Beyond Medical Treatment: Surgical Treatment of Gout

(2021) 23:1 Current Rheumatology Reports https://doi.org/10.1007/s11926-020-00969-6 CRYSTAL ARTHRITIS (M PILLINGER & M TOPROVER, SECTION EDITORS) Beyond Medical Treatment: Surgical Treatment of Gout Jonathan Carcione 1 & Shari Bodofsky 1 & Brian LaMoreaux 2 & Naomi Schlesinger 3 Accepted: 15 November 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract Purpose of Review Medical treatment with urate-lowering therapy (ULT) is efficacious. A recent publication suggested that surgery in gout is more prevalent than previously reported. This revelation led us to review what is known about surgical treatment of gout. Recent Findings The Google Scholar database (January 1, 2014–January 1, 2020) found 104 publications with a total of 169 gout patients, with an average disease duration of 6.7 years. Most (68%) were not on ULT. The mean pre-operative serum urate levels were 9.19 mg/dL. One hundred thirteen patients underwent tophi excision, while in 33 patients, tophi were found during surgery. The majority of the surgeries were performed in Asia and Europe. Summary Most patients were not taking ULT at the time of surgery, leading to hyperuricemia. This can result in tophi reformation post-surgery. The role of surgery should be a last-line treatment and until recently has only been demonstrated through case reports. Keywords Gout . Tophaceous gout . Surgery . Surgical treatment Introduction Gout is the most common inflammatory arthritis worldwide. Hyperuricemia is defined as a serum urate (SU) level ≥ 6.8 mg/dL, the physiologic saturation threshold for uric acid. Persistent SU levels above 6.8 mg/dL can lead to monosodium urate (MSU) crystals deposition in and around joints and soft tissue. Lowering SU to a target of ≤ 6 mg/dL in combination with acute and chronic anti-inflammatory drugs can lead to gout being under control. Since its Food and Drug Administration (FDA) approval in 1966, allopurinol has been the drug of choice for treating hyperuricemia in gout patients. Febuxostat, another xanthine oxidase inhibitor, was FDA approved in 2009 [1], This article is part of the Topical Collection on Crystal Arthritis * Jonathan Carcione [email protected] 1 Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA 2 Horizon Therapeutics, Lake Forest, USA 3 Division of Rheumatology, Department of Medicine, Rutgers Robert Wood Johnson Medical School Gout Center, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA becoming a mainstay ULT alongside allopurinol [2]. However, in 2019, the FDA issued a public safety alert due to a reported increased risk of death in febuxostattreated patients than allopurinol-treated patients, leading to a boxed warning for febuxostat [3]. In addition, lesinurad, a uricosuric drug, was taken off the US market in February 2019. With febuxostat being a limited option for many gout patients who have a risk of cardiovascular disease, lesinurad off the market, probenecid contraindicated or not recommended in many patients due to renal considerations or drug interactions, the options for urate-lowering in gout are limited. Thus, healthcare professionals (HCPs) must reconsider chronic tophaceous gout management. One such option is intravenous pegloticase, usually reserved for treating refractory gout patients or those with active gout despite urate-lowering therapy. Pegloticase is more efficacious in lowering SU and does so quicker than oral ULT, leading to a more rapid reduction in tophi leading to improved healthrelated quality of life (HRQoL) [4]. Because medical treatment is efficacious and leads to gout remission, surgery is seldom indicated. Historically, gout’s surgical treatment dates to 1250 BC and is mentioned in the Indian Veda book and Persian texts [5]. Surgery was recommended to “disburden” the joints affected by MSU crystals deposition and cosmetic reasons [6]. Hippocrates in the fifth century BC reported regression of intense pain after 1 Page 2 of 8 cauterization of tophi with burning hemp. Dr. Paré, a French surgeon and gout a sufferer himself, performed gout operations in the sixteenth century. He applied the roots of the hermodactylus plant (genus Colchicum) to tophi that had been opened surgically [7]. In the 1950s, the indications for surgical interventions changed and included conditions caused by tophi, including impairment in the function of tendons and joints, skin ulceration or necrosis over the tophi, local infections, or septicemia caused by tophi, and nerve compression [8]. In the 1960s, reports on surgical removal of tophi and limb amputations were suggested to treat gout [9]. Surgery in gout has been a recent topic of discussion. Published data from 2020 suggest that surgery in gout is perhaps much more prevalent than previously reported. Data collected in 2019 by the TriNetX “Diamond” Network, which included over 190 million patients, showed that gout patients undergo a similar amputation rate to patients with diabetes, in part, owing to tophaceous damage/tophectomy [10]. This revelation led us to review what is known about surgery in gout. Curr Rheumatol Rep (2021) 23:1 Results The search yielded 1175 publications in the English language medical literature from January 1, 2014, to January 1, 2020. In total 1071 publications were of no relevance, and 104 publications were eligible for inclusion (Fig. 1; Supplementary file: Table 1) [7, 11–113]. We found no randomized or quasirandomized controlled trials, cross-sectional studies, casecohort studies, or meta-analysis. We found 20 case series (Supplementary file: Table 2) [9, 17, 41, 42, 69–71, 88, 89, 108–110, 112–119]. The remainders were case reports. Patient Demographics One hundred and sixty-nine patients were represented in 104 publications. The average age was 53.5 ± 15.1 years (range 20–84 years). Most (n = 150; 89%) were males; their average age was 52.8 ± 15.2 years. The women (n = 19; 11%) were older, and their average age was 58.5 ± 13.2 years. The average disease duration before surgery was 6.7 ± 7.6 years. In 83 (49%) patients, the length of disease was not reported. Objective This review aims to evaluate published studies regarding the surgical treatment of gout. Methods A systematic literature review was performed using the Google Scholar database. The search was limited to publications published in the English Medical literature from January 1, 2014, to January 1, 2020. The database search was performed using the terms “surgical treatment” AND “tophaceous gout,” as well as “tophaceous” AND “gout” AND “surgery.” We considered only studies that were published as full articles. Abstracts were reviewed and analyzed for non-relevance, including non-human studies, duplicate studies, and foreign language (non-English). Studies were included if they were randomized or quasi-randomized controlled trials, cross-sectional studies, case-cohort studies, metaanalysis, or cases. Two review authors (JC, NS) independently identified studies that fulfilled the inclusion criteria. Titles and abstracts were reviewed, and if more information was required to determine whether the study met the inclusion criteria, the full text was obtained. Two review authors independently extracted relevant information from the included studies, including study design, characteristics of the study population, surgical treatment and medical treatment, and duration. Treatment with ULT A minority of patients (n = 27; 16%) were on ULT, while 115 patients (68%) were not. Seven (4%) patients had been prescribed ULT but were not compliant, and the ULT status of 20 (12%) patients was not reported. Hence, the average preoperative SU level was 9.19 ± 2.75 mg/dL in the 74 (44%) patients for which it was reported. In the 27 patients on ULT, the SU was reported in 12 (44%) and was 7.65 ± 3.0. The SU levels of 95 patients were not reported. Surgical Procedures Surgical techniques varied widely due to the variability in tophi location and size. One hundred fifty-seven (93%) surgeries were performed with an open approach, while 12 surgeries (7%) were performed with arthroscopic/endoscopic technique (Fig. 2). Three (2%) surgeries were amputations— 2 of the metatarsophalangeal joint (MTPj) and 1 of the index finger. Surgical Sites Surgical sites included the head (n = 8; 5%), arm (n = 4; 2%), hand (n = 30; 18%), spine (n = 34; 20%), leg (n = 21; 12%), and foot (n = 46;27%). Twenty-five (15%) of surgical case reports were in other anatomical locations including one (1%) in the mediastinum. Curr Rheumatol Rep (2021) 23:1 Page 3 of 8 1 Fig. 1 Literature review search. This flow diagram depicts the process by which publications discussing the surgical treatment of gout were selected Tophi Diagnosed at Surgery Complications Post-surgery Most (n = 133; 79%) underwent surgery to excise tophaceous material. However, 36 (21%) patients were diagnosed with tophaceous gout post-histological examination of specimens extracted during surgery. This included 15 (42%) in the spine, 6 (17%) in the leg/knee, 6 (17%) in the ankle/foot, 4 (11%) in the hand/wrist, 3 (8%) in the ear, 1 (3%) in the elbow, and 1 (3%) in the mediastinum. Four patients required multiple surgeries at the same anatomic location for complete tophi resection. Overall, 22 (13%) of the patients suffered a reported complication after their surgery. The most common complication was recurrence of tophi (n = 6; 4%) followed by worsening of motor deficits (n = 4; 2%); worsening of sensory disturbances (n = 3; 2%); delayed surgical wound healing (n = 3; 2%); post-operative infection (n = 2; 1%); painful scar (n = 1; 1%); worsening range of joint motion (n = 1; 1%); gout flares (n = 1; 1%); and return of pain and loss of function 8 years after his surgery in one patient (1%). Outcomes in 15 patients (9%) were not reported. 1 Page 4 of 8 Curr Rheumatol Rep (2021) 23:1 Fig. 2 Open and arthroscopic surgery versus standard of care medical treatment of gout Study Populations Most surgical case reports were from Asian and underserved countries (8, 17–119): Asia (n = 61; 59%) including China, Hong Kong, India, Indonesia, Iran, Japan, Korea, Malaysia, Saudi Arabia, Taiwan, and Turkey; Europe (n = 20; 19%) including Austria, Bulgaria, France, Germany, Greece, Italy, Poland, Portugal, Spain, Switzerland, and the UK; North America (n = 17; 16%) from the USA; Africa (n = 1; 1%) from Tunisia; South America (n = 4; 4%) including Argentina, Brazil, and Colombia; and Australia (n = 1; 1%). Conclusions The mainstay of gout treatment is medical treatment using ULT in combination with acute and chronic antiinflammatory drugs. In this review, most gout patients were not taking ULT at the time of surgery. Thus, it is not surprising that the average pre-operative SU level in these patients was over 9 mg/dL. It is also important to note that only 44% of these patients even had a SU level checked before surgery. Long-term ULT aims to reduce SU levels below the point of saturation of 6.8 mg/dL, and this was not achieved in the reported patients, including those on ULT, leading to severe tophaceous gout requiring surgery. Most published reports of surgeries were from Asian and underserved countries, and this could be in part because ULT is not readily available in these countries. In the US publications encompassing 18 patients, 33% (n = 7) patients were on ULT, which reflects overall nationwide use [120], as opposed to only 4% (n = 4) on ULT in the Asian reports. Thus, education regarding medical therapy for gout is of utmost importance. Surgical excision of tophi has been reported as uncommon in the past and is suspected to be under-reported. No randomized controlled trials (RCTs) have been published comparing the effectiveness of medical versus surgical treatment in patients with tophaceous gout. We found 13 case series and several case reports published since 2014 and no RCTs. In total, including results from a 2016 comprehensive review and analysis of published surgical cases and case series, by Kasper et al. [121], 20 case series have been published (Supplementary file: Table 2). Surgery may be indicated for complications due to tophi, including infection, joint deformity and decreased joint function, compression (e.g., cauda equina or spinal cord impingement), and intractable pain, as well as for ulcers related to tophaceous erosions. Subcutaneous tophus extraction by open Curr Rheumatol Rep (2021) 23:1 excision was the most common surgery. The type of surgery may be based on the extent of tophi, tophi consistency, joint deformity, vasculature status, and comorbidity profile and whether the patient has a previous operation at the surgical site [121]. While we found reports of open excision of tophi to be the most commonly reported surgical technique for tophi resection, an arthroscopic shaver has been used successfully in several reports [115, 119, 122]. A previous study found that tophi resection performed using an arthroscopic, intra-lesion shaver is allowed for quick removal of tophi with limited blood loss and preservation of the subdermal vasculature. To the best of our knowledge, no study exists comparing outcomes of patients treated with open excision versus arthroscopic shaving for gouty tophi. Kasper et al. acknowledged that the most appropriate surgical approach is dependent on several factors, including the extent of tophi invasion into the joint, the consistency of the tophi, the presence or absence of a deformity, vasculature status, and whether or not the patient has previously had an operation at the surgical site [121]. Best results from surgery were achieved when the surgery was performed before joint destruction [117]. For less severe soft tophi, incision with aspiration may be recommended. However, the risk of creating a fistula is heightened. Curette and debridement may be recommended when tophi are found within joints or tendons. Tophi that have destroyed the articular cartilage and joint may lead to complete joint resection and arthroplasty. Due to large tophi, large skin defects may be difficult to close after surgery and may require skin reconstruction [123]. In a minority of patients, tophi were diagnosed during surgery, mostly spinal tophi. Outcomes were underreported in the 104 publications. Risks should always be kept in mind when considering surgery. Although a surgical procedure can potentially produce a more rapid effect, one must consider possible operative and post-operative complications. The most common complication was delayed surgical wound healing, mostly in patients with underlying comorbidities such as diabetes mellitus and peripheral vascular disease, which are commonly seen in gout patients. In addition, tophi may adhere to the skin, leading to stretching and thinning of the skin, making it prone to vascular damage during surgery, leading to skin necrosis. Percutaneous arthroscopic resection may reduce this risk [122]. Tophus shaving through small skin incisions has also been proposed [115], but this is a blind procedure that carries the risk of injury to any adjacent vessel, nerve, or tendon. Therefore, it should not be performed at inter-phalangeal joints. When tophi are softened and liquefied, needle aspiration may be preferable to surgical excision, but the risk of creating a fistula is increased [8]. Due to large tophi, large skin defects may be difficult to close after surgery and may require skin reconstruction [123]. When the vasculature has been compromised, an amputation may be necessary [90]. This is not uncommon. A recent Page 5 of 8 1 study, discussed earlier, evaluating 190 million patient US claims datasets over 7 years, found a high risk of limb amputations in gout patients [10]. Patients suffering from either gout or diabetes had a significantly increased risk of limb amputation (0.434% versus 0.484%). This effect was further amplified in patients with both gout and diabetes (0.77% versus 0.03% in the control group with neither gout nor diabetes). The high amputation rate found in gout patients was surprising since gout’s surgical treatment is seldom reported. The role of surgery in gout has only been demonstrated through case reports. This leads to a broader question—is there a point at which surgery is indicated? What are the appropriate or compelling indications for doing surgery on tophaceous gout patients? There have been no controlled clinical trials comparing the effectiveness of pharmacotherapy and surgical treatment in patients with gout nor have there been randomized controlled trials evaluating different gout surgical treatments. No official surgical recommendations have been published, though Kasper et al. [121] reported that uncontrollable infection as part of sepsis was the most compelling indication, with nerve compression, tendon or joint functional limitations, and skin ulceration/infection as other cases where surgery on tophi is necessary. The Roman Emperor Charles V, also known as King Charles I of Spain, suffered from severe tophaceous gout [124]. He stated that “patience and some crying are the best drugs for gout.” Fortunately, much has changed since then. We found that most gout patients were not taking ULT at the time of surgery. Effective treatment with ULT may have prevented the need for surgery in these patients. Because gout is a systemic disease, tophi’s surgical removal addresses mechanical issues but not the underlying hyperuricemia. Today, gout can be in remission with medical treatment but is often poorly managed. Enhancing knowledge of the disease and its treatment will lead to improved care and surgery being considered only for the rare patient. Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s11926-020-00969-6. Authors’ Contributions All authors take responsibility for the integrity of the review. JC and NS drafted the initial manuscript. NS and BL provided critical review. All authors reviewed and provided input at each step. Compliance with Ethical Standards Conflict of Interest JC and SB declare that they have no conflict of interest. BL receives consulting fees from Horizon Therapeutics. NS receives research grant funding from AMGEN and consulting fees from Horizon Therapeutics, IFM Therapeutics, and Johnson & Johnson. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors. 1 Page 6 of 8 References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/ 021856s000toc.cfm. Accessed 18 Aug 2019. Becker MA, Schumacher HR Jr, Wortmann RL, MacDonald PA, Eustace D, Palo WA, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353: 2450–61. 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