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Rheum Dis Clin N Am 32 (2006) ix

Erratum

Erratum to ‘‘New Therapeutics in Rheumatoid Arthritis’’ [Rheum Dis Clin N Am 32 (1) (2006) 57-74]
Christine Savage, MD, E. William St. Clair, MDT
Duke University Medical Center, Durham, NC, USA

In the February 2006 issue of Rheumatic Disease Clinics of North America, an incorrect drug dosage was printed. On page 66 in the article ‘‘New Therapeutics in Rheumatoid Arthritis,’’ the correct dosage for rituximab should be 1000 mg intravenously once on days 1 and 15.

DOI of original article title 10.1016/j.rdc.2005.10.004. * Corresponding author. E-mail address: stcla003@mc.duke.edu (E.W. St. Clair). 0889-857X/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.rdc.2006.05.009 rheumatic.theclinics.com

Rheum Dis Clin N Am 32 (2006) xi – xii

Preface

Gout

Hyon Choi, MD, DrPH, FRCPC Guest Editor

Crystal deposition arthropathy continues to be one of the most common inflammatory rheumatic disorders that constitutes significant public health problems. These problems are anticipated to grow in scope in view of the growing elderly population worldwide and increasing prevalence of risk factors for these disorders. There have been many exciting recent developments in crystal arthropathy research, and the current issue of Rheumatic Disease Clinics of North America intends to summarize these data and put them into context. First, recent epidemiologic data are reviewed, including the overall disease burden and modifiable risk factors of gout, which have implications for the prevention and management of this painful condition. An article discusses the major chronic disorders associated with hyperuricemia or gout and acknowledges the ongoing research and debate on their independent pathogenetic links. Recent elucidation of molecular mechanisms of urate crystal–induced inflammation and renal urate transport mechanisms is reviewed in two articles, both of which represent substantial advancement in our pathogenetic understanding with potential therapeutic implications. Two articles review therapeutic approaches for crystal deposition arthropathy: one for overall therapeutic modalities, including history and recent advances, and the other for all relevant human clinical trials, including trials of the new potent agents in development. Specific to calcium deposition diseases, one article updates their overall pathogenesis and clinical manifestations. Two separate articles review the potential pathogenetic roles of calcium deposition on other major disorders in a balanced
0889-857X/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.rdc.2006.04.002 rheumatic.theclinics.com

FRCPC Division of Rheumatology Vancouver General Hospital The University of British Columbia Arthritis Research Centre of Canada Vancouver. diagnosis. MD. Hyon Choi. BC. Special thanks are owed to Anthony Reginato. Finally. and treatment. another article reviews radiographic modalities that are used for crystal arthropathy.xii preface manner: one for osteoarthritis and the other for nonrheumatic disorders. It is hoped that putting these articles together will help disseminate these important recent developments among clinicians and researchers in the field and stimulate research that will elucidate further the pathogenesis of these disorders and their associated conditions and lead to improved methods of prevention. MD. PhD. DrPH. USA E-mail address: hchoi@partners. Canada Channing Laboratory Department of Medicine Brigham and Women’s Hospital Boston. for assisting reviews of these last four articles. MA.org .

895 West 10th Avenue. several criteria for gout case definition have been developed. As more scientific data on these modifiable risk factors and comorbidities of gout become available. For this reason.b. USA a Gout is an inflammatory arthritis mediated by the crystallization of uric acid within the joints and often is associated with hyperuricemia. including the Rome criteria [3]. Identifying and characterizing important modifiable risk factors for gout is a major step in the prevention and management of this painful condition.theclinics. E-mail address: hchoi@partners. 895 West 10th Avenue. MA 02115.T Division of Rheumatology.rdc. DrPHa. MD.03. BC V5Z 1L7. 181 Longwood Avenue.Rheum Dis Clin N Am 32 (2006) 255 – 273 Epidemiology of Crystal Arthropathy Hyon Choi. doi:10. Epidemiologic data suggest that the overall disease burden of gout remains substantial and may be increasing. Vancouver General Hospital. integration of these factors into gout prevention and care strategies may become essential [1]. This article reviews the relevant epidemiologic data on gout. with a focus on recent progress and available data on other crystal arthropathies.2006. BC V5Z 1L7. All rights reserved. Brigham and Women’s Hospital. Canada. Arthritis Research Centre of Canada. Vancouver General Hospital. this method of identification is impractical. Vancouver. Vancouver. Canada b Channing Laboratory. Although the ACR cri- T Division of Rheumatology. Suite 300.002 rheumatic. the New York criteria [4]. Department of Medicine. although existing data on the latter are limited.com . Boston.org 0889-857X/06/$ – see front matter D 2006 Elsevier Inc. The University of British Columbia. In population surveys designed to estimate the prevalence of gout. and the American College of Rheumatology (ACR) criteria [2]. Prevalence of gout Definitive diagnosis of gout requires either the presence of monosodium urate monohydrate crystals in joint fluid or a tophus [2].1016/j. The University of British Columbia. Arthritis Research Centre of Canada. Suite 300. however.

The United States national prevalence of gout has been estimated using selfreported data from various years of the National Health Interview Survey (NHIS) and the Third National Health and Nutrition Examination Survey (NHANES III. the ACR survey criteria. the validation rate of self-reported gout in a recent large pro- Table 1 Prevalence of gout in the United States in regional population studies Prevalence (per 1000) Source (year) Tecumseh Community Health Study (1960) Framingham Heart Study (1964) Sudbury study (1972) a b Gout definition ‘‘Rome’’a Arbitraryb Romec and NYd Age ! 20 ! 42 (mean. 1988–1994). the presence of gout during a 1-year period was recorded if a respondent answered ‘‘yes’’ to the question. and 4626. Data from the Sudbury study shows that 44% of self-reported cases could be validated according to Rome or New York criteria [10]. Furthermore.2 Female 4.8 3. These data are summarized in Table 1. Overall. all subjects were asked. ‘‘Have you or any member of your household had gout within the past year?’’ In contrast.6].0 14. Arbitrary: at least 2 of the following 3 features — a typical attack of arthritis. c Rome: Rome criteria for gout. validation data from other studies may help understand the general accuracy of self-reported gout. . These studies were conducted in confined geographic regions and were relatively small (total participants: 7207. The validation rate from a physician cohort (Johns Hopkins Precursor Study) was much higher. 5127. d NY: New York criteria for gout. the Framingham Heart Study [9]. during the home interview of the NHANES. and hyperuricemia.256 choi teria are applicable in clinical and population-based research [2].6 ‘‘Rome’’: ‘‘insofar as possible’’ on the Rome criteria. these studies were done before the ACR criteria were developed [2]. The National Arthritis Data Workgroup reviewed earlier population-based studies that estimated the prevalence of gout [7]—the Tecumseh Community Health Study [8]. an attack of arthritis with a prompt response to colchicine therapy. resulting in a higher prevalence than in the other two (see Table 1). If the respondent stated that it was another health professional who gave the diagnosis of gout to him or her. however—80% according to the ACR survey criteria applied by mail and 100% by mail combined with medical record review [6]. have been used widely in recent epidemiologic studies of gout [5.9 1.8 3. 58) ! 15 Total Male 7.7 28. the age distribution of the Framingham study population was older. in particular. ‘‘Has a doctor ever told you that you had gout?’’ Interviewers were instructed to emphasize the word. doctor. Similarly. Although the accuracy of these self-reported data has not been studied specifically in these surveys.5 6. respectively). In the NHIS. then the answer was coded as ‘‘no’’ [11]. and the Sudbury study [10].

epidemiology of crystal arthropathy Table 2 Annual prevalence of gout per 1000 in the United States by age, sex, race, and income, 1996 Age, year b 45 Sex Male Female Race White Black Income b $10,000 $10,000–$19,999 $20,000–$34,999 ! $35,000 3.4 0.2 1.9 0.7 — — 1.4 2.8 45–64 33.5 12.0 21.0 35.6 54.9 23.9 29.8 18.3

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! 65 46.4 19.5 31.0 35.2 36.6 34.9 21.5 28.5

spective cohort of male health professionals (Health Professionals Follow-Up Study [HPFS]) was approximately 70% according to the ACR survey criteria assessed by a mailed survey [5]. The difference in the validation rate of selfreported gout between these studies likely reflects differences in level of health knowledge in the study populations, although the contribution of the differences in the criteria used cannot be eliminated. The most recent available NHIS data on self-reported gout are from the 1996 survey (Table 2) [12]. The overall prevalence for the 1-year period was 9.4 cases per 1000 persons in the United States. The prevalence increased with age, from 1.8 per 1000 in persons aged 18 to 44 to 33.5 per 1000 in persons aged 45 to 64, and to 46.4 per 1000 in persons aged 65 and older. The prevalence was higher in men at all ages and higher in blacks aged 45 and older than in whites in the same age group (see Table 2) [12]. In addition, the prevalence tended to be higher with lower family income levels (see Table 2). In the NHANES III, the lifetime prevalence of gout was lowest (0.4%) in subjects aged 20 to 29 and highest (8%) in those aged 70 to 79 (Table 3). Among men, the prevalence of gout increased from 0.2% in subjects aged 20 to 29 to
Table 3 Life-time prevalence of gout per 1000 in the United States (Third National Health and Nutrition Examination Survey, 1988–1994)T Age, year ! 20 20–29 30–39 40–49 50–59 60–69 70–79 ! 80 Total 26 4 11 17 39 61 80 59 Male 38 2 21 26 56 94 116 71 Female 16 5 1 9 23 32 52 53

T Lifetime prevalence of gout obtained by the question, ‘‘Has a doctor ever told you that you had gout?’’

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choi

Table 4 Annual prevalence of gout per 1000 in the United States by survey year (National Health Interview Survey)T Age group, year All ages 1969 1976 1988 1996 4.8 7.8 8.5 9.4 17/18–44 3.1 3.8 3.1 1.8 45–64 12.0 18.4 21.0 22.4 ! 65 12.7 24.1 27.0 30.8

T 1-Year prevalence of gout obtained by the question, ‘‘Have you or any member of your household had gout within the past year?’’

11.6% in those aged 70 to 79. Although gout was reported more often in men than in women overall, the prevalence in women approached that of men after menopause (see Table 3). The prevalence of gout was 3.2% in women aged 60 to 69 and increased to 5.2% in women aged 70 to 79 and 5.3% in women 80 years and older [11]. These national data suggest that the prevalence of gout is approximately 2.7% in the United States. This corresponds to an estimated 5.9 million persons who have gout: 4.0 million men and 1.9 million women. Despite the emphasis on physician diagnosis of gout, however, these estimates may be overestimated, because they were based on self-reported data. Available data suggest that the prevalence of gout is increasing. Prevalence estimates derived from the NHIS over time can be compared directly (Table 4), because the survey instrument has not changed. The prevalence more than doubled, and the steepest increase occurred between 1969 and 1976 [13]. More recent NHIS data from the 1992 to 1996 surveys suggest the increasing trend seemed to slow substantially between 1992 and 1996 (8.4 and 9.4 per 1000) (see Table 4). Similarly, a multicenter study of general practices in the United Kingdom reports that the prevalence of gout in 1991 increased threefold compared with the estimates from the 1970s [14]. An increasing trend between the 1960s and 1992 also was observed in Maori Indians and in European descendants in New Zealand [15]. More recently, a study based on a United States managed care population recently reported that the overall prevalence of gout or hyperuricemia requiring a gout or serum urate-lowering medication in 1999 increased by 80% compared with that in 1990 [16]. A similar increasing trend was observed in Chinese population surveys performed in the 1990s [17].

Incidence of gout Data on the incidence of gout are limited. The Rochester Epidemiology Project identified 39 new cases of acute gout meeting the ACR criteria [2] during the 2-year interval, 1977 to 1978, resulting in an age- and sex-adjusted annual incidence rate of 45.0 per 100,000 (95% confidence interval [CI], 30.7–59.3) [18]. In comparison, for the interval 1995 to 1996, 81 cases were diagnosed,

epidemiology of crystal arthropathy Table 5 Annual incidence of gout per 1000 (Rochester County residents) (1977–1978) Age 20–29 30–39 40–49 50–59 60–69 70–79 ! 80 Male 0.2 0.6 1.1 1.6 1.3 2.3 2.6 Female 0.0 0.0 0.2 0.4 0.5 0.6 0.9 (1995–1996) Male 0.1 0.8 1.0 1.6 2.5 4.6 3.4

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Female 0.0 0.1 0.1 0.0 0.6 1.3 1.6

providing an annual incidence rate of 62.3 per 100,000 (95% CI, 48.4–76.2). These rates resulted in a greater than twofold increase in the rate of primary gout (ie, no history of diuretic exposure) during the 20-year period. In contrast, the incidence of secondary, diuretic-associated gout did not increase over time [18]. The age-specific incidence rates stratified by sex are summarized in Table 5. The Johns Hopkins Precursor Study documents 60 cases of incident gout that developed in 1216 male physicians during a median follow-up of 29 years (34,729 person-years of observation) [19]. These figures indicated an annual incidence rate of 1.7 per 1000 (95% CI, 1.3–2.2). Recently, the HPFS documented a comparable incidence rate (1.5 per 1000).

Risk factors for gout Demographic factors Age Prevalence and incidence of gout increase with age in men and women [5,7, 11,18]. Serum urate rate levels also tend to increase with aging in women, but the trend is less clear in men [8]. For example, the Normative Aging Study finds no independent association between normal aging and serum uric acid levels in healthy men [20]. Age-associated risk factors for hyperuricemia and gout might explain some portion of the increasing incidence of gout with older age, including increased prevalence of chronic medical conditions and medication use and deterioration of renal function. Gender Although the prevalence and incidence of gout are substantially higher in men than in women before menopause, the disease burden in women tends to approach that of men after menopause. For example, the prevalence of gout in NHANES III (discussed previously) may be overestimated given that they were based on self-reports of physician-diagnosed gout; however, even if the true agespecific prevalences were 50% lower, they still would be substantial, with the

These data call for gender-specific epidemiology studies to quantify the magnitudes of associations in the different sexes.0% for greater than 10.80) compared with the white men [25]. Modifiable risk factors Serum uric acid and gout Although hyperuricemia is considered the precursor of gout.9 mg/dL.9 mg/dL.0 mg/dL.0 mg/dL (Fig. and these hospitalbased case series are open to a referral bias. 5.0 to 9.5% for 8. the all-male study found that annual incidence of gout was less than 0. showed that the relative risk (RR) for gout in the black men was 1. 1) [27].9 mg/dL.0 mg/dL) during a 5-year period and documented 42 cases of incident gout [27]. 4. Although these data are intriguing. Annual incidence rates of gout in this study were 2. Conversely. Gender also may alter the magnitude of the effect of certain risk factors.02–2. the Rochester Epidemiology Project data indicate that the incidence of primary gout has doubled in women during the past 20 years [18]. and 12.27].0 to 7.2% for 7. The Normative Aging Study evaluated incidence of gout stratified by prior uric acid levels [26].0 mg/dL. For example.9 mg/dL. suggesting that alcohol intake may not be a major factor contributing to the development of gout in female patients [22–24].1% for men who had serum uric acid level less than 7. 352 black men in the Meharry Cohort Study and 571 white men in the Johns Hopkins Precursor Study. only a few epidemiologic studies have prospectively investigated the relation between prior uric acid levels and risk for incident gout in men [26.0 to 8. Furthermore.4% for 7.8% for 8. 0. 0.2% for greater than or equal to 9.0 to 7. these differences may reflect the difference in background prevalence of these factors between men and women. The Normative Aging Study reported . case series of gout comparing distributions of risk factors between men and women suggest that risk factors for gout in women may be different from those for men [22.69 (95% CI. more males than female patients reported heavy lcohol intake (especially beer). A Chinese population study followed men who had hyperuricemia (defined by ! 7. Based on 84 incident cases of gout during a 15-year period. Race A study based on two cohorts of former medical students. A higher proportion of female than male patients who had gout had hypertension and renal insufficiency and were treated with diuretics [22–24].23].0 to 8. The excess risk for gout in black men was explained by a greater risk for incident hypertension among them [25].3% for 9. 1.260 choi prevalence of gout in this population approaching that of rheumatoid arthritis (2% in the NHANES III) [21]. No data on the impact of prior uric acid levels on incident gout specifically in women are available. It remains unclear if dietary and other risk factors predict the risk for incident gout independent of prior uric acid levels.9 mg/dL. and 7.

although the study had similar limitations [26].1% for men who had serum uric acid level less than 7 mg/dL. and 7.82:421–6. with permission. (From Campion EW. Asymptomatic hyperuricemia. The Johns Hopkins Precursor Study reported that increased BMI at age 35.02) [19]. De Labry LO.9 mg/dL. P = . 0.3% for 9 to 9. The Framingham study found a . was associated with the risk for gout (RR 1.9 8-8. Am J Med 1987.4% for 7 to 7. 0.0% for greater than 10 mg/dL. Several prospective cohort studies have evaluated the association between obesity and gout [19. body mass index (BMI). 1. 4. restricted to men who had hyperuricemia.29].9 mg/dL. the absorption of dietary purines causes a steeper increase in the blood uric acid level than do equivalent quantities in persons who have normouricemia [28.9 mg/dL.26. These data suggest that certain risk factors may be associated more strongly in men who have hyperuricemia. Risks and consequences in the Normative Aging Study. the same study found a significant interaction between persistent alcohol consumption and baseline uric acid levels in the hyperuricemic range [27]. Furthermore. The Normative Aging Study showed BMI at baseline (mean age.30].) that age. 52) significantly associated with hyperuricemia or gout. Adiposity Adiposity has been noted to be associated with serum uric acid levels and proposed to increase the risk for gout. and diuretic use (for hypertension) independent of uric acid levels [27]. showed significant associations with obesity. Glynn RJ. however. The Chinese study.12 for 1 unit increase in BMI. Solid line denotes these data points and dotted line shows an exponential projection of the data points. Annual incidence of gout was less than 0.9 >10 Serum Uric Acid (mg/dL) Fig. For example. Relation between prior serum uric acid levels and incidence of gout. because renal urate clearance is impaired in those who have hyperuricemia (such as gouty patients).epidemiology of crystal arthropathy 9% 8% 261 Annual Incidence of Gout 7% 6% 5% 4% 3% 2% 1% 0% <6 6-6. alcohol consumption. and hypertension no longer were associated significantly with the risk for incident gout after adjusting for baseline serum uric acid levels [26].25.9 9-9. but not at baseline (mean age.8% for 8 to 8. 22).9 7-7.

61 (95% CI.262 choi significantly higher BMI in patients who had gout after adjusting for age [30].36) for 30 to 34. The HPFS data showed a substantial attenuation of RR after adjustment for confounders.65) for men who had BMI 25 to 29. compared with men who maintained their weight (À4 to +4 lb) since age 21.39. In a recent prospective analysis in the HPFS. the multivariate RR of gout for men who gained 30 pounds or more was 1.001). 6 Multivariate Relative Risk 5 4 3 2 1 0 <21 21-22. BMI and waist-to-hip ratio were strongly associated with the risk for incident gout after adjusting for various confounders including dietary factors [31].44–2. In these studies.70–0. Compared with men who had BMI 21 to 22.9 kg/m2. emphasizing the importance of multivariate models. and 2. . which themselves may be risk factors for gout and vary with adiposity.98–1.39) compared with those in the lowest (0.97 (1.40–0. P for trend b . The 1999 to 2000 National Health and Nutrition Examination Survey estimated that the age-adjusted prevalence of obesity (BMI N 30) in United States adults is 30.9 kg/m2.001) (Fig. such as chronic joint trauma resulting from excess weight. a small number of gout cases or the lack of data limited the comprehensive adjustment of relevant covariates.88) was 1.73–5.9 25-29.66). are proposed as an additional explanation for the association between obesity and gout [6. 2. 2.9 30-35 >=35 P for trend = < 0. no prospective information had been available about the relation between obesity and incident gout after adjusting for dietary factors. Further.92) [31]. Relation between BMI and incidence of gout in men.82 (95% CI.001 BMI (kg/m2) Fig. The multivariate RR for gout in men in the highest waist-to-hip ratio quintile (0. The impact of adiposity on gout adds to the already substantial hazards associated with the obesity epidemic in the United States. the multivariate RR for men who lost 10 pounds or more since the study baseline was 0. Specifically. The prevalence of class 3 obesity (BMI index ! 40) in adults has more than doubled in 10 years.33 (1.49–2. Factors not related to uric acid.5% [34]. 0. 1.33].9 23-24.99 (1. In contrast. 2).95 (1. the multivariate RRs of gout were 1.33]. Increased adiposity may lead to hyperuricemia via increased production and decreased renal excretion of urate [32.9 kg/m2.62–3.10) for greater than 35 kg/m2 ( P for trend b .39–2.

however.2% in the year 2000 [35].000 deaths per year in the United States [37]. kidney stone [43]. Upward solid arrows denote an increased risk for gout. 3) [1. Mount DB. Dietary influences on the risk for gout and their implications within the Healthy Eating Pyramid. and gallstones [44]. and horizontal arrows denote no influence on risk.45]. placing them at the foundation of the pyramid (Fig. the associations had not confirmed prospectively.39]. A new Healthy Eating Pyramid strongly recommends daily exercise and weight control. Small-scale case- Fig.) . Diet Purine-rich foods and high protein intake long had been believed risk factors for gout [32. type 2 diabetes [41. For example. downward solid arrows denote a decreased risk. Comprehensive persistent efforts to reduce adiposity could contribute to reducing the disease burden from gout and associated morbidities [46]. Reginato AM. Broken arrows denote potential effect but without prospective evidence for the outcome of gout. hypertension [40]. Pathogenesis of gout.33]. and problem drinking [36] and leads to approximately 300.epidemiology of crystal arthropathy 263 with an estimated prevalence of 2. Data on the relationship between diet and the risk for gout are derived primarily from the recent HPFS. (Adapted from Choi HK. Ann Intern Med 2005. Obesity is associated with at least as much morbidity as poverty. with permission. smoking. weight gain is linked to increased risks of coronary heart disease (CHD) [38.143:499–516. Metabolic experiments in animals and humans demonstrated the urate-raising effect of artificial short-term loading of purified purine [47–50].42]. 3.

Purine-rich vegetable consumption. that other factors in dairy products may be responsible for the inverse association. Further. the relation between these purported dietary risk factors and incident gout during a 12-year period in 47. failed to find an association between purine intake and gout [51. Q1 to Q5 denote first quintile (lowest) to 5th quintile (highest). the possibility that the consumption of dairy products has a role in protecting against gout has been raised by previous studies [53.58–60].5 0. however.016 P for trend = 0. men in the highest quintile of vegetable protein had a 27% lower risk for gout compared with those in the lowest quintile.1) (0.7) Q1 Q3 Q5 (0.779 Q1 Q3 Q5 (0. . In addition. was examined prospectively [5]. It also is possible. 5). The reference group for comparisons is the men who have the lowest intake quintile in each food group. 4). however. In a recent study (HPFS). given that dairy products have a low purine content [54. and men in the highest quintile of seafood intake had a 51% higher risk compared with the lowest quintile (Fig.6) (1.0 P for trend = 0.55].3) (0.264 choi control studies that assessed dietary intake retrospectively in confirmed cases of gout and controls. was not associated with an increased risk for gout. however.016 P for trend = 0.0 1.4) Purine-rich Food Group Quintile (serving/d) Fig.0 0.57]. 4.6) (1.52]. who had no history of gout at baseline. thus raising serum uric acid levels [46. The absence of the inverse association with high-fat dairy products could result from the counteracting effect of saturated fats contained in high-fat dairy products.3) Q1 Q3 Q5 (0. such as meat and seafood.5 1. Men in the highest quintile of meat intake had a 41% higher risk for gout compared with those in the lowest quintile.3) (2. men in the highest quintile of dairy intake had a 44% lower risk for gout compared with those in the lowest and the inverse association was limited to low-fat dairy consumption (Fig. Relative risk for incident gout according to intake of purine-rich food groups in men. which reduces renal excretion of urate.150 male participants (730 incident gout cases).2) (0. These fats are associated positively with insulin resistance [56. Dairy protein may exert its urate-lowering effect without the concomitant purine load contained in other animal protein sources. and men in the highest quintile of dairy protein intake had a 48% lower risk for gout compared with those in the lowest quintile. A recent Taiwanese case-control study (91 gout cases and 91 controls) suggested Total Meat Seafood Purine-rich Vegetables Multivariate Relative Risk 2. Although total and animal protein intake were not associated significantly with risk for gout.54].

64) for alcohol consumption (5 to 9.26. respectively) [52]. the association had not been confirmed prospectively.61] In the recent HPFS.4) (0. except for fish intake [1].8) (1. Q1 to Q5 denote first quintile (lowest) to 5th quintile (highest).0 Q1 Q2 Q3 Q4 Q5 (0.0 0.2) (2. Omega-3 fatty acids also may have anti-inflammatory effect against gouty flares [1]. Compared with men who did not drink alcohol. The reference group for comparisons is the men who have the lowest quintile of dairy intake.73–3.5) (0.9 g per day) to 2. 3). 0.5) Dairy Intake Quintiles (serving/d) Fig. 5.5 265 Low-Fat Dairy Intake High-Fat Dairy Intake 1. Several cohort studies previously evaluated the association between alcohol intake and gout but were limited by small sample size and lack of comprehensive adjustment of relevant variables [19.001 P for trend = 0.8) (1. The use of plant-derived omega-3 fatty acids or supplements of eicosapentaenoic acid and docosahexaenoic acid in place of fish consumption could be considered to provide the benefit of these fatty acids without increasing the risk for gout. This risk varied substantially according to type of alcoholic beverage: beer conferred a larger risk than liquor. increasing alcohol intake was associated with increasing risk for gout (a dose-response relationship) [62].1) (0. they suggest that certain nonalcoholic components that vary among these alcoholic beverages play a role in the incidence of gout. Alcohol The association between alcohol consumption and risk for gout has been suspected since ancient times. Implications of these findings for dietary recommendation for patients who have hyperuricemia or gout generally are consistent with the new Healthy Eating Pyramid (see Fig. 0.37 between the extreme tertiles.2) (2.30.6) Q1 Q2 Q3 Q4 Q5 (0.648 0. whereas moderate wine drinking did not increase the risk (Fig.25.95–1. Relative risk for incident gout according to dairy intake in men. the multivariate RR of gout increased from 1.53 (1.2) (0.epidemiology of crystal arthropathy Multivariate Relative Risk 1. These findings confirmed the longheld belief of relation between alcohol intake and risk for gout. 6) [62].5 P for trend < 0. a protective effect of folate and dietary fiber against gout (odds ratios.43 and 0. In addition. These interesting findings call for prospective confirmation.25 (95% CI. however.001).70) (!50 g per day) ( P for trend b. Beer is the only alcoholic beverage .

1. Relative risk for incident gout according to individual alcoholic beverage intake in men. and ingestion of ascorbic acid (8 g for 3 to 7 days) reduced the serum uric acid by up to 3. Several studies suggest that high doses of vitamin C show a uricosuric effect [64–68]. producing a greater risk for gout than liquor or wine. . it is important to adjust appropriately for these indications in determining the independent impact of these medications.5 mg/dL [68].1 mg/dL as a result of a sustained uricosuria [67].01 P for trend = 0. diuretics are shown to independently increase the actual risk for gout in a prospective population-based study [31]. For example. potentially affecting the risk for gout (Table 6).20) [31]. particularly in beer. supplements. its uricosuric effect may provide a useful option for the prevention and management of hyperuricemia and gout. During the HPFS 12 years of follow-up of men who had no previous history of gout. A recent trial showed that supplementation with vitamin C (500 mg per day for 2 months) reduces serum uric acid by 0. less than 1 serving per month.77. The reference group for comparisons in the lower panel is the men who have the lowest intake category. Because vitamin C generally is considered safe. and toxins Many medications and substances affect serum urate levels.42–2. Medications.63]. or perhaps protective factors in wine mitigating the alcohol effect on the risk for gout [62]. Among these.68 0 < 1/m 5-7/w >1/d < 1/m 5-7/w >1/d < 1/m 5-7/w >1/d Alcohol Types (serving/time) Fig. which is predominantly guanosine.001 P for trend = 0. The effect of ingested purine in beer on blood uric acid may be sufficient to augment the hyperuricemic effect of alcohol itself. acknowledged to have a large purine content. Because the indications for these urate-raising medications may pose an increased risk for gout by themselves. 95% CI. a readily absorbable nucleoside [51. It remains unclear whether or not there are other nonalcoholic offending factors. 6. ingestion of ascorbic acid (4 g) led to a twofold increase in fractional clearance of uric acid up to 6 hours after the ingestion.266 4 choi Multivariate Relative Risk Beer 3 Liquor Wine 2 1 P for trend < 0. diuretic use was associated independently with an increased risk for incident gout independent of hypertension (RR 1.

may stimulate URAT1 [73] A Renal urate excretion [74] Unknown (no change in renal urate excretion [75] Trans-stimulation of URAT1 [73] Trans-stimulation of URAT1 [73] A Renal urate excretion zRenal tubular reabsorption associated with A glomerular filtration [76–80].epidemiology of crystal arthropathy Table 6 Substances affecting urate levels Substances Urate-raising agents Diuretics Implicated mechanisms and comments 267 Salicylate (low dose) b-blockers Lactate. nicotinate Ethambutol Cyclosporin. urate transporter-1.58–60]. no such relation was found with bone or blood lead levels arising from community exposure in the Normative Aging Study [61]. hypertension. Although toxic levels of lead (ie. however. Further research on large populations with variable lead exposure levels would be helpful in determining the threshold for saturnine gout and the importance of this variable in relation to other known risk factors for gout [61]. acetoacetate Pyrazinamide. blood lead levels N60 mg/dL) clearly are associated with gouty arthritis [69]. May stimulate URAT1 [73] or the Na+-dependent anion cotransporter in brush border membranes of the renal proximal tubule [1] A Renal urate excretion from chronic lead nephropathy [84] Inhibition of URAT1 [73] Inhibition of URAT1 [73] Inhibition of URAT1 [73] May inhibit URAT1 zRenal urate excretion [81] Via uricosuric effect due to a competition for renal reabsorption via an anion-exchange transport system at the proximal tubules Inhibition of xanthine oxidase Oxidation of urate to allantoin Allopurinol. Associated medical conditions Various medical conditions have been suspected of being associated with hyperuricemia and gout. febuxostat Uricase Abbreviation: URAT1. suggested that chronic low-level environmental lead exposure may inhibit urate excretion and that lead chelation therapy reduces this inhibition [70]. A clinical study based on 111 Taiwanese adults. interstitial nephropathy [82.83] Higher insulin levels are known to reduce renal excretion of urate [46. including the metabolic syndrome. b-hydroxybutyrate. hypertension [81]. obesity. benzbromarone Losartan Salicylate (high dose) Fenofibrate Amlodipine Vitamin C zRenal tubular reabsorption associated with volume depletion [71. tacrolimus Insulin Lead Urate-lowering agents Probenecid. . including 27 who had gout [70]. sulfinpyrazone.72].

A history of kidney stone. Studies have suggested that the prevalence of radiographic chondrocalcinosis increases with age [88–90]. whereas a confirmed diagnosis of gout increased the risk for kidney stone (2. and cardiovascular disorders. gout was associated with a 60% increased risk for CHD in men (95% CI. No population epidemiologic data exist for pyrophosphate arthropathy or ‘‘pseudogout’’ per se [87]. Because joint aspiration or biopsy is impractical in population studies. Hereditary CPPD deposition diseases are reported in several ethnic populations. It has been proposed that the presence of synovial fluid crystal identification using polarized light microscopy and radiographic calcification of the cartilage would make a definitive diagnosis and either one would make a probable diagnosis [86. The same study also reported a modest cross-sectional association between radiographic chondrocalcinosis and knee osteoarthritis (RR 1.25]. Most of available cases series suggest that mean age at presentation of between seventh and eighth decades of life with a female predominance (2–3:1) [87. 1. although the estimate was not statistically significant (RR 1. usually with autosomal dominance inheritance pattern [87.54–2.92].268 choi renal insufficiency.07]). A critical review reported that there were better evidences for the association with hyperparathyroidism. the validity of many of these associations remains unclear [93]. Calcium pyrophosphate dihydrate deposition and pseudogout A definitive diagnosis of calcium pyrophosphate dihydrate (CPPD) deposition disease would require unequivocal identification of CPPD crystals in joint fluid or articular tissue [86.60. presence of radiographic chondrocalcinosis often has been used in epidemiologic and clinical investigations to study CPPD disease [86–91].72] and 4. hypomagnesemia.94. Hypertension and renal insufficiency have been shown in the HPFS to be associated independently with the risk for incident gout (RR 2. type 2 diabetes. Available data on the link between hyperuricemia and these disorders are reviewed in detail in the article by Becker and Meenakshi elsewhere in this issue.1–2.87].12 [1.33 [95% CI.92]).22–3.88–11. this section discusses the relation with the risk for gout.93–1. In the Framingham study. limited a meaningful analysis (three cases of CHD in 19 women) [24]. kidney stone. 0.87].96–2. The potential independent link with other disorders remains to be clarified. hemochromatosis. however.05 [95% CI. however. [1.31 [95% CI. respectively) [31]. 1. and hypothyroidism than with other suspected conditions [93]. The Framingham Knee Osteoarthritis Study. was not associated with the risk for incident gout (RR 1. Two .68]) [85]. hypophosphatasia. reported that the prevalence of radiographic chondrocalcinosis in the knee joints increased from less than 4% in those under age 70 to 27% in those over 85.52) and females tending to have a slightly increased age-adjusted prevalence.95]. 0. Although many metabolic and endocrine diseases are reported to predispose to CPPD deposition. based on 1402 elderly adults. The small number of women who had gout.2) [24].

Population data on these conditions are scarce. Atkinson K. Arthritis Rheum 1977. [5] Choi HK. From 1937 through 1939. Arnett FC. florid.31:166 – 9. et al. Duff IF. Oxford7 Blackwell Scientific. Masi AT. [9] Hall AP.20:895 – 900. Preliminary criteria for the classification of the acute arthritis of primary gout. Ball J. Karlson EW. et al. A long-term population study. Epidemiology of gout and hyperuricemia. Recent clinical studies indicate that the prevalence of intra-articular BCP crystals in joints with osteoarthritis may be high (67%) [98]. Purine-rich foods. Dodge HJ.96]. and the risk of gout in men. Michigan. [8] Mikkelsen WM. editors. Wood PHN. dairy and protein intake. Ann Rheum Dis 1972. Pathogenesis of gout.41:778 – 99. In: Kellgren JH. An abstract of a Spanish familial study reported a comparison between 21 kindreds with definite CPPD of ‘‘sporadic cases’’ and 15 kindreds of patients who had other rheumatic disease (controls) [87. Jeffrey MR.8% compared with 0% in the controls.143:499 – 516. Helmick CG. 1959–60. Gout in a New England town. Basic calcium phosphate deposition arthropathy Basic calcium phosphate (BCP) crystal deposition is associated with several clinical manifestations. Amsterdam7 Excerpta Medica Foundation. Gout and hyperuricemia. Arthritis Rheum 1998. Robinson H. Thirty-five percent of shoulders with calcium deposition were associated with some degree of pain or discomfort before or during the time of the study. Rheum Dis Clin North Am 1990. reported in 1941 [97]. A prevalence study in Sudbury. [7] Lawrence RC. [3] Criteria CIOMS. called Milwaukee shoulder syndrome.epidemiology of crystal arthropathy 269 main clinical types are reported. Mount DB.16:539 – 50. The epidemiology of chronic rheumatism. Am J Med 1967. J Chronic Dis 1967. 6061 office workers and candidates underwent physical and fluoroscopic examination of both shoulders in connection with an insurance company. Population studies of the rheumatic diseases.5% in females). Massachusetts. The prevalence of calcium deposition was 2. polyarticular chondrocalcinosis and the second by late-onset oligoarticular with arthritis resembling sporadic pyrophospate arthropathy [87]. 1966. The familial aggregation rate for chondrocalcinosis in these kindreds was 38. Estimates of the prevalence of rheumatic diseases in the population of Tecumseh. et al. these and other related data are reviewed in detail in the article by Rosenthal elsewhere in this issue. Proposed diagnostic criteria for use in population studies. Barry PE. there is only one large-scale study.20:351 – 69. N Engl J Med 2004. Proceedings of the 3rd International Symposium. References [1] Choi HK. 1963. [4] Bennett PH. [2] Wallace SL. the first characterized by early-onset. editors. Dawber TR. [6] Roubenoff R. Ann Intern Med 2005. 457 – 8. [10] O’Sullivan JB. Rome. ranging from asymptomatic status to destructive arthropathy. et al.7% (3. June 5–10.42:27 – 37.6% in males and 2. et al.350:1093 – 103. p. Reginato AM. Appendix 1. p. . 1968. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. 324 – 6. New York.

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Meenakshi Jolly. the association of hyperuricemia and gout with other important disorders continues to be documented and. University of Chicago Medical Center. All rights reserved. Whether or not hyperuricemia (or even ‘‘high normal’’ serum urate levels) plays a causal role or simply is a marker arising in the course of each related disorder remains unresolved. Nevertheless. Chicago. These studies prompted the current conservatism in the management of asymptomatic hyperuricemia. IL. Chicago. cardiovascular disease (coronary heart disease.Rheum Dis Clin N Am 32 (2006) 275 – 293 Hyperuricemia and Associated Diseases Michael A. 5841 Maryland Avenue. Chicago. MC 0930. IL. stroke and peripheral artery disease. insulin resistance.com . combined with experimental data derived from studies in rats.2]. chronic kidney disease.2006.02.rdc. Becker). obesity. Becker. 0889-857X/06/$ – see front matter D 2006 Elsevier Inc. The University of Chicago Pritzker School of Medicine. T Corresponding author. Epidemiologic studies in the late 1970s [1.A. such as hypertriglyceridemia.uchicago. and aberrant metabolic states. and congestive heart failure). many persons who had hyperuricemia but no symptoms of gout were treated with allopurinol or uricosuric agents in the belief that the previously demonstrated association of gout with chronic structural and functional renal abnormalities denoted a causal relationship. MDb a Rheumatology Section. seemed to allay the concern that hyperuricemia and gout were independent risk factors for chronic kidney disease.T.theclinics. E-mail address: mbecker@medicine.005 rheumatic.bsd. Rheumatology Section. and metabolic syndrrome. doi:10. Rush University Medical Center. MDa. USA In the years after introduction of effective urate-lowering therapy. This article reviews the current status of the relationship between hyperuricemia and associated disorders.edu (M. however. USA b Department of Medicine. has led to reconsideration of a pathogenetic role for hyperuricemia independent of crystal deposition in hypertension.1016/j. IL 60637.

Increasing prevalence of hyperuricemia with increasing blood pressure in the general population 5. Gout prevalences of 2% to 12% in hypertensive patients 3. the limit of urate solubility in serum) is preferable in the context of gout. as exemplified by the studies of juvenile-onset hypertension and cardiovascular disease (discussed later). conflicting results of epidemiologic studies and the existence of multiple potentially confounding variables preclude establish- . 25% to 50% hypertension prevalences in groups of patients who have documented gout 4. children have lower serum urate levels. than with a definition of hyperuricemia based on serum urate values 2 standard deviations or more above the mean population value. With respect to the issue of crystal deposition and independent roles of hyperuricemia. Furthermore. The physicochemical definition (serum urate concentration in excess of 6. Hyperuricemia and hypertension An association of hyperuricemia and hypertension [8–12] long has been recognized and is supported by the following observations: 1. however.8 mg/dL. with adult male levels reached at the time of puberty and female levels changing little before menopause. Increasing risk for development of hypertension with increasing baseline serum urate levels Despite these findings. it is important to acknowledge the results of population studies of serum urate. showing that values are higher in men than in women before menopause and are more comparable thereafter. Prevalences of hyperuricemia of approximately 20% to 40% in untreated hypertensive patients and approximately 50% to 70% in treated or renally impaired hypertensive patients 2. Hyperuricemia without gout (asymptomatic hyperuricemia) is more common with this definition. In fact. with prevalence rates of 5% to 8% in men in the United States [4–6] and up to 25% in adult men of Polynesian derivation [7].276 becker & jolly Definition of hyperuricemia Physicochemical and population definitions of hyperuricemia exist [3]. to stress that the risk for crystal deposition disease imparted by urate supersaturation of extracellular fluids begins at approximately this concentration and probably is equivalent in comparably affected men and women. it may become necessary to frame new definitions of ‘‘high’’ serum urate levels as distinct from physicochemical or populationbased hyperuricemia.

selectively increased renal vascular resistance and total peripheral resistance are documented in subjects who have essential hypertension and hyperuricemia. These findings contrast with longitudinal studies in which the risk for future hypertension is correlated with serum urate levels [9. In contrast. in part. allopurinol-reversible high blood pressure [21].16]. by renal blood flow. Urate is reported to activate critical proinflammatory pathways in vascular smooth muscle cells and. raising the possibility that hyperuricemia is a consequence of early nephrosclerosis in patients who have essential hypertension [17]. only 1% of blood pressure variation could be accounted for by serum urate values in the Israel Ischemic Heart Disease Study of 10.hyperuricemia & associated diseases 277 ment of a cause-effect relationship in either direction. who initially were normotensive. hence. Furthermore. A similar argument is made for the early appearance of hyperuricemia in patients who have familial juvenile hyperuricemic nephropathy (FJHN) [18].10.001) in adolescents who have new-onset hypertension [24]. when high.14]. In fact. increasing attention is devoted to mechanistic and experimental studies. implicating the respective mediator systems in the dysregulation of blood pressure. not reversible by lowering of serum urate levels [23]. P b 0. which are reported to be inappropriately low relative to glomerular filtration rates in adult and childhood essential hypertension [3. a direct correlation is observed between serum urate level and the development of salt-resistant. Johnson and colleagues [26–29] review in detail the evidence for a role of urate in human hypertension. Renal uric acid clearances depend on tubular secretory and postsecretory reabsorption rates. the high prevalence of hypertension in patients who have classical gout is related more closely to obesity than to the duration of gout [13. Because of difficulty in distinguishing epidemiologically between causal and epiphenomenologic bases for the hyperuricemia-hypertension association.000 men ages 40 or older [15]. For example. Urate stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase 2. predicted the development of hypertension [8].20]. . Moreover. In Sprague-Dawley rats with serum urate levels raised by oxonate inhibition of uricase activity. may have a role in the vascular changes associated with hypertension and vascular disease [19. and may be regulated. allopurinol administration results in urate lowering and normalization of blood pressure [25]. in whom serum urate levels remained positively and significantly associated with systolic and diastolic blood pressures for 12 years and. Feig and Johnson recently demonstrated a linear relationship between serum urate levels and systolic blood pressure (r = 0. Preglomerular arteriolopathy [22] accompanying these changes may account for the subsequent development of a salt-sensitive hypertensive state. a causal role for hyperuricemia in hypertension is suggested by the results of other experimental and clinical studies. in a pilot study of such individuals.8.12] and a trial of individuals. Also demonstrated is increased juxtaglomerular renin content and decreased macula densa neuronal nitric oxide synthase content.

39].22.43]. The shift of investigative focus to crystal-unrelated effects of urate on the kidney holds more promise for resolution of the question of a causal role of hyperuricemia in progressive renal disease. this entity only rarely is of clinical consequence [37].2] in subjects who have gout and hyperuricemia failed to corroborate a renal risk of hyperuricemia or gout. Recently. a reciprocol relationship between serum urate levels and renal vascular responsiveness to angiotensin II administration was reported [47]. but not all [18]. renin-dependent systemic hypertension and afferent arteriolosclerosis. . to retard or prevent progression. earlier studies [1.31–35]. urate levels are reported to correlate with development of chronic renal insufficiency in patients who have hypertension [42. Although a pathologically demonstrable interstitial urate crystal deposition nephropathy (called urate nephropathy) does exist. a fact that should allow early identification of at-risk family members in whom the benefits of early urate-lowering therapy can be assessed. so that confirmation of a benefical effect of allopurinol in this process is important in assessing the role of hyperuricemia in the renal disease. Finally. ultimately. Mild oxonate-induced increases in serum urate levels in Sprague-Dawley rats result in glomerular hypertension. commonly progressing to end-stage renal disease. Most families who have the FJHN phenotype have mutations in the UMOD gene encoding uromodulin (Tamm-Horsfall protein) [41]. sclerosis.0 mg/dL at baseline was significantly higher than in their counterparts who had lower urate levels [48]. activate the renin-angiotensin system. and. Although gout occurs in some patients who have FJHN. and allopurinol treatment is reported by some investigators [38. terminating in fibrosis [21. and interstitial renal inflammation. All of these changes occur at high but subsaturating urate levels and are independent of urate crystal deposition. evidence for a pathogenetic role of hyperuricemia in the initiation or progression of chronic renal impairment comes mainly from animal studies [30]. at least at serum urate levels (b13 mg/dL in men. suggesting that increased urate levels may. as in rats. and patients who have impaired renal function have higher serum urate levels [44–46]. b10 mg/dL in women) commonly encountered in clinical practice. As discussed previously. for which alternative mechanisms are proposed [40]. Few studies in humans are available to support the potential implications of the rat studies. A role for increased urate levels in worsening structural and functional renal disease also is demonstrated in the cyclosporine-induced [36] and remnant kidney [33] models of chronic kidney disease in rats. there is little evidence for crystal deposition as a mediator of renal impairment [18]. FJHN is an autosomal dominantly inherited hyperuricemic disorder. In epidemiologic studies.278 becker & jolly Hyperuricemia and chronic kidney disease Despite the nearly invariable occurrence of hyperuricemia in chronic kidney disease in humans and the high frequency of chronic renal impairment in patients who have gout. hypertrophy. the incidence of end-stage renal disease developing over 7 years in Okinawan women who had serum urate levels greater than or equal to 6.

Other published studies. hypertension. overall mortality rates in patients either whose serum urate was greater than 7. independent of preexisting myocardial infarction. In the NHANES III study.27. alcohol intake.62]. serum urate levels greater than or equal to 6 mg/dL were found to be an independent predictor of coronary heart disease [61]. Additional study of the Framingham cohort [53] supports the contention that risk factors other than hyperuricemia are causal in atherosclerotic heart disease. race. Wannamethee and coworkers did not find hyperuricemia a risk factor for coronary heart disease in men. in two studies including more than 2600 patients who had angiographically confirmed coronary artery disease [57. increasing serum urate concentration was related to increasing cardiovascular mortality in both sexes and in blacks and whites [56]. smoking status.50].00 in women). In the National Health and Nutrition Examination Survey (NHANES) I study. or death from all causes) in men or. Finally. the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study reported a significant association between baseline serum urate level and risk for a morbid or fatal .50. however. and resolution of this issue will likely require large interventional trials assessing the proposition that prevention or reversal of hyperuricemia has beneficial effects on the course of cardiovascular disorders in at-risk patients. Whether or not hyperuricemia is only a marker or is a pathogenetic factor in cardiovascular diseases remains uncertain (Table 1). body mass index (BMI). Clustering of hyperuricemia with cardiovascular risk factors also is reported by others [55]. favor a more direct role for hyperuricemia in cardiovascular events or mortality [26. atherosclerosis. Similarly. in women. Also. The issue of hyperuricemia as an independent risk factor for atherosclerotic cardiovascular disease is controversial [49]. cholesterol. and cardiac and overall cardiovascular mortality risks of hyperuricemia persisted even after adjustment for age. after adjustment for other cardiovascular risk factors.4 mg/dL) were increased substantially and independently.hyperuricemia & associated diseases 279 Hyperuricemia and cardiovascular disease Coronary heart disease The weight of recent evidence supports the view that hyperuricemia is an important risk factor for ischemic heart disease and probably other forms of cardiovascular disease [49. hyperuricemia was not associated (by 1994) with an increased risk for adverse outcome (coronary heart disease.1 mg/dL (compared with those whose had serum urate was b 5. and diabetes.56–68]. Multivariate analysis of cardiac risk factors in the original Framingham cohort did not identify an independent predictive role for serum urate values in coronary heart disease [51] but did show a 60% excess of coronary disease in gouty men never treated with diuretics [52].1) [57] or who were in the highest quintile for serum urate ( N6. In 6763 subjects who had baseline serum urate levels established from 1971 to 1976.77 in men and 3. Death rates resulting from ischemic heart disease increased in relation to serum urate quartile (relative risk 1. and the cluster of risk factors associated with the insulin resistance syndrome [54]. death from cardiovascular disease.

1985 [51] Culleton.] Subjects/study name Brand. coronary heart disease. 2000 [67] Tuttle. 2004 [69] Yes Yes Yes. cardiovascular.017 CHD (angiographic) GREACE study. CVD. all cause/CV mortality SUA and CHD Mortality All vascular events CV/all cause mortality Fatal/nonfatal MI. ischemic heart disease) CV events CHD. 1044 subjects. healthy Finnish men 9193 Subjects. in men Yes. 2000 [63] Lin.280 Table 1 Studies relating serum urate concentrations and cardiovascular disease Longitudinal study Yes Yes Yes Yes Yes Yes No No Yes. 2000 [45] 7978 Mild–moderate HTN subjects MONICA cohort. 2001 [60] Bickel. hypertension. 2004 [68] Hoieggen. coronary artery disease. 40–59 years ARIC cohort. 1600 with CHD 1423 Middle-aged. 2004 [139] Abbott.504 healthy subjects 391 Men with hyperuricemia 5209. 2002 [57] Athyros. year [ref. CV. cardiovascular disease.413 Healthy Japanese 25–60 years Madsen. in women Yes Yes Yes Yes Yes Yes Tomita. Subjects 25–74 years (NHANES 1 follow-up) 4327 Systolic HTN subjects ! 60 years (SHEP) 1720 Subjects with untreated HTN 277 Patients undergoing cardiac catheterization 1. 1995 [64] Framingham cohort Framingham cohort 6763 Participants 7688 Men. 1999 [50] Liese. 1988 [52] Freedman. 45–64 years 5926. 2000 [66] Verdecchia. 2004 [71] Niskanen. 13.595 Angiographically defined CAD patients CV events. 55–80 years old with untreated HTN and LVH (LIFE study) 49. CHD. 2000 [56] Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes CHD Incident CHD. all cause mortality CV events. 1999 [53] Wannamethee. HTN. 1997 [54] Moriarity. 1999 [65] Fang. CV mortality. all cause/CV mortality Yes Yes Yes jolly Franse. Framingham cohort with gout 5. in women No No Outcome variables Serum urate as independent predictor of CVD Author. all cause and CVD mortality Fatal/nonfatal CHD events CHD events (fatal/nonfatal) CVD CHD Mortality (all cause. fatal/nonfatal stroke CHD and stroke events. all cause mortality Mortality Abbreviations: CAD. 2005 [62] 1. all cause/CV mortality CHD. .421 (NHANES 1) 25–74 years becker & Alderman.

losartan therapy is associated with lower rates of cardiovascular morbidity and death [70]. higher serum urate levels are associated with poorer outcomes in stroke.8 years of the trial. in the Greek Atorvastatin and Coronary-Heart-Disease Evaluation (GREACE) study [71]. In the Cardiovascular Study in the Elderly (CASTEL) study [79]. Stroke and peripheral artery disease Uric acid administration is protective against experimental ischemic stroke in rats [76]. In the LIFE study [69].024 per 10 mmol/L increment in baseline serum urate) [69]. Data supporting a role for serum urate as a determinant of coronary heart disease also have emerged from two cardiovascular disease interventional studies. serum . patients who had coronary heart disease treated with atorvastatin showed an in-trial 8. which compares losartan-based and atenolol-based therapy in high-risk hypertensive patients who had left ventricular hypertrophy.3% mean increase in urate in patients who were untreated. Other possible mechanisms relating hyperuricemia and cardiovascular disease are reviewed by Gavin and Struthers [75]. and the significantly lower baseline FMD in the hyperuricemic group was normalized. A direct relationship between plasma homocysteine and serum urate levels is reported in patients who have atherosclerosis [72]. The risks of recurrent coronary disease events were correlated significantly with the serum urate levels. suggesting that restoration of normal serum urate levels improved this measure of vascular function [74].hyperuricemia & associated diseases 281 cardiovascular event (hazard ratio 1. and serum urate greater than or equal to 7 mg/dL is described as an independent risk factor for stroke [61]. non–insulin-dependent diabetics. Allopurinol (300 mg daily) reduced serum urate levels in both groups of subjects. Lehto and coworkers [78] found hyperuricemia a predictor (hazard ratio 1. Analysis of baseline and in-trial serum urate levels indicates that 29% of the cardiovascular benefit of losartan-based therapy could be ascribed to the urate-lowering (uricosuric) effect of losartan (not shared by atenolol) therapy. flow-mediated arterial dilation (FMD) in healthy hyperuricemic and normouricemic control patients who hade high cardiovascular risk was determined before and after 3 months of allopurinol treatment.80]. Similar findings are reported by others [79. there is only one report of a more favorable outcome of stroke in individuals who are hyperuricemic [77]. In a recent study [74]. Similarly. Mechanisms by which hyperuricemia may promote vascular occlusive disease are under study.2% reduction in serum urate levels compared with a 3. such that serum urate was regarded an independent predictor of recurrent coronary heart disease events. In humans. however. which prevented increases in serum urate levels during the 4. In fact.93) of nonfatal and fatal stroke in a population-based study of middle aged. the latter a state associated with thrombotic disease [73]. A mutation in the methyl tetrahydrofolate reductase (MTHFR) gene is correlated with hyperuricemia and hyperhomocysteinemia.

there is evidence for direct and indirect pathophysiologic roles of abnormal urate metabolism in congestive heart failure [90]. Ongoing interventional trials [89] assessing cardiovascular outcomes resulting from inhibition of urate production with allopurinol and oxypurinol should provide useful information relative to these proposed relationships.88]. and subsequent vascular events. Endothelial damage resulting from local xanthine oxidase-generated oxygen free radicals is proposed as a basis of cardiac dysfunction in hyperuricemic states. in their prospective case control study [85]. the cardiovascular benefits of losartan extended to a reduced incidence of cerebrovascular events. The serum antioxidant capacity. Nieto and coworkers. and allopurinol inhibition of xanthine oxidase is reported to improve endothelial dysfunction in patients who have heart failure [86. and higher serum urate levels are associated with increasing severity and poorer outcomes in heart failure [87.59]. raising the speculation that under circumstances of alternative antioxidant depletion. however. In animal models. Congestive heart failure Hyperuricemia is a common finding in congestive heart failure [86]. especially in diabetics [81]. was elevated unexpectedly in individuals who had atherosclerosis. but these potential mechanisms are under investigation [84]. a causal role for hyperuricemia in cardiovascular disease events and mortality is not established unequivocally [26. Anker and colleages [87] found high serum urate levels an independent marker for impaired prognosis in patients who have moderate to severe congestive heart failure.282 becker & jolly urate also was an independent predictor of stroke mortality [79. such as ascorbate. Thus. suggesting that hyperuricemia may be a compensatory rather than a causative factor. There seem to be more than sufficient grounds. Even though levels of antioxidants. Hyperuricemia also is a significant and independent risk factor for peripheral arterial disease in Taiwanese men who have type 2 diabetes [84] and for carotid artery atherosclerosis. however. Overall. .93]. poor outcome.58]. In patients in the LIFE study who were hyperuricemic [69]. are reduced immediately after acute ischemic stroke. patients who have the worst early outcome are those who have higher plasma urate levels [82]. Urate also may contribute to more severe heart failure via its role in hypertension [89]. urate may become prooxidant [82. Whether or not the increased risk of stroke in individuals who are hyperuricemic is mediated by increased predilection for the development of hypertension or through a urate effect on the vascular endothelium is unclear. allopurinol decreases myocardial oxygen consumption [91] and improves systolic function [92]. to support new clinical (interventional) and experimental initiatives for studying the potential causal mechanisms by which hyperuricemia may promote cardiovascular disease [27]. find baseline serum urate levels associated significantly and independently with increased carotid artery atherosclerosis 13 years later.83].

confirm reductions in BMI. waist circumference.110]. hyperlipidemia. A corollary of these observations is that individuals who are hyperuricemic and hyperlipidemic. all the features of metabolic syndrome). The fact that acute elevations of serum triglycerides. high-density lipoprotein (HDL) cholesterol levels. fasting and postprandial glucose levels. plasma free fatty acids. and systolic blood pressure in children and adolescents who are obese and may be a reliable marker of ‘‘premetabolic syndrome’’ [98]. Obesity Epidemiologic studies have established a strong positive correlation between body weight and serum urate concentration. studies of weight loss-inducing medications. and serum levels of cholesterol. In addition. Direct and indirect evidence for excessive body weight promoting hyperuricemia and gout is presented in many studies [56. or serum insulin do not effect serum urate levels in health volunteers supports this view [96]. In interventional studies. BMI. triglycerides. such as hypertension and atherosclerotic cardiovascular disease. Included in the diagnostic criteria for the metabolic syndrome are waist circumference. lipoprotein a. the weight loss associated with moderate calorie and carbohydrate restriction and increased proportional intake of protein and unsaturated fat (as recommended for insulin-resistant states) is accompanied by a . metabolic syndrome. triglyceride levels. and urate uric acid [99] (ie. and its components Metabolic syndrome Complexity in defining the role of hyperuricemia in chronic diseases. in particular those who have abdominal obesity.111–115]. Obesity is associated with decreased renal uric acid clearance and increased urate production [109. is underlined by additional associations of hyperuricemia with the clinical and biochemical abnormalities of the metabolic syndrome: obesity. but a role of hyperuricemia influencing development of obesity emerges from a few other studies (Table 2). apolipoprotein B. blood pressure. and fasting blood glucose levels. weight reduction is associated with a modest lowering of serum urate concentration and a decrease in the rate of de novo purine synthesis [109]. insulin resistance. such as sibutramine and orlistat. and insulin resistance. Emmerson [94] has reviewed evidence supporting inclusion of hyperuricemia resulting from impaired renal uric acid clearance [95.hyperuricemia & associated diseases 283 Hyperuricemia. The inverse correlation of serum urate and insulin sensitivity and the positive correlation of urate and triglyceride levels may explain up to 50% of urate variation [96]. but the basis of the relationship is complex and multifactorial [100–108]. In addition. It also is suggested that hyperuricemia may be used as a simple marker of insulin resistance [96]. may be a high-risk group for the cardiovascular correlates of insulin resistance.96] as an intrinsic component of the metabolic syndrome of hyperinsulinemia and resistance to insulin action [97]. Serum urate levels contribute significantly to levels of HDL cholesterol and total cholesterol. blood pressure.

Study included only men jolly Masuo. body mass index. BP. weight gain. and 5 kg for women Observations Remarks Author.] Study design Subjects Loenen. normotensive men BMI and BP increased with increasing quartiles of SUA in men and women at baseline SUA predicts subsequent weight gain and BP elevation Serum uric acid levels tightly related to BMI Ogura. diabetics were excluded. nonobese. serum urate. and blood pressure elevation SUA and obesity or related factors Abbreviations: BMI. 2000 [56] Longitudinal 5926 Subjects ages 25–74 Cardiovascular and all cause mortality An association between body weight and SUA present Study included whites only. 2003 [114] Longitudinal 433 Young. year [ref. 2004 [113] Longitudinal 17. SUA. and 30% participants were on prescribed dietary restrictions Independent risk factor status not evaluated SUA was an independent risk factor for weight gain and BP Independent association between SUA and BMI not clear. .155 Students Relation between serum urate. 1990 [107] Cross sectional 460 Healthy Dutch ages 65–79 becker & Fang.284 Table 2 Characteristics of selected studies on relationship of hyperuricemia and obesity Question addressed Demographic correlates of obesity Average 7-kg difference between lowest and highest tertiles of SUA for men. blood pressure.

128–131]. fasting serum triglyceride levels may be the most important determinant of serum urate levels [132]. CII. the hormone product of the obese (ob) gene. sibutramine and orlistat. triglycerides. . By regression analysis. at least in part. Women have a higher mean leptin and lower mean urate and triglyceride concentrations than men even after adjustment for BMI [126]. amelioration of insulin resistance by a low-energy diet decreases serum urate levels in individuals who are overweight and hypertensive [117]. Finally.133]. Furthermore. B.118.119]. Obesity and excessive alcohol intake confound these issues.hyperuricemia & associated diseases 285 decrease in serum urate levels and dyslipidemia in patients who have gout [116]. hypertriglyceridemia also may be seen in 50% to 75% of patients who have gout. 2. and. is expressed in adipocytes and acts through the hypothalamus to regulate food intake and energy expenditure. in the prospective Swedish Obese Subjects Study [120]. lower serum urate levels [99. even after adjusting for BMI and percent body fat [125]. by leptin expression and that leptin levels may prove to be a link between obesity and hyperuricemia. obesity. triglyceride levels. and an independent relation between serum leptin and urate was found in 822 Japanese women. CIII. Leptin. suggesting that reduced HDL levels are attributable to altered triglyceride metabolism [133]. In humans. leptin. and apolipoproteins AII. Similar findings are observed in children who are obese [127]. and increased leptin levels are associated with insulin resistance in individuals who are nondiabetic [121]. insulin. Furthermore. Concentrations of serum Lp(a) lipoprotein.and 10-year hyperuricemia and hypertriglyceridemia incidence rates were lower in patients who had undergone bariatric surgery than in unoperated obese control subjects. and triglyceride levels account for significant variability in serum urate in men and women [126]. Hyperlipidemia The issue of hypertriglyceridemia and hyperuricemia is addressed in many studies [56. Hyperuricemia is observed in up to 80% of patients who have hypertriglyceridemia. These studies suggest that the association of serum urate. Insulin response. and HDL-C was decreased in patients who had gout [134]. Serum urate and leptin levels correlate in healthy male adolescents [123] and in women who are moderately obese [124]. no association between gout and HDL levels or BMI index was seen. Reductions in serum HDL-C and HDL2-C concentrations also are observed in individuals who are hyperuricemic [125. Creatinine. and insulin resistance may be mediated. and E reportedly were increased. and its presence was associated with higher triglyceride levels in very lowdensity and intermediate-density lipoproteins and with reduced renal uric acid excretion [135]. and BMI are associated independently and significantly with leptin concentrations [122]. The prevalence of apolipoprotein E2 allele was greater in patients who had gout. Most persons who are obese show leptin resistance. the weight-reduction agents.98.

286 becker & jolly In the prospective GREACE study. a strong association between serum urate and subsequent development of hypertension or type 2 diabetes was found [141]. In the atorvastatin treatment group.and 10-year incidence rates of hypertriglyceridemia and hyperuricemia were observed in obese patients who underwent bariatric surgery. addition of atorvastatin to the standard treatment of coronary heart disease patients resulted in serum urate reduction averaging 8. An association between hyperinsulinemia and decreased renal uric acid clearance also is reported in another study [96]. Persistent hyperuricemia in postmenopausal women in the Kinmen study also is associated with subsequent development of diabetes [139. and the LDL-C/HDL-C ratio decreased by 50%. triglyceride levels fell by 31%. resulting in increased serum urate concentration. In a study of the relationship of insulin-mediated glucose disposal and serum urate in 36 healthy nondiabetic volunteers [95].140]. renal uric acid clearance decreased in proportion to increased insulin resistance. however. The relationship with diabetes was stronger in men who had BMI less than 24. thus. lower 2. Relationships between hyperuricemia and each of these morbid states do. in one or more of these disorders. exist and may. In another prospective study.136]. Similarly.2% compared with an average 3. urate suppresses basal insulin release in isolated rat pancreatic islets and inhibits glucose-stimulated insulin secretion [137]. Finally. In experimental animals. Although experimental studies performed in animals .2 kg/m2 compared with higher BMI. hyperuricemia is associated with the development of hypertension but not type 2 diabetes [10]. but the absolute risk was greater in more men who were obese. In a longitudinal study of Japanese male office workers. Increased serum urate concentration is among the significant risk factors associated with non–insulin-dependent diabetes mellitus in Japanese Americans living in Hawaii and Los Angeles [138].3% increase in patients receiving standard care without atorvastatin [71]. prove causal and. metformin administration not only reduces postprandial and fasting blood glucose levels but also serum urate levels [99]. HDL-C rose by 7%. exploitable by urate-lowering intervention. Insulin resistance The relationship between hyperuricemia and insulin resistance may be indirect and mediated through increased fasting plasma triglyceride levels or BMI [96. in another prospective study [120]. however. Summary It is the authors’ belief that the literature to date has not established a causal link between hyperuricemia and the previously discussed disorders that justify the use in clinical practice of urate-lowering treatment in aymptomatic hyperuricemia to avoid or modify the course of the associated diseases.

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the ARPS.rdc.b ´ ´ ´ Federation de Rhumatologie. the ionized form. such as spinal ligaments This work was supported by grants from the INSERM. 2. MDa.b. doi:10. As urate concentrations increase in physiologic fluids. but also in the skin or other structures. however.aphp. All rights reserved.T.2006. new imaging aspects. Hang-Korng Ea. France ´ ´ a Gout nowadays is under the scope of fame. T Corresponding author. but pathogenesis of gout inflammation is reviewed.theclinics. ` ´ E-mail address: frederic.fr (F. New preliminary insights are beginning to be available from MRI and ultrasound studies. Assistance Publique-Hopitaux de Paris (AP-HP). Hopital Lari´ ´ ˆ boisiere. Paris. ´ ´ ˆ Hopital Lariboisiere. mainly within and around joints. remain to be elucidated. Paris. New pathogenic mechanisms (including autolimitation of acute attacks). MD. providing possible tools for evaluation of tophi in clinical trials. thousands of years after its description by Hippocrates. Paris.8) that is present mainly as urate. Hopital Lariboisiere. The pathogenesis of hyperuricemia is not addressed in this article. Pole Appareil Locomoteur (Centre Viggo Petersen).c. and the ART. a frequent metabolic disorder. F-75475 PARIS CEDEX 10. AP-HP. rue Ambroise Pare. Federation de Rhumatologie (Centre Viggo Petersen). ´ 0889-857X/06/$ – see front matter D 2006 Elsevier Inc.liote@lrb.com . Pathogenesis of urate crystal deposition and tophus Uric acid is a weak acid (pKa 5. PhDa. and (as described by Choi elsewhere in this issue) new epidemiologic insights and therapeutic advances recently have been reported in the English literature. France ˆ ` ˆ b INSERM U606 (IFR139).03. at physiologic pH.Rheum Dis Clin N Am 32 (2006) 295 – 311 Gout: Update on Some Pathogenic and Clinical Aspects Frederic Liote.1016/j.001 rheumatic. Denis Diderot. France. urate can crystallize as a monosodium salt in oversaturated tissues. The genetics of primary gout and hyperuricemia. France ˆ ` c Universite Medecine Paris 7. new clinical complications. Liote).

followed by the recruitment and activation of mastocytes and peripheral blood monocytes through endothelial cell activation. At the onset of crystalinduced arthritis (CIA). with phagocytic properties. This direct crystal-cell membrane interaction is reported in several studies: within minutes. activating synovial lining cells. pH variations. either physically or through electrostatic bounds. triggering a typical phagocytic inflammatory response [7]. The solubility of urate is modulated by temperature (lower temperature at the foot). followed in some cases by low-grade residual synovitis or by restitution ad integrum. and cation concentration.8 mg/dL. free crystals or even naked crystals with no protein coating are released from a remodelling tophus [6]. These cells are fibroblast-like synoviocytes and macrophage-derived cells. Autolimitation of acute inflammation is driven by macrophages. Recently. however. and apoptosis.5]: MSU crystals first are released in the joint cavity. and sustaining an intense inflammatory response. They can be opsonized by proteins and phagocytosed as particles.8]. Once released within the joint cavity. infection. Tophus can grow from urate crystals depending on urate sursaturation and on increased promoters or loss of inhibitors of crystallization. The physiochemical properties of monosodium urate (MSU) cause crystals to precipitate in body fluids if the concentration is greater than 6. leading to further MSU crystal phagocytosis and cell activation. cartilage fragments. a so-called ‘‘acute attack. Initiation As discussed recently by Liu-Bryan and Terkeltaub. Sequential cellular activation is postulated from in vivo studies focusing on tissue pathology analysis [4. synovial fluid contains low protein content. MSU crystallization is dependent on nucleating agents. neutrophil necrosis. toll-like . under specific local and systemic circumstances (temperature. Neutrophils are recruited and egress into the joint cavity. chondroitin sulfate. and other crystals [1]. because MSU crystals are negatively charged. MSU crystals should interact with the synovial lining cells. or surgery).’’ because of their ability to activate humoral and cellular inflammatory components. especially regarding immunoglobulins.296 ´ liotE & ea and fibrous tissues [1]. intra-articular fluid dehydration (onset at night). The putative initial mechanism involves the physicochemical surface properties of MSU particles interacting directly within minutes [8] with membrane proteins [6] and lipids. Pathogenesis of urate crystal-induced inf lammation MSU crystals are capable of directly triggering. amplifying. for instance in chondrocytes [6. such as insoluble collagens. local articular traumatism. The pathogenic inflammatory pathways of MSU crystal-induced inflammation recently have been reviewed [1–3]. proteoglycans. the crystal contact can trigger signal transduction.

They infiltrate the tissues of animal models of MSU CIA at a rate 10 times higher than neutrophils [5]. as shown in vivo using the airpouch model developed in TLR-2. Maximal expression of TREM-1 messenger RNA (mRNA) and protein occurs early after MSU crystal exposure. and the three mitogen-activated protein kinases. Factors. which mediates neutrophil adhesion and recruitment. and interleukin [IL]-1b) can activate endothelial cells. because costimulation of peritoneal macrophages with MSU crystals and an anti–TREM-1 agonist antibody increase the production of IL-1b and monocyte chemotactic protein [11]. Studies of cellular kinetics using animal models of MSU crystal-induced inflammation demonstrate that monocytes recruited from the blood and resident mastocytes are the first cells to infiltrate or be activated [5]. but several studies clearly show that other cells play a central role in the early phase of CIA. tyrosine kinases associated with the FAK complex. Histamine is well documented as having multiple effects leading to increased vascular permeability and enhanced adhesion molecule expression. as histamine1 antagonist and PAF antagonist reduce neutrophil influx into the peritoneal cavity [16].pathogenic & clinical aspects of gout 297 receptors (TLR) 2 and 4 present at the cell surface have been implicated in the chondrocyte and macrophage signaling. In the murine air-pouch model. a role for endogenous mast cells is suggested. recently have been identified as other mediators of acute MSU crystal-induced inflammation. an acute phase reagent [15]. cell recruitment. tumor necrosis factor [TNF]-a.10]. As discussed earlier. therapeutic issues can be raised. TLR-4. platelet activating factor [PAF]. phospholipase C and D. Mast cell activation and histamine release are observed in CIA inflammation model in vivo [5]. a new cell surface molecule was reported that triggering receptors expressed on myeloid cells 1 (TREM-1). such as the myeloid related proteins [12] and the complement membrane attack complex [13]. MSU crystals actually have the ability to trigger an . vascular endothelial growth factor. and increase vascular permeability. and myeloid differentiation factor 88 (MyD88) knockout mice and in vitro in cultured cells [9. Other preformed and stored mastocyte mediators (eg. because in MSU crystal-induced murine peritonitis. Finally. such as upregulating P-selectin. including G proteins. Crystal-induced cellular activation and recruitment Neutrophils are the hallmark of inflammatory cells recruited into the synovial fluid (SF) in gouty attack. which could be induced rapidly on neutrophils and resident peritoneal macrophages by MSU crystals in vivo [11]. In February 2006. Mast cells are proposed as playing a role in innate immunity [14] and can be an important cell component of MSU CIA because they contain preformed granules with cytokines and also histamine. It is speculated that cell membrane modulation leads to cross-linking and clustering of membrane as an initial event for activation of several and redundant signal signaling pathways. rapid induction of TREM-1 can trigger inflammation. Monocytes also are implicated in the early onset of MSU CIA. present on monocytes and neutrophils. MSU crystals also induce TREM-1 rapidly.

Nishimura and colleagues show that MSU CIA in rabbits is attenuated by a neutralizing antibody against IL-8 [24]. As a ‘‘newcomer. resident and differentiated monocytes) could represent the major cell in this . Spontaneous resolution of acute attack In spite of the intensity and sudden onset of an acute bout of gout. These cytokines and chemokines also are able to activate endothelial cells and promote monocyte and neutrophil adhesion.298 ´ liotE & ea inflammatory response by freshly isolated monocytes and THP-1 monocytic cells [7. are measured in SF from patients who have gout [27]. the selflimitation of joint inflammation that results in an apparent return of the joint apparently ad integrum is puzzling. CXCR-2.28]. an angiogenic factor with antiinflammatory properties. IL-1b. IL-8 is a central player. Reduced cytokine response by monocytes to MSU crystals could be an explanation for reduced gout attack in patients who have chronic renal failure [26]. IL-18 is not a player in neutrophil recruitment in in vivo MSU crystal-induced inflammation model [25]. but these processes are not considered major players. including TNF-a. Protein and lipoprotein crystal-coating changes [30–32] have been discussed by several investigators. high levels of angiogenin. and tissue infiltration. stimulate chemotaxis. Crystal properties can be modified and represent a first target: crystal size reduction and crystal clearance. using knockout mice for IL-8 receptor. Macrophages (eg. Angiogenic factors also have cytokine properties and are expressed in gout. Monocytes play a central role in the regulation of acute attack. For example. the processing enzyme for IL-18 activation [25]. a member of IL-1 family. Similar results are achieved in MSU crystal-induced rabbit arthritis [22. This is supposed to be determined by effects of cytokines (TNF-a and IL-1b) and chemokines (IL-8 and macrophage inflammatory protein-1a) [22. such as C5a and IL-8. and IL-8 (but not IL-10) secretion. is reported to be increased in plasma from patients who have gout arthritis and secreted by monocytes after MSU crystal stimulation along with an activation of caspase-1. because they also are implicated in the self-limitation of inflammation. Their roles were distinguished early by Schumacher and coworkers in gouty arthritis in dogs [4]. or neutralizing anti–IL-8 antibody. Amplification Neutrophils are recruited into synovium and migrate within the synovial cavity along with serum proteins. By contrast. Neutrophils follow concentration gradients of chemoattractants.23].17–21]. as demonstrated in in vivo models (air-pouch in mice and arthritis in rabbits) by Terkeltaub and colleagues [29] and Nishimura and colleagues [24].’’ IL-18. IL-6. respectively. Activated endothelium allows neutrophil adhesion dependent on E-selection and P-selectin upregulation and migration into the synovium. which in turn promote endothelial cell E-selectin expression and secondary neutrophil adhesion under dynamic conditions.

These findings are consistent with results obtained by the injection of recombinant human IL-10 into air pouches [40]. Under MSU crystal stimulation. NO synthase 2 or inducible NO synthase is induced in vitro by freshly isolated human monocytes by MSU crystals [47]. The intrinsic mechanisms underlying the anti-inflammatory switch are understood poorly but it seems. Therefore. mainly. and lower IL-10 (and normal IL-4) mRNA levels are determined in SF mononuclears from patients who have gout compared with those who have rheumatoid arthritis [42]. macrophages produce IL-10 and.45]. Conversely. conversely.35]. to stimulate anti-inflammatory cytokine secretion (IL-10 and transforming growth factor [TGF]-b1) when stimulated by phagocytosed MSU crystals [34. in MSU-crystal inflammation. reduce monocyte and neutrophil adhesion and recruitment [37]. Il-6. They demonstrate that a switch from homologous monocytes to macrophages leads to the loss of ability to produce proinflammatory cytokines (IL-1. TGF-b1. 1). NO also is detected in vivo in rat air-pouch fluids after MSU crystal activation [2]. It is observed in SF from various diseases. Landis and Haskard have promoted the idea that the mononuclear phagocyte may play a key role within the synovial compartment. and TNF-a) and. tipping the balance from the asymptomatic state to acute inflammation. such as IL-10. depending on the state of monocyte to macrophage differentiation [33]. but not rheumatoid arthritis [46]. however.39]. Therefore. Other anti-inflammatory cytokines. for example. TGF-b1 can lower endothelial activation. because no IL-10 is detected in any of the 17 sera tested from patients with gout [41]. but not necrotic or lysed cells [44.and anti-inflammatory cytokines by phagocytic monocytes is regulated delicately during the ingestion of apoptotic cells as part of an intrinsic mechanism to prevent inflammatory autoimmune reactions [43]. induces active anti-inflammatory or suppressive properties in human macrophages [44]. a pivotal cytokine in the anti-inflammatory process [36].pathogenic & clinical aspects of gout 299 regulatory process. NO inhibition maintains the inflammatory cellular reaction evidenced in vivo [2]. Other anti-inflammatory compounds also are released by MSU crystalstimulated macrophages. Binding or phagocytosis of apoptotic cells. that the production of pro. TGF-b1 secretion also can be triggered by ingestion of apoptotic cells [38. it is likely that resolution of inflammation depends not only on the removal of apoptotic cells but also on active suppression of inflammatory mediator production (Fig. Relevance for humans is debated. Recently. such as reactive arthritis and CIA. This monocyte-macrophage switch and its ability to control inflammation is a well-known mechanism not related specifically to MSU crystals. are shown to reduce in vivo MSU crystal inflammation. or vice versa. NO seems to act as an anti- . Retrovirally transfected IL-10 cells injected in murine air-pouch model significantly inhibited MSU crystal-induced cellular infiltration and production of the mouse CXC chemokine KC. and reduce IL-1 expression and IL-1 receptor expression. NO donor can inhibit MSU-crystal inflammation when administered either before or at the onset of acute inflammation in the rat air-pouch model. namely nitric oxide (NO) and peroxisome proliferatoractivated receptor (PPAR)-g.

In turn.49]. leukocyte migration. resulting in accelerated resolution of inflammation (Fig. necrosis. reduce proinflammatory cytokine production. inflammatory compound. suggesting a regulatory mechanism for monocyte-MAC switch in acute gout attack. A role for apoptotic neutrophil bodies to trigger the MAC ability to secrete TGF-b1 is demonstrated in various situations but not yet in acute gout. leading to endothelium activation. They undergo various processes: death process from within. MSU crystals are unable to stimulate mature and differentiated MAC to produce proinflammatory cytokines. Recruited neutrophils (PNN) migrate into the joint cavity and further phagocytize MSU crystals and release mediators. via exposure of phosphatidyl serine and ligation of its receptor. 1). Apoptotic bodies from neutrophils are demonstrated to enhance MAC differentiation and TGF-b1 production. which can act as a transcriptional regulator of certain genes. (A) Monocytes are recruited from the blood. suggesting a direct role for crystals to avoid resolution of attack. . suggest that MSU crystals can delay neutrophil apoptosis [48. it inhibits the gene expression of cytokines. Neutrophil apotosis also is advocated as a possible mechanism for resolution. with the ability to block endothelial cell activation. PPAR-g production is achieved in vivo in the rat air-pouch model as early as 12 hours after crystal stimulation.300 ´ liotE & ea Fig. Schematic representation of monocyte-macrophage switch in the installation and resolution of acute MSU crystal-induced inflammation.39. such as cyclooxygenase. apoptotic cell recognition and clearance. innate and adaptative immunity. and increase IL-1ra production. Similarly. 1. however. (B) Differentiation of monocytes to MAC seems to be a paradigm in inflammation. Early PPAR-g stimulation and production by adherent monocytes by MSU crystals is achieved in vitro.45]. they produce various cytokines and chemokines. and apoptosis. In vitro experiments. yet immature macrophages (MAC) can be stimulated by MSU crystals. Conversely. induce TGF-b1 secretion [38. PPAR-g is a member of the nuclear hormone superfamily. leukocyte adhesion and recruitment. TGF-b1 is a pivotal anti-inflammatory cytokine. and further cell activation.

In parallel. S100A9+. Corticosteroids could enhance tophus formation. In vitro chondrocytes can phagocytize particles. These macrophages coexpress TNF-a and matrix metalloproteinases (MMPs) 2 and 9. Direct cartilage-tophi contact is demonstrated by arthroscopy. a phenomenon that may restrict the destructive potential of inflammatory macrophages [53]. Once developed in situ in cartilage or in synovium. almost all CD68+ mono. even subsiding after clinical resolution of gout attacks or to foreign body synovitis around crystals. S100A9À. and also between attacks.’’ Treatment with colchicine decreases white cell counts in synovial fluid of asymptomatic knees that contain MSU crystals [52].and multinucleated macrophages surrounding deposits of MSU microcrystals. because MSU crystals also are detected in joints from some patients who had asymptomatic hyperuricemia and hyperuricemic patients who had chronic renal failure. which can contribute to cartilage degradation and further tophus breaking [6]. experimental studies related to tophi pathogenesis are lacking. it is assumed that MSU crystals may contribute to chronic synovitis and associated joint damage. Gout tophi are characterized by foreign body granulomas consisting of mono. Chronic tophaceous gout After years of chronic and untreated hyperuricemia. granulomas grow associated with degradation of the extracellular matrix. and in vitro nonadherent chondrocytes also can produce active MMPs after MSU [8] or even calcium crystal stimulation [56]. and MMP expression [8].51] clearly identify MSU crystals in SF taken from up to 70% of asymptomatic first metatarsal or knee joint of patients who had proven gout during the so-called ‘‘intercritical period.and multinucleated cells arranged within granulomas are S100A8À. In contrast to acute inflammation. representing freshly migrated monocytes/macrophages. Tophi can grow at the cartilage surface and within the synovium. such as latex beads [55].pathogenic & clinical aspects of gout 301 Intercritical gout Although MSU crystals are the hallmark of gouty arthritis. MSU crystals can con- . After primary formation. and 25F9+. In addition. representing mature (nonmigrating) macrophages. In contrast. IL-1b activation. gouty arthritis can develop with its hallmark. Low-grade asymptomatic synovitis and associated intra-articular dormant tophi can be postulated but await evidence. Direct chondrocyte cell membrane crystal can trigger cell activation. macrophages undergo apoptosis. Immunohistochemistry studies performed on tophi show that perivascular localized mononuclear cells are CD68+. intrarticular and periarticular tophi. Two studies from Pascual and coworkers [50. because they remain in the joint. NO synthase expression and NO production. they can be found even during the resolution phase but have lost their ability to stimulate further inflammation. S100A8+. leading to lowgrade synovitis. and 25F9À. A preclinical phase of gout is ascertained. as shown in the air-pouch model by Rull and colleagues [54] and in clinical reports. as evidenced by histologic studies.

As discussed previously. on gout diagnosis and management.62]. but SF can be kept at À208C before analysis: in these conditions. namely rapid onset of severe pain. presence of tophus. Before proper studies are done. Classification of gout is a different issue that is approached partly with the (former) American Rheumatism Association preliminary criteria [59]. Diagnosis of gout Diagnosis of gout relies on the association of acute attacks. standard quality for crystal examination. because MSU crystal detection can be considered a gold standard for gout. because room temperature can modify crystals and cells can be lysed. there is a smaller risk . Based on a systematic literature search and expert consensus achieved through Delphi procedures. a retrospective diagnosis of gout can be achieved when asymptomatic metatarsophalangeal (MTP) or knee joints are tapped and MSU crystals are detected easily at first look in the polarizing microscope. it can be speculated that a defect in antiinflammatory properties of macrophages. This examination should be done routinely (but always carefully). there is a large consensus on the diagnostic value of MSU crystal identification in SF and tophus. Microscopic analysis should be performed as soon as possible with a polarizing microscope. hyperuricemia. Preliminary diagnostic recommendations were reported at the 2005 EULAR meeting in Vienna (Box 1) and currently are under review [60]. Therefore. and. identification training should be better defined [61. such as calcium pyrophosphate or apatite or other rarer inflammatory conditions. could contribute to low-grade inflammation by residual MSU crystals. joint swelling and local tenderness. Bouchard’s group shows that MSU crystals reduce the activity of osteoblasts in vitro [57]. Overall. chronic and destructive arthropathies. Suspected tophus can be sampled carefully for MSU crystal to ascertain diagnosis. with a peak in symptoms occurring within 6 to 12 hours. This is typical for crystal acute attack but can be related to another crystal type. there are no diagnostic recommendations or evidenced-based medicine recommendations for gout. and 34 out of 48 after treatment was begun [51]. Only clinical issues are discussed briefly. in some advanced diseases. This gap will be filled by a task force of the European League Against Rheumatism (EULAR) Standing Committee on International Clinical Studies Including Therapeutic Trials (ESCISIT). thereby limiting the healing process of erosions. Forty-three joints in gouty patients were positive for MSU before any hypouricemic drug was started. as observed in other chronic diseases [58]. it should be recalled that proper conservation of SF has to be achieved. To date. because MSU crystals are strongly birefringent. 10 recommendations have been sorted out and validated. Based on the anti-inflammatory effects of macrophages triggered by either MSU crystals or apoptotic cells.302 ´ liotE & ea tribute to bone lesions. and overlying erythema. however. Clinical issues discussed by the EULAR task force relate mainly to the clinical characteristics of crystal inflammation.

a clinical diagnosis alone is reasonably accurate but not definitive without crystal confirmation. Risk factors for gout and associated comorbidity should be assessed. even if MSU crystals are identified. 10. Gout and sepsis may coexist. swelling. 7. Microcrystals are identified better when looking in the clot formed by fibrins and cell debris. Renal uric acid excretion should be determined in selected patients who have gout. they are not useful in confirming the diagnosis of early or acute gout. EULAR evidence based recommendations for gout. and hypertension). in press. onset of gout under age 25. and serum levels may be normal during acute attacks. although not specific for gout. et al. Demonstration of MSU crystals in synovial fluid or tophus aspirates permits a definitive diagnosis of gout. for crystal dissolution. 4. especially those who have a family history of young-onset gout. For typical presentations of gout (such as recurrent podagra with hyperuricemia). Report of a task force of the standing committee for ESCISIT. Part I diagnosis. 6. allowing a definite diagnosis in intercritical periods [50. including features of the metabolic syndrome (obesity. Ann Rheum Dis 2006. or renal calculi. eventually after centrifuging the SF. 3. Although radiographs may be useful for differential diagnosis and may show typical features in chronic gout. is highly suggestive of crystal inflammation. 9. especially with overlying erythema. From Zhang WDM. Gram’s stain and culture of synovial fluid still should be performed. and tenderness that reaches its maximum within just 6 to 12 hours. A routine search for MSU crystals is recommended in all synovial fluid samples obtained from undiagnosed inflamed joints. Identification of MSU crystals from asymptomatic joints may allow definite diagnosis in intercritical periods. the rapid development of severe pain. 8. . Detection of MSU crystals has excellent value in the diagnosis of symptomatic gout or even of asymptomatic gout (knee or first MTP joint).pathogenic & clinical aspects of gout 303 Box 1. although cells usually are lysed.51]. hyperglycemia. with permission. 2. hyperlipidemia. serum uric acid levels do not confirm or exclude gout. In acute attacks. Pascual E. 5. Ten key recommendations for the diagnosis of gout from the European League Against Rheumatism Standing Committee for International Clinical Studies Including Therapeutic Trials 1. because many people who have hyperuricemia do not develop gout. Although they are the most important risk factor for gout. so when septic arthritis is suspected.

including the knee and hip joint or upper limb. with multiple hypointense speckles. starting at the foot joint. Preoperative diagnosis is uncommon but should be suggested when addressing patients who have long-standing gout. but rheumatologists should be aware of isolated skin involvement.and T2-weighted images. septic arthritis. Spinal involvement Tophus of various sizes can develop in any anatomic structure of the spine. Skin involvement Unusual sites for tophi are reported. leading to nerve root. Gout can represent a significant etiologic factor in the development of symptomatic spinal stenosis associated with cyst formation from a facet joint. this frequently is referred to as pseudopodagra. other joints may be involved. are observed commonly in elderly women receiving diuretics for hypertension [63] and more rarely in men. and tophi. because fixation in water dissolves MSU crystals. Long-standing tophus could represent a risk factor for angiosarcoma [65]. alcoholic conservative should be used. material should be sent for examination under polarized light. In addition to standard histologic examination. Podagra is located by definition in the first MTP joint. As the disease progresses. cord compression [2. Cutaneous tophi with inflammatory aspects. Radiographs can show erosive and destructive changes in cervical disks. radiographs can be suitable in some unusual settings. Surgical decompression is mandatory and effective. to rule out apatite calcification.304 ´ liotE & ea Unusual clinical involvement Common clinical aspects Acute gout attacks occur mainly in the lower extremities. It is not possible to diagnose gout of the spine by standard examination of a fixed specimen. psoriatic arthritis. chronic arthropathy. When fever is present. and women show a higher frequency of upper limb joint involvement [63]. or even lumbar spinal stenosis. The most common diagnoses of arthritis in the first MTP joint are crystal-induced synovitis. clinical features and even imaging can mimic epidural abcess or spondylodiscitis [69]. traumatic conditions.66–68]. because pre- . MSU deposits might be responsible for unusual panniculitis [64]. calcium pyrophosphate deposit. Gout tophi by MRI studies yield homogeneous and hypointense masses on T1. and reactive arthritis. such as those involving young patients. De Galantha staining allows direct visualization of MSU crystals. Therefore. Podagra is more common in men. Cervical cord compression by tophus [68] is rare compared with those associated with calcium pyrophosphate dihydrate deposition (CPPD) deposits. In this setting. as has been known for centuries. or necrosis of the sesamoid bone. or at the opposite indolent. When causes other than gout involve the first MTP joint. which can reveal deposition of urate crystals in such cases.

a sesamoid necrosis or fracture of the first MTP should be discussed and a specific radiograph prescribed (Walter-Muller view). The portal of entry clearly was related to skin changes or complications associated with tophi in 60% of the patients. radiocarpal joint. provides confirmation [72]. Gout and septic arthritis Fever is a common feature of acute gout attack. Staphylococcus aureus and streptococcus and gram-negative bacterias are responsible for fasciitis in patients who have gout. including CT scan. when diagnosis is suspected. Peripheral nerve root compression Clinicians should be aware of the possibility of tophi causing nerve root compression. such as carpal tunnel syndrome (CTS) and cubital compression. and Gram’s stain and culture of SF are mandatory. including amputation and antibiotherapy. Because the breakdown of the skin around tophi carries a high risk for infection. Again. when young patients present with subacute or acute pain under the first MTP after a walk. fasciitis should be discussed when facing tissue inflammation that resembles erysipelas or cellulitis.74]. Septic shock. Infectious necrotizing fasciitis recently has been reported in gouty patients. occurring. Also. . including Yu and colleagues’ [73. regression of cord compression is achieved under urate-lowering agents [70]. Outcome was poor in the Taiwan series and carried a 20% high mortality rate in spite of surgical procedures. and ultrasound. A pseudopodagra can be observed in apatite or CPPD deposit. even if MSU crystals are identified readily. It is necessary to rule out septic arthritis. MRI. with a prevalence of 4. multiorgan failure. Imaging. and even death can occur. shortly before bullae appears as a late manifestation of fasciitis. the intensity of pain is out of proportion to the physical findings. Surgical liberation usually is mandatory to avoid sequellae. it is of importance to get a local treatment to prevent extensive infection. mainly in polyarthritis. as expected. Tophi can be found in the floor of the carpal tunnel.8% of fasciitis observed at a Taiwanese hospital [73].6% in a large series of 2649 CTS releases.pathogenic & clinical aspects of gout 305 operative diagnosis of spinal gout rarely is evoked preoperatively. In these series. mainly in men [71]. in rare cases. Therefore. Prevalence of CTS was estimated at 0. Imaging Radiographs are not useful for the diagnosis of acute gout except for differential diagnosis. carpal bones. Aggressive treatment with antibiotics and surgical cleaning is mandatory. Several dozen such cases are published. Organisms grew from SF taken from 73% of their 30 patients. and extensor tendons or tendon sheaths of the wrist.

2). Note the well-defined. various skin nodules have been imaged by comparing rheumatoid nodules. and cysts. and MRI studies are of major interest in evaluating spinal involvement. Ultrasound could be promising. and extension around phalangeal bones. Radiographs of chronic gout arthropathy of the ankle and midfoot joints. gout tophus. .306 ´ liotE & ea Fig. asymmetric involvement. 3). lack of periarticular osteopenia. soft tissue nodules. 3. punched-out erosions with overhanging edges. sarcoid nodules. a lateral view can exhibit osteophytes on the dorsal part of the joint (Fig. punchedout erosion with overhanging edges. In chronic disease evolving to destructive arthropathy. asymmetric involvement. the radiologic hallmark of tophus is well known (Fig. At the midfoot joint. can present postacoustic shadow. Characteristic of gout is well-defined. 2) [75]. To date. Tophi can contribute to soft tissue swelling. and extension around bone diaphysis (see Fig. are more hypoechoic. with secondary calcium deposits in longstanding disease. lipomas. soft tissue swelling. and are more prone to be adjacent to bone erosions or at Fig. with preservation of the joint space. Anatomic distribution recently had been reviewed [76]. Modern imaging is still being evaluated. Radiographs of chronic gout arthropathy of the hands. Tophi appear different from rheumatoid nodules: they are more heterogeneous. 2. Note the spikes of the dorsum side of the midfoot and severe joint destruction and ankylosis.

Outcome and evaluation of gout As new treatments are developed. (C) T2-weighted sequence with fat sat sequence: lateral and axial views. erosive prepatellar and pretibial tophi (arrow). with dippled calcium deposits. CT scan has been obtained in some cases. least cortical irregularity [77]. Bursitis can occur. tophi present as masses that usually have low or intermediate signal intensity on T1-weighted images. Diagnostic values of color Doppler technique remains to be evaluated [78]. On MRI. CT disclosed osteolytic lesions containing round or oval opacities. Nodules can be measured readily but reproducibility is ongoing.pathogenic & clinical aspects of gout 307 Fig. especially for intra-articular tophi (Fig. Large tophi around the knee: large ovalar tophus at the posterior lower thigh (*). (B) gadolinium T1-weighted sequence. there are no well-established outcome measures or data on follow-up and outcome of gout cohorts. and (D) lateral views. 4) [75]. Soft tissue tophi. and a variable but characteristic enhancement pattern. MRI study of the knee (A) T1-weighted sequence. Gadolinium can disclose an enhanced homogeneous or heterogenous rim signal around the tophus. regarding chronic joint clinical and radiologic symptoms or . can result in bone erosion clearly depicted at CT scan [72]. Hypoechoic areas might decrease after aspiration of chalky material. As described by Gerster and coworkers [78]. 4. low to intermediate T2-weighted images. including patients treated long-term. with a mean density of approximately 160 Hounsfield units.

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Kwon.b. Boston. and American Heart Association Postdoctoral Fellowship Award 0225706T (KZ). This brief review focuses on recent developments in the molecular physiology and genetics of urate homeostasis.10]. MDa. E-mail address: dmount@rics. 4 Blackfan Circle. Boston. MA 02115. cardiovascular disease [11]. USA b Several recent developments have created a renaissance of sorts for uric acid homeostasis.c.d. USA c Division of General Internal Medicine.13]. 0889-857X/06/$ – see front matter D 2006 Elsevier Inc. and the metabolic syndrome [14–16].com . a Pediatric Scientist Development Award from the National Institutes of Health (CYK).edu (D. All rights reserved. provocative roles for uric acid have also been proposed in inflammation [9. such that urate homeostasis is of relevance to an increasing number of disorders.rdc.Rheum Dis Clin N Am 32 (2006) 313 – 331 Renal Urate Transport David B. Brigham and Women’s Hospital. Room 540. the urate exchanger in the proximal tubule that reabsorbs the bulk of filtered urate from the glomerular ultrafiltrate [1]. Mount. Charles Y. heart failure [12.B.8]. Mount). MA. Boston. HIM Building. These developments include the molecular characterization of urate transporter-1 (URAT1). MDa. Renal Division.1016/j. MA.006 rheumatic. doi:10. Novel. In particular. Kambiz Zandi-Nejad.bwh.2006. MDa. an Advanced Research Career Development Award from the Veterans Administration (DBM). Work in the authors’ laboratory has been supported by RO1 DK-57708 from the National Institutes of Health (DBM). two candidates have emerged for the sodiumdependent anion transporters that collaborate with URAT1 in urate reabsorption by the proximal tubule [2–5]. More recently. There also is an increasing interest in the role of uric acid in hypertension [6] and progressive renal disease [7] (reviewed elsewhere) [6.harvard. Children’s Hospital of Boston. Boston.theclinics.T. USA d Renal Division.b a Harvard Medical School. there have been major advances in the molecular understanding of renal urate transport. MA. BWH.b. VA Boston Healthcare System.02. The physiologic relationships between these apical transporters are relevant particularly for the pathogenesis of hyperuricemia and gout. USA Renal Division. MA. T Corresponding author.

in addition to the host of other disorders in which hyperuricemia is postulated to play a role. exhibit fractional excretion for urate of approximately 10%. transcription of this gene is considerably more widespread and robust in mice [26. the uricase gene is crippled by two mutations that introduce premature stop codons [17]. underlining the divergent evolutionary pressure on these pathways. Subsequent bidirectional transport along the nephron results either in net reabsorption (humans. The fractional excretion of urate differs considerably in mammals: 10% in humans versus approximately 40% in rats [32] and 200% in pig [33]. however. Highly speculative advantages conferred by the relative hyperuricemia in these species include reduced oxidant stress and a decreased incidence of cancer [20]. several other genes involved in urate homeostasis are differentially conserved or preserved in various mammalian species. and even increased intelligence [23]. In humans.27]. Cebus monkeys also exhibit fractional excretion of approximately 10% [34]. chimpanzees lack uricase activity. pigs and rabbits [30. The absence of uricase. the evolutionary loss of uricase and the development of highly efficient reabsorptive mechanisms for urate seem to be separate.31] seem to lack the apical urate-anion exchanger that is found in all the ‘‘reabsorptive’’ species. In contrast. the existence of independent loss-of-function mutations in the genome of gibbon apes suggests that this gene was subject to significant negative pressure during the evolution of hominoids [19]. member 12) encoding URAT1 (discussed later).27]. and have circulating uric acid levels that approximately are equal to those of humans [36]. Therefore. a more soluble metabolite. unlike other New World monkeys. an enhanced ability to survive under conditions of low dietary salt [22]. uric acid circulates primarily as urate and is filtered freely by renal glomeruli. rats. presumably because of inactivation of the SLC22A12 gene (Solute Carrier gene family 22. Cebus monkeys possess an active uricase enzyme and have uric acid levels that are approximately half those of humans [35]. share the same truncating mutations in uricase. Whereas primates. . the enzyme that mediates the last two steps of purine metabolism [28]. combined with extensive reabsorption of filtered urate. and dogs) or secretion (pigs and rabbits).314 mount et al Phylogeny and uric acid In most mammalian species. additive events that result in relative hyperuricemia in humans and related hominoids. complexation of circulating iron and inhibition of iron-catalyzed oxidation [21]. such as the chimpanzee. with the remainder excreted in the urine [29]. In plasma. uric acid generated from purine metabolism undergoes oxidative degradation via the uricase enzyme to produce allantoin. primates. results in urate levels in human plasma that are approximately 10 times those of most other mammals [18]. The purported benefits of an increase in uric acid are offset in part by the risk of gout [24] and nephrolithiasis [25]. This is a recurrent theme. The risk of hyperuricemia in humans is mitigated genetically by comparative repression of the human xanthine oxidoreductase gene [26. Approximately one third of urate elimination occurs in the gastrointestinal tract.

The four-component model evolved in the 1960s and 1970s from an interpretation of the competing effects of uricosuric and antiuricosuric agents. By extension. In addition. Renal urate secretion can be unmasked in humans after treatment with mannitol and a uricosuric agent [43]. subsequent secretion. the serious flaws in this model [29. The relative dominance of reabsorption or secretion. the primary source of this urinary 14 C-urate peak was believed to be tubular secretion rather than glomerular ultrafiltration.45]. this effect is mediated by pyrazinoate (PZA). Reabsorption and secretion can each be detected in reabsorptive species. in Dalmatian dogs. Dalmatians exhibit significant hyperuricosuria and modest hyperuricemia as a result of defective hepatic transport of urate that limits metabolism via uricase [40]. chlorothiazide [50]. including probenecid [37. with minimal or nonexistent contributions from the distal nephron [35]. Elements of this four-component model appear in the current editions of leading physiology and nephrology textbooks. Dog experiments from the mid 1960s revealed that pyrazinamide abolished the secretory peak of 14C-labeled urate (14C-urate) injected into the renal artery. The key assumption underlying this model is that the antiuricosuric agent pyrazinamide inhibits proximal tubular urate secretion. and sulfinpyrazone [37]. The full four-component model subsequently evolved to explain the interactions between pyrazinamide and uricosuric agents. mongrel dogs exhibit a predominance of urate reabsorption. indicative of tubular secretion [44. such as the dog [35]. given that the initial urinary bolus of radioactive urate preceded that of 14C-inulin. with fractional reabsorption of approximately 50% [39]. Regardless of the species studied. suggesting minimal reabsorption or modest secretion [39]. the oral administration of 2 to 3 g results in a marked decrease in the fractional excretion of urate. encompassing glomerular filtration. the deamidated metabolite [47]. the antiuricosuric effect of pyrazinamide was attributed to an inhibition of urate secretion [48]. however. the fractional excretion of urate can equal 100% or just above 100%. In a typical pyrazinamide suppression test [46]. and pyrazinamide-sensitive tubular secretion [49]. and then ‘‘postsecretory reabsorption’’ [37]. In contrast. can be influenced by pharmacologic manipulation or by genetic background. The pyrazinamide suppression test thus was adopted as a pharmacologic method to quantify tubular urate secretion [46]. patients who have renal hypouricemia (discussed later) can have fractional excretions of urate that are greater than unity. When these . however. Thus.50]. reabsorption from the glomerular ultrafiltrate. the bulk of urate transport occurs within the proximal tubule.renal urate transport 315 The four-component model The dominant model of renal urate excretion has for decades consisted of four steps: glomerular filtration. however. benzbromarone [51]. bidirectional transport can be detected in mongrels [41] and secretion can be induced by a combination of urate loading and osmotic diuresis [42]. probenecidsensitive tubular reabsorption.38] necessitate a brief review. The three-component model of renal urate handling originally was proposed by Gutman and Yu in 1961.

in addition to chloride (ClÀ) and hydroxyl (OHÀ). was considered ‘‘rather awkward’’ [43] and ‘‘extremely unlikely’’ [46] during the initial formulation of the four-component model. suggesting that the absorptive mechanism for PAH and urate are distinct in this species [57]. The URAT1 protein is encoded by the SLC22A12 gene. Using brushborder membrane vesicles (BBMV) from renal cortex. suggested that PZA does indeed stimulate tubular reabsorption [38].’’ given that their ability to increase urate excretion was blunted when putative ‘‘upstream’’ secretion was inhibited with pyrazinamide. Urate transporter-1 is the reabsorptive urate-anion exchanger An apical urate-anion exchange activity was described first in nonprimate. however. Physiologic studies of reabsorptive species. This is reflected in the modest effect of PAH infusion on urate excretion in humans. the same investigators previously reported analogous data for lactate [30]. there is a striking attenuation of their uricosuric effect [29]. part of the rapidly expanding SLC22 family of organic ion transporters. urate-reabsorbing species (ie.55]. PZA. furthermore. This anion exchanger accepts various monovalent organic anions. PAH and OHÀ are not substrates for the human exchanger [56]. Apical urate-anion exchange activity evidently is absent in species with net urate secretion [30. it was demonstrated that sodium-dependent uptake of PZA or lactate results in a marked stimulation of vesicular urate uptake via the brush-border urate-anion exchanger (these and subsequent insights discussed later). A seminal observation in 1985 by Guggino and Aronson. To explain this phenomenom. notably. Although . other subgroups include organic cation transporters and organic cation transporter novel type/carnitine transporters [58]. although it is present and highly sensitive to uricosuric agents in urate-reabsorbing species [52. including urate. is without effect on PAH homeostasis.52–54]. and lactate. however. A similar urate exchanger has been demonstrated in BBMV from human kidneys. p-aminohippurate (PAH). divalent anions are not substrates [30]. The recent molecular identification of URAT1 as the dominant apical urate exchanger of human proximal tubule [1] was a landmark event in the physiology of urate homeostasis. The alternative possibility. rats and dogs) [30. It follows that these processes occur serially in anatomically separate segments of the proximal tubule.53]. that PZA does not inhibit secretion but instead stimulates urate reabsorption.316 mount et al drugs are administered after pyrazinamide. URAT1 primarily is homologous to members of the organic anion transporter (OAT) branch of this gene family. such a progression is incorporated in current textbook models of renal urate transport. albeit with some important distinctions. typically indicate a coexistence of reabsorption and secretion along the entire length of the proximal tubule [35]. these observations suggest a significant role for urate exchange in proximal reabsorption. uricosuric agents were postulated to have a dominant effect on ‘‘postsecretory reabsorption.

however. Uricosuric drugs. URAT1 is the human ortholog of renal-specific transporter (RST). and inorganic anions. this generates a secondary sodium dependency of urate reabsorption. immunohistochemistry reveals the URAT1 protein at the apical membrane of proximal tubules in human [1] and mouse [60] kidney. are potent inhibitors of URAT1. followed by lactate. indicating that this exchanger is essential for the proximal tubular reabsorption of urate [1]. Independent. b-hydroxybutyrate. cloned from murine kidney several years ago [59]. The same anions are capable of cis-inhibiting the uptake of 14C-urate when present in the extracellular medium. Regardless. Enomoto and coworkers provide unequivocal genetic proof that this anion exchanger is essential for normal urate homeostasis: a handful of patients who had ‘‘renal hypouricemia’’ (OMIM #220150) [63] were shown to carry loss-of-function mutations in the human SLC22A12 gene encoding URAT1. URAT1 reabsorbs urate from the glomerular ultrafiltrate by exchanging luminal urate with monovalent intracellular anions. Heterologous expression in Xenopus oocytes indicates that human URAT1 is capable of urate transport (14C-urate uptake). such as nicotinate and PZA. such as probenecid and losartan [61]. that anion transporters other than URAT1 may participate in the luminal reabsorption of urate from the glomerular ultrafiltrate [45]. the relative response fits with the trans-stimulation of urate exchange in human BBMV sodiumdependent transport of these monovalent anions [62] (discussed later). Patients who have homozygous loss-of-function mutations in SLC22A12 do not respond to pyrazinamide and benzbromarone loading with urate retention and uricosuria. with detectable transcript in lung and brain (Zandi Nejad. In their report describing the identification of URAT1. These relative affinities are manifest by a marked activation (trans-stimulation) of 14C-urate uptake in URAT1-expressing oocytes that have been microinjected individually with PZA. with a Michaelis constant (Km) of 371 F 28 mM. this indicates that their effect on serum urate is mediated through inhibition of urate reabsorption rather than an activation of renal secretion. 2004). such as ClÀ and nitrate. in-trans to the 14C-urate). A very modest response to probenecid suggests. URAT1 has the highest affinity for aromatic organic anions. The nephron thus is primed for urate reabsorption by the sodium-dependent loading of proximal tubule cells with antiuricosuric anions. respectively (discussed later). another operative characteristic of the anion exchanger. nicotinate. The intracellular concentration of these anions is determined largely by sodium-dependent absorption from the same glomerular ultrafiltrate. URAT1/ RST is in point of fact not renal specific. unpublished data. such as PZA. because these anions increase proximal urate reabsorption via subsequent anion exchange. acetoacetate. The secondary sodium dependency of urate reabsorption As discussed previously. and lactate (ie.renal urate transport 317 not acknowledged initially [1]. overlapping studies from several laboratories suggest that a single cotransport activity in renal BBMV is responsible for the sodium-dependent .

This provides genetic confirmation of the linkage between PZA and urate reabsorption. the murine Slc5a8 protein can transport both PZA and nicotinate [4]. Atkins diet.318 mount et al uptake of PZA. b-hydroxybutyrate. Hyperuricemia is a well-recognized concomitant of the increased concentration of b-hydroxybutyrate and acetoacetate found in diabetic ketoacidosis [67. Hyperuricemia also is a long-appreciated complication of high-fat diet [74] and of starvation ketosis [75]. however. there is no evidence for direct sodiumdependent urate uptake). These observations all tend to refute the four-component model. The molecular identity of the sodium-dependent anionÀ cotransporter(s) is not as yet clear. nicotinate. hyperuricemia is assumed to also occur in ketotic patients. showing that PZA requires a functioning reabsorptive transporter for its antiuricosuric effect. More recently. and acetoacetate [64–66]. intrarenal localization of the Slc5a8 and Slc5a12 proteins indicate expression at the apical .62]. Increases in intracellular activity of these anions in turn induce urate reabsorption and hyperuricemia.79]. presumably. a functional urate exchanger is necessary for the antiuricosuric effect of PZA. as predicted by the model shown in Fig. The effects of ketoacids and lactate do not appear to be secondary to the respective acidoses. the related cotransporter Slc5a12 was reported to transport nicotinate and other monocarboxylates [5]. There are clear clinical consequences for this physiology. and preliminary data indicate that this transport can potentiate urate uptake in cells that coexpress URAT1 [2]. Ketoacidosis is thought to be necessary for the weight-reduction seen with low-carbohydrate diets. 1. the SLC22A12 gene is inactivated in these species.73]. result in hyperuricemia resulting from increased urate reabsorption [70]. given that the experimental infusion or ingestion of these anions also can lead to urate retention [66. which encodes a sodium-dependent lactate and butyrate cotransporter [3] expressed in the proximal tubule. much as the uricase gene is inactivated in humans and other hominoids. Increases in lactic acid. as seen in alcohol intoxication [69]. A leading candidate gene.68]. PZA has no effect on urate transport in species in which secretion predominates [29]. pyruvate. transient increases in lactate or keto acids may contribute to the association between gout and alcohol [71]. BBMV urate exchange is not detectable in animal species that secrete urate in the absence of significant reabsorption [30]. increased plasma concentrations of antiuricosuric anions result in increased glomerular filtration. Again. as can the treatment of tuberculosis with pyrazinamide [78. and increased intracellular concentration in tubular epithelial cells. with the recent report of a particularly severe case of diet-associated ketosis [76]. By extension from the BBMV data [38. lactate.72. increased delivery to the proximal tubule. urate is not a direct substrate (ie. Patients who have renal hypouricemia and loss-of-function mutations in URAT1 are found to lack a response to pyrazinamide and uricosurics [45]. These anions all are substrates for URAT1 and share a tendency to increase serum uric acid in vivo. Furthermore. Finally. on such a lowcarbohydrate. via trans-stimulation of URAT1 from inside the cell. the treatment of hypercholesterolemia with nicotinic acid (niacin) can be complicated by hyperuricemia [77]. is SLC5A8.

although urate retention is caused by the low concentrations of circulating PZA generated in the typical pyrazinamide suppression test (approximately 80 mM. Basolateral entry of urate during urate secretion by the proximal tubule is stimulated by sodium-dependent uptake of the divalent anion a-ketoglutarate via SLC13A3.81] modalities for BBMV sodiumdependent monocarboxylate and/or nicotinate/PZA transport. 1. prior evidence suggests electrogenic [80] and electroneutral [64. Urate transport mechanisms in the proximal tubule. Pharmacologic implications The monovalent anions that interact with URAT1 have the dual potential to increase urate absorption and urate excretion. Apical secretion of urate may occur through an ATP-driven efflux pathway (MRP4) or through voltage-sensitive electrogenic pathways (OATv1 or UAT1). Thus. 2006). membrane of S2/S3 and S1 segments of the proximal tubule (Zandi-Nejad and colleagues. submitted for publication. Finally. through the SLC5A8 and SLC5A12 cotransporters stimulates the absorption of luminal urate via the anion exchanger URAT1. 10 mg/ml). respectively. there is a residual question of molecular heterogeneity in proximal tubular sodium-anionÀ cotransport. whereas SLC5A8 [3] and Slc5a12 [5] appear to be electrogenic cotransporters. such that the two cotransporters may contribute serially to sodium-dependent anionÀ transport within the proximal nephron.renal urate transport 319 Fig. leading to urate-a-ketoglutarate exchange via OAT1 or OAT3. because they can trans-stimulate and cis-inhibit apical urate exchange. such as lactate and PZA. The identity of the exit pathways for urate during urate reabsorption is not as yet known. higher concentrations . Sodium-dependent entry of monovalent anions.

Urate uptake by brush border membrane vesicles isolated from dog kidney cortex is shown. J Clin Invest 1985. Salicylate inhibits human BBMV urate exchange [85] and human URAT1 [1]. Regardless. Finally. 1). antiuricosuria at low dose and uricosuria at high dose) long have been appreciated for salicylate [84]. Again. although 0. these observations remain consistent with the basic scheme of apical urate transport in the proximal tubule (Fig. with permission. in the presence of 100 mM sodium (Na+) with either 0. Thus. providing an explanation for the high-dose uricosuric effect. salicylate has a similar effect. because of trans-stimulation of urate exchange. Paradoxical effects of pyrazinoate and nicotinate on urate transport in dog renal microvillus membranes.1-mM sodium-PZA stimulates urate uptake by dog BBMV preparations. 5-mM PZA inhibits the exchanger via extracellular cis-inhibition (see Fig. the antiuricosuric effect at low dose conceivably is the result of a trans-stimulation by intracellular salicylate [85]. Aronson PS.) . The antiuricosuric agent pyrazinoate (PZA). markedly reducing the uricosuric effect of probenecid at low dose but not at high dose [84]. the stimulatory effect of PZA persists at 5 mM [62].76:543–7. suggesting that there are species-specific differences in the ability of PZA to induce uricosuria. dissenting opinions notwithstanding [83]. 0 PZA (&). 2. thus reducing urate uptake by the membrane vesicles. the historically important effect of PZA to inhibit pharmacologic uricosuria in humans likely is the net result of partial inhibition of renal urate reabsorption by uricosurics and the particularly high affinity of URAT1 for intracellular PZA. The low concentration results in sodium-dependent uptake of PZA and a potentiation of urate uptake via URAT1. similar biphasic effects on urate excretion (ie.1-mM PZA (E). In human BBMV. Fig. has dual effects on urate transport by the proximal tubule. in contrast. such that the antiuricosuric effect of PZA is dominant [29].320 mount et al achievable in chimpanzees result in uricosuria [82]. or 5-mM PZA (. a metabolite of pyrazinamide.). the higher concentration cis-inhibits URAT1. (From Guggino SE. 2) [38].

Molecular candidates for this electrogenic pathway include urate transporter/ channel-1 (UAT1) [104] and voltage-driven organic anion transporter-1 (OATV1) [105].93]. such that proximal hyperabsorption of sodium (decreased lithium clearance) is associated with hyperuricemia [87]. The apical ATP-driven efflux pump multidrug resistance protein 4 (MRP4) . Other mediators with potential effects on renal urate transport include adenosine [96. There is evidence. it is intuitively obvious from the antiuricosuric effect of PZA and other anions that hyperuricemia and gout could result from increases in the activity of either sodium-anion cotransport (SLC5A8/12) or of urate-anion exchange (URAT1).91]. however. Indices of proximal salt absorption show a significant correlation with serum urate. SLC5A8.103]. for a voltage-sensitive urate transport pathway in apical BBMV preparations from humans. This effect of AT-II is relevant particularly to the hyperuricemia of the metabolic syndrome [14. and SLC5A12 proteins end with C-terminal sequence motifs capable of interacting with scaffolding proteins that contain PDZ domains [99]. such that salt-avid states (eg.101] and functional [102] interactions already have been reported between URAT1 and PDZK1.85]. decrease fractional excretion of urate. The URAT1.95]. The proposed tethering of URAT1 to the sodium-anion cotransporters may have additional roles in the coordinated regulation of renal urate reabsorption. Biochemical [100. In rats. it has been reported that patients who have essential hypertension have a decreased fractional excretion of urate [84–89].97] and parathyroid hormone [98]. however. the mechanisms involved in the regulation of urate reabsorption by extracellular volume status are not yet known.renal urate transport 321 Regulation of renal urate transport Classical clinical teaching asserts that the serum concentration of uric acid parallels extracellular volume status and salt absorption by the kidney [83]. Angiotensin II (AT-II) infusion does. The lumen-positive voltage of the apical membrane of the proximal tubule is hypothesized to favor urate secretion by this mechanism [56]. Indeed. such that hyperinsulinemia may have a direct impact on renal urate transport. weakly sensitive to uricosuric drugs and PZA [56. however. one of a family of four PDZ proteins (PDZK1/2 and NHERF1/2) that play increasingly appreciated roles in the regulation of proximal tubular ion transport [102. volume depletion stimulates a marked increase in proximal tubular reabsorption of urate [90]. those induced by diuretics) are characterized by hyperuricemia and often complicated by gout [86]. however. conceivably this is the result of either hemodynamic effects or direct stimulation of tubular reabsorption [89. Even in the absence of such a direct interaction.15]. Acute insulin infusion also is reported to reduce urate excretion [94. Other urate transporters in the proximal tubule Considerably less is known regarding the molecular physiology of renal urate secretion. in that crosstalk between AT-II and insulin may play a significant role in insulin resistance [92.

a recent study implicates a major gene on chromosome 4q25 in the gout susceptibility of Taiwanese aborigines. it is difficult to speculate on the underlying pathophysiology of this association. suggesting perhaps that basolateral transporters other than OAT1 or OAT3 function in the reabsorption of urate. In this regard. partial deficiency of this enzyme is a well-described cause of hyperuricemia and gout (Kelley-Seegmiller syndrome) [122. studies in most populations suggest a polygenic mode of inheritance without a major gene effect [115].123].127]). Genetic influences on urate homeostasis Although twin and family studies suggest a genetic influence on serum uric acid levels.111]. In addition to Lesch-Nyhan syndrome resulting from complete deficiency of hypoxanthine hypoxanthine-guanine phosphoribosyltransferase (HPRT) (OMIM #300322) [63]. Most prominently. A recent report from the Framingham Heart Study reveals several potential loci that affect serum uric acid [116]. progressive renal dysfunction. each of which functions as anion1À-dicarboxylate2À exchangers [111–113]. This . who share genetic ancestry with other Pacific islanders [121]. are characterized by a reduced fractional excretion of uric acid. Candidate proteins for this basolateral urate exchanger include OAT1 (SLC22A6) [109] and OAT3 (SLC22A8) [110. 1). suggesting a role in urate secretion by the proximal tubule (see Fig.000) [63]. Several genetic causes of renal disease are associated with hyperuricemia and gout. OAT1-deficient knockout mice exhibit a secretory defect for organic anions [114]. frequent but variable hyperuricemia (92% hyperuricemia in one kindred [125] and 0% in another [126. such as PZA and lactate [107. the entry of urate from the surrounding interstitium appears to be driven by sodium-dependent uptake of divalent anions. Another X-linked cause is overactivity of the phosphoribosylpyrophosphate synthetase (PRPS1) enzyme (OMIM #311850) [63] resulting from a variety of point mutations or to increased PRPS1 transcription. (OMIM #300323) [63]. What currently is unknown is whether or not there are separate pathways for urate exit at the basolateral membrane during urate reabsorption across the proximal tubule or whether or not OAT1 or OAT3 functions in this capacity via the exchange of intracellular urate with extracellular a-ketoglutarate. rather than monovalent carboxylates. 1) [106]. the latter reported in kindreds with structurally normal enzyme [124]. Of particular interest. medullary cystic kidney disease type 2 (MCKD2) (OMIM #603860) [63] and the allelic disorder. familial juvenile hyperuricemic nephropathy (FJHN) (OMIM #603860 and #162.322 mount et al also is shown to mediate substantial urate efflux.108] (see Fig. Two specific enzyme defects are shown to lead to overproduction of uric acid. such as a-ketoglutarate. At the basolateral membrane of proximal tubular cells. Perhaps the strongest evidence for a genetic basis for gout and hyperuricemia is provided by indigenous Pacific islanders [117–121]. Prior to molecular characterization of the predisposing gene. and a high incidence of early-onset gout.

138]. Although experimental [130] and genetic [123] forms of hyperuricemia may lead to renal injury. with urinary supersaturation of sodium urate and calcium oxalate resulting from concomitant increases in urinary calcium and sodium [143. a glycosyl-phosphatidylinositol-anchored membrane protein with restricted expression at the luminal membrane of the thick ascending limb and distal convoluted tubule. Finally. demonstrated evidence of acute tubular necrosis. When analyzed biochemically. as discussed previously. however. Bartter’s syndrome [131]. and subsequent uric acid crystallization [147]. which can be recurrent. without intratubular deposition of uric acid [137]. is associated with renal stones in approximately 10% of affected patients [45. and secondary neurohumoral activation of the renin-angiotensin-aldosterone axis or other mediators. hyperuricemia is well described in other cellular and functional defects of the distal nephron. affected patients generally have a urine pH greater than 5. dysplastic. hyperuricemia in these patients is secondary to renal tubular dysfunction. typically greater than 900 mg per day. Altered biosynthesis results in markedly reduced uromodulin excretion and intracellular aggregation within the distal nephron [129].144]. loss-of-function mutations in URAT1 are associated with renal hypouricemia (OMIM #220150). these episodes of nephrolithias have included calcium oxalate [142] and uric acid [140. The mechanism of this renal injury is not known. hypovolemia. a known antioxidant [20. with marked increases in their fractional urate clearance [45]. The hyperuricosuria associated with URAT1 dysfunction. Mutations in HNF-1b are associated with a spectrum of cystic. In contrast. it is not yet known how dysregulated transcription of this or related transporters contributes to the renal phenotype or hyperuricemia in patients who have HNF-1b mutations. The lesser role of hyperuricosuria per se in uric acid stones . reduces the ability to cope with the increase in free radicals associated with strenuous exercise [139]. the absence of hyperuricemia in some affected patients suggests that the renal impairment in MCDK2 and FJHN is not a consequence of hyperuricemia. Indeed. Presumably. These patients typically have serum uric acid levels of approximately 1 mg per day.renal urate transport 323 disorder is caused primarily by mutations in uromodulin or Tamm-Horsfall glycoprotein [128]. Hyperuricemic renal disease also has been reported in a kindred with mutations in the hepatocyte nuclear factor-1b (HNF-1b) transcription factor [133]. generating an acid urine.136].146].140] stones. Clinical manifestations include a characteristic syndrome of exercise-associated acute renal failure. Recent data indicate a role for systemic insulin resistance in reducing urinary ammonium excretion. and familial hypomagnesemia [132]. An attractive hypothesis is that the reduction in circulating uric acid. The majority of renal biopsies in a recent series. Although the related transcription factor HNF-1a is likely to regulate the expression of URAT1 [135.140–142]. with urine pH approximately 5 [145.0. including MCKD1 (chromosome 1q21). Hyperuricosuria is a well-described risk factor for calcium-oxalate stones [143]. and developmental abnormalities of the kidney [134]. the uric acid stones in patients who have ‘‘gouty diathesis’’ typically occur in the context of hyperuricemia and reduced fractional excretion of urate.

In particular. and URAT1/SLC22A12). with hyperuricosuria (N700 mg/d) in 35% [148]. as in other genes that have a role in uric acid homeostasis (uricase. the Talanin transcript shares coding exons with one of the other three major transcripts. the loss of a PZA response in patients lacking URAT1 [45]. Approximately 85% of the affected patients in this population have low urine pH. the durable four-component model should. The open reading frame of the Talanin transcript is specific to humans. uric acid stones are not a universal problem in this syndrome. the major reabsorptive pathway for urate. Therefore. xanthine oxidase. the pathophysiology underlying this defect is not completely clear. denoted Talanin. A novel gene. perhaps. although more recent evidence suggests that patients who have higher levels of uric acid excretion also have a diminished fractional excretion [88]. there seems to be differential evolutionary pressure on ZNF36/Talanin. What is the projected impact of the recent advances in molecular physiology on the understanding and management of gout? The immediate effect is conceptual. is contained within a 67-kilobase ‘‘critical region’’ of 10q21-22 that is associated with severe UAN by linkage-disequilibrium mapping.324 mount et al is underlined in renal hypouricemia. a genetically isolated village in Sardinia [148. however. the molecular characterization of proteins in this . in that a reconsideration of the relationship between sodium-anion cotransport (SLC5A8/ A12) and urate-anion exchange (URAT1) provides a framework to understand the effect of uricosuric and antiuricosuric physiology. have a similar fate. sequence analysis suggests that it might by an O-glycosylated transmembrane protein. Talanin is encoded by one of at least four alternative transcripts generated from within the larger ZNF36 gene.149]. Although reduced urinary ammonium and a low urine pH is the most consistent finding in idiopathic uric acid nephrolithiasis (UAN). Although the function of Talanin is completely unknown. or the scaffolding proteins that potentially bind them together [101]. The gene involved. Moreover. recently was implicated in the high incidence of UAN observed in Talana. despite the marked increase in urinary uric acid [45]. On a more practical level. if one extrapolates from the effect of changes in circulating PZA/lactate/keto acids on serum urate. should lay to rest the concept that this drug has a dominant effect on urate secretion rather than reabsorption. with transcriptional initiation at a unique TATA-box promoter just 5V of the critical region [149]. the possibility is apparent that hyperuricemia might result from changes in the activity of URAT1. SLC5A8/A12. there is no conservation of exon structure in this segment of the mouse and rat ZNF36 gene. with inactivating mutations in the coding sequence of the Talanin transcripts of Old World and New World monkeys [150]. Perspectives Reduced renal excretion of urate [151] is the underlying pathophysiology in the majority of gouty patients who have an underexcretor phenotype [152].

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Casula S. Esposito T. (D)-beta-hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. Chandalia M. N Engl J Med 1979. The metabolic syndrome and uric acid nephrolithiasis: novel features of renal manifestation of insulin resistance. Seegmiller JE. Diminished renal urate secretion per nephron as a basis for primary gout. Casu G. et al. [153] Taggart AK. Sorensen LB.9:352 – 5. et al.280:26649 – 52. PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect. [151] Rieselbach RE. [152] Boss GR. et al. Gene 2004.73:359 – 66. [150] Gianfrancesco F.300:1459 – 68. Am J Hum Genet 2003. Emergence of Talanin protein associated with human uric acid nephrolithiasis in the Hominidae lineage. complications and management. Hyperuricemia and gout.68:1119 – 29. Gan X. Am J Hum Genet 2001.72:1479 – 91. Kero J. et al. Kero J.renal urate transport 331 [147] Abate N. et al. Cabo-Chan Jr AV. Forabosco P. [148] Ombra MN. Nat Med 2003. Classification. Identification of a novel gene and a common variant associated with uric acid nephrolithiasis in a Sardinian genetic isolate. et al. [154] Tunaru S. Schaub A. Ann Intern Med 1970. 65:386 – 92. J Biol Chem 2005. Kidney Int 2004. Ombra MN. [149] Gianfrancesco F. et al. Identification of a new candidate locus for uric acid nephrolithiasis.339:131 – 8. . Esposito T. Shelp WD.

after the first chemical identification of uric acid (‘‘lithic acid’’). Scotland. 1) are those of Antoni Van Leeuwenhoek. T University of Edinburgh.com . Wollaston.23). FRCPET Queen’s Medical Research Institute. was able to show that material obtained from a tophus in his own ear was composed of sodium urate [5].003 rheumatic. Emerging recognition of crystal-associated arthropathy The earliest recorded drawings of crystals taken from a tophus from a patient who had gout (Fig. Flavors of this rich and colorful story are captured in a charming and scholarly set of historical essays by Copeman [1].nuki@ed. the English chemist.Rheum Dis Clin N Am 32 (2006) 333 – 357 Treatment of Crystal Arthropathy—History and Advances George Nuki.03. in 1769 [4]. UK. Edinburgh EH16 4TJ.2006. UK The history of gout and the many distinguished historical figures who have suffered the agonies of this crystal deposition disorder have claimed the attention of medical historians like no other disease. University of Edinburgh. Rodnan’s beautiful collection of prints and illustrations [2]. E-mail address: g. the pioneer Dutch microscopist. and an excellent introductory chapter to their comprehensive monograph on gout by Wyngaarden and Kelley [3]. All rights reserved.1016/j. 47 Little France Crescent.uk 0889-857X/06/$ – see front matter D 2006 Elsevier Inc. MB. in urinary calculi.theclinics.ac. Scheele. by the Swedish apothecary.rdc. The Queen’s Medical Research Institute (C2. doi:10. At the time he did not recognize that they were crystals and was unaware of their chemical composition. A century later. Osteoarticular Research Group. a nephew of William Heberden. FRCP. Scotland. who worked after hours in the kitchen of his apotheke in Koping in 1776 [6].

Crystals of uric acid. 2). F. Elevated levels of uric acid in the serum of patients who had gout were demonstrated by Sir Alfred Baring Garrod. that subsequently could be weighed. were seen to form along a linen fiber suspended for 18 to 48 hours in the acidified serum of patients who had gout (Fig. . It was in his Fig. in 1679. (A–D) Crystals of sodium urate from a gouty tophus drawn by Antoni van Leeuwenhoek. In what is now widely believed to be a milestone in the development of the discipline of clinical chemistry. L.334 nuki Fig. 1. He first reported his findings in the Transactions of the Medical Chirurgical Society of Edinburgh in 1848 [7]. 2. Crystals of sodium urate have formed along a linen thread suspended for 48 hours in acidified serum from a patient who had gout and hyperuricaemia. Currey at the London Hospital. he subsequently described his semiquantitative thread test for the measurement of urate [8]. the Dutch pioneer microscopist. Demonstration of Garrod’s thread test by the late Professor H.

who was able to mimic acute attacks of gout by the intra-articular injection of microcrystals of sodium urate [12]. The renewed interest in the role of microcrystals at that time followed key clinical observations by McCarty and Hollander. best known as the Milwaukee shoulder syndrome [29] but probably the same condition previously described as l’epaule senile haemorrhagique [30]. ‘‘that the deposited urate of soda may be looked upon as the cause. often in the absence of overt inflammation. first published in 1859 [9]. These include calcific periarthritis [26]. of the gouty inflammation. Cadaver studies undertaken approximately 80 years ago showed that meniscus calcification is a common age-related finding. octacalcium phosphate. BCP crystals are found in up to 70% of OA synovial fluids. however.16] rediscovered the capacity of microcystals of sodium urate to induce inflammatory responses in joints. including partially carbonatesubstituted hydroxyapatite. confirmed by x-ray diffraction to be calcium pyrophosphate dehydrate (CPPD) in some patients with acute synovitis and pseudogout [18. and by the experimental work of His. In a landmark paper published in 1961 [17].’’ and his subsequent proposal [11]. and tricalcium phosphate. skin. This is confirmed by radiographic surveys. Support for the fourth of these. also have been associated with several age-related joint pathologies. that acute attacks of gout were triggered by the precipitation of sodium urate crystals in the joint or neighboring tissues. Basic calcium phosphate (BCP) crystals. first demonstrated radiographically approximately 100 years ago [27].21]. osteoarthritis (OA). and. The historical importance of these observations came to light only after Faires and McCarty [14] and Seegmiller and colleagues [15.19]. most commonly. were provided by the experiments of Freudweiler. in the wide range of clinical settings subsequently described and classified by McCarty as manifestations of CPPD deposition disease [22] remains much less certain. the extent to which they are pathogenic. The application of this diagnostic technique soon led to the identification of positively birefringent crystals. who showed that subcutaneous injection of urate crystals in rabbits was followed by the formation of nodules with the histologic characteristics of tophi [13]. a destructive form of apatite-associated arthritis [28]. although there is some evi- .10]. and subcutaneous tissues in the early 1960s. The prevalence of meniscal chondrocalcinosis was approximately 27% in people more than 85 years of age in an elderly cohort [24] and in the population at large in the Framingham community study [25]. Wyngaarden and Kelley [3] have drawn attention to the remarkable prescience of Garrod’s propositions (Box 1) [9.treatment of crystal arthropathy 335 book. and not the effect. or an epiphenomenon. that Garrod first described clearly the roles of hyperuricemia and urate crystals in the pathogenesis of gout. The Nature and Treatment of Gout and Rheumatic Gout. Although the demonstration that acute synovitis could be induced by the experimental injection of microcrystals of CPPD into normal canine and human joints seemed to confirm the pathogenic role of CPPD crystals in patients who have pseudogout [20. even in individuals who are asymptomatic [23]. they demonstrated the diagnostic value of detecting negatively birefringent crystals of monosodium urate within synovial fluid leucocytes by polarizing light microscopy during acute attacks of gouty arthritis.

and certainly in its chronic. Sixth. in some cases of lead poisoning and in a few other instances. in no disease but true gout is there a deposition of urate of soda in the inflamed tissues This fact I wish to impress forcibly on the minds of my readers. for the time. because in the constancy of such deposition lies the clue that has long been wanting: the occurrence of the deposit is perfectly pathognomonic and at once separates gout from other diseases that at first sight may appear allied to it. the deposited urate of soda may be looked on as the cause. therefore. Its mere presence. and is essential to its production. for example. subsequently becomes structural. the impure state of the blood. probably in its early. the investigations recently made in the morbid anatomy of gout prove incontestably that true gouty inflammation is always accompanied with a deposition of urate of soda in the inflamed part. before and at the period of the seizure. invariably          is present in the blood in abnormal quantities. of the gouty inflammation. and when once the cartilage and ligamentous structures become infiltrated.336 nuki Box 1. uric acid.a Third. of the system generally. arising principally from the presence of urate of soda. Ninth. Garrod’s propositions relating to uric acid. and gout  First. Tenth. but this acid occasionally may exist largely in the circulating fluid without the development of inflammatory symptoms. From Garrod AB. a . is the probable cause of the disturbance that precedes the seizure and many of the anomalous symptoms to which gouty subjects are liable. consequently. stages. and not the effect. perhaps only functional at first. the inflammation that occurs in the gouty paroxysm tends to the destruction of the urate of soda in the blood of the inflamed part and. The nature and treatment of gout and rheumatic gout. Eighth. Fifth. the formation of uric acid. Seventh. or such as temporarily check the elimination power of the kidneys. in the form of urate of soda. the kidneys are implicated in gout. does not explain the occurrence of the gouty paroxysm. in true gout. Fourth. the causes that predispose to gout. the urinary secretion also is altered in composition. London: Walton and Maberly. such deposition remains for a lengthened time. urate of soda. the deposit is crystalline and interstitial. and renal affection. the causes exciting a gouty fit are those that induce a less alkaline condition of the blood or that greatly augment. 1859. as. independent of those connected with individual peculiarity are either those that produce an increased formation of uric acid in the system or that lead to its retention in the blood. Second.

’’ which resulted in the painful distension of joints after dietary and sexual excess and a sedentary life.’’ Uncertainty about the best approach to the local treatment of acute gout persisted for the next 2500 years. although Hippocrates often was bold in recommending other surgical procedures. painful. and he recommended moderation. such as ‘‘phlegm. Approaches to management A bladder calculus recovered by Elliot Smith from an Egyptian mummy at El Amrah in 1901 probably is the earliest physical evidence of a human disease associated with crystal deposition. Ptisan. from wine. Hippocrates’ remarkable clinical observations on gout and its natural history contained in his aphorisms [34] include some of the earliest references to the management of this disease. lithotomy is singled out as a practice not to be undertaken by his fellow physicians [33]. In the Hippocratic oath. But he also recommended heat and counter irritation: ‘‘This is a long. such as thoracotomy or trephining the skull [1]. believing that this could frustrate nature’s efforts to dispel the disease through the medium of an acute attack [1]. the Roman writer. but not abstinence. and lithotomy for bladder stones may have been among the earliest treatments for a crystal deposition disorder. but leave this to be done by men who are practitioners of this work’’ [33]. which reduces the swelling and removes the pain’’ [34]. Local approaches to treating painful joints Hippocrates’ advice concerning local therapy is best known from his aphorism X-25: ‘‘swellings and pains in the joints. ‘‘whereby the humours may be kept in healthy balance and disease obviated’’ [1]. Avicenna. but not a mortal illness. Celsus. Hippocrates believed that gout developed after accumulation of bodily humors. Although he advocated the use of all empirically proven remedies if used ‘‘in such a way as to do good. a type of barley water. advocated warm applications according to the intensity of the inflammation but advised great caution with regard to cold. possibly as early as the sixth century bc [32]. or at least do no harm’’ [1]. also was recommended. written in the first century ad. in most cases are relieved by a copious affusion of cold water. if the pain still continue. without sores. his approach predominantly was dietary and conservative. In his De re Medicina [35]. His dictums on diet include advice on the preparation and the content of foods. ‘‘I will not cut persons labouring under the stone. the great Arabic Persian physician of . and it is clear that lithotomists were active in Ancient Greece at the time of Hippocrates.treatment of crystal arthropathy 337 dence to suggest that the presence of crystals in synovial fluid in OA may be associated weakly with radiographic evidence of cartilage destruction [31]. This dates back to 4800 bc. whether from gout or from sprains. burn the veins above the joint with raw flax. Shushruta was removing vesical calculi in India.

however. by the Dutch (Fig. He advocated cold sea water baths followed by an inunction of the joint with oil or a cold poultice of cucumber. Nevertheless. 3. Moxa was a fluffy.’’ was the cause of gout. who worked in Rome and was the first to suggest that a specific toxic product.338 nuki the eleventh century. Sir William Temple. such as Bath and Buxton. from the East Indies. Thomas Sydenham. in the second century ad.. in 1681. plantain leaves. in his Treatise on the Gout. Hydrotherapy was reintroduced at spas. based on his personal experience. predominantly for the treatment of Fig. and throughout Europe in the Middle Ages (Fig. which had been used by the Greeks. lemon peel. believed that he had succeeded in curing himself with ‘‘the moxa’’ [38]. the Romans. or ‘‘peccant humor. Yet earlier. 4). published in 1683 [39].. based on his own and his patients’ experiences. observed that local refrigeration was more helpful than warmth in patients who have ‘‘hot species’’ of arthritis [37]. subscribed to this belief and recommended that intractable joints could be cauterized lightly with a hot iron through a layer of salt and oil [36]. and rose petals wrapped in the unscoured wool of a sheep to which a little rose oil or wine was added periodically. enjoyed a fashionable vogue in Britain in the eighteenth century. which contains his most famous classical clinical description of an acute attack of gout. 3). extreme heat and counter irritation became fashionable for the treatment of acute gout in the seventeenth century with the introduction of the new treatment with moxa. the Cappadochian from Asia Minor. Spa therapy with natural mineral waters. an English diplomat who wrote the celebrated Essay on the Cure of the Gout. . ‘‘The new treatment’’ of burning with moxa (1629). cotton-like plant that was placed on the inflamed joint and ignited.let them be used (by the patient) in the beginning of a fit and he will soon be convinced of their insignificancy’’ [39]. was skeptical about the value of all local applications: ‘‘to ease the pain in the joint I know of none (though I have tried abundance in myself and others) beside coolers and repellents which I have already shown to be unsafe. Aretaeus.

either when the distemper was present or in its absence. spa therapy was not without its contemporary critics. gout. therapeutic value. and sea bathing has contributed for more to recover the strength of gouty persons.12) in relieving pain in acute attacks of gout in a small randomized controlled trial (RCT) in which it was used as an adjunct to colchicine and prednisolone [41]. 4. Spa treatment for gout and arthritis at Plomieres (1553). probably temporary. More recently. Intra-articular approaches to therapy The treatment of acute attacks of gouty arthritis with intra-articular injections of corticosteroids is a relatively recent recommended approach. although it has been the treatment of choice for pseudogout associated with CPPD crystal .15. Heberden wrote: I have not been able to observe any good in arthritic cases from the external use of these waters. local therapy with ice has been shown effective (Effect size [ES] 1.treatment of crystal arthropathy 339 Fig. 0. confidence interval [CI]. In his celebrated Commentaries [40]. on the contrary it is rather appeared to increase the weakness of the limbs.15–2. Although the lifestyle modification that accompanied the waters no doubt was of some.

It was approximately 1000 years later. used Hermodactyl extracted from the corm of Colchicum variegate. myopathy. . of intra-articular triamcinolone acetonide (10 mg) in 19 patients who had acute gouty arthritis. Colchicine The history of more targeted. Five hundred years later. In Ancient Greece. and neuropathy [47]. Because of its narrow therapeutic margin and its powerful purgative effects. Alexander of Tralles. probably was the first to understand clearly that the therapeutic effects of Hermodactyl were distinct from its gastrointestinal (GI) side effects [44]. Aetius of Amida. Because of his considerable influence. Intravenous administration no longer is recommended because of reports of several sudden deaths [48]. the seventeenth and early eighteenth centuries. The use of a plant extract believed to be similar to colchicine is recorded in the Ebers papyrus (1550 bc) [43]. in the sixth century AD. pharmacologic therapy for crystal arthropathies began with the use of colchicum for the treatment of ‘‘arthritis’’ approximately 4000 years ago. particularly in patients who have impaired renal function. all patients had complete pain relief within 48 hours. The use of intra-articular steroid injections for acute attacks of gout is not mentioned in Wyngaarden and Kelley’s comprehensive monograph published in 1976 [3]. also rejected all medicines that were purgatives as too toxic to use. more specific. Thomas Sydenham.340 nuki deposition since McCarty first drew attention to pseudogout in 1961 [17]. often known as the English Hippocrates. a species similar to Colchicum autumnale (autumn crocus or meadow saffron). as he believed ‘‘that the best natural relief for this disease is an attack of dysentery’’ [1]. Although colchicine has been shown to be symptomatically effective in approximately 75% of patients who have acute gouty arthritis in one small. and again in more recent times. another Christian physician from Byzantium in the sixth century AD. as a more selective and specific remedy [44]. colchicum or white Hellebore (Veratrum album) was used predominantly as a purgative. In one uncontrolled trial. that the Byzantine Christian physician. Hippocrates advocated powerful purgation with white Hellebore for intractable cases of chronic gout. the use of colchicine was diminished greatly for long periods in the twelfth and thirteenth centuries. Colchicine use virtually was discontinued in continental Europe in the Middle Ages after its use was forbidden by the influential Abbess Hildegard of Bingen (1098–1179 ad): ‘‘It is a deadly poison and not a health giving drug’’ [44]. but there is nothing to suggest that he was aware that it might have more specific value in patients who had acute attacks of gout. published in 1999 [42]. In more recent times physicians also have been deterred from using colchicine because of reports of bone marrow suppression [46]. colchicine was not used for the treatment of gout for approximately 150 years until it was rediscovered by Baron Von Stoerk in Vienna in the middle of the eighteenth century [45].

25–1. Clinical experience also suggests that BCP-associated arthropathies are managed best with nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular therapies.6 mg twice a day).62]. A single study of colchicine prophylaxis in 10 patients who had recurrent attacks of pseudogout. all patients who received colchicine (1 mg immediately followed by 0.40) [51] or allopurinol (number needed to treat. central nervous system symptoms.2 to 1 attack per patient per year [53]. 1–6) [52]. followed by a tapering protocol). vomiting. placebo-controlled RCT [49] (SE for pain relief 0.87. or diarrhea). Indomethacin became the yardstick for comparing the efficacy of newer antiinflammatory drugs in patients who have acute gout after its efficacy was first demonstrated in 1963 [58.74. CI. when such high doses were used. followed for a year before and after receiving colchicine (0.50). .treatment of crystal arthropathy 341 short-term.64]. CI.5 mg every 2 hours) developed GI side effects (nausea. 0. confirming the age-old adage ‘‘that patients treated with colchicine often run before they can walk.5 mg once a day for 6 months [51] or 0.57] than for pseudogout. Over the years. Colchicine is used to treat patients who have refractory CPPDassociated arthropathies [54] but good controlled trial data are lacking. provided there are no contraindications. demonstrates a reduction from 3. and subsequent recommendations were for doses of 50 mg every 6 to 8 hours in the first 24 hours [63. there have been many short-term comparative trials of newer NSAIDs using a variety of trial designs and outcome measures in patients who have acute gout. Others. perforation.59].5 mg daily). however. used at maximum recommended doses. Initially. soon reported a high incidence of headaches. and GI side effects [61.’’ Suggestions that use of colchicine in reduced doses (eg. renal insufficiency. The effectiveness of prophylactic colchicine (0.08–1. but GI side effects were not increased in those receiving only colchicine (0.57]. Diarrhea occurred in 38% of patients receiving the higher dose of colchicine. Even for short-term treatment. for short periods have become the oral drugs of choice for the symptomatic treatment of acute gouty arthritis [55] and pseudogout [56]. without any good evidence emerging to suggest that any particular NSAID has superior efficacy or safety for treating acute gouty arthritis [55. 0. Nonsteroidal anti-inflammatory drugs Fast-acting NSAIDs. NSAIDs are contraindicated in patients who have heart failure. was shown to be followed by pain relief in 82% of patients within 4 hours of taking the first dose and seemed to be associated with remarkably few adverse effects [60]. the high-dosage Emmerson regime (indomethacin 100 mg every 4 hours until symptoms begin to resolve. or a history of previous peptic ulceration.5 mg 3 times daily) may have a more acceptable harm-to-benefit ratio [50] await substantiation with controlled clinical trials. 2. CI.6 mg twice a day for 3 months [52]) is demonstrated in two placebo-controlled RCTs in patients commencing urate-lowering drug therapy with probenecid (SE 0. The evidence base for the use of NSAIDs is much stronger for acute gout [55. 0.

‘‘such fishes as inhabit rocky places’’. in view of recent studies highlighting the potential cardiovascular toxicity of coxibs [66. pending the acquisition of better data on the relative CVS/GI risks and benefits of these agents in the treatment of patients who have gout. such as ‘‘mutton. etoricoxib (120 mg). and sea urchin soup.67] and the weak evidence of increased risk of cardiovascular thrombogenic events (odds ratio 1. and a little cabbage half boiled.’’ in view of recent studies that confirm the association of gout with diets rich in shellfish and red meat [70]. it probably is wise to avoid the use of a selective COX-2 inhibitor for treating acute gout in patients who have established cardiovascular or cerebrovascular (CVS) disease. and meats.57]. cardiovascular comorbidity [55. believed that tophi result from the local accumulation of ‘‘humours’’ and that they could be treated by a combination of dietary restriction and prophylactic bleeding [69].57]. Approaches to lowering blood and tissue urate Four therapeutic approaches to lowering plasma urate and the tissue pool of urate have been undertaken over the years:   Dietary modification Uricosuric drugs  Uricostatic drugs  Uricolytic drugs Dietary modification Dietary restriction was advocated as a treatment for gout long before the importance of hyperuricemia and tissue accumulation of urate of soda first were demonstrated in the middle of the nineteenth century by Garrod [7]. It already has been emphasized that dietary advice was central to the recommendations for treating gout made by Hippocrates [34]. the selective cyclooxygenase (COX)-2 inhibitor. Hippocrates’ most illustrious follower.’’ such as oyster.’’ It is.42–5.342 nuki or hemorrhage. Cardiovascular risk assessment is an important part of the management of patients who have gout and hyperuricemia who frequently have. or bleeds [55. 0. Galen. double-blind RCT. perhaps. . and indomethacin (50 mg 3 times a day) gave comparable rapid pain relief in patients who had acute gout [65]. particularly disappointing that he recommended ‘‘sea foods. and a sausage in due season. limpet. perforations. and great caution needs to be exercised when considering their use in patients who are frail and elderly and who have multiple pathologies.49. The basis for his dietary recommendations is not easy to understand: ‘‘Barley bread is a very excellent thing. Nevertheless. Current guidelines for gastroprotection are advised when their use is considered in patients at increased risk for peptic ulcers. In one well-designed.31) in a systematic review and meta-analysis of placebo-controlled trials of etoricoxib [68]. or develop. CI. goat. hares and wild boar. with a soup of mixed vegetables.

’’ wrote Bernadino Rammazzini of Padua in his De Morbus Artificiam (English translation.73]. 0. Modest beer intake was associated with greater risk than spirits. Ambroise Pare. not a few rich and riotous persons. the long-held perception that alcohol consumption is an important risk factor for the development of gout [80]. in particular.42–0.. and diets rich in meat and alcohol were well recognized in eighteenth-century England. CI. the relative risk (RR) of developing gout was reduced significantly (RR 0. suggesting that lead poisoning (saturnine gout). ‘‘capon and suchlike birds are not good. ‘‘Such gouty persons as remain intemperate and given to gluttony. In a subgroup of a male professionals cohort. By this means Nature is rendered incapable of managing the large quantity of blood. have therewith changed their health together with their fortune and their diet. as I know. Analysis of fortified wines from 1770 to 1820. himself a sufferer of gout. Consumption of milk proteins is shown . Physiologic studies undertaken in the 1970s on chickens with an inherited susceptibility to dietary induction of gout and tophi show this to be the result of impaired renal clearance of uric acid [72. Alcohol raises the serum urate by enhancing urate production and by reducing renal clearance.74) [82]. and drink large amounts of generous wines. The relationship between gout.56. 1746) [1]. seems to have been more in tune with current medical teaching when he wrote [71]. for the first time. There is some reason to suppose that this was at least in part attributable to the prodigious consumption of wine and port at this time. reveal significant contamination with lead [75]. whose diet contained a high intake of dairy products. the popular nineteenth-century stereotype of the gout sufferer as a portly wine drinker (Fig. however. may be protective. and carrying off the secretions which ought to be made from it. he suggested that. the French surgeon. Recent studies of a large cohort of male health professionals followed for 12 years confirmed.treatment of crystal arthropathy 343 In the sixteenth century. More importantly.. 5). the metabolism of alcohol to lactic acid results in inhibition of uric acid secretion and a reduction in the fractional clearance of uric acid by the kidney [78]. who having spent their estaites. It has been known for decades that high protein diets may increase urinary uric acid excretion [81] and milk proteins. and so have been freed from the goutte. ‘‘The people of distinction and opulence indulge themselves.. as well as alcohol. being themselves subject to goute in their feet’’ [1]. contradicting. Acetate conversion to acetyl coenzyme A in the metabolism of alcohol [76] leads to degradation of adenine nucleotides and accelerated urate production [77]. Sydenham recommended a light but adequate diet but also was aware that ‘‘fasting and actual abstinence is not good’’ [1]. and regular consumption of two glasses of wine was not associated with increased risk [80].’’ Although he advocated chicken.may hope for no health by the use of medicines’’ and ‘‘There have been. Gout reached almost epidemic proportions in early nineteenth-century England when ‘‘tophi like crocuses were bursting every where’’ [74]. to some extent. The purine content of beer also may contribute [79].. may have contributed. despite lower alcohol content.eating the most rich and luscious fleshes in great quantity.

The Rev. Much of this is related in his book. Eighteenth-century print by Henry William Bunbury (1750–1811). and a notable nineteenth-century sufferer of gout. first published in 1892. Admiral Nelson. Uric Acid as a Factor in the Causation of Disease. interest began to stir into the role of dietary purines and endogeous purine metabolism in the synthesis of uric acid. hypertension. Origin of the gout.87]. wrote of the need for ‘‘stomatic monasticism’’: ‘‘The sufferer must also enter into a solemn compact with his stomach to relinquish all serious flirting with the sirens of the kitchen and the houris of the wine cellar’’ [85]. At the turn of the twentieth century. Sydney Smith.344 nuki Fig. after Miescher’s demonstration that nucleoproteins were the main constituents of cell nuclei [88] and Nobel laureate Emil Fischer’s landmark discovery that uric acid could be derived from purine bases. and depression. Haig was among the first people to undertake detailed analyses of the purine content (uric acid and xanthine) of various dietary . 5. and water [1]. who began to have frequent attacks of gout when stationed in Malta. to result in a fall in serum urate levels [83]. and serum urate levels rose significantly in a RCT 4 weeks after starting a dairy-free diet [84]. In Britain. such as xanthine and hypoxanthine [89]. although restricting the intake of purine-rich foods has a greater effect. became obsessed with the notion that uric acid plays a role in the causation of many diseases. ceased to be troubled with gout some months after abstaining from all animal food and adopting a diet of milk. including his own headaches. Alexander Haig (1853–1924). known as the witty canon of St Paul’s. a physician at St Bartholomew’s Hospital. vegetables. Observational studies in small numbers of obese patients who had gout have shown that gradual weight reduction by restriction of carbohydrate intake can be associated with decreases in serum urate [86.

Current guidelines for the treatment of gout emphasize the importance of advice about lifestyle modification. 7th edition. coffee. and eventually in the urine. London: J&A Churchill. 799. The considerable magnitude of the contribution of dietary purines to serum urate and urinary uric acid excretion were demonstrated clearly 70 years later in physiologic studies in which healthy volunteers were fed isocaloric.treatment of crystal arthropathy 345 constituents. 6. Dr. Alexander Haig’s chart of his own urine uric acid. I saw that I could take as much nitrogen as was necessary for nutrition as long as I avoided substances containing much uric acid or xanthin. and cocoa (Fig. tea. In the course of his experiments. The sharp fall in uric acid excretion in 1895 illustrates the effect of his purine-free diet. Uric acid as a factor in the causation of disease.. I believed that the only way to reduce uric acid was to reduce total nitrogen. coffee. tea. For before I became aware that the uric acid which poisoned me was being poured in ready formed in flesh foods. etc. with the unfortunate result of reducing myself to a condition of extreme debility and asthenia. Recommendations include weight reduction Fig. 6). urea and acid excretion from 1893 to 1897. that all uric acid and xanthin swallowed appeared in the blood.) . 1908. and this I proceeded to do. He also spent much of his professional career promoting a lowpurine diet after undertaking a series of physiologic studies on himself in which he demonstrated that serum urate levels and urinary uric acid excretion could be reduced by a diet from which he excluded all fish and animal proteins. he also came to understand that uric acid in the body was derived from both endogenous synthesis and the intake of purine-containing food and beverages [90]: I have had in my experimental work the most absolute proof that a sufficient supply of nitrogen is the prime necessity of nutrition. purine-free formula diets [91]. (From Haig A. But when I found out in 1893. p.

Gout.) . for decades despite reports of agranulocytosis and liver toxicity [93. and limited consumption of foods with high purine contents (especially offal. It also had been known for 50 years that salicylates have sufficiently potent uricosuric properties to control hyperuricemia in patients who have gout.346 nuki to ideal body weight. is antiuricosuric when administered in lower doses [96]. and aspirin. red meat.57]. cinchophen. restriction of alcohol (especially beer) intake. Early case chart demonstrating the effect of probenecid on serum urate and time lost from work because of recurrent episodes of acute gouty arthritis. sulphinpyrazone in 1957 [98]. The effectiveness of probenecid is illustrated in one of Talbott’s case reports (Fig. and shellfish) [55. New York: Grune & Stratton. (From Talbott JH. Mobilization of tophi after long-term treatment with probenecid was demonstrated first Fig.94]. with permission. when given in doses of 4 to 6 g daily [95]. and benzbromarone in 1965 [99] that physicians first were provided with agents that could be used to control hyperuricemia and gout safely and effectively in the majority of patients for long periods of time. 7) [100]. Uricosuric drugs Many analgesic and anti-inflammatory drugs also increase renal excretion of uric acid. paradoxically. but not in the United States. The uricosuric effects of the quinoline analgesic. were recognized approximately 100 years ago [92] and the drug continued to be used for the treatment of gout in Europe. 7. 1967. Few patients can tolerate such a regime. It was with the introduction of treatment with probenecid in 1951 [97].

it was used to inhibit the degradation of 6-mercaptopurine [112] and found to be an inhibitor of xanthine oxidase [113]. All uricosuric agents now are contraindicated in patients who have a history of urolithiasis. can be effective in patients who have moderate renal insufficiency. Sulphinpyrazone (200–400 mg/day) is more potent than probenecid (1–2 g/day). 6. indomethacin.2–9. naproxen. Because of a small number of reports of hepatic toxicity and failure. After examination of the United Kingdom General Practice database demonstrated that its use in general practice was associated with a relatively high risk of upper GI bleeds and perforations (RR 23. adequate control of hyperuricemia cannot be achieved [103. Gradual resolution of tophi can be observed if the serum urate level is maintained below 6 to 6.06 per year in a cohort of 60 patients followed longitudinally [118]. Serum and urinary uric acid were reduced dramatically when allopurinol was used first as an adjunct in a trial of 6-thiopurine in patients who had leukemia and.6 for high-dose ibuprofen. Serum urate levels begin to fall 1 to 2 days after starting allopurinol with maximal decrements in 1 week [115]. diclofenac. A case chart from one of . Benzbromarone (100–200 mg/day) is a more potent uricosuric. CI.treatment of crystal arthropathy 347 by Yu and Gutman in 1951 [101]. 5. and can be useful particularly for patients who cannot tolerate allopurinol and for managing transplant patients when allopurinol is contraindicated [105]. The number of acute attacks of gout was diminished from 4. and it never has been licensed for use in the United States. Uricostatic drugs The development of allopurinol in the late 1950s by scientists at the Burroughs Wellcome research laboratories led to the most important advance in the treatment of gout and the control of uric acid production. The work leading to this discovery was a brilliant example of Gertrude Elion and George Hitchings’ targeted approach to developing analogs of purine metabolites that selectively inhibited key steps in cellular metabolic pathways and DNA synthesis. and ketoprofen) [110]. and in patients who are receiving them.117]. CI. care needs to be taken to ensure that a high fluid intake and urine output are maintained [63].2 mg/dL (360–370 mmol/L) [116. the use of benzbromarone recently has been restricted in several European countries [106]. Azapropazone (1200–1800 mg/day) is a NSAID shown to have moderate uricosuric potency [107] and efficacy in acute gouty arthritis [108] and in reducing the frequency of attacks of gout during the intercritical period compared with indomethacin plus allopurinol [109]. however. Initially developed as a putative. subsequently. Elion and Hitchings shared the 1988 Nobel Prize in Physiology or Medicine with Sir James Black for ‘‘discoveries of important principles for drug treatment’’ [111]. and in approximately 25% of patients who have gout.4 per year to 0. but neither is effective in patients who have renal insufficiency (creatinine clearance less than 30 mL/min) [102]. cancer chemotherapeutic agent. use of this uricosuric NSAID largely was discontinued in the United Kingdom. in patients who had gout [114]. and it never has been licensed for use in the United States. but not promising. however.0.104].9–79.5 compared with RR 7.4.

the primary endpoint (serum urate measurements less than 6 mg/dL at the final 3 monthly measurements) was achieved in only 21% of the patients receiving allopurinol compared with 53% of those receiving febuxostat (80 mg) and 62% of those receiving 120 mg per day [122]. except in rare patients who have primary purine overproduction associated with mutations of the purine salvage enzyme. in a recent study of 762 patients who had gout where the effects of allopurinol (300 mg daily) were compared with a new xanthine oxidase inhibitor.4-d)pyrimidine (allopurinol). with permission. Although clearly this suggests that Fig. Also. febuxostat (80 mg and 120 mg daily).) . hyperuricaemia and gout. The reduction in urine uric acid excretion is not replaced stoichiometrically by excretion of oxypurines (xanthine and hypoxanthine). (From Rundles RW. Serum urate and urine uric acid and oxypurine values in a 58-year-old man treated with allopurinol in 1963. In one open comparison of allopurinol (300 mg daily) and benzbromarone (100 mg daily). Effects of a xanthine oxidase inhibitor on thiopurine metabolism. illustrating many of these improvements. is shown in Fig. Although it previously was suggested that doses of 300 mg of allopurinol reduce serum urate to normal levels in 85% of patients and that in some patients doses of 100 or 200 mg are adequate [120]. 8.76:126–40. Hitchings GH. hypoxanthine guanine phosphoribosyltransferase [119]. Wyngaarden JB. et al.348 nuki Rundles’ early patients. 8. as allopurinol has an additional effect of inhibiting de novo purine synthesis. 4-hydroxypyrazolo(3. HPP. Trans Assoc Am Physicians 1963. the plasma urate fell to 6 mg/dL (360 mmol/L) in all patients treated with benzbromarone but only in 53% of those receiving allopurinol in this dose [121]. more recent studies suggest that frequently this is not the case.

Combining uricosuric and uricostatic drugs Combining allopurinol treatment with probenecid or sulphinpyrazone for patients who have extensive tophaceous deposits and adequate renal function was shown to result in increased elimination of urinary uric acid shortly after the introduction of allopurinol therapy [127. and more effective in reducing the size of tophi during 12 months [126] in phase III comparisons. safe and more effective than allopurinol (300 mg per day) in maintaining serum urate levels less than 6 mg/dL [122]. rasburicase has been administered monthly for more than a year without significant immune reactions [138]. this also has been demonstrated when allopurinol is combined with benzbromarone [121. rasburicase has been given by repeated intravenous injection with good effect in isolated cases of tophaceous gout in transplant recipients [136] and patients who have tophaceous gout resistant to combined treatment with allopurinol and benzbromarone [137]. urate oxidase (uricase). the cost. Transient reduction of serum urate after infusion of purified uricase was reported first in a paper in Science in 1957 (Fig. in phase II studies. as there is evidence that adverse events. Uricolytic agents Humans are susceptible to developing gout because they lack the enzyme. which metabolizes uric acid to allantoin in most mammalian species. repeated injection of urate oxidase purified from Aspergillus fumigatus (uricozyme) and the recombinant enzyme expressed in Strep Mitis (rasburicase) have been used to prevent the development of the tumor lysis syndrome in patients undergoing chemotherapy for malignancies [134. oxipurinol. Although currently not approved for the management of gout. It is not yet approved for the treatment of gout in the United States or Europe. which is eliminated by the kidney [124]. especially rashes. More recently.63]. This may be associated with raised plasma concentrations of the allopurinol metabolite.128]. 9) [133]. studies are required to confirm that such a strategy will result in optimal control of hyperuricemia in patients who have gout without adverse effects.treatment of crystal arthropathy 349 allopurinol doses should be adjusted upwardly in many patients who have gout and are being treated with this agent. to be safe and effective in lowering serum uric acid levels in patients who have gout and hyperuricemia [125]. Although this approach currently is limited by the need for repeated intravenous infusions.129]. These combinations are effective despite the fact that uricosuric drugs increase the clearance of the active allopurinol metabolite. More recently.135]. Care should be taken to reduce the dose of allopurinol according to renal function in all patients who have a reduction in estimated glomerular filtration rate [55. oxypurinol [130–132]. and concerns about the development of antibodies. In the . Febuxostat (80 mg and 120 mg per day) has been shown. are more frequent in patients who have impaired renal function [123].

) United States. sustained and substantial reduction of serum urate was confirmed [140].and BCP-associated crystal arthropathies. (From London M. and nonpharmacologic support have been the core approach to management.350 nuki Fig. Calcium pyrophosphate dehydrate– and basic calcium phosphate–associated arthropathies The history of therapy for pseudogout. based on the premise that it depresses the synthesis of the vitamin K–dependent Gla protein. with permission. Serum uric acid and urine allantoin before and after IV administration of purified uricase in 1957. Hudson PB. Rapid resolution of tophi was observed within 3 months in two patients [141]. and crystal-associated periarthritis has been less exciting than the history of the treatment of gout. Science 1957. After the demonstration that probenecid could block the production or release of pyro- . Uricolytic activity of purified uricase in two human beings. 9. and no serious immunologic side effects were observed [140]. Single subcutaneous injections were followed by prolonged reduction of serum urate in 13 patients who had severe refractory gout in an open phase I trial. In a phase II open study where multiple intravenous injections of PEG-uricase were given to a similar cohort of 41 severe refractory gout patients.125:937–8. which may be involved in the process of ectopic calcification [143]. a polyethylene glycol (PEG)–modified mammalian urate oxidase is undergoing orphan drug development. joint aspirations. Historical approaches to inhibiting pathologic calcification have included administration of bisphosphonates to try and prevent heterotopic bone formation after hip surgery [142] and the administration of warfarin in low dosage. Symptomatic therapy with NSAIDs. chronic CPPD. intra-articular steroids. but there are few controlled clinical trials. but there was some evidence of development of antibodies to the PEG [139].

87:386 – 415. Philos Trans R Soc Lond 1797. Gout and hyperuricaemia. editors. Kelley WN. nucleoside triphospate pyrophosphohydrolase isoenzyme PC-1 ( NTP-PPH PC1) [152].13:414 – 8. Observations on certain pathological conditions of the blood and urine in gout. [6] Scheele KW. In 1967. Examen chemicum calculi urinarii.31:83 – 97. Kelley WN. 1976. in humans. 2 – 12. [2] Rodnan GP. and the treatment of gout with uric acid–lowering drugs became a paradigm for the successful treatment and prevention of a chronic rheumatic disease. as this naturally occurring pyrophosphate analog can inhibit calcium crystal nucleation and several crystal-induced inflammatory mediators (reviewed in [147]) and has been shown to inhibit disease progression in murine progressive ankylosis [148]. Arthritis Rheum 1961. . In: Wyngaarden JB. Trans Med Chir Soc Edinburgh 1848. hopefully. Berkeley7 University of California Press. rheumatism and Bright’s disease. and the ANK gene [153]. will lead to new therapeutic approaches for controlling CPPD and BCP crystal deposition. some of the clues are emerging from examining the consequences of critical gene mutations. [7] Garrod AB. In mice. As in gout. led to an explosion of knowledge about the regulation of purine metabolism in humans and the pathogenesis of gout that rapidly led to the development of rational and effective treatment and prevention of this disease. are associated with phenotypes that include progressive ankylosis and matrix calcification with BCP. Being a miscellany of prints and caricatures from the 16th century to the present day. This was characterized as the ‘‘purine revolution’’ [150]. familial [154] and sporadic [155] forms of CPPD disease are associated with mutations in ANKH. which codes for a transmembrane channel protein involved in pyrophosphate extrusion from cells. mutations of the pyrophosphate-generating ectoenzyme. [3] Wyngaarden JB. There now are indications that we may be on the brink of an analogous breakthrough in understanding how extracellular pyrophosphate promotes CPPD deposition and inhibits the formation of apatite crystals in crystal-associated disorders [151]. References [1] Copeman WSC.treatment of crystal arthropathy 351 phosphate by chondrocytes in vitro in response to transforming growth factor b [144]. [4] McCarty DJ. the key discovery that primary purine overproduction and severe premature gout in boys who had Lesch-Nyhan syndrome resulted from an inherited deficiency of the purine salvage enzyme. On gouty and urinary concretions. An abbreviated history of gout. Cheung proposed the use of phosphocitrate as a potential therapeutic strategy for calcium crystal deposition disorders [146]. probenecid was used to treat patients who had refractory CPPD-associated arthritis with some success in an uncontrolled trial [145]. A short history of the gout and the rheumatic diseases. hypoxanthine guanine phosphoribosyltransferase [149]. however. New York7 Grune and Stratton. This. [5] Wollaston WH.4:27 – 46. 1964. Paradoxically. the human homolog of the ANK gene.2:73. Arthritis Rheum 1970. A historical note: Leeuwenhoek’s description of crystals from a gouty tophus. A gallery of gout. Opuscula 1776. p.

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b. hyperuricemia. USA A literature search was conducted in the MEDLINE. Lake Forest. FL. MDa. crystal deposition. T Corresponding author.. E-mail address: Nancy. All rights reserved. hydroxyapatite. monosodium urate. In addition. Joseph-Ridge). pseudogout. regardless of the type of crystal. basic calcium phosphate. and clinical trial. USA University of Florida College of Pharmacy. Gainesville. doi:10. the full text was evaluated. and International Pharmaceutical Abstracts databases using various combinations of search terms.1016/j. PharmD Candidatea. The manuscript preparation was supported by a grant from TAP Pharmaceutical Products. Patricia MacDonald. IL.Rheum Dis Clin N Am 32 (2006) 359 – 382 Clinical Trials in Crystal Arthropathy Nancy Joseph-Ridge.2006. Current Contents. EMBASE. BIOSIS. Inc. including selective and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine [1–7]. Susan Cazzetta.com . crystal arthritis. NPa b a TAP Pharmaceutical Products. TAP Pharmaceutical Products. gout. BSN.rdc. (Lake Forest. crystal arthropathy.T. BS Pharm. including apatite.com (N.theclinics. IL 60045. and if relevant. Inc.002 rheumatic. Clinical trials in the management of acute crystal arthropathy The initial management of acute arthritis resulting from crystal arthropathy. Lake Forest. calcium pyrophosphate dihydrate. 675 Field Drive. a manual search of review articles was conducted to identify other studies.02. Derwent Drug File. is symptomatic therapy. Illinois). 0889-857X/06/$ – see front matter D 2006 Elsevier Inc. The abstracts of the identified articles were reviewed.joseph-ridge@TAP.

or 7 days (mean pain score . 1987 [19] Indomethacin (I) versus azapropazone (A) 93 Pain: improved by !50% (10/15. Pb. wrist. 4.35) No statistically significant difference in the proportion of patients who reported that the treatment ‘‘suited them’’ after 4 days (I. Maccagno. of patients joseph-ridge et al Garcia de la Torre.360 Table 1 Selected clinical studies of nonsteroidal anti-inflammatory drugs in the treatment of gout Regimen T: 40 mg once daily Diagnosis Outcomes Reference NSAIDs studied No.05 Tenderness: improved by !50% (6/15.05 Pain: no difference after 2 to 5 days using 5-point Likert scale (difference +0. 35/47 [74%] versus A. 40/46 [87%]). 95% confidence interval À0. 26%). 2002 [27] Acute gout Indomethacin (I) versus etoricoxib (E) 150 men I: 50 mg 3 times daily E: 120 mg once daily Acute gout of knee. Pb.14 to +0. 1987 [23] Tenoxicam (T) versus placebo (P) 30 Schumacher. ankle. 67%) with T versus P (4/15. 1991 [31] Etodolac (E) versus naproxen (N) 61 I: 200 mg/d in divided doses followed by a reducing regimen for 28 days A: 600 mg 3 times daily for 4 days followed by 600 mg twice daily for 28 days E: 300 mg twice daily Acute gout Pain score: no significant difference in 0 to 5 pain score (higher score indicating worse pain) after 2. 40%) with T versus P (1/15. 7%). or elbow Acute gout for b24 hours Fraser.11. big toe.

4.3 for I versus 1. and 0. respectively Improved pain: no signfiicant difference between I and F in the proportion of patients who had improved pain at rest after 2 days (I. and 0.1. or 8 days using 0.6 with E versus 2. 1.4) Pain: no signfiicant difference after 1.8. and 7 days Pain scores: no significant difference after 2.to 3-point scale (higher score indicating greater pain). and 8 were 0. 1986 [17] Indomethacin (I) versus flurbiprofen (F) 29 E: 300 mg twice daily N: 500 mg twice daily I: up to 225 mg for 1 day in divided doses followed by 50 mg 3 times daily K: 450 mg in divided doses for 1 day followed by 100 mg 3 times daily I: 50 mg 4 times daily for 4 days followed by 25 mg 4 times daily for 5 days F: 100 mg 4 times daily for 1 day followed by 50 mg 4 times daily for 5 days Acute gout 361 .N: 500 mg twice daily 60 Acute gout for b 48 hours Acute gout Lederman. Mean scores at days 2. 11/12 [92%] versus F.8 with E versus 2. 1988 [18] Etodolac (E) versus naproxen (N) Indomethacin (I) versus ketoprofen (K) 59 at 2 days: 2. mean pain score at 4 days: 1. 2.8 with N. 1990 [30] Altman.0 with N) Pain score mean improvement: no significant difference between E (1.4 for K. 0.4 at day 8) versus N (1. 11/12 [92%]) clinical trials in crystal arthropathy Lomen.9.3. 5. 5.

each administered once daily for 7 days in a single-blind. colchicine for an acute attack of arthropathy often is reserved for those who cannot take or tolerate NSAIDs [34]. with some rebound of pain in ketorolac patients after 6 hours. meclophenamate [20]. Both trials showed similar efficacy between treatment arms at all points of the trials. via oral. ibuprofen [12. it is less effective in those who have pseudogout than those who have gout [8. Corticosteroids. with these agents generally considered first-line therapy for those who have gout or pseudogout (Table 1) [8–10]. oxamethacin [15]. 31) versus naproxen (500 mg) two or three times daily (n = 31. indomethacin [11.13]. In both double-blind studies. Subjects (n = 62) received rofecoxib (50 mg). and meloxicam on 62 patients experiencing an acute attack of gout. and sulindac [24].32]. randomized double-blind trials [30. 29) for between 3 and 7 days for the treatment of acute gout attacks. This study was followed by a randomized. are used in patients who have acute attacks of gout. there were no statistical differences among the three treatment groups. There was no statistically significant difference between patient-rated responses for rofecoxib and diclofenac. Two studies investigated the effect of eterocoxib versus indomethacin in acute gout [26. intra-articular. Until 1990. Improvement by the end of treatment occurred in 87% to 97% of subjects in each treatment arm. Pain scores decreased similarly in both groups during the first 120 minutes of the study. a total of 349 subjects were randomized to eterocoxib (120 mg daily) or indomethacin (50 mg 3 times daily) for 8 days. fenoprofen [21. In more recent studies. Two small. Therefore. NSAID studies involved acemethacin [11]. rofecoxib. There were no significant differences between the treatment groups at any visit or at the final evaluation. randomized controlled trial. One small (n = 43). or meloxicam (15 mg). flurbiprofen [17]. Investigator ratings were similar and by day 8. however. diclofenac. No significant differences in pain relief were found between the various NSAIDs. tenoxicam [23]. pseudogout. randomized. intravenous.14–20].21]. double-blind study examining the efficacy of intramuscular ketorolac (60 mg) versus oral indomethacin (50 mg) in 20 patients presenting to an emergency department with acute gout [29]. All patients were satisfied with ketorolac treatment. azapropazone [19]. Colchicine is considered the classic treatment for acute crystal arthropathy management. proquazone [16]. Cheng and colleagues studied [25] the effect of rofecoxib. and ketorolac have been investigated.31] evaluated the use of etodolac (300 mg) twice daily (n = 29. or intramuscular routes.362 joseph-ridge et al Clinical studies comparing the various NSAIDs find similar pain relief efficacy and tolerability profiles. diclofenac. placebo-controlled trial finds colchicine associated with pain improvement after 48 hours. phenylbutazone [14. Shrestha and colleagues [28] studied the effects of intramuscular ketorolac (60 mg) in nine patients presenting to an emergency department with attacks of acute gout. ketoprofen [18].27]. eterocoxib. and basic cal- .22]. diclofenac sodium (150 mg sustained release). Colchicine also is associated with diarrhea or vomiting within the first 24 hours [33].

These case reports are difficult to assess because of the multiple medications that the .51]. open-label study in which patients experiencing acute gout attacks were assigned randomly to indomethacin (50 mg 3 times daily. open-label study [41] evaluated the use of one dose of intra-articular betamethasone (7 mg.clinical trials in crystal arthropathy 363 cium phosphate (BCP) deposition. and inflammation decreased although serum urate values remained similar. Roane and coworkers [42] prospectively investigated the use of triamcinolone acetonide (60 mg intramuscularly) in 14 patients who had pseudogout and conclude that it was safe. with conversion to oral prednisone as soon as possible. Like that of corticosteroids.53]. although studies are limited. n = 10). there have been case reports regarding the use of the tumor necrosis factor (TNF) inhibitors. its clinical usefulness is limited by the need to administer multiple injections [8. n = 10) or triamcinolone acetonide (60 mg intramuscularly. well tolerated. painful flares. in the treatment of patients who have acute pain and inflammation who are unable to use NSAIDs or colchicine [52. The intensity and frequency of the attacks decreased after four injections. n = 7) in patients who had contraindications to NSAIDs versus diclofenac (150 mg daily for 3 days titrated to 75 mg daily for 3 additional days. the use of corticotropin generally is reserved for those who cannot tolerate NSAIDs or colchicine treatment [8]. Oral prednisone dosages varied from an initial dose of 20 mg to 50 mg per day (range 30 mg to 160 mg). There was no statistically significant difference in the number of days to resolution of all symptoms at each evaluation period. Two patients received parenteral methylprednisolone at doses ranging from 30 mg to 160 mg. n = 10) or intravenous methylprednisolone (125 mg. and significant joint inflammation who was given infliximab (400 mg intravenously [5 mg/kg] at weeks 0. Alloway and colleagues [43] conducted a prospective. Complete resolution of symptoms occurred within 7 to 10 days. Although it was effective in relieving pain.10]. and 6). with dosages tapered during a mean of 11 days. There is general agreement that corticosteroids should be reserved for those who cannot be treated with NSAIDs or colchicine [8. infliximab was administered (400 mg intravenously every 6 weeks) with good response. The patient experienced fast relief from pain and inflammation. Adrenocorticotropic hormone or corticotropin has been studied in patients who have acute gout or pseudogout [44–50].10.34–39]. in one study quicker than indomethacin [44]. After experiencing a flare 6 weeks after the third injection. Patient-reported improvement and severity of joint swelling improved promptly in all three groups. A more recent prospective. with an absence of systematic reviews or randomized controlled trials to confirm their efficacy [5. Recently. Etanercept was injected subcutaneously twice weekly in a 53-year-old man who had frequent recurrent attacks of gout and who was taking probenecid and urine alkalizers [52]. Fiehn and colleagues [53] describe a 44-year-old man who had chronic gouty tophi. 2. and effective. n = 10) plus acetaminophen plus codeine as needed. etanercept and infliximab. One prospective trial [40] investigated the use of oral prednisone and intravenous methylprednisolone for acute gout attacks in 13 patients during a 12-month period.

an increase in acute gout flares also was noted after discontinuation of prophylaxis after 8 weeks [62]. Allopurinol was initiated (100 mg per day) with the dose titrated to serum urate less than 6. Multiple retrospective studies postulate that colchicine prophylaxis is an effective means of preventing acute gout [54–56]. Subjects treated with colchicine had fewer gout flares in the first 3 months of treatment and fewer flares in the 3. prospective. Clinical trials in the prophylaxis of recurrent crystal arthropathy Preventative measures or prophylaxis may be required to reduce the frequency and severity of acute crystal arthropathy episodes or gout flares. febuxostat. Because inflammation in osteoarthritis often is secondary to the presence of calcium-containing crystals. The investigators analyzed only 38 subjects who were assessed as compliant with probenecid. The overall expense of these agents may preclude their use in gout.5-gm daily) and either colchicine (1. based on a reduction in serum urate. Randomized controlled clinical trials are needed to confirm the safety and efficacy in gout patients.to 6-month treatment period. randomized. placebo-controlled study was conducted in which colchicine (0.to 4-week period [60].364 joseph-ridge et al patients were taking. In phase III studies. double-blind study [57]. double-blind. Das and coworkers [59] investigated whether or not colchicine would prevent crystal-induced acute inflammatory flares in patients who have osteoarthritis.5-mg daily) or placebo.6 mg. Acute gout flares occurred in 14% of the colchicine group and 63% in the placebo group (P = 0.6 mg once or twice daily) or naproxen (250 mg twice daily) [60–62]. Clinical studies of a new nonpurine selective inhibitor of xanthine oxidase (XO). 6-month clinical trial using colchicine as prophylaxis when initiating therapy with allopurinol.008). When targeted serum urate was reached and maintained. n = 21) or placebo (n = 22) twice daily. In phase II studies. Borstad [58] conducted a randomized.5 mg/dL in 100-mg increments (mean dose 265 mg per day). Improvement was higher by 30% after 20 weeks in the colchicine group compared with the placebo-treated group. 51 subjects were treated with probenecid (1. gout flares during colchicine prophylaxis occurred in approximately 10% of subjects and increased to 40% to 53% of subjects when prophylaxis was withdrawn after the mandated 2. doubleblind. Forty-three subjects initiating allopurinol therapy received colchicine (0.5 mg twice daily) or placebo was added to NSAID treatment in 36 patients who had osteoarthritis. The investigators conclude that further evaluation of colchicine’s role in osteoarthritis is needed to determine if the effect seen is the result of crystal-induced inflammation or to other mechanisms. Few randomized controlled trials for preventing acute gout attacks have been conducted. and found that colchicine reduced the frequency of acute attacks significantly. subjects reported fewer gout flares after 6 months. A randomized. In a 6-month. also include prophylaxis with either colchicine (0. .

Long-term symptomatic treatment with an NSAID or colchicine may provide some benefit. hypophosphatasia. Each of these agents has clinical advantages and limitations. however. the underlying cause of this disease. In those who have pseudogout. however. treated. A prospective. An observational study notes that after the initial presentation of acute gout. should be ruled out and. long-term treatment exists for those who have calcium pyrophosphate dihydrate deposition (CPPD) or BCP crystal deposition disease [4]. Currently.66–68]. and allopurinol. self-controlled trial shows that chronic long-term treatment with colchicine (0. A reasonable pharmacologic therapeutic target is to reduce serum urate to subsaturation levels of 6. underlying conditions that are associated with this disorder. there is a 62% recurrence rate within 1 year.6 mg twice daily) reduces the number of recurrences of pseudogout [32]. haemochromatosis. Clinical trials of agents in the treatment of gout There have been few advances in the management of chronic gout in the past 40 years. In contrast to other crystal arthropathies. which reduces uric acid production.clinical trials in crystal arthropathy 365 Clinical trials in management of chronic crystal arthropathy Pseudogout and basic calcium phosphate Strategies for the chronic management of those who have crystal arthropathy depend on causative crystal identification and underlying or associated disease states. 78% by year 2. a purine analog and the only XO inhibitor available. and 89% by year 5 [54]. with the latter generally resulting from dosing or tolerability and safety profiles (Table 2). the most commonly used agents are probenecid. recent studies find promising results with new . a uricosuric. Another study notes that the frequency of recurrence of acute gouty arthritis also increases after withdrawal of long-term urate-lowering treatment [63–65]. such as hyperparathyroidism. hypomagnesaemia. To date. and Wilson’s disease.0 mg/dL or less [3. Although probenecid and allopurinol remain the antihyperuricemic agents prescribed most frequently. Given the low frequency of recurrent attacks of pseudogout or BCP arthropathy. The cause of BCP arthropathy is less clear but is known to occur with degenerative joint disease. no effective chronic. if identified. gout recurrence is high. This may be attained with a uricosuric that increases uric acid excretion or pharmacologic agents that inhibit the enzyme XO.56. Gout Chronic management of gout is defined based on correction of hyperuricemia. neither addresses the hyperuricemic etiology of gout. the benefits of long-term colchicine need to be weighed against the risks for side effects [2].

NSAIDs or captopril) Available in Europe. oral anticoagulants. theophylline. headache. and joint-related signs and symptoms Probenecid Uricosuric agent that reduces uric acid in underexcretors and those who have normal renal function without renal stones or massive tophi Benzbromarone Uricosuric agent that effectively lowers serum uric acid in underexcretors and overproducers Like its parent compound. and serious events. limited availability in United States May precipitate acute gout flare on initiation Concerns regarding hepatotoxicity Patients who are intolerant of allopurinol may exhibit toxicity to oxypurinol May precipitate acute gout flare on initiation May precipitate acute gout flare on initiation Most common side effects are liver function abnormalities. gastrointestinal symptoms.366 joseph-ridge et al Table 2 Summary of advantages and disadvantages of current and investigational agents used in the treatment of hyperuricemia and gout Drug Allopurinol Mechanism of action and advantages Widely used XO inhibitor Once-daily administration Effective in underexcretors and overproducers Can be used (with dosage modification) in those who have renal impairment Disadvantages May be associated with acute gout flare on initiation Adverse events are common and may be severe and serious (ie. a good inhibitor of xanthine oxidase May be useful in patients who are allopurinol intolerant Nonpurine selective inhibitor of XO Effectively lowers serum urate in underexcretors and overproducers Administered orally and once daily Oxypurinol Febuxostat (continued on next page) . such as nephrotic syndrome and blood dyscrasias Drug-drug interactions (ie. azathioprine) May be associated with acute gout flare on initiation Ineffective in those who have diminished renal function (creatinine clearance b50 mL/min) Diminished efficacy in those treated with acetylsalicylates Adverse events include rash. diarrhea. increased plasma levels of concurrent agent) may occur resulting from interference with urinary excretion of other agents (eg. hypersensitivity syndrome. liver and renal toxicity) and occur with greater frequency in those receiving concomitant diuretic agents or ampicillin Must modify dose in those who have renal impairment Associated with drug-drug interactions (ie. headache.

clinical trials in crystal arthropathy Table 2 (continued ) Drug Febuxostat Mechanism of action and advantages May be used without dosage adjustment in those who have renal insufficiency or hepatic impairment Found safe and effective in large. long-term clinical trials Potent recombinant uric acid oxidase compound that catalyzes enzymatic oxidation of uric acid Useful in patients who have tumor lysis syndrome Disadvantages 367 Rasburicase PEG-uricase (Puricase)/ uricase-PEG20 Fenofibrate Losartan E3040 Effective recombinant porcine urate oxidase compound that produces rapid and profound decrease in serum urate Potentially useful in patients who have tumor lysis syndrome and possibly those who have refractory gout PEG strands may reduce the risk for immunogenicity compared with rasburicase Hypolipidemic agent that increases clearance of purine bases including uric acid Orally administered useful adjunct to hyperuricemic therapy in patients who have concurrent hypertriglyceridemia Orally administered angiotensin II receptor antagonist that interferes with urate reabsorption Useful adjunct to hyperuricemic therapy in patients who have concurrent hypertension Member of a new class of antiinflammatory agents found to reduce plasma urate levels. Parenteral route of administration Rapid reduction of serum urate may precipitate acute gout flare on initiation May administer only one course of rasburicase during patient’s lifetime because of potential for antibody formation Potential for anaphylactoid reactions Carries black box warning for anaphylactoid reactions and for hemolysis and methemoglobinemia. such as probenecid Agent in early stages of investigation Efficacy and safety data still evolving (continued on next page) . especially in those who have glucose-6-phosphate dehydrogenase deficiency Long-term safety is unknown Administered intramuscularly May precipitate acute gout flare Potential for allergic reactions from foreign protein Well-described safety and efficacy data not yet published Effects of fenofibrate on serum urate are modest compared with allopurinol or febuxostat Hypouricemic efficacy not yet determined in long-term studies Effects of losartan are modest compared with other uricosurics.

Uricosurics in general.6 months.67. The results of this trial are difficult to interpret because of the randomization treatment allocation and because of the five patients who were allocated to probenecid but were switched to sulphinpyrazone because of adverse events. a uricosuric agent. are ineffective in those who have reduced renal function and efficacy may be diminished in those taking salicylates [4. It is effective in lowering serum urate in patients who have hyperuricemia resulting from underexcretion and normal renal function without renal stones or massive tophi [10]. as plasma levels of these agents may be increased with concurrent probenecid use [72]. Caution is advised in patients who have a history of peptic ulcer disease and those taking NSAIDs or captopril.51].73–75]. Benzbromarone Benzbromarone. There is insufficient evidence from systematic reviews or randomized trials on the effects of probenecid to prevent gout attacks [69] and the clinical usefulness of probenecid is limited by its tolerability profile. however. Benzbromarone is effective in those who have reduced renal .368 Table 2 (continued) Drug Y-700 joseph-ridge et al Mechanism of action and advantages XO inhibitor shown more potent than allopurinol May be safe in those who have renal impairment Agent with weak uricolytic and potent uricosuric activity Disadvantages Agent in early stages of investigation Efficacy and safety data still evolving Scopoletin In early stages of investigation Efficacy and safety data still evolving agents designed specifically for the treatment of hyperuricemia and those designed for other indications but are found also to lower serum urate levels. drug-drug interactions. 45% (9/20) of those treated with allopurinol and 47% (8/17) of those treated with uricosurics were recurrence free. and rare but serious reactions. gastrointestinal symptoms. Probenecid is associated with rash. One study of 37 male patients assigned to treatment based on the last digit of their hospital number [70] finds no significant difference between treatment with allopurinol (300 to 600 mg per day) and probenecid (1 to 2 g per day) in reducing acute gout recurrence. such as nephrotic syndrome and blood dyscrasias [71]. Probenecid Probenecid is the uricosuric prescribed most commonly in the United States [4]. is available for the treatment of gout in select European countries but is not available in the United States. Clinical trials show it to be an effective uricosuric and more effective than allopurinol [66. After a mean follow-up period of 18. headache.

75 mg/dL (from 8. Although a dose of 300 mg per day is standard in those who have normal renal function. in which patients develop toxic epidermal necrolysis. It is postulated that clinicians often undertreat gout patients on a longterm basis with allopurinol in an attempt to lessen the small risk of major allopurinol sensitivity [92]. Allopurinol hypersensitivity syndrome can range from a severe skin rash to a life-threatening illness. At doses ranging from 100 to 900 mg per day. This agent has been available for more than 40 years and historically is the urate-lowering agent prescribed most commonly [10. with these agents often requiring dose adjustment [72]. Allopurinol Allopurinol is a purine analog that inhibits XO along with other enzymes in the purine and pyrimidine pathway. This syndrome occurs more frequently in those who have renal insufficiency or those taking concomitant diuretic agents or ampicillin [88–91].76 mg/dL) in underexcretors.clinical trials in crystal arthropathy 369 function [67].85 mg/dL) in normal excretors and of 3.6 to 5. Although effective. A prospective study by Perez-Ruiz and colleagues [67] evaluates the efficacy of allopurinol in reducing serum urate. Desensitization to allopurinol is attempted in patients who have minor hypersensitivity reactions with some success [93].79]. fever. there is insufficient evidence from randomized controlled clinical trials on the ability of this agent to prevent gout attacks. eosinophilia. Allopurinol is compared with benzbromarone in 86 male patients who have primary chronic gout. Less common but more severe adverse events. and worsening renal function [86. Only 53% of patients. theophylline. therefore. are described.0 mg/dL.34 mg/dL (from 9. In addition. Allopurinol is excreted mainly through the kidneys. with the most commonly prescribed dose 300 mg per day. and azathioprine.10 to 5. Allopurinol-treated patients (300 mg per day) exhibited a mean reduction of plasma urate of 2. This result was similar to that of other studies that found the majority of patients who have gout who were treated with allopurinol (300 mg per day) fail to attain serum urate targets of less than or equal to 6 mg/dL [83–85]. Some nonrandomized studies report that allopurinol reduces acute gout attacks over time [80–82] and is comparable to probenecid [70] in reducing the frequency of gout attacks. it is recommended that the dose be reduced in those who have impaired renal function. dosage adjustments are necessary in patients who have renal impairment. Although allopurinol has been available for a long time. however. including headache and gastrointestinal irritation [10]. it produces a dosedependent reduction in serum urate. achieved the targeted serum urate concentration of less than 6. hepatitis. . there are several clinically relevant drug-drug interactions that may occur when allopurinol is given to patients receiving oral anticoagulants. there is concern that benzbromarone is hepatotoxic [76–78].87]. such as bone marrow suppression and hypersensitivity syndrome. Up to 5% of patients are unable to tolerate allopurinol because of adverse events.

120 mg [94%]. demonstrates that febuxostat has sustained uratelowering effects [108]. reports 3% of subjects having related adverse events and concludes that only approximately one half of patients who are allopurinol hypersensitive can tolerate oxypurinol [95].96 mg/dL). Febuxostat Febuxostat. double-blind trial of oxypurinol. Significantly greater proportions of subjects who were febuxostat treated than those who were placebo treated (febuxostat. Oxypurinol compassionate-use protocols. randomized. 40 mg [56%].0 mg/dL) and gout [60]. A phase II.90 mg/dL (baseline mean 10.and comparator-controlled clinical trials performed in North America and Japan have been conducted and confirm the efficacy and safety of febuxostat in patients who have hyperuricemia and gout. which. placebo [0%]) achieved a serum urate less than or equal to 6. its usefulness in the treatment of gout may be limited given the advent of newer antihyperuricemic agents. currently is in late-stage development for the treatment of hyperuricemia and gout [97–101]. serum urate was lowered by 2. 4-week. Evidence of toxicity identical to that observed with allopurinol. placebocontrolled. the primary endpoint is the reduction in serum urate of 2. however. 80 mg [76%]. multicenter. Oxypurinol’s half-life is 9 to 15 times longer than that of allopurinol and is shown to be effective in at least 50% of patients who are allergic to allopurinol. post-baseline mean 7. potent nonurine selective inhibitor of the oxidized and reduced forms of XO. unlike allopurinol. is a good inhibitor of XO. have been conducted since 1966.370 joseph-ridge et al Oxypurinol Oxypurinol is the primary metabolite of allopurinol and. in a 2-year interim analysis. is seen in 30% to 50% of treated patients [94–96]. One safety study conducted in 99 allopurinol-naive subjects.11 mg/dL. receiving 384 mg per day of oxypurinol for 14 days. Therefore. Several placebo. In a phase II. in subjects intolerant or allergic to allopurinol. and 120 mg once daily) in 153 patients who had hyperuricemia (baseline serum urate !8. a new orally administered.102–104]. double-blind study performed in the United States evaluated the dose-response efficacy of febuxostat (40 mg. Pharmacokinetic clinical studies indicate that febuxostat does not require dosage adjustment in those who have renal insufficiency or those who have mild to moderate hepatic dysfunction [105–107].0 mg/dL at the end of the study (day 28). The phase II study has an ongoing open-label extension study. One hundred and sixteen subjects who had gout were . In another phase II trial. Febuxostat is specific for inhibition of XO and. like its parent compound. A similar response was seen at each weekly visit.0 mg/dL between baseline and week 14. 80 mg. does not inhibit other enzymes involved in purine or pyrimidine metabolism [98. randomized. The 77 enrolled subjects achieved a mean serum urate decrease of 1.87 mg/dL in 190 (of 533) compassionate-use patients in a 1-year treatment period [95].

and joint-related or musculoskeletal and connective tissue signs and symptoms. with between 74% and 81% of subjects obtaining serum urate values less than 6.clinical trials in crystal arthropathy 371 given febuxostat (80 mg once daily. These clinical trials used lower doses of febuxostat (10 mg. At the end of the 28-week study. febuxostat (120 mg.0 mg/dL at the last 3 monthly visits. or allopurinol (300 mg once daily.001 for each febuxostat group versus allopurinol). n = 253). or allopurinol (100 mg per day for subjects who had renal impairment or 300 mg per day for subjects who had normal renal function) for 28 weeks [109].or allopurinol-controlled trials conducted in Japan evaluating the efficacy and safety of febuxostat in subjects who had gout or hyperuricemia (baseline serum urate !8.0 mg/dL were 0% among those treated with placebo. 120 mg. titrated to 40 mg or 120 mg per day based on serum urate and adverse events). The effects of febuxostat were sustainable. or 240 mg).05). 69% in those treated with febuxostat (240 mg). the percentages of subjects who met the primary endpoint of last three serum urate values less than 6. n = 256). Between 44% and 60% of these subjects treated with febuxostat achieved serum urate less than 6. A post hoc analysis of the effect of serum urate levels on gout flare incidence shows that subjects who achieved an average post-baseline serum urate level of less than 6. There were 40 subjects in this study who had moderate to mild renal impairment. and 22% in those treated with allopurinol. The most frequent treatment-related adverse events with febuxostat were liver function abnormalities. These percentages were significantly higher in all febuxostat dose groups compared with placebo or allopurinol ( Pb. n = 251). The most frequent treatment-related adverse events were similar to those in the previously reviewed phase III study [62]. The rate of adverse events was low and similar between those who had normal renal function and those who had moderate impairment. 20 mg. diarrhea. There are three double-blind. Significantly greater percentages of patients treated with febuxostat (80 mg or 120 mg once daily) attained this primary endpoint and maintained their last three serum urate levels of less than 6.0 mg/dL at each of the last three visits compared with 0% treated with placebo or allopurinol. The primary efficacy endpoint was the percentage of patients reaching a serum urate level of less than 6.0 mg/dL were randomized in a 1:2:2:1:2 ratio to once-daily fixed dose of placebo. regardless of therapy. A total of 760 patients (96% men) was randomized to 52 weeks of treatment with febuxostat (80 mg.0 mg/dL had fewer gout flares requiring treatment (6% versus 14%) and a greater median reduction in tophus area (75% versus 50%) at week 52 compared with those who did not. febuxostat (80 mg.0 mg/dL at each visit during the 2-year analysis period [108]. In a phase III North American trial (United States and Canada). headaches. 1067 subjects who had gout and serum urate levels greater than or equal to 8.0 mg/dL (53% and 62%. and 40 mg) and were of shorter duration than the North American trials. 65% in those treated with febuxostat (120 mg). placebo.0 mg/dL) [110–112]. In another phase III study of febuxostat. multicenter. the serum urate lowering efficacy and safety of febuxostat was compared with those of allopurinol [62]. respectively) compared with patients treated with allopurinol (21%) (P b. The . 48% in those treated with febuxostat (80 mg).

and for the rest of the 3 years of monthly rasburicase therapy. Rasburicase is a recombinant uric acid oxidase made from Aspergillus flavus with a terminal half-life of approximately 17 hours [113]. resulting in the product carrying a black box warning to that effect and for hemolysis and methemo- . 8 to 12 acute attacks of gout per year. Despite the exclusion of patients who have a history of significant atopic allergy or bronchial asthma in clinical studies. Cases of anaphylactoid reactions also are reported. with febuxostat having significantly greater reduction in serum urate compared with placebo or allopurinol. that catalyzes the enzymatic oxidation of uric acid into the more (10 times) water-soluble allantoin. lymphoma.15 mg/kg). eliminated gout recurrence. Furthermore.372 joseph-ridge et al dose of allopurinol also was lower. administered intravenously every 2 weeks for 2 months and monthly thereafter.43 mg/dL) at baseline to less than 50 mmol (0. its parenteral route of administration is an undesirable treatment mode. Rasburicase was well tolerated with the patient having mild inflammation of multiple joints (symmetrically fingers. antibodies to uricase still occurred in 7% to 14% of patients treated [116–118]. decreased serum urate levels. is an enzyme found in most mammals. Thereafter. and decreased tophi size substantially. The viability of rasburicase as a therapeutic treatment option for those who have gout likely is limited [10]. as the treatment regimen used 100 mg once or twice daily. In addition to its limitation of only one course per lifetime. there is a significant risk for anaphylactoid reactions [113]. The profound and rapid effects that it has on serum urate may be associated with an increased risk for acute gout flare. which then is excreted easily. A recently published case [115] involving a 33-year-old allopurinol-intolerant female patient who had an 8-year history of hyperuricemia. An intravenous formulation of rasburicase recently was approved by the United States Food and Drug Administration for the initial management of plasma urate levels in pediatric patients who have leukemia.08 mg/dL) during the first week after therapy and increased steadily during the subsequent weeks to levels before therapy during the first 6-month treatment period. or uricase. These studies show similar results to the North American trials. and severe tophi reports that rasburicase (0.11 mg/dL). Serum urate levels decreased from approximately 850 mmol (1. and feet) during the first 2 months and no side effects during the following 3 years of treatment. because rasburicase is a foreign protein. Rasburicase Uric acid oxidase. especially given the options for oral agents. but not humans. knees. serum urate decreased from 850 mmol (1. The profound effects of rasburicase on serum urate suggest that it may be a useful agent in the management of patients who have gout [92] and. and solid tumor malignancies who are receiving anticancer therapy expected to result in tumor lysis and subsequent elevation of plasma urate [114]. the agent currently is under evaluation in gout clinical trials in the United States.43 mg/dL) to 658 mmol (1. as such.

125]. polyethylene glycol (PEG) has been added to the uricase compound [119]. PEG-uricase has received orphan drug designation for the treatment of refractory gout by the FDA Office of Orphan Products Development. As a result.0 mg/dL and a reduction in the ratio of urate to creatinine in urine to less than 0.000 are attached.05) reduction in urate from baseline was observed. fenofibrate was administered (150 mg three times daily for 3 days) with allopurinol (300 mg) given 4 hours after the last dose [126].2. the attachment of PEG greatly prolongs the circulating half-life of the compound. and uric acid. those who have hypertriglyceridemia). and the developing company recently announced completion of patient dosing in a phase II clinical trial [124]. In this phase II study. a stable nonradioactive isotope of nitrogen) will be evaluated in a subset of subjects [121]. A significant 46% ( P b.clinical trials in crystal arthropathy 373 globinemia. In a study of five healthy subjects. Case reports suggest that the reductions in serum urate seen with fenofibrate range between 15% and 35% [10. This mammalian PEG-uricase is reported to be nonimmunogenic and effective in preventing urate nephropathy in a uricase-deficient strain of mice [120]. Takahashi and coworkers [127] assessed the effect of fenofibrate . especially for patients who have glucose-6-phosphate dehydrogenase deficiency. with its uricosuric effect independent of its lipid-lowering efficacy. The ability of PEG-uricase to lower the total urate pool size (measured using a method involving an infusion of uric acid labeled with N15. xanthine. The primary measure of efficacy is a reduction in plasma urate to less than 6. however. some subjects entered in a phase I trial exhibited antibodies [121].0 mg/dL in a patient who has non-Hodgkin’s lymphoma without producing antibodies [122] and shows promise in the treatment of patients who have hyperuricemia and gout [123]. Clinical trials of other agents with antihyperuricemic effect Fenofibrate Fenofibrate is a hypolipidemic fibric acid derivative used commonly that increases the clearance of purine bases hypoxanthine. subjects who have refractory gout are administered PEG-uricase (8 mg by intravenous infusion) once every 3 weeks for a total of five infusions. Polyethylene glycol–uricase/uricase–polyethylene glycol 20 In an attempt to neutralize the immunogenicity issues associated with rasburicase. In addition to reducing the immunogenicity. PEG-uricase is found effective in treating tumor lysis by maintaining a plasma urate of 9. PEG-uricase is described as a recombinant porcine urate oxidase to which multiple strands of PEG of average molecular weight of 10. The results of several studies suggest that fenofibrate may be a useful adjuvant with traditional antihyperuricemic therapy in selected patients who have gout (ie.

although the effects were modest (approximately 15%) and less than that observed in other studies.5 mg/dL). The effect on serum urate was reversible.017–1. As discussed previously. After 2 months. Feher and colleagues report that fenofibrate has a rapid and reversible urate-lowering effect in patients who have hyperuricemia and gout currently receiving allopurinol therapy [128]. Ten men ranging in age from 38 to 74 who had chronic tophaceous or recurrent gout were treated with allopurinol (300 to 900 mg daily) for at least 3 months and were given open-label fenofibrate (200 mg) once daily for 3 weeks. Fenofibrate offers a modest decrease in serum urate compared with several other agents. fatal or nonfatal myocardial infarction. Fenofibrate also produced a 36% increase in urate clearance (7. with levels returning to baseline within 3 weeks of fenofibrate discontinuation. such as probenecid [92. the maximal serum urate-lowering effects of losartan (7% to 15%) seem to be less than the effect achievable with standard dosing regimens of primary uricosuric drugs.0 mmol/L [0.0001). a significant (P = 0.0001).075 mg/dL] versus 17. nonetheless. At the 3. In the Losartan Intervention For Endpoint (LIFE) reduction in hypertension study [134]. the addition of fenofibrate resulted in a statistically significant drop in serum urate.6.024 [1. Serum urate as a time-varying covariate was associated strongly with cardiovascular events in the entire population (P b.30 F 0. thereby lowering serum urate. This finding suggests attenuating serum urate . n = 27) or losartan (50 mg once daily. the use of losartan in combination with antihyperuricemic patients who have gout may offer a modest additional decrease in serum urate in addition to its effects on hypertension [127]. Losartan Losartan is an angiotensin II receptor antagonist that interferes with urate reabsorption in the proximal tubule.2 F 0.04 to 0.4 mmol/L [0. P b. fatal or nonfatal stroke in the entire study population (hazard ratio 1.02). The baseline-to-end-ofstudy increase in serum urate was significantly greater in those treated with atenolol versus those treated with losartan (44. Like fenofibrate.286 mg/dL]. Its hypouricemic efficacy needs to be confirmed in larger and longer-term studies [10.37 F 0. The investigators note that baseline serum urate is associated significantly with an increased rate of the composite outcome of cardiovascular death.130–132].129].0001).004) 19% decrease in serum urate was observed (0.374 joseph-ridge et al (300 mg once daily.168 mg/dL].006) with no change in creatinine clearance. P = 0.4 F 1. and the contribution of serum urate to the treatment effect of losartan on cardiovascular events was 29%. P b. the effect of losartan is compared with atenolol (a b-blocker with no known effect on serum urate concentration) in patients who were not hyperuricemic (mean serum urate of 5. n = 25) in patients who had gout receiving treatment with benzbromarone or allopurinol. Two studies performed in patients post renal [132] or heart [133] transplantation report significant reductions in serum urate. it may be considered a useful agent for patients who have hyperlipidemia and gout.032] per 10 mmol/L [0.9 to 11.week visit.

effective management of acute arthritis. or corticosteroids. Clinical trials in gout demonstrate effective urate-lowering therapies. A single oral dose of Y-700 (5 mg. an agent with uricolytic and uricosuric effects. Newer agents. allopurinol. perhaps more importantly. a new class of anti-inflammatory agents. In a rat model of hyperuricemia. although abdominal cramps. male Japanese volunteers caused a dose-dependent reduction of serum urate levels [140]. Higher (120 mg) and repetitive doses (once daily for 10 days) also have been assessed in male volunteers [142]. male Japanese volunteers [141]. was found to reduce the plasma urate level in phase I clinical studies. 100. and XO inhibitor. 20 mg. Y-700 was absorbed orally rapidly and was eliminated with a half-life of between 23. Urinary excretion was less than 1.clinical trials in crystal arthropathy 375 not only may reduce gout recurrence but also. This suggests that Y-700 may be safe in patients who have renal failure. A series of 1-phenylpyrazoles demonstrate XO inhibitory activity in vitro and in a rat model of hyperuricemia [139]. These clinical trials demonstrate. abdominal pain. Summary There are few clinical trials evaluating crystal arthropathy. may reduce cardiovascular events in a population already at high risk [135–137]. a nonpurine selective . Other early investigational antihyperuricemic agents E3040. or MSU deposition. Of these. and flatulence occurred. probenecid. In a pharmacokinetic analysis that also enrolled healthy. colchicine. therapies include NSAIDs. CPPD. Of the three types of crystal arthropathies. was found in a study of hyperuricemic mice to be a potent uricosuric (at doses of 100 and 200 mg) and a weak uricolytic (at doses of 50. Yamada and colleagues [138] assessed the fractional excretion of urate in an animal model of hyperuricemia and found E3040 to have uricosuric activity in the proximal tubules. only that of gout. Crystal arthropathy requires identification of the crystal (monosodium urate monohydrate [MSU]. These clinical trials indicate that XO inhibitors are the most effective in reducing serum urate in chronic treatment of gout and work well in patients who are overproducers or underexcretors of uric acid. or BCP) and the underlying cause for appropriate management.5% at doses of 0. such as febuxostat. has effective therapies aimed at reversing the underlying cause of hyperuricemia. No serious adverse events are reported. Intraperitoneal administration of scopoletin.5 and 40. or 80 mg) in healthy. Y-700 shows a more potent and longer-lasting hypouricemic action than allopurinol [140]. including the uricosuric. the compound 1-(3-cyano4-neopentyloxyphenyl)pyrazole-4-carboxylic acid (Y-700) has the most potent enzyme inhibition. For acute arthritis.2 hours. Uricosuric agents are not as effective in patients who have renal impairment. and 200 mg) [143].5 to 80 mg. however.

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Calcium Crystal Deposition Diseases: Update on Pathogenesis and Manifestations
E.S. Molloy, MBa,T, G.M. McCarthy, MDb,c
Department of Rheumatic and Immunologic Diseases, Cleveland Clinic Foundation, 9500 Euclid Avenue, A50 Cleveland, OH 44195, USA b Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St Stephen’s Green, Dublin 2, Ireland c Department of Rheumatology, Mater Misericordiae University Hospital, Eccles Street, Dublin 7, Ireland
a

Basic calcium phosphate (BCP) and calcium pyrophosphate dihydrate (CPPD) crystals are associated with several human diseases, especially various forms of acute and chronic joint inflammation and joint degeneration. This article reviews recent work that has advanced knowledge of the clinical syndromes associated with calcium crystal deposition and the underlying mechanisms that may contribute to these pathologic manifestations.

Basic calcium phosphate crystals BCP crystals are composed predominantly of partially carbonate-substituted hydroxyapatite and include octacalcium phosphate (OCP), tricalcium phosphate, and magnesium whitlockite. BCP crystals are associated with several rheumatic syndromes, including acute calcific periarthritis, soft tissue calcification, osteoarthritis (OA), and other degenerative arthropathies, such as Milwaukee shoulder syndrome (MSS). Recently, they also have been linked to breast cancer and atherosclerosis. The key mechanisms whereby BCP crystals may cause tissue damage are (1) induction of mitogenesis; (2) upregulation of matrix metalloproteinase (MMP)
T Corresponding author. Cleveland Clinic Foundation, Department of Rheumatic and Immunologic Diseases, 9500 Euclid Avenue, A50, Cleveland, OH 44195. E-mail address: eamonn.molloy@ireland.com (E.S. Molloy). 0889-857X/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.rdc.2006.02.001 rheumatic.theclinics.com

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mccarthy

production; (3) stimulation of cyclooxygenase (COX) 1 and 2 and prostaglandin E2 (PGE2) production; (4) stimulation of cytokine production, in particular interleukin (IL) 1b; and (5) induction of nitric oxide (NO) production. Pathogenesis The degree of damage that can occur in apatite-associated destructive arthropathies is marked. The basis of cartilage damage by calcium-containing crystals still is somewhat speculative. Theoretically, crystals in cartilage may injure chondrocytes directly. BCP crystals are shown to stimulate production of MMP-1 and -13 from porcine chondrocytes [1] and NO production from bovine chondrocytes [2], making in vivo pathologic interaction between these crystals and chondrocytes feasible. In pathologic specimens, however, crystals rarely are seen in immediate contact with chondrocytes and found engulfed by chondrocytes even less frequently. A significant contribution to BCP crystal-associated cartilage damage ultimately may be derived from effects of these crystals on synoviocytes (discussed later). Basic calcium phosphate crystal-cell interaction One of the earliest cellular effects of BCP crystals is a bimodal increase in intracellular calcium ([Ca2+]i). Using the photoactive dye, fura-2, in a human fibroblast model, Halverson and colleagues demonstrated that BCP crystals induce a rapid tenfold increase in [Ca2+]i within seconds, returning to baseline within 8 minutes [3]. As this increase was not apparent when BCP crystals were added in calcium-free media, this immediate rise in [Ca2+]i was the result of an influx predominantly of calcium from the extracellular space, not a release of calcium from intracellular stores. A second increment in [Ca2+]i started at 60 minutes and continued to increase up to at least 3 hours after stimulation. In contrast, epidermal growth factor induced the early transient rise of [Ca2+]i but not the later sustained release. Increasing phagolysosomal pH by pretreatment with ammonium chloride prevented crystal dissolution and abolished the second rise in [Ca2+]i but had no effect on the early transient peak [3]. More recent work has further elucidated the mechanisms by which BCP crystals can interact with cells [4]. Sun and coworkers evaluated the hypothesis that BCP crystals could stimulate the influx of other molecules, such as DNA fragments and small peptides from the extracellular space, and thus modulate normal molecular signaling. Luciferase activity was enhanced greatly (500–1000-fold) in a dosedependent manner in cancer cell lines treated with a BCP crystal-cytomegalovirus promoter (pCMV) luciferase plasmid mixture. The time course of luciferase activity followed a pattern similar to the first, rapid, transient rise in [Ca2+]i that occurs in response to BCP crystals. These effects of BCP crystals were inhibited by several anticalcification agents, including etidronate and, in particular, phosphocitrate [4]. These results suggest that BCP crystals may stimulate the endocytosis of various extracellular molecules, such as DNA fragments, nucleotides, or

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small peptides, that might exert important but as yet uncharacterized effects, potentially contributing to the pathogenesis of BCP crystal-associated diseases.

Induction of mitogenesis BCP crystals demonstrate a mitogenic effect in vitro in fibroblast cell lines and osteoarthritic synovial fibroblasts [1,5], which may explain the synovial proliferation seen in BCP crystal-associated degenerative arthropathies. Increased cellularity in the synovial lining enhances the capacity for secretion of MMPs and cytokines, which may promote chondrolysis. BCP crystals also enhance survival of and induce DNA synthesis in murine macrophages in vitro [6]. Enhanced local macrophage survival or proliferation in the synovium also could contribute to the synovial hypertrophy seen in association with BCP crystals. It has been established that the mitogenic response to BCP crystals requires endocytosis and intracellular crystal dissolution [7]. BCP crystals increase phospholipase C (PLC) activity in synovial fibroblasts [8], which should result in accumulation of diacylglycerol and enhanced protein kinase C (PKC) activity. Mitchell and colleagues show that downregulation of PKC is associated with inhibition of crystal-induced mitogenesis in Balb/c-3T3 fibroblasts [9]. Further investigation of the molecular mechanisms behind the mitogenic response to BCP crystals indicates a role for nuclear factor kB (NF-kB), PKC, and activator protein 1 (AP-1) induction [10]. The PKC inhibitor, staurosporine, prevents BCP crystal-induced NF-kB and c-fos messenger RNA (mRNA) expression and mitogenesis but not c-jun mRNA upregulation. Although high-affinity receptor protein tyrosine kinases with resultant recruitment and activation of phosphatidylinositol 3-kinase (PI3K) mediate the mitogenic response to other stimuli, neither is required for BCP crystal-induced cell proliferation [10]. BCP crystals activate extracellular signal-regulated kinase 1 and 2 (ERK1/2) but not the p38 mitogen-activated protein kinase (MAPK) pathway in human foreskin fibroblasts (HFF) [11]. BCP crystals also cause phosphorylation of cyclic adenosine monophosphate response element-binding protein (CREB) on serine 133, a step critical to CREB’s activity as a nuclear transcription factor. C-fos activation is believed to occur by a mechanism involving CREB phosphorylation. PD98059, an inhibitor of MEK1, an upstream activator of the MAPK pathway, and U0126, an inhibitor of MEK1/2, significantly inhibited crystal activation of p42/44 MAPK, CREB serine 133 phosphorylation, c-fos, and cell proliferation in a dosedependent fashion [11]. Zeng and colleagues describe the induction of early growth response gene (Egr) 2 by BCP crystals, which could stimulate the activities of several transcription factors that are associated with cell proliferation, such as c-fos, serum response factor (SRF), and c-myc [12]. This upregulation of Egr-2 is abrogated by U0126, a specific p44/p42 MAPK inhibitor, and TMB8, a calcium chelator, but not by p38 MAPK or PKC inhibitors. BCP crystals also may induce fibroblast mitogenesis via induction of Egr-1. Zeng and colleagues demonstrate by reverse transcription polymerase chain reaction (RT-PCR) and Egr-1 promoter analysis that BCP crystals induce Egr-1 transcription via a PKC-

Sun and coworkers [24] report that human MMP-1 induction by BCP crystals is Ras dependent and involves multiple elements. which are known to be induced by BCP crystals [16].21]. By transfecting canine synovial fibroblasts with human MMP-1 luciferase reporter plasmids. These observations correlate with the detection of collagenase and neutral protease activities in synovial fluid from patients who have MSS [18]. including AP-1 and polyomavirus enhancer activator 3 (PEA-3). BCP crystals are shown to upregulate MMP-1. Although crystal endocytosis is necessary for BCP crystals to induce MMP-1 and MMP-3 synthesis. The collagenase promoter contains a 12-O-tetradecanoyl-phorbol-13-acetate (TPA) response element. and proteoglycan. and -9 production from human fibroblasts [14–17] and MMP-1 and -13 from porcine chondrocytes [1]. AP-1 is a heterodimer of the c-fos and c-jun proteins. laminin. fibronectin. abrogates BCP crystal MMP-1 and c-fos induction. intralysosomal crystal dissolution is not. Induction of matrix metalloproteinases production MMPs are proteases that accelerate the degradation of cartilage matrix components. The investigators conclude that multiple elements. it is demonstrated that the induction of MMP-1 promoter by BCP crystals is mediated largely through the À72AP-1 element. The collagenase subfamily of the MMPs includes MMP-1 (collagenase 1). in contrast to the requirement for both events to occur to obtain the maximal mitogenic response to BCP crystals [22]. including AP-1 and PEA-3. are involved in BCP crystal-induced MMP-1 gene expression and that the induction follows the Ras/Raf/MAPK/c-fos/AP-1/MMP-1 signaling pathway [24]. -3. and MMP-13 (collagenase 3). It previously has been postulated that loss of coordinated regulation of MMP/TIMP underlies the cartilage degradation in OA [20. It also is shown that cotransfection of plasmids encoding dominant negative Ras. This shifts the balance of MMP/TIMP activity further in favor of excess protease activity. BCP crystals also can downregulate the synthesis of tissue inhibitor of metalloproteinases (TIMP) 1 and 2 [19]. Elimination of either the À72AP-1 or the À88PEA-3 elements abolishes the hMMP-1 promoter activity in response to BCP crystals. and their cooperation also is reported for other promoters.386 molloy & mccarthy a–dependent ERK1/2 MAPK pathway. which are capable of inhibiting the activities of all known MMPs. Recent studies have further characterized the molecular mechanisms involved in BCP crystal induction of MMP production. and MEK1/2 can block BCP crystal induction of MMP-1 and that U0126. Raf. Reuben and colleagues [25] demonstrate that BCP crystal stimulation of MMP-1 and MMP-3 mRNA and protein expression in human fibroblasts is de- . Overexpression of Egr-1 stimulates mitogenesis in a human fibroblast cell line [13]. such as type II collagen. a MEK1/2-specific inhibitor. Plasmids encoding dominant negative Rac or Rho have no effect on MMP-1 upregulation. MMP-8 (collagenase 2). AP-1 and PEA-3 are implicated in MMP-1 induction by phorbol ester. the transcriptional activity of which depends on AP-1. It also previously has been demonstrated that the ERK1/2 MAPK pathway is a key signal transduction pathway involved in crystal-induced MMP-1 and -3 expression [23]. -8.

however. They also identified that the calcium-dependent PKC pathway cooperates with the distinct calciumindependent p44/p42 MAPK pathway. Increased prostaglandin production Although the contribution of PGs to inflammation and nociception presumably is the basis of the symptomatic benefit derived by OA patients taking NSAIDs. ERK1/2. Knorth and colleagues. which releases PGE2 spontaneously in quantities 50-fold higher than normal cartilage and 18-fold higher than normal cartilage in the presence of proinflammatory stimuli [35]. In turn. IL-1b is believed the key cytokine involved in progression of OA. PKC-m. Augmented proinflammatory cytokine (TNF-a. Nevertheless. COX-2 expression is increased in the synovial blood vessels. lining cells. COX-2 also is expressed in OA cartilage [33–35]. The precise contribution of cytokine production in mediating the pathologic effects of BCP crystals requires further clarification. which is also activated by BCP crystals in human fibroblasts. PKC-a. in BCP crystal-induced MMP-1 and -3 upregulation [26]. TGF-b1 and IL-1b in particular are implicated in the regulation of crystal formation [28]. BCP crystals also are shown to induce TNF-a mRNA expression and protein synthesis in a murine monocyte cell line known to produce high levels of TNF-a. the role of PGs in the pathophysiology of OA is not defined clearly. . The investigators conclude that there are two independent but parallel pathways through which BCP crystals activate fibroblasts. it is demonstrated that PGE2 mediates the IL-1b–induced cartilage degradation in a synovial membrane-cartilage coculture model [32]. although the capacity of BCP crystals to directly induce TNF-a and IL-1b in human monocytes is weaker and less consistent than monosodium urate [30]. such as transforming growth factor-b1 (TGF-b1). and fibroblast-like cells in OA synovium [33]. and c-jun N-terminal kinase (JNK) activity are required for BCP crystal-induced TNF-a synthesis. and tumor necrosis factor a (TNF-a). in the pathogenesis of OA [27]. BCP crystals are shown to increase IL-1b expression in HFF [29] and in chondrocytes [2]. BCP crystals can upregulate expression of various cytokines. whereas TNF is involved at disease onset. More recently. IL-1b and IL-8) mRNA expression and protein secretion are detected in BCP crystal-stimulated monocyte-derived macrophages in vitro [31]. IL-1b.calcium crystal deposition diseases 387 pendent on the calcium-dependent PKC signal transduction pathway and also show the specific involvement of the PKC-a isoenzyme. Cytokine upregulation Evidence is accumulating regarding the role of cytokines. it has been demonstrated that activation of ERK1/2 lies downstream of the calcium-independent PKC isoform. PKC-a is an upstream activator of ERK1/2 but not JNK. a calcium-dependent PKC-a–mediated pathway and a calcium-independent pathway that involves sequential activation of PKC-m and ERK1/2 MAPK. demonstrate that COX-1 may contribute to the pool of PGs in OA synovium [36].

Thus. although IL-1b may contribute to the observed COX-2 upregulation. IL-1b expression. most likely under the control of AP-1. BCP crystal-induced COX-2 mRNA expression also is abrogated by phosphocitrate. and PGE2 production is not elucidated but is of considerable interest as it would confirm the potential of iNOS as an attractive therapeutic target in BCP crystal-associated arthritis. NO also is implicated in chondrocyte apoptosis. PGE2 production at 4 hours is abolished by pretreatment with NS398. a selective COX-2 inhibitor. NO is generated by oxidation of arginine. and amelioration of structural damage [41–44].37. the different time courses of induction suggest that BCP crystals induce COX-2 directly. Intra-articular . NS398. IL-1b expression. This is mediated by activation of p38 MAPK and JNK pathway by OCP. only partially inhibits PGE2 production at 30 hours. however. Nonetheless. The involvement of NO production in BCP crystal-induced MMP synthesis. Only recently. however. Increased nitric oxide production NO is a pleiotropic mediator that is implicated in structural damage to OA cartilage [39].75-fold) COX-1 mRNA induction is seen at 24 hours. Other work suggests that BCP crystals induce iNOS and increase NO production in OA synovial fibroblasts [46]. Ea and coworkers find that OCP induces NO production and upregulated iNOS expression in bovine chondrocytes [2]. PGE2 production.388 molloy & mccarthy It has been known for some time that BCP crystals can increase PGE2 production in mammalian cells [14. Although OCP crystals also upregulate IL-1b expression. has it been demonstrated that this induction of PGE2 is associated with induction of both COX isoforms in HFF [29]. Their study identified another potential mechanism whereby BCP crystals can damage cartilage. which can in turn promote the formation of calcium-containing crystals [45]. Real-time PCR demonstrates a 23-fold upregulation of COX-2 mRNA by BCP crystals. Clinical manifestations of basic calcium phosphate crystal deposition Intra-articular basic calcium phosphate deposition The understanding of the exact relationship between intra-articular BCP crystals and joint pathology is incomplete. maximal at 4 hours. which seems to inhibit all biologic activities of BCP crystals. Maximal (1. Inhibition of PKC and PI3K diminishes BCP crystal-induced COX-2 mRNA expression. suggesting that COX-1 also contributes to BCP crystal-induced PGE2 production in human fibroblasts [29]. catalyzed by the NO synthases (NOS). BCP crystals also upregulate IL-1b mRNA expression peaking at 8 hours. especially because specialized techniques are required to identify the crystals.38]. Selective inhibition of iNOS in a canine OA model results in reductions in MMP synthesis. existing data support the pathogenic role of BCP crystals in articular tissue degeneration. chondrocyte apoptosis. iNOS expression is upregulated in human OA cartilage [40]. the induction of iNOS expression and NO production is independent of IL-1b. One inducible NOS (iNOS) and two constitutive NOS are identified.

seven had MSS. The prevalence of intra-articular BCP crystal deposition is not established. Joint effusion typically is present and may be massive. predominantly mononuclear.6 F 1. MSS. MSS and related BCP crystal-associated destructive arthropathies also are of unknown prevalence. Twenty-eight patients had varying degrees of upward subluxation of the humeral head. Extra-articular basic calcium phosphate deposition BCP crystals may form periarticular deposits that frequently are asymptomatic or give rise to acute calcific periarthritis or chronic calcific tendonitis. including erosive OA. OA is the most common form of arthritis and its prevalence is expected to rise considerably as the population ages. The natural history of the condition is unclear. Concurrence of BCP crystals and OA is well established. connective tissue diseases (in particular derma- . It is associated with rotator cuff defects and numerous aggregates of BCP crystals in the fluids of affected joints [55]. synovium. joint effusions. suggesting that BCP crystals are generated as part of the pathologic process in OA [49]. but in 58% at the final aspiration (at a mean interval of 3.6 years). and no further radiographic changes.52]. and larger joint effusions are seen in affected knee joints when compared with joint fluid from OA knees without crystals [53]. BCP crystals are found in 23% at first aspiration. elbows. and synovial fluid. extending into the subdeltoid region. hips. knees. The mild to moderate upward subluxation of the glenohumeral head observed in 22 remaining affected family members is believed possibly a precursor to the development of MSS. Estimates of the annual cost of OA to the United States economy exceed $60 billion [51]. It is the foremost cause of disability in the elderly population. a distinctive type of destructive arthropathy found in elderly patients. Rupture of the effusion can lead to a massive extravasation of blood and synovial fluid into the surrounding tissues [57]. It is suggested that many OA joint fluids contain clusters of BCP crystals that are too small or too few in number to be identified by conventional techniques [50]. The prevalence in normal joints at different ages is not known.calcium crystal deposition diseases 389 BCP crystal deposition is associated with OA and MSS and with acute synovitis and chronic arthritis. is prototypic of BCP crystal-associated joint degeneration [54–56]. BCP crystals also may be deposited in the soft tissues secondary to other diseases. Aspiration of affected shoulder joints routinely yields 3 to 160 mL of synovial fluid that frequently is blood tinged and has a low. BCP and CPPD crystals may coexist in 16% of OA synovial fluids [49]. Apatite crystals are found in up to 67% of synovial fluid samples from patients who have knee joint OA [47–50]. as their presence correlates strongly with severity of radiographic OA [49. cell count. disabling approximately 10% of those over age 60 [51]. Of these 28 patients. Although the shoulder predominates. such as chronic renal failure. with reduction of symptoms. Crystals of BCP frequently are found in OA cartilage. A kindred of five generations affected with familial OA and MSS recently was described [58]. Ample data support the role of BCP crystals in cartilage degeneration. but many cases seem to stabilize after a year or 2. and other joints may be involved [54].

recurrent acute attacks around the shoulder. It most commonly involves the shoulder but can occur at any joint. The most striking clinical presentation of juxta-articular BCP crystal deposits is acute calcific periarthritis [61. it is difficult to define what contribution.7% prevalence of shoulder deposits was noted in a North American. This is followed by local deposition of hydroxyapatite crystals within extracellular matrix vesicle-like structures derived from these chondrocytes [60]. Pathologic assessments show that the calcific deposits are located in tendons. and chronic neurologic conditions. In some patients. This suggests that many of the deposits seen in young adults disappear spontaneously. Idiopathic BCP crystal deposition (or CPPD crystal deposition) also can occur. suggesting local necrosis followed by ectopic calcification. Similarly. Phagocytosis may be one of the main ways in which the crystals are removed. . and injection into the tissues of human volunteers results in an inflammatory response [64]. the deposits themselves make to the clinical findings. Damage to the tendons and muscles of the rotator cuff may result and may lead to total disruption of the cuff apparatus.62]. Other evidence indicates that calcifying tendinitis is an active. When the latter surrounds the odontoid process. it is termed the ‘‘dcrowded dens’’ syndrome. separated by pain-free periods of months or years. predominantly white. Calcific periarthritis is reported in children as young as 3 but seems uncommon in the elderly. bursae. Acute calcific periarthritis seems to be induced by rupture of the deposit. It is suggested that ‘‘dystrophic’’ tendon calcification occurs as a consequence of local trauma. In the shoulder.390 molloy & mccarthy tomyositis and scleroderma). if any. cell-mediated process in which local vascular and mechanical changes result in focal transformation of tendinous tissues into fibrocartilaginous material containing chondrocytes. giving rise to ’’tumoral calcinosis. calcification in other tendons seems to occur preferentially in hypovascular segments. They are phagocytosed in vitro resulting in the release of inflammatory mediators [63]. peritendinous tissues. a few millimeters from the bone insertion. or ligaments.’’ or ligamentous calcification. and necrosis of tendons. because chronic shoulder pain and calcification are common and because prior damage to tendons may predispose to the calcification.5%). ischemia. population. Women were affected more commonly than men and the prevalence was highest in those between ages 31 and 40 (19. BCP crystals are shown to be intrinsically phlogistic. 34% to 45% of which were associated with clinical problems [59]. are followed by the development of chronic pain. Calcific periarthritis frequently localizes to the supraspinatus tendon in a poorly vascularized area of the tendon sheath known as the critical zone. Similarly. These deposits often are asymptomatic and noted most commonly by chance on radiographs taken for other reasons. in vivo models of inflammation show a brisk inflammatory reaction to apatite. a 2. possibly exposing the crystals to phagocytes. There are few systematic studies of the incidence or prevalence of juxtaarticular deposits of BCP crystals. In a large study of office workers published in 1941. however. Calcific deposits in the periarticular tissues also are associated with chronic pain syndromes.

Morgan and coworkers demonstrate that BCP crystals augment mitogenesis in breast cancer cell lines MCF7 and Hs578T and in normal human mammary epithelial cells [74]. Engulfment of BCP crystals by monocyte-derived macrophages results in secretion of TNF-a. by TNF-a–mediated VSMC apoptosis. the process of arterial calcification may be an active cell-mediated process analogous to the deposition of hydroxyapatite in bone and in articular tissues in BCP crystal-associated joint disease. The consequent production of TNF-a could promote smooth muscle cell osteoblastic differentiation. It has been demonstrated that macrophages colocalize with hydroxyapatite particles in the atheromatous plaque [65].73]. The supernatants from BCP crystalstimulated macrophages activate endothelial cells in vitro as assessed by flow cytometry measuring adhesion molecule expression and promotion of leukocyte rolling and adhesion as visualized in a flow chamber. These calcifying vascular cells. which could explain the observed positive correlation between coronary arterial calcification and cardiovascular events. Other potential. Recent work by Nadra and colleagues implicates BCP crystals in the pathophysiology of atherosclerosis [31]. thus increasing hydroxyapatite deposition and establishing a vicious circle of events within the vessel wall. and JNK pathways in BCP crystalinduced TNF-a production is demonstrated. a potent osteogenic factor. recent work has elucidated their potential involvement in other diseases. Breast tissue calcification in the form of hydroxyapatite is associated strongly with malignancy [71] and with poorer outcomes compared with patients who do not have mammographic calcification [72. Vascular smooth muscle cells (VSMCs) also may undergo osteoblastic differentiation. a proton pump . ERK1/2.67]. as they were termed. possibly. effects of BCP crystals within atherosclerotic plaque include increase in plaque instability via induction of MMPs or. Involvement of PKC. Bostrom and colleagues describe a microvascular pericyte-like cell that could undergo osteoblastic differentiation under certain in vitro conditions in normal and diseased arteries [68]. IL-1b. Macrophages play a key role in plaque development and rupture [70]. localized to areas with increased expression of bone morphogenetic protein 2. As these osteoblasts and chondrocytes have the potential to generate matrix vesicles and promote tissue calcification. through their interaction with intimal macrophages. likely act as an inflammatory nidus by activating endothelial cells and promoting inflammation. Treatment with bafilomycin A1.calcium crystal deposition diseases 391 Basic calcium phosphate crystal deposition in other diseases Although BCP crystals long have been implicated in the pathogenesis of several rheumatic syndromes. Arterial intimal calcification is a common clinical and pathologic finding in patients who have atherosclerosis [65] and the degree of intimal calcification has prognostic significance [66. Radiographic mammary microcalcifications are one of the most pertinent diagnostic markers of breast cancer. including atherosclerosis and breast cancer. These data suggest that BCP crystals within the atherosclerotic lesion. Hydroxyapatite is the major constituent of the calcific deposits seen in atherosclerotic vessels. Chondrocytes and osteoclasts also are identified in arterial tissue [69]. but unproved. and IL-8.

BCP crystals also stimulated production of MMP-1 in Hs578T cells. such as endosomes. and MMP production. triggers the initial innate immune response that leads ultimately to inflammatory gene expression and clearance of the . and MMP-9 in human mammary epithelial cell lines [75]. TLR1. including basement membranes. Calcium pyrophosphate dihydrate crystals crystals bind Toll-like receptors Toll-like receptors (TLRs) are the human homologs of a family of receptors with roles in host defense and inflammation that are widespread throughout nature. mitogenesis. TLR2 is found to localize to phagosomes after exposure to certain microbial products. -4. which can upregulate MMP-1 gene expression and PGE2 production in human cells. diminishes BCP-induced mitogenesis to control levels [75]. and IL-1b induction at the transcriptional level [75]. which was attributable at least in part to upregulation of COX-2 and can be prevented by pretreatment with aspirin [75]. Recognition of microbial components. and -13 in MCF7 cells. Calcium pyrophosphate dihydrate crystals Pathogenesis CPPD crystals have several in vitro properties in common with BCP crystals. Furthermore. MMP-2. MMP-1. with a resultant release of reactive oxygen species and degranulation. a potent neutrophil chemoattractant. underlies the acute inflammation of pseudogout. such as induction of proto-oncogenes. and to activate neutrophils. BCP crystals enhanced PGE2 levels in Hs578T cells considerably. that may contribute to joint degeneration. Treatment with phosphocitrate block BCP crystalinduced mitogenesis and COX-2. whereas the others are expressed preferentially in intracellular compartments. Moreover. is induced potently by BCP crystals at 2 and 4 hours. -5. These results suggest that BCP crystals contained in mammary microcalcifications are not an innocent bystander and may aggravate the pathologic process of breast cancer. MMPs can facilitate invasion and metastasis of tumor cells by degrading connective tissue matrix components. In addition. IL-1b. for example lipopolysaccharide (mainly TLR4) and peptidoglycan (TLR2). -2.392 molloy & mccarthy ATPase inhibitor. the ability of CPPD crystals to upregulate production of IL-8. which share a cytosolic Toll/IL-1 receptor (TIR) domain that also is found in members of the IL-1 receptor family and an extracellular leucine-rich repeat region that mediates ligand recognition [77]. and -6 are localized to the plasma membrane. CPPD crystals increase synovial neutrophil numbers not only by cellular recruitment but also by inhibiting neutrophil apoptosis. TLRs are not restricted to the site of preferential expression. Eleven TLRs are identified. suggesting endocytosis and intracellular crystal dissolution are required for BCP-induced mitogenesis. -9. for example. high levels of PGE2 often are associated with estrogen-receptor negative tumors that exhibit a high metastatic potential [76].

couple TLRs through the TIR domain to downstream signaling pathways and activation of transcription factors [77]. CPPD crystals induce activation of JNK. indicating the potential for innate immune responses to be driven by mesenchyme-derived cells in arthritis. These results indicate that innate immunity may contribute to inflammation and cartilage degradation in pseudogout. MyD88. A novel study by Liu-Bryan and coworkers investigates the potential role of TLR2 in CPPD crystal-induced NO production in chondrocytes [84]. Thus. Mal). known as adaptor molecules (eg.calcium crystal deposition diseases 393 infectious agent [78]. IL-8 can augment neutrophil activation and protease release [85]. Neutrophil chemotaxis In addition to a direct chemotactic effect. The TIR domain transduces upregulation of proinflammatory genes through activation of NFkB. and NF–IL-6. Cytosolic proteins. but this cascade may participate in regulation of activation of AP-1. Neutrophil activation Tudan and colleagues demonstrate that CPPD crystal-induced neutrophil oxidative and degranulation responses are mediated via PKC. Certain TLRs are expressed in normal and rheumatoid arthritis synovial fibroblasts [81–83]. such as IL-1. Activation of the p38 MAPK pathway modulates AP-1 binding to the IL-8 promoter in response to CPPD crystals. although the downstream effectors of this response remain to be elucidated. Liu and colleagues [87] have explored the signal transduction pathways involved in CPPD crystal-induced IL-8 expression in human monocytic cells. and PI3K/Akt pathways [73. are identified for certain TLRs. NF-kB. They also note an association between ERK1/2 and neutrophil activation that is PI3K independent. Furthermore. TNF-a. and p38 MAPK pathways. The significance of activation of the JNK pathway by CPPD crystals in this study is not certain at this time. and COX-2. . and hyaluronic acid [79. IL-8 also can enhance neutrophil chemotaxis by stimulating production of other chemotactic factors (eg. IL-8 also can promote neutrophil recruitment by enhancing neutrophil-endothelial cell adhesion by upregulation of neutrophil integrins [86]. fibronectin.80]. may play a role given that p38 MAPK inhibitors can suppress these responses in CPPD crystal-stimulated cells. Several nonbacterial ligands. such as fatty acids. PLC (probably the PLC g2 isoform). IL-8 can play a key role in the generation of the acute inflammation typical of pseudogout and also may contribute to matrix degradation in CPPD crystal-associated arthritis. CPPD crystal induction of the IL-8 promoter is mediated through ERK1/2 signaling and requires NF-kB complex c-Rel/RelA and AP-1 transcriptional activity. This study demonstrates that CPPD crystals use TLR2-mediated signaling to initiate NO production in chondrocytes. TLR2 is expressed constitutively in chondrocytes and upregulated in articular cartilage in OA.88–90]. however. leukotriene B4 and platelet activating factor) by activated neutrophils [85]. ERK1/2. NF–IL-6 is involved to a lesser degree. Upregulation of expression of certain genes that can promote IL-8 expression.

typically macrophages. the asymptomatic radiographic finding of calcification of articular or fibrocartilage. CPPD deposition is associated with attacks of acute pseudo- . potentially reducing the anabolic effect of osteoblasts on bone. A significant delay in apoptosis and clearance may lead to excessive accumulation and tissue damage by prolonging neutrophil responses to the inflammatory stimulus. In the study by Tudan and colleagues [91]. Bouchard and coworkers examined the interaction between CPPD crystals and human osteoblastic cells in vitro [93]. CPPD crystal-induction of p38 MAPK also is only partly responsible for the neutrophil oxidative and degranulation response. results in only a partial suppression of CPPD crystal-induced neutrophil activation not exceeding 50% inhibition. however. CPPD crystals adhered to and were phagocytosed partly by the cells and stimulated COX-2. despite their frequent coexistence within articular tissues. Furthermore. as evidenced by the reduction by approximately 50% of CPPD crystal-induced superoxide anion generation and myeloperoxidase and lysozyme release after pretreatment with SB203580. CPPD crystal-related suppression of TNF-a–induced caspase 3 activation and neutrophil apoptosis is abrogated by inhibition of the MEK1/2-ERK1/2 or PI3K/Akt pathways. previously noted to be involved in CPPD crystalinduced repression of TNF-a–induced neutrophil apoptosis [92]. CPPD crystals induces a twofold transient increase in p38 phosphotransferase kinase activity above basal levels but suppressed the TNF-a–associated sixfold induction of p38 activity to levels seen with CPPD stimulation alone. The most frequent manifestation of CPPD deposition is chondrocalcinosis. Clinical manifestations of CPPD crystal deposition Although there is some overlap. This probably occurs via the inhibition of caspase 3. Most recently.394 molloy & mccarthy Full inhibition of any of these pathways. and IL-8 production. PGE2. This modulatory effect of CPPD crystals seems to reduce p38 MAPK activity below a threshold level required to induce apoptosis in neutrophils. after which they undergo apoptosis facilitating their clearance by other phagocytic cells. Inhibition of neutrophil apoptosis Neutrophils generally have short lifetimes of less than 24 hours. which may contribute to damage to juxtaarticular bone in crystal-associated arthritis. They also diminished the 1.25 dihydroxycholecalciferol-induced activity of alkaline phosphatase and osteocalcin. Thus. IL-6. a specific p38 MAPK inhibitor. Effects on chondrocytes and osteoblasts The deposition of monosodium urate (MSU) crystals in the joint can promote not only acute inflammation but also chronic inflammation that may result in cartilage damage and bony erosions. CPPD crystals can alter the phenotype of these cells. they examined the role of p38 MAPK in CPPD crystalinduced neutrophil responses [91]. CPPD crystals differ from BCP crystals in spectrum of their clinical manifestations.

CPPD crystals. and ankles.50]. analogous to the tumoral calcinosis of BCP crystals.60:399 – 406. Intracellular calcium responses to basic calcium phosphate crystals in fibroblasts. as CPPD crystals can be generated within this metaplastic cartilage analogous to the postulated mechanism in articular cartilage. Advances have been made in the understanding of the pathophysiology of crystal-associated diseases. whereas the distal type generally presented with a painless mass or swelling (57%) or an acute attack with a picture resembling tophaceous gout (38%). There was a histologic finding of chondroid metaplasia within and around these lesions. Masuda I. Tenosynovitis also is reported and is associated with tendon rupture [94].7:R915 – 26. hips. et al. et al. Wenger L. may present with a pseudorheumatoid or pseudoankylosing spondylitis pattern or may mimic neuropathic arthropathy. characterized by joint effusions with marked neutrophilia and a form of secondary OA (pyrophosphate arthropathy) with a pattern of joint involvement that differs from primary OA. Osteoarthritis Cartilage 1998.6:324 – 9. Softtissue CPPD deposits may present as tumor-like masses. shoulders. Yamakawa and colleagues describe five cases of tumoral CPPD deposition and review the 54 case reports in the literature [98]. Summary BCP and CPPD crystals are associated with distinct clinical syndromes. [4] Sun Y. They propose that these patients can be divided into two broad categories based on the location of the deposit: central (head and neck) and distal (extremity). specific effects of each crystal type are reported that may explain their differing clinical presentations.97]. The most notable difference between these groups was the differing modes of presentation. which may in the future be translated into effective treatments for these disorders. metacarpophalangeal joints. Greene A. Basic calcium phosphate crystals stimulate the endocytotic . including presentation as the crowded dens syndrome [95]. Westfall PR.calcium crystal deposition diseases 395 gout. et al. Octacalcium phosphate crystals directly stimulate expression of inducible nitric oxide synthase through p38 and JNK mitogen-activated protein kinases in articular chondrocytes. The latter most commonly involves the knee followed by the wrists. Rey C. These lesions may present with severe neurologic symptoms [96. Zeng XR. Cheung HS. The central deposits presented most frequently with a painful mass (46%) or neurologic disturbance (33%). Uzan B. Arthritis Res Ther 2005. either alone or in association with BCP crystals [49. References [1] McCarthy GM. elbows. also may be found in the synovial fluids of patients who have primary OA. CPPD also. however. Although there are some similarities in the cellular responses to these crystals. Ann Rheum Dis 2001. [3] Halverson PB. Basic calcium phosphate crystals activate human osteoarthritic synovial fibroblasts and induce matrix metalloproteinase-13 (collagenase-3) in adult porcine articular chondrocytes. more rarely. [2] Ea H-K.

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Medical College of Wisconsin. 5000 West National Avenue. it is unlikely that chance explains the coexistence of these two processes. All rights reserved. Department of Medicine. E-mail address: ann.T a Division of Rheumatology. This article reviews some background about calcium crystals and summarizes the evidence that they are biologically active particles that develop in the setting of cartilage damage and contribute to osteoarthritis. WI 53295-1000. Zablocki VA Medical Center. MDa.rosenthal@med. USA Articular calcium crystal deposition diseases and osteoarthritis are highly prevalent conditions in elderly populations. Rosenthal.004 rheumatic. Milwaukee. USA b Zablocki VA Medical Center. T Rheumatology Section.com .Rheum Dis Clin N Am 32 (2006) 401 – 412 Calcium Crystal Deposition and Osteoarthritis Ann K. further study of the complex factors involved in the pathogenesis of calcium crystal deposition disease and osteoarthritis will lead to better treatments for the many causes of cartilage degeneration.2006.theclinics. WI.b. doi:10. CC-111W. They are visible under polarizing light microscopy in This work was supported by a Merit Review grant from the Department of Veterans Affairs and Grants AG015337 and AR052615 from the National Institutes of Health. Calcium pyrophosphate dihydrate (CPPD) and basic calcium phosphate (BCP) crystals are the two most common forms of pathologically relevant calcium crystals in articular tissues. Milwaukee. Calcium pyrophosphate dihydrate crystals CPPD crystals occur commonly in articular hyaline and fibrocartilage in persons over age 60 [1]. Milwaukee. Hopefully.02. Good evidence from the clinic and laboratory suggests that the presence of one of these pathologic processes influences the development of the other.gov 0889-857X/06/$ – see front matter D 2006 Elsevier Inc. Although the relationship between calcium crystal deposition diseases and osteoarthritis remains somewhat controversial.1016/j.va. WI.rdc.

The strongest associations are with gout. Chondrocalcinosis often is not visible in severely damaged or small joints or with certain radiographic techniques. They can be identified radiographically as dense linear cartilage calcifications. This dual description accurately predicts the heterogeneity of the clinical settings in which CPPD crystals are found. Data from the Framingham study demonstrate an 8% prevalence of knee chondrocalcinosis in people ages 63 to 93. known as pseudogout. . hyperparathyroidism. familial. such as the metacarpal-phalangeal joints or wrist. Sokoloff and Varma show that 52% of osteoarthritis patients over age 75 had CPPD crystals in articular tissue specimens [11]. This finding may either underestimate or overestimate clinically relevant CPPD crystal deposition [7]. There are a handful of metabolic syndromes that clearly promote CPPD crystal deposition.13]. Recent evidence confirms these findings. and certain radiographic features [5] suggest the presence of articular CPPD crystals. some patients who have chronic degenerative arthritis associated with CPPD crystals describe acute attacks of inflammation. As discussed previously. or a more diffuse inflammatory syndrome similar to rheumatoid arthritis. For sporadic CPPD deposition disease. hemochromatosis. Rates increase to 27% when only people over 85 are included [9]. Premature CPPD crystal deposition may be familial or metabolic. age is the best characterized and strongest risk factor. Twenty-five to 33% of synovial fluids from patients who had osteoarthritis contained CPPD crystals at the time of joint replacement for osteoarthritis (Fig. 1) [12. Less commonly. and hypomagnesemia [15. The vast majority of cases are sporadic. much higher rates are described. For example. Clinically evident sporadic CPPD deposition is rare under age 60. CPPD crystals also can be found in asymptomatic joints and in association with neuropathic arthritis [6]. hypophosphatasia. such as standing knee films. The presence of significant cartilage degeneration in unusual locations. showing that ultrasonography can identify CPPD deposits too small to be visible on plain radiographs [8]. and higher rates are seen in hospitalized patients [10]. Almost simultaneously. CPPD crystals cause an acute monoarticular arthritis. Many studies exploring the epidemiology of CPPD crystal disease use radiographic chondrocalcinosis as a diagnostic criterion. In addition. Prior injury. The prevalence of CPPD crystal deposition in the population remains uncertain. CPPD crystals initially were recognized as pathogens in patients who had gout-like arthritis and who had uricase-resistant intraarticular crystals [2].16]. In the few studies in which articular tissues were examined directly for CPPD crystals. or metabolic. the best estimates rely on these studies.402 rosenthal synovial fluids of affected joints as positively birefringent rhomboid particles. or when only osteoarthritic joints are included. Nonetheless. CPPD deposition can be categorized as sporadic (idiopathic). The most common clinical presentation of CPPD crystal deposition is as a chronic degenerative arthritis [4]. known as chondrocalcinosis. also predisposes to CPPD deposition [14]. in particular meniscal damage in the knee. CPPD crystal deposits were described in a family that had early onset of osteoarthritis-like joint pathology [3]. osteoarthritis significantly increases the risk for CPPD crystal deposition [11].

In addition. a putative pyrophosphate transporter [21]. extracellular matrix changes likely promote the activity of extracellular organelles. (Black bars represent data from Nalbant S. Chondrocytes near CPPD crystal deposits are abnormally large and share some characteristics with the hypertrophic chondrocytes responsible for matrix mineralization in growth plate cartilage [17.18]. known as matrix vesicles [24]. Hatched bars represent data from Derfus B. The high prevalence of pathologic calcium crystals in pre-operative knees. Osteoarthritis Cartilage 2003. et al.11:50–4. Basic calcium phosphate crystals BCP crystals include partially carbonate-substituted hydroxyapatite. Frequency of BCP and CPPD crystals in synovial fluids from patients who have osteoarthritis. and tricalcium phosphate. Excess pyrophosphate production may be related to abnormalities of the recently described ANK protein. Excess extracellular inorganic pyrophosphate produced by chondrocytes complexes with ambient calcium to form crystals.20]. Synovial fluid features and their relations to osteoarthritis severity: new findings from sequential studies. These include loss of pericellular proteoglycans. Martinez J. These small membrane-bound. There also is increasing evidence that alterations in cartilage extracellular matrix facilitate CPPD crystal formation. chondrocyte-derived vesicles act as sites for nucleation and growth of crystals in cartilage matrix [25]. and increased concentrations of some matricellular proteins [23]. Overproduction of inorganic pyrophosphate.29:570–4. 1.) Although the cause of CPPD deposition disease is not known. octacalcium phosphate. These crystals comprise calcium and inorganic phosphate and often are referred to as hydroxyapatite because of their chemical similarity to the normal calcium phosphate mineral found in bones and . Butler J.calcium crystal deposition and osteoarthritis 403 Fig. Kitumnuaypong T. et al. Kurian J. the current paradigm of crystal formation in cartilage involves multiple participants. is a key feature of these chondrocytes. the anionic component of CPPD crystals [19. collagen fibril disruption. J Rheumatol 2002. Mutations in the ANK protein are linked to some cases of familial CPPD crystal deposition disease [22].

soft tissues. swelling.33]. and have limited practical use [26]. are significantly under-recognized.31]. currently. often affecting large joints [29]. There is some support for the hypothesis that they develop at sites of cartilage metaplasia. von Kossa’s stain can be used to identify BCP crystals in tissues. large cool effusions often are noted. Radiographs confirm the diagnosis by demonstrating severe rotator cuff thinning. there are no readily available tests for bedside identification. Unfortunately. In its full-blown form. and loss of motion of the shoulder. Clinical syndromes associated with BCP crystals seem slightly more common in women. peaks at 30 to 60 years of age [36]. Milwaukee shoulder syndrome typically affects elderly women.35]. similar to those responsible for CPPD .13]. such as x-ray diffraction and Fourier transform infrared spectrophotometry. 1) [12. When deposits occur near the small joints of the hands and feet. patients present with acute pain. they are associated with a severe destructive degenerative arthritis. where they are markers for severe joint degeneration (see Fig. Like CPPD crystals. They are certainly less stringently associated with cartilage than CPPD crystals and are found commonly in skin. often female. this is known as Milwaukee shoulder syndrome [30. Matrix vesicles. even in noncartilage containing tissues [37]. Around the shoulder. The incidence of calcifying tendonitis. and neurologic abnormalities involving the affected joint [31]. lacking good diagnostic techniques.404 rosenthal teeth. chronic renal failure. syndromes associated with periarticular BCP crystals have a different population distribution. for example. are expensive. stiffness. articular BCP crystals occur in a wide range of clinical settings. In its less extreme form. BCP crystals occur in the synovial fluids of 40% to 70% of patients who have clinical osteoarthritis. Less is known about the genesis of BCP than CPPD crystals. Intra-articular BCP crystals almost invariably are associated with advanced age and worsening radiographic grade of degenerative arthritis [13. they can cause an acute inflammatory periarthritis [34]. For research purposes. with low white blood cell counts and high levels of active proteases [32. but unfortunately. Knees may be affected similarly. a semiquantitative radioactive binding assay based on the ability of BCP crystals to bind to bisphosphonates is used [27]. The clinical syndromes associated with BCP crystals frequently are misdiagnosed [28] and. When BCP crystals are found in joints. they cause the common clinical syndrome known as calcifying tendonitis. and redness around a finger or toe associated with flecks of soft tissue calcium on radiographs [34]. In contrast. require large volume samples. They are not visible under light or polarizing light microscopy. highly accurate techniques. and. trauma. On physical examination. BCP crystal deposits also are clinically significant when they occur periarticularly. and extensive bone destruction. The lack of a good clinical test for BCP crystals limits knowledge of the prevalence of BCP-associated syndromes. loose bodies. this dye also binds to other calcium-containing particulates [26]. They have pain. Synovial fluids show little evidence of inflammation. Other possible risk factors for intrarticular BCP crystals include CPPD deposition disease. These young. and blood vessels. BCP crystals are visible under light microscopy with alizarin red staining.

calcium crystal deposition and osteoarthritis 405 crystal formation. Second. is considered. A familial form of calcium crystal deposition in which CPPD and BCP crystals coexist also recently has been reported [42]. Mixed calcium crystal deposition Although there are some conditions that clearly are associated with one or the other of the pathogenic calcium crystals. Sokolov and Varma show that CPPD crystals are six times more likely to be found in osteoarthritic than in normal joints [11]. the evidence is considered that calcium crystals cause or worsen osteoarthritis. Isolated matrix vesicles from osteoarthritic cartilage can generate BCP crystals in vitro [24]. For example. Although the presence of CPPD crystals in knee fluids from patients who have osteoarthritis is associated with increased disability [45].40]. There is significant clinical support for the hypothesis that intra-articular calcium crystals are risk factors for incident or progressive osteoarthritis. Two potential hypotheses are explored.44]. For example. these crystals often coexist in a single patient [12. Caspi and coworkers were unable to demonstrate a similar relationship in hand joints [46]. Others confirm these findings [43. First. Ample evidence also supports a role for disruption of the normal extracellular matrix at sites of BCP crystal formation [38. Relationship between crystals and osteoarthritis There are clear and important differences between CPPD and BCP crystals in terms of their associated clinical patterns and etiologies. the opposite hypothesis. likely participate in BCP crystal formation [38]. that osteoarthritis causes or worsens calcium crystal deposition. Histologic studies demonstrate the presence of matrix vesicles near BCP crystals deposits in tendon [38] and cartilage [39]. For purposes of efficiently discussing the relationship between calcium crystals and osteoarthritis. CPPD and BCP crystals considered together. however. A recent study by Nalbant and colleagues find that synovial fluid CPPD and BCP crystals are predictors of rapidly worsening knee . whether or not this relationship can be extrapolated to small joints is unclear. Indeed. These two hypotheses are not mutually exclusive and it is likely that elements from both are true. the presence of both CPPD and BCP crystals in a single joint is not uncommon [41]. examining their role in osteoarthritis. Multiple studies correlate the presence of intra-articular BCP crystals with severe radiographic destruction [13.41].13]. Evidence that calcium crystals cause or worsen osteoarthritis Clinical evidence Most evidence supporting the hypothesis that calcium crystals cause or worsen osteoarthritis is based on epidemiologic studies. There is a paucity of studies.

Calcium crystals are phlogistic and can initiate a strong inflammatory response under certain conditions [51. The investigators propose that mechanical changes in the calcified meniscus alter the biomechanics of the joint and contribute to hyaline cartilage damage [50]. In some animals with spontaneous osteoarthritis. in the guinea pig model of spontaneous osteoarthritis. The development of severe and premature osteoarthritis in patients who have familial forms of CPPD crystal deposition supports a causal association [3]. however. interleukins.52]. such as rheumatoid arthritis. There is support for theories involving the induction of an inflammatory response by calcium crystals and those postulating direct deleterious effects of crystals on articular tissues.55]. Laboratory evidence Animal studies. Like gout crystals. calcific deposits precede significant articular damage. Conversely. There are only a handful of studies that directly examine the effects of calcium crystals in animal models of osteoarthritis. Articular CPPD crystals also correlate with higher rates of proteoglycan turnover in cartilage of affected joints [47]. Similarly. the role of inflammation in clinical calcium crystal deposition diseases and osteoarthritis is debated. Many laboratory studies support the hypothesis that calcium crystals contribute to osteoarthritis.406 rosenthal osteoarthritis [12]. Calcium crystals are less inflammatory than urate crystals [54]. . They injected CPPD crystals into rabbit knees rendered osteoarthritic by partial meniscectomy and resection of the collateral and sesamoid ligaments. Perhaps the strongest work is from Fam and colleagues [49]. Calcium crystals often are found in uninflamed joints. This hypothesis is refuted further by the rarity of calcium crystals in joints damaged by inflammatory arthritis. such as monosodium urate crystals. and cytokines from phagocytes and activate neutrophils and the complement cascade [52]. Most do so by demonstrating potential mechanisms through which calcium crystals cause damage to articular tissues. For example. increasing evidence exists to suggest it may be an excellent predictor of rapid progression of joint damage in osteoarthritis [56]. although inflammation of the synovium in osteoarthritis also is variable. CPPD and BCP crystals elicit the production of prostaglandins.or low-dose CPPD crystals compared with controls. Even highly phlogistic crystals. In vitro studies. the presence of CPPD crystals in relatively normal cartilage in patients who have familial CPPD disease precludes the theory that these particles simply are epiphenomena of severe cartilage degeneration [48]. can be present in joints in the absence of clinical signs or symptoms of inflammation [53]. Despite these clear effects in vitro. calcifications in the meniscus occur before the development of visible hyaline articular cartilage degeneration. Histologic osteoarthritis worsened significantly with exposure to repeated injections of either high. their inflammatory potential likely is modulated by their size and shape and the nature and extent of adherent proteins [52.

Calcium crystals also can induce secretion of prostaglandin E2. There is little experimental evidence to suggest that calcium crystals act as mechanical irritants in the joint. but it remains an intriguing possibility. For example. Laboratory studies that support the hypothesis that osteoarthritis causes or worsens calcium crystal formation typically support one of two hypotheses. even in the absence of inflammatory mediators. BCP crystals elicit a similar response from osteoarthritic human synovial fibroblasts and adult porcine articular chondrocytes [59]. Nitric oxide production also is stimulated in articular chondrocytes by BCP crystals [60]. Calcium crystals elicit mitogenesis in fibroblast cultures [57. potentially mimicking synovial overgrowth and attendant articular damage. calcium crystals were present. including the production of type X collagen and changes in cell shape [63]. calcium crystals form in cartilage after the disease is well established. however. collagenases. This observation sheds little light on the causal nature of this association.43.58].calcium crystal deposition and osteoarthritis 407 There also is ample and elegant support for the hypothesis that CPPD and BCP crystals affect cartilage and synovium directly and adversely. yet this hypothesis remains equally compelling. The first is that the damaged extracellular matrix in osteoarthritic cartilage facilitates matrix mineralization by reducing inhibitors or increasing . In some animal models of osteoarthritis. such as tissue inhibitor of metalloproteases [61]. When fluids from these same joints.44]. The epidemiologic studies (discussed previously) suggest that calcium crystals occur commonly in osteoarthritic joints. A recent longitudinal study of synovial fluids. and neutral proteases from canine synovial cells [57]. suggesting that crystals may develop as a result of progressive osteoarthritis [12]. as is increased production of key proteases. Laboratory evidence Animal studies. although they are relatively rare in normal joints or in inflammatory joint disease [11. and decreased production of protease inhibitors. such as stromelysin and gelatinase. Hayes and colleagues find an increase in proteoglycan turnover and cartilage wear after exposure of equine cartilage plugs to CPPD or BCP crystals [62]. in a rabbit model of osteoarthritis based on transection of the anterior cruciate ligament. Evidence that osteoarthritis causes or worsens calcium crystal formation Clinical evidence There is less direct evidence to support the hypothesis that osteoarthritis causes or worsens calcium crystal formation. calcification of the meniscal fibrocartilage occurs late in the development of the disease. Nalbant and coworkers show that some osteoarthritic synovial fluids have no crystals when sampled early in the disease. however. were examined years later. In vitro studies. suggests that osteoarthritis may facilitate the development of calcium crystals. These calcium deposits correlate with other stigmata of phenotypic changes in chondrocytes.

These features are not seen in chondrocytes from healthy articular cartilage but are well described in cartilage containing CPPD or BCP crystal deposits [17]. The strongest support comes from work with model systems of calcium crystal formation in solution and by matrix vesicles. polymorphisms in the gene coding for an enzyme responsible for pyrophosphate elaboration. Few mechanistic studies have explored the role of matrix changes in calcium crystal development. disrupted collagen fibrils. Identical changes also occur in osteoarthritis [64]. These enzymes contribute to cal- . For example.408 rosenthal stimulants of pathologic mineralization in the normally unmineralized articular cartilage matrix. which also are markers of chondrocyte hypertrophy in growth plate chondrocytes [75]. are linked to hand osteoarthritis [74]. These altered chondrocytes then promote mineralization of their surrounding matrix. Recently. Other features of hypertrophic chondrocytes that might promote calcium crystal formation also are documented in osteoarthritis. ANK. There also is excellent evidence to support the hypothesis that phenotypic changes in chondrocytes from osteoarthritic cartilage facilitate calcium crystal formation. Mandel and Mandel demonstrate a marked reduction in concentrations of calcium and pyrophosphate necessary for CPPD crystal formation in a solid matrix compared with those necessary to generate crystals in solution [67]. and other mineral-promoting factors are found in osteoarthritic cartilage. calcium and phosphate [66]. are increased in osteoarthritic cartilage [76]. Similarly. they elaborate matrix vesicles. high levels of osteopontin [65]. also is demonstrated in osteoarthritic chondrocytes [73]. Histologic studies show a loss of proteoglycans and disruption of collagen fibril formation around calcium crystals [18]. They suggest this paradoxic finding strongly supports an important role for the extracellular milieu in matrix vesicle mineralization. They show that chondrocytes in osteoarthritic cartilage have many features of the hypertrophic phenotype.70]. These chondrocytes display increased alkaline phosphatase enzyme activity and higher levels of annexins and type X collagen. ENPP1. pyrophosphate levels are increased in osteoarthritic synovial fluid [72]. The second is that osteoarthritis produces changes in the chondrocyte that force it to assume a hypertrophic phenotype. which seem to be actively involved in mineral formation. This is demonstrated elegantly by the work of Kirsch and coworkers [71]. It is likely that normal articular cartilage matrix contains mineralization inhibitors whereas osteoarthritic matrix contains less large proteoglycans. Upregulation of the putative pyrophosphate transporter. One theory explaining both osteoarthritis and calcium crystal formation is that in these diseases. Levels of activity of transglutaminase enzymes. There is ample evidence to support the hypothesis that extracellular matrix changes in osteoarthritic cartilage facilitate crystal formation. Furthermore. and increased quantities of matricellular proteins that promote mineralization. Derfus and coworkers show that matrix vesicles from osteoarthritic cartilage have identical mineralization capacities to those isolated from normal cartilage [68]. chondrocytes undergo terminal differentiation and assume characteristics similar to those of hypertrophic chondrocytes responsible for endochondral bone formation [69.

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74. L Sacco University Hospital. Italy. Italy Endocrine and Diabetes Unit. Under pathogenic situations. (2) as a consequence of the replacement or transition of injured. Maorizio Bevilacqua. Rheumatology Unit. Piercarlo Sarzi-Puttini. osteocalcin.it (F. and necrotic tissue by mineral depositions (dystrophic calcification).2006. Milan. however. Department of Medicine. PhDa.02. and Others) Fabiola Atzeni. Milan. L Sacco University Hospital. Calcification in atherosclerotic lesions involves factors that are important for bone mineralization.Rheum Dis Clin N Am 32 (2006) 413 – 426 Calcium Deposition and Associated Chronic Diseases (Atherosclerosis. MDa. and collagen I [3. 0889-857X/06/$ – see front matter D 2006 Elsevier Inc.rdc. Diffuse Idiopathic Skeletal Hyperostosis. L Sacco University Hospital.1016/j.2]. vascular wall calcification is the most common and is known to involve two mechanisms: passive calcification resulting from the breakdown of the protection system (a form of dystrophic calcification) and active calcification resulting from the transdifferentiation of mesenchymal cells in the vascular wall (ectopic ossification). or (3) by means of the transdifferentiation of mesenchymal cells into bone tissue (ectopic calcification) [1. MDb b a Rheumatology Unit.T. doi:10. degenerated.theclinics.003 rheumatic. ectopic calcification may occur (1) when the concentrations of calcium and phosphate in extracellular fluid exceed the saturation point (metastatic calcification). All rights reserved. Italy Extracellular matrix mineralization or calcification is regulated strictly under physiologic conditions and usually confined to bone tissue. E-mail address: sarzi@tiscali.4]. 20157 Milano. Both mechanisms contribute to the formation of vascular lesions and play a central role in the development of atherosclerotic plaque calcification in the elderly [3]. T Corresponding author. osteopontin (OPN). Via GB Grassi. Atzeni). Among the various forms of ectopic calcification. including matrix vesicles. bone morphogenetic protein (BMP-2). MD.com .

hypercholesterolemia. Vascular calcification Vascular calcium deposition can be divided into four histoanatomic variants: atherosclerotic calcification. Calcium can be deposited throughout the vasculature in various forms of calcium phosphates. including calcium hydroxylapatite (CHA) and basic calcium phosphate (BCP). medial arterial calcification. inflammation.14]. are identified as protective factors against dystrophic calcification in nonosseous tissues [5. and cardiac valve calcification (Table 1) [3]. and osteocalcin. but a major difference between vascular calcification and bone mineralization is the presence of oxidized lipids. As the inactivation of MGP in knockout animals leads to heavy and diffuse vascular calcification. the accumulation of which in the subendothelial space of arteries promotes arterial calcification whereas. and the lesions frequently become calcified [11. Cardiovascular calcification is a common consequence of aging. they inhibit bone formation [9. vascular calciphylaxis.8]. such as matrix Gla protein (MGP). MGP is an important regulator of calcification in cartilage and blood vessels. and vascular calcification and bone modeling may have common mechanisms. The Table 1 Histoanatomic variants of vascular calcification and examples of associated diseases Histoanatomic variants Atherosclerotic calcification Medial arterial calcification Associated diseases Atherosclerosis Hypercholesterolemia Type 2 diabetes Type 1 diabetes End-stage renal disease Acute renal insufficiency with muscle injury Iatrogenic hyperphosphatemia Senile calcific aortic sclerosis Vascular calciphylaxis Cardiac valve calcification . in skeletal bone. diabetes. OPN.6]. Data suggest that calcium deposition in arteries and calcium loss from bone resulting from osteoporosis often coexist. and lipoprotein and phospholipid complexes [13. Atherosclerotic calcification Atherosclerosis is characterized by inflammatory metabolic changes with arterial lipid accumulation.10]. MGP seems to play a central role in protecting the vascular wall from dystrophic calcification.12].414 atzeni et al Several matrix proteins. and MGP deficiency or altered carboxylation also causes a high level of BMP-2 activity that leads to hyperostosis in diffuse skeletal idiopathic hyperostosis (DISH) [7. and chronic renal insufficiency and is a type of dystrophic calcification characterized initially by cellular necrosis. mechanically abnormal valve function.

but observations of bonelike plaque regions and a series of remarkable studies published in the past decade support the idea that calcium deposition in plaque is an active and regulated process akin to bone formation. RANKL Mononuclear phagocytic-cell Osteoclastlike cells Calcium Deposition Fig.) Osteogenic signals CSF-1. 1. Gla-containing proteins play an essential role in clearing calcium phosphate (hydroxyapatite) for which Gla residues have a strong affinity [18]. OPN. and blood vessels and protects arterial walls and permanent cartilage from mineral deposits [16. 1) [6. Possible mechanisms involved in atherosclerotic calcification. but it is not necessarily true that the absence of coronary calcium indicates an absence of atheromatous plaque [15].17]. TNF-a.7]. Calcium deposits in coronary arteries indicate the presence of plaque. cartilage. ONS etc. . the elastic laminae of the tunica Plaque Lipid oxidation (LDLcholesterol) Foam cells Necrotic foam cells debris Dysregulated calcium homeostasis Dysregulated Collagen Matrix protein (MGP. MGP is 10-kd circulating protein containing five Gla residues shown to be present in association with vascular smooth muscle cells (VSMCs). Matrix protein MGP is a member of the family of extracellular mineral-binding Gla proteins expressed in various tissues. In atherosclerotic arteries. It accumulates particularly in bone.calcium deposition & associated chronic diseases 415 process may begin early and accelerate as the disease progresses and more complex lesions develop. Plaque structure and composition greatly affect the clinical expression of atherosclerosis. Gla is formed post-translationally from glutamic acid as a result of g-carboxylation by vitamin K–dependent g-glutamate carboxylase. A plaque may be diffuse or amorphous. Recent evidence indicates that many matrix elements play a significant role in atherosclerotic calcification (Fig.

how differently these functions affect osseous and extraosseous tissue remains to be clarified. Etiopathogenesis There are strong. Schurgers and colleagues [29] demonstrate that low levels of circulating MGP and its impaired g-carboxylation at its tissue expression site are associated with the development and progression of cardiovascular disease. the inhibition of vitamin K–dependent carboxylation in mice by vitamin K antagonism or poor vitamin K intake also promotes vascular calcification [23–25]. The expression of the MGP gene depends on various growth factors and hormones [30]. It is assumed that MGP precursors are processed into the general circulation in an active or secretory form.416 atzeni et al media. osteoclast formation and function are influenced by other cytokines. and atherosclerosis. Similarly. Parhami and coworkers [9] and Parhami and Demer [10] examined the role of oxidized LDL cholesterol on calcifying vascular cell (CVC) activity in vitro and found that it upregulates CVC osteogenic mineralization and differentiation but only in concert with physical cell-cell interactions between CVCs and macrophages. the presence of which indicates the importance of MGP in preventing dystrophic calcification [22]. but only recently has a connection has been made between elevated low-density lipoprotein (LDL) cholesterol levels and dysregulated calcium homeostasis [10. suggesting that vitamin K– induced modification is essential to the function of MGP as an inhibitor of ectopic calcification. therefore. Human MGP promoter polymorphisms are identified and prove associated with low MGP expression and low serum MGP levels and. cholesterol-laden foam cells.31].34]. indicating the existence of reciprocal cell type-specific responses [32]. participate in generating multiple osteogenic signals that potentially are mediated by tumor necrosis factor (TNF)-a and oxidized lipids [33. a rare human recessive disorder characterized by diffuse cartilage calcifications. The osteogenic differentiation of CVCs can be recapitulated by inducing oxidative stress. lead to an increased risk of myocardial infarction [27. intriguingly.20]. It is expressed in chondrocytes and in normal and atherosclerotic arteries [18]. Activated. however. lipid oxidation. and well-recognized links between hypercholesterolemia. In addition to colony-stimulating factor 1 (CSF-1) and receptor activator of nuclear factor kB ligand (RANKL). and the extracellular matrix of the adventitia [19. Schurgers and colleagues [26] demonstrate that impaired MGP carboxylation is associated with intimal (atherosclerosis) and medial vascular calcification (Mfnckeberg’s sclerosis). concomitantly suppresses osteoblast differentiation. Mice lacking the gene encoding MGP show extensive calcification of cartilage and the medial layer of arteries [21]. a single mutation in MGP gene-coding regions is capable of causing Keutel syndrome. some of which (in particular proinflammatory cyto- .28]. so the physiologic functions of MGP can be local and systemic. well-documented. Furthermore. which. as suggested by animal models of impaired MGP expression.

Several studies demonstrate the upregulation of bone-associated proteins.calcium deposition & associated chronic diseases 417 kines) also are implicated in atherogenesis [34. the few remaining chondrocyte-like cells are located adjacent to. therefore. Medial artery calcification Medial artery calcification is the nonendochondral ossification process of the arterial tunica media that is highly characteristic of diabetes and end-stage renal disease [45. osteocalcin. In tissues as functionally diverse as cartilage and arteries. BMP-2a. Rattazzi and coworkers [43] recently have shown that the deposition of hydroxyapatite is preceded by the formation of fibro-fatty nodules populated by cells that resemble chondrocytes morphologically and are surrounded by dense connective tissue that stains positive for type II collagen. The molecular mechanisms regulating vascular calcification remain obscure. Recent studies suggest that vascular calcification not only is the result of passive calcium-phosphate deposition on atherosclerotic arteries but also of active mechanisms regulated by bone-associated genes [9. CSF-1. The microenvironments in atherosclerotic plaques may foster conditions that favor the precipitation of calcium: in particular. at the sites of calcified atherosclerotic plaques [18. and under normal circumstances. It is possible. and osteonectin (OSN). but it is expressed in plaque and colocalizes with calcified plaque regions [42].35]. The expression patterns of RANKL. and Speer and coworkers [41] demonstrate that it inhibits the calcification of vascular structures in vivo. OPN is another bone-matrix protein expressed in arteries. and this series of events could tip local ionic balance sufficiently to instigate precipitation [12].36]. Its ability to inhibit cell-mediated calcification is dependent on serine phosphorylation. the arterial wall is protected from mineral deposits by MGP [20. MGP has the general function of inhibiting mineral precipitation in extracellular fluid. that it may play a protective role where necessary and only be expressed in plaque in response to local conditions that might tend to favor mineralization.29]. At the same time. OPN is not found in normal arteries.37–40]. but it is suggested that locally disturbed calcium and phosphate metabolism in atherosclerotic plaques may contribute to its development [44]. and TNF-a in atherosclerotic plaques are consistent with arterial osteoclast-like cells developing from mononuclear phagocytic cell precursors (see Table 1) [34]. the large areas of calcification.46]. or inside. and others support that the these cells are . Vattikuti and Towler [47] hypothesize that a migratory adventitial cell myofibroblast population responding to VSMC-OPN production contributes to vascular remodeling. in which the concentrations of calcium and phosphate approach the salt solubility product. plaque sites containing necrotic foam cells debris may act as a locus for mineral precipitation because they can release high concentrations of mitochondrial phosphate and phosphatidylserine-containing molecules. such as OPN. This finding suggests that the mechanism of calcification partially may recapitulate the process of endochondral bone formation [43].

) .418 atzeni et al implicated in the medial calcification of diabetes and (potentially) end-stage renal disease [48–50]. leading to increased intracellular Pi in VSMCs. It seems that vascular calciphylaxis has led to the evolution of various mineralization inhibitors. High serum phosphate levels correlate closely with the extent of vascular calcification and vascular disease. Jono S. Nishizawa and colleagues [55] hypothesize that elevated extracellular Pi levels increase Pi transport. et al. Hyperphosphatemia and vascular calcification in end-stage renal disease. It is known that hyperglycemia and hyperphosphatemia (Pi) induce OPN expression [50–52].15:178–82. By means of a still unknown mechanism. Tissue pyrophosphate is generated by a family of three ectonucleotide pyrophosphatase/ Hyperphosphatemia Elevated extracellular Pi levels increased intracellular Pi in VSMCs.54]. J Ren Nutr 2005. high intracellular Pi levels activate specific signaling pathways that increase the expression of osteogenic genes (including Cbfa1 and osteocalcin) and stimulate the secretion of potential mineral nucleating molecules. Increase Pi transport Expression of osteogenic genes (including Cbfa-1 and osteocalcin). which typically lead to serum inorganic phosphate levels of more than 2 mmol [53. Vascular calciphylaxis Vascular calciphylaxis is a component of widespread soft tissue calcification that occurs when the physiologic calcium phosphate solubility threshold is exceeded [56]. and OPN. and one of the most frequent causes of hyperphosphatemia is chronic renal failure and subsequent kidney dialysis. tissue pyrophosphate generating systems. Ishimura E. ( Adapted from Nishizawa Y. Secretion of potential mineral nucleating molecules such as calcium-binding proteins. Mechanism of medial artery calcification. 2) [55]. The net effect is enhanced susceptibility to vascular calcification (Fig. 2. Vascular Calcification Fig. such as calcium-binding proteins.

How is the process initiated.calcium deposition & associated chronic diseases 419 phosphodiesterases and plays an important role in limiting the calcification of ‘‘soft tissues. Given the aging and ‘‘dysmetabolic’’ population. and cardiovascular mortality [45. in particular ligaments and entheses. Arterial obstruction resulting from calcification and other processes can lead to heart attack and stroke. obesity. Other entheseal regions in the peripheral joints may be affected. The deposition of calcification in valves and arteries diminishes their elasticity. dyslipidemia. amputation. the plantar fascia. leading to decreased mobility. Patients who have diabetes have an increased mortality rate and are at higher risk of lowerextremity amputation in the setting of medial artery calcification [45].57–59]. is increased in the presence of aortic arch calcification [57.’’ such as ligaments and tendons [56]. It involves the calcification and ossification of soft tissue. It leads to the ossification of the spinal anterior longitudinal ligament and causes the production of flowing osteophytes that involve particularly the right side of the spine while preserving the intervertebral disc space [64]. The risk of stroke.58]. which is a major cause of aneurysm and stenosis. Diffuse idiopathic skeletal hyperostosis DISH. and the olecranon [65]. including the peripatellar ligaments. a better understanding of vascular calcification is sorely needed to improve human health and health care [58–61]. hypertension. Mineralization in the femoral arteries can cause intermittent claudication. Etiopathogenesis The cause of DISH remains unknown. was described first by Forestier and Rotes–Querol [62] more than 50 years ago. and the prolonged use of isoretinol [67–70]. the Achilles tendon insertion. however. and what is the link between these metabolic disorders and new bone formation in DISH (Fig. particularly high in postmenopausal women. hyperuricemia. including hyperinsulinemia with or without diabetes mellitus.63]. Diagnosis is based solely on radiographic abnormalities defined using the criteria of Resnick and Niwayama [66]. Consequences of vascular calcification The deleterious clinical consequences of vascular calcification are clear: the anatomy and extent of calcific vasculopathy lead to stroke. and has a marked predilection for the axial skeleton (especially the thoracic spine) but also may affect peripheral joints [8. but several risk factors are implicated on the basis of its frequent association with various metabolic conditions. a skeletal disease characterized by the ligamentous ossification of the anterolateral spine. 3)? The ossification .

El Miedany and coworkers [71] suggest that hypervascularity could be the localizing factor in the process. finally. It is believed that this new formation is the result of abnormal osteoblast cell growth/activity in the bony ligamentous region. and then extends to meet the other arm of ossification coming from the vertebra above or below. osteoblast proliferation. Denko and colleagues [73] find that patients who have DISH have high insulin and growth hormone levels. at the site of its attachment to the vertebral body. and. hypertension. or (possibly) hyperinsulinemia. there is an increased likelihood of atherosclerosis. glucose intolerance. Kosaka and coworkers [74] indicate the possibility that. process starts in the innermost layer of the anterior longitudinal ligament. The growth of osteoblasts is maintained by several growth factors that may not be confined to bone. Insulin-like growth factor I stimulates alkaline phosphatase activity and type II collagen in osteoblasts and growth hormone can induce the local production of insulin-like growth factor I and insulin-like growth factor binding proteins in chondrocytes and osteoblasts [72]. Furthermore. the earliest stages of which leads to endothelial damage. Because the ossification starts in certain sites. in predisposed patients who have hyperlipidemia. diabetes mellitus. 3.420 atzeni et al Environmental factors Anatomical factors ligament cell Mechanical stress atherosclerosis damage to the endothelium and aggregation of blood platelets NFkappaB PDGF-BB and TGFbeta1 immobility of the hypervascularity thoracic spine and rarefaction of prolonged use of isoretinol deficit of BMP-2 ? PGI2 production altered carboxylation ? Toxic factors Metabolic disorders (diabetes mellitus. which may explain the osteoblast cell growth and proliferation. . which may be a clue to the pathogenesis of DISH [71]. the aggregation of blood plateletderived growth factor. after being stimulated by environmental factors involving platelet-derived growth factor-BB and transforming growth factor-1b in ligament cells.hyperuricemi a) Matrix Gla protein (MGP/Mgp) growth factor (IGF-I ) the adjacent bone Genetic factors osteoblast proliferation Bone deposition Fig. nuclear factor kB influences the osteoblastic differentiation of undifferentiated mesenchymal cells. dyslipidemias. Etiopathogenesis of DISH.

The mechanisms.77].78]. Milwaukee shoulder . OPN. Miscellaneous BCP crystals frequently may form asymptomatic deposits that may give rise to several clinical syndromes. another calcium-binding protein. and isolated scapho-trapeziotrapezoid arthritis is specific to CPDD [77. Laboratory findings also support the role of enzymes called transglutaminases. including calcific periarthritis. and (3) changes in cartilage extracellular matrix.3 nmol/L.001) and conclude that MGP may be a marker of hyperostosis because it is produced in larger amounts by patients who have hyperostosis-inducing osteometabolic syndromes. joint space narrowing. The levels of calcium-binding proteins. are increased in the extracellular matrix of CPPD-diseased cartilage [83]. OPN may play an important role in CCPD crystal formation because (1) it has a large calcium-binding capacity. such as DISH. The levels of S-100. bone sclerosis. 30% of the elderly ages N80) [76. and large intraosseous geodes. (2) it is seen in other conditions involving pathologic calcification. however. are increased around CCPD crystals [84–86].7 nmol/L versus 3. and (4) it is a transglutaminase substrate. Triangular fibrocartilage calcification frequently is found. by means of which the extracellular matrix changes and matrix vesicles form CPPD crystals are understood poorly. The characteristic radiographic features of CPDD disease include soft tissue calcification. It is believed [81] that matrix vesicles are involved in CCPD crystal formation insofar as those isolated from articular cartilage can produce CCPD in vitro. but three participants now are recognized: (1) the overproduction of pyrosphosphate secreted by chondrocytes. such as atherosclerosis. The molecular mechanisms regulating joint calcification remain obscure. It is frequent in the second half of life (6% of the population ages 60 to 70. subchondral cyst formation without osteophyte formation. P b 0. (2) increased calcium concentration. Histologic evidence further supports the role of extracellular matrix changes in the formation of CPPD crystals in areas of abnormal pericellular matrix (they are not seen in normal matrix). (3) it is increased in the areas in which the crystals are formed. which modify extracellular matrix protein in CPPD disease post-translationally: the activation of extracellular tranglutaminases promotes CCPD crystal formation [79–82].calcium deposition & associated chronic diseases 421 Sarzi-Puttini and colleagues [75] find higher serum MGP concentrations in male and female patients who have DISH than in healthy control subjects (5. and OSN (secreted protein acid-rich and rich in cysteine). Chondrocalcinosis Calcium pyrophosphate dihydrate deposition (CPPD) disease is a metabolic arthropathy caused by calcium pyrophosphate crystal deposits. including S-100.

suggesting that this matrix protein may play a pathogenetic role [89]. suggesting that the ectopic expression of bone matrix proteins may be involved in conferring osteotropic properties to circulating metastatic breast cancer cells [93].142:2731 – 3. and alterations in them are found associated with several calcium deposition diseases. have strengthened the argument that BCP crystals. Osteogenic regulation of vascular calcification: an early perspective. have many potential pathophysiologic functions. Circ Res 2004. Renal disease may be a predisposing factor. Z Kardiol 2001.90: 31 – 7. Metalloproteinases are found in the synovial fluids of patients who have rotator cuff tears [90. Pathophysiology of vascular calcification in chronic kidney disease. Recent advances in multifactorial regulation of vascular calcification. Demer LL. calcific tendinitis and bursitis.286:E686 – 96. The level of BSP expression correlates with the development of bone metastases and poor survival. an Arg-Gly-Asp (RDG)–containing phosphoprotein. [3] Vattikuti R. . OPN. [4] Tintut Y. [2] Karsenty G. [5] Moe SM. once believed inert structures. Curr Opin Lipidol 2001.422 atzeni et al syndrome. Recent advances in areas of medicine. and mixed crystal deposition in and around joints [87. Hirota and coworkers [92] find that the OPN protein produced by macrophages seems to play a significant role in the development of calcifying foci within the necrotic areas of breast cancers. and bone sialoprotein (BSP). Chen NX. Towler DA. Minireview: transcriptional control of osteoblast differentiation. Microcalcifications containing CHA often are associated with malignant human breast lesions. initiates CHA deposition and mediates the attachment of osteoclasts to the same crystals before their resorption [93]. Resorption probably is mediated by cathepsin K–containing multinucleated giant cells. References [1] Giachelli CM. three bone matrix proteins involved in bone matrix mineralization.95:560 – 7.91]. such as oncology. Am J Physiol Endocrinol Metab 2004. Endocrinology 2001. The pathogenesis of Milwaukee shoulder syndrome remains obscure but recent data show that low doses of warfarin are effective in some cases of soft tissue calcification because it depresses the synthesis of the vitamin K–dependent Gla protein. Ectopic calcification: new concepts in cellular regulation. It is reported that the cells surrounding tendon calcifications contain OPN [90]. several matrix proteins are identified as protective factors in nonosseous tissues.12:555 – 60. Recent studies show that BSP. In conclusion. Milwaukee shoulder syndrome is one of the better-defined BCP crystalassociated syndromes [88]. osteoarthritis. are expressed in human breast cancers.88]. OSN. It is characterized by the gradual onset of mild to moderate shoulder pain that often is bilateral and worse at night. Calcific tendinitis of the shoulder is a dynamic process.

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doi:10. Gout Gout is a common peripheral arthritis that develops from the deposition of sodium urate crystals in one or more joints. crystal deposition leads to recurrent episodes of joint inflammation and joint destruction.001 rheumatic.2006. The three most common types of crystal-induced arthropathy are gout.com . Sometimes these diseases may coexist in the same joint or individual. 0889-857X/06/$ – see front matter D 2006 Elsevier Inc. Each of these entities may occur as a primary abnormality or secondary to an underlying disorder. MacKenzie. A variety of microcrystals may be deposited and can induce an inflammatory response. The clinical manifestations of gout may be subdivided into early and late presentations and acute and chronic attacks of arthritis. John D.dalinka@uphs. Murray K.upenn. T Corresponding author. 3400 Spruce Street/1 Silverstein. Philadelphia.rdc.theclinics. Each has a characteristic clinical presentation. and calcium hydroxyapatite deposition disease (HADD). PA 19104.edu (M. Dalinka). Imaging aids in the clinical evaluation of patients who have gout aids in monitoring patients with this disorder. E-mail address: murray.04.K. When left untreated. Choi.Rheum Dis Clin N Am 32 (2006) 427 – 446 Imaging Features of Crystal-Induced Arthropathy Marc H. crystal type that may be aspirated from affected tissues. DalinkaT Department of Radiology. Imaging frequently plays a crucial role in the diagnosis of crystal-induced arthropathies and may help to monitor disease progression and treatment response. and radiographic appearance.1016/j. All rights reserved. USA Crystal-induced arthropathies constitute a spectrum of inflammatory arthritides that is induced by cellular reaction to crystal deposition in and around joints. Hospital of the University of Pennsylvania. calcium pyrophosphate dihydrate (CPDD) deposition disease.

or radiation therapy. The combination of elevated serum and soft tissue uric acid levels and acidosis likely accelerates urate crystal formation. Rapid changes in uric acid levels are believed to be responsible for acute attacks of gout. and eventually in 90% of patients who have untreated gout. biopsy rarely is necessary because the diagnosis of gout usually is well established by the time . the prevalence of the disease increases with age [4]. After an initial series of acute attacks. hemoglobinopathies. Although gout affects less than 0. such as myeloproliferative and lymphoproliferative disorders. patients present with acute signs and symptoms years before radiographic abnormality is manifest. patients may enter a symptom-free period (‘‘intercritical gout’’) that may last from months to years [2]. the disease begins at night in men between the ages of 30 to 60 years with the sudden onset of acute and severe pain with a predilection for the metatarsophalangeal (MTP) joint of the first digit (podagra). The first MTP joint is involved in approximately 50% of patients at onset. the presence of hyperuricemia is not diagnostic of gout because most patients who have hyperuricemia do not have gout. Altered metabolism of urate precipitates urate salt deposition and leads to gout [1]. hyperuricemia increases the risk for gout.5% of the population. The acute attacks of gout recur frequently and when they increase in number the disease is more likely to become polyarticular. The key to the diagnosis is joint aspiration with synovial fluid analysis depicting negatively birefringent urate crystals on polarized light microscopy. Typically. Classically. Patients with early onset of gout typically have more frequent attacks than do patients in the chronic stage. Clinical features Gout is the most common form of crystal arthropathy. thiazide or other diuretic therapy. Approximately 25% of patients have five or more acute attacks per year before treatment. however. Diseases that are associated with uric acid overproduction include primary enzymatic defects of purine synthesis or increased nucleic acid turnover. or pharmacologic agents that alter renal function. The excruciating joint pain usually subsides within 2 to 24 hours with less severe pain occasionally lasting for a few weeks. If untreated. tophi are deposited in a periarticular location. and approximately 90% of patients who have chronic hyperuricemia develop gout within 30 years [2]. however. Tophi are the hallmark of chronic gout and they may be identified on radiographs. Imaging in conjunction with tissue aspiration/biopsy helps to establish a firm diagnosis of gout before initiating potentially toxic therapy. and saturnine gout. massive cell lysis from chemo. With chronic gout.428 choi et al Etiology Gout may be caused by uric acid overproduction or underexcretion. or classic radiographic findings [3]. Decreased uric acid excretion and elevated serum uric acid levels may occur secondary to chronic renal failure. on rare occasions patients may present with chronic arthritis.

Generally. hip. but the disease tends to affect the lower extremities more often than the upper extremities and the small joints more often than the large joints. small. to document the presence of tophi. approximately half of the patients who have untreated gout develop tophi after 10 years and more than 70% have tophi after 20 years [5].9]. which occurs between the acute period and the development of chronic tophaceous gout. well-defined erosions) may be visualized at the periphery of affected joints. and wrist [7]. however. elbow. These include tophi. Faint calcification may occur in up to 50% of tophi. and to help exclude other diagnoses. and lack of osteopenia. Characteristic findings occur in chronic gout. mismanagement. proteinaceous deposits. All compartments of the hand and wrist. subtle joint alterations (eg. and the more specific changes of chronic tophaceous gout [3]. Other causes of monoarticular soft tissue swelling. shoulder. and poor patient compliance/adherence. and lipids with a surrounding foreign body reaction. including infectious arthritis. capsular distention. In the intercritical period. must be excluded [6]. they are ovoid and asymmetric and usually are radiographically invisible until they reach 5 mm to 10 mm in diameter [8. relative preservation of the joint space. Approximately 85% to 90% of patients who have gout experience podagra at some point in the disease. The early diagnosis and treatment of gout has resulted in a decline in the incidence of chronic tophaceous gout although it still occurs.imaging features of crystal-induced arthropathy 429 tophi appear. 1 and 2)—a mixture of monosodium monohydrate crystals in a matrix of amorphous debris containing urate. the radiographic abnormalities usually disappear [3]. Imaging gout Radiographic examination in patients who have gout is used mainly to evaluate joint destruction and disease progression. Radiographic findings may be categorized into the nonspecific changes that are seen in early gout. cloudlike masses of densely calcified tophi are atypical [9] and may reflect a coexisting abnormality of calcium metabolism. and periarticular soft tissue edema. Most first presentations are monoarticular. The rate of tophi formation is dependent upon the level of uric acid. and knee are involved frequently early in the course of the disease. knee. the subtle alterations of intercritical gout. An asymmetric and monoarticular distribution is characteristic of gout with the first MTP joint (podagra) affected most often followed by the first interphalangeal and tarsometatarsal joints. tarsal. As the attack subsides. the radiographs usually are normal or show nonspecific soft tissue swelling in the affected joint secondary to synovitis. pseudogout. Large tophi may be palpable. The distribution of radiographic abnormalities in gouty arthritis is variable. The ankle. erosions with overhanging edges. There is preference for peripheral joints with the feet. and trauma. in part secondary to misdiagnosis. The hallmark of chronic gout is the presence of multiple macroscopic tophi (Figs. . In the early stage of gout. Bilateral and symmetric or asymmetric polyarticular involvement may be present within any of the foot joints. and sacroiliac joint (15% unilateral) are favored sites.

. Additional small erosions are present at the medial cuneiform–first metatarsal articulation. A characteristic feature of gouty erosions is the overhanging edge. such as renal insufficiency (Fig. Large tophus at MTP joint of first toe and erosion with overhanging edge at fifth metatarsal. Interosseous erosions may have sclerotic borders that produce a punched-out appearance [12]. When characteristic erosions are seen along with tophi the diagnosis of gout is almost certain. Tophaceous gout. 2. these erosions are round or oval in shape and well circumscribed. Multiple changes of gouty arthritis are present in the hand. Erosions in chronic gout are common and usually are associated closely with the tophaceous deposits because the erosions may occur secondary to chronic pressure from the adjacent tophus. Large erosions are identified about the proximal interphalangeal joint of the second digit that are more marked on the radial aspect of the joint where there is an overhanging edge. Frequently. 1. and typically are eccentric and oriented along the long axis of bone (see Figs. Gouty arthritis. 1 and 2).430 choi et al Fig. an elevated margin of bone that extends over the expected confines of the cortex at the site Fig. 3) [10. There is asymmetric soft tissue swelling and small erosions at the second metacarpophalangeal articulation. Most often they are juxta-articular but may be intraarticular or located at a distance form the joint.11]. Smaller erosions are present in the other digits. Intra-articular erosions tend to involve the joint margins before extending to the middle of the joint [5].

If joint space narrowing has occurred. this is transient and the bone density tends to be preserved. Periarticular osteopenia may be seen during an acute gouty attack. disuse is believed to be the underlying cause of the osteopenia [15]. 3. predominantly in the hands and feet. Calcified tophus. Localized increased bone density may be seen in a minority of patients (~ 6%) that has advanced tophaceous gout. 1) [13]. a zone of osteoporosis in the subchondral bone may progress to a cystic abnormality [9].imaging features of crystal-induced arthropathy 431 Fig. Large tophi are an important radiographic feature that helps to differentiate gout from other causes of arthritis. however. Interosseous tophi and subchondral cysts may mimic focal osteoporosis and should not be confused with diffuse periarticular osteopenia. Occasionally. of erosion (see Fig. however. The joint space is relatively well preserved. the radiographic appearance may mimic the uniform narrowing of rheumatoid arthritis or advanced osteoarthritis (OA) [2]. Classic tophus with increased density at the first MTP joint and additional tophus at the medial aspect of the interphalangeal joint of the first digit in this patient who had gout and renal failure.15]. The overhanging edge is seen in approximately 40% of patients who have tophaceous gout and may represent new bone formation around a gradually enlarging tophus. presumably from inflammation-induced hyperemia. even in advanced chronic gout with articular destruction. patients who have joint space narrowing generally have had long-standing disease and the clinical diagnosis of gout already is well established (Fig. Enlargement of the ends and shafts of involved bones can produce club-shaped metatarsal and . When bone density is diminished in long-standing gouty arthritis. extensive osseous erosions produce a mutilating arthritis that mimics the opera-glass hand deformity that is seen occasionally with rheumatoid or psoriatic arthritis [14]. Occasionally. The radiographic appearance may resemble an area of bone infarction or enchondroma. Infrequently. Osteopenia is an atypical feature of gout. 4). The increased bone density may represent calcification of interosseous monosodium urate deposits [5]. bone proliferation is present in gouty arthritis. Ankylosis with obliteration of the joint space is rare [11. even in the presence of extensive juxta-articular erosions.

this is seen best on the medial aspect of the first MTP joint [17]. olecranon. Joint destruction and erosions are identified at the tarsometatarsal joints and the second MTP joint with lateral subluxation. . Soft tissue swelling and calcification about the olecranon bursa. A fine lacy periosteal new bone formation may occur secondary to periosteal reaction that is caused by cortical destruction by adjacent crystal deposition. a characteristic finding in gout that often is bilateral. This is termed ‘‘mushrooming. Radiograph of the foot shows marked joint destruction and large tophus at the first MTP joint. Urate stones as small as 2 mm may be detected readily [20]. 4. 5) is characteristic of gout as is bilateral swelling at the dorsum of the foot and calcaneus. such as the calcaneus. Hyperuremic patients may present with urinary calculi before developing gouty arthritis [18]. Although several papers have de- Fig. phalangeal heads (see Fig.’’ Irregular bone spicules at sites of muscle and tendon insertion. often. 1). A non-contrast CT scan performed with thin slices (3–5 mm) through the urinary-collecting system has replaced intravenous urography as the gold standard for detecting urinary calculi [19]. Advanced gout with joint destruction. Olecranon bursitis. and patella. Bilateral olecranon bursitis (Fig. 5.432 choi et al Fig. may be observed [16]. CT rarely is useful in patients who have gout other than for the detection of urinary calculi.

Most often.imaging features of crystal-induced arthropathy 433 scribed MRI findings in patients who have gout. CPPD deposition disease describes a crystal arthropathy that is induced by CPPD crystals. chondrocalcinosis also may occur from the deposition of calcium apatite. synovitis. CPPD deposition has been reported in association with a host of disorders. it affects both sexes equally. CPPD crystals elicit an inflammatory response that results in arthritis. . MRI is not used in diagnosis or management. An autosomal dominant form of CPPD has been described with an earlier age of onset than the idiopathic form [25]. Chondrocalcinosis is found in up to 41% of patients who have hemochromatosis and the articular manifestations share many similarities with CPPD arthropathy [27–29]. Articular and periarticular calcifications are general terms that are used for the radiologic description of calcification in or around a joint but not necessarily in cartilage. CPPD deposition disease may cause an idiopathic arthritis in middle-aged or elderly patients. it often is associated with severe symptoms. The soft tissue calcification from CPPD crystal deposition and the joint degeneration that result from CPPD arthropathy tend to have characteristic imaging appearances. It is characterized by joint inflammation and a typical pattern of structural joint damage that may occur with or without radiographically visible chondrocalcinosis [22. Before discussing the clinical and imaging features. Chondrocalcinosis signifies deposits of calcium salts in cartilaginous tissue. a review of nomenclature is helpful to understand better the clinical and radiographic manifestations of CPPD deposition disease [21]. dicalcium phosphate dehydrate. or tendonitis. or calcium oxalate. Additionally. articular chondrocalcinosis results from CPPD crystal deposition in hyaline and fibrocartilage. it is common in the geriatric population where it frequently is asymptomatic.23]. The incidence of primary hyperparathyroidism is as high as 15% in patients who have CPPD [26]. Pseudogout syndrome is a subset of CPPD deposition disease that mimics the clinical manifestations of gout. Clinical features The prevalence of CPPD deposition increases with age. Calcium pyrophosphate dihydrate deposition disease CPPD deposition disease is characterized by the presence of CPPD crystals within and around joints. however. CPPD deposition disease also has been described in patients with secondary hemochromatosis related to hereditary spherocytosis [29]. Chondrocalcinosis may be seen without symptoms of arthropathy. CPPD deposition disease is synonymous with CPPD arthropathy and pyrophosphate arthropathy. There is a 5% incidence of radiographic chondrocalcinosis by age 70 and a 50% incidence by age 90 [24]. but is caused by calcium pyrophosphate crystals rather than monosodium urate crystals.

but without radiographic chondrocalcinosis. pseudorheumatoid arthritis. The pseudogout syndrome manifests with self-limited acute or subacute episodes of mono.434 choi et al Although common. CPPD crystal deposition in cartilage seems to be related to defects in calcium and inorganic phosphate metabolism [24]. . and elevated erythrocyte sedimentation rate with a symmetric pattern. however. In some cases. The lanthanic or asymptomatic type is the most common clinical pattern of CPPD deposition disease. some patients present with progressive joint degeneration that is typical of OA. OA. often with chondrocalcinosis superimposed upon the typical radiographic findings of OA. traumatic arthritis. the presence of classic chondrocalcinosis differentiates the two [34]. although symptomatic CPPD arthropathy may be present in other joints. The pathophysiology of CPPD deposition disease is not understood completely. The phenomenon of CPPD crystal shedding is believed to explain acute bouts of arthritis [37]. rheumatic fever. but without neurologic abnormality [35.31]. Cartilaginous deposits of crystals are cast into the articular cavity and subsequently precipitate acute arthritis. The pseudo-OA pattern may be present in approximately 50% of patients who have CPPD arthropathy. There may be superimposed acute inflammatory episodes in addition to the chronic arthritic symptoms. Because not all individuals who have hypercalcemia or hypophosphatasia develop calcium pyrophosphate crystals other factors must be involved. the aspirated crystals are weakly positive under polarizing light and are characteristic for CPPD as is the radiographic appearance. CPPD deposition disease is a great mimic. rheumatoid arthritis. osteophyte formation. pseudoneuropathic arthropathy. predominant involvement of the patellofemoral joint in the knee and the radiocarpal and metacarpophalangeal (MCP) joints in the wrist and hands). In the pseudoneuropathic type patients present with radiographic findings that simulate a neuropathic joint (joint destruction. however. pseudogout syndrome. The pseudoosteoarthritis type (pseudo-OA) of CPPD deposition disease simulates OA clinically and radiographically. This theory is supported by the association of CPPD with hypophosphatasia and hyperparathyroidism.36]. synovial thickening. or psychogenic arthritis [32]. because the clinical presentation may resemble gout. ankylosing spondylitis. and subchondral sclerosis and cysts. subluxation. fatigue. An atypical joint distribution may occur in joints that are not affected readily by OA (ie. with joint space narrowing. and pseudoostoeoarthritic types [33]. Additionally. Synovial fluid pyrophosphate has been found to be increased in patients who have CPPD. CPPD deposits are visible on radiographs but the particular joint is without the clinical signs and symptoms of an arthropathy. The pseudorheumatoid type manifests with symptoms and signs that are similar to rheumatoid arthritis: morning stiffness that lasts for weeks to months. and heterotopic new bone formation). CPPD deposition disease was described first in the 1960s [30. The clinical presentation of CPPD arthropathy generally falls into five distinct clinical patterns: lanthanic. restricted joint motion.or pauci-articular arthritis similar to gout. neuropathic joint.

evaluate disease progression. the incidence of intra-articular calcifications increased with age. Because the diagnosis and the consequent therapeutic measures may be based. Radiographs can document the presence of chondrocalcinosis and periarticular calcifications. characterize the distribution and severity of the arthritis. probable. From anatomic and radiologic studies of knee joints. A definite diagnosis is established when a characteristic x-ray diffraction pattern of crystals from aspiration/biopsy of the joint is demonstrated or when the combination of polyarticular chondrocalcinosis on radiographs and absent/weakly birefringent crystals from joint aspiration/ biopsy is found on polarizing microscopy. 6. symphysis pubis. an understanding of the varied radiographic manifestations of CPPD deposition disease is important. If only one of the latter two criteria is present then the diagnosis is probable [38].and 69-year age group and the older than 80-years age group the incidence increased from 11% to 38% for women and from 20% to 29% for men [40]. elbow. Fig. without chondrocalcinosis. in part. wrist. or possible CPPD deposition disease were outlined by McCarty [26]. and hip [36]. CPPD crystals may be deposited in and around joints and often have a characteristic radiographic appearance and distribution. CPPD knee. Characteristic radiographic findings coupled with absent/weakly birefringent crystals on polarizing microscopy makes a definitive diagnosis of CPPD deposition disease. . The calcifications clearly outline the fibrocartilage in the menisci and the more central hyaline articular cartilage. the prevalence of cartilage CPPD deposits in the elderly is between 2% and 28% [39]. between the 60.imaging features of crystal-induced arthropathy 435 The diagnostic criteria for definitive. Imaging features in calcium pyrophosphate dihydrate deposition disease Radiography is the imaging modality of choice for the diagnosis and evaluation of patients who are suspected of having CPPD deposition disease. upon the radiographs. A possible diagnosis can be suggested when acute or chronic arthritis occurs in a typical location and is accompanied by the characteristic radiographic features. most frequently in the knee. and exclude other diagnoses. In one autopsy survey. The crystal deposits occur in fibrocartilage and hyaline cartilage.

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Fig. 7. CPPD wrist. The triangular fibrocartilage is calcified densely as is the articular cartilage over the distal ulna (arrows).

Fibrocartilage calcification is most common in the menisci of the knee, triangular fibrocartilage of the wrist, symphysis pubis, annulus fibrosis, and glenoid and acetabular labrum (Figs. 6 and 7). Fibrocartilaginous calcifications are shaggy and irregular radiodense areas that most often are located centrally in the joint. Hyaline cartilage calcifications are identified as a thin line parallel to, and a few millimeters subjacent to, the subchondral bone (Fig. 8). Hyaline cartilage calcification occurs most commonly in the wrist, knee, elbow, and hip (Fig. 9). Calcification within the synovial membrane is a common feature of CPPD; it usually is seen with chondrocalcinosis, but at times it may be the dominant radiographic feature. Synovial calcification is seen most often about the knee, MCP and MTP joints, and the radiocarpal and distal radioulnar articulations of the wrist (see Fig. 9). They tend to appear amorphous or cloudlike and are located at the joint margins where they may simulate idiopathic synovial osteochondromatosis.

Fig. 8. (A,B) CPPD elbow and shoulder. The articular cartilage calcification (arrows) parallels the subchondral bone. Note the synovial calcification in the lateral elbow (arrowhead).

imaging features of crystal-induced arthropathy

437

Fig. 9. CPPD knee. Extensive calcification in the meniscus (large arrow), articular cartilage (arrows), and synovium (long arrows).

CPPD crystal deposition of the joint capsule is most common in the elbow and MTP articulations, but it also may be found in the MCP and glenohumeral joints. Capsular calcifications tend to be fine, irregular linear densities that span the articulation. They may be associated with joint contractures, particularly in the elbow [36]. Tendon calcifications occur commonly in the Achilles, triceps, quadriceps, and supraspinatus tendons. Tendon calcifications are thin, linear, and extend a considerable distance from the osseous insertion; they imitate findings of idiopathic calcific tendonitis. Unlike the thin and linear appearance of tendon and ligament calcification, bursa calcifications typically are amorphous or cloudlike [41]. Bursa calcification is associated commonly with olecranon bursitis. In the shoulders, tendon and bursa calcifications frequently are asymptomatic; when symptomatic, they present with acute pain and tenderness. Occasionally, CPPD may be be mistaken for gout, particularly in the digits where CPPD soft tissue tumorlike collections of calcifications can resemble gouty tophi [42]. Structural joint changes that are associated with CPPD crystal deposition are common and often are characteristic of the disease. The changes are similar to OA with joint space narrowing, subchondral sclerosis, and subchondral cyst formation (Figs. 10 and 11). They are not always accompanied by radiologically evident calcification [41], and in the absence of calcification it may be difficult to differentiate OA from CPPD arthropathy. The intra-articular joint distribution and the joints that are involved aid in this differentiation. The location of the structural damage in particular joints helps to distinguish CPPD arthropathy from OA. As with OA, CPPD arthropathy tends to be bilateral and asymmetric and is most common in the knee (see Fig. 11); however, advanced, asymmetric, or isolated involvement of the patellofemoral compartment should raise the possibility of CPPD, particularly when accompanied by erosions of the adjacent supracondylar femoral cortex. CPPD favors the radiocarpal

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Fig. 10. CPPD arthropathy with scapholunate advanced collapse of the wrist. There is narrowing of the radiocarpal joint with a large ‘‘cystic’’ lesion (geode) in the distal radius. There is widening of the scapholunate ligament with proximal migration of the capitate. Calcification adjacent to the proximal lunate is likely in articular cartilage.

compartment of the wrist and frequently involves the MCP joints, atypical locations for OA. Isolated involvement of the radiocarpal or trapezioscaphoid articulations in the wrist is much more typical of CPPD crystal deposition disease. Scapholunate advanced collapse of the wrist is seen in OA, rheumatoid arthritis, and CPPD. CPPD crystal deposition in the scapholunate ligament predisposes to disruption of the joint with subsequent scapholunate-associated collapse [43]. A pattern of joint degeneration that is atypical of OA, but typical for CPPD, involves the MCP joints. Nonweight-bearing joints, which are affected infrequently by OA, are involved commonly by CPPD arthropathy. The subchondral cysts that are associated with CPPD arthropathy often are more numerous and larger. Cysts in

Fig. 11. CPPD arthropathy simulating neuropathic joint. AP (A) and lateral (B) view of knee reveal extensive joint destruction, particularly in the medial compartment. The widening of the lateral compartment may be from ligamentous laxity. There is extensive lateral meniscal and synovial calcification (arrows).

symptoms occur in 34% to 45% of patients in whom calcifications are present. particularly scleroderma and mixed connective tissue disease. Deposition of this crystal also may be seen in patients who have tumoral calcinosis and as a complication of multiple intra-articular steroid injections [47]. The crystal deposits may be asymptomatic. Hydroxyapatite deposition disease In 1966. The crystal deposition also may occur in an intra-articular location. and collagen vascular disease. Typically.49]. although other or multiple joint involvement may occur. renal osteodystrophy. This entity has been described under several names. Large.’’ and ‘‘calcifying tendinitis’’ [45]. The disorder may be familial.’’ ‘‘periarticular apatite deposition. It is now known that deposits of this crystal may be responsible for an idiopathic disorder (HADD). recently. with less severe symptoms leading to various degrees of incapacitation [44]. including trauma. HADD is a well-recognized cause of periarticular inflammation that may cause bursitis or tendonitis. the disorder may be chronic. mainly tendons and bursa. Variable osteophyte formation is seen more commonly with CPPD arthropathy. including ‘‘calcific periarthritis. It may be a primary phenomenon or occur in association with other disorders. in which HA crystals are deposited particularly in the periarticular tissues. intra-articular HA deposition has been implicated as a cause of acute arthritis [48. More recently. metabolic. tenderness. irregular bony excrescences are sometimes present in CPPD arthropathy. A ‘‘degenerative theory’’ proposes that trauma or stress that is associated with a local decrease in blood supply leads to tendinous tears with resulting calcification [50]. Clinical features HADD usually is monoarticular and occurs most frequently about the shoulder. or other factors . particularly in the shoulder [44]. calcium hydroxyapatite (HA) crystals were implicated as a cause of calcifications of the periarticular soft tissues and tendons. Less commonly. certain histocompatibility antigens were identified as having a frequent association with this disorder [46]. and a local inflammatory response that may be associated with restrictive motion. the onset of symptoms is acute with severe pain.imaging features of crystal-induced arthropathy 439 CPPD arthropathy also tend to have sclerotic margins and vary more in shape and size. Uhthoff and coworkers [51] suggested that hypoxia in the region of the tendon that is induced by mechanical. The disease has no gender predilection and typically occurs between the ages of 40 and 70 years. Etiology The mechanism by which calcification occurs within a tendon is understood poorly.

(B) T2-weighted fat-suppressed coronal image reveals low signal (calcification) in supraspinatus tendon with extensive edema and fluid in the subacromial-subdeltoid bursa. with a linear or circular configuration. depending on the chronicity and activity of disease. . Although osteoporosis. homogenous. With time the HA crystal deposition may appear denser. Calcification may not be the inciting agent. infection. which sets off the acute inflammatory response. Classic HADD in supraspinatus tendon. Radiographic examination frequently allows a definitive diagnosis of HA deposition. and more sharply delineated. imaging features vary. tendinous. Complementary techniques for identifying the crystals include electron microscopy and electron probe analysis [45]. Capsular. and contour irregularities may be present. cystic lesions. or CPPD crystal deposition disease. Imaging features in hydroxyapatite crystal deposition disease The clinical features of periarticular HADD may mimic fracture. mainly about the calcification. and symptoms may occur with the dissolution of calcium. The calcification is mediated by the chondrocytes and is associated with vascular proliferation and subsequent resorption of the calcific focus by macrophages. and bursal tissues about the shoulder are the most common sites of articular and periarticular calcific deposits. reactive sclerosis. The needlelike crystals on electron microscopy may be identified as purple clumps by light microscopy with Wright’s stain. gout. Often. (A) Calcification in supraspinatus tendon adjacent to its insertion into the greater tuberosity of the humerus. 12.440 choi et al results in transformation of this region into fibrocartilage. When rupture of the calcific deposit occurs the HA crystals are spilled into the surrounding soft tissue space or bursa. The general radiographic features of periarticular HA crystal deposition are cloudlike and poorly defined calcific deposits that initially blend into the surrounding soft tissues. HA Fig. adjacent osseous tissues usually are normal. In the shoulder.

or ‘‘skullcap’’ radiodensity that extends under the greater tuberosity [52]. 14. Fig. These may be associated with marrow edema on MRI. Osseous erosions may be located adjacent to tendon and ligament insertion sites (Fig. HADD deposition in distal supraspinatus tendon with adjacent erosion in the humeral head (arrow). 13). . 13. Besides the shoulder. The other tendons of the rotator cuff and the bicipital tendon may be involved. Calcification in the subacromial bursa appears as a teardrop-shaped.imaging features of crystal-induced arthropathy 441 Fig. 12). Extensive calcification in triceps tendon. HADD in a patient who had chronic renal failure and was on dialysis. HA crystal deposition may occur in the collateral ligaments of the elbow—at the insertion of the triceps tendon into the olecranon process (Fig. Calcific tendonitis with adjacent erosion. crystal deposition is bilateral in nearly 50% of cases. 14)—which is associated occasionally with triceps tendon rupture. ulcerated. and it is most common in the supraspinatus tendon (Fig.

the principal flexor of the cervical spine. HADD with disappearance of calcification. and thighs. 16). these changes in size and appearance occur in the Fig.442 choi et al Fig. Frequently. reappearance of calcification also has been reported [45]. Other locations with HA crystal deposition in the spine have been reported. The longus colli muscle. calcifications that have a varied appearance are frequent in the gluteal insertions into the greater trochanter and surrounding bursae (Fig. however. HA crystal deposition may remain static for a long time. Deposition of HA crystal also may occur in the axial skeleton. is involved most commonly in the neck. In other instances. or disappear entirely (Fig. pelvis. 16. (B) Two years later the calcification has resorbed completely. Calcific periarthritis HADD in the gluteus maximus tendon at its insertion into the greater trochanter (arrow). 15) [53–57]. . In the hip. calcified deposits may change in size over time and become larger. including the infraoccipital region and interspinous bursae in association with neck pain. (A) Calcification adjacent to lateral acetabular margin in patient who had acute hip pain. 15. smaller.

in the joint capsule. Because HA crystal deposition is associated with OA. Articular deposition HA crystals may become deposited in the synovial membrane. Intra-articular accumulation of HA crystals may occur in the absence of radiographically apparent calcification. the calcifications appear as homogeneous. In some patients. Synovial membrane. subchondral sclerosis. osseous debris. particularly the lateral fibisfemoral articulation. collapse of the articular surface. there is no definite correlation between the sizes of periarticular calcifications and symptoms. Unicompartmental involvement is typical. or occasionally in cartilage (chondrocalcinosis). This consists of joint space loss. The humeral head is displaced superiorly. cloudlike. Generally. have been reported. Radiographic findings are a late manifestation of the disease. and small joints of the hand and feet. Summary The radiographic appearance of MSU. A large effusion that contains calcified debris may be present. the radiographic feature of one may accompany the other. and HA crystal-induced arthropathies have been reviewed. Typically.’’ This disorder should be suspected if radiographs reveal extensive cartilage calcification and diffuse intra-articular and capsular calcification or dense. The recognition of the often distinctive radiographic appearance of crystal-induced disease may allow a specific diagnosis. sclerosis and fragmentation. CPPD. knee. and shoulder. knee. synovial fluid or cartilage may reveal calcium HA and CPDD crystals. small joints are affected. joint disorganization. and even may contact the acromion as a result of associated disruption of the rotator cuff with remodeling and erosion of the acromial undersurface. intra-articular and extra-articular osseous erosions. or both can be involved that contain amorphous or fluffy cloudlike areas of increased radiodensity. which leads to narrowing. subperiosteal apposition . and include lobulated eccentric soft tissue masses. and deformity. chondrocalcinosis also is present within the meniscus of the knee.imaging features of crystal-induced arthropathy 443 absence of symptoms. intra-articular radiodensities that do not follow anatomic structures. Associated arthropathy of the knee in patients who had shoulder arthropathy has been reported. hip. In addition. hip. a condition that is termed ‘‘mixed calcium phosphate crystal deposition disease. Rarely. and valgus angulation. Radiography has a small role in the diagnosis of initial attacks of acute gouty arthritis. Destructive arthropathy that is associated with HA crystal deposition in the shoulder is referred to as a Milwaukee shoulder syndrome. capsule. homogeneous calcific deposits within tendons. relative preservation of joint space. such as the wrist. but involvement of other joints. Joints frequently involved by HA crystal deposition include the shoulder.

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