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LEARNING OBJECTIVES

Extra-articular symptoms could be the first manifestation of gouty arthritis (GA); polyarticular GA can mimic an infectious arthritis; infection can complicate GA.

CASE

A 66-year-old male with a history of gout presented with high fever and excruciating bilateral calf pain for 1 day. Examination revealed chronic knee effusions; range of motion in both knees was limited by calf pain. Joint aspiration showed negatively birefringent intracellular crystals and normal gram stain.

HOSPITAL COURSE

While receiving empiric antibiotics fever continued and he developed bilateral knee, right ankle, and shoulder pain. After demonstration of urate crystals and exclusion of infection, antibiotics were discontinued and steroids initiated. Fever, calf pain, and polyarthritis quickly resolved.

DISCUSSION

Polyarticular gouty attack is an uncommon presentation of gout, and can mimic several other conditions. An exceptional presentation of this entity is excruciating calf pain, probably caused by tenosynovitis or referred pain preceding an acute polyarticular gouty attack.

Methods: Four male patients with chronic gout with tophi affecting the knee joints (three cases) or the olecranon processes of the elbows (one case) were assessed. Crystallographic analyses of the synovial fluid or tissue aspirates of the areas of interest were made with polarising light microscopy, alizarin red staining, and x ray diffraction. CT was performed with a GE scanner, MR imaging was obtained with a 1.5 T Magneton (Siemens), and ultrasonography with colour Doppler was carried out by standard technique.

Results: Crystallographic analyses showed monosodium urate (MSU) crystals in the specimens of the four patients; hydroxyapatite and calcium pyrophosphate dihydrate (CPPD) crystals were not found. A diffuse soft tissue thickening was seen on plain radiographs but no calcifications or ossifications of the tophi. CT disclosed lesions containing round and oval opacities, with a mean density of about 160 Hounsfield units (HU). With MRI, lesions were of low to intermediate signal intensity on T1 and T2 weighting. After contrast injection in two cases, enhancement of the tophus was seen in one. Colour Doppler US showed the tophi to be hypoechogenic with peripheral increase of the blood flow in three cases.

Conclusion: The MR and colour Doppler US images showed the tophi as masses surrounded by a hypervascular area, which cannot be considered as specific for gout. But on CT images, masses of about 160 HU density were clearly seen, which correspond to MSU crystal deposits.

Hypercalcemia has been widely associated with granulomatous processes. This is due to enhanced extra-renal conversion of calcidiol to calcitriol by activated macrophages within the granuloma. Symptomatic hypercalcemia due to granulomatous disorders is not common, with the incidence in sarcoidosis ranging from 10–20%. Large aggregates of monosodium urate crystals in patients with longstanding chronic tophaceous gout can serve as the inciting antigen for the development of granuloma, but hypercalcemia has not been described in this context. We report a case of symptomatic hypercalcemia due to gouty tophi induced granulomatous inflammation. Long term treatment with immunosuppressants, in addition to bisphosphonates and uric acid lowering therapy, has led to stabilization of serum calcium levels and other lab parameters indicative of granulomatous burden.

An association between urate gout and chondrocalcinosis has been suggested in several studies, but the situation remains ill-defined because of lack of appropriate controls, small numbers of patients studied, or retrospective investigation. An association has also been claimed between gout and avascular necrosis of the femoral head. 138 patients with gout and 142 non-gouty control subjects were carefully matched for age and x-rays were taken of the knees and pelvis. Chondrocalcinosis of the knees was detected in 8 patients with gout (5.8%), no cases being found in the control group. The difference is significant (P less than 0.025). Deposits were linear or irregular. Six of the 8 patients gave a history of acute synovitis of the knees; fluid had been aspirated in 2 of them, urate crystals being found in one and no crystals in the other. Six of 8 patients showed evidence of chondrocalcinosis elsewhere. No association was apparent between chondrocalcinosis and the presence of tophaceous deposits or renal impairment, though the duration of gout appeared to be longer in the patients with chondrocalcinosis than in the other gout patients and osteoarthrosis of the knees commoner. There was no evidence of other metabolic disorders commonly associated with chondrocalcinosis. No cases of avascular necrosis of the femoral head were found.

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Crystal deposition in asymptomatic knee and first metatarsophalangeal (MTP) joints has been studied in 31 patients with previously proven gout. All had had clinical gout in their MTP joints but their knee joints had never been the site of acute gout. Knee arthroscopy was performed permitting synovial membrane inspection, photography and biopsy. Crystalline material was seen in 9 knees (28%) and confirmed histologically as monosodium urate (MSU) in 4 (12.5%). Synovial fluid analysis on 26 samples using a polarizing light microscope demonstrated MSU crystals in 4 (12.5%) and calcium pyrophosphate dihydrate (CPPD) in 2 (6%). Fluid aspirated from 27 of the metatarsophalangeal joints revealed MSU crystals in 14 (52%) and no CPPD crystals.

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Ten cases of gouty arthritis are described in association with psoriasis. Eight were receiving intensive inpatient treatment for their skin condition. Diagnosis was based on clinical grounds or, in 3 cases, by compensated polarizing microscopy (CPM) of synovial fluid. All patients were male and 5 of them had conditions other than psoriasis known to predispose to hyperuricaemia. The patients appeared to fit into three groups: five had typical lower limb gout occurring in conjunction with long-standing extensive psoriasis; 3 patients had preceding features of inflammatory synovitis, one of whom subsequently developed typical distal interphalangeal involvement of peripheral psoriatic arthritis; two patients appeared to have coincident gout and psoriasis.

We believe that an association of gout with extensive long-standing psoriasis may exist particularly in male patients with an additional cause for hyperuricaemia. Long-term studies of a large population of psoriatics are required. Previous reports may have underestimated the incidence of gout because of failure to examine synovial fluid for crystals particularly from those patients with a subacute large joint arthropathy.

Objectives

To determine whether hypouricaemic treatment results in the disappearance of urate crystals from gouty joints and to define the time required.

Methods

In 18 patients with monosodium urate (MSU) crystal proven gout, and after the initiation of successful serum uric acid (SUA)‐lowering treatment, an arthrocentesis of the asymptomatic signal joint (11 knees, 7 first metatarsophalangeal joints) was performed every 3 months to obtain a synovial fluid (SF) sample. The sample was then analysed for the presence of MSU crystals, and the number of crystals/400× field was noted. SUA levels and the duration of gout were also noted.

Results

MSU crystals disappeared from the SF of all 18 joints after reduction of SUA to normal levels. The time required for disappearance ranged from 3 to 33 months; disappearance time correlated with the duration of gout (rs = 0.71; p<0.01). The median number of MSU crystals in the SF samples before urate‐lowering treatment was 7.5 (2.5–11) crystals/400× field, reducing to 3 (1–6.5) crystals/400× field (p<0.05) at 3 months. Crystal counts continued to decrease after 3 months.

Conclusions

In gout, reduction of SUA to normal levels results in disappearance of urate crystals from SF, requiring a longer time in those patients with gout of longer duration. This indicates that urate crystal deposition in joints is reversible. Normalisation of SUA levels results in a decrease in the concentration of MSU crystals in SF in the asymptomatic gouty joints. This may partially explain the reduced frequency of gouty attacks when a patient has been treated with SUA‐lowering drugs.

There are many exciting new applications for advanced imaging in gout. These modalities employ multiplanar imaging and allow computerized three-dimensional rendering of bone and joints (including tophi) and have the advantage of electronic data storage for later retrieval. High-resolution computed tomography has been particularly helpful in exploring the pathology of gout by investigating the relationship between bone erosions and tophi. Magnetic resonance imaging and ultrasonography can image the inflammatory nature of gouty arthropathy, revealing synovial and soft tissue inflammation, and can provide information about the composition and vascularity of tophi. Dual-energy computerized tomography is a new modality that is able to identify tophi by their chemical composition and reveal even small occult tophaceous deposits. All modalities are being investigated for their potential roles in diagnosis and could have important clinical applications in the patient for whom aspiration of monosodium urate crystals from the joint is not possible. Imaging can also provide outcome measures, such as change in tophus volume, for monitoring the response to urate-lowering therapy and this is an important application in the clinical trial setting.

Objectives

To assess concordance of the management of chronic gout in UK primary care with the European League Against Rheumatism (EULAR) gout recommendations.

Methods

A postal questionnaire was sent to all adults aged >30 years registered with two general practices. Patients with possible gout attended for clinical assessment, at which the diagnosis was verified clinically. Aspects of chronic gout management, including provision of lifestyle modification advice, use of urate‐lowering therapies (ULT) including dose titration to serum urate (SUA) level, prophylaxis against acute attacks, and diuretic cessation were assessed in accordance with the EULAR recommendations.

Results

Of 4249 (32%) completed questionnaires returned, 488 reported gout or acute attacks and were invited for clinical assessment. Of 359 attendees, 164 clinically confirmed cases of gout were identified. Advice regarding alcohol consumption was recalled by 59 (41%), weight loss by 36 (25%) and diet by 42 (29%). Allopurinol was the only ULT used and was taken by 44 (30%); 31 (70%) were taking 300 mg daily. Mean SUA was lower in allopurinol users than non‐users (318 vs 434 μmol/l) and was less often >360 μmol/l in allopurinol users (23% vs 75%). Eight patients had recently commenced allopurinol; two of these also were taking prophylactic colchicine or non‐steroidal anti‐inflammatory drugs. Of 25 patients with diuretic‐induced gout, 16 (64%) were still taking a diuretic.

Conclusion

Treatment of chronic gout is often suboptimal and poorly concordant with EULAR recommendations. Lifestyle advice is infrequently offered, and allopurinol is restricted to a minority. Persistent hyperuricaemia was often seen in allopurinol non‐users, but was also in allopurinol users, suggesting that doses >300 mg are often necessary.

Gout is an autoinflammatory disorder associated with deposition of monosodium urate (MSU) crystals in joints and periarticular tissues. Recent advances suggest that the innate immune system may drive the gouty inflammatory response to MSU. These findings prompt questions concerning how the innate immune system recognizes MSU and the identities of the receptors involved. In this issue of the JCI, Chen et al. show that the IL-1 receptor and its signaling protein myeloid differentiation primary response protein 88 (MyD88) but not the “classical” innate immune receptors, TLRs, are central for MSU-induced inflammation (see the related article beginning on page 2262).

OBJECTIVE: To establish if computed tomography (CT) imaging, which has proved helpful in detecting intra-articular tophi in gout, can also be used to document gouty enthesopathy and tendinopathy. METHODS: Three patients with tophaceous gout and clinical involvement of the Achilles tendon (two cases) or patellar tendon (one case) were assessed with CT examination and plain radiographs. RESULTS: In the first two cases, CT images revealed linear or nodular high attenuation opacities within the substance of the Achilles tendons and their calcaneal insertion. In case 3, dense linear opacities were seen within the patellar tendon and within its tibial insertion. No such opacities of the tendons and entheses were seen on standard radiographs of these patients. CONCLUSIONS: CT appears to be the imaging method of choice for demonstrating monosodium urate deposits in entheses and tendons in tophaceous gout.

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Background

Gout is a prevalent inflammatory arthritis affecting 1–2% of adults characterized by activation of innate immune cells by monosodium urate (MSU) crystals resulting in the secretion of interleukin-1β (IL-1β). Since neutrophils play a major role in gout we sought to determine whether their activation may involve the formation of proinflammatory neutrophil extracellular traps (NETs) in relation to autophagy and IL-1β.

Methodology/Principal Findings

Synovial fluid neutrophils from six patients with gout crisis and peripheral blood neutrophils from six patients with acute gout and six control subjects were isolated. MSU crystals, as well as synovial fluid or serum obtained from patients with acute gout, were used for the treatment of control neutrophils. NET formation was assessed using immunofluorescence microscopy. MSU crystals or synovial fluid or serum from patients induced NET formation in control neutrophils. Importantly, NET production was observed in neutrophils isolated from synovial fluid or peripheral blood from patients with acute gout. NETs contained the alarmin high mobility group box 1 (HMGB1) supporting their pro-inflammatory potential. Inhibition of phosphatidylinositol 3-kinase signaling or phagolysosomal fusion prevented NET formation, implicating autophagy in this process. NET formation was driven at least in part by IL-1β as demonstrated by experiments involving IL-1β and its inhibitor anakinra.

Conclusions/Significance

These findings document for the first time that activation of neutrophils in gout is associated with the formation of proinflammatory NETs and links this process to both autophagy and IL-1β. Modulation of the autophagic machinery may represent an additional therapeutic study in crystalline arthritides.

The prevalence of gout is increasing with increased life expectancy. Approximately half of the patients with gout have some degree of renal impairment. If both conditions persistently coexist, and in severe tophaceous gout, in particular, treatment has been difficult. We here report on the case of an 87-year-old woman, who had been suffering from recurrent gouty arthritis over 4 years. Monthly polyarthritis attacks were accompanied by subcutaneous tophi. Serum uric acid levels were constantly above 600 μmol/L (10 mg/dL). Allopurinol was no option because of intolerance, while benzbromarone was ineffective because of renal impairment. Therefore, the novel xanthin oxidase inhibitor febuxostat was started, achieving rapid control of serum urate levels (<360 μmol/L). After initial worsening of inflammation in the first weeks, gouty attacks stopped and all tophi resolved within the following 10 months. Renal function remained stable.

The cervical spine is a rare site where tophaceous gout has been identified. There are currently 15 described cases in the literature of gouty involvement of the cervical spine with only three cases involving only the atlanto-axial region. We add the fourth of such cases and only the second to be managed operatively.

Introduction

Gout is a common inflammatory arthritis caused by articular precipitation of monosodium urate crystals. It usually affects the first metatarsophalangeal joint of the foot and less commonly other joints, such as wrists, elbows, knees and ankles.

Case presentation

We report the case of a 75-year-old Caucasian man with tophaceous multiarticular gout, soft-tissue involvement and ulcerated tophi on the first metatarsophalangeal joint of the left foot, on the first interphalangeal joint of the right foot and on the left thumb.

Conclusion

Ulcers due to tophaceous gout are currently uncommon considering the positive effect of pharmaceutical treatment in controlling hyperuricemia. Surgical treatment is seldom required for gout and is usually reserved for cases of recurrent attacks with deformities, severe pain, infection and joint destruction.

In five patients with acute arthritis in whom gout was eventually documented, an initial synovial fluid analysis failed to reveal urate crystals. Four of the patients were seen in one hospital during a period of 30 months in which 103 cases of gout were documented on initial aspiration. While this is an uncommon event, the importance of being able to make a definitive diagnosis of gout is such that re-aspiration of the same or other joints may be justified under certain circumstances.

Gouty arthritis is a characteristically intense acute inflammatory reaction that erupts in response to articular deposits of monosodium urate (MSU) crystals. Important recent molecular biologic advances in this field have given us a clear picture of the mechanistic basis of gouty inflammation. The innate immune inflammatory response is critically involved in the pathology of gout. Specifically, MSU crystals promote inflammation directly by stimulating cells via Toll-like receptor signaling and by providing a surface for cleavage of C5 and formation of complement membrane attack complex (C5b-9), culminating in secretion of cytokines, chemokines, and other inflammatory mediators with a dramatic influx of neutrophils into the joint. Despite the detailed mechanistic picture for gouty inflammation, there are no placebo-controlled, randomized clinical studies for any of the therapies commonly used, although comparative studies have demonstrated that many nonsteroidal anti-inflammatory drugs are equivalent to indomethacin with respect to controlling acute gouty attacks. In general, the first line of anti-inflammatory therapy for acute gout is nonsteroidal anti-inflammatory drugs, and the selective cyclo-oxygenase-2 inhibitor celecoxib can be used where appropriate. The second line of treatment is glucocorticosteroids, given systemically (oral, intravenous, or intramuscular) or intra-articularly. Alternatively, synthetic adrenocorticotropic hormone is effective, partly via induction of adrenal glucocorticosteroids and partly via rapid peripheral suppression of leukocyte activation by melatonin receptor 3 signaling. The third line of treatment is oral colchicine, which is highly effective when given early in an acute gouty attack, but it is poorly tolerated because of predictable gastrointestinal side effects.

Understanding how uric acid crystals provoke inflammation is crucial to improving our management of acute gout. It is well known that urate crystals stimulate monocytes and macrophages to elaborate inflammatory cytokines, but the tissue response of the synovium is less well understood. Microarray analysis of mRNA expression by these lining cells may help to delineate the genes that are modulated. Employing a murine air-pouch model, a number of genes expressed by innate immune cells were found to be rapidly upregulated by monosodium urate crystals. These findings provide new research avenues to investigate the physiopathology of gouty inflammation, and may eventually lead to new therapeutic targets in acute gout.

In the past few decades, gout has increased not only in prevalence, but also in clinical complexity, the latter accentuated in part by a dearth of novel advances in treatments for hyperuricemia and gouty arthritis. Fortunately, recent research reviewed here, much of it founded on elegant translational studies of the past decade, highlights how gout can be better managed with cost-effective, well-established therapies. In addition, the advent of both new urate-lowering and anti-inflammatory drugs, also reviewed here, promises for improved management of refractory gout, including in subjects with co-morbidities such as chronic kidney disease. Effectively delivering improved management of hyperuricemia and gout will require a frame shift in practice patterns, including increased recognition of the implications of refractory disease and frequent noncompliance of patients with gout, and understanding the evidence basis for therapeutic targets in serum urate-lowering and gouty inflammation.

Two gouty patients developed bullae containing massive numbers of monosodium urate crystals. Both patients had had treatment with systemic corticosteroids. A burn precipitated one bulla, showing that local tissue injury can be a factor in tophus localization.

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The plasma levels of the urate-binding α1-α2-globulin, as determined by its urate-binding capacity, have been recorded in 19 individuals from two gouty kindreds. A significantly reduced binding capacity, accounting for 13-30% of the mean value obtained in healthy, unrelated control subjects, was found in all cases of gout and in the single case of essential hyperuricemia included in the present study. In addition, six apparently healthy members of one of these kindreds also exhibited this characteristic. The distribution of the characteristic in three subsequent generations from this kindred further supported the hypothesis that the reduced binding capacity was inherited as an autosomal trait for which affected subjects were heterozygous.

Based on the present observation, the mechanisms of inheritance in primary gout are discussed with special emphasis on the possible cooperation of genetic and environmental factors.

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Purpose of review

Growing awareness of patients with refractory gout is prompting a reassessment of treatment strategy. This article reviews the current practice of targeting serum urate concentrations (sUA) in the mid-normal range (roughly 4–6 mg/dL), and considers the rationale for more aggressively lowering sUA in patients with poorly controlled chronic gout. Some hypothetical concerns with inducing hypouricemia are considered, and relevant clinical evidence is evaluated.

Recent findings

Recent studies confirm the benefits of modestly reducing sUA in many gout patients. However, tophi and tissue stores of monosodium urate crystals resolve slowly, particularly in patients with longstanding disease. Consistent with physicochemical principles, the rate of decrease in tophus size increases with a reduction in sUA concentration over a broad range. Reducing sUA to near or below 2 mg/dL can be achieved in some patients with current urate lowering drugs, but new drugs now under investigation may be more effective. As a free radical scavenger, uric acid has been postulated to protect from oxidative stress. However, inherited disorders associated with profound, lifelong hypouricemia indicate that maintaining sUA near or below 2 mg/dL would probably be safe.

Summary

Targeting low sUA could improve the elimination of tissue urate stores and achieve better control of disease in patients with refractory gout.

Recent studies have confirmed that gout is an inborn error of metabolism. It has now become evident that the hyperuricemia associated with gout might occur either due to overproduction of uric acid, underexcretion of uric acid or a combination of these processes. Furthermore, patients with excessive purine synthesis may have a specific enzyme defect resulting in altered feedback inhibition of purine synthesis. A neurological disease manifest by mental retardation, choreo-athetosis, aggressive behavior, lip-biting and self-mutilation and associated with decidedly increased purine biosynthesis serves as a prototype of this kind of disorder. Other defects in regulation of purine biosynthesis have been postulated but their existence not yet confirmed.

It has been demonstrated that urate crystals which are deposited from hyperuricemic body fluids set up an acute inflammatory reaction by means of a variety of chemical mediators. Thus, acute gouty arthritis is now recognized as an example of “crystal induced” synovitis.

The treatment of gout consists of (1) the control of acute gouty attacks, and (2) the maintenance of normal serum uric acid concentrations. This latter may be achieved either with uricosuric drugs or with xanthine oxidase inhibition. With these principles in mind, it is now possible to avoid many of the severe crippling effects of gout and to restore the vast majority of gouty patients to useful and productive lives.

OBJECTIVES—Insulin resistance (IR) has been increasingly implicated in the pathogenesis of gout. The lipoprotein abnormalities described in hyperuricaemic subjects are similar to those associated with IR, and insulin influences renal urate excretion. In this study it was investigated whether dietary measures, reported to be beneficial in IR, have serum uric acid (SU) and lipid lowering effects in gout.
METHODS—Thirteen non-diabetic men (median age 50, range 38-62) were enrolled. Each patient had had at least two gouty attacks during the four months before enrolment. Dietary recommendations consisted of calorie restriction to 6690 kJ (1600 kcal) a day with 40% derived from carbohydrate, 30% from protein, and 30% from fat; replacement of refined carbohydrates with complex ones and saturated fats with mono- and polyunsaturated ones. At onset and after 16 weeks, fasting blood samples were taken for determination of SU, serum cholesterol (C), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides (TGs). Results were expressed as median (SD).
RESULTS—At onset, the body mass index (BMI) was 30.5 (8.1) kg/m2. Dietary measures resulted in weight loss of 7.7 (5.4) kg (p=0.002) and a decrease in the frequency of monthly attacks from 2.1 (0.8) to 0.6 (0.7) (p=0.002). The SU decreased from 0.57 (0.10) to 0.47 (0.09) mmol/l (p=0.001) and normalised in 7 (58%) of the 12 patients with an initially raised level. Serum cholesterol decreased from 6.0 (1.7) to 4.7 (0.9) mmol/l (p=0.002), LDL-C from 3.5 (1.2) to 2.7 (0.8) mmol/l (p=0.004), TGs from 4.7 (4.2) to 1.9 (1.0) mmol/l (p=0.001), and C:HDL-C ratios from 6.7 (1.7) to 5.2 (1.0) (p=0.002). HDL-C levels increased insignificantly. High baseline SU, frequency of attacks, total cholesterol, LDL-C and TG levels, and total C:HDL-C ratios correlated with higher decreases in the respective variables upon dietary intervention (p<0.05).
CONCLUSION—The results suggest that weight reduction associated with a change in proportional macronutrient intake, as recently recommended in IR, is beneficial, reducing the SU levels and dyslipidaemia in gout. Current dietary recommendations for gout may need re-evaluation.



OBJECTIVE--To define the clinical characteristics of gout and determine if there were any genetic associations with gout in black South Africans. METHODS--The records of 107 patients with gout seen over a five year period were retrospectively analysed. The HLA class I and class II antigens were studied in a prospective survey of 46 patients. RESULTS--The male to female ratio was 6.6:1. The diagnosis of gout was based on identification of monosodium urate crystals from the synovial fluid, synovial tissue or tophaceous material in 62 patients (58%) and on clinical criteria in the remaining 45 patients (42%). The mode of presentation was monoarthritis in 40 patients (37.4%), pauciarthritis in 30 (28%) and polyarthritis in 37 (34.6%). The joints which were most frequently involved were the knee in 91 patients (85%), the first metatarsophalangeal in 80 (74.8%) and the ankle in 66 (61.7%). A secondary cause was identified in 52 patients (48.6%) (diuretic therapy in 48 patients and chronic renal impairment in four); 55 patients (51.4%) had primary gout. The genetic study showed an increased frequency of HLA-B14 in patients with primary gout compared with controls. CONCLUSIONS--Gout is more common in black Africans than previously recognised and frequently presents with involvement of more than one joint. There was an increased frequency of HLA-B14 in patients with primary gout but the clinical significance of this is uncertain.