Biomedical subjects

H Ralph Schumacher

Publications and source records attributed to H Ralph Schumacher.

At least 19 recordsLinked to original sources

PubMed2006

Hyperuricemia and incidence of hypertension among men without metabolic syndrome.

The aim of this project was to study the risk of developing hypertension over a 6-year follow-up in normotensive men with baseline hyperuricemia (serum uric acid >7.0 mg/dL) but without diabetes/glucose intolerance or metabolic syndrome. We analyzed the data on men without metabolic syndrome or hypertension at baseline from the Multiple Risk Factor Intervention Trial. These men (n=3073; age: 35 to 57 years) were followed for an average of 6 years by annual examinations. Follow-up blood pressure among those with baseline was consistently higher than among those with normal serum uric acid concentration. We used Cox regression models for adjustment for the effects of serum creatinine, body mass index, age, blood pressure, proteinuria, serum cholesterol and triglycerides, alcohol and tobacco use, risk factor interventions, and use of diuretics. In these models, normotensive men with baseline hyperuricemia had an 80% excess risk for incident hypertension (hazard ratio: 1.81; 95% CI: 1.59 to 2.07) compared with those who did not. Each unit increase in serum uric acid was associated with a 9% increase in the risk for incident hypertension (hazard ratio: 1.09; 95% CI: 1.02 to 1.17). We conclude that the hyperuricemia-hypertension risk relationship is present among normotensive middle-aged men without diabetes/glucose intolerance or metabolic syndrome.

Adult↗

PubMed2006

[Decision-making about gout by physicians of China and influencing factors thereof].

OBJECTIVE: To investigate the decision-making about gout by physicians of China and influencing factors thereof. METHODS: A questionnaire survey, including 13 multiple choice questions, was divided into 2 stages. The first/stage questionnaire survey was conducted among 121 physicians of the departments of internal medicine and rheumatology respectively during the grand ward rounds, and the second-stage questionnaire survey was conducted among 75 physicians attending a national continuous medical education (CME) workshop of rheumatology. The data thus collected were pooled and analyzed by logistic regression models. RESULTS: 62 effective questionnaires were collected in the first/stage survey, and 38 effective questionnaires were collected in the second-stage survey, both with a missing rate < 10%. 78.3% of the respondents considered aspiration of the joint fluid as critical for the definitive diagnosis of gout, but only 2.4% of the respondents did so frequently. When treating acute gout in otherwise healthy patients, 69.2% of the respondents preferred oral colchicine, and while treating the patients with renal dysfunction, 41.7% of the respondents used corticosteroids or corticotrophin as the first choice. For long-term uric acid-lowering therapy, 99 of them (82.5%) described a variety of incorrect indications, 107 of them (89.2%) initiated the treatment too early (< or = 2 weeks after the remission), and 92 of them (76.7%) failed to sustain the treatment for at least 5 years. Only 17 physicians (14.2%) used prophylaxis while initiating the uric acid-lowering treatment and only 7 of them (5.8%) selected a prophylaxis time of 7 approximately 12 months. Multiple logistic regression analysis showed that only CMD on gout was associated with correct diagnosis strategy (OR 7.1, 95% CI 2.1 approximately 23.7). CONCLUSION: The management of gout by the physicians in China is often not consistent with that generally accepted internationally. High quality CME may improve the decision-making ability of physicians.

Decision Making↗

PubMed2006

Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis.

BACKGROUND: Glucosamine and chondroitin sulfate are used to treat osteoarthritis. The multicenter, double-blind, placebo- and celecoxib-controlled Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) evaluated their efficacy and safety as a treatment for knee pain from osteoarthritis. METHODS: We randomly assigned 1583 patients with symptomatic knee osteoarthritis to receive 1500 mg of glucosamine daily, 1200 mg of chondroitin sulfate daily, both glucosamine and chondroitin sulfate, 200 mg of celecoxib daily, or placebo for 24 weeks. Up to 4000 mg of acetaminophen daily was allowed as rescue analgesia. Assignment was stratified according to the severity of knee pain (mild [N=1229] vs. moderate to severe [N=354]). The primary outcome measure was a 20 percent decrease in knee pain from baseline to week 24. RESULTS: The mean age of the patients was 59 years, and 64 percent were women. Overall, glucosamine and chondroitin sulfate were not significantly better than placebo in reducing knee pain by 20 percent. As compared with the rate of response to placebo (60.1 percent), the rate of response to glucosamine was 3.9 percentage points higher (P=0.30), the rate of response to chondroitin sulfate was 5.3 percentage points higher (P=0.17), and the rate of response to combined treatment was 6.5 percentage points higher (P=0.09). The rate of response in the celecoxib control group was 10.0 percentage points higher than that in the placebo control group (P=0.008). For patients with moderate-to-severe pain at baseline, the rate of response was significantly higher with combined therapy than with placebo (79.2 percent vs. 54.3 percent, P=0.002). Adverse events were mild, infrequent, and evenly distributed among the groups. CONCLUSIONS: Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee. Exploratory analyses suggest that the combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain. (ClinicalTrials.gov number, NCT00032890.).

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2006

Gout and the risk of acute myocardial infarction.

OBJECTIVE: To determine if hyperuricemia and gouty arthritis are independent risk factors for acute myocardial infarction (MI) and, if so, whether they are independent of renal function, diuretic use, metabolic syndrome, and other established risk factors. METHODS: We performed multivariable logistic and instrumental variable probit regressions on data from the Multiple Risk Factor Intervention Trial (MRFIT). RESULTS: Overall, there were 12,866 men in the MRFIT who were followed up for a mean of 6.5 years. There were 118 events of acute MI in the group with gout (10.5%) and 990 events in the group without gout (8.43%; P = 0.018). Hyperuricemia was an independent risk factor for acute MI in the multivariable regression models, with an odds ratio (OR) of 1.11 (95% confidence interval [95% CI] 1.08-1.15, P < 0.001). In multivariable regressions in which the above risk factors were used as covariates, gout was found to be associated with a higher risk of acute MI (OR 1.26 [95% CI 1.14-1.40], P < 0.001). Subgroup analyses showed that a relationship between gout and the risk of acute MI was present among nonusers of alcohol, diuretics, or aspirin and among those who did not have metabolic syndrome, diabetes mellitus, or obesity. In separate analyses, a relationship between gout and the risk of acute MI was evident among those with and without those hyperuricemia. CONCLUSION: The independent risk relationship between hyperuricemia and acute MI is confirmed. Gouty arthritis is associated with an excess risk of acute MI, and this is not explained by its well-known links with renal function, metabolic syndrome, diuretic use, and traditional cardiovascular risk factors.

Arthritis, Gouty↗

PubMed2006

Gout: can we create an evidence-based systematic approach to diagnosis and management?

The management of gout can be subdivided into four phases. Asymptomatic hyperuricaemia represents the basic underlying metabolic abnormality that can lead to gout. Studies are evaluating whether interventions may be indicated in some cases. Diagnostic criteria for gout and acute flares are still not well defined unless urate crystals are found. Acute attacks of gout are treated with anti-inflammatory measures and the agent of choice is often determined by attack stage, severity and comorbidities that may contra-indicate one or more agents. After attacks subside, there are asymptomatic periods during which decisions must be made about when and how to start urate-lowering measures. If hyperuricaemia persists, there is generally persistence of urate crystals in the joint. Anti-inflammatory prophylaxis is needed when urate-lowering therapy is started. Lifestyle measures should be addressed. If chronic tophaceous gout is diagnosed, urate lowering should be started without delay. New agents are under development that may help with difficult cases.

Acute Disease↗

PubMed2006

Newer therapeutic approaches: gout.

Newer approaches to the treatment of gout have included modifications and further attention to aspects of current therapies, and development of interesting new therapies. Colchicine prophylaxis appears to be needed longer than previously recognized after introduction of a urate-lowering agent. Diet has received attention, though most dietary effects are small. New agents under investigation include pegylated formulations of uricase and a new potent xanthine oxidase inhibitor, febuxostat. Some cardiovascular drugs have been shown to be uricosuric.

Anti-Inflammatory Agents↗

PubMed2006

Current trends in crystal identification.

PURPOSE OF REVIEW: This review is an attempt to keep current in the sparse literature addressing the still underutilized area of crystal identification. RECENT FINDINGS: The emphasis has been on the subtleties of the microscopic identification of common crystals and other less common potentially confusing crystals. Imaging is noted to provide increasing help, but microscopic crystal identification remains the gold standard. SUMMARY: Quality control is still a concern as is the infrequency of attempted arthrocentesis for crystal identification.

Calcinosis↗

PubMed2006

Serum urate levels and gout flares: analysis from managed care data.

BACKGROUND: The desired serum urate level (SUA) for prevention of gout attacks is widely recommended to be in the subsaturating range, <6.0 mg/dL. OBJECTIVES: The objectives of this study were to evaluate attainment of this target SUA among gout patients on allopurinol in a naturalistic setting and to assess its impact on gout flare risk. METHODS: : This was a retrospective, observational study in a southeastern U.S. managed care organization of approximately 2.2 million members. The first gout claim/prescription within the intake period (January 1, 2000-December 31, 2002) was the index date. Included patients had > or =2 visits with gout International Classification of Diseases, 9th Revision code (274.xx) or > or =1 pharmacy script(s) for allopurinol, colchicine, probenecid, or sulfinpyrazone. Excluded patients were <18 years and/or did not have a 1-year continuous eligibility pre-/postindex date. Gout flares were defined by office/emergency room visit with gout or joint pain code(s) and > or =1 of the following within 7 days of the visit: intraarticular aspiration/injection, joint fluid microscopy, or pharmacy claim for nonsteroidal antiinflammatory drug, colchicine, corticosteroid, or ACTH. Multivariable regression analyses were conducted to evaluate gout flare risk/rate and association with target SUA. RESULTS: Approximately 40% of 5942 gout patients identified used allopurinol postindex. Among allopurinol users with pre-/postindex SUA data (n = 162), mean SUA was lowered from 8.7 mg/dL to 7.1 mg/dL; reduction was significant (P < 0.001). Among allopurinol users who did not have SUA <6.0 mg/dL preindex (n = 147), only 25% reached target levels during postindex. Despite pharmacotherapy, patients with nontarget levels were 59% more likely to flare than those at target. Allopurinol users who were not at target were 75% more likely to flare. CONCLUSION: The failure of allopurinol users to achieve target SUA levels of <6.0 mg/dL may be attributed to lack of awareness of optimal SUA, allopurinol dosing, compliance, and efficacy. Patients who did not achieve target SUA were at increased flare risk.

Adolescent↗

PubMed2006

What is that nodule? A diagnostic approach to evaluating subcutaneous and cutaneous nodules.

The evaluation of patients with subcutaneous nodules remains a diagnostic challenge. The presence of nodules can be a clue to an underlying systemic disease; however, the varied presentations of nodules and numerous disease associations make the assessment of patients with nodules far from simple. With further investigation into the appearance, location, and symptoms associated with nodules, the clinical significance of these lesions can become clearer and aid in logical diagnostic evaluation. We have reviewed the causes of nodules with emphasis on those associated with rheumatic disease and provide guidelines for nodule evaluation to better characterize disease association and lead to directed diagnostic assessment.

Diagnosis, Differential↗

PubMed2006

Gout medication treatment patterns and adherence to standards of care from a managed care perspective.

OBJECTIVE: To determine allopurinol treatment patterns and adherence to published standards of care for patients with gout. PATIENTS AND METHODS: This retrospective claims analysis in a managed care database included patients 18 years or older, with continuous eligibility for 1 year before and after the start date and 2 or more visits during which the gout disease code (274.xx) was assigned or 1 or more pharmacy prescriptions for a gout-specific medication between January 1, 2000, and December 31, 2002 (intake period). Factors associated with compliance with allopurinol therapy were measured based on the medication possession ratio, and adherence to 2 quality-of-care indicators for gout management was assessed using multivariable logistic regression analysis. RESULTS: A total of 64.9% of allopurinol users had a modal daily dose or the most commonly observed daily dose of 300 mg/d, median length of therapy was 3 months, and a high proportion of patients had a medication possession ratio of 10% or less. Suggested quality-of-care Indicators for gout had low performance: 53% of patients with renal impairment received a modal daily dose of 300 mg or greater, and 83% of patients who started taking allopurinol did not have their serum urate levels measured within 180 days. Patients with gout flares were less likely to be compliant with allopurinol (odds ratio, 0.50; 95% confidence interval, 0.40-0.63). Patients with renal impairment at baseline were 3.2 times more likely to undergo serum urate testing than patients without renal impairment (odds ratio, 3.20; 95% confidence Interval, 1.25-8.23). CONCLUSION: There was low compliance with allopurinol therapy for treatment of gout. Patients potentially received suboptimal quality of care as measured by serum urate testing and appropriateness of allopurinol dosing in patients with renal impairment.

Adolescent↗

PubMed2006

Characteristics of chronic gout in Northern Sulawesi, Indonesia.

OBJECTIVE: To identify associations and possible risk factors for gout that may contribute to chronic tophaceous gout in rural and urban districts of North Sulawesi, Indonesia. METHODS: A total of 190 patients with chronic gout and 190 age and sex matched controls were selected from 28 community health centers. Potential risk factors including alcohol consumption, food habits, family history, body weight, related medical conditions, drug use, and laboratory investigations were sought. RESULTS: Alcohol consumption and certain food habits were associated with gout. A positive family history of gout and overweight were also significant risk factors. Renal impairment was found in 86.3% of patients and hyperuricemia in 92.1%. In controls, renal impairment and hyperuricemia were 7.4% and 32.6%, respectively. Patients with hypertension and nephrolithiasis were more at risk of having associated gout. There was a significant association between gout, hyperuricemia, hypercholesterolemia, hypertriglyceridemia, and higher levels of creatinine and urea. There was also a significantly lower level of urine uric acid in gout cases compared with controls. Gouty tophi were found in 91% of these cases with chronic gout. The use of diuretics for treating hypertension, continuing excessive alcohol consumption and purine-rich food habits in untreated gout, and hyperuricemia were associated with chronic and tophaceous gout. Urate-lowering drugs were not available in the community health centers. CONCLUSION: Severe tophaceous gout with deformities and disability is found in North Sulawesi. Prominent risk factors include alcohol, obesity, renal impairment, diet, hypertension, and family history. Improved education about gout seems needed. Urate-lowering drugs are not available in community health centers but are needed, especially in rural areas, as studied here.

Demography↗

PubMed2006

The management of gout at an academic healthcare center in Beijing: a physician survey.

OBJECTIVE: Gout is a less commonly diagnosed rheumatic disease in China compared with Western countries, but its prevalence appears to be climbing. It is not known how Chinese physicians diagnose and treat their patients with gout, so we evaluated physician management of gout at a major academic healthcare center in Beijing, and investigated factors associated with better decision-making. METHODS: A 13-question anonymous survey was distributed and collected at a medical grand rounds and then at a rheumatology grand rounds at a major teaching hospital in Beijing. Physician demographic data including educational background, work experience, job titles, specialty or subspecialties, gout patient volume seen in a year, and continuing medical education (CME) in gout were also collected in the survey. Data were analyzed by multivariate regression models to identify factors associated with appropriate answers. RESULTS: Twenty-seven residents and general internists, 26 rheumatologists and fellows, and 28 physicians and fellows of other medical subspecialties from the Department of Medicine including visiting physicians responded to the survey. Among respondents, 78% think it is important for a definitive diagnosis of gout, but few actually perform aspiration of the affected joint fluid. Eighty-four percent report that they often follow the serum urate level of their patients with diagnosed gout. When treating acute gout in otherwise healthy patients, most physicians (77%) prefer oral colchicine, and in patients with renal impairment, about half of them (48%) choose corticosteroids or corticotropin as their first treatment. For longterm urate-lowering therapy, most physicians (87%) described a variety of indications that we consider less appropriate. They (86%) tend to initiate it early (< 2 weeks) after acute flares. When urate-lowering therapy is used, 80% of physicians sustain it less than 5 years. Further, only 12% of physicians use antiinflammatory prophylaxis during the initiation of urate-lowering treatment, and only 5% maintain it for an appropriate period of time. Logistic regression analysis of physician demographic data, educational background, and work experience found no consistent independent factors associated with better decision-making, other than CME, that were associated with establishing the definite diagnosis correctly. Specifically, the number of gout patients seen by physicians was not related to better decision-making. CONCLUSION: The physicians' reported management of gout at this major academic healthcare center in Beijing was often inconsistent with current evidence. High quality CME is required to improve Chinese physician management of gout.

Academic Medical Centers↗

PubMed2006

A survey of current evaluation and treatment of gout.

OBJECTIVE: To record diagnostic and treatment approaches to gouty arthritis among US rheumatologists. METHODS: Questionnaires were faxed to 2500 US rheumatologists. RESULTS: Responses were received from 518 rheumatologists. Respondents reported performing crystal analysis 80% of the time for new suspected gout; 64% use combination therapy for acute gout; nonsteroidal antiinflammatory drugs alone are used in only 27%. Urate-lowering drugs (ULD) are given to most patients. ULD treatment is given occasionally to patients with asymptomatic hyperuricemia (4%) but most frequently to patients after 2 (59%) or 3 (34%) attacks. ULD are given with the aim of achieving a serum urate (SU) level of 6 mg/dl. CONCLUSION: Combination antiinflammatory agents are used frequently for acute gout despite absence of evidence in the literature to support this practice. There seems to be consensus regarding the necessity of lowering SU to < 6 mg/dl. Approaches vary widely, supporting the need for longterm prospective, placebo controlled studies to provide more evidence-based guidance.

Adrenal Cortex Hormones↗

PubMed2005

Febuxostat compared with allopurinol in patients with hyperuricemia and gout.

BACKGROUND: Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol for patients with hyperuricemia and gout. METHODS: We randomly assigned 762 patients with gout and with serum urate concentrations of at least 8.0 mg per deciliter (480 micromol per liter) to receive either febuxostat (80 mg or 120 mg) or allopurinol (300 mg) once daily for 52 weeks; 760 received the study drug. Prophylaxis against gout flares with naproxen or colchicine was provided during weeks 1 through 8. The primary end point was a serum urate concentration of less than 6.0 mg per deciliter (360 micromol per liter) at the last three monthly measurements. The secondary end points included reduction in the incidence of gout flares and in tophus area. RESULTS: The primary end point was reached in 53 percent of patients receiving 80 mg of febuxostat, 62 percent of those receiving 120 mg of febuxostat, and 21 percent of those receiving allopurinol (P<0.001 for the comparison of each febuxostat group with the allopurinol group). Although the incidence of gout flares diminished with continued treatment, the overall incidence during weeks 9 through 52 was similar in all groups: 64 percent of patients receiving 80 mg of febuxostat, 70 percent of those receiving 120 mg of febuxostat, and 64 percent of those receiving allopurinol (P=0.99 for 80 mg of febuxostat vs. allopurinol; P=0.23 for 120 mg of febuxostat vs. allopurinol). The median reduction in tophus area was 83 percent in patients receiving 80 mg of febuxostat and 66 percent in those receiving 120 mg of febuxostat, as compared with 50 percent in those receiving allopurinol (P=0.08 for 80 mg of febuxostat vs. allopurinol; P=0.16 for 120 mg of febuxostat vs. allopurinol). More patients in the high-dose febuxostat group than in the allopurinol group (P=0.003) or the low-dose febuxostat group discontinued the study. Four of the 507 patients in the two febuxostat groups (0.8 percent) and none of the 253 patients in the allopurinol group died; all deaths were from causes that the investigators (while still blinded to treatment) judged to be unrelated to the study drugs (P=0.31 for the comparison between the combined febuxostat groups and the allopurinol group). CONCLUSIONS: Febuxostat, at a daily dose of 80 mg or 120 mg, was more effective than allopurinol at the commonly used fixed daily dose of 300 mg in lowering serum urate. Similar reductions in gout flares and tophus area occurred in all treatment groups.

Allopurinol↗

PubMed2005

Elimination of rheumatoid synovium in situ using a Fas ligand 'gene scalpel'.

Surgical synovectomy to remove the inflammatory synovium can temporarily ameliorate rheumatoid inflammation and delay the progress of joint destruction. An efficient medically induced programmed cell death (apoptosis) in the rheumatoid synovium might play a role similar to synovectomy but without surgical tissue damage. Gene transfer of Fas ligand (FasL) has increased the frequency of apoptotic cells in mouse and rabbit arthritic synovium. In this study, we investigated whether repeated FasL gene transfer could remove human inflammatory synovial tissue in situ and function as a molecular synovectomy. Briefly, specimens of human synovium from joint replacement surgeries and synovectomies of rheumatoid arthritis (RA) patients were grafted subcutaneously into male C.B-17 severe combined immunodeficiency (SCID) mice. Injections of a recombinant FasL adenovirus (Ad-FasL) into the grafted synovial tissue at the dosage of 10(11) particles per mouse were performed every two weeks. Three days after the fifth virus injection, the mice were euthanized by CO2 inhalation and the human synovial tissues were collected, weighed and further examined. Compared to the control adenovirus-LacZ (Ad-LacZ) and phosphate buffered saline (PBS) injected RA synovium, the Ad-FasL injected RA synovium was dramatically reduced in size and weight (P < 0.005). The number of both synoviocytes & mononuclear cells was significantly reduced. Interestingly, an approximate 15-fold increased frequency of apoptotic cells was observed in RA synovium three days after Ad-FasL injection, compared with control tissues. In summary, our in vivo investigation of gene transfer to human synovium in SCID mice suggests that repeated intra-articular gene transfer of an apoptosis inducer, such as FasL, may function as a 'gene scalpel' for molecular synovectomy to arrest inflammatory synovium at an early stage of RA.

Adenoviridae↗

PubMed2005

Decreased pain and synovial inflammation after etanercept therapy in patients with reactive and undifferentiated arthritis: an open-label trial.

OBJECTIVE: Elevated levels of tumor necrosis factor alpha (TNFalpha) have been identified in the synovium of patients with reactive and undifferentiated arthritis, implicating TNFalpha in the pathogenesis of these disorders. This finding has provided a rationale for the use of TNFalpha antagonists in the treatment of reactive arthritis; however, the possibility that the triggering microorganism might persist in affected joints and become activated with use of these agents has been of concern. METHODS: The efficacy and safety of etanercept (25 mg subcutaneous twice weekly) in 16 patients with undifferentiated or reactive arthritis was assessed in a 6-month open-label trial. Synovial biopsies were performed before and after treatment with etanercept. Polymerase chain reaction (PCR) analysis was performed on the synovial biopsy samples to evaluate for the presence of nucleic acid material of bacterial organisms. Outcome measures including tender and swollen joint counts, pain assessment on a 10-point visual analog scale, and functional ability as measured by the Health Assessment Questionnaire were determined before and after etanercept therapy. RESULTS: Ten of 16 patients completed the trial. Six patients withdrew, but none had a worsening of arthritis or infection. Of the 10 completers, 9 could be classified as treatment responders, despite the evidence of bacterial organisms on PCR analysis prior to initiating etanercept in 3 patients; 2 patients became PCR negative on etanercept. Five of 6 patients with adequate synovial biopsy specimens showed improvement, but not normalization of histology. CONCLUSION: Etanercept was well-tolerated without clinical exacerbation of any suspected underlying infections and appeared to provide therapeutic benefit in our cohort of patients with reactive and undifferentiated arthritis.

Adolescent↗

PubMed2005

A locus on chromosome 9p predisposes to a specific disease manifestation, acute anterior uveitis, in ankylosing spondylitis, a genetically complex, multisystem, inflammatory disease.

OBJECTIVE: Uveitis or intraocular inflammation is a major cause of visual loss. Acute anterior uveitis (AAU) affects approximately 40% of patients with ankylosing spondylitis (AS) but also affects patients with no evidence of spondylarthritis. We sought to determine whether a unique genetic region could be implicated in a specific manifestation-AAU-of a multisystem, inflammatory, genetically complex disease, AS. METHODS: Individuals from families multiplex for AAU were genotyped at 400 markers representing the ABI PRISM linkage map MD-10, and at the HLA-B, DRB1, DQA1, DQB1, and DPB1 alleles. Among the family members with AAU, 76 affected sibpairs were analyzed (6 without concomitant AS, 12 discordant for AS, and 58 concordant for AS). Two-point and multipoint nonparametric linkage analyses were performed, and 1-parameter allele-sharing model logarithm of odds (LOD) scores were determined. RESULTS: As previously reported for AS, linkage at the major histocompatibility complex region (chromosome 6p21) was evident, exhibiting the highest multipoint LOD score (4.96 at marker HLA-B). Strong linkage was seen at a region on chromosome 9p21-9p24, with a LOD score of 3.72 at marker D9S157. When compared with a companion cohort of AS families, the linkage at this region was found in association with AAU but not with AS. A third region on chromosome 1q23-1q31 was observed to have suggestive linkage (LOD 2.05 at marker D1S238), which overlaps with a region associated with AS. CONCLUSION: This is the first study in which a genetic region for AAU has been identified by genome-wide scan. Even though AS was highly prevalent in this cohort of families, a locus at chromosome 9p21-9p24 was identified that uniquely associates with AAU. Identifying the genetic perturbation at this region may advance our understanding of the mechanisms involved in tissue-specific pathology of complex inflammatory diseases.

Acute Disease↗

PubMed2005

Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout.

OBJECTIVE: Gout affects approximately 1-2% of the American population. Current options for treating hyperuricemia in chronic gout are limited. The purpose of this study was to assess the safety and efficacy of febuxostat, a nonpurine selective inhibitor of xanthine oxidase, in establishing normal serum urate (sUA) concentrations in gout patients with hyperuricemia (>or=8.0 mg/dl). METHODS: We conducted a phase II, randomized, double-blind, placebo-controlled trial in 153 patients (ages 23-80 years). Subjects received febuxostat (40 mg, 80 mg, 120 mg) or placebo once daily for 28 days and colchicine prophylaxis for 14 days prior to and 14 days after randomization. The primary end point was the proportion of subjects with sUA levels <6.0 mg/dl on day 28. RESULTS: Greater proportions of febuxostat-treated patients than placebo-treated patients achieved an sUA level <6.0 mg/dl at each visit (P < 0.001 for each comparison). The targeted sUA level was attained on day 28 in 0% of those taking placebo and in 56% of those taking 40 mg, 76% taking 80 mg, and 94% taking 120 mg of febuxostat. The mean sUA reduction from baseline to day 28 was 2% in the placebo group and 37% in the 40-mg, 44% in the 80-mg, and 59% in the 120-mg febuxostat groups. Gout flares occurred with similar frequency in the placebo (37%) and 40-mg febuxostat (35%) groups and with increased frequency in the higher dosage febuxostat groups (43% taking 80 mg; 55% taking 120 mg). During colchicine prophylaxis, gout flares occurred less frequently (8-13%). Incidences of treatment-related adverse events were similar in the febuxostat and placebo groups. CONCLUSION: Treatment with febuxostat resulted in a significant reduction of sUA levels at all dosages. Febuxostat therapy was safe and well tolerated.

Adult↗