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EDITORIAL STAFF

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EDITORIAL BOARDStanley M. Aronson, MD, MPHJohn J. Cronan, MDJames P. Crowley, MDEdward R. Feller, MDJohn P. Fulton, PhDPeter A. Hollmann, MDAnthony E. Mega, MDMarguerite A. Neill, MDFrank J. Schaberg, Jr., MDLawrence W. Vernaglia, JD, MPHNewell E. Warde, PhD

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DISTRICT & COUNTY PRESIDENTS

Geoffrey R. Hamilton, MDBristol County Medical Society

Robert G. Dinwoodie, DOKent County Medical Society

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Patrick J. Sweeney, MD, MPH, PhDProvidence Medical Association

Nitin S. Damle, MDWashington County Medical Society

RHODE ISLANDPUBLICATION OF THE RHODE ISLAND MEDICAL SOCIETY

Medicine � Health VOLUME 92 NO. 11 November 2009

COMMENTARIES

350 Medication Trials: In an Imperfect World: Gout and Parkinson’s DiseaseJoseph H. Friedman, MD

351 An Ailment for the Royally NourishedStanley M. Aronson, MD

CONTRIBUTIONS

SPECIAL ISSUE: Hyperuricemia and GoutGuest Editor: Bernard Zimmermann, MD

352 Introduction: Hyperuricemia and GoutBernard Zimmermann, MD

353 Medical Implications of HyperuricemiaLarissa Sachs, MD, Kerri L. Batra, MD, and Bernard Zimmermann, MD

356 Diagnosis and Management of Acute GoutNazli Conway, MD, and Stuart Schwartz, MD

359 Approach To the Treatment of HyperuricemiaSamuel H. Poon, MD, Harald A. Hall, MD, and Bernard Zimmermann, MD

363 Gout In WomenJill McClory, MD, and Nuha Said, MD

369 Treatment Failure GoutSaman Ali, MD, and Edward V. Lally, MD

COLUMNS

372 IMAGES IN MEDICINE: Intranasal Mucosal Malignant Melanoma Robert Bagdasaryan, MD, and Mark Andreozzi, DO

373 ADVANCES IN PHARMACOLOGY: Use of Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers and Lipid-lowering Therapies Among RhodeIsland With Diabetes Enrolled In Medicare Part D Plans in 2006 and 2007Stephen Kogut, PhD, MBA, RPh, Aisling Caffrey, PhD, and Lynn Pezzullo, RPh

377 GERIATRICS FOR THE PRACTICING PHYSICIAN: Asymptomatic Versus SymptomaticUrinary Tract Infections In Long-Term-Care-Facility ResidentsPorpon Rotjanapan, MD, and David Dosa, MD, MPH

379 PHYSICIAN’S LEXICON: The Wanderings of the Vagus NerveStanley M. Aronson, MD

380 HEALTH BY NUMBERS: Diabetes Prevention and Control: Progress Towards HealthyPeople 2010 GoalsAnnie Gjelsvik, PhD, Dona Goldman, RN, MPH, and Marilyn Moy, RN, MSW

382 POINT OF VIEW: Prevention of Relapsing Mediocrity: How To Maintain PerformanceImprovement In HospitalsJohn S. Coldiron, MD, MPH

385 November Heritage

Cover: Monosodium urate crystals aspiratedfrom the subcutaneous tissue of a patient withcutaneous manifestations of gout and viewedwith a polarized light microscope, by BernardZimmermann, MD, and Peter Libbey, MD

350MEDICINE & HEALTH/RHODE ISLAND

drug that may induce gout and all its com-plications to be prescribed for people withPD? Will people with PD be willing to takea drug that may cause gout? At the initialmeeting of site investigators, I asked thegroup who had made the observationsabout urate levels and PD, and who haddesigned this trial, if any of them had everhad a kidney stone. No one in the roomhad besides myself. Having had a few Ican vouch for each one being memorablypainful. Would I take a medication thatmight precipitate such a thing? Maybe, ifit really slowed PD down a lot. What aboutcardiovascular disease? I’ve got that too.How keen am I to further increase my risk?

Most patients don’t have a history ofkidney stones, and if they did, they wouldnot be urate stones, and the connectionbetween cardiovascular disease and uratelevels is no more solid than that betweenurate and PD.

So the final decision rests, as itshould, on clinical equipoise. Should we,or shouldn’t we? We simply have insuffi-cient data to make a decision. When thishappens, and the stakes are high, it is timefor a study to answer the question. Un-fortunately for those in the early studies,safety comes first. The later subjects havethe benefit of helping determine if thedrug actually works.

If there were medals for altruism,those who volunteer for safety studiesshould get the gold ones. They truly reapno substantive gain.

– JOSEPH H. FRIEDMAN, MD

Disclosure of FinancialInterests

Joseph Friedman, MD, Consultant: AcadiaPharmacy, Ovation, Transoral; Grant ResearchSupport: Cephalon, Teva, Novartis, Boehringer-Ingelheim, Sepracor, Glaxo; Speakers’ Bureau:Astra Zeneca, Teva, Novartis, Boehringer-Ingelheim, GlaxoAcadia, Sepracor, Glaxo SmithKline, Neurogen, and EMD Serono.

Medication Trials In an Imperfect World:Gout and Parkinson’s Disease

�

Commentaries

This issue of Medicine & Health, RhodeIsland is the perfect venue to discuss anew, potentially useful treatment for slow-ing progression of Parkinson’s disease(PD), because it is based on increasinguric acid levels, hence putting people atrisk for gout and possibly cardiovasculardisease. It forces us to focus on severalimportant clinical issues, includingiatrogenesis, and how does one, bothpractically and ethically, recruit for astudy that may cause significant compli-cations in return for which the subject isrewarded with a clap on the back and anenhanced feeling of altruism but noth-ing else?

The basic facts are straightforward.A few large studies of PD, performed fora variety of different reasons, have in-cluded, for safety purposes, uric acid lev-els. Analyses have shown, without con-flict, that PD patients with higher uricacid levels progress more slowly than PDpatients with lower levels. Studies com-paring people with PD to those withoutPD have consistently shown that PD pa-tients have lower uric acid levels. Uricacid is one of the body’s strongest anti-oxidants, and PD has been thought toresult from excess oxidation within neu-rons. Thus elevated uric acid levels maybe beneficial for people with PD. Andalthough diet plays a role in uric acid lev-els, and diet may be altered in PD, ex-perts believe that the differences in uricacid levels found in PD vs. controls can-not be explained by diet alone. Theseobservations led to the idea of increasinguric acid serum levels to determine if thiswill slow PD progression. It must alwaysbe kept in mind that when one sees asso-ciations between potential cause and ef-fect, that the connection, while robust,may not be what it seems. The connec-tion between alcohol and lung cancer isstrong, but is mediated via cigarettes, forexample. Decreasing alcohol alone willnot decrease lung cancer.

The first step required to study a newdrug to determine if it will slow diseaseprogression is to perform a safety study, toprove to the Food and Drug Administra-tion (FDA), which regulates testing of ex-perimental medications, that this drug issafe to test in PD. Of course, this requirestesting the drug in PD patients, but thestructure of the study is quite different fora safety study than it is for an efficacy trial,for the goal of the preliminary study is todemonstrate that the drug is safe, not thatit is therapeutically effective. The rationalefor this is that safety studies require far fewersubjects, and generally are much shorterin duration so that fewer people are putat risk should the drug ultimately beshown to be unsafe.

It is not easy to recruit for a studywhen the goal is safety, not efficacy. Mostpatients do not want a placebo; they wantto feel better. Many of our efficacy stud-ies promise the subjects that they will beable to take the experimental medicineonce the placebo phase has ended on anopen label basis. This is considered “fair”although it is an oddity of our testing sys-tem since the efficacy study is performedexactly to find out if the drug is, in fact,effective; so how, without knowing theresults of the study, can we justify givingit to patients? In a safety study, we don’teven have any data, other than experi-mental, to indicate that the drug will beeffective. In the case of a drug intendedto slow disease progression, one doesn’teven feel better while taking the drug.Furthermore, in this particular study, weare even requiring a lumbar puncture todetermine how well the study drug is al-tering urate levels within the cerebrospi-nal fluid, and, presumably, the brain.

Would I enroll in this study if giventhe chance? I like to think so. I’m not sureI should be running a trial that I wouldn’tparticipate in as a subject. My own reser-vations have to do with the long-termsafety of the drug. Will the FDA allow a


An Ailment For the Royally Nourished�

increased acidity of the circulating blood. Victims of gout of-ten developed uric acid kidney stones, yet another source ofexquisite pain.

Many victims of gout in the wine-consuming populationof the 18th Century concurrently suffered from lead poisoning(saturnine gout) since many wines, then, were intentionallyadulterated with sweetening agents such as lead acetate. Theincidence of gout, as an inheritable disorder, is quite high inthe indigenous populations of the Pacific region, particularlythe Maori of New Zealand.

Gout can be reproduced in experimental animals; but it isalso encountered as a hereditary trait in some species of birdsand reptiles. And paleontologists are quick to point out thatsome fossil remains of Tyrannosaurus rex, the great lizard of theage of dinosaurs, contained the bony changes seen in gout.

Gout does not hide. Patients with gout tell the world oftheir affliction in their correspondence, diaries, autobiographiesand even complaints to strangers on the streets. Amongst thefounding fathers of this nation, the following had declaredthemselves to be the targets of gout: Benjamin Franklin, Tho-mas Jefferson, Alexander Hamilton, John Hancock, GeorgeMason and John Jay. Historians have speculated that it mayhave required the anguish of gout to stir their strivings for in-dependence. But when the biographies of the English leader-ship, on the other side of the Atlantic, are then examined, itappears that gout showed no political favoritism. Gout sur-faced in William Pitt, Benjamin Disraeli, King George IV andQueen Anne. Other historic sufferers included John Calvin,John Milton, Isaac Newton, Samuel Johnson and even thatchampion of the proletariat, Karl Marx.

Sydenham concluded: “Gout, unlike any other disease,kills more rich men than poor, more wise men than simple.Great kings, emperors, generals, admirals have all died of gout.”He might have added: “And countless commoners.”

– STANLEY M. ARONSON, MD

Disclosure of Financial InterestsStanley M. Aronson, MD, has no financial interests to

disclose.

CORRESPONDENCEe-mail: [email protected]

A 59 yea- old British physician, in 1683, describes an attack ofarticular pain in his patient: “The victim goes to bed andsleeps in good health. About two o’clock in the morning heis awakened by a severe pain in the great toe, more rarely inthe heel, ankle or instep. The pain is like that of a dislocationand yet the parts feel as though cold water were poured overthem. Then follows chills and shiver and a little fever. Thepain, at first moderate, becomes more intense. After a timethis comes to full height accommodating itself to the bonesand ligaments of the tarsus and metatarsus. Now it is a violentstretching and tearing of the ligaments – now it is a gnawingpain and now a pressure and tightening. So exquisite andlively meanwhile is the feeling of the part affected, that itcannot bear the weight of the bedclothes nor the jar of aperson walking in the room.”

Truly an authentic description of an age-old disorder calledgout. The physician was Thomas Sydenham (1624 – 1689)and the patient was himself. When physicians describe diseasesin their patients, the descriptions tend to be starkly objectiveand coldly impersonal with little of the patient’s inner reac-tions to the ailment. But when the physician is both victim andportrayer of the disease, the narration inevitably takes on di-mension, greater accuracy and more benevolence.

Gout was well known to the ancient Egyptians; and de-spite the passage of millennia, some of their mummified re-mains still contain toes with the characteristic anatomic changesof gout. The Classical-era Greeks were also familiar with thisunique form of arthritis, calling the disorder podagra.

This much was known about the predilection, pathologyand prognosis of gout by the late 17th Century, the dawn ofscientific inquiry: It was a disease selectively but not exclusivelyof affluent society with a typical onset in late adult life. Men, tothe exclusion of eunuchs, were its prime victims. Women be-came vulnerable to gout, but only beyond the menopause. Goutseemed to choose its victims from amongst those who ate in-temperately, especially a diet rich in dark meats; those who drankmuch, especially red wines such as port; and those who wereobese and exercised little beyond their eccentricities. The Brit-ish widely believed that gout was an inevitable retribution forthe excesses of food, wine and debauchery.

There is nothing timid or subtle about gout. It announcesitself stridently; and if the walls are thin enough, even theneighbors will know when an attack of gout resumes. A pow-dery substance infiltrates the tissues near and within the af-fected joints. Occasionally this infiltrate accumulates to form apainful nodule, a calcareous concretion called a tophus. TheDutch scientist, Anton Leeuwenhoek (1632 - 1723) used hisnewly devised microscope to examine the gouty tophi and ob-served its white sediment to be composed of microscopic crys-tals. About two centuries latter the British physician, ArchibaldGarrod (1857 – 1936) demonstrated that gout represented adisorder of purine metabolism, sometimes hereditary, and wascharacterized by an excessive concentration of monosodiumurates in the bloodstream (hyperuricemia) associated with an


Introduction: Hyperuricemia and GoutBernard Zimmermann, MD

�The pathophysiology of gout is well

understood, and effective treatments foracute gout and hyperuricemia leading togout are widely available. Nonetheless,many patients suffer from severe topha-ceous gouty arthritis, adverse effects ofmedications for gout, and inadequatetreatment of hyperuricemia. The inci-dence of gout is rising in both men andwomen. The diagnosis and treatment ofgout are challenging in patients with ar-thritis, renal and hepatic diseases. Acutegout is usually not difficult to treat, butevidence to guide therapeutic decisionsfor gout patients with complex medicalproblems is woefully lacking. Fortunately,new medications for treatment of goutand hyperuricemia are becoming avail-able, and exciting new research is increas-ing our understanding of the role of hy-peruricemia in the pathogenesis of hy-pertension and cardiovascular disease.

In this issue of Medicine and Health/Rhode Island we discuss the epidemiol-ogy of gout in women, and review newdata regarding the importance of hype-ruricemia as a marker and perhaps a caus-ative agent involved in the pathogenesisof the metabolic syndrome. We reviewthe risks and benefits of various treatmentoptions for acute gout and discuss thepotential utility of febuxostat, the firstnew drug approved for treatment of hy-peruricemia in 40 years. In addition, wedescribe ongoing studies of rasburicaseand pegloticase which may offer dramaticimprovement for patients with severetophaceous gout.

We hope to share the excitement inthe rheumatology community that hasbeen generated by the potential of newtherapies and advances in our understand-ing of gout and hyperuricemia, and toimprove the care of all patients with gout.

Bernard Zimmermann, MD, is Di-rector of the Division of Rheumatology atRoger Williams Medical Center, and Asso-ciate Professor of Medicine at the BostonUniversity School of Medicine.

Disclosure of Financial InterestsThe author has no financial inter-

ests to disclose.

CORRESPONDENCEBernard Zimmermann, MDRoger Williams Medical CenterDivision of Rheumatology825 Chalkstone AveProvidence, RI 02908e-mail: [email protected]


Medical Implications of HyperuricemiaLarissa Sachs, MD, Kerri L. Batra, MD, and Bernard Zimmermann, MD

�WHAT IS HYPERURICEMIA?

Uric acid is an oxidation product ofpurine metabolism, which in primates (in-cluding humans) is largely eliminated bythe kidney and the gut. Most non-primatemammals express uricase, an enzyme thatconverts serum uric acid into allantoin,which is easily excreted by the kidneys. Non-primate mammals thus usually have lowserum uric acid (SUA) levels (below 2 mg/dl), while primates have the potential todevelop hyperuricemia, because they lackuricase. In humans, renal under excretionof uric acid is the cause of 90% of hyperu-ricemia, while 10% is due to overproduc-tion of uric acid. Uric acid is more toxic totissues than other purine metabolites suchas xanthine, hypoxanthine and allantoin.

Hyperuricemia is defined as a serumurate level greater than 6.0 mg/dl inwomen, and 7.0 mg/dl in men. Abovethis concentration, urate is supersaturatedin body fluids, and is prone to crystalliza-tion and subsequent tissue deposition. Therising prevalence of hyperuricemia overthe last several decades can be attributedto several factors. Westernization of dietsand widespread use of high-fructose syrupmay play a role in increasing SUA levels.1

Other factors that might be involved in-clude increased lifespan and more com-mon use of certain medications, includ-ing diuretics and cyclosporine. The preva-lence of asymptomatic hyperuricemia inUS is estimated to be 5-8 % among adultCaucasian men and it is even more com-mon in some ethnic groups, such asPhilippinos and Polynesians.

While a few studies have noted a po-tential beneficial antioxidative effect of uricacid and even suggested a neuroprotectiverole, most studies link hyperuricemia withsuch co-morbidities as hypertension, renaldisease, metabolic syndrome and cardiovas-cular disease (CVD).

HYPERURICEMIA AND GOUTThe most well known medical mani-

festation of hyperuricemia is gout. Gout iscaused by deposition of uric acid crystals inand around the joints and has 4 stages: as-ymptomatic hyperuricemia, acute gout,intercritical gout, and chronic tophaceous

gout. The duration of each stage varies sig-nificantly among individuals. (Table 1)

Fewer than one-third of individualswith asymptomatic hyperuricemia will de-velop gouty arthritis. The risk of develop-ing gout increases with age and the de-gree of hyperuricemia. In the NormativeAging Study, the 5-year cumulative inci-dence of gout among those with a uric acidlevel between 7.0 and 8.0 mg/dl was 3%,compared to 22% in those with a uric acidlevel of 9.0 mg/dl.2 (Figure 1)

Acute gouty arthritis occurs when uricacid crystals interact with synovial phago-cytes, which in turn activate neutrophilsand initiate an inflammatory cascade. Uratecrystals that serve as a trigger for an acuteattack may derive from preformed synovialdeposits or precipitate in the joint de novo.Clinically, acute gout presents with rapidonset of a painful, erythematous and swol-

len joint that may be accompanied by fe-ver. Inflammation of the first metatarsopha-langeal joint (also known as podagra), is themost characteristic presentation but otherjoints are often involved.

Intercritical gout is the name givento the asymptomatic interval betweenacute attacks. In early gout, intercriticalperiods may last for years, but with pro-gression of the disease the time betweenattacks tends to lessen.

Chronic tophaceous gout is charac-terized by the development of tophi in andaround the joints, which can cause destruc-tive arthritis. (Figure 2) Tophi are com-monly found in the soft tissues, includingtendons, pinnae and subcutaneous fat.Tophi have been reported in such unusuallocations as heart valves, spinal cord,sclerae, breast and even Cushing’s striae.

Table 1. Stages of Hyperuricemia and Gout.

Stage Duration Clinical FeaturesAsymptomatic >10-15 years AsymptomatichyperuricemiaAcute gout 1-2 weeks Sudden onset of acute

mono- or oligoarthritis(e.g., podagra)

Intercritical gout From weeks Asymptomatic intervals betweento years acute attacks

Chronic tophaceous 10 or more years Development of tophi in andgout after the first episode around the joints and soft

of acute gout tissues

Figure 1. Cumulative Incidence of Gouty Arthritis by Prior Serum Urate Levels.The numbers refer to the number of examination intervals for each group. Reprinted fromAmerican Journal of Medicine, 1987 March 82(3); Campion EW, Glynn RJ, DeLabry LO.

Asymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study.Pages: 421-6 Copyright 2009, with permission from Elsevier.


HYPERURICEMIA AND HYPERTENSIONNumerous studies have demonstrated

an association between hyperuricemia andhypertension, and recent evidence evensuggests there may be a causal relation-ship. This evidence was first noted in ani-mal studies: in Sprague-Dawley rats, hy-peruricemia can be induced by feedingwith an uricase inhibitor. Mildly increasedSUA is associated with development ofhypertension in the rats within 3 weeks.The development of hypertension in therats can be prevented by co-treatmentwith a uric acid lowering therapy such asallopurinol or a uricosuric agent.3

Upon pathologic evaluation, thehyperuricemic rats have lower levels ofnitric oxide in the renal endothelium, sug-gesting increased renal vasoconstrictionand activation of the renin-angiotensinsystem, leading to ischemic tissue damage.Uric acid crystal deposition is not seen inthe kidneys of the hypertensive rats.

In humans, a prospective study in-volving more then two thousand patientsdemonstrated that an increased SUAlevel predicts development of future hy-pertension independent of age, alcoholuse or renal function.4

Further evidence of the associationbetween hyperuricemia and hypertensioncomes from pediatric literature: 90% ofadolescents with newly diagnosed hyper-tension are found to have hyperuricemia.5

In a double-blind placebo-controlledstudy involving 30 adolescents with hy-

peruricemia and hypertension, allopurinoltherapy normalized blood pressure in 86%of patients compared to 3% of patients ina placebo group.6 This suggests not onlyan early role of uric acid in the pathogen-esis of primary hypertension, but also thepossibility that early treatment of hyperu-ricemia may prevent the development ofhypertension. Clearly, more clinical trialsare needed to explore these issues.

HYPERURICEMIA AND RENAL DISEASEBefore uric acid lowering therapy was

available, hyperuricemia was thought to bea cause of chronic kidney disease becauseof their frequent coexistence. However, in

the late 1970s the results of several epide-miologic studies made a direct causal rela-tionship between elevated uric acid andrenal impairment questionable.7 It is clearthat chronic kidney disease is associatedwith hyperuricemia. However, it is not clearwhether renal impairment is due to a di-rect nephrotoxic effect of uric acid, or dueto the conditions that are caused by hype-ruricemia (e.g., hypertension).

Most of the recent evidence for a di-rect pathogenic effect of hyperuricemia onthe kidneys comes from animal studies, asnoted above. In humans, epidemiologicstudies demonstrate that hyperuricemia isassociated with decline in kidney function.8

It has also been shown that allopurinolmight slow this decline. In one prospectivestudy patients with asymptomatic hyperu-ricemia treated with 300 mg of allopurinolshowed significant improvement in glom-erular filtration rate (GFR) after 3 monthsof the therapy.9 Siu et al. reported thatamong the patients with chronic kidneydisease treated with allopurinol, 16% pro-gressed to end stage renal disease, comparedto 46% in the control group.10

URIC ACID AND METABOLICSYNDROME

Metabolic syndrome is defined as agroup of modifiable risk factors that areassociated with an increased risk for CVD,type 2 diabetes mellitus, and mortalityfrom CVD. The factors that define meta-bolic syndrome include systolic hyperten-sion, hypertriglyceridemia, central obesity,and impaired glucose tolerance. Hyperu-ricemia has been shown to be significantlymore common in patients with metabolicsyndrome than the normal population.11

In a recent population-based study allmetabolic syndrome components corre-lated with elevated SUA level, with waistcircumference being the strongest.11

It has been generally thought that hy-peruricemia was a result ofhyperinsulinemia in those with metabolicsyndrome, as insulin decreases the renal ex-cretion of uric acid. However, animal stud-ies showed that the opposite scenario mightbe the case. Nakagawa et al. showed in fruc-tose-fed rats with hyperuricemia, that treat-ment with allopurinol or benzbromarone(a uricosuric agent) prevented developmentof features of metabolic syndrome includ-ing hyperinsulinemia, systolic hypertension,hypertriglyceridemia, and weight gain.1

Epidemiologicevidence shows that

there may be aconnection betweenthe rise of the use of

high-fructose cornsyrup, the increasing

prevalence ofmetabolic syndrome,

and the rapidincrease inworldwide

hyperuricemia

Figure 2. Severe tophaceous gout in the hands. Photograph by Harald A. Hall, MD


It has been suggested that uric acidmay cause metabolic syndrome by pro-moting a state of insulin resistance. It iswell known that insulin stimulates glu-cose intake in skeletal muscle via increasedblood flow to these tissues through a ni-tric oxide-dependent pathway. Uric aciddecreases levels of nitric oxide and arte-rial dilatation and blocks the action ofinsulin, resulting in increased insulin re-sistance and hyperinsulinemia.

One of the most interesting recentfindings in hyperuricemia and gout con-cerns high-fructose corn syrup. Epidemio-logic evidence shows that there may be aconnection between the rise of the use ofhigh-fructose corn syrup, the increasingprevalence of metabolic syndrome, and therapid increase in worldwide hyperuricemia.Unlike glucose or other sugars, fructose rap-idly increases uric acid production in hu-mans and its consumption is associated withan increased incidence of gout. Animalstudies have shown that when glucose andfructose-fed rats are compared, only fruc-tose-fed animals developed metabolic syn-drome as well as hyperuricemia.1 Severallarge population-based studies have con-firmed the correlation between increasedfructose intake and hyperuricemia andmetabolic syndrome in humans.12

HYPERURICEMIA ANDCARDIOVASCULAR DISEASE (CVD)

Hyperuricemia is frequently associatedwith CVD. However, conflicting data havecaused controversy whether hyperuricemiais an independent risk factor for CVD orsimply an indicator for co-morbidities thatare frequently seen in patients with CVD(e.g., hypertension, insulin resistance).Analysis of data from the FraminghamHeart study showed no association betweenhyperuricemia and cardiovascular out-comes.13 On the other hand, a study basedon data from the first National Health andNutrition Examination Survey(NHANES-1) did find an independentrelationship between hyperuricemia andCVD, but only in women.14 A meta-analy-sis of 21 prospective cohort studies by Bakeret al. suggested a moderate and indepen-dent association between SUA and CVDin patients at high risk for CVD.15 As forindividuals with low risk for CVD, that cor-relation was not found to be consistent (only4 out of 6 studies demonstrated an inde-

pendent link). It should be mentioned,however, that the studies of healthy indi-viduals in which correlation between hy-peruricemia and cardiovascular mortalitywas not found tended to have a low num-ber of events per- person-years.

Hyperuricemia has also been associ-ated with peripheral vascular disease andall cause mortality. Baker et al. found thatelevated level of SUA, independent of otherco-morbidities, predicted worse outcomesafter an acute stroke over 2 years. The as-sociation was so strong that it was suggestedthat in-house SUA level should be consid-ered as a useful prognostic indicator in pa-tients hospitalized for acute stroke.

New data from the Chinese CohortStudy involving 93,393 participants (abouthalf male, half female) demonstrated thathyperuricemia was an independent risk fac-tor of mortality from all causes, total CVDand ischemic stroke.16 This correlation wasmore significant in women than men. Thisstudy also found a linear relationship betweenSUA and all-cause and CVD mortality. Inconclusion, hyperuricemia is clearly an im-portant risk factor for not only for develop-ing gout but also for other co-morbiditieswhich are associated with cardiovascular andall-cause mortality. More clinical trials areneeded to determine whether the treatmentof asymptomatic hyperuricemia may reducethe incidence of severity of hypertension, car-diovascular and renal disease and related co-morbid conditions.

REFERENCES1. Nakagawa T, Hu H, et al. A causal role for uric

acid in fructose-induced metabolic syndrome. AmJ Physiol Renal Physiol 2006; 290:F625-31. Epub2005 Oct 18.

2. Campion EW, Glynn RJ, DeLabry LO. Am J Med1987; 82:421-6.

3. Mazzali M, Hughes J, et al. Elevated uric acidincreases blood pressure in the rat by a novel crys-tal-independent mechanism. Hypertension2001;38:1101-6.

4. Perlstein TS, Gumieniak O, et al. Uric acid andthe development of hypertension. Hypertension2006; 48:1031-6. Epub 2006 Oct 23.

5. Feig DI, Johnson RJ. Hyperuricemia in childhoodprimary hypertension. Hypertension2003;42:247-52. Epub 2003 Aug 4.

6. Feig DI, Soletsky B, Johnson RJ. Effect of al-lopurinol on blood pressure of adolescents withnewly diagnosed essential hypertension. JAMA2008;300:924-32.

7. McLean L, Becker MA. The pathogenesis of gout.In Hochberg MC, editors. Rheumatology. ElsevierLimited; 2008. P.1824-5.

8. Feig DI, Kang DH, Johnson RJ. Uric acid andcardiovascular risk. NEJM 2008; 359:1811-21.

9. Kanbay M, Ozkara A, et al. Effect of treatment ofhyperuricemia with allopurinol on blood pres-sure, creatinine clearance, and proteinuria in pa-tients with normal renal functions. Int UrolNephrol 2007;39:1227-33. Epub 2007 Aug 15.

10. Siu YP, Leung KT, et al. Use of allopurinol inslowing the progression of renal disease throughits ability to lower serum uric acid level. Am JKidney Dis 2006;47:51-9.

11. Puig JG, Martínez MA, et al. Serum urate, meta-bolic syndrome, and cardiovascular risk factors.Nucleosides Nucleotides Nucleic Acids 2008;27:620-3.

12. Choi JW, Ford ES, et al. Sugar-sweetened softdrinks, diet soft drinks, and serum uric acid level.Arthritis Rheum 2008; 59:109-16.

13. Abbott RD, Brand FN, et al. Gout and coronaryheart disease. J Clin Epidemiol 1988;41:237-42

14. Fang J, Alderman MH. Serum uric acid and car-diovascular mortality the NHANES I epidemio-logic follow-up study, 1971-1992. NationalHealth and Nutrition Examination Survey. JAMA2000; 283:2404-10.

15. Baker JF, Krishnan E, et al.. Serum uric acid andcardiovascular disease. Am J Med 2005;118:816-26.

16. Chen JH, Chuang SY, et al. Serum uric acid levelas an independent risk factor for all-cause, cardio-vascular, and ischemic stroke mortality. ArthritisRheum 2009; 61:225-32.

Larissa Sachs, MD, formerly a Fellowin Rheumatology at Roger Williams Medi-cal Center, is a rheumatologist with ThePinnacle Health Hospital in Harrisburg,Pennsylvania.

Kerri Batra, MD, is a rheumatologistat Rhode Island Hospital, and ClinicalAssistant Professor at the Warren AlpertSchool of Medicine of Brown University


DISCLOSURE OF FINANCIALINTERESTS

The authors have no financial inter-ests to disclose.



Diagnosis and Management of Acute GoutNazli Conway, MD and Stuart Schwartz, MD

�Risk factors for the development of acutegout include hyperuricemia, increased age,and a family history of gout. Consumptionof alcohol and purine-rich foods and medi-cations such as thiazide diuretics, loop di-uretics, and cyclosporine contribute to thedevelopment of hyperuricemia. Hyperten-sion, diabetes, obesity, and chronic renalfailure are often associated with gout.When gout is suspected, aspiration of theaffected joint should be performed to con-firm the presence of intracellular negativelybirefringent needle-shaped crystals by com-pensated polarized light microscopy. How-ever, in some situations this is not practical.The most recent European League AgainstRheumatism report proposes ten key rec-ommendations for the diagnosis of gout:1

(1) The rapid onset of severe pain and swell-ing (especially with overlying erythema)within 6 to 12 hours is highly suggestive ofcrystal inflammation. However, this is notspecific for gout. (2) Classic podagra, in-volvement of the first metatarsophalangealjoint, has a high sensitivity and specificity,but is not definitive without crystal identi-fication. (3) Definitive diagnosis is made bydemonstration of monosodium urate(MSU) crystals in synovial fluid or tophus.(4) Synovial fluid from undiagnosed inflam-matory arthritis should be routinely exam-ined for the presence of monosodium uratecrystals. (5) Identification of MSU crystalsmay be possible in intercritical periods (be-tween attacks). (6) If septic arthritis is sus-pected, gram stain and culture of synovialfluid should be performed even if MSUcrystals are present. (7) Serum uric acid lev-els alone cannot confirm or exclude gout,as patients with hyperuricemia may notdevelop gout, and uric acid may be normalduring acute attacks. (8) In selected patients(those with a personal or family history ofonset of gout before age 25, or patients withrenal calculi), determination of renal uricacid excretion is useful for evaluation andmanagement. (9) Radiographs are nothelpful in confirming the diagnosis of earlyor acute gout, although they may be usefulfor differential diagnosis and may showcharacteristic changes in chronic gout. (10)Risk factors for gout and associatedcomorbidities should be assessed, includ-

ing features of the metabolic syndrome(obesity, hyperglycemia, hyperlipidemia,and hypertension).

The differential diagnosis for symp-toms suggesting an acute gout attack in-cludes acute pseudogout, septic arthritis,inflammatory arthritis, cellulitis, andtrauma. Because these diagnoses may havesimilar presentations, it is important to es-tablish a correct diagnosis, as the treatmentimplications are significant. For example,pseudogout, caused by calcium pyrophos-phate crystals, should not be treated withurate-lowering therapy; and septic arthritisdemands immediate attention with antibi-otics and joint drainage.

MEDICAL TREATMENT FOR ACUTEGOUTColchicine

Colchicine has been used both in theacute setting and in the management ofchronic gout. It exerts anti-inflammatoryeffects through several mechanisms. Colchi-cine binds to tubulin causing anti-prolifera-tive effects by arresting cell growth. It alsoinhibits phagocytic and cytokine secretoryfunctions of leukocytes. Chemotactic re-sponses of neutrophils to leukotriene B4, IL-8, and other cytokines are disrupted. Athigh concentrations, colchicine has recentlybeen shown to inhibit urate crystal-inducedactivation of NALP3 inflammasome.2 Thisprotein complex cleaves caspase-1 which

then activates interleukin 1-β, a pro-inflam-matory cytokine felt to be central in thepathogenesis of gout.

The optimal dosing of colchicine fortreatment of acute gout remains controver-sial. In the only published randomized, pla-cebo-controlled study of colchicine therapy,patients in the treatment group received oralcolchicine 1 mg then 0.5 mg every 2 hoursuntil a complete response or until side ef-fects developed.3 Of the 22 patients in thetreatment group, 73% achieved greater thana 50% reduction in pain within 48 hours.However, gastrointestinal toxicity (diarrheaand/or vomiting) developed in 55% of thepatients before the reduction in pain wasachieved, and all patients experienced theseadverse side effects at some point during thestudy. A randomized, controlled multicentertrial, presented in abstract form, comparedhigh-dose colchicine (1.2 mg, then 0.6 mghourly for six hours) versus low-dose colchi-cine (1.2 mg, then 0.6 mg in one hour) andshowed equivalent efficacy and less gas-trointestinal toxicity with the lower dose regi-men.4 Recently, the European League AgainstRheumatism issued consensus guidelines infavor of lower doses of colchicine to avoidunacceptable side effects while maintainingefficacy.5 They recommend a maximum ofthree tablets of 0.5 mg in the first 24 hours.

Overdose or chronic administration ofcolchicine may result in side effects includ-ing granulocytopenia, aplastic anemia, andreversible myopathic and neuropathic tox-icity.6 Patients with abnormal renal func-tion are at increased risk for developing neu-romuscular toxicity by accumulation oftoxic plasma levels of colchicine. This con-dition typically presents with proximalmuscle weakness and elevated CPK, whichcan mimic polymyositis. Symptoms ofcolchicine myopathy resolve within threeto four weeks after discontinuing the medi-cation. Colchicine is contraindicated inpatients on hemodialysis and should be used

yp

Table 1. Half-Life of Various NSAIDs.12

Short Half-Life (<6 hours) Long Half-Life (>6 hours)Ibuprofen (2 hours) Nabumetone (24 hours)Diclofenac (1-2 hours) Naproxen (14 hours)Indomethacin (2.5 hours) Etodolac (7 hours)Ketoprofen (2 hours) Sulindac (13 hours)

A definitive diagnosisof acute gout is

made by detection ofmonosodium urate

crystals in thesynovial fluid of an

inflamed joint.


with caution in patients with renal insuffi-ciency or hepatobiliary dysfunction.7 Druginteractions have been reported withcyclosporine, statins, and macrolides.

The FDA recently withdrew its ap-proval for the use of intravenous colchicine.2

The most common side effect associated withIV colchicine is local extravasation of the drugwhich can lead to painful inflammation andnecrosis of surrounding tissue.8,9 Increasedrisk of systemic side effects such as renal andhepatic toxicity, bone marrow suppression,and congestive heart failure have also beenreported with IV colchicine.8 Fifty reportsof adverse events, including 23 deaths, weresubmitted to the FDA through June 2007.10

Three of these deaths were attributed to anIV colchicine compounding error.

Non-steroidal Anti-inflammatoryDrugs (NSAIDs)

NSAIDs are commonly used for treat-ment of acute gout. The anti-inflamma-tory effects of these medications occurmainly through inhibition of the cyclo-oxy-genase enzyme which prevents the trans-formation of arachidonic acid to prostag-landins, particularly prostaglandin E2.Other NSAID mechanisms include inhi-bition of lipooxygenase with reduced gen-eration of leukotriene B4 and inhibition ofneutrophil activation and aggregation.11

Early administration and appropriatedosage of NSAIDs are more important inachieving a therapeutic response than theparticular NSAID used. However,NSAIDs with short half-lives (less than sixhours) reach steady-state levels morequickly than NSAIDs with long half-lives(more than six hours) and may be preferredin managing acute gout. (Table 1)

Regardless of which NSAID is admin-istered, large initial doses are recommended(indomethacin 150-200 mg/day, naproxen1000 mg/day, diclofenac 150 mg/day).Duration of treatment is generally 4-8 dayswhich minimizes potential adverse side ef-fects. Patients should be treated until symp-toms resolve and then gradually tapered.

Traditional NSAIDs inhibit both COX-1 and COX-2, with their main anti-inflam-matory effects being via inhibition of COX-2 and most adverse effects by inhibition ofCOX-1.13 While both selective and non-selective NSAIDs inhibit COX-2 equally, theselective COX-2 inhibitors spare inhibitionof COX-1 therefore reducing gastrointesti-nal toxicity. Etoricoxib, a selective COX-2inhibitor, was shown to be as efficacious asindomethacin for treatment of acute goutwith fewer gastrointestinal side effects.14 Thismedication is not FDA-approved for use inthe United States because of potential car-diovascular side effects. Celecoxib is the onlyapproved selective COX-2 inhibitor avail-able in the US; however, no trials of its use ingout have been published.

Relative contraindications to the use ofNSAIDs include severe heart failure, pepticulcer disease, gastrointestinal hemorrhage,aspirin-induced or NSAID-induced asthmaand renal impairment. There is an increasedrisk of bleeding when NSAIDs are used con-comitantly with warfarin.

CORTICOSTEROIDSSystemic corticosteroids

Systemic corticosteroids may be usedfor treating acute gout when NSAIDs andcolchicine are contraindicated. Corticos-teroids exert their anti-inflammatory effectby inhibition of pro-inflammatory cytokines(IL-1, IL-6, IL-8, and TNF-α) andupregulation of genes for lipocortin andvasocortin, which have anti-inflammatoryeffects by inhibiting phospholipase A2.

A Cochrane review evaluated the effi-cacy and safety of systemic corticosteroids forthe treatment of acute gout.15 Only three

studies involving a total of 74 patients werefound that met the search criteria. In thefirst study, intramuscular (IM) injections oftriamcinolone were compared to oral in-domethacin. Intramuscular triamcinolonewas compared to IM injections of ACTHin the second study. Oral prednisolone wascompared to IM diclofenac combined withoral indomethacin in the third study. Theresults of these three studies show no clini-cally relevant differences between systemiccorticosteroids and comparator drugs. Nosignificant adverse side effects attributableto corticosteroids were found. This reviewconcluded that systemic steroids are a safeand effective treatment for acute gout, butmore studies are needed.

One randomized, controlled trial pub-lished after the Cochrane review tested theequivalence of prednisolone and naproxenfor treatment of monoarticular gout.16

One-hundred and twenty primary carepatients with confirmed gout were randomlyassigned to receive either prednisolone (35mg daily) or naproxen (500 mg twice daily)for five days. The primary outcome waspain. After 90 hours, the reduction in painscore was similar for both groups. Adverseeffects were also comparable between bothgroups. This study suggests that corticos-teroids are as effective and as safe as NSAIDsin the acute setting.

Corticosteroids should be used withcaution in patients with poorly controlleddiabetes mellitus, hypertension, congestiveheart failure, advanced coronary artery dis-ease or severe infection. When using pred-nisone most practitioners start at a dose of20-40 mg per day and gradually taper anddiscontinue the drug over 10-14 days.

Intraarticular corticosteroidsIntraarticular corticosteroids have a role

in the treatment of mono- or oligoarticulargout.11 The absence of joint infection shouldbe confirmed before injection of corticos-teroid. The dose of steroid varies based onthe size of the joint involved. (Table 2) Somepotential (but rare) side effects of intra-ar-ticular corticosteroids include skin atrophyand septic arthritis. Systemic absorption doesoccur, but the clinical impact of this effect ismild and short-lived.

ACTHSynthetic adrenocorticotropic hor-

mone (ACTH) is another steroid prepara-tion that has been useful in the acute set-

Table 2. Recommended Corticosteroid Dose Based on Joint Size.17

Joint Intra-articular corticosteroid doseKnee 40 mg triamcinoloneAnkle 30 mg triamcinoloneWrist 30 mg triamcinoloneElbow 30 mg triamcinoloneMetacarpophalangeal joints 10 mg triamcinoloneProximal interphalangeal joints 10 mg triamcinolone

The FDA recentlywithdrew its

approval for the useof intravenous

colchicine


ting; however, it is not universally avail-able.18 It is administered by intramuscularor intravenous injection of 40-80 IU.ACTH induces glucocorticoid release fromthe adrenal cortex.11 Drawbacks includerebound attacks, mild hypokalemia, wors-ening of glycemic control, and fluid reten-tion. Other features that render this a lessattractive option are cost, inconvenience ofparenteral administration, and dependenceon the sensitivity of the adrenal cortex.11

AnakinraThe inhibition of IL-1 has been inves-

tigated as a novel therapeutic option for thetreatment of acute gout. Monosodium uratecrystals activate toll-like receptors and theNALP3 “inflammasome complex” to releaseIL-1b from monocytes and synovial mono-nuclear cells. So, et al conducted a pilot studyin which 10 patients with gout who wereunable to tolerate conventional anti-inflam-matory medication were given anakinra, anIL-1 inhibitor, daily at a dose of 100 mg sub-cutaneously for three days.19 All 10 patientshad a rapid response and no adverse sideeffects were noted. While these preliminarydata are promising, these findings need tobe confirmed in a larger, controlled study.

COMMON PITFALLS IN THEMANAGEMENT OF ACUTE GOUT

Patients taking uric acid loweringagents (allopurinol, febuxostat, orprobenecid) should continue these medi-cations during an acute attack. There areno data to suggest that a flare is exacerbatedby continuing anti-hyperuricemics. Anacute attack may, however, be precipitatedduring initiation or dose adjustment ofurate lowering therapy if the patient is notalso taking a prophylactic medication(colchicine or NSAIDs). This occurs as aresult of fluctuations in serum uric acid lev-els that may trigger an acute attack.

In one study, a retrospective chart re-view was performed to assess the treatmentof acute gout in hospitalized patients.20

Only 25% of patients diagnosed with acutegout had arthrocentesis performed for crys-tal analysis, despite this being the gold stan-dard. Combination anti-inflammatoryagents (prednisone with colchicine,NSAIDs with colchicine, and steroid withNSAIDs) were used in over 50% of pa-tients. There is a paucity of evidence to sup-port such treatment, and this practice in-creases the risk of combined side effects.

Over 80% of patients given colchicine orNSAIDs had renal failure. Renal failureincreases the time needed for clearance ofcolchicine, thereby increasing the risk oftoxic side effects. NSAIDs should beavoided in patients in this setting given theirpotential for further renal toxicity.

Other pitfalls in management includedelays in treatment, insufficient doses ofmedications, and premature termination oftreatment. An appropriate dose of anti-in-flammatory medication (NSAIDs, colchi-cine, or corticosteroids) should be given atthe first onset of symptoms. Treatment shouldbe continued until symptoms have resolvedand then tapered for at least 2-3 days untilall signs of inflammation are absent.7

SUMMARYA definitive diagnosis of acute gout is

made by detection of monosodium uratecrystals in the synovial fluid of an inflamedjoint. However, when this is not feasible aclinical diagnosis can sometimes be madewith reasonable accuracy. The mainstaysof acute gout management are colchicine,NSAIDs, and systemic or intra-articular cor-ticosteroids. NSAIDs are preferable tocolchicine because of their more favorableside effect profile. Successful treatment oc-curs with the prompt initiation of high doseshort half-life NSAIDS. Since many pa-tients with gout have comorbidites that pre-clude the use of NSAIDS or colchicine, sys-temic corticosteroids are commonly used totreat acute gouty arthritis. Intra-articularinjections are appropriate in the setting ofmono- or oligoarticular involvement. Ad-equate duration of anti-inflammatorytherapy and careful patient education areessential elements of successful therapy foracute gout. Evaluation and managementof hyperuricemia should be undertakenwhen all symptoms of acute gout are re-solved and the patient is stable on daily pro-phylaxis with NSAIDs or colchicine.

REFERENCES1. Zhang W, Doherty M, et al. EULAR evidence based

recommendations for gout. Part I: Diagnosis. Report ofa task force of the standing committee for internationalclinical studies including therapeutics (ESCISIT). AnnRheum Dis 2006; 65:1301-11.

2. Terkeltaub RA. Colchicine update: 2008 [publishedonline ahead of print October 28, 2008]. Semin ArthritisRheum.

3. Ahern MJ, Reid C, et al. Does colchicine work? Aust NZJ Med 1987; 17: 301-4.

4. Terkeltaub R, Furst D, et al. Low dose (1.8 mg) vs highdose (4.8 mg) oral colchicine regimens in patients withacute gout flare in a large, multicenter, randomized,

double-blind, placebo-controlled, parallel group study.Arthritis Rheum 2008; 58; (Abstract) (in press).

5. Zhang W, Doherty M, et al. EULAR evidence basedrecommendations for gout. Part II: Management. Re-port of a task force of the EULAR Standing Committeefor International Clinical Studies Including Therapeu-tics (ESCISIT). Ann Rheum Dis 2006; 65:1312-24.

6. Kuncl RW, Duncan G, Watson D, et al. Colchicinemyopathy and neuropathy. NEJM 1987; 316:1562-1568.

7. Schumacher HR, Jr. The practical management of gout.Cleveland Clinic J Med 2008; 75 Suppl 5: S22-5.

8. Emmerson BT. The management of gout. NEJM 1996;34:445-51.

9. Wortmann RL. Treatment of acute gouty arthritis. Cur-rent Rheumatol Reports 2004; 6:235-9.

10. US Food and Drug Administration Center for DrugEvaluation and Research. Questions and answers aboutFDA’s enforcement action against unapproved injectablecolchicine products. http://www.fda.gov/cder/drug/unapproved_drugs/colchicine_qa.htm.

11. Fam AG. Current therapy of acute microcrystalline ar-thritis and the role of corticosteroids. J Clin Rheumatol1997; 3:35-40.

12. Carlo P. Non-steroidal anti-inflammatory drugs. In:Hochberg MC, Silman AJ, et al , editors. Rheumatology,Fourth Edition. Mosby Elsevier; 2008. p. 404

13. Fam AG. Treating acute gouty arthritis with selective COX2 inhibitors. BMJ 2002; 325:980-1.

14. Rubin BR, Burton R, et al. Efficacy and safety profile oftreatment with etoricoxib 120 mg once daily comparedwith indomethacin 50 mg three times daily in acutegout. Arthritis Rheumatism 2004; 50:598-606.

15. Janssens HJ, Lucassen PLBJ, et al. Systemic corticoster-oids for acute gout (Review). Cochrane Database SystemicRev 2008, Issue 2.

16. Janssens HJ, Jansen M, et al. Use of oral prednisolone ornaproxen for the treatment of gout arthritis. Lancet 2008;371:1854-60.

17. Roberts Jr. WN. Intraarticular and soft tissue injections.Rose, BD, ed. UptoDate. Waltham, Mass: UpToDate,2009. Available at: http://www.utdol.com.

18. Terkeltaub RA. Gout: recent advances and emergingtherapies. Rheumatic Dis Clin 2008; 3.

19. So A, De Smedt T, et al. A pilot study of IL-1 inhibitionby anakinra in acute gout. Arthritis Research Therapy 2007,9:R28.

20. Petersel D, Schlesinger N, et al. Treatment of acute goutin hospitalized patients. J Rheumatol 2007; 34:1566-8.

Nazli R. Conway, MD, is a Fellow in Rheu-matology at Roger Williams Medical Center.

Stuart T. Schwartz, MD, is Clinical As-sociate Professor of Medicine at the WarrenAlpert Medical School of Brown University.

Disclosure of Financial InterestsNazli R. Conway, MD, has no finan-

cial interests to disclose.Stuart T. Schwartz, MD. Grant Re-

search Support: Pfizer. Speaker’s Bureau:Forest, Cypress, Takeda

Discussion of off-label use of medica-tion: anakinra

CORRESPONDENCEStuart Schwartz, MD2 Dudley Street, Suite 370Providence, RI, 02905e-mail: [email protected]


Figure 1. Purine Metabolism Pathway.

XO: xanthine oxidase; HPRT: hypoxanthine-guanine phosphoribosyltransferase; APRT:

adenine phosphoribosyltransferase; PRPS: phosphoribosyl pyrophosphate synthetase.

AMP: adenosine monophosphate; GMP: guanosine monophosphate; IMP: inosine

monophosphate; ATP: adenosine triphosphate; R5P: ribose-5-phosphate.

Adapted from Kassimatis et al, J Nephrol 2005; 18: 447-451. (3)

Approach To the Treatment of HyperuricemiaSamuel H. Poon, MD, Harald A. Hall, MD, and Bernard Zimmermann, MD

�Despite a sound understanding of thesynthetic and metabolic pathways thatcontrol serum uric acid levels, clinicianshave been limited to a few urate lower-ing agents and one urate synthesis inhibi-tor since the development of allopurinolin 1956.1 Febuxostat (Uloric) becamethe second urate synthesis inhibitor whenthe Food and Drug Administration(FDA) approved it in early 2009. Therole of febuxostat in the management ofhyperuricemia and gout remains to befully determined. This review will dis-cuss the traditional agents used for thelowering of serum uric acid and addressthe potential benefits febuxostat may of-fer in clinical practice.

SOURCES OF SERUM URATESerum uric acid accumulates from

the metabolism of purine nucleic acidswhich are derived either from cellularbreakdown or directly from foods richin purines such as red meats, beer, shell-fish, and yeast extracts.2 Catabolism ofpurines is mediated through a cascade ofwell regulated enzymes that includesphosphoribosyl pyrophosphate syn-thetase (PRPS), hypoxanthine-guaninephosphoribosyltransferase (HRPT), andxanthine oxidase (XO).3 (Figure 1) Adeficiency in HRPT or PRPS over-activ-ity results in hyperuricemic syndromes likeLesch-Nyhan and Kelley-Seegmiller, withresultant gouty arthropathy in some pa-tients. Unlike other animal species, hu-mans and other primates do not expressuricase, the enzyme which converts uricacid into the more soluble allantoin forexcretion. Uric acid is therefore the endproduct in human purine catabolism andis ultimately excreted in urine and also,to a lesser proportion, in the stool. Drugsthat inhibit xanthine oxidase and urico-suric agents that increase renal uric acidexcretion are the cornerstone of therapyfor hyperuricemia.

ASYMPTOMATIC HYPERURICEMIAUric acid exceeds its solubility in ex-

tracellular spaces such as the joint or softtissue at a concentration of 6.8 mg/dL.Uric acid precipitates as monosodium

and Kelley-Seegmiller syndromes, ormore frequently as prophylaxis before cy-tolytic therapy for cancer.

TREATING HYPERURICEMIA:DIETARY APPROACH ANDADJUNCTIVE THERAPY

Approximately 60% of patients whohave experienced acute gout arthritis ex-perience a repeat attack within one year,based on historical data.5 Prospective datato guide physicians are lacking, but it maybe beneficial to attempt lifestyle and di-etary modification rather than to com-mit to lifelong therapy in patients with asingle attack of gout. If this fails, anti-hyperuricemic therapy will be necessary.

Patients should be educated on di-etary and lifestyle modifications that canreduce serum urate levels. These patientsshould attempt to reduce purine-richfoods such as red or organ meats andshellfish, and they should avoid alcoholintake, especially beer. Weight loss and

urate (MSU) crystals in these compart-ments but for varying reasons, does notalways cause an inflammatory response.The risk of having symptomatic hyperu-ricemia is related to the degree of serumurate elevation. In an early study, Cam-pion et al. demonstrated that in patientswith serum urate levels less than 7.0mg/dL, the annual incidence of gouty arthri-tis was only 0.1% as compared to 4.9%in patients with serum rate greater than9.0 mg/dL.4 However, after five years offollow-up even patients with serum urategreater than 9.0mg/dL only had a cumu-lative incidence of gouty arthritis of 22%,demonstrating that a large proportion ofpatients with increased serum uric acidremain unaffected by gout. While theextent of hyperuricemia is correlated witha higher risk for gouty arthritis, hyperu-ricemia for any individual can persists foryears without symptoms. Therefore,empiric treatment of asymptomatic hy-peruricemia is not advised.

INDICATIONS FORTREATMENT OFHYPERURICEMIA

Pharmacologicreduction of hype-ruricemia is gener-ally required in pa-tients with symp-tomatic disease.Most commonly,urate loweringagents are indicatedfor patients withmore than one epi-sode of acute goutyarthritis, all patientswith tophaceousgout and chronicgouty arthritis, andpatients with uricacid renal stones.Other situations thatrequire the use of al-lopurinol includehyperuricemia asso-ciated with knowninherited disorderslike the Lesch-Nyhan


exercise have been also been shown tohave a positive impact on urate reduc-tion.6 From the clinician’s standpoint,loop diuretics or thiazide diuretics shouldbe avoided when possible. Agents withmild uricosuric effects like losartan maybe considered instead for patients withhypertension. Likewise, fenofibrate maybe preferred for select patients with hy-percholesterolemia and gout.

WEIGHING THE DECISION TO TREATHYPERURICEMIA

The decision to initiate and committo treatment with a long term serumurate lowering agent is not an easy onefor patients. In a retrospective study of9,482 patients prescribed allopurinol forgout, only 65.9% filled their initial pre-scription; of these, 18% were fully com-pliant with the treatment regimen rec-ommended by their primary providers.7

It is often difficult for clinicians to con-vince patients of the need to continuethese medications during clinically qui-escent periods, especially given the highmedical costs incurred by patients withmultiple medical conditions.8

Measurements of urine uric acid lev-els are no longer routinely performed dur-ing the workup of gout. Twenty-four hoururine uric acid and creatinine measure-ments continue to be useful in patientswho are younger than 25 years old, thosewith strong family history of early onsetgout, or patients with nephrolithiasis.9 Ifurine uric acid is greater than 800mg perday, the patient is likely an over-producerof purines where hemolytic syndrome orlymphoproliferative disorders might beconsidered. If the patient has a uric acidclearance of less than 6ml per minute,then renal excretory defects such as Barter’sor Gitelman’s disease or lead nephropa-thy may be possible.9 The urinary excre-tion of uric acid should be measured ifuricosuric therapy is being considered, asthese drugs will increase the possibility ofrenal stone formation in patients with highuric acid excretion.

The treatment of acute gout is dis-cussed elsewhere in this journal. It isimportant to note that during the“intercritical” period, when the patientis tapering off higher doses of non-ste-roidal anti-inflammatory drugs (NSAIDs)or oral prednisone, colchicine at 0.6 mgtwice daily has been shown to be useful

for preventing recurrent flares. Colchi-cine or NSAID prophylaxis should begiven during the initiation of anti-hyperuricemic therapy and continueduntil the patient has been free of acuteattacks for a prolonged period of time.

URICOSURIC AGENTSUricosuric agents are employed less

frequently than allopurinol primarilybecause of the need for three times dailydosing and the requirement for measur-ing 24-hour urinary uric acid before be-ginning therapy. Uricosurics continue tobe useful in patients with allopurinol in-tolerance or hypersensitivity or in patientswith known defects in renal excretion ofuric acid.

Probenecid is the primary uricosu-ric agent available in the United States.It blocks the renal proximal tubule ex-changer URAT1, which reabsorbs uricacid. A study of forty patients with un-complicated chronic gout receivingprobenecid, or sulfinpyrazone versus al-lopurinol found the similar recurrencerates of acute gouty attacks, although se-rum urate level was lower in the allopu-rinol group. Other smaller trials suggestthat uricosuric agents are just as effica-cious as allopurinol in chronic gout pa-tients without renal impairment.8

Initial dosing of probenecid is rec-ommended to start at 0.5 grams per dayto minimize flares, and then titrated to atypical dose of 0.5 grams twice a day tothree times a day to a maximum dose of3 grams per day. The contraindicationsfor uricosurics are patients who have anyhistory of nephrolithiasis, patients withlow urine output, or patients with re-duced renal excretion (GFR less than60ml per minute). Significant drug in-teractions include the elevation of peni-cillin, salicylate, dapsone, heparin orzidovudine serum concentration by in-hibition of renal tubular excretion.2

XANTHINE OXIDASE INHIBITORSAllopurinol

Allopurinol and its metabolite,oxypurinol, competitively block xanthineoxidase conversion of hypoxanthine toxanthine and xanthine to uric acid. It isvery effective in lowering serum urate lev-els and reducing tophus size as shown ina study of sixty-three patients who re-ceived allopurinol with or without con-current bezbromarone, a uricosuric usedin Europe and Asia.10

Allopurinol is generally well toler-ated, with mild gastrointestinal intoler-ance being the most common side effectexperienced. Allopurinol hypersensitiv-

Table 1. Suggested Dosing of Allopurinol . Treatment should be initiated on a dose of

allopurinol adjusted according to renal function. Then the dose of allopurinol should be

titrated until serum uric acid is less than 6.0 mg/dL.

CrCl: creatinine clearance; HD: hemodialysis.


ity syndrome (AHS) may occur duringthe first three months of therapy. It isestimated to occur in 0.1% of patientsand has a mortality rate of as high as26%.11,12 Signs and symptoms of AHSinclude severe exfoliative dermatitis pro-gressing to toxic epidermal necrolysis, sto-matitis, peripheral eosinophilia, leukocy-tosis, fever, hepatitis, and acute renal in-sufficiency. There exists no specific treat-ment for AHS other than discontinua-tion of allopurinol and supportive care,with the role of systemic steroids unsub-stantiated.13

Patients who develop an allergic re-action to allopurinol can be treated us-ing an allopurinol desensitization proto-col. Desensitization, however, should beattempted only in patients with mild tomoderate reactions to allopurinol rang-ing from maculopapular rash, mild feverto peripheral eosinophilia without anyliver or renal impairment.11,14

Initial allopurinol dose should bebased on the patient’s GFR. A suggestedstarting dose according to creatinineclearance is provided in Table 1.15 Thestarting dose, however, is often inadequateto reduce serum urate to target levels. Ina study of 250 patients in New Zealandwho were prescribed a fixed allopurinoldose based on renal dosing calculator,only 19% of the study cohort reached atarget serum urate level of less than 6.0mg/dL.16 Uric acid levels should be moni-tored at six to eight week intervals, andallopurinol increased until the serum uricacid is less than 6.0 mg/dL.

FebuxostatFebuxostat is a non-purine inhibitor

of xanthine oxidase. Because it is dissimi-lar from the structure of purines, it doesnot interfere with purine and pyrimidinemetabolism. Furthermore, it is degradedby glucuronide formation and oxidationin the liver, with half of all febuxostat andits active metabolites excreted in the stool,with the other half in the urine.17 Unlikeallopurinol, febuxostat does not requirerenal dose adjustment.18,19 The major res-ervation is its use in patients with underly-ing liver disease, current alcohol use, orhistory of alcohol abuse, but short termuse of febuxostat 80mg daily for seven dayswas demonstrated to be safe in 8 patientswith Child-Pugh A liver disease and 8 pa-tients with Child-Pugh B disease.17

In the first phase III randomized-double-blind 52-week multicenter trialof 762 patients with gout with serumurate levels greater than 8.0 mg/dL(FACT trial), febuxostat 80mg daily orfebuxostat 120mg daily was comparedwith allopurinol 300mg daily.18 Thestudy population was composed prima-rily of Caucasian men with a mean ageof 51 years. Patients with a creatininegreater than 1.5mg/dL, any history ofalcohol abuse, or current alcohol use ofmore than fourteen drinks a week wereexcluded from the study. The authorsfound that a higher proportion of pa-tients in the two febuxostat groups (53%& 62%) achieved serum urate levels ofless than 6.0mg/dL than patients in al-lopurinol controls (21%). Patients receiv-ing febuxostat also experienced a largerdecrease in tophus size compared to pa-tients on allopurinol. An important criti-cism is that patients given allopurinolwere not allowed dose increases duringthe study. This arbitrary distinction un-derestimates the true efficacy of allopu-rinol in clinical practice.

Adverse events were minor across allgroups. Self limited reactions like diar-rhea, headache, joint discomfort, andmild elevations in transaminase levels oc-curred in similar frequency in all groups.However, it was noted that significantlymore patients in the febuxostat groupsdropped out of the study and experi-enced more acute gout flares. An unex-pected finding was four deaths in thefebuxostat cohorts, as opposed to nonein the allopurinol arm. The cause ofdeath appeared unrelated to febuxostatand ranged from congestive heart failure,metastatic colon cancer complications,cardiac arrest, and anti-coagulation re-lated diathesis.

To address some of the concernsraised in the FACT trial, a 28-week, phaseIII randomized-double-blind placebocontrolled trial was completed in 2008(APEX trial).19 The same investigatorsstudied 1,072 gout patients with serumurate greater than 8.0mg/dL. This studyincluded patients with creatinine be-tween 1.5 mg/dL to 2.0mg/dL. The de-mographics of the study population weresimilar to the FACT trial, composed pre-dominantly of Caucasian men. The au-thors looked at five study cohorts: patientseither received febuxostat 80mg daily,

120mg daily, 240mg daily, allopurinoldosed according to serum creatinine lev-els, or placebo. Similar to the FACT trial,the APEX trial found that febuxostatreached the primary endpoint of serumurate less than 6.0 mg/dL in higher pro-portion by the end of the study: 36% ofpatients on febuxostat 80mg; 52% ofpatients on febuxostat 120mg; 66% ofpatients on febuxostat 240mg; 10% ofpatients on allopurinol; 0% of patientson placebo. Similar results were seen inpatients with renal impairments. Theywere unable to demonstrate a decreasein tophus size or number due to the shortlength of the study. The occurrence ofminor and serious adverse reactions re-quiring hospitalization was similar acrossstudy group. Liver enzyme dysfunctionwas higher in patients receiving eitherfebuxostat or allopurinol compared toplacebo controls (19%-25% versus15%). Unlike the FACT trial, no deathswere reported during the study.

Though the authors had intendedto study febuxostat in patients with im-paired renal function, only 40 patientsrecruited had creatinine between 1.5mg/dL to 2.0mg/dL. Additionally, patientswith more impaired renal functions wereexcluded from this study, as in the FACTtrial. Published data on febuxostat usepatients with renal impairment or hepaticimpairment continue to be lacking andwill require ongoing post-market surveil-lance.

CONCLUSIONManagement of hyperuricemia in

the setting of recurrent or tophaceousgout has traditionally relied on the use ofallopurinol. Uricosuric agents haveproven utility but are beneficial in a lim-ited number of situations. Febuxostat asdescribed here and synthetic uricase asdescribed elsewhere in this journal aremuch welcomed additions to therheumatologist’s armamentarium. Expe-rience with these agents is limited andtheir cost-effectiveness remains unstud-ied. Therefore, allopurinol will remainthe first line agent for uric acid loweringtherapy. In patients with clinical factorsthat preclude the use of probenecid andin those who had experienced allopurinolhypersensitivity, febuxostat may prove tobe a valuable alternative.


REFERENCES1. Robins RK. Potential purine antagonists. J Am

Chem Soc 1956;78: 784-90.2. Hochberg MC, Silman AJ, et al. Clinical features

of gout. Rheumatology, 4th Ed.. Elsevier Limited,Philadelphia, 2008, pp. 1827-37.

3. Kassimatis TI, Simmonds HA, et al. HPRT defi-ciency as the cause of ESRD in a 24-year-oldpatient. J Nephrol 2005; 18:447-51.

4. Campion EW, Glynn RJ, DeLabry LO. Asymp-tomatic hyperuricemia. risks and consequences inthe normative aging study. Am J Med 1987;82:421–6.

5. Mandell, BF. Clinical manfestations of hyperuri-cemia and gout. Cleveland Clinic J Med2008;75(5): S5-8.

6. Dessein PH, Shipton EA, et al. Beneficial effectsof weight loss associated with moderate calorie/carbohydrate restriction, and increased propor-tional intake of protein and unsaturated fat onserum urate and lipoprotein levels in gout. AnnRheum Dis 2000;59:539-43.

7. Riedel A, Becker M. Compliance with allopu-rinol therapy among managed care enrollees withgout. J Rheumatol 2004; 31: 1575-81.

8. Zhang W, Doherty M, et al. EULAR evidencebased recommendations for gout. Part II: Man-agement. Ann Rheum Dis 2006; 65; 1312-24.

9. Zhang W, Doherty M, et al. EULAR evidencebased recommendations for gout. Part I: Diagno-sis. Ann Rheum Dis 2006; 65:1301–11.

10. Perez-Ruiz F, Ruibal A. Effect of urate-loweringtherapy on the velocity of size reduction of tophiin chronic gout. Arthritis & Rheum 2002;47:356-60.

11. Fam AG, Lewtas J, et al. Desensitization to al-lopurinol in patients with gout and cutaneousreactions. Amer J Med 1992;93: 299-302.

12. Singer J, Wallace S. The allopurinol hypersensitiv-ity syndrome. Arthritis Rheum 1986;29: 82-7.

13. Stamp, L, Dalbeth, N. Allopurinol dosing inrenal impairment. Seminars in Dialysis 2007;20:391–5.

14. Fam A, Dunne S, Paton TW. Efficacy and safetyof desensitization to allopurinol following cuta-neous reactions. Arthritis & Rheumatism 2001;44: 231–8.

15. Hande KR, Noone RM, Stone WJ. Severe al-lopurinol toxicity. Am J Med. 1984 76:47-56.

16. Dalbeth N, Gow P. Dose adjustment of allopu-rinol according to creatine clearance dose not pro-vide adequate control of hyperuricemia in patientswith gout. J Rheum 2006; 33: 1646-50.

17. Khosravan R, Mayer M, Joseph-Ridge N.Febuxostat, a novel non-purine selective inhibi-tor of xanthine oxidase – effect of mild and mod-erate hepatic impairment on pharmacokinetics,pharmacodynamics, and safety. TAP Pharmaceu-tical Products Inc Study.

18. Becker MA, Schumacher R, Joseph-Ridge N.Febuxostat compared with allopurinol in patientswith hyperuricemia and gout. NEJM 2005;353:2450-61.

19. Schumacher HR, Becker MA, Joseph-Ridge N.Effects of febuxostat versus allopurinol and pla-cebo in reducing serum urate in subjects withhyperuricemia and gout. Arthritis & Rheumatism(Arthritis Care & Research) 2008;59:1540-8.

Samuel H. Poon, MD, is a Fellow inRheumatology at Rhode Island Hospital

Harald A. Hall, MD, is a rheuma-tologist at Roger Williams Medical Center,and is Assistant Professor of Medicine atthe Boston University School of Medicine.


Disclosure of Financial InterestsThe authors have no financial inter-

ests to disclose.



Gout In WomenJill McClory, MD, and Nuha Said, MD

�Gout has long been associated with oldmen with red faces who imbibe heavyalcohol and eat rich meats. Because ofthis, it was dubbed “the disease of Kings.”These misconceptions persist, and manypeople continue to believe that gout is acondition that is self-inflicted by overin-dulgence, occurs only in men, with symp-toms confined to the foot.

WOMEN GET GOUT TOOGout is not rare in women. Although

women comprise approximately 5% of allgout patients, the incidence has risen.According to Arromdee, et al, the inci-dence of gout in men and women hasdoubled over the past 20 years.1 Becauseit is principally a disease seen in men, goutis often misdiagnosed in women, and/orthe diagnosis is often delayed.

In this article we will discuss someof the epidemiological, clinical and treat-ment aspects that distinguish femalefrom male gout patients.

Women are older than men at thetime of diagnosis of gout. In several stud-ies, the mean age at diagnosis of gout was7-12 years greater in women than inmen.2-6 In patients older than 60 yearswith newly diagnosed gout, approxi-mately half will be women. The inci-dence of females with gout peaks at age80 years and older.

One important difference betweenwomen and men with gout is the changein urate levels that occurs in women af-ter menopause. Serum urate concentra-tions in men average about 1mg/dlhigher than those in adult women untilafter menopause, at which time the se-rum levels of uric acid in women approachor equal those in men. In 2008, Hakand Choi reviewed data from the ThirdNational Health and Nutrition Examina-tion Survey, and published their findingson menopause, postmenopausal hor-mone use, and serum uric acid levels inwomen.7 They concluded that meno-pause was associated with higher serumuric acid levels, and that postmenopausalhormone replacement was associatedwith lower serum uric acid levels, suggest-ing that estrogen plays a key role in pro-

tecting women from hyperuricemia andgout.

Pui et al found further evidence ofthe role of estrogens in regulating serumuric acid: they found early onset hyperu-ricemia and gout following hormonetreatment given for the purpose of femaleto male gender reassignment.8 Estrogenmay enhance renal uric acid excretion.During gender reassignment, testoster-one treatment likely dampens the effectof estrogen, and causes increased serumurate concentrations by reducing renalexcretion of uric acid. It was also sug-gested that sex hormones may also influ-ence the expression of acute gout througheffects on the inflammatory response tomonosodium urate crystals.

Another important risk factor forgout in women is the use of diuretics.Both loop and thiazide diuretics increaseserum uric acid. Meyers, et al., analyzing92 women with gout, found that 78%of them were receiving diuretic treat-ment.6 Although many of the womenwho were taking diuretics were postmeno-pausal, diuretic use appears to be an in-dependent risk factor. Yu, et al found that18% of premenopausal women had “di-uretic-induced acute gouty arthritis.”9 Ina case report Hayem et al. showed thatdiuretic abuse for the purpose of weightloss was implicated in three premeno-pausal women with tophaceous gout.10

Another case report described a 32-year-

old woman with anorexia nervosa whodeveloped tophaceous gout. This case wasalso attributed to diuretic abuse, as shehad been taking furosemide to lose weightsince age 18.11

Several studies have shown an in-creased incidence of renal insufficiency inwomen with gout. Renal insufficiency canreduce the serum uric acid excretion,thereby increasing risk for hyperuricemiaand gout.12 Puig, et al. found that morethan 50% of women with gout had renalinsufficiency, whereas approximately 11%of men with gout had renal insufficiency.This report described four of five pre-menopausal women with gout, none ofwhom were taking diuretics. Also, Yu’sstudy noted some form of renal disease in85% of premenopausal women withgout.9 Many of the reports that showedhigher prevalence of renal insufficiencyin gouty women also showed a higherprevalence of hypertension and diureticuse.

A widely observed association in fe-male gout is the presence of pre-existingjoint disease, in particular, osteoarthritis(OA). (Figure 1) Lally, et al. found pre-existing joint disease in 70% of womenand in only 37% of men. This paperdescribed 6 women with tophi and/oracute gouty arthritis in association withHeberden’s or Bouchard’s nodes.2 Simi-larly, Puig et al. reported 76% of womenwith gout had OA compared to 40% ofmen.5 The latter study also found a rela-tionship between nodal OA and mono-sodium urate crystal deposition in womenwith gout and nodal disease in the hands.The presentation of acute or subacutegout in the fingers of a woman with nodalOA may contribute to a delayed or in-

Table 1. Differences between Women and Men with Gout

Women MenAge at presentation Older (50s-60s) Younger (40s)Renal insufficiency More (~28%) Less (~16%)Alcoholism Less MoreFamily history More LessPre-existing joint disease More (~50%) Less (~25%)Obesity Less MoreDiuretic use More (~30%) Less (~13%)

…gout is oftenmisdiagnosed in

women


correct diagnosis.Although environmental factors in-

fluence gouty arthritis, hereditary factorsalso play a role. Studies demonstrate anincreased prevalence of gout in relativesof patients with gout. Serum uric acidlevels are controlled by multiple genes inboth genders. However, this seems to bemore strongly associated with women. Inone example, Yu found a higher familialinfluence in premenopausal gout pa-tients, citing a positive family history ofgout in 59% of premenopausal patients,versus 34% in postmenopausal ones.9

There also seems to be a relationshipbetween serum glucose levels and uricacid levels. In the Third National Healthand Nutrition Examination Survey, Choiand Ford observed that individuals withmoderately elevated hemoglobin A1c lev-els (6.0-6.9), may be at higher risk ofhyperuricemia and gout, particularly inwomen, however, higher HbA1c levelswere associated with a lower risk of theseconditions, particularly in men.13 Thisobservation corresponds to Chou’s reportin 2001, which states that hyperuricemiain women was correlated with older age,higher fasting serum insulin levels, plasmaglucose and hyperinsulinemia.14 It is sug-gested that there is a uricosuric effect ofglycosuria, which occurs when the bloodglucose level is greater than 10 mmol/l.

Several articles on risk factors forhyperuricemia and gout note the asso-ciation of obesity and alcohol consump-tion; however, these associations are notas strong in women as they are in men.Puig reported the incidence of obesityseen in his gout population was approxi-

mately 10% less in women, comparedwith the men in the study. And, in thecomparison between women and menwith gouty arthritis in Lally’s study, thatless than 9% of the women had associ-ated alcoholism, compared to 45% ofmen.2,5

CLINICAL MANIFESTATIONSThe articular findings of gout are

similar in men and women. Podagra iscommonly the initial manifestation ofgout in both genders. However, duringthe course of the disease, women tend tohave more upper extremity joint involve-ment, and the onset of the gout attack ismore often insidious in women. In somestudies, women were more often afflictedwith polyarticular gout. In fact, in ananalysis of 92 women with gout byMeyers, et al, 70% of women presentedwith pauciarticular or polyarticular dis-ease, and only 24% of those patients gavea history of preceding acutemonoarticular attacks.6 In some studies,women were shown to have higher inci-dence of tophi at presentation. Lally’sstudy, however, did not find a significantdifference between tophi in men versuswomen at presentation.2

According to the data reported byPuig, et al. the mean serum uric acid lev-els in women (541µmol/L) with gout hasbeen shown to be significantly higherthan those seen in men (476µmol/L).This finding was supported by severalother studies, including the studies byLally and Meyers.2,6 Puig also noted alower mean urinary uric acid excretionin women with gout. This finding was

independent of age, renal insufficiency,alcoholism or previous diuretic use.5

The diagnosis of gout should espe-cially be considered in postmenopausalwomen, women who have associated co-morbidities, women who are taking di-uretics, women who have a positive fam-ily history, or women who present withan atypical pattern of inflammatory ar-thritis. Special attention should be givento women with nodal OA in order thatcoexisting gouty arthritis not be over-looked.

TREATMENT CONSIDERATIONSOnce the diagnosis of gout is made,

treatment is basically the same in men andwomen. Recommendations are aimed atdecreasing the modifiable risk factors, i.e.,avoid alcohol, discontinue diuretics if pos-sible, maintain normal serum glucose lev-els and blood pressure, maintain ideal bodyweight and consume a diet low in redmeat, fructose, and shell fish.

The use of medications is often re-quired for treatment of acute gout andmaintenance of normal serum uric acid.The most commonly recommendedtherapies for acute gout include nonste-roidal anti-inflammatory drugs(NSAIDs), such as indomethacin ornaproxsyn, intra-articular corticosteroidinjections, oral colchicine, and oral cor-ticosteroids. Uricosuric drugs such asprobenecid, and the xanthine oxidaseinhibitors allopurinol, and the newlyFDA approved drug febuxostat are indi-cated for the control of hyperuricemiain gouty patients. The proper use of thesemedications is discussed elsewhere in thisjournal.

Premenopausal women who arepregnant, or plan to become pregnantrequire special consideration. Colchicineand allopurinol are both classified as cat-egory C. Both enter the breast milk, andshould be used with caution. NSAIDsare category C/D. They also enter thebreast milk, and use is not recommendedin females who are or may become preg-nant. Sufficient data on febuxostat is notavailable for use in pregnant or lactatingwomen, therefore, avoidance is recom-mended in that group. For acute flaresof gout in pregnant or lactating women,prednisone may be the best option fortreatment.

Figure 1: The hand of a 90-year-old woman with her first presentation of gout.Inflammation occurring in a joint with preexisting nodal osteoarthritis may obscure the

correct diagnosis.

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REFERENCES1. Arromdee E, Michet CJ, et al. Epidemiology of

gout. J Rheumatol 2002; 29:2403-6.2. Lally EV, Ho Jr G, Kaplan SR. The clinical spec-

trum of gouty arthritis in women. Arch InternMed 1986; 146:2221-5.

3. De Souza AWS, Fernandes V, Ferrari AJL. Fe-male gout. J Rheumatol 2005; 32:2186-8.

4. Harrold LR, Yood RA, et al. Sex differences ingout epidemiology. Ann Rheum Dis 2006;65:1368-72.

5. Puig JG, Michan AD, et al. Female gout. ArchIntern Med 1991; 151:726-32.

6. Meyers OL, Monteagudo FS. A comparison of goutin men and women. S Afr Med J 1986; 70:721-3.

7. Hak EA, Choi HK. Menopause, postmenopausalhormone use and serum uric acid levels in USwomen – The third national health and nutri-tion examination survey. Arthritis Research &Therapy 2008; 10:R116.

8. Pui K, Waddell C, Dalbeth N. Early onset ofhyperuricaemia and gout following treatment forfemale to male gender reassignment. Rheumatol(Oxford) 2008;;47:1840-1.

9. Yu T. Some unusual features of gouty arthritis infemales. Semin Arth Rheum 1977; 6:247-55.

10. Hayem G, Delahousse M, et al. Female premeno-pausal tophaceous gout induced by long termdiuretic abuse. J Rheumatol 1996; 23:2166-7.

11. Nakazawa F, Ishihara H, Tanaka K. A case of femalepremenopausal tophaceous gout requiring surgicalmanagement. Mod Rheumatol 2004; 14:383-7.

12. Rott KT, Agudelo CA. Gout. JAMA 2003;289:2857-60.

13. Choi HK, Ford ES. Haemoglobin A1C, fastingglucose, serum C-peptide and insulin resistancein relation to serum uric acid levels-the third na-tional health and nutrition examination survey.Rheumatol 2008; 47:713-7.

14. Chou P, Lin KC, Tsai ST. Gender differences inthe relationships of serum uric acid with fastingserum insulin and plasma glucose in patients with-out diabetes. J Rheumatol 2001; 28:571-6.

Jill McClory, MD, formerly a Fellowin Rheumatology at Rhode Island Hospital,is a rheumatologist with Piedmont Rheuma-tology, PA, in Hickory, North Carolina.

Nuha Said, MD, is a member of theacademic rheumatology faculty at RogerWilliams Medical Center.

Disclosure of Financial InterestsThe authors have no financial inter-

ests to disclose.

CORRESPONDENCENuha Said, MDRoger Williams Medical CenterDivision of Rheumatology825 Chalkstone AveProvidence, RI 02908e-mail: [email protected]


Treatment Failure GoutSaman Ali, MD, and Edward V. Lally, MD

�Treatment options for gout are wellestablished and reasonably effective.1

They include anti-inflammatory agentssuch as non-steroidal anti-inflammatorydrugs (NSAIDS), glucocorticoids andcolchicine and urate-lowering therapiessuch as allopurinol and probenecid.However, despite the availability of effec-tive urate-lowering therapy, there remainsa subset of patients with gout who, de-spite aggressive therapy, have intractabledisease, manifest as recurrent gout flares,chronic arthritis and progressive topha-ceous deposits. These patients are referredto as having “refractory gout” or “treat-ment failure gout” (TFG).1 The term“treatment failure gout” includes five waysby which patients may develop poorlycontrolled disease. These pertain mainlyto the use of urate-lowering therapy andinclude delayed prescribing, inadequatedosage, intolerance, noncompliance andinadequate response in spite of generallyacceptable dosages.2 (Table 1) The newxanthine oxidase inhibitor febuxostat(Uloric) has not been studied in TFG,but may ultimately prove useful for thisindication. Febuxostat is discussed else-where in this journal.

Regardless of the pathway, all pa-tients with treatment failure gout areunable to reduce and maintain serumurate below the therapeutic target of 6mg/dl. 2 An estimated 100,000 to300,000 of the nearly 3 million cases ofgout in the US are not adequately man-aged with current therapies.3 Addition-ally, many patients with gout have signifi-cant and multiple co-morbidities thatpreclude the use of those therapies.

Allopurinol, the most common treat-ment used to lower serum urate levels, isgenerally regarded as safe and effective.3

It lowers serum urate by inhibiting thepurine nucleotide pathway enzyme xan-thine oxidase. However, about 20% ofpatients receiving allopurinol report sideeffects and about 5% discontinue themedication due to intolerance.4 Allopu-rinol may also be contraindicated becauseof potential adverse drug interactionwith azathioprine.5 Moreover, the pres-ence of kidney disease may preclude ad-

equate dosing because allopurinol-relatedtoxicity is increased in the presence of sig-nificant renal impairment. Even thoughsevere toxicity is rare, inadequate dosingof allopurinol to achieve target serumurate level <6.0 mg/dl is common. Non-compliance is another common problemwith allopurinol: in one study patients ina managed care cohort were non-com-pliant with allopurinol about 44% of thetime.2

Probenecid is the only uricosuricagent available in the United States. How-ever, its use has declined due to impor-tant interactions with several other medi-cations such as heparin, furosemide, as-pirin and NSAIDS. Dosing is also a prob-lem since probenecid is optimally admin-istered twice or thrice daily, making fullcompliance difficult. There is also risk ofcentral nervous system toxicity manifest-ing as seizures and respiratory arrest athigher doses.4,5 Most importantly,probenecid loses all of its uricosuric ac-tivity when the glomerular filtration ratefalls below 50 ml/minute, a common situ-ation in patients with gout.3

Benzbromarone is a more potenturisocuric agent than probenecid. It iseffective even in patients with moderaterenal failure. However, it is potentiallyhepatotoxic, with reports of fatal hepati-tis, and is not commercially available inthe United States.4,6

Additionally, the use of uricosuricagents requires that patients maintainadequate hydration because the risk ofnephrolithiasis is increased in poorly hy-drated patients, particularly individuals

with cardiovascular disease or those re-ceiving diuretic agents.

Patients with TFG experience signifi-cant joint pain and swelling, impairedfunctional status, chronic pain and re-duced quality of life. In a recent study toassess the quality of life and disability in agroup of subjects with TFG, the authorsfound that severe gout is associated withpoor health related quality of life(HRQOL) and disability, especially forpatients who experience more gout flaresand have greater number of joints in-volved.7

Accordingly there is a need for im-proved therapies that will allow treatmentfor this population by controlling theconsequences of hyperuricemia. Fortu-nately, several newer agents developed orbeing developed will be useful for patientswith TFG. We will review pharmacologictherapy and also address the role of sur-gery in patients with TFG.

URICASE“Urate oxidase” or “uricase” is a he-

patic enzyme that catalyses the enzymaticoxidation of uric acid to allantoin, a moresoluble and easily excreted end productof purine metabolism.4 Humans andhigher primates experienced the muta-tional loss of the enzyme uricase duringthe process of evolution. The absence ofa functional urate oxidase gene predis-poses humans to hyperuricemia andgout.2

In contrast to allopurinol, whichprevents the production of uric acid,uricase is capable of reducing existingurate stores such as found in gouty jointsand tophi. Thus treatment with uricasehas potential as a powerful therapy forthe management of severe tophaceousgout.4

Two types of uricase, rasburicase andpegloticase, have been studied for thetreatment of gout.

RASBURICASEA purified fungal (Aspergillus flavus)

uricase has been used for many years inEurope to prevent urate nephropathyduring chemotherapy for hematologic

…before surgery isconsidered for thetreatment of gout,

optimal urate-lowering medicaltherapy should be

employed to reducethe size of tophi.


malignancies. A recombinant Aspergillusflavus uricase, known as rasburicase, be-came available in the US in 2002 andhas been approved by the Food and DrugAdministration (FDA) for use in patientsfor the prevention of tumor lysis syn-drome after chemotherapy.8,9 For thisindication, the recommended dosage is0.20 mg/kg per day for 5-7 days admin-istered intravenously (IV). It has beendemonstrated to be superior to allopu-rinol in the control of serum urate in arandomized trial of pediatric and adultpatients at risk for tumor lysis syndrome.10

Although the FDA has not approvedrasburicase for the management of gout,a number of case reports and small serieshave described its use in patients withsevere tophaceous gout.

A 56-year-old woman with chronicrenal insufficiency and severe recurrentgouty arthritis who had an allopurinolhypersensitivity reaction was treated suc-cessfully with 10 IV infusions ofrasburicase over 16 months. Rasburicasetreatment was well tolerated without al-lergic side effects, but she did have goutflares during the first three infusions.After the sixth infusion, the patient haddramatic regression of hand synovitis,resolution of gouty tophi and restorationof functional capacity to both hands. Herrenal function remained stable.11

Another case was reported of a 33-year-old renal transplant patient with re-current gout attacks and an allergy to al-lopurinol. She had also had surgery forrecurrent tophi. She was begun onrasburicase infusions at a dose of 0.15mg/kg IV monthly. Rasburicase therapywas well tolerated and produced no ad-verse effects other than occasional goutflares which resolved with a decrease inthe dose. During the 3 years of treatmentthe patient experienced resolution of goutattacks; the size of tophi decreased sub-stantially and her functional status im-proved.12

In a retrospective study of 10 pa-

tients, the short term safety and efficacyof rasburicase 0.2 mg/kg in monthly vs.daily dosing schedules was compared inpatients with renal failure and tophaceousgout, not adequately treated by allopu-rinol. The 5 patients receiving a daily in-fusion for 5 days had rapid but not sus-tained reduction in serum urate concen-tration and did not have any reductionin tophus size. Fifty percent of the pa-tients in the group receiving monthly in-fusions for 6 months had reduction intophus size. Serum urate was dramaticallydecreased with maximal decline at 7 days.Eight of ten patients experienced goutflares that were treated with colchicineand NSAIDs. Two patients also had hy-persensitivity reactions to the medica-tion.13

Rasburicase has a short half-life (18hours) requiring repeated infusions. It isknown to be antigenic. This raises theconcern for hypersensitivity and de-creased efficacy with repeated adminis-tration. Studies have demonstrated thattime to detection of antibodies rangesfrom 1-6 weeks after administration andthat the presence of antibodies is not as-sociated with severe side effects. One ofthe byproducts of urate breakdown byuricase is hydrogen peroxide. ThereforeG6PD deficiency contraindicates treat-ment with rasburicase because of risk ofhemolysis. Other side effects include fe-ver, respiratory distress, sepsis, neutrope-nia and mucositis.14

Although the results from these re-ports appear promising, data regardingoptimal dosing and interval between in-fusions are lacking due to the absence oflarger clinical studies of rasburicase ingout.

PEGLOTICASEPegloticase is a genetically engi-

neered, recombinant polyethylene glycol(PEG)-conjugated mammalian uricase. Apegylated form of uricase has been for-mulated with the potential for reduced

immunogenicity and a longer half-life.Pegloticase has been studied extensivelyto evaluate both efficacy and safety intreatment failure gout. It is undergoingclinical trials in human subjects.

The results of two phase I clinicaltrials involving subcutaneous and IV in-fusions of PEG-conjugated uricase(pegloticase) demonstrated that this agentrapidly lowered and maintained serumurate levels at <6.0 mg/dl for a 2-3 weekperiod. The bioavailability, efficacy andtolerability of IV pegloticase were greaterthan that of subcutaneous pegloticase.15,16

In a phase II trial, 41 patients wererandomized to undergo 12 weeks of treat-ment with IV pegloticase at 4 or 8 mgevery 2 weeks for six doses, and 8 or 12mg every 4 weeks for three doses. Serumuricase activity, serum urate and antipegloticase antibodies were measured.Pegloticase was effective in rapidly reduc-ing and maintaining serum urate levelsat <6mg/dl in most patients in whomconventional therapy had been unsuc-cessful. The most effective dose was 8 mgevery 2 weeks. The most common sideeffects were gout flares, which were mildto moderate in severity.17

The results of phase III clinical tri-als were presented in abstract form at theAmerican College of Rheumatologymeeting in 2008. Two hundred twelvepatients with TFG were treated with IVpegloticase or placebo in replicate 6month randomized, double blind stud-ies. Subjects were randomized topegloticase 8 mg q2week, 8mg q4weekor placebo. The primary endpoint wasplasma uric acid concentration <6mg/dland the secondary endpoints were reduc-tion in tophus size, gout flare incidence,swollen joints, tender joints, quality of lifeby SF-36 and disability by HAQ-DI andsafety. Complete resolution of =1 tophusoccurred in 21/52 q2week, 11/52q4week and 2/29 placebo subjects. SF-36 physical component summary scoreand HAQ-DI for physical functioningimproved significantly in both groups.

Gout flares and infusion reactionswere the most common adverse events.Infusion reactions were the most com-mon reason for withdrawal. The studyconcluded that 40% of patients treatedwith pegloticase achieved primary end-point.

Table 1. Mechanisms of Treatment Failure Gout

1.Physician failure to diagnose and treat gout2.Inadequate dosing of urate-lowering therapy3.Allergy or intolerance to urate-lowering therapy4.Inadequate response to adequate dosing of urate-lowering therapy5.Lack of compliance with prescribed therapy


SURGICAL THERAPY FOR GOUTThe use of surgical intervention for

gout dates back to the time ofHippocrates, when relief from severepain was provided by burning the pain-ful tophus with crude flax. Before theintroduction of effective urate loweringtherapy in the management of gout, sur-gery was frequently used for cosmetic rea-sons or for removal of large deposits ofsodium urate.18

Tophi are characteristically depositedin articular and periarticular structures,and have a predilection for avascular struc-tures. Nerves, blood vessels and musclesare not usually involved. Straub et al con-densed and reclassified the earlier indica-tions of Linton and Talbot for surgery ingout into four main categories: 1) func-tional: excision to permit wearing of shoesand clothing, restoration of motion, andstabilization of joints; 2) symptomatic: con-trol of drainage and infection, reductionof pain and decompression of nerves; 3)cosmetic restoration and 4) metabolic:decrease of total body urate.19

The role of surgery for gout is nowgenerally limited to the complications oftophaceous disease which include infec-tion, nerve compression due to mass ef-fect of the tophus, joint deformity andintractable pain. Tophaceous gout maycompress peripheral nerves, the caudaequina or the spinal cord in which caseprompt surgical intervention is neededto prevent permanent neurological im-pairment.

In a retrospective analysis of 45 pa-tients who underwent surgery for goutytophi, sepsis control in infected or ulcer-ated tophi was the main indication forsurgery (51%), followed by mechanicalproblems caused by foot, elbow and handtophi (27%). Four percent of patientsunderwent tophus surgery mainly forpain control.20

Recurrence of tophi is unpredict-able. In the series of Straub, 36 proce-dures were performed and tophi re-curred in only 3 cases. However, fewclinical trials address the long term effi-cacy of surgery in the management oftophaceous disease.

It is universally recommended thatbefore surgery is considered for the treat-ment of gout, optimal urate-loweringmedical therapy should be employed toreduce the size of tophi.

REFERENCES1. Fels E, Sunday JS. Refractory gout. Current Opin-

ion Rheumatol 2008; 20:198-202.2. Sundy JS, Hershfield MS. Uricase and other novel

agents for the management of patients with treat-ment failure gout. Curr Rheumatol Rep 2007; 9:258-64.

3. Edwards NL. Treatment-failure gout. ArthritisRheum 2008; 58: 2587-90.

4. Stamp LK, O’Donnell JL, Chapman PT. Emerg-ing therapies in the long-term management ofhyperuricemia and gout. Intern Med J 2007 Apr;37: 258-66.

5. Bardin T. Current management of gout in pa-tients unresponsive or allergic to allopurinol. JointBone Spine 2004; 71: 481-5.

6. Chohan S, Becker MA. Update on emergingurate-lowering therapies. Curr Opin Rheumatol2009; 21: 143-9.

7. Becker MA, Schumacher HR, et al. Quality of lifeand disability in patients with treatment-failuregout. J Rheumatol 2009; 36: 1041-8.

8. Bomalaski JS, Clark MA. Serum uric acid-loweringtherapies. Curr Rheumatol Rep 2004; 6:240-7.

9. Schumacher HR, Chen LX. Newer therapeuticapproaches. Rheum Dis Clin North Am 2006; 32:235-44.

10. Goldman SC, Holcenberg JS, et al. Blood 2001;97:2998-3003.

11. Richette P, Bardin T. Successful treatment withrasburicase of a tophaceous gout in a patient aller-gic to allopurinol. Nat Clin Pract Rheumatol 2006;2:338-42.

12. Vogt B. Urate oxidase (rasburicase) for treatmentof severe tophacheous gout. Nephrol Dial Trans-plant 2005:20: 431-3.

13. Richette P, Briere C, et al Rasburicase for topha-ceous gout not treatable with allopurinol. JRheumatol 2007; 34: 2093-8.

14. Pui C. Rasburicase. Expert Opin Pharmacother2002; 3: 433-42

15. Ganson NJ, Kelly SJ, et al Control of hyperurice-mia in subjects with refractory gout, and induc-tion of antibody against poly (ethyleneglycol)(PEG), in a phase I trial of subcutaneousPEGylated urate oxidase. Arthritis Res Ther2006;8(1):R12.

16. Sundy JS, Ganson NJ et al. Pharmacokinetics andpharmacodynamics of intravenous PEGylated recom-binant mammalian urate oxidase in patients with re-fractory gout. Arthritis Rheum 2007; 56: 1021-8.

17. Sundy JS, Becker MA, et al. Reduction of plasmaurate levels following treatment with multipledoses of pegloticase (polyethylene glycol-conju-gated uricase) in patients with treatment-failuregout. Arthritis Rheum 2008; 58: 2882-91.

18. Casagrande PA. Surgery for tophaceous gout. Semi-nars Arthritis Rheumatism 1971; 1: 262-73.

19. Straub LR, Smith JW, et al The surgery of gout inthe upper extremity. J Bone Joint Surg Am 1961;43:731-74.

20. Kumar S, Gow P. A survey of indications, resultsand complications of surgery for tophaceous gout.N Z Med J 2002; 115:U109.

Saman Ali, MD, is a Fellow in Rheu-matology at Roger Williams Medical Center.

Edward V. Lally, MD, is Director ofthe Division of Rheumatology at Rhode Is-land Hospital and Professor of Medicineat the Warren Alpert Medical School ofBrown University.

Disclosure of Financial InterestsSaman Ali, MD, has no financial in-

terests to disclose.Edward V. Lally, MD. Consultant:

Abbott Laboratories, Gilead Science.

Discussion of off-label usage of product:pegloticase, rasburicase

CORRESPONDENCEEdward V. Lally, MD2 Dudley Street, Suite 370Providence, RI, 02905e-mail: [email protected]


Intranasal Mucosal Malignant MelanomaRobert Bagdasaryan, MD, Mark Andreozzi, DO

Images In Medicine

A 84-year old woman with left-sided pansinusitis had alarge mass in the left nasal cavity which was removed withendoscopic surgery. Histologically, the tumor demon-strated highly abnormal malignant cells with increasedmitotic activity without necrosis. Immunohistochemically,malignant cells express Pan-Melanoma Marker and S-100protein. All others, including organ-specific markers arenot expressed.

Fortunately, primary malignant mucosal melanomaof the head and neck is rare. Approximately 1% of allmelanomas are mucosal melanomas, and ~55% of theminvolve mucous membranes of head and neck.1

In sinonasal melanoma, ~57% patients present withsymptoms of obstruction, followed by epistaxis (52%).In the late stages of disease, rhinorrhea, epiphora, prop-tosis, facial pain, and swelling may occur.

Once mucosal melanoma is discovered, the maingoal is to gain local control at the primary site. If localcontrol is achieved, patients have a better survival and adecreased chance of developing distant metastasis.2

Drug regimens for treating mucosal melanoma arestill in the trial phase.

Gene therapy is also a possible treatment modality.Mucosal melanoma is a rare disease that even with

aggressive resection and treatment still has a poor 5-yearsurvival.

REFERENCES:1. Mucosal melanoma. J La State Med Soc 2005; 157:147-51.2. Malignant mucosal melanoma of head and neck. Cancer 1997,

80:1373-86.

Robert Bagdasaryan, MD, is an attending patholo-gist, Kent County Memorial Hospital.

Mark Andreozzi, DO, is an otolaryngologist, Cranston,Rhode Island.

Disclosure of Financial InterestsThe authors have no financial interests to disclose.

CORRESPONDENCERobert Bagdasaryan, M.D.E-mail: [email protected]

H&E, high power view.

Pan-Melanoma marker expression.

S-100 protein expression.


Use of Angiotensin-Converting Enzyme Inhibitors/AngiotensinReceptor Blockers and Lipid-lowering Therapies among RhodeIslanders with Diabetes Enrolled in Medicare Part D Plans in

2006 and 2007Stephen Kogut, PhD, MBA, RPh, Aisling Caffrey, PhD, and Lynn Pezzullo, RPh

ADVANCES IN PHARMACOLOGY

DISCLAIMERThe analyses upon which this publication is based were per-formed under Contract HHSM-500-2006-RI, ‘‘Utilizationand Quality Control Peer Review Organization for the Stateof Rhode Island,’’ sponsored by CMS, Department of Healthand Human Services. The contents of this publication do notnecessarily reflect the views or policies of the Department ofHealth and Human Services, nor does mention of trade names,commercial products, or organizations imply endorsement bythe U.S. government. The authors assume full responsibility forthe accuracy and completeness of the ideas presented. This ar-ticle is a direct result of the Health Care Quality ImprovementProgram initiated by CMS, which has encouraged identifica-tion of quality improvement projects derived from analysis ofpatterns of care and therefore required no special funding onthe part of this contractor. Feedback to the authors concerningthe issues presented is welcomed.

WITH THE INTRODUCTION OF MEDICARE PART D IN 2006, MEDICARE

Quality Improvement Organizations (QIOs) were directedto collaborate with Medicare Part D prescription drug planproviders to improve the safety, efficiency and effectiveness ofprescription drug use.1 Quality Partners of Rhode Island, theMedicare-contracted QIO for Rhode Island, initiated an ef-fort to improve the quality of medication use among that state’sMedicare beneficiaries with diabetes mellitus. Selecting diabe-tes presented a logical starting point, because epidemiologicstudies have described the under-use of medications.2-7 Addi-tionally, patients with diabetes can be identified from phar-macy claims data with an acceptable level of specificity.

This initiative sought to increase the use of lipid-loweringand angiotensin-directed drug therapies (i.e. angiotensin-con-verting enzyme inhibitors (ACEIs) and angiotensin receptorblockers (ARBs)), from the perspective of both prescribing andpatient adherence. When this study was initiated, the Ameri-can Diabetes Association (ADA) recommended that all seniorpatients with diabetes be treated with statin therapy to achievecholesterol reduction, regardless of baseline LDL level.8 TheADA also recommended that ACEI/ARB therapy be pre-scribed for patients having both diabetes and hypertension, a

group which comprised “the majority of people with diabe-tes”.8 The ADA noted that “ACE inhibitors have been shownto improve cardiovascular outcomes in high–cardiovascular riskpatients with or without hypertension.”

Quality Partners collaborated with the University of RhodeIsland College of Pharmacy, provider groups, and several Medi-care Part D drug plans in the state. The initiative included aca-demic detailing by a clinical pharmacist, presentations at phy-sician group meetings, dissemination of educational materials,and targeted letters presenting physician-level prescribing ratesfor ACEI/ARB and lipid-lowering therapies. The audiencelearned the utilization rates of ACEI/ARB and lipid-loweringtherapies among Part D plan enrollees having diabetes, andthe significant differences in the rates of use of these therapiesamong sub-groups. This report presents that data.

METHODSWe conducted cross-sectional analyses of dispensings of

ACEI/ARB and lipid-lowering drugs for two 6-month peri-ods: January 1 - June 30th, 2006; and January 1 - June 30th,2007. Pharmacy data were provided by several but not allMedicare Part D prescription drug plans operating in RhodeIsland during 2006 and 2007. The pharmacy data includedpatient age and gender; a prescriber identifier (DEA number);the drug name and quantity, and the date of dispensing. For2007, information describing gender was missing for approxi-mately one-third of patients and was imputed based on thepercentage of patients in the population for which gender wasdocumented.

Among patients receiving medications for diabetes, wedetermined the percentage of patients who were dispensed anACEI/ARB and a lipid-lowering drug therapy at least onceduring a 6-month period. Lipid-lowering therapies includedboth statin and non-statin medications.

We classified age as 50-64 years, 65-74 years, or 75 years ofage or older. We hypothesized that medication utilization wouldbe higher among patients with coronary artery disease, and weused the proxy of receiving a prescription for a nitrate-contain-ing product to identify this comorbidity. We also sought to de-termine if ACEI/ARB and lipid-lowering therapy utilization rateswere higher among patients receiving care from one of the phy-sician group practices that were participating in this initiative,


and thus compared rates of use among patients receiving pre-scriptions from physicians affiliated with these groups versus pa-tients receiving prescriptions from physicians not affiliated withthese groups. ACEI/ARB and lipid-lowering therapy rates wereassessed among patients receiving at least one dispensing for anymedication from an endocrinologist as compared to patients whodid not receive prescriptions from an endocrinologist.

Within-group comparisons for each year were conducted,and reported here as the frequency and percent of use of ACEI/ARB and lipid-lowering medications. For these analyses we as-sessed the statistical significance of group differences using thechi-square test.

RESULTSPart D pharmacy data were provided for nearly 38,000

Medicare beneficiaries, representing approximately 40% of thepopulation of beneficiaries enrolled in Medicare drug plans inRhode Island during 2006 and 2007. For 2006, we identified5,009 patients who received medications for diabetes; in 2007,7,331 such patients.

Table 1 presents descriptive statistics for the patients. Mostwere older: roughly 12% were younger than 65 years. Ap-proximately 9% of patients received dispensings for nitrate-containing medications. Slightly more than half of patients(56%) received medications from a practitioner affiliated withone of the collaborating group practices. Roughly 15% of pa-tients received medication from an endocrinologist.

Table 2 presents overall rates of use of ACEI/ ARB andlipid-lowering therapies for the two periods. For the analysisusing 2006 data, 69% of beneficiaries received at least onedispensing for an ACEI or ARB medication, and 63% of pa-

tients received at least one dispensing for a lipid-lowering drug.In the following year, 70% of patients received at least onedispensing for an ACEI or ARB medication, and 65% receivedat least one dispensing for a lipid-lowering drug. The increasedutilization of lipid-lowering therapy observed between 2006and 2007 was statistically significant (p<0.05).

Table 3 presents the patient characteristics identified inTable 1 by ACEI/ARB and lipid-lowering therapy utilizationfor the 2007 period. Statistically significant differences (p<0.05)were found for nearly all comparisons. Both the youngest andoldest patient groups were found to be less likely to receivethese drug therapies, compared with patients in the 65-74 agecategory. Women received these drug therapies more frequentlythan men (74% versus 70% for ACEI/ARB therapy; 70% ver-sus 63% for lipid therapies), as did patients who also receiveddispensings for nitrate-containing products (75% versus 69%for ACEI/ARB therapy; 77% versus 64% for lipid therapies).Patients receiving prescriptions from physicians affiliated withone of the group practice collaborators more frequently re-ceived an ACEI/ARB or lipid-lowering therapy (72% versus68% for ACEI/ARB therapy; 68% versus 62% for lipid-low-ering therapies, p<0.05 for both comparisons ). Patients whoreceived prescription dispensings from an endocrinologist re-ceived both ACEI/ARB and lipid-lowering therapies more fre-quently, yet only the latter was a statistically significant differ-ence (p<0.05).

DISCUSSIONOur study reveals that a majority of the Medicare benefi-

ciaries with diabetes identified in this analysis were receiving lipid-lowering and ACEI/ARB therapies. But a substantial percent-age of patients with diabetes did not receive these therapies.

These results suggest higher ACEI/ARB and lipid-lower-ing therapy utilization rates in Rhode Island than those reportednationally and in other locales. For example, using data from the2003 Medicare Current Beneficiary Survey, Tjia and Briesacher3

reported ACEI/ARB and statin rates of use among seniors withdiabetes to be less than 50%. In another study using data fromthe National Ambulatory Medical Care Survey, Segars and Lea2

found that fewer than one in four visits made by diabetic pa-tients included mention of the prescribing of a statin medica-tion. In another study of more than 30,000 diabetic Medicarepatients in Pennsylvania, Winkelmayer et al4 reported rates ofuse of ACEI/ARB therapy to be approximately 50%.

Table 1. Patient and Provider Characteristicsamong a Sample of Diabetic Medicare Part D

Plan Enrollees in Rhode Island, 2006 and 2007

Characteristics January 1 – January 1 –June 30, 2006 June 30, 2007N = 5,009 N = 7,331n (%) n (%)

Age (years) 50-64 621 (12.4) 916 (12.5) 65-74 2,080 (41.5) 3,108 (42.4) 75 + 2,308 (46.1) 3,307 (45.1)Gender Female 2,989 (59.7) 4,390 (59.9) Male 2,020 (40.3) 2,940 (40.1)Coronary arterydisease(receiving nitrates) Yes 461 (9.2) 635 (8.7) No 4,548 (90.8) 6,696 (91.3)Physician affiliation Group practice collaborator 2,795 (55.8) 4,083 (55.7) Other 2,214 (44.2) 3,248 (44.3)Endocrinologist care Yes 708 (14.1) 1,071 (14.6) No 4,301 (85.9) 6,260 (85.4)

Table 2. Use of ACEI/ARB and Lipid-loweringMedications among a Sample of DiabeticMedicare Part D Plan Enrollees in Rhode

Island, 2006 and 2007

January 1 – January 1 –June 30, 2006 June 30, 2007N = 5,009 N = 7,331n (%) n (%)

ACEI/ARB 3,478 (69.4) 5,123 (69.9)Lipid therapy 3,165 (63.2) 4,796 (65.4)Abbreviation: ACEI/ARB = angiotensin-converting enzyme inhibitors andangiotensin receptor blockers


Caution should be applied in comparing our results withother research, given differing data sources, populations, andmethodologies. Yet it is evident that in our study, ACEI/ARBand lipid-lowering medications were frequently prescribedamong diabetic Medicare beneficiaries, and at higher rates thanreported elsewhere.

Patients in the 65-74 year old age group received bothmedication classes more frequently than those in the youngerand older age categories. Perhaps this indicates a greater preva-lence of severe illness among the oldest patients, such as ad-vanced renal disease and other conditions where lipid man-agement was a lesser priority. Yet the less frequent utilization oflipid-lowering medications among the oldest patients perhapsreflects a lack of clinical aggressiveness that may not be justi-fied.9 The lower frequency of use of these medications amongyounger patients is also of concern. Physicians may be less in-clined to prescribe these medications among younger, healthierdiabetic patients. Perhaps this results from younger patients’poorer adherence in refilling medications. Regardless of thecause, our analyses point out that younger diabetic patientsreceived these medications less frequently.

To determine if these medications were more likely to bereceived among patients having coronary disease, we used aproxy of receiving nitrate-containing prescriptions to identifysuch patients. While this method is a poorly sensitive means foridentifying patients with coronary disease, we believed it to besufficiently specific, and would provide some evidence ofknown-groups validity. The results revealed that patients re-

ceiving prescriptions for nitrate-containing medications alsomore frequently received ACEI/ARB and lipid-lowering medi-cations. Among users of nitrate-containing products, approxi-mately 1 in 4 did not receive a dispensing for a lipid-loweringmedication during the study timeframe.

This project entailed collaboration with local physiciangroup practices. We sought to determine if ACEI/ARB andlipid-lowering drug utilization rates were higher among physi-cians affiliated with these practices, compared with overall ratesamong physicians not affiliated with these practices. We foundthat rates of use of these medications were higher for patientsreceiving prescriptions from physicians affiliated with one ofthe collaborating group practices

As a final sub-group analysis, we determined if rates ofmedication use were higher when a patient was receiving carefrom an endocrinologist. Indeed, patients receiving medica-tions from an endocrinologist more frequently filled prescrip-tions for ACEI/ARB and lipid-lowering therapies, with a sub-stantial and statistically significant difference in the use of lipid-lowering therapies (72% versus 64%, p<0.05). While one maytheorize that patients receiving care from an endocrinologistmay have been further along the continuum of disease, we notethat statin therapy is recommended for most senior patientswith diabetes.10, 11

Several factors may explain why the utilization rates for thesemedications are less than 100%. First, the pharmacy claims dataused for this analysis identified dispensed prescriptions only. It islikely that many patients were prescribed these medications yetdid not refill them, because patient adherence to chronic medi-cation therapies is poor.12, 13 For this reason we applied a liberalthreshold in classifying patients as using these therapies, givingcredit even if a patient received just one prescription dispensingduring the 6-month measurement period.

A second explanation for the lower calculated rates of useof these medications pertains to our inability to identify andexclude patients having a contraindication to these drug thera-pies. However, for both lipid-lowing and ACEI/ARB medica-tions, many types of contraindications to one class of drugswould not preclude the use of a medication from a differentclass. For example, ARB medications would be an acceptablealternative for most patients that experienced a bothersomecough from an ACEI. Similarly, because some patients arepoorly tolerant of statin medications, we also included non-statin lipid-lowering medications such as fibrates and bile acidresins in our analysis. We do not mean to imply that these otherclasses of lipid-lowering medications are acceptable and evi-dence-based alternatives to statin therapy, but rather may havebeen a necessary second-line option.

Third, patients may have received medications as samples,or bought these medications for cash through discount pro-grams (e.g. $4 generics). The data provided by the Part Ddrug plans would not have captured this data. Yet the pa-tients in this study were identified as having diabetes basedon their receipt of prescription medication dispensings forhypoglycemic medications under Part D, indicating that pa-tients were utilizing their Part D benefit at least to purchasesome drugs.

Table 3. Use of ACEI/ARB and Lipid-loweringMedications According to Patient and Provider

Characteristics, January 1 – June 30, 2007(N = 7,331)

Characteristic ACEI/ARB Lipid therapyn (%) n (%)

Overall percentage: 5,123 (69.9) 4,796 (65.4)Age (years) 50-64 611 (66.7) 591 (64.5) 65-74 2,280 (73.4) 2,190 (70.5) 75 + 2,232 (67.5) 2,015 (60.9)Gender Female 3,236 (73.7) 3,090 (70.4) Male 2,063 (70.2) 1,840 (62.6)Coronary artery disease(receiving nitrates) Yes 473 (74.5) 488 (76.9) No 4,650 (69.4) 4,308 (64.3)Physician affiliation Group practice collaborator 2,930 (71.8) 2,769 (67.8) Other 2,193 (67.5) 2,027 (62.4)Endocrinologist care Yes 770 (71.9) 774 (72.3) No 4,353 (69.5) 4,022 (64.3)Abbreviation: ACEI/ARB = angiotensin-converting enzyme inhibitors andangiotensin receptor blockers p < 0.05 for all comparisons except by endocrinologist care among patientsreceiving ACEI/ARB therapy


Fourth, to mitigate the potential effect of being in the PartD coverage gap (i.e. the “donut hole”), we analyzed pharmacyclaims data from the first 6 months of the year, before mostpatients would have fallen into that gap.

CONCLUSIONThis report describes rates of use of two clinically impor-

tant drug therapies for patients having diabetes mellitus. Whilea majority of patients were receiving these medications, approxi-mately 30% of patients did not fill prescriptions for an ACEI/ARB therapy, while 35% of patients did not receive a dispens-ing for a lipid-lowering medication. We note that this may re-flect either failure to prescribe, or the failure of patient persis-tence in refilling medication. We cannot ascertain which causemay have contributed the most to our findings.

Patients received these medications more frequently if theywere age 65-74 years (compared with younger and oldergroups), and also if they were female. Patients dispensed medi-cations prescribed by a physician affiliated with one of the col-laborating provider groups more frequently received thesetherapies. Lipid-lowering medications were more frequentlyutilized by patients under the care of an endocrinologist.

We hope these findings may help identify patients whoshould be receiving these therapies.

Stephen Kogut, PhD, MBA, RPh, is Associate Professor of Phar-macy Practice, College of Pharmacy, University of Rhode Island.

Aisling Caffrey, PhD, a graduate of the Program inPharmacoepidemiology and Pharmaceconomics, College of Pharmacy,University of Rhode Island, is with the Infectious Diseases ResearchProgram, Providence Veterans Affairs Medical Center.

Lynn Pezzullo, RPh, is Senior Program Administrator, Qual-ity Partners of Rhode Island.


REFERENCES1. Schulke DG, Krantzberg E, Grant J. Introduction: Medicare quality improve-

ment organizations—activities and partnerships. J Manag Care Pharm2007;13:S3-6.

2. Segars LW, Lea AR. Assessing prescriptions for statins in ambulatory diabeticpatients in the United States. Clin Ther 2008;30:2159-66.

3. Tjia J, Briesacher BA. Prescription drug benefits and use of guideline recom-mended medications by elderly Medicare beneficiaries with diabetes mellitus.J Am Geriatr Soc 2008;56:1879-86.

4. Winkelmayer WC, Fischer MA, et al. Underuse of ACE inhibitors and angio-tensin II receptor blockers in elderly patients with diabetes. Am J Kidney Dis2005;46:1080-7.

5. Yan AT, Yan RT, et al. Contemporary management of dyslipidemia in high-riskpatients: targets still not met. Am J Med 2006;119:676-83.

6. Rosen AB. Indications for and utilization of ACE inhibitors in older individu-als with diabetes. J Gen Intern Med 2006;21:315-9.

7. Toth PP, Zarotsky V,et al. Dyslipidemia treatment of patients with diabetesmellitus in a US managed care plan. Cardiovasc Diabetol 2009;8:26.

8. Standards of medical care in diabetes—2006. Diabetes Care 2006;29 Suppl1:S4-42.

9. Ko DT, Mamdani M, Alter DA. Lipid-lowering therapy with statins in high-risk elderly patients. JAMA 2004;291:1864-70.

10. Third Report of the National Cholesterol Education Program (NCEP) ExpertPanel on Detection, Evaluation, and Treatment of High Blood Cholesterol inAdults (Adult Treatment Panel III) final report. Circulation 2002;106:3143-421.

11. Snow V, Aronson MD, et al. Lipid control in the management of type 2diabetes mellitus. Ann Intern Med 2004;140:644-9.

12. Benner JS, Glynn RJ, et al. Long-term persistence in use of statin therapy inelderly patients. JAMA 2002;288:455-61.

13. McDonald HP, Garg AX, Haynes RB. Interventions to enhance patient adher-ence to medication prescriptions. JAMA 2002;288:2868-79.

CORRESPONDENCEStephen Kogut, PhD, MBA, RPh41 Lower College RoadCollege of PharmacyUniversity of Rhode IslandKingston, RI 02881phone: (401) 874-5370e-mail: [email protected]

Maura Goodwin, VP HRGateway Heathcare, Inc.249 Roosevelt Avenue,

Suite 205, Pawtucket, RI 02860Fax 401/722-2250

Email: [email protected] apply online at

www.gatewayhealth.org and click on the employment tab.

Gateway Healthcare is a non-profit behavioral health care organization that provides a wide array of services toadults, children and families in Rhode Island. We provideservices to people of all cultural and economic backgrounds,who may not otherwise have access to the services theyneed. GHI has grown to include more than 41 locationsacross Rhode Island, including Pawtucket, Central Falls,Johnston, Cranston, Middletown, Lincoln, Smithfield,Woonsocket and West Greenwich. Gateway’s tenure in the Rhode Island community boasts an annual clientele ofover 14,000 men, women and children with over $3 milliondollars given in free care each year. Together with our staffof over 700, we continue to expand our services to reflectthe needs of the clients and communities we serve.

We are currently seeking both full time and part time

PSYCHIATRISTSTo join our medical staff in Adult Services. Must be Adultboarded or board eligible. On-call required for two monthsper year. Benefits include malpractice insurance, fourweeks vacation, CME time of one week as well as compet-itive health, dental and other benefits.

Please send current CV as well as references, salary history and cover letter to:


Asymptomatic Versus Symptomatic Urinary Tract InfectionsIn Long-Term-Care-Facility Residents

Porpon Rotjanapan, MD, and David Dosa, MD, MPH

GERIATRICS FOR THEPRACTICING PHYSICIANDivision of Geriatrics Quality Partners of RI

Department of Medicine EDITED BY ANA TUYA FULTON, MD

THE WARREN ALPERT MEDICAL SCHOOLOF BROWN UNIVERSITY

You are in your office seeing patients when a nurse callsfrom the nursing home to report the urinalysis results of Mrs. X.Mrs. X, 75 years-old, with mild Alzheimer’s dementia, was ad-mitted to the facility for rehabilitation and low back pain con-trol after two falls. Her medical history also includes hyperten-sion, hyperlipidemia, chronic obstructive pulmonary disease(COPD), osteoporosis, and two new vertebral compression frac-tures. Yesterday the nursing staff noticed foul smelling urine andcontacted your covering physician for an order to obtain a cleancatch urine. Currently, Mr.s X is afebrile, without any specificcomplaints. She takes oxycodone and acetaminophen for paincontrol, donepezil for her Alzheimer’s, a bisphosphonate for herosteoporosis, and an albuterol inhaler for her COPD. She hasno medication allergies. The urinalysis reveals 20-30 WBC/ml,5-10 RBC /ml, and numerous bacteria. A urine culture has beensent but results are unavailable. The nurse asks whether you wouldlike to start antibiotics.

Urinary tract infections (UTIs) are the most commonbacterial infection in older populations, both in the commu-nity and in the nursing home (NH).1UTIs are the most com-mon reason for antimicrobial prescriptions in NHs, and areresponsible for the initiation of 20-60% of systemic antimi-crobial courses in long term care residents. 2 Fifty percent offemale and 40% of male residents have been reported to havea UTI at one time or another. Nursing home residents are atparticular risk for UTIs. Risk factors for infection in this popu-lation include immobility, which leads to incomplete bladderemptying; poor hygiene, which favors bacterial growth; in-continence; and age-associated physiological changes, suchas a decline in the effectiveness of immune function, loss ofestrogen effect on genitourinary mucosa, and changes in colo-nizing flora. 3-5

Despite the high prevalence of UTIs in the NH, mostpatients are clinically asymptomatic. Numerous organizations(e.g., the American Medical Director’s Association, The In-fectious Disease Society of America) have advocated againstthe treatment of asymptomatic bacteriuria for a number ofreasons. First, the presence of asymptomatic bacteriuria inthe older patient - including the diabetic - does not predictfuture UTI or mortality. 2,6,7 Furthermore, treatment of as-ymptomatic bacteriuria does not prevent recolonization orreduce the risk of developing symptomatic UTI. On the otherhand, unnecessary treatment of asymptomatic UTIs has beencorrelated with increased resistance in colonizing bacteria.

Are there criteria that I can use to determine if my patienthas asymptomatic or symptomatic bacteriuria?

The Department of Health and Human Services and theCenters for Medicare and Medicaid Services issue yearly guide-lines for NHs that state that only residents meeting the McGeerCriteria should be treated for UTI. 8,9 Urine culture results arenot required by these criteria to make a decision on empiricalcoverage. The McGeer criteria for NH residents without anindwelling catheter state that 3 of the following criteria mustbe met to identify a UTI: (1) a temperature of 38 C (100.4 F)or higher; (2) new or increased burning sensation on urina-tion, frequency of urination, or urgency of urination; (3) newflank or suprapubic pain or tenderness; (4) change in charac-ter of urine; and (5) worsening of mental or functional status.Other guidelines for UTIs proposed by Loeb et al. can also beuseful as minimum criteria necessary for empirical antibiotictherapy.10 For nursing home residents without an indwellingcatheter, the Loeb criteria recommend empirical coverage inthe setting of: acute dysuria alone or fever (a temperature ofgreater than 37.9 C (100 F) or an increase of 1.5 C (2.4 F)above baseline temperature) plus at least 1 of the followingsymptoms: new or worsening urgency or frequency of urina-tion, suprapubic pain, gross hematuria, costovertebral angletenderness, or urinary incontinence. 11,12

You decide not to start antimicrobial therapy for Mrs. X,since her clinical presentation does not meet either the McGeer orLoeb criteria. Three months later, Mrs. X develops dysuria and afever to 101. Examination reveals tachycardia and suprapubictenderness. Her urinalysis reveals 30 WBC/ml, 3-5 RBC /ml, 1+squamous epithelial cells. Given her overt symptoms, you decide tostart empiric antibiotic,s pending results from a urine culture.Your patient has no known drug allergies. Which antibiotic is thebest option?

EMPIRICAL TREATMENT FOR SYMPTOMATIC UTISThe treatment of a lower tract UTI can usually be man-

aged in the NH. Choices for empiric regimens should alwaysbe made with the knowledge of the individual nursing home’santibiogram and resistance pattern, and resistance patterns ofthe usual colonizing flora. In most nursing homes, the medicaldirector leads the infection control team and assembles anantibiogram for distribution to other clinicians practicing there.If one is not available, there are several general recommenda-tions.


In the setting of an acute uncomplicated bacterial cysti-tis in an otherwise healthy adult nonpregnant woman, cur-rent recommendations suggest that a 3-day course of a rec-ommended antibiotic is as effective as the same antimicrobialgiven for a longer duration. 13,14 Trimethoprim-Sulfamethoxazole (TMP-SMZ) for 3 days is generally con-sidered first line therapy in non-sulfa allergic patients. Otherantibiotics that have been shown to be as equally effective asTMP-SMZ for empiric therapy include: Trimethoprim alone,and renally excreted members of the fluoroquinolone family(e.g., ofloxacin, ciprofloxacin, levofloxacin). Although empiri-cal therapy with a quinolone or other broad-spectrum anti-microbial may be appropriate in selected clinical presenta-tions, the universal application of empirical therapy with agiven agent should be discouraged, given the developing re-sistance to these drugs and the overall expense related to pre-scribing these medications compared with less costly alterna-tives. 6,7,14,15

Other drugs to consider empirically include Nitrofuran-toin and fosfomycin, both of which may become more usefulin the future as resistance to TMP-SMZ and trimethoprimalone increases. Nevertheless, nitrofurantoin should not be pre-scribed for patients with a creatinine clearance < 60 ml/min.14,15 Oral amoxicillin-clavulanate may be used as an alternateagent, and is especially useful when a patient has a polymicro-bial infection with both susceptible gram-negative rods andEnterococcus spp. Finally, several oral second-and third-genera-tion cephalosporins, such as cefuroxime axetil, cefixime,ceftibuten, and cefpodoxime, may be used as alternate thera-pies in the management of UTI when patients cannot toleratefirst-line therapies or have organisms with resistance to first-line agents. 6,7

There are many antibiotics that should be avoided for em-piric therapy. For example, when given for 3 days, B-lactampenicillins and cephalosporins as a group are less effective thanthe previously described drugs. Amoxicillin and ampicillinshould not be used empirically because many community-ac-quired and nursing home-acquired strains of E coli produce B-lactamase, which renders these agents inactive. Additionally,numerous studies over the years have shown that B-lactam an-tibiotics, such as penicillins and cephalosporins are not as effi-cacious in curing cystitis or eradicating uropathogens from theirperineal reservoirs. 6,7

When an oral agent cannot be used, IM ceftriaxone,cefotaxime, or another injectable cephalosporin is appropri-ate. The duration of treatment for older women with uncom-plicated cystitis can be 3 days. Seven to 10 days of treatmentshould be prescribed for: 6,7

• Women with more than 1 week of symptomsprior to diagnosis

• Women with structural or functional abnormali-ties of the urinary tract

• Infection caused by S saprophyticus• Men

Double strength TMP-SMZ is started on Mrs. X. At 48 hours,she feels much better and final urine culture report reveals E colithat is sensitive to TMP-SMZ, ciprofloxacin, levofloxacin,

amoxicillin/clavulanic acid, nitrofurantoin, and ceftriaxone. Youopt not to change her previous antibiotics. After the three-daycourse of TMZ-SMZ, MRs X’s family raises a concern as to whethershe should repeat urine tests to confirm success of treatment.

Routine follow-up, including urine culture, is generallyunnecessary after treatment for cystitis, unless symptoms donot abate.16

A review of Mrs. X’s medical records reveals that this isher 3rd UTI in 6 months. The nurse asks you if you would liketo consider prophylactic antibiotics to prevent future infec-tions.

Prophylaxis should not be initiated until the eradicationof active infection is confirmed by a negative urine culture atleast one to two weeks after treatment is discontinued. Con-tinuous prophylaxis, typically with medication taken oncedaily at bedtime, is an option for women who have had twoor more symptomatic infections during one 6-month periodor three or more such infections over a 12- month period. 16

Acceptable choices for prophylaxis include single strengthTMP-SMZ ½ tablet a night or three times weekly;Trimethoprim 100 mg nightly; or Nitrofurantoinmacrocrystals 50-100 mg nightly. 16

The TMP-SMZ prophylaxis is initiated after a negative urineculture at two weeks confirms sterile urine.

Summary of recommendations: 1. Only patients meeting the McGeer or Loeb cri-

teria should be treated for UTI based on cur-rently accepted guidelines.

2. Screening for and treatment of asymptomatic bac-teriuria is not recommended for diabetic women,elderly, institutionalized patients, and catheter-ized patients while the catheter remains in situ

3. Most patients with consistent symptoms and apositive dipstick test can be treated without theneed to obtain a urine culture unless any of thefactors associated with an upper tract or compli-cated infection is present

4. Cultures are warranted to identify usual or resis-tant organisms in women whose symptoms eitherdo not abate or recur within two to four weeksafter the completion of treatment

5. Prophylaxis might be warranted for two or moresymptomatic infections during one 6-month pe-riod or three or more such infections over a 12-month period

REFERENCES1. Yoshikawa TT. Epidemiology and unique aspects of aging and infectious dis-

eases. Clin Infect Dis 2000;30:931-3.2. Schweizer AK. Managing urinary tract infections in nursing homes. Pharm

World Sci 2005;27: 159-65.3. Nicolle LE. Urinary tract infections in long-term-care facilities. Infection Con-

trol Hospital Epidemiol 2001; 22: 167-75.4. Whippo CC. Bacteriuria and urinary incontinence in aged female nursing

home residents. J Advance Nurs 1989;14:287-225.


9SOW-RI-GERIATRICS-112009

THE ANALYSES UPON WHICH THIS PUBLICATION IS BASED were per-formed under Contract Number 500-02-RI02, funded by theCenters for Medicare & Medicaid Services, an agency of theU.S. Department of Health and Human Services. The contentof this publication does not necessarily reflect the views or poli-cies of the Department of Health and Human Services, nor doesmention of trade names, commercial products, or organizationsimply endorsement by the U.S. Government. The author as-sumes full responsibility for the accuracy and completeness ofthe ideas presented.

5. Strausbaugh LJ. Emerging health care- associated infections in the geriatricpopulation. Emerging Infectious Dis 2001;7:268-71.

6. Davey P. Management of suspected bacterial urinary tract infection in adults, Anational clinical guidelines, Scottish Intercollegiate Guidelines Network, July 2006

7. Treatment Guidelines from The Medical Letter 2007; 5 (57).8. McGeer A, Campbell B, et al. Definitions of infection for surveillance in long-

term care facilities. Am J Infect Control 1991;19:1-7.9. Centers for Medicare & Medicaid Services. State Operations Manual. Appen-

dix PP, Section 483.25(d); 2005. Publication #100-07. http://cms.hhs.gov/manuals/Downloads/som107ap_pp_guidelines_ltcf.pdf.

10. Loeb M, Bentley DW, et al. Development of minimum criteria for the initia-tion of antibiotics in residents of long-term care facilities. Infect Control HospEpidemiol 2001;22:120-4.

11. Juthani-Mehta M. Asymptomatic bacteriuria and urinary tract infection inolder adults. Clinics Geriatric Med 2007; 23:585-94.

12. Juthani-Mehta M. Nursing home practitioner survey of diagnostic criteria forurinary tract infections. J Amer Geriatrics Soc 2005; 53:1989-90.

13. Warren JW. Guidelines for antimicrobial treatment of uncomplicated acute bacterialcystitis and acute pyelonephritis in women. Clin Infectious Dis 1999; 29:745-58.

14. Hummers-Pradier E. Management of urinary tract infections in female gen-eral practice patients. Fam Practice 2005; 22:71-7.

15. Nicolle LE. Resistant pathogens in urinary tract infections. J Amer GeriatricsSoc .2002;50S230-5.

16. Fihn SD. Acute uncomplicated urinary tract infection. NEJM 2003;349:259-66.

Porpon Rotjanapan, MD, is an Infectious Disease Fellow atthe University of Iowa Hospitals and Clinics.

David Dosa, MD, is Assistant Professor of Medicine andCommunity Health, The Warren Alpert School of Medicine.


The Wanderings of the Vagus Nerve�

Physician’s Lexicon

The vagus nerve, sometimes called thepneumogastric nerve, is the tenth oftwelve paired nerves emanating from theprimate brain stem and are collectivelycalled the cranial nerves. It is the longestand most complex of the cranial nerves.It emerges from the medulla oblongata,between the olivary nucleus and the in-ferior cerebellar peduncle; it then exitsthe infratentorial space through the jugu-lar foramen, courses caudally through thecarotid sheath and finally distributes itsroots to structures in the neck, thoraxand, via the diaphragm, the abdomen.About 80% of its fibers are sensory but itdoes innervate numerous muscles includ-ing those of the larynx and also carriesparasympathetic fibers.

The phrase, vagus nerve, is derivedfrom the Latin, nervus vagus, meaningwandering nerve. A number of otherEnglish words are also descended fromthe Latin, vagus, all reflecting the senseof wandering or impermanence. Thus,one encounters the word, vagabond, (a

person leading a wandering, nomadic lifeand sometimes thought to be shiftless,irresponsible and without a permanenthome); the word, vagrant, (a person withneither home not visible means of sup-port, a wanderer); the word, vague,(something not clearly perceived or un-derstood, something imprecise); and ex-travagant (spending too much; wander-ing beyond the bounds of fiscal reasonand prudence). And the words reverieand rave are distantly related.

Still further English words trace backto the Latin, vagus. A vade mecum (liter-ally, in Latin, “go with me”) defines work-ing or instructional manuals in variousoccupations and avocations (in more mod-ern vernacular, “how-to” books). Even theslang, vamoose (directly from the Span-ish, vamos, meaning let us go; previouslyfrom the Latin, vadere, meaning to go, andultimately from the Latin, vagus.)

The word, wander, however, ispurely Germanic (through various northTeutonic permutations including Old

English) with not a trace of Latin orGreek. The word, vandal, derives fromit; and through a reverse linguistic mi-gration then turns up in Latin asVandalus, the name that the Romans be-stowed upon the pagan Germanic tribesthat ravaged Spain and Gaul particularlyduring the Fifth Century.

The vagus nerve has been a sturdymainstay within textbooks on neu-roanatomy for centuries. No medical stu-dent could possibly consider promotionto the clinical years without knowing thedistribution and sensory/motor respon-sibilities of this important cranial nerve.And now, with the increasing employ-ment of the vagus nerve stimulator(VNS) as a therapeutic adjunct, the nervehas assumed even greater practical im-portance.

– STANLEY M. ARONSON, MD


Diabetes Prevention and Control:Progress Towards Healthy People 2010 Goals

Annie Gjelsvik, PhD, Dona Goldman, RN, MPH, and Marilyn Moy, RN, MSW

RHODE ISLAND DEPARTMENT OF HEALTH • DAVID GIFFORD, MD, MPH, DIRECTOR OF HEALTH EDITED BY SAMARA VINER-BROWN, MS

Diabetes is the seventh leading cause of death in the UnitedStates. People with diabetes have twice the risk of death of peoplewithout diabetes of the same age,1 and complications from thedisease can diminish the quality of life. However, people withdiabetes can take steps to control the disease and minimize therisks of complications.1 Rhode Island tracks several Healthy People2010 goals (HP2010) goals for diabetes.2 The RI Diabetes Pre-vention and Control Program is preparing to lead the StatewideDiabetes Health System (SDHS) in strategic planning for thenext five years. Prevalence estimates and progress towards clinicalpreventive services and mortality goals are presented here.

METHODSRI Behavioral Risk Factor Surveillance System (RI

BRFSS) data were used to obtain prevalence estimates, trackclinical preventive services and obtain denominator data formortality rates.3 Methodology of the BRFSS is described else-where.4 In order to increase the statistical reliability of the esti-mates three years of data (2006, 2007 and 2008) were com-bined for prevalence estimates among subgroups.

RI mortality data were obtained using the Office of VitalRecords of the Rhode Island Department of Health death cer-tificate data. Diabetes (ICD-10 E10-E14) was coded if it wasmentioned on the death certificate as either the underlying ora contributing cause of death. A cardiovascular death had car-diovascular disease (ICD 10 I00-I78) listed as the underlyingcause and diabetes as any other listed cause. Denominators wereobtained from the 2007 US census population estimates.5 Cen-sus denominators were adjusted to produce estimates of thenumber of diabetics through weighting with three-year age-,race-, and sex- specific average prevalence rates for diabetesfrom the RI BRFSS.

Prevalence and death rates were age-adjusted to the 2000United States Standard Population using age groups 0-44, 45-64and 65+ for general population estimates and age groups 18-44,45-64 and 65+ for diabetic population estimates. To allow com-parisons between groups age-adjusted estimates are reported.

US age-adjusted estimates for clinical preventive serviceswere downloaded from the Centers for Disease Preventionand Control (CDC) Division of Diabetes Translation’s Diabe-tes Data and Trends webpage.6 US age-adjusted estimates fordiabetes related mortality were downloaded using CDC’sWONDER system.7

RESULTSThe increase in diabetes among adults in RI closely re-

sembled the nation’s trend. In 2007, an estimated 7.2% ofRhode Island adults aged 18 years or older had diagnosed dia-betes compared to 8.0% of United States adults.8 The propor-

tion of adults in RI with diabetes rose to 11% when the ap-proximately 30,000 adults with diabetes but who were undi-agnosed were included with the known 60,000 cases.9

Older adults had a high prevalence of diagnosed diabetescompared to younger adults (3% age 18-44, 9% age 45-64and 17% age 65+). Men had a higher prevalence comparedto women (8.1% compared to 6.5%). In Rhode Island theprevalence of diagnosed diabetes was highest among Black, non-Hispanic adults (15.7%) and Hispanic adults (11.3%) com-pared to White non-Hispanic adults (6.7%) and adults of otheror multiracial identity (6.9%). People who preferred to speakSpanish had a higher prevalence (14.4%) compared to thosewhose preferred language was English (7.1%).

Table 1: Prevalence of diagnosed diabetes amongcivilian, non-institutionalized adults age 18+

Population Age-adjusted 95%Group prevalence Confidence

estimate IntervalAll 7.2 6.8, 7.7Age Group

18-44 2.6 2.0, 3.245-64 9.2 8.3, 10.165+ 16.9 15.7, 18.3

SexMale 8.1 7.3, 8.9Female 6.5 5.9, 7.0

Race/EthnicityWhite, Non-Hispanic 6.7 6.2, 7.2Black, Non-Hispanic 15.7 11.7, 19.7Hispanic 11.3 8.7, 13.9Other/multi-racial 6.9 4.5, 9.3

Preferred LanguageEnglish 7.1 6.6, 7.6Spanish 14.4 10.5, 18.3

IncomeLess than $25,000 11.4 9.9, 13.0$25,000 - $74,999 7.3 6.5, 8.1$75,000+ 5.2 4.4, 6.0

EducationLess than High School 11.9 9.9, 14.0High School Graduate 7.5 6.6, 8.5At least Some College 6.4 5.8, 7.0

Insurance StatusMedicare 16.2 12.0, 20.5Private 6.6 5.9, 7.2Fee for Service Medicaid 16.4 11.4, 21.5Uninsured 4.4 1.5, 7.3RIte Care 8.9 0.0, 19.9Other 9.4 7.3, 11.4


Nationally, low income populations have a diabetes preva-lence of up to two times higher compared to wealthy popula-tions.10 In RI 11.4% of those with an income less than$25,000, 7.3% of those with an income between $25,000 and$75,000, and 6.9% of those with and income greater than$75,000 had diagnosed diabetes. A similar trend was seen ineducation: those without a high school education had the high-est prevalence of diagnosed diabetes (11.9%) compared to highschool graduates (7.5%) or people who had attended college(6.4%). In addition, prevalence of diabetes differed by insur-ance status. The highest prevalence was among those withMedicare (16.2%) and Fee-for-Service-Medicaid (16.4%) com-pared to those with RIte Care (8.9%), private insurance (6.6%),other insurance (9.4%), or the uninsured (4.4%). It should benoted, however, that those without insurance were less like tobe screened for diabetes (only 40% screened in the past threeyears compared to greater than 57% for all other groups).

HEALTHY PEOPLE 2010 GOALSRI met or exceeded the HP2010 goals

for adults with diabetes having at least twoA1C test in the past year, having an annualdilated eye exam, and for having an annualfoot exam. (Table 2) In addition, while RIhas not yet met the HP2010 goal for hav-ing ever had a pneumococal vaccine or hav-ing had an annual influenza vaccine, RI wassubstantially higher than the national aver-ages for these clinical preventive services (andfor the age group 45-64 RI has met theHP2010 goal for annual influenza vaccine).Only in ever having attended diabetes out-patient education has RI not surpassed thenational average or met the HP2010 goal.

RI reduced diabetes-related deaths from86.3 in 1999 to 78.9 per 10,000 people withdiabetes in 2007. This met the HP2010 goalbut was higher than the national rate. Car-diovascular disease is a major cause of deathamong persons with diabetes. Adults withdiabetes have heart disease rates about two tofour times higher than adults without heartdisease.1 RI reduced deaths due to cardiovas-cular disease among persons with diabetesfrom 50.5 in 1999 to 29.0 per 10,000people with diabetes in 2007. This exceededthe HP2010 goal but was higher than thenational rate. Perhaps due to the increasingprevalence of diabetes, diabetes-related deathsamong the general population rose from 6.4in 1999 to 7.8 per 10,000 general popula-tion, failing to meet the HP2010 goal andremaining higher than the US average.

DISCUSSIONWhile RI met or exceeded five HP2010

goals, more work remains for the SDHS, toreduce the prevalence of diabetes and meet

patients’ needs for clinical preventive services.11

Acknowledgement: We thank Kathy Taylor from the Center forHealth Data and Analysis for providing death certificate data.

This work supported in part by the Rhode Island Col-laborative Chronic Disease, Health Promotion, and Surveil-lance Award (1U58DP001988-01)

REFERENCES1. Centers for Disease Control and Prevention. National diabetes fact sheet. At-

lanta, GA: US Department of Health and Human Services, CDC, 2008.2. US Department of Health and Human Services. Healthy People 2010. 2nd ed.

With Understanding and Improving Health and Objectives for Improving Health.2 vols. Washington, DC: US Government Printing Office, November 2000.

3. Rhode Island Behavioral Risk Factor Surveillance System, [2006-2008] Cen-ter for Health Data and Analysis, Rhode Island Department of Health, andsupported in part by the National Center for Chronic Disease Preventionand Health Promotion Programs, Centers for Disease Control and Preven-tion, Cooperative Agreement (2003 – 2007), 5U58DP122791 (2007 –2008).

Table 2: Healthy People 2010 Diabetes Goals for RI adults age 18+

Clinical Preventive HP 2010 2007 US 2007 RI 2007 RIServices Goal Goal (Age- (Crude) (Age-

Adjusted) Adjusted)At Least 2 A1c 50% 69.6% 73.1 73.1Tests in Past Year (67.7, 78.6) (66.3, 80.0)

Annual Dilated 75% 66.3% 81.8 78.7Eye Exam (77.6, 86.0) (73.1, 84.3)

Annual Foot 75% 69.4% 74.9 75.1Exam (70.0, 79.9) (68.9, 81.4)

Attended Diabetes 60% 57.7% 46.8 45.5Outpatient Education (41.0, 52.5) (38.3, 52.7)Ever

Ever had 60% 38.9% 59.0 47.7Pneumococcal (18-64) (53.3, 64.7) (40.8, 54.6)Vaccine 90%

(65+)

Annual Influenza 60% 51.3% 69.4 62.3Vaccine (18-64) (64.0, 74.7) (55.4, 69.3)

90%(65+)

Mortality Goal HP 2010 2006 US 2007 RI 2007 RIGoal (Age- (Crude) (Age-

Adjusted) Adjusted)

Reduce diabetes-related 78 per 62 15.5 78.9deaths among people 10,000 (15.0, 16.0) (75.1, 82.7)with diabetes adults with

diabetes

Reduce deaths from 30.9 deaths 20.2 58.7 29.0cardiovascular disease per 10,000 (55.6, 61.8) (26.8, 31.1)in people with diabetes. adults with

diabetes.

Reduce the diabetes 4.5 deaths 7.4 8.8 7.8death rate. per 10,000 (8.5, 9.1) (7.5, 8.2)

population.


4. Centers for Disease Control and Prevention. CDC’s Behavioral Risk FactorSurveillance System Website. [http://www.cdc.gov/brfss/]

5. http://www.census.gov/popest/states/asrh/files/SC-EST2008-AGESEX-RES.csv

6. ` http://www.cdc.gov/diabetes/statistics/preventive_national.htm accessed on9/8/09

7. http://wonder.cdc.gov/data2010/8. Behavioral Risk Factor Surveillance System: Prevalence Data. Centers for Disease

Control and Prevention. (2007). http://apps.nccd.cdc.gov/brfss/list.asp?cat=DB&yr=2007&qkey=1363&state=All.

9. Prevalence of Diabetes and Impaired Fasting Glucose in Adults — UnitedStates, 1999–2000. MMWR 2003;52:833-837.

10. Rabi DM, et al. Association of socio-economic status with diabetes preva-lence and utilization of diabetes care. BMC Health Services Research. 2006;6:124.

11. Kondilis B, Lindenmaye J, Goldman G. Diabetes: An ppidemic of a chronicdisease. Health by Numbers. RI Department of Health (April 2002) 4: 4.

Annie Gjelsvik PhD, is the Epidemiologist for the RI Diabe-tes Prevention and Control Program. She is an Assistant Professor(Research) at the Warren Alpert Medical School at Brown Uni-versity.

Dona Goldman, RN, MPH, is the lead for the RI ChronicCare and Disease Management Team and Director of the Dia-betes Prevention and Control Program.

Marilyn Gurney Moy, RN, MSW, is the Program Coordina-tor of the RI Diabetes Prevention and Control Program.


Point of ViewPrevention of Relapsing Mediocrity:

How to Maintain Performance Improvement in HospitalsJohn S. Coldiron, MD, MPH

Anyone experienced in performancemeasurement and improvement has feltthe frustration of maintaining high per-formance levels. Complex systems thatwe frequently rely on in hospitals are sub-ject to breakdown through distractingforces such as changing priorities, staffturnover without adequate training,shortcutting due to excessive workload,etc. These systems that are codified aspolicies, procedures and processes seemsubject to unforgiving degradation.This predictable deterioration can be re-ferred to as “relapsing mediocrity”. Howcan one maintain high levels of perfor-mance?

IMPLEMENTATION ISSUESIt is a basic tenet that processes and

procedures should be simple and unam-biguous in design. Complexity begets er-rors through the possibilities of poorhandoffs, misapplication, etc. Secondly,complex processes are high maintenancesystems that require more resources tokeep them functioning at the top level.Managers often do not recognize, oroverlook, this second reality. Resourcesfor the ongoing orientation of new em-ployees, refresher training for existingstaff, performance measurement of suf-ficient frequency to be meaningful, peri-odic feedback reports at both the groupand individual level, and, if necessary,

revision and retraining must be antici-pated in order to avoid relapse (deterio-ration of performance). A myriad ofonce-touted creative initiatives that havefallen to mediocre levels because of lostleadership or shifted resource priority canbe cited. While organizations can, withfanfare, implement data-based “best prac-tices,” it can be difficult to sustain thoseinitiatives.1

The evidence is that reimbursementconcerns have long had a higher prior-ity than the quality of care, including pa-tient safety. Concern for the accuracyof financial data in the hospital infor-mation system has exceeded the concernfor accurate clinical data at the indi-vidual provider level. The funds to pur-chase software and consulting for fiscalservices have exceeded those available forrisk management and quality manage-ment. Quality managers’ failure tomaintain many of the past improvementsin performance has not helped to for-ward the argument for resources. Staff-ing levels of the typical medical staff of-fice and quality management and riskmanagement programs are usually verysmall compared to the expectations de-manded by even the basic requirementsof the Joint Commission. The reasonseems related to the focus on short term“return-on-investment” priority in re-source allocation. Organizations may be

reluctant to implement or sustain im-proved care practices unless they canproject a financial benefit.2 Clinicaloutcomes have only recently become aconsideration in this decision-makingprocess. There are and will be increas-ing financial consequences of qualityproblems that will work to shift this bal-ance.3

HOLDING THE LEVEL OFPERFORMANCE

What can be done now?Most important is the establish-

ment of genuine organizational support.If there is not commitment and advo-cacy within senior management that in-cludes willingness to create the properorganizational structure, develop andenforce the necessary policies and pro-cedures and provide adequate resources,it will not be possible to sustain and im-prove the level of performance withinthe organization. “Proper organizationalstructure” is an organizational chart thatgroups the departments that are key toexecution of the collection, performancemonitoring, training for performanceimprovement, performance measure-ment, quality, risk management/patientsafety, physician credentialing and pro-filing and all related reporting into oneadministrative division. The “necessary”policies and procedures must be writ-


ten to ensure coordinated, uninterrupted flow of informa-tion and data that enables accurate monitoring, measurementand reporting, and unambiguous delineation of accountabilityfor performance of each function. “Adequate resources,” ata minimum, means sufficient software and programming torelieve the staff of the mountains of paperwork involved inaggregating data from dissimilar and non-communicatingdatabases to produce non-standardized, individualized reportsto countless committees, managers and other publics. It alsomeans providing funds for a dedicated position with Staffresponsibility for oversight of the key aspects of performancemeasurement and improvement within the organization. Thisposition should be viewed as similar to an internal auditorbut with an expert level of familiarity with the tools of qualityimprovement and quality management. The authority to holdany group or individual at any level within the organizationaccountable for compliance with the established PerformanceImprovement Plan should be granted. Accountability andreporting should be to a top manager and/or the top Qualityoversight body.

The next most important activity is the provision of feed-back, formatted to be useful to the target audience. This usu-ally requires multiple revisions to reach a report that conveysthe intended information to a large majority of the users. Thisis the reason for the data collection and analysis and perfor-mance measurement. Without the feedback of results, thecollection and analysis activities are wasted.

OTHER CONSIDERATIONSAs one confronts new issues requiring improvement, the

process designed is likely to include new work for someone. Itmay be a simple item for documentation. But, how long will itreally take? How inconvenient is it within the existing workflowof the provider? Is it truly “simple” to do or is it going to placeadditional stress on individuals who already struggle to meet allthe demands placed on their time? Will this “last straw” force adecision to trade one task for another or as a last resort, sincedocumentation is audited, to supply false documentation? Don’tforget the relationship between workload and performance asone approaches capacity for added duties. It may require awork analysis prior to process implementation.

Prudent direct observation of how a process is actuallybeing performed is often dropped from consideration since itcan embarrass the observer and is perceived to demean theobserved. None-the-less, this is an important function withinthe performance management program. Familiar examples areanonymous observation of hand-washing and use of a disclos-ing compound to measure housekeeping effectiveness. Someactivities, such as pre-operative protocols to prevent wrong sitesurgery, are too important to leave any doubt as to whetherthere is 100% compliance. Documentation is not the same aswitnessing it happen.

Don’t forget the characteristics of memory that should in-fluence planning for training and retraining. The simple ruleis, the amount learned depends on the time spent learning.4

This, of course, is impacted by the quality of the teaching pro-vided and how well accelerated learning techniques can be

applied. Also to be incorporated in the planning is the realitythat there is a rapid loss of material that has been learned. Thefrequency of retraining is modified by the complexity of theprocess design, the critical rating of the process or procedure,and the frequency the task is performed.

CONCLUSIONNo professional wishes to affiliate with an institution that

is not committed to achieving and maintaining a high level ofperformance. Mediocre performance demeans the providerand inevitably results in patient harm and wasted resources.Prevention of relapse in performance levels requires planning,persistence and a reward structure that promotes performanceadvances. Inattention will result in frustration and rework thatcompetes with new initiatives. The energy devoted to main-taining improvement levels should be valued as equally satisfy-ing and beneficial to patients as efforts given to new improve-ment projects. It requires both to produce a high level of per-formance throughout the institution.

REFERENCES1. Beck C, et al. Sustaining a best-care practice in a nursing home. J Healthcare

Quality 2005;27:5-16.2. Leatherman S, et al. The business case for quality. Health Affairs 2003; 22:17-

30.3. Milstein A. Ending extra payment for “never events.” NEJM 2009;360:2388-

90.4. Ebbinghaus H. Memory: A Contribution to Experimental Psychology. New

York City: Teachers College, Columbia University; 1913.

John S. Coldiron, MD, MPH, is Vice President, MedicalManagement Insight Health Solutions.

Disclosure of Financial InterestsThe author has no financial interests to disclose.

CORRESPONDENCEJohn S. Coldiron, MD, MPHInsight Health Solutions2377 Pawtucket AvenueEast Providence, RI 02914phone: (866) 743-9481e-mail: [email protected]


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�VOLUME 1 PER YEAR $2.00NUMBER 1 SINGLE COPY, 25 CENTSPROVIDENCE, R.I., JANUARY, 1917

The Official Organ of the Rhode Island Medical SocietyIssued Monthly under the direction of the Publications Committee

FIFTY YEARS AGO - NOVEMBER 1959Captain George Calvy, MC, NSN, Commanding Officer,

the Naval Medical Field Research Lab, Camp Lejeune, pre-sented the following talk at the Interim Meeting of the RhodeIsland Medical Society, September 1959: “Staphylococcal Pul-monary Infections.” He reflected on his personal experiencein a large hospital, seeing more than 40 cases of antibiotic-resistant staphylococcal pneumonia, “principally due to a hos-pital acquired strain, diagnosed and treated over 20 years.”Seven members of his staff were infected. He found that add-ing ristocetin to the medications was effective.

Joseph S. Kars, MD, Kenneth B. Nanian, MD, Lester L.Vargard, MD, and Frank Merlino, MD, all from Rhode Is-land Hospital, discussed six cases in “Combined Left Ventricularand Suprasternal Percutaneous Puncture in Assessment of Mi-tral and Aortic Valve Disease.”

Seebert J. Goldowsky, MD, in “The Hospital at Ports-mouth Grove,” recounted the history of this Civil War Hospi-tal (called Lovell General) at Portsmouth Grove Avenue onAquidneck Island. In July 1862 two reporters noted: “Thestern realities of war are now brought to our own doors.” Shipsbrought 1724 sick and wounded patients, casualties from theArmy of the Potomac, who had been evacuated from the hos-pital at Yorktown, PA. A reporter noted that 1800 citizens,including physicians, greeted the patients. At the time theMedical Director at Yorktown was Dr. Francis L. Wheaton,son of Dr. Levi Wheaton (Brown Medical School 1826).

An Editorial, “Quackery on Television,” railed against the“outpouring of tawdry and misleading advertising by the patentmedicine industry…There are products for ‘tired blood,’ toquench burning fires in the stomach and to still the hammersthat pound and the lightning that flashes inside the cranium.Diagrams show drugs that go ‘round and round and come outhere…’” The Editorial contrasted the surge of misleading ad-vertising with the industry’s efforts to stop rigged quiz shows.

TWENTY-FIVE YEARS AGO – NOVEMBER 1984Sarah C. Aronson, Kemi Nakabashi, Michael Siegel, Wil-

liam Q. Sturner, MD, and Stanley M. Aronson, MD, in “Traf-fic Fatalities in Rhode Island: Part IV. The Pedestrian Victim,”recounted results from a statistical analysis of the 173 pedes-trian deaths recorded by the Medical Examiner’s Office 1977-1982 (22.6% of the registered 766 traffic fatalities). Pedes-trian fatalities occurred more frequently on weekends, espe-cially Saturdays. Victims had blood alcohol levels at > .06 gmper cent in one-third of the cases. Most fatalities happenedafter dark.

A.A. Savastano, MD, Chair, Rhode Island Board of Medi-cal Review (established 1976 by the General Assembly) de-scribed the make-up: 9 members appointed by the Governor“for not more than 2 consecutive 3-year terms.” The nine com-prised 5 physicians, 1 hospital administrator, 2 public sectormembers, and the Department of Health Director ex officio.As of 1982, the board had heard 73 allegations (24 related toinsurance company repeals, 16 to JUA malpractice cases, 15to allegations of unprofessional conduct).

John DiOrio, MD, in “Short-Course Antibiotic Prophy-laxis in First-Trimester Abortion,” noted: “Complications wereacceptably low and consistent with previous studies.” The studyfollowed 478 patients at a local outpatient ambulatory facilityfrom October 1982 to January 1983. A study group received500 mg tetracycline at the time of the procedure, 500 mg 6hours later. A standard group received 250 mg at the onset,then 250 mg every 6 hours for 4 days.

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