The clinical presentations of any disease that occur more frequently are regarded as typical and prompt a straightforward diagnosis. Conversely, other presentations different to the classical may hamper reach the correct diagnosis and increase the possibility of misclassification. This situation occurs in gout, despite having an immediate and reliable technique – the synovial fluid analysis under the polarized microscope – that provides a diagnosis of certainty.1 The hallmark picture is the acute inflammation of the big toe in a middle-aged man often suffering from renal and cardiovascular comorbidities. Besides the detection of subcutaneous tophi, this presentation poses the highest diagnostic utility compared to the microscopic evaluation.2 However, in general terms, gout diagnoses solely based on clinical data misclassify up to one out of four patients.3 Incorporating the routine microscopic analysis of every synovial fluid sample obtained in clinical practice is a crucial strategy to avoid misdiagnoses. Increasing the knowledge on the clinical spectrum of gout can be useful as well.

The monosodium urate (MSU) crystals deposition occurs in the musculoskeletal (MSK) system, as is demonstrated by the overt manifestations (flares, tophi) suffered by gout patients. However, the deposition and clinical picture probably is more generalized.4 Feet are major MSK sites of MSU crystal deposition, but there are other frequent locations such as knee, wrist, fingers or elbow bursae. In terms of gout flares, old series already reported that big toe and ankle/foot involvement affect to 76% and 50% of gout patients, respectively.5 At the primary care level, 53% of gout flares affected the big toe, while other areas of foot and ankle comprised 18% of episodes. Beyond flares, nonspecific complains focused on feet and ankles are commonly stated by patients with gout in clinical practice, such as persistent walking pain, stiffness or numbness. Subcutaneous tophi are frequently found at Achilles tendon regions, ankle malleoli, lateral aspects of tarsi, over toes (especially the big toes) and even on the plantar surface.

The predilection for feet and ankles of MSU crystals is also confirmed by ultrasound and dual-energy computed tomography (DECT), the imaging techniques that better ascertain the crystal deposition in gout, despite not being interchangeable.6 By ultrasound, reported rates of deposits are 14.2–35.0% in first metatarsophalangeal (MTP) joint, 15.8% in the ankle and 1.6% in the midfoot.7,8 Using DECT, crystal deposits in 1st MTP, midfoot and ankle are seen in 12.1–57.4%, 0.8–7.5%, and 10.8–53.4% respectively.8–12 Prevalence rates vary according to several factors, such as age, disease duration, serum urate (SU) levels or use of urate-lowering agents. Interestingly, crystal deposits were strongly associated with the presence of joint damage such as erosions or joint space narrowing.7,9 Beside joints, imaging techniques also revealed tendon deposition of MSU crystals in feet, with a predominance for Achilles tendons – 26% by ultrasound,13 52% by DECT14 – while other tendons, such as peroneal, extensor digitorum longus, extensor halluces longus, and tibialis anterior, are commonly affected (>10%).

The reason for the predominant involvement of lower limbs, and notably foot and ankle, in gout, remains to be determined. Urate forms MSU crystals when its levels are persistently above the saturation point, that was determined at 6.8mg/dL with a normal body temperature of 37°C.15 At lower values, the saturation level for urate also lowers. Interestingly, an old study proved that the temperature at the big toe is about 35°C,16 thus theoretically facilitating the crystallization of urate.17 Besides temperature and urate concentration, other determinants of the crystallization appear to be the proteins.18 MSU crystals form through templated nucleation, a form of biomineralization that requires the presence of a complementary structure to facilitate a low-energy requiring crystallization. One of the potential protein candidates is the type II collagen, present at both joints and tendons: (i) fragments of proteins containing adhered and well-organized MSU crystals are occasionally seen in the synovial fluid from gout patients19; (ii) the crystal deposition is majoritary on the cartilage surfaces, as demonstrated by arthroscopy20 and ultrasound21; and (iii) at tendons, crystals deposits are mostly seen in the enthesis,14 an area of high mechanical stress for tendon fibers.22 Lower limbs are the leading sites for developing osteoarthritis, as they are weight-bearing. Gout, both as MSU crystal deposition and clinical flares, has been associated with osteoarthritis in some reports,9,23 though not in others.24 Joints affected with osteoarthritis developed cartilage fibrillation, likely facilitating the initial MSU crystal deposition. Afterwards, while hyperuricemia persists, the formation of further MSU crystals continues, now probably using another crystal as the template, as seen in the tophi.18

For this narrative review, an electronic search in MEDLINE, Cochrane, Embase and PEDro databases was performed. The search strategy, run at 2019 July 4th, with its used terms, can be found at the Annexed 1. Title and abstracts of retrieved articles were reviewed by all four authors to exclude papers unrelated to the topic of interest. Also, articles known by the authors and others obtained through reviewing the retrieved bibliography were included. The gout nomenclature recommended by the Gout and Crystal Arthritis Network (G-CAN)25 was followed in the writing of this review.

Tophi

The presence of tophi in gout indicates chronicity and a lack of effective treatment. They can be found in joints, cartilages, tendons, muscles and periarticular structures.30,31 As stated above, feet are preferred sites for tophi development [Fig. 1], especially in the 1st MTP joints and ankles,27,32 although they may appear in other places of the body such as knees, upper limbs (olecranons, knuckles) or even ears. Presence of tophi in feet has been associated with a decrease in muscle strength32 while some cases of pathological fractures directly related to tophi have been described.33

Fig. 1.

The figure depicts three different cases of foot involvement in tophaceous gout, shown by a clinical picture (left), plain radiography (center) and T1-weighted magnetic resonance (right).

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Although ulceration of tophi is not common, those located in the feet tend to ulcerate more frequently.27,34 Risk factors for ulceration include the number of tophi, their duration, and excessive use of glucocorticoids.34 The presence of small ulcerated areas is common in gout, particularly in cases of chronic polyarticular involvement with tophi. The study by Rome et al.27 performed on seven patients showed the presence of ulcerations on the dorsal side of the middle toes, likely related to unsuitable footwear. Ulcers in patients with gout tend to be highly exudative while carrying with a moderate amount of pain.27 This situation can be worsened by the presence of comorbidities frequently associated with gout such as obesity, type 2 diabetes or peripheral arterial disease, which may delay healing and increase the risk of infection. Tophi ulceration, especially those located in the feet, must be distinguished from infected ulcers of diabetic patients given the frequent association between gout and diabetes.31

Beside ulcers, other skin manifestations are usually present when gout affects superficial synovial structures and joints; this is the case of the podagra, in which peeling often occurs after intense swelling, erythema and edema of the affected joint. When the disease involves deeper joints such as the tibiotalar, dermatological alterations are unusual.

After the review of the literature, a few papers were retrieved in relationship with specific treatment of gout in foot and ankle, most of them related to surgical procedures. In 2018, the American College of Foot and Ankle Surgeons, together with the American Association of Nurse Practitioners, performed a consensus about etiology, diagnosis and treatment of gouty arthritis affecting foot and ankle.50 In this consensus, the experts agreed that nonsteroidal anti-inflammatory drugs (NSAIDs) are the first-line therapy for a flare. From the authors’ point of view, NSAIDs are many times contraindicated or not appropriate, while colchicine and corticosteroids (oral or intraarticular) are also effective and safe options. At this consensus, it was also settled the need of urate-lowering therapies, such as allopurinol, to reach the SU target below 6mg/dL. It is also important to mention that the 2016 EULAR treatment guidelines recommend a lower target – <5mg/dL – in severe gout (defined as tophi, chronic arthropathy or with frequent flares) to enhance crystal dissolution.51

Regarding pharmacological treatment, no references dealing with specific management of gout in foot and ankle were found. Nevertheless, it seems reasonable that the treatment would not be different from the ordinary gout patient. Gout must be understood as an MSU crystal deposition disease secondary to hyperuricemia. These MSU crystals are recognized by the innate immune system, causing inflammation.52 The treatment aims to dissolve the MSU crystal storage by achieving a persistent normalization of SU levels. Until MSU crystals are entirely removed, it is also mandatory the flare prophylaxis and, in advance cases, the control of persistent clinical inflammation.

Most of the articles found in the review regarding the targeted management of foot and ankle involvement deal with surgical techniques for cases of tophaceous gout. Interventions can be divided into five types: arthroscopic cleaning, joint replacement, arthrodesis, surgical debridement and graft techniques. In 2016, a systematic review of surgical procedures could not reach a specific recommendation due to the limited good quality studies.53 In addition, a Cochrane review concluded more randomized-controlled trial data for surgical interventions of tophi is needed before drawing firm conclusions.54 One paper assessed the arthroscopic removal of MSU crystals from 1st MTP joints, comparing outcomes against “anti-gout therapy” in 28 patients.55 After more than two years, functional scores and number of attacks significantly favored the surgical group; furthermore, the final SU levels were also lower. Surprisingly, no patient in the control group showed SU levels under 6mg/dL, and the authors did not provide the mean dose of urate-lowering therapy in both groups. Concerning joint replacement, one article reports 16 patients with gout undergoing total ankle arthroplasty, with good results in terms of pain and disability.56 These outcomes were also shown in patients in whom an arthrodesis was performed after tophi excision compared with the excision alone. In fact, in this work, the authors noted that osteoarthritis progressed more frequently in patients without arthrodesis and those with intraarticular tophi.57 Surgical debridement is the classic technique for tophi removal,58 despite being supported only by two relatively recent articles. In the first one, a surgical debridement with a free flap reconstruction in six patients is described with favorable results.59 In the other paper, Lee et al.60 described an intralesional shaving technique focused on reducing the burden of MSU. More recently, a modified bone graft technique called Masquelet's technique was used in situations with significant bone losses, as sometimes occurs in tophaceous gout, with successful results.61

The prescription of footwear considered appropriate is controversial. It produces improvements in pain and foot disability in the short term (2 months),62,63 but eventually, this effect disappears. However, improvements in comfort and fit using suitable footwear tend to persist in time.62 All the studies related to footwear were performed in New Zealand, a fact that needs to be taking into account as could affect data extrapolation.

In the authors’ opinion, the timing and indications for surgical procedures in case of gouty involvement remain to be determined. What is mandatory is to optimize the urate-lowering therapy, because gout is too often poorly managed,64 even by rheumatologists, as it has been demonstrated that only 66% of treated patients reached the targeted SU level.65 Footwear interventions could improve patients’ foot comfortability. Probably in severe gout with considerable structural damage, surgical procedures could be an option, always together with urate-lowering therapies.

The result of the present review highlights that the foot and ankle involvement in gout overtakes the classical picture of recurrent episodes of acute arthritis. Patients affected with gout, even in a non-tophaceous stage, deal with persistent pain and gait impairment. Their ranges of movement at lower limbs are limited, and the choice of footwear may be troublesome for these subjects, especially when tophi are present, all resulting in an impaired quality of life. Focused attention and management appear convenient, where close collaborations between rheumatologists and podiatrists can be constructive. Gout is a curable disease as MSU crystals dissolve when SU levels are persistently normalized; however, the specific effect on these foot and ankle manifestations remains to be determined.

The present work received no funding.

MA declares speaking fees and research grants from Grunenthal, Menarini, Astra-Zeneca and Horizon. The rest of the authors declares no conflicts of interest in the making of the present manuscript.