Monosodium urate crystals in the knee joints of patients with asymptomatic nontophaceous gout

We aspirated synovial fluid from the knees of 50 patients with asymptomatic, nontophaceous gout, in whom synovial fluid monosodium urate (MSU) crystals had previously been documented in the knees or other joints. Fifty-eight percent of these asymptomatic patients had MSU crystals in their knee joints. Serum uric acid levels, serum creatinine levels, volume of synovial fluid aspirated, and cell counts of the aspirated fluid did not differentiate the MSU crystal-positive group from the group without MSU crystals. Clinical factors such as alcohol abuse, coronary heart disease, hypertension, duration of gout, duration of the intercritical period, and drug therapy did not differentiate the 2 groups. Nineteen patients consented to aspiration of their other knee. Seven of these patients (37%) had MSU crystals bilaterally, and 6 patients (32%) had them unilaterally. The implications of the persistence of MSU crystals (including those in intracellular locations) in many patients, despite normalization of serum uric acid levels, should be determined. Knee joint aspiration is a sensitive method for the demonstration of MSU crystals in asymptomatic patients. The procedure might also be useful in documenting these crystals in patients who have had attacks of arthritis with features consistent with a diagnosis of gout, but in whom MSU crystals have not been documented.     

Regulation of osteoclast development by Notch signaling directed to osteoclast precursors and through stromal cells

Osteoclasts are derived from hematopoietic precursor cells belonging to the monocyte/macrophage lineage. Osteoclast development has been reported to be regulated by several molecules such as macrophage colony-stimulating factor (M-CSF), receptor activator of nuclear factor (NF)-kappaB ligand (RANKL), and a decoy receptor of RANKL, osteoprotegerin (OPG). Recently, it was demonstrated that the Notch signaling pathway regulates myeloid differentiation and antagonizes cell fate determination, however, the effect of Notch signaling on the osteoclast lineage has not been reported. In this study, we examined the effect of signaling via Notch receptors on the differentiation into osteoclasts by using cells from the bone marrow, spleen, and peritoneal cavity, and a cloned macrophagelike cell line. Osteoclastogenesis was inhibited by an immobilized Notch ligand, Delta-1. The dish-adherent bone marrow cells precultured with M-CSF expressed both Mac-1 and M-CSF receptors, c-Fms; osteoclastogenesis of these cells was efficiently inhibited. The immobilized Delta-1 also down-regulated the surface c-Fms expression, while the c-Fms gene expression was not changed. Genes for Notch receptors and Notch ligands are expressed in not only hematopoietic cells but also stromal cells that support osteoclast development. Constitutively active Notch1-transfected stromal cells showed increased expression of RANKL and OPG genes, and strong inhibition of M-CSF gene expression, resulting in reduction of their ability to support osteoclast development. Taken together, these findings indicate that Notch signaling affects both osteoclast precursors and stromal cells and thereby negatively regulates osteoclastogenesis.     

Studies on the interaction of rheumatoid factor with monosodium urate crystals and case report of coexistent tophaceous gout and rheumatoid arthritis.

Gout and classical rheumatoid arthritis rarely coexist. We report a patient with strong evidence for both these diseases. Possible reasons for the negative correlation between these diseases are summarised. One hypothesis suggests inhibition of surface activity of monosodium urate crystals (MSU) by binding of rheumatoid factor (RF). This was studied with a purified monoclonal rheumatoid factor (mRF) with specificity for IgG. The mRF bound preferentially to MSU coated with IgG in contrast with the IgM control. Inhibition of the neutrophil chemiluminescence (CL) response to IgG-coated MSU was observed at concentrations of mRF that had no effect on the CL response to uncoated crystals. Neutrophil activation was not altered by coating crystals with an IgM control at the same concentration. These data suggest that RF may bind to antigenic determinants on exposed Fc of adsorbed IgG and block the interaction of crystal-bound IgG with Fc receptors. Although crystal coating by RF may modify the expression of gouty arthritis, it is unlikely to be the sole explanation for the dissociation between gout and RA.     

痛风患者足踝双能CT尿酸盐结晶沉积特点分析

目的 应用双能CT分析关节周围尿酸盐结晶沉积特点,预测与痛风性关节炎急性发作相关的解剖和形态学特征.方法 选择近期足踝部发作过关节肿和(或)痛患者84例(其中确诊痛风患者68例,无症状高尿酸血症患者1 1例,单纯其他类型关节炎患者5例),入选患者均完成足踝部双能CT检查.应用x2检验及Logistic回归模型分析尿酸盐结晶沉积的解剖、形态学特征与关节炎症急性发作的关系.结果 痛风组共发现278处尿酸盐结晶,最常出现结晶沉积的部位依次为第一趾中远端(18.2％)、第一跖趾关节(16.8％)、跟骨(17.5％)、胫骨下端(11.8％),无症状高尿酸血症组发现34处尿酸盐结晶沉积,分布趋势与痛风组相似.对患者结晶沉积部位与关节炎症急性发作情况进行分析后发现,第一跖趾关节(x2=8.47,P＜0.01)及胫骨下端(x2=3.93,P＜0.05)出现结晶沉积的患者临床上更易出现相应部位关节炎的急性发作.且第一跖趾关节附近的尿酸盐结晶如果沉积于肌腱(x2=5.03,P＜0.05)或软组织(x2=5.19,P＜0.05)中,更易引起痛风性关节炎;而对于踝关节周围的尿酸盐结晶,如果其沉积于踝关节伸面(x2=4.42,P＜0.05)或呈点状(x2=4.76,P＜0.05)或为多个(x2=4.97,P＜0.05)则更易出现关节炎症发作.并且Logistic多元回归分析结果也提示,痛风性关节炎急性发作有潜在的危险因素.结论 双能CT可以清晰显示尿酸盐结晶,有助于痛风的诊断及随防研究.尿酸盐结晶沉积的部位、形状、大小、数量以及受累部位是否伴有软组织肿胀、骨侵蚀等因素,对痛风性关节炎的急性发作有影响.     

Persistence of monosodium urate crystals and low-grade inflammation in the synovial fluid of patients with untreated gout

Synovial fluid (SF) from 74 asymptomatic knees of patients with gout was analyzed. These patients had never been treated with serum uric acid-lowering agents. SF samples were analyzed for the presence of crystals and for cell counts, using undiluted SF directly in a Niebauer cell counting chamber. Thirty-seven of the aspirated knees had previously been inflamed, and monosodium urate (MSU) crystals were seen in SF aspirates from 36 of them (97%). Of the 37 knees that had never been inflamed, only 8 contained MSU crystals (P less than 0.00001). After reaching the joint, MSU crystals will persist in the SF as long as the serum uric acid level has not been lowered by appropriate treatment. In this situation, analysis of SF is an excellent diagnostic test for the intercritical gout. The mean cell count in the 44 SF samples that contained MSU crystals was 449/mm3 (95% confidence interval 310-589); the mean cell count in the 30 SF without MSU crystals was 64/mm3 (95% confidence interval 34-95) (P less than 0.00002). The SF samples that contained MSU crystals also had a higher percentage of polymorphonuclear leukocytes than those without MSU crystals (P less than 0.002). These data suggest that there is a low-grade inflammation present in the knees of patients with MSU crystals, the consequences of which should be investigated.     

Measurement of health-related quality of life and functional capacity in patients with chronic tophaceous gout

IntroductionIn gout there are few instruments validated for the evaluation of activity, functional capacity or quality of life. It is not known if generic instruments such as the MOS-20, or specific for other illnesses, such as the AIMS, can be applied to patients with Gout.ObjectiveTo evaluate the clinimetric characteristic of the MOS-20 and AIMS questionnaires, and their correlation with HAQ-DI, as well as with clinical variables in patient with tophaceous gout (TG).Methods49 patients with TG were included. Demographic and clinical variables were obtained. The 3 questionnaires were applied at the basal evaluation. A second evaluation was applied to 20 patients, 8 weeks later.ResultsAll patients were male. The time of since onset of the illness was 14.9±8.3 years. The HAQ-DI was 0.43±0.56 with an alpha of Cronbach (αC) of 0.95 and the intraclass correlation coefficient (ICC) was 0.86. The MOS-20 had an αC of 0.68 to 1.0 and a ICC of 0.27 to 0.61 between the several components. The AIMS had an αC of 0.66 to 0.96, and a ICC of 0.11 to 0.79 between the several components. Reliability was better between the physical components in MOS-20 and AIMS. The MOS-20, AIMS and the HAQ-DI correlated with the presence of joints with functional limitation. There weren’t any significant differences among the patients with inflamed joints, nor in those with tophi. The HAQ-DI was best correlated with the physical component than with the mental component of the AIMS and the MOS-20.ConclusionThe AIMS, the MOS-20 and the HAQ-DI are useful in measuring the functional capacity and the quality of life in patient with TG.     

双源CT双能量成像在痛风患者尿酸盐沉积结晶中的诊断价值

目的探讨双源CT(DECT)双能量成像诊断痛风患者尿酸盐沉积结晶的临床效果。方法对90例疑似痛风的患者行DECT检查及病变部位穿刺活检检查,观察DSCT检测痛风性尿酸盐沉积的特异性、敏感性、假阳性率、假阴性率、阳性预测值及阴性预测值,并对病变发生部位作统计。结果 (1)DECT检测痛风性尿酸盐沉积的的敏感性为95.23%,特异性为91.66%,假阴性率为4.76%,假阳性率为8.33%,阳性预测值为90.90%,阴性预测值为95.65%;(2)本研究应用DECT所检出的44例痛风尿酸盐沉积结晶患者共发现结晶沉积132处,部位在双足58处,占43.9%;双膝50处,占37.9%;双手22处,占16.7%;双肘2处,占1.5%。结论 DECT能够准确快捷地对痛风患者尿酸盐沉积结晶做出诊断,可作为临床筛查痛风病的重要辅助检查之一。     

Dual energy computed tomography for quantification of tissue urate deposits in tophaceous gout: help from modern physics in the management of an ancient disease

Gout has been recognized for centuries but is also a modern day scourge. It is the most common type of inflammatory arthritis in men and appears to be increasing in both incidence and prevalence (Arromdee et al. in J Rheumatol 29(11):2403–2406, 2002). Despite these facts, few advances have been made in the diagnosis and treatment of gout for over 50 years. Difficult cases of gout challenge available therapeutic options. It is only recently that the Food and Drug Administration has approved febuxostat as a treatment option for patients intolerant of allopurinol. We describe a difficult case of tophaceous gout notable for several reasons: utilization of rasburicase as uricolytic treatment to dramatically reduce tissue urate burden; treatment of gout flares with interleukin-1β inhibition; and quantification of tissue urate with novel dual energy computed tomography technology before and after uricolytic therapy.     

Pharmacokinetics and pharmacodynamics of intravenous PEGylated recombinant mammalian urate oxidase in patients with refractory gout

OBJECTIVE: To evaluate the efficacy, immunogenicity, and tolerability of intravenous (IV) PEGylated recombinant mammalian urate oxidase (PEG-uricase) for the treatment of severe gout. METHODS: Single infusions of PEG-uricase (at doses ranging from 0.5 mg to 12 mg) were administered to 24 patients (6 cohorts of 4 patients each) in a phase I clinical trial. Plasma uricase activity (pUox), the plasma urate concentration (pUAc), and the uric acid-to-creatinine ratio (UAc:Cr) in urine were monitored for 21 days after dosing. Adverse events and the IgG antibody response to PEG-uricase were followed up for 35 days. RESULTS: All patients completed the trial. Maximum pUox was linearly related to the IV dose of PEG-uricase, the area under the curve (AUC) value increased linearly (up to a dose of 8 mg), and the pUox half-life was 6.4-13.8 days. After doses of 4-12 mg, the pUAc fell within 24-72 hours, from a mean +/- SD value of 11.1 +/- 0.6 mg/dl to 1.0 +/- 0.5 mg/dl; the AUC value for the pUAc was equivalent to maintaining the pUAc at 1.2-4.7 mg/dl for 21 days postinfusion. The UAc:Cr ratio in urine fell in parallel with the pUAc. IgG antibodies to PEG-uricase, mostly IgG2 and specific for PEG, developed in 9 patients, who had more rapid enzyme clearance but no allergic reactions. All adverse events were mild to moderate, with gout flares being most common. CONCLUSION: The bioavailability, efficacy, and tolerability of IV PEG-uricase were greater than the bioavailability, efficacy, and tolerability observed in a previous phase I trial of subcutaneous PEG-uricase. Infusing 4-12 mg of PEG-uricase every 2-4 weeks should maintain the pUAc well below the therapeutic target of 6 mg/dl and greatly reduce renal uric acid excretion. This treatment could be effective in depleting expanded tissue urate stores in patients with chronic or tophaceous gout.     

Impaired arterial responsiveness in untreated gout patients compared with healthy non-gout controls: association with serum urate and C-reactive protein

To determine whether arterial responsiveness is impaired among patients with gout, and whether arterial responsiveness inversely correlates with serum urate and inflammatory measures. This is a cross-sectional study of untreated gout subjects (n?=?34) and non-gout healthy controls (n?=?64). High-resolution dynamic ultrasound-measured flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD) assessed endothelium-dependent and endothelium-independent arterial responsiveness respectively. Serum urate (sUA) and high-sensitivity C-reactive protein (hsCRP) were measured in the gout group, and correlated with FMD and NMD responses. Both FMD (2.20?±?0.53 vs 3.56?±?0.31, p?=?0.021) and NMD (16.69?±?1.54 vs 24.51?±?0.90, p?=?0.00002) were impaired in the gout versus control group. Stratification for individual comorbidities suggested that no single risk factor accounted for impaired FMD/NMD in the gout subjects. However, the degree of association between gout and FMD, but not NMD impairment, was dampened after multivariable adjustment (FMD unadjusted beta?=???1.36 (SE 0.58), p?=?0.02; adjusted beta?=???1.16 (SE 0.78), p?=?0.14 and NMD unadjusted beta?=???7.68 (SE 1.78), p?<?0.0001; adjusted beta?=???5.33 (SE 2.46), p?=?0.03). Within the gout group, there was an inverse correlation between FMD and sUA (R?=???0.5, p?=?0.003), and between FMD and hsCRP (R?=???0.42, p?=?0.017), but not between NMD and sUA or hsCRP. Compared with healthy controls, subjects with gout have reduced arterial function. Individual comorbidities are insufficient to account for differences between gout and control groups, but multiple comorbidities may collectively contribute to impairment in endothelium-dependent arterial responsiveness. Endothelial impairment is also related to sUA and hsCRP, markers of gout severity and inflammation respectively. Studies to determine whether gout therapy may improve arterial responsiveness are warranted.     

Calcium pyrophosphate and monosodium urate crystal interactions with neutrophils: effect of crystal size and lipoprotein binding to crystals

"Small" (between 75-98% of crystals less than or equal to 10 microns) and "large" (between 81-93% of crystals greater than 10 microns) size fractions of monosodium urate monohydrate (MSUM) and calcium pyrophosphate dihydrate triclinic (CPPD) crystals were incubated with human neutrophils and crystal induced neutrophil cytolysis monitored by measuring the release of lactate dehydrogenase. "Small" size fractions of MSUM and CPPD gave higher percent lysis values than "large" crystals. The binding of high density lipoproteins (HDL) and low density lipoproteins (LDL) to the crystals was quantitated. HDL and LDL bound in significant amounts to both CPPD and MSUM and strongly inhibited CPPD and MSUM induced neutrophil cytolysis. We propose that HDL and LDL bound to MSUM and CPPD may play important roles in the regulation of gouty inflammation.     

Reciprocal control of expression of mRNAs for osteoclast differentiation factor and OPG in osteogenic stromal cells by genistein: evidence for the involvement of topoisomerase II in osteoclastogenesis.

Osteoclast-like cells, in cocultures with mouse spleen cells and clonal osteogenic stromal ST2 cells, are formed from spleen cells with monocyte/macrophage lineage in response to a combination of osteoclast differentiation factor (RANKL) and OPG, a decoy receptor for RANKL, produced by ST2 cells in response to 1alpha,25-dihydroxyvitamin D(3). Treatment of ST2 cells with the natural isoflavonoid genistein for 6 h before coculture with spleen cells inhibited the formation of tartrate-resistant acid phosphatase-positive osteoclast-like cells. When we measured levels of RANKL mRNA in ST2 cells, we found that genistein decreased the level of this mRNA. By contrast, the level of OPG mRNA was enhanced by genistein. Genistein is a specific inhibitor of topoisomerase II (topo II) and an inhibitor of protein tyrosine kinase, as well as being a potent phytoestrogen. To characterize the mode of action of genistein, we examined the effects of an inactive form of genistein (daidzein), 17beta-estradiol, inhibitors of topo II, and inhibitors of tyrosine kinases on the formation of tartrate-resistant acid phosphatase-positive osteoclast-like cells. Among the compounds tested, two inhibitors of topo II, amsacrine and etoposide, attenuated the formation of osteoclast-like cells via reciprocal regulation of the expression of mRNAs for RANKL and OPG in ST2 cells, acting similarly to genistein. Our findings indicate that genistein might inhibit the formation of osteoclast-like cells via inhibition of the activity of topo II, suggesting the novel possibility that topo II might play an important role in osteoclastogenesis.     

Temporal evolution of urate crystal deposition over articular cartilage after successful urate-lowering therapy in patients with gout: An ultrasonographic perspective

Objective: To detect evolution of ultrasonographic signs of deposition of monosodium urate crystals (MSUC) in gouty joints by serial ultrasonography after initiation of urate-lowering therapy (ULT).

Methods: Adult gout patients were examined by serial ultrasonography after initiation of ULT with target serum uric acid (SUA) Results: Thirty-eight male patients with gout with mean age of 50?±?11?years, median disease duration of 48 months and baseline mean SUA level of 8.8?±?1.5?mg/dL were recruited. Ultrasonographic evidence of MSUC deposition was detected in 89.74% of first metatarsophalangeal (MTP) joints and 27.63% of knee joints. Double contour sign (DCS), tophi, and hyperechoic spots (HES) were detected in 77.63%, 43.42%, and 19.74% of first MTPs, respectively. SUA level normalizes and plateaus after fourth month of follow-up. DCS thickness reduced significantly throughout the follow-up period. Overall, 86.25% DCS and 100% HES disappeared with median time of 6 months and 5.7 months, respectively. SUA normalization was the only significant predictor of DCS disappearance.

Conclusions: Serial ultrasonographic determination of DCS, tophi, or HES during hypouricemic therapy is a noninvasive, effective method to detect the lowering of burden of urate load in gouty joints.