptoms in between attacks.4 Patients with poorly controlled hyperuricemia can progress to the second phase, chronic gout. Chronic gout is characterized by polyarticular involvement, tophi formation, and the presence of symptoms between acute attacks.4 Diagnosis of gout is typically made using the American College of Rheumatology criteria; the primary criteria are joint swelling/pain/tenderness, monosodium urate crystals in the synovial fluid, and presence of tophi.3,5

Gout tophi are subcutaneous accumulations of monosodium urate crystals in a matrix of lipids, protein, and mucopolysaccharides, surrounded by chronic mononuclear and giant cell inflammation.2,3 The most common site of tophi formation is the first metatarsophalangeal joint.3,6 Other typical sites of tophi formation include the finger and toe joints and around the knees, elbows, wrists, and ankles.2,3 However, urate crystals can deposit in other locations throughout the body, including the vertebrae, soft tissues, and skin.3,7

Although the soft tissue overlying tophi might seem thinned or stretched and particularly vulnerable to trauma and breakdown, ulcers at these sites are surprisingly uncommon.2,6 However, when breakdown does occur, chronic ulcers with persistent discharge can develop (Figure).6 Ulcers on the feet at sites of joint deformity and weight bearing are especially prone to delayed healing.6 To compound the problem, patients with gout are more likely to have other comorbidities that predispose them to impaired wound healing, including diabetes, obesity, and peripheral vascular disease.8,9 Thus, treating these ulcers is an uncommon but important clinical challenge.

The goal of this study was to perform a systematic review of the literature pertaining to the management of patients with chronic ulcers associated with tophaceous gout, a task that to the authors’ knowledge has not been previously undertaken.

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METHODS

An electronic search of MEDLINE (PubMed) was conducted for English-language articles only, without any year limits. Search terms included (gout and ulcer), not “peptic ulcer,” and (gout, chronic wound) or (gout, nonhealing wound). All articles mentioning ulcers or nonhealing wounds in patients with gout were examined. Those that focused on the presentation, characterization, or treatment of these ulcers were included in this study. Excluded from the study were 2 broad review articles on the surgical management of tophaceous gout and 1 article that described soft tissue shaving to reduce the size of tophi because they merely listed ulcers as an indication for surgery, without further discussion.10–12 In addition, an article that described ulceration in 5 cases of intradermal tophi (vs the typical subcutaneous tophi) was excluded because the report focused on the unusual location of the tophi and did not report ulcer healing outcomes.7 The reference listings of every included article were also examined to ensure all relevant studies were captured.

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RESULTS

The literature search, after application of inclusion/exclusion criteria, yielded 9 articles for final analysis (Table 1). These were published between 2009 and 2014 and represented reports from 8 different countries. There were 3 case series and 6 case studies reporting lower quality evidence. Unfortunately, no randomized controlled studies or review articles were found in the search. Eight of the included articles reported on specific interventions performed to treat ulcers associated with tophaceous gout, whereas the remaining article by Rome et al6 described the characteristics of these wounds without detailing an intervention.

These 9 case series and case reports included a total of 22 patients. Their ages ranged from 36 to 95 years, with a mean of 61 (excluding 4 patients, as Patel et al2 did not report individual ages), and 82% (18/22) of them were male. Three of these patients did not have a previous diagnosis of gout prior to their presentation with an ulcer (age at presentation ranged from 74 to 84 years), whereas the other patients had received a diagnosis of gout 2 to 35 years prior (Table 2). Comorbidities were reported in 19 of 22 cases. The most common comorbidity was diabetes mellitus (n = 11), followed by hypertension (n = 9). Two patients had chronic venous insufficiency, and 1 patient had peripheral artery disease. Other comorbidities included hyperlipidemia, ischemic heart disease, cerebrovascular disease, and kidney disease.

Among these 22 patients, there were a total of 43 ulcers; the number of ulcers per patient ranged from 1 to 7. The vast majority of ulcers were located on the foot, especially over the toe joints, but they also occurred on the heel, thumb, and second finger. Two nonhealing ulcers occurred after procedures: 1 occurred over the lateral malleolus after the excision of a soft tissue mass (later determined to be bursitis with tophus), and the other occurred at the amputation site of the third and fourth toes (reason for amputation not reported).6,13 One nonhealing ulcer developed after mild trauma (scraping the toe against the ground).14

On physical examination, chalky exudate and tophi were observed with most ulcers. Defect sizes ranged widely from 0.04 to 195 cm2; however, the studies did not specify whether measurements were made before or after debridement. Tanabe et al15 and Ou et al16 reported tendon exposure after debridement, and Lin et al17 reported both tendon and bone exposure after debridement.

The interventions varied greatly among the 8 studies. From least invasive to most invasive, they included the simple topical application of 3% citric acid in petroleum jelly,13 1-time debridement with or without subsequent topical treatments (ie, allogeneic culture dermal substitute or silver-containing dressing and heterologous lyophilized collagen),14,15,18 gentle monthly debridements after using hydrogel to soften the tophus,2 and free flap coverage of defects.16,17,19 Many of these patients were also medically treated with allopurinol. All studies reported good healing outcomes with their respective interventions, except for 1 patient who died of an unrelated cause before healing occurred. Time to healing was reported by 3 studies and ranged from 7 to 40 days.14,15,18 Seven of the studies reported no complications. Ou et al16 reported dehiscence and ulcer recurrence requiring further debridement after bilateral anterolateral thigh flaps, but this patient’s ulcer ultimately healed well.16

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DISCUSSION

Ulcers resulting from tophaceous gout are quite uncommon, which makes it challenging to develop high-quality studies on the management of these wounds. Yet, the fact that they have been treated and reported by physicians of 8 diverse countries, despite their low incidence, reflects the fact that ulcerated gout is a worldwide problem that should be discussed and addressed to ensure prompt diagnosis and improve treatment practices.

It is well established that the prevalence of gout increases with age and is significantly higher in men.1,20,21 This pattern holds true for ulcerated gout. Among the reported cases, the mean age was 61 years, and 82% were men. Nevertheless, the development of ulcers is not limited to older adult patients or to those who have had chronic gout for many years. At the time of presentation, 5 patients were in their 30s or 40s, and 3 patients had not previously received a diagnosis of gout. Others had a variable history, having received a diagnosis of gout anywhere from 2 to 35 years prior to presentation with an ulcer.

The variability in gout history may also be because patients did not seek medical attention until their wounds were quite advanced. Tophaceous gout tends to occur in patients with poorly controlled hyperuricemia, and nonhealing ulcers primarily develop over sites of tophi.2,4 This suggests that patients who are at greater risk of developing chronic tophaceous ulcers are those who have limited access to healthcare or are noncompliant with medical recommendations.

There are other factors that may contribute to chronic ulcerated tophaceous gout. Multiple studies have demonstrated that patients with gout are more likely to have other comorbidities that impair wound healing, such as diabetes and vascular disease, and the patients in this study were no exception: they had diseases including diabetes, hypertension, chronic venous insufficiency, peripheral arterial disease, and ischemic heart disease.8,9,20

It is not surprising that the feet are the most common site of ulcerated tophaceous gout, not only because tophi frequently occur here, but also because they are subject to weight-bearing stress.2,3,6 Rome et al6 noted that 3 of their 6 patients frequently wore ill-fitting shoes such as slippers and flip-flops; these provided inadequate cushioning and support and may have contributed to delayed wound healing.

There is little consensus about the treatment of these ulcers. Patel et al2 observed that none of the 4 patients in their case series (wound size 0.04–2.25 cm2) formed granulation tissue prior to treatment. They proposed that tophi impair wound healing by inhibiting the formation of granulation tissue. Their solution was to apply hydrogel to soften the tophi to facilitate gentle monthly debridement.2 Yet, Rome et al6 observed granulation tissue in 3 of 6 patients in their study.

Other groups reported successes with topical treatments—allogeneic cultured dermal substitute, topical collagen, and citric acid gel—with and without prior debridement. Unfortunately, the literature on the use of allogeneic cultured dermal substitute, as used by Tanabe et al,15 is limited to case reports and case series, although they do report successes in promoting granulation tissue formation in patients with chronic leg ulcers associated with antiphospholipid syndrome, pyoderma gangrenosum, epidermolysis bullosa, and status post–tumor resection.15,22–25 Similarly, although a few reports from the 1990s suggest that topical collagen promotes wound healing,26,27 other studies have refuted the efficacy of topical collagen when compared with “topical hydrocolloid” and “no topical treatment” controls.28,29 Falidas et al18 reported effective healing in 1 patient after debridement, followed by application of antibacterial silver-containing dressings and topical collagen. However, topical collagen’s role in the management of tophaceous ulcers remains unclear. The use of topical citric acid to improve wound healing is marginally better supported. Virtually all of the literature on this treatment comes from the same group, Nagoba et al.13,30 They have published several other studies on the efficacy of citric acid to treat other wounds, including 1 study demonstrating improved burn wound healing after use of citric acid gel compared with conventional antibiotic therapy and dressings.13,30 Proposed mechanisms of action of citric acid include antibacterial activity and improving wound vascularity.13 Debridement and appropriate dressings certainly have a role in treating nonhealing ulcers associated with gout, but further study is required to determine the most effective regimen.

Patients with much larger wounds (32–195 cm2) were treated with free flaps. Specifically, 3 of the included 9 articles described use of 6 anterolateral thigh, 1 medial sural, and 1 superficial peroneal nerve accessory artery perforator flaps to treat 7 patients (1 patient had bilateral ulcers and received 2 flaps).16,17,19 Free flaps are frequently used to cover large traumatic defects, but their use to cover chronic wounds has been more limited. Small vessel disease associated with diabetes and vascular disease raises concerns for an increased risk of flap loss.31,32 However, free tissue transfer is gaining acceptance as an alternative to amputation in the treatment of chronic wounds and has been shown to provide good outcomes in patients with peripheral arterial disease.32 The cases included in this study also support its use in patients with large defects secondary to tophaceous gout.

One final treatment to consider is skin grafting. Lin et al17 briefly mentioned 2 patients who did not require free flaps and were instead treated with debridement, vacuum-assisted closure, and split-thickness skin grafts. Because these patients were only discussed as exclusions from the authors’ free flap case series, the details and outcomes of their presentation and management were not provided.17

The primary goal in treating ulcerated tophaceous gout is treating the underlying disease. Collaborating with the patient’s primary care provider to optimize gout medications to decrease hyperuricemia and inflammation is fundamental to wound healing. Treating the whole patient and not only the ulcer reduces the likelihood of ulcer recurrence. In the included studies, improved medical management of the patients’ gout and comorbidities may have played a role in promoting wound healing, but limited information was provided on medical management. This potential cofounder cannot be properly addressed without a controlled trial.

The primary weakness in this study is that the literature regarding the management of ulcerated tophaceous gout consists of case series and case reports that provide much lower quality evidence compared with randomized controlled trials. Also, Ou et al16 reported 1 incidence of ulcer recurrence at 3 months following the initial treatment. Unfortunately, the duration of follow-up was varied and often not clearly reported, so the recurrence rate of ulcers after all these interventions remains undetermined. Future studies are needed to identify the risk factors that predispose patients with gout to developing ulcers and to define effective treatment protocols. A clearer understanding of gout wound formation and wound healing mechanisms could also be achieved by creating and studying an animal model.

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CONCLUSIONS

Nonhealing ulcers associated with tophaceous gout are an uncommon but worldwide problem. They can be challenging to treat because of their tendency to develop on the feet, a high-stress weight-bearing area. The comorbidities seen among patients with gout, including diabetes and peripheral vascular disease, compound the difficulties. The reported approaches to ulcer management vary greatly from debridement with or without topical treatments to microvascular free flap coverage, with successful outcomes in case reports and case series. Unfortunately, no controlled studies exist to evaluate the risk factors for developing ulcerated tophaceous gout. The role of medical management and the benefits of these treatments need further study.

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PRACTICE PEARLs

* Chronic tophaceous wounds are uncommon, but they affect patients worldwide and are challenging to treat.

* Small ulcers can be treated with standard wound care and debridement.

* Topical treatments, such as collagen and silver-containing dressings, may help but the clinical evidence is limited.

* Large ulcers may be successfully treated with flap coverage. However, patients with gout often have medical comorbidities such as diabetes, which may negatively impact free tissue transfer outcomes.

* Medical management of gout is a key component to treating chronic tophaceous wounds.

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REFERENCES

1. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008. Arthritis Rheum 2011;63:3136–41.
2. Patel GK, Davies WL, Price PP, Harding KG. Ulcerated tophaceous gout. Int Wound J 2010;7:423–7.
3. Hainer BL, Matheson E, Wilkes RT. Diagnosis, treatment, and prevention of gout. Am Fam Physician 2014;90:831–6.
4. Neogi T. Clinical practice: gout. N Engl J Med 2011;364:443–52.
5. Neogi T, Jansen TL, Dalbeth N, et al. 2015 Gout classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheumatol 2015;67:2557–68.
6. Rome K, Erikson K, Otene C, Sahid H, Sangster K, Gow P. Clinical characteristics of foot ulceration in people with chronic gout. Int Wound J 2014;13:209–15.
7. Fam AG, Assaad D. Intradermal urate tophi. J Rheumatol 1997; 24:1126–31.
8. Zhu Y, Pandya BJ, Choi HK. Comorbidities of gout and hyperuricemia in the US general population: NHANES 2007-2008. Am J Med 2012;125:679–87.
9. Clarson LE, Hider SL, Belcher J, Heneghan C, Roddy E, Mallen CD. Increased risk of vascular disease associated with gout: a retrospective, matched cohort study in the UK clinical practice research datalink. Ann Rheum Dis 2015;74:642–7.
10. Larmon WA. Surgical management of tophaceous gout. Clin Orthop Relat Res 1970;71:56–69.
11. Kumar S, Gow P. A survey of indications, results and complications of surgery for tophaceous gout. N Z Med J 2002;115(1158): U109.
12. Lee SS, Lin SD, Lai CS, Lin TM, Chang KP, Yang YL. The soft-tissue shaving procedure for deformity management of chronic tophaceous gout. Ann Plast Surg 2003; 51:372–5.
13. Nagoba BS, Punpale A, Poddar A, Suryawanshi NM, Swami GA, Selkar SP. Citric acid treatment of chronic nonhealing ulcerated tophaceous gout with bursitis. Int J Low Extrem Wounds 2013;12:276–8.
14. Simman R, Kirkland B, Jackson S. Posttraumatic tophaceous gout: a case report and literature review. J Am Col Certif Wound Spec 2009;1(4):114–6.
15. Tanabe K, Amoh Y, Katsuoka K, Kuroyanagi Y. Intractable leg ulcer associated with gouty tophi: treatment with allogeneic culture dermal substitute. J Dermatol 2010;37:998–9.
16. Ou KL, Tzeng YS, Yu CC, Chen TM. Resurfacing tophaceous gout in the foot with anterolateral thigh flap. Microsurgery 2010; 30(1):79–82.
17. Lin CT, Chang SC, Chen TM, et al. Free-flap resurfacing of tissue defects in the foot due to large gouty tophi. Microsurgery 2011;31:610–5.
18. Falidas E, Rallis E, Bournia VK, Mathioulakis S, Pavlakis E, Villias C. Multiarticular chronic tophaceous gout with severe and multiple ulcerations: a case report. J Med Case Rep 2011;5:397.
19. Lee KS, Lee HS, Kim NG, Kim JS, Lee SI, Choi TH. Treatment of chronic tophaceous gout with a free flap. Clin Rheumtol 2010;29:333–4.
20. Annemans L, Spaepen E, Gaskin M, et al. Gout in the UK and Germany: prevalence, comorbidities and management in general practice 2000-2005. Ann Rheum Dis 2008;67:960–6.
21. Kuo CF, Grainge MJ, See LC, et al. Epidemiology and management of gout in Taiwan: a nationwide population study. Arthritis Res Ther 2015;17:13.
22. Nisimoto J, Amoh Y, Tanabe K, Niiyama N, Katsuoka K, Kuroyanagi Y. Interactable leg ulcer associated with anti-phospholipid syndrome with stasis dermatitis: treatment with allogeneic cultured dermal substitute. Eur J Dermatol 2007;17:350–1.
23. Moroi Y, Fujita S, Fukagawa S, et al. Clinical evaluation of allogeneic cultured dermal substitutes for intractable skin ulcers after tumor resection. Eur J Dermatol 2004;14:172–6.
24. Hasegawa T, Suga Y, Mizoguchi M, et al. Clinical trial of allogeneic cultured dermal substitute for the treatment of intractable skin ulcers in 3 patients with recessive dystrophic epidermolysis bullosa. J Am Acad Dermatol 2004;50:803–4.
25. Toyozawa S, Yamamoto Y, Nishide T, et al. A case of pyoderma gangrenosum with intractable leg ulcers treated by allogeneic cultured dermal substitutes. Dermatol Online J 2008;14(11):17.
26. Palmieri B. Heterologous collagen in wound healing: a clinical study. Int J Tissue React 1992;14 Suppl:21–5.
27. Spenceri EA, Nahass GT. Topically applied bovine collagen in the treatment of ulcerative necrobiosis lipoidica diabeticorum. Arch Dermatol 1997;133:817–8.
28. Graumlich JF, Blough LS, McLaughlin RG, et al. Healing pressure ulcers with collagen or hydrocolloid: a randomized, controlled trial. J Am Geriatr Soc 2003;51:147–54.
29. Becker GD, Adams LA, Hackett J. Collagen-assisted healing of facial wounds after Mohs surgery. Laryngoscope 1994;104:1267–70.
30. Nagoba BS, Gandhi RC, Hartalkar AR, Wadher BJ, Selkar SP. Simple, effective and affordable approach for the treatment of burn infections. Burns 2010;36:1242–7.
31. Ong YS, Levin LS. Lower limb salvage in trauma. Plast Reconstr Surg 2010;125:582–8.
32. Kolbenschlag J, Hellmich S, Germann G, Megerle K. Free tissue transfer in patients with severe peripheral arterial disease: functional outcome in reconstruction of chronic lower extremity defects. J Reconstr Microsurg 2013;29:607–14.
Keywords:

chronic wounds; foot ulcers; gout; tophaceous gout; tophi; urate crystals in wounds

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