From skin to microscope, case report of a rare manifestation of tophaceous gout: Miliary gout

Joint symptoms associated with gout, mostly characterized by joint flare‐ups, are well known. Tophi represent the main cutaneous manifestation of gout, most often associated with a chronic and inadequately controlled disease. On rare occasions, atypical skin manifestations may occur. We present the case of a miliary form of gout in a 36‐year‐old man known to have hyperuricemia. Microscopic direct analysis of the skin material revealed the presence of monosodium urate (MSU) crystals. Rash disappeared with corticosteroid therapy in parallel with joint symptoms recovery. Knowledge of this unusual gout‐related skin disease is essential to diagnosing uncommon presentations of gout, which sometimes occur before joint symptoms. This case highlights the importance of sampling any skin lesion suspected of being tophus, for MSU crystal identification, and provides a definitive diagnosis.


| INTRODUC TI ON
Gout is a well-known metabolic disease resulting from hyperuricemia.Under physiological conditions, monosodium urate (MSU) deposition occurs in affected joints and periarticular tissues when serum uric acid (SUA) levels exceed a threshold of 60 mg/dL (360 μmol/L). 1,2e clinical presentation of an acute gout flare is mainly characterized by joint pain and swelling, primarily in and around the distal joints.In untreated cases, patients can develop chronic arthropathy and joint destruction.
In addition to joint symptoms, skin disease can occur.Tophi represent the main cutaneous manifestation of gout and are most often associated with chronic and inadequately controlled disease.
Tophi are stone-like nodules composed of MSU crystal granulomas in the dermal and subcutaneous tissues.They are typically located near the joints, tendons, olecranon bursae, helix, and finger pads. 3][9][10][11][12] Microscopic analysis of such lesions reveals MSU crystals, giving this clinical form its particular feature.
We present here the case of a 36-year-old man with a miliary form of gout.

| C A S E PR E S E NTATI O N
In November 2020, a 36-year-old man was admitted to the rheumatology unit of Rennes Hospital for the management of a gout attack.He had a history of oligoarticular gout disease with a SUA of 10.7 mg/dL (636 μmol/L) in a context of poor therapeutic compliance.A physical examination revealed a localized skin rash on the chest and abdomen.It was a non-pruritic, papular, erythematous rash.Lesions were yellowish with a thick consistency (Figure 1A,B).This rash was with oligoarthritis affecting both knees and tenosynovitis of the left carpal extensors, confirmed by ultrasonography.The patient remained apyretic.
Anti-cyclic citrullinated peptide, rheumatoid factor and antinuclear antibody tests were negative.Gout genetic research (for ABCG2, ALHD16A1, SLC22A12, SLC2A9, UMOD, LDHD, and HPRT1) did not detect any pathogenic variants.An X-ray examination of the hands, wrists, knees, and feet showed no radiographic signs of chronic gouty arthropathy.
Joint fluid analysis of the right knee showed 5600 leukocytes/ μL and demonstrated the presence of MSU crystals without bacterial germs.Microscopic analysis of the discharge from a skin lesion revealed needle-shaped crystals, strongly birefringent in polarized light, typical of MSU crystals (Figure 2).A skin biopsy was also performed and unfortunately did not detect any MSU crystals, perhaps due to the fact that it was fixed in formalin which dissolved the crystals present in the sample.Histological analysis showed a lymphocyte-rich inflammatory reaction within the dermis.
In light of these arguments, a short course of corticosteroid therapy (prednisone 30 mg/d) was initiated along with colchicine 1 mg/d.This allowed progressive improvement of the described articular and cutaneous manifestations (Figure 1C,D).CRP at hospital discharge decreased to 14 mg/L.The reintroduction of allopurinol at 100 mg/d was planned to lower SUA.
Miliary gout can be symptomatic, as presented in our case report, or asymptomatic, which supports the importance of performing a careful clinical skin examination. 7,9,11 wanted to emphasize that skin lesions related to gout are not restricted to the classical tophi.These other cutaneous fea-  ultrasonography, intradermal and subcutaneous deposits of MSU may appear before the first joint gout attack. 6garding miliary gout, unusual locations of tophi (eg, chest, abdomen, back, arms, forearms, thighs) should draw attention to this entity because they have associated with it. 8,10,12Thus, in contrast to the peripheral sites, low distal temperature does not appear to play a major role in the pathophysiology of such cutaneous lesions.Hypotheses regarding the clearance ability of MSU by tissue macrophages have been put forward, but the pathogenesis of this clinical expression remains unknown. 7One particular factor associated with tophaceous gout is the use of diuretics, especially high-dose loop diuretics, in the context of chronic kidney disease or chronic hepatic failure.Drug-induced hyperuricemia may increase the occurrence of tophi in this population.It could be the same with the presentation of miliary gout.[11] Ultrasound analysis can help differentiate gouty lesions from other lesions.Contrary to the differential diagnoses, in the case of a tophus, ultrasonography shows a hyperechogenic aggregate typical of gout.It can be confused with an osteoma or calcinosis, but the latter will then appear to have a more homogeneous ultrasonographic structure with a large posterior shadow cone.To support the hypothesis of gout, a quick ultrasonography of the knee and the first metatarsophalangeal joint may be profitable.Research has reported the diagnostic value of these 2 joints to be particularly helpful and time-effective. 15 all cases, performing a skin biopsy is easy and removes any doubt.Histopathological analysis provides the diagnosis, hence the importance of sampling any suspicious lesion.Even atypical tophi, such as those present in miliary gout, should be analyzed under the microscope.Indeed, the presence of MSU crystals enables a definite diagnosis of gout. 3 However, technical considerations regarding tissue sampling are important to know in order to ensure proper histological analysis.Skin biopsy should be fixed in alcohol rather than formalin in order to avoid crystal dissolution, as in our case. 6,10Under such conditions, the crystals appear as an amorphous material with a sharp shape, surrounded by a granulomatous inflammatory reaction rich in histiocytes and lymphocytes. 11other way to show the presence of MSU crystals is to collect the chalky material coming out of skin lesions and observe it under a microscope.The doubly refractive property of MSU crystals in polarized light enables confirmation of the diagnosis.
Dissolution of tophaceous deposits can occur by lowering SUA levels below their saturation point, but complete resolution is rarely the rule. 109]11 The relatively prompt improvement of the rash in parallel with joint symptoms is not classically reported but was observed in our case.
To the best of our knowledge, we have reported the first description of direct visualization of MSU crystals in skin material.
The originality of our case was to identify a MSU crystal within the discharge of an eruptive skin lesion.As tophi can take different clinical forms, it remains a crucial step to biopsy any suspicious lesion in order to detect MSU crystals.Collecting the discharge from a suspected lesion appears to be a valuable method to perform microscopic crystal identification, such as in the case of joint puncture.This case illustrates the importance of a skin examination in patients who might have gout disease.Skin biopsy or flow analysis of skin lesions is minimally invasive, easy to perform, and can be useful.

AUTH O R CO NTR I B UTI O N S
CT prepared the initial draft.BP took the pictures.RF and GP revised the manuscript.All authors reviewed and approved the final version of the manuscript.

None.
F I G U R E 2 Extraction of material from a skin lesion observed under polarized light microscopy shows a fine elongated crystal (magnification x1000).The blue color indicates positive birefringence (A) and the yellow color negative birefringence (B), consistent with a monosodium urate crystal.
tures are important for rheumatologists to recognize.Most of the skin manifestations are only visible in chronic tophaceous gout.However, as described in the joints with the double contour sign on F I G U R E 1 Confluent papular erythematous lesions on the chest and abdomen (A).A close-up view allowed us to distinguish yellowish material within some skin lesions (B).Evolution of skin lesions after corticosteroid therapy (C), with a closer view showing regression of most of the papular component and improved erythema (D).