There are more than 100 joint diseases in humans, and the three most common ones are osteoarthritis, also known as degenerative arthritis; rheumatoid arthritis, which is characterized by inflammation of the synovium; and gout, where deposition of uric acid crystals in the synovium leads to immune and physical reactions (1). Gout is a metabolic and inflammatory disease whose causes, mechanisms, and treatments have long been identified in humans (2). Monosodium urate (MSU) crystals, the less-soluble crystal form of urate, are the causative agent of gout (3). These crystals can be formed when the body fluid's temperature and pH are lowered to MSU saturation (4). After growth, the crystals promote various inflammatory cascades and arachidonic acid metabolism, resulting in extreme joint pain (4). Gout was initially regarded as rheumatism, which was then distinguished by Sydenham in 1683 (2). Eighty years later, McCarty and Hollander used polarized light microscopy to differentiate it from pseudogout, whose causative crystals show positive birefringence while MSU crystals show negative (2). This method is still the gold standard for diagnosis (2, 5, 6).

Non-human mammalians, including dogs and cats, are known to have urate oxidase (uricase) which catalyzes uric acid into a soluble form. Therefore, these animals seem to be unaffected by uric acid crystals excluding conditions when these crystals lead to urolithiasis (2, 7). Although a gout-like disease was reported in animals by Miller and Kind (8), and Watson (9), these were only tentative diagnoses, without any confirmation.

To the authors' best knowledge, there have been no other reports of naturally occurring articular gout with confirmation of MSU using polarized microscopy in dogs and cats. However, we recently discovered suspicious materials in the synovial fluid of companion animals. In this report, we aimed to describe these cases confirmed to have articular gout using polarized microscopy, in addition to comparing the findings with those in humans.

Four dogs and one cat were presented at our hospital because of lameness due to an unknown cause. The characteristic observations of each case are summarized in Table 1. Although the degree of lameness was diverse, the dogs commonly exhibited pain, warmth, and swelling in multiple joints in physical examinations. Through orthopedic and neurological examinations, ligament damage such as collateral ligament and neurological causes were ruled out. In comparison, the cat only showed symptoms on the right stifle joint where a cystic mass recurred; this mass was resected and diagnosed as cellulitis 3 years prior (Supplementary Figure 1). On radiographic imaging, erosive changes were noted in the juxta-articular bones in dogs 1, 3, and 4 (Figures 1A–C). Osteophytes were also observed in dogs 1, 3, and 4; however, diseases such as osteochondritis dissecans were radiologically less likely, and the cause of polyarthritis could not be identified. In dog 2, however, we could not find any signs except for increased soft tissue opacity and thickness, which is only an indication of swelling (Figure 1D). In case of the cat, there was an increase in soft tissue opacity, and osteophytes were found on the juxta-articular bones (data not shown). The cystic mass seemed to be continuous with the stifle joint on computed tomography imaging (Figure 1E). On ultrasonography, it exhibited irregular margins and contained intraluminal echogenic material (Figure 1F). Despite the disease severity, the four dogs only had a mild inflammatory response with elevated C-reactive protein. Dog 2 had elevated neutrophil count as well; however, the cat did not have any remarkable changes in complete blood count and serum chemistries (Supplementary Table 1).

To identify the cause of polyarthritis in the four dogs and the cystic mass in the cat, arthrocentesis was indicated. The synovial fluid from the four dogs and the cat was clear and colorless, with a slight yellow tinge. Because the patients were small breed, fluid volume sampled was limited to <1 ml, and therefore only cytologic examination and bacterial culture were indicated. Microscopically, a coarsely granular background was observed, which indicated the hyaluronic acid-rich characteristic of synovial fluids. This was accompanied by brown, needle-shaped debris. The total nucleated cell count (TNCC) was below 3000 cells/μL or 3 cells/HPF in the four dogs. The cells were mainly large and mononuclear in dogs 1 (Figure 2A) and 2 (Figure 2B), with few neutrophils seen in the second (Figure 2B). Both large and small mononuclear cells were seen in dog 3, with a few neutrophils (Figure 2C), and aggregation large mononuclear cells (Figure 2D). In dog 4, however, cellular components were not analyzed as the few white blood cells were presumed to result from blood contamination during the procedure (Figure 2E). The synovial fluid of the cat was also composed of both small and large mononuclear cells. However, the TNCC of the cystic fluid was 46 × 10³/μL, mainly composed of neutrophils (Figures 2F,G). Based on these findings, immune-mediated polyarthritis and septic arthritis were considered in the differential diagnosis.

Laboratory testing for antinuclear antibody (ANA) and rheumatoid factor (RF) were negative and no organisms were cultured from the synovial fluid of the four dogs, be it fungi, aerobic, or anaerobic bacteria. Therefore, the tentative diagnosis of immune-mediated polyarthritis was made (10–12) with the exclusion of septic causes, and immunosuppressive and anti-inflammatory therapies were initiated since the sensitivity of RF test is low (13).

Dog 1 was treated with prednisolone (0.5 mg/kg, BID, PO) and cyclosporine (5 mg/kg, SID, PO). After 6 weeks, the symptoms resolved and did not recur for 3 months. The symptoms of dog 2, however, had been exacerbated despite the 2-week treatment with non-steroidal anti-inflammatory drugs (NSAIDs) (carprofen 2.2 mg/kg, BID, PO). Immunosuppressive therapy was then initiated with prednisolone (1 mg/kg, BID, PO) and cyclosporine (5 mg/kg, BID, PO). Even though the symptoms reduced and worsened repeatedly, they resolved after 7 weeks of immunosuppressive therapy. The treatment was continued by tapering the dose, but mild warmth and swelling were observed in the joints after another 6 weeks. Moreover, side effects such as pruritus and dermatitis occurred, so the prednisolone was changed to tacrolimus (0.05 mg/kg, BID, PO), but eventually, the lameness recurred after 1 year (Supplementary Figure 2). Dog 3 was also treated with prednisolone (1 mg/kg, SID, PO) and cyclosporine (5 mg/kg, BID, PO). Although the initial symptoms markedly resolved after 2 weeks, polyuria and polydipsia developed. Moreover, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase were increased to 671, 113, 1,804, and 47 U/L, respectively. Therefore, lepotil (4 mg/kg, BID, PO) was prescribed in addition to ademetionine (20 mg/kg, BID, PO) and ursodiol (10 mg/kg, BID, PO). Moreover, allopurinol (10 mg/kg, SID, PO) was added because of the suspicion that the needle-shaped debris was MSU crystals, and prednisolone tapering was indicated. Unfortunately, the owner notified us that the dog died after 3 weeks. Dog 4 was also given NSAIDs (firocoxib, 5 mg/kg, SID, PO), and ademetionine (12.5 mg/kg, SID, PO). The symptoms improved after 1 month similar to the other dogs. However, the needle-shaped material was confirmed to be MSU crystals by polarized microscopy and the final diagnosis of articular gout was made. To treat the disease properly, a xanthine oxidase inhibitor (allopurinol, 10 mg/kg, SID, PO) was prescribed and a low-protein diet and weight loss were recommended. After 3 months, the symptoms completely resolved and the dog was not brought again to the hospital for 3 years.

In case of the cat, however, we excluded crystal-induced arthritis from the differential diagnosis since there were no reports of feline articular gout. We continued antibiotic therapy (enrofloxacin, 5 mg/kg, SID, PO) for 2 more weeks with side effects including ocular toxicity monitored because septic arthritis was the most suspected cause. Over the next 2 months, the lumen refilled again twice, which was treated with drainage and intra-articular dexamethasone injections (5 mg/ml, 1 ml). The cat underwent surgical cyst removal because of the recurrence, despite the subsiding inflammation measured by TNCC. After post-operative care, specific treatment for feline articular gout will be considered.

The common finding in all these case reports was the presence of needle-shaped material in the synovial fluid. They were all confirmed later as MSU crystals, showing characteristic negative birefringence on polarized microscopy (Figure 2H). Therefore, the final diagnosis of articular gout was made in all five cases. For further verification, we scraped the archived slides with MSU for scanning electron microscopy with energy-dispersive spectroscopy (SEM-EDS) analysis (Supplementary Figure 3). We confirmed that the observed crystals do not contain calcium (Ca, differentiation point from calcium pyrophosphate crystals) and have elements of MSU, carbon (C), nitrogen (N), oxygen (O), and sodium (Na).

In this case report, we highlighted the fact that articular gout does occur in dogs and cats. As far as we know, this is the first report to confirm it using polarized microscopy in the veterinary literature. The needle-shaped material should not be dismissed as artifacts but included in the arthritis diagnostic process. Medicine is a science aimed at diagnosing, treating, and preventing diseases, and we should not practice it only with algorithms of biased experience. Many mammals have idiopathic arthritis and immunosuppressive therapy may result in overtreatment of those who actually have gout (11, 23). We have provided strong evidence through demonstrating several cases with articular gout confirmed by polarized microscopy. Frontline clinicians should decide whether to apply this case report in practice to accurately diagnose and treat these mammals, or manage them as “idiopathic arthritis.”

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

H-SK drafted the manuscript. H-JH and H-JK edited the manuscript. SD confirmed the cases and revised the final submission. All authors contributed to the article and approved the submitted version.

This article was supported by Konkuk University in 2021.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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