Gouty Arthritis: Schumacher HR

Schumacher HR. · University of Pennsylvania, Philadelphia, PA, USA. · Cleve Clin J Med. · Pubmed #18822468 links to  free full text

Abstract: An elevated serum urate level, together with local factors, can result in the deposition of urate crystals into the joints. Once crystals are deposited into a joint, they can be released into the joint space and initiate an inflammatory cascade causing acute gouty arthritis. These acute flares resolve, but the crystals remain in the joint. The way to ultimately correct the underlying metabolic problem of hyperuricemia and the crystal deposition is to lower the serum urate level and dissolve the crystal deposits. This will stop both the acute attacks and the progressive joint damage.

Taylor WJ, Schumacher HR, Singh JA, Grainger R, Dalbeth N. · Department of Medicine, Wellington School of Medicine and Health Sciences, University of Otago, PO Box 7343, Wellington 6242, New Zealand. · Rheumatology (Oxford). · Pubmed #17650521 No free full text.

Abstract: There has been renewed interest in the treatment of gout with recent reported intervention studies of new agents such as etoricoxib, febuxostat and pegylated-uricase. However, these studies have highlighted the relative paucity of validated outcome measures with which to judge efficacy. This review outlines the published information regarding which endpoints have been measured in randomized clinical trials, what should be measured, what tools or instruments are available for this and the technical properties of such instruments. It highlights recent work that validates measures of tophi, radiographic damage and patient-reported outcomes. The absence of a valid definition of gout-flare or how flare reduction defines response is problematic; this forms the basis for a current ACR-EULAR sponsored project.

Schumacher HR, Chen LX. · Division of Rheumatology, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA 19104, USA. · Rheum Dis Clin North Am. · Pubmed #16504833 No free full text.

Abstract: 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.

Schumacher HR, Edwards LN, Perez-Ruiz F, Becker M, Chen LX, Furst DE, Joseph-Ridge N, Schlesinger N, Horowitz Z, Saag K, Boice JA, Yamanaka H, Anonymous00376. · University of Florida, Gainesville, Florida, USA. · J Rheumatol. · Pubmed #16331785 No free full text.

Abstract: Gout provides some unique challenges in classification and measurement of outcomes. Our aim was to evaluate criteria for classification and to develop and validate optimal instruments to measure outcomes for acute and chronic gout. A planning committee and interested attendees met to propose classification criteria and domains for outcomes. Seven of the current American Rheumatism Association preliminary criteria for classification were proposed as the best current criteria for acute gouty arthritis, pending further studies. The presence of gout is best established by crystal identification, although this technique has limitations. Five domains for acute gout outcomes and 9 for chronic gout were identified along with proposed instruments for testing and validation. The unique problems of gout evaluation can and will be addressed.

Schumacher HR, Boice JA, Daikh DI, Mukhopadhyay S, Malmstrom K, Ng J, Tate GA, Molina J. · Division of Rheumatology, University of Pennsylvania School of Medicine and Department of Veterans Affairs Medical Center, Philadelphia, PA 19104, USA. · BMJ. · Pubmed #12077033 links to  free full text

Abstract: OBJECTIVE: To assess the safety and efficacy of etoricoxib, a selective cyclo-oxygenase-2 inhibitor, in comparison with indometacin in the treatment of acute gouty arthritis. DESIGN: Randomised, double blind, active comparator controlled trial. SETTING: 43 outpatient study centres in 11 countries. PARTICIPANTS: 142 men and eight women (75 patients per treatment group) aged 18 years or over presenting with clinically diagnosed acute gout within 48 hours of onset. Interventions: Etoricoxib 120 mg administered orally once daily versus indometacin 50 mg administered orally three times daily, both for 8 days. MAIN OUTCOME MEASURES: Patients' assessment of pain in the study joint over days 2 to 5 (primary end point); investigators' and patients' global assessments of response to treatment and tenderness of the study joint (key secondary end points). RESULTS: Etoricoxib showed efficacy comparable to indometacin. Patients' assessment of pain in the study joint (0-4 point Likert scale, "no pain" to "extreme pain") over days 2 to 5 showed a least squares mean change from baseline of -1.72 (95% confidence interval -1.90 to -1.55) for etoricoxib and -1.83 (-2.01 to -1.65) for indometacin. The difference between treatment groups met prespecified comparability criteria. All other efficacy end points, including those reflecting reduction in inflammation and analgesia, provided corroborative evidence of comparable efficacy. Significant pain relief was evident at the first measurement, 4 hours after the first dose of treatment. Prespecified safety analyses revealed that drug related adverse experiences occurred significantly less frequently with etoricoxib (22.7%) than with indometacin (46.7%) (P=0.003), although overall adverse experience rates were similar between the two treatment groups. CONCLUSION: Etoricoxib 120 mg once daily provides rapid and effective treatment for acute gouty arthritis comparable to indometacin 50 mg three times daily. Etoricoxib was generally safe and well tolerated in this study.

Schlesinger N, Detry MA, Holland BK, Baker DG, Beutler AM, Rull M, Hoffman BI, Schumacher HR. · Department of Medicine and New Jersey Medical School-University of Medicine and Dentistry of New Jersey, Newark, USA. · J Rheumatol. · Pubmed #11838852 No free full text.

Abstract: OBJECTIVE: To evaluate the effect of local application of ice on duration and severity of acute gouty arthritis. METHODS: Nineteen patients with acute gout were enrolled and randomized into 2 groups. Group A (n = 10) received topical ice therapy, oral prednisone 30 mg PO tapered to 0 over 6 days and colchicine 0.6 mg/day. Group B was the control group (n = 9), given the same regimen but without the ice therapy. The patients were followed for one week. RESULTS: The mean reduction in pain for those patients treated with ice therapy was 7.75 cm (on 10 cm visual analog scale) with standard deviation +/- 2.58 compared with 4.42 cm (+/- SD 2.96) for the control group. Using a Wilcoxon rank-sum test there was a significant difference (p = 0.021 ) in pain reduction between the ice therapy and control groups. Joint circumference and synovial fluid volume also tended to be more effectively reduced after one week of therapy in the ice group compared with controls, but these did not achieve statistical significance. CONCLUSION: The group treated with ice had a significantly greater reduction in pain compared with the control group. Although the clinical improvement was impressive, due to the small sample size we could not show statistically significant improvement in all the variables that tended to suggest that effect was more than simply analgesic. Cold applications may be a useful adjunct to treatment of acute gouty arthritis.

Baker JF, Schumacher HR, Krishnan E. · Department of Medicine, University of Pennsylvania, USA. · Angiology. · Pubmed #17875958 No free full text.

Abstract: Although several studies report an association between hyperuricemia and coronary artery disease, little is known about the effect of hyperuricemia and gout on the risk of peripheral arterial disease (PAD). Data on 283 incident clinical cases of PAD during a randomized controlled trial of multiple cardiovascular risk factor intervention are evaluated. The serum uric acid levels among these individuals are compared with those of individuals who did not develop PAD during the study period. Multivariate logistic regression analyses measure the risk of developing PAD associated with higher levels of serum uric acid after adjusting for the effect of traditional vascular risk factors. Age and smoking are independently associated with development of PAD, with odds ratios of 1.08 (95% confidence interval [CI], 1.06-1.09) and 3.83 (95% CI, 2.49-5.91) per year, respectively. Hyperuricemia (serum uric acid level, >7.0 mg/dL) is an independent risk factor, with an odds ratio of 1.23, but the confidence interval of the estimate is wide (95% CI, 0.98-1.54). In this multivariate model, a history of gout was associated with an odds ratio of 1.33 (95% CI, 1.07-1.66). Serum uric acid level is independently associated with a higher (but statistically nonsignificant) risk of PAD. A history of gouty arthritis is an independent and statistically significant predictor of incidence of PAD even after adjustment for the effect of underlying hyperuricemia.

Jung SM, Schumacher HR, Kim H, Kim M, Lee SH, Pessler F. · Division of Rheumatology, University of Pennsylvania, 3600 Spruce St, Philadelphia, PA 19104, USA. · Arthritis Res Ther. · Pubmed #17612394 links to  free full text

Abstract: Dried roots of the plants Acanthopanax senticosus, Angelica sinensis and Scutellaria baicalensis are used in traditional oriental medicine and reportedly possess anti-inflammatory properties. Using the murine air pouch model of inflammation, we investigated the efficacy and mode of action of an extract from these three plants in crystal-induced inflammation. Air pouches were raised on the backs of 8-week-old BALB/c mice. Mice were fed 100 mg/kg body weight of root extracts (A. senticosus:A. sinensis:S. baicalensis mixed in a ratio of 5:4:1 by weight) or vehicle only on days 3-6. Inflammation was elicited on day 6 by injecting 2 mg of monosodium urate (MSU) crystals into the pouch. Neutrophil density and IL-6 and TNF-alpha mRNA levels were determined in the pouch membrane, and the leukocyte count and IL-6, prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2) levels were determined in the pouch exudate. Treatment with the root extracts led to a reduction in all inflammatory parameters: the leukocyte count in the pouch exudate decreased by 82%; the neutrophil density in the pouch membrane decreased by 68%; IL-6 and TNF-alpha mRNA levels in the pouch membrane decreased by 100%; the IL-6 concentration in the pouch fluid decreased by 50%; and the PGE2 concentration in the pouch fluid decreased by 69%. Remarkably, the concentration of the potentially anti-inflammatory PGD2 rose 5.2-fold in the pouch exudate (p < 0.005), which led to a normalization of the PGD2:PGE2 ratio. A 3.7-fold rise in hematopoietic PGD synthase (h-PGDS) mRNA paralleled this rise in PGD2 (p = 0.01). Thus, the root extracts diminished MSU crystal-induced inflammation by reducing neutrophil recruitment and expression of pro-inflammatory factors and increasing the level of the potentially anti-inflammatory PGD2. These results support a need for further studies of the efficacy of these extracts in the treatment of inflammatory arthropathies and suggest elevation of PGD2 levels as a novel mechanism for an anti-inflammatory agent.

Schumacher HR, Taylor W, Joseph-Ridge N, Perez-Ruiz F, Chen LX, Schlesinger N, Khanna D, Furst DE, Becker MA, Dalbeth N, Edwards NL. · Division of Rheumatology, University of Pennsylvania School of Medicine, and Veterans Affairs Medical Center, Philadelphia, Pennsylvania 19104, USA. · J Rheumatol. · Pubmed #17552064 No free full text.

Abstract: Methods to measure outcomes in gout still require consensus and validation. This Special Interest Group was assembled to identify domains of interest and is now evaluating a series of outcomes for features of acute gouty arthritis and chronic gout. To accomplish this, working groups have been formed and domains identified. Delphi methodology has been used to address gouty flares as an outcome of greatest interest. Studies addressing other outcome measures were reported at the OMERACT 8 meeting and validation has begun on some outcomes. There has been progress on developing a definition of a flare, and validating reproducibility of some chronic gout outcome measures in some domains, such as tophus size and patient perceptions. Use of these outcomes as well as a health-related quality of life measure are being studied in clinical trials. Pain on a Likert scale appears to be a valid outcome in acute gout. Final validation of these outcomes has not yet been achieved. In summary, the unique problems of evaluating outcomes in gout are finally being addressed. While no measures are available for use yet, an agenda has been developed.

Schumacher HR. · From the University of Pennsylvania School of Medicine, Veterans Affairs Medical Center, Philadelphia, Pennsylvania. · J Clin Rheumatol. · Pubmed #17043496 No free full text.

Abstract: Rheumatic diseases are among the most frequent causes of pain and disability. Effective management of rheumatic diseases including osteoarthritis (OA), ankylosing spondylitis (AS), and gouty arthritis requires an understanding of the underlying disease mechanisms.Symptoms of OA result from both mechanical factors and elements of inflammation. Current management strategies target both of these factors and generally consist of nonpharmacologic and pharmacologic interventions, including use of nonspecific nonsteroidal antiinflammatory drugs (NSAIDs) and cyclooxygenase-2-specific inhibitors (coxibs), which have analgesic and antiinflammatory properties. Other approaches include intraarticular hyaluronate and the use of alternative therapies under investigation such as acupuncture or glucosamine.Disease mechanisms in AS involve enthesitis, an inflammation at the site of insertion of ligaments, tendons, or joint capsules to bone. Posture and exercise are important nonpharmacologic strategies that may be made easier with the use of NSAIDs or coxibs. Recently developed therapies, including tumor necrosis factor inhibitors, target the underlying disease mechanisms and have demonstrated dramatic symptomatic effects. Disease-modifying effects still need to be established.In gout, hyperuricemia leads to crystal-induced inflammation in some patients. Etoricoxib, one of the newer coxibs, has shown promise in treating acute gout, with efficacy similar to indomethacin, the current standard NSAID often used in these patients. Oral or intraarticular steroids can also be considered. For chronic care uricosurics can be beneficial if renal function is normal and excretion is not excessive, but allopurinol is used most often. Nonpharmacologic modalities, such as rest and cold applications, are useful for acute episodes, and lifestyle modification in the form of diet can also play a role in chronic disease management.

Schlesinger N, Moore DF, Sun JD, Schumacher HR. · Department of Medicine, The School of Public Health, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey 08903-0019, USA. · J Rheumatol. · Pubmed #17014020 No free full text.

Abstract: 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.

Krishnan E, Baker JF, Furst DE, Schumacher HR. · University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA. · Arthritis Rheum. · Pubmed #16871533 links to  free full text

Abstract: 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.

Du Y, Pullman-Mooar S, Schumacher HR. · Division of Rheumatology, Department of Medicine, University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104, USA. · J Rheumatol. · Pubmed #16206359 No free full text.

Abstract: Synovial sarcoma is a slow-growing soft tissue sarcoma that mainly affects young adults. Patients commonly present with a slowly enlarging mass in the paraarticular regions of extremities. We describe a case of synovial sarcoma with an unusually acute presentation near the first metatarsophalangeal joint that resembled acute gouty arthritis.

Nalbant S, Chen LX, Sieck MS, Clayburne G, Schumacher HR. · University of Pennsylvania School of Medicine and the Arthritis Center, VA Medical Center, Philadelphia, Pennsylvania 19104-4283, USA. · J Rheumatol. · Pubmed #16142876 No free full text.

Abstract: OBJECTIVE: To examine the ability of rofecoxib prophylaxis to blunt the effect of monosodium urate (MSU) crystal inflammation induced in the rat subcutaneous air pouch. METHODS: Eight rats were used in each of 4 groups. On day one, air was injected subcutaneously to create the pouches and gavage feedings were started with placebo or 2 different doses of rofecoxib. Six days later MSU crystals or saline were injected into the pouches. Twenty-four hours later, rats were examined, sacrificed, and pouch fluid studied. RESULTS: Rofecoxib 15 or 30 mg/kg given for 6 days before MSU crystal injection into rat air pouches significantly suppressed the inflammation following injection of 10 mg crystals (p = 0.001) and tended to suppress the milder inflammation induced by 5 mg MSU. Greater effects on phagocytosis were seen with 30 mg/kg rofecoxib. Tumor necrosis factor-alpha levels in pouch fluid measured by ELISA were not suppressed by the rofecoxib. CONCLUSION: Prophylactic use of this cyclooxygenase 2 (COX-2) selective inhibitor in this pilot study suppressed acute MSU crystal induced inflammation. Effects on cytokines need further investigation. COX-2 inhibitors deserve consideration for prophylactic use in interim gout.

Rull M, Clayburne G, Sieck M, Schumacher HR. · Veterans Affairs Medical Center and University of Pennsylvania, Philadelphia, PA 19104, USA. · Rheumatology (Oxford). · Pubmed #12777646 links to  free full text

Abstract: OBJECTIVE: To examine the effects of three commonly used intra-articular depot corticosteroid preparations tested in a rat air pouch model and their effect against monosodium urate (MSU) crystal-induced inflammation. Rheumatologists use intra-articular corticosteroid preparations to relieve pain and inflammation of acute monoarthritis without really knowing their effects on the synovial fluid and membrane or the differences between distinct preparations. This work compares the effect of three commonly used corticosteroid preparations in vivo, showing that they behave differently. METHODS: A subcutaneous air pouch was formed in male Sprague-Dawley rats. A first group of 6-day-old air pouches were injected with 10 ml of 6 mg/ml normal saline solution, 6 mg/ml betamethasone containing both depot betamethasone acetate and soluble betamethasone phosphate (Celestone) in 9 ml of normal saline solution, 20 mg/ml of prednisolone tebutate (Hydeltra) in 9 ml of normal saline solution or 20 mg/ml of triamcinolone hexacetonide (Aristospan) in 9 ml of normal saline solution. A second group (group 2) of air pouches were injected with 15 mg of synthetic MSU crystals and 24 h later they were reinjected with 1 ml of the same three corticosteroid suspensions. For each condition four rats were killed at 6, 24, 48 h and 7 days. Pouch fluid and tissue were analysed. RESULTS: In the first 6 h after normal saline solution or corticosteroid injection into the air pouch there were mildly increased leucocyte counts in the air pouch fluid. Betamethasone-injected pouches showed no cells in the fluid after 6 h and no crystals after 24 h, triamcinolone-injected pouches still showed rare cells at 7 days. Both triamcinolone and prednisolone crystals persisted in higher numbers and lasted longer in the fluid than did betamethasone (P<0.05). In group 2 MSU crystal phagocytosis in the fluid was decreased in the betamethasone- (P<0.01), prednisolone- (P<0.003) and triamcinolone- (P<0.006) injected pouches when compared with the MSU crystal-injected pouches alone. Pouches injected with MSU crystals alone showed the most intense tissue inflammation at all times. After MSU, betamethasone-injected pouches had a rapid but mild decrease in the number of lining cells and inflammation. In contrast, triamcinolone- and prednisolone-injected pouches showed a very thin tissue with few or no vessels and almost no inflammation at 7 days. The pouches injected with MSU crystals and any of the corticoid preparations had three times more tophus-like structures and persistent crystals identified than the ones injected with MSU crystals alone. CONCLUSION: Each of the corticosteroid preparations by themselves produced very mild transient inflammation. The betamethasone preparation with a soluble steroid component had a quicker but milder anti-inflammatory effect on MSU crystal-induced inflammation. In contrast to the doses used, prednisolone tebutate and triamcinolone hexacetonide preparations dramatically suppressed urate crystal-induced inflammation at 7 days, but both produced atrophy and necrosis of the membrane, yielding a very thin membrane with almost no vessels. When used for MSU crystal-induced inflammation these corticosteroid preparations suppressed some aspects of inflammation but may actually promote the persistence of MSU crystals and the formation of tophi.