bahan tutorial - gout

7/21/2019 Bahan Tutorial - Gout

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GOUT

Background

Gout is a common disorder of uric acid metabolism that can lead to deposition of monosodium urate (MSU) crystals insoft tissue, recurrent episodes of debilitating joint inflammation, and, if untreated, joint destruction and renal damage.

Gout is definitively diagnosed based on the demonstration of urate crystals in aspirated synovial fluid.

Improvements in early diagnosis and the availability of definitive treatment have significantly improved the prognosis ofgout, as evidenced by the declining incidence of disabling chronic tophaceous gout. o!ever, tophaceous gout may stildevelop because of misdiagnosis, poor management, medication intolerances, and"or poor patient compliance.

Pathophysiology

#lthough the presence of urate crystals in the soft and synovial tissues is a prere$uisite for a gouty attac%, the fact thaturate crystals can also be found in synovial fluid in the absence of joint inflammation suggests that the mere presence ofintrasynovial urate crystals is not sufficient to cause flares of gouty arthritis

&ne e'planation for this may lie in the observation that clumps or microtophi of highly negatively charged and reactive

MSU crystals are normally coated !ith serum proteins (apolipoprotein apo * or apo +) that physically inhibit thebinding of MSU crystals to cell receptors.,- # gout attac% may be triggered by either a release of uncoated crystals (egdue to partial dissolution of a microtophus caused by changing serum urate levels) or precipitation of crystals in asupersaturated microenvironment (eg, release of urate due to cellular damage). rom either source, na%ed uratecrystals are then believed to interact !ith intracellular and surface receptors of local dendritic cells and macrophages,serving as a danger signal to activate the innate immune system./

0his interaction may be enhanced by immunoglobulin G (IgG) binding.1,2 0riggering of these receptors, including 0oll3li%ereceptors, 4#56/ inflammasomes, and the triggering receptors e'pressed on myeloid cells (07*Ms) by MSU, results inthe production of interleu%in (I5)8, !hich in turn initiates the production of a cascade of pro3inflammatory cyto%ines,including I539, I53:, neutrophil chemotactic factors, and tumor necrosis factor (04)8alpha. 9 4eutrophil phagocytosisleads to another burst of inflammatory mediator production

Subsidence of an acute gout attac% is due to multiple mechanisms, including the clearance of damaged neutrophilsrecoating of urate crystals, and the production of anti3inflammatory cyto%ines including, I537#, I53;, and transforminggro!th factor (0G)8beta.<,:,=,2

Frequency

United States

#ppro'imately > of the general population have gout.

International

Gout has a !orld!ide distribution? regional differences may reflect environmental, dietary, and genetic influences.

Mortality/Morbidity

• Gout is associated !ith considerable morbidity. #cute episodes of gout often lead to incapacitation.

• Untreated chronic tophaceous gout can lead to severe joint destruction.

• MSU deposition in the %idney can result in inflammation and fibrosis, leading to reduced renal function or

chronic renal nephropathy.

• yperuricemia and gout are associated !ith an increased overall li%elihood of mortality. @hether this is directly

attributable to hyperuricemia or gout or to gout3associated diseases (eg, insulin resistance, type - diabetes

http://emedicine.medscape.com/article/241767-overview









mellitus, abdominal obesity, hypercholesterolemia, hypertension) has been much debated. #lthough noevidence has sho!n that gout or hyperuricemia causes any of these disorders, elevated urate levels have beensho!n to correlate !ith blood pressure in adolescents,; and, among middle3aged men, hyperuricemia !ith gout!as a significant independent ris% for death due to cardiovascular disease.

ace

• Gout is slightly more prevalent in blac%s than in !hites.

Se!

• 0he prevalence of gout is /.9 cases per ;;; men and 9.1 cases per ;;; !omen.

• 0his difference is largely a conse$uence of age at onset because estrogenic hormones have a mild uricosuric

effect? therefore, gout is unusual in premenopausal !omen.

"ge

• #s a rule, uric acid levels are elevated for -; years before the onset of gout.

• In men, uric acid levels rise at puberty, and the pea% age of onset of gout in men is in the fourth to si'th decade

of life. In !omen, uric acid levels rise at menopause, and pea% age of onset in !omen is in the si'th to eighthdecade of life. Gout is unli%ely to present in premenopausal !omen or in men younger than /; years !ho donot have renal insufficiency or a genetic abnormality of purine metabolism (eg, hypo'anthine3guaninephosphoribosyltransferase deficiency, phosphoribosylpyrophosphate synthetase superactivity). 0he higheprevalence of gout in elderly persons may also reflect an increased prevalence of metabolic syndrome, highrates of diuretic treatment for hypertension and congestive heart failure, and the use of lo!3dose acetylsalicylicacid. 0ophi are typically detectable clinically appro'imately ; years after the first gout attac%.

• Ayclosporin # can cause an accelerated form of gout, even in premenopausal !omen, that can present after

only a fe! years of hyperuricemia, particularly if the patient is also receiving diuretics.

#linical

$istory

• #cute monoarticular arthritis is the initial presentation of gout in =;> of patients.

o In early gout, only or - joints are usually involved. 0ypically, they are the smaller, lo!er3e'tremity

joints. 6odagra (inflammation of the first metatarsophalangeal joint) is the initial joint manifestation in2;> of cases. *ventually, it is involved in =;> of cases. 6odagra is not synonymous !ith gout.6odagra may be observed in patients !ith pseudogout, sarcoidosis, gonococcal arthritis, psoriaticarthritis, and reactive arthritis.

o 0he attac%s begin abruptly and reach ma'imum intensity !ithin :3- hours. 0he joints are red, hot,

and e'$uisitely tender? even a bed sheet on the s!ollen joint is uncomfortable. Untreated, the firstattac%s resolve spontaneously in less than - !ee%s.

o # history of intermittent inflammatory arthritis, in !hich the joints return to normal bet!een attac%s, is

typically caused by crystalline disorders and is characteristic of gouty arthritis early in its course.o Gout initially presents as polyarticular arthritis in ;> of patients. *lderly !omen, particularly !omen

!ith renal insufficiency on a thiaBide diuretic, can develop polyarticular arthritis as the first manifestation

of gout. 0hese attac%s may occur in coe'isting eberden and +ouchard nodes. Such patients may alsodevelop tophi more $uic%ly, occasionally !ithout prior episodes of acute gouty arthritis.-,/,1

0he pattern of symptoms in untreated gout change over time.o 0he attac%s become more polyarticular.

o #lthough more joints may become involved, inflammation in a given joint may become less

intense.o More pro'imal and upper3e'tremity joints become involved.

o #ttac%s occur more fre$uently and last longer.
















o *ventually, patients may develop chronic polyarticular arthritis, sometimes nearly symmetrical,

that can resemble rheumatoid arthritis. Indeed, chronic polyarticular arthritis that began as anintermittent arthritis should prompt consideration of a crystalline disorder in the differentiadiagnoses.

#lthough gout typically causes joint inflammation, it can also cause inflammation in other synovial3based structures

such as bursae and tendons. 0ophi are collections of urate crystals in the soft tissues. 0hey develop in more than half of patients !ith untreated

gout and may be reported as lumps or nodules. @hile the classic location of tophi is along the heli' of the ear, they canbe found in multiple locations, including the fingers, toes, in the olecranon bursae, and along the olecranon, !here theycan resemble rheumatoid nodules. 0he finding of a rheumatoid nodule in a patient !ith a negative rheumatoid factorresult or a history of drainage from a nodule should prompt consideration of gout in the differential diagnoses. 0ophi arenot commonly found during the first gout episode. 0hey tend to develop after ; years in untreated patients !ho developchronic gouty arthritis. 0ophi tend to develop earlier in !omen, particularly those receiving diuretics.-,/,1

• #cute flares of gout can result from situations that lead to increased levels of serum uric acid, such as the

consumption of beer or li$uor, overconsumption of foods !ith high purine content, trauma, hemorrhagedehydration, or the use of medications that elevate levels of uric acid. #cute flares of gout also can result fromsituations that lead to decreased levels of serum uric acid, such as the use of radiocontrast dye or medicationsthat lo!er the levels of uric acid, including allopurinol and uricosurics.

•

6atients !ith gout are profoundly more li%ely to develop renal stones than are healthy individuals (by a factor of;;;)? therefore, they may have a history of renal colic. Indeed, renal stones may precede the onset of gout in1;> of affected patients. @hile :;> of these patients may have stones composed entirely of uric acid, -;>may develop calcium o'alate or calcium phosphate stones !ith a uric acid core.

• #lthough patients !ith gout often have other ris% factors for renal disease, including hypertension and diabetes

chronic urate nephropathy can contribute to renal insufficiency. Ahronic urate nephropathy in patients !ithchronic tophaceous gout can result from the deposition of urate crystals in the medullary interstitium andpyramids, resulting in an inflammatory reaction that can lead to fibrotic changes. 0his process is characteriBedby hyperuricemia that is disproportional to the degree of renal impairment and is associated !ith a benignurinary sediment.

• 5ead into'ication can damage the renal tubules, leading to impaired pro'imal tubular function !ith resultant

hyperuricemia and gout.

• +ecause gout is fre$uently present in patients !ith the metabolic syndrome (eg, insulin resistance or diabetes,

hypertension, hypertriglyceridemia, and lo! levels of high3density lipoproteins) and because the presence ofthese associated disorders can lead to coronary artery disease, these problems should be sought and treated inpatients diagnosed !ith gout.

• Importantly, as% about a history of peptic ulcer disease, renal disease, or other conditions that may complicate

the use of the medications used to treat gout.

Physical

• Curing an acute gout attac%, e'amine all joints to determine if the patientDs arthritis is monoarticular or

polyarticular.

• Involved joints have all the signs of inflammationE s!elling, !armth, erythema, and tenderness.

• 0he erythema over the joint may resemble cellulitis? the s%in may des$uamate as the attac% subsides.

• 0he joint capsule becomes $uic%ly s!ollen, resulting in a loss of range of motion of the involved joint.

•Curing an acute gout attac%, patients may be febrile, particularly if it is an attac% of polyarticular gout.

• 5oo% for sites of infection that may have seeded the joint and caused an infectious arthritis that can resemble or

coe'ist !ith acute gouty arthritis.

• 0he presence of tophi suggests long3standing hyperuricemia.

#auses

Gout develops in the setting of e'cessive stores of uric acid in the form of monosodium urate. Uric acid is an end3stageby3product of purine metabolism. 5ac%ing uricase, humans remove uric acid primarily by renal e'cretion. @hen










e'cretion is insufficient to maintain serum urate levels belo! the saturation level of 9.: mg"d5 (!ith some variabilitydepending on temperature and p), hyperuricemia may develop, and urate can crystalliBe and deposit in soft tissues4inety percent of patients !ith gout develop e'cess urate stores due to an inability to e'crete sufficient amounts ofnormally produced uric acid in the urine (undere'cretion). 0he remaining patients either overconsume purines orproduce e'cessive amounts of uric acid endogenously (overproduction).

•

In rare cases, overproduction of uric acid is primary, due to a genetic disorder. 0hese disorders includehypo'anthine3guanine phosphoribosyltransferase deficiency (5esch34yhan syndrome), glucose393phosphatasedeficiency (von Gier%e disease), fructose 3phosphate aldolase deficiency, and 663ribose36 synthetasevariants.

• &verproduction of uric acid may also occur in disorders that cause high cell turnover !ith release of purines.

0hese disorders include myeloproliferative and lymphoproliferative disorders, psoriasis, chemotherapy (tissuelysis), hemolytic anemias, pernicious anemia, ineffective erythropoiesis (as in +3- deficiency), e'cessivee'ercise, and obesity.

• &verproduction of uric acid can occur from overconsumption of foods high in purines.

• Aommon causes of secondary gout due to undere'cretion of uric acid include renal insufficiency, lead

nephropathy (saturnine gout), starvation or dehydration, hypothyroidism, hyperparathyroidism, drugs (includingdiuretics and cyclosporine #), and chronic ethanol (especially beer and hard li$uor) abuse. 0hese disordersshould be identified and corrected, if possible.

Individual gout flares are often triggered by acute increases or decreases in urate levels that may lead to the productione'posure, or shedding of crystals that are not coated !ith apo + or apo *. 0his can result from acute alcohol ingestion,acute overindulgence in foods high in purines, rapid !eight loss, starvation, trauma, or hemorrhage. Medications thatincrease uric acid levels via effects on renal tubular transport include diuretics and lo!3dose aspirin. Gout flares canalso result from agents that lo!er levels of uric acid, including the use of radiocontrast dyes and medications such asallopurinol or uricosurics.

%i&&erential %iagnoses

Aalcium 6yrophosphate Ceposition Cisease7eactive #rthritisAellulitis 7heumatoid #rthritis

Gonococcal #rthritis Sarcoidosis4ephrolithiasis Septic #rthritis4ephropathy, Uric #cid6soriatic #rthritis

Other Proble's to Be #onsidered

ypo'anthine3guanine phosphoribosyltransferase deficiency (5esch34yhan syndrome6hosphoribosylpyrophosphate synthetase superactivityAongenital fructose intolerance

(orkup

)aboratory Studies

• Synovial fluidE @hen a patient presents !ith acute inflammatory monoarticular arthritis, aspiration of the

involved joint is critical to rule out an infectious arthritis and to attempt to confirm a diagnosis of gout orpseudogout based on identification of crystals.

o 0he critical and essential study is synovial fluid analysis to identify urate crystals. inding intracellular

urate crystals !ith polariBing light microscopy firmly establishes the diagnosis of gouty arthritis.
















































o Urate crystals are shaped li%e needles or toothpic%s !ith pointed ends.

o Urate crystals are negatively birefringent, meaning that the crystals are yello! !hen aligned parallel to

the slo! ray of the compensator and that they are blue !hen they are perpendicular.o 6seudogout crystals (calcium pyrophosphate) are rod3shaped !ith blunt ends.

o 6seudogout crystals are positively birefringent. 6ragmatically, this means that their colors are opposite

those of gout. 0hus, pseudogout crystals are blue !hen aligned parallel to the slo! ray of the

compensator and yello! !hen they are perpendicular.o Arystals need to be distinguished from birefringent cartilaginous or other debris. Cebris may have fuBBy

borders and may be curved, !hereas crystals have sharp borders and are straight.o Aorticosteroids injected into joints have a crystalline structure that can mimic monosodium urate

crystals. 0hey can be either positively or negatively birefringent.o 0he sensitivity of a synovial fluid analysis for crystals is :1>, !ith a specificity of ;;>. If gout remains

a clinical consideration after negative analysis findings, the procedure can be repeated in another jointor !ith a subse$uent flare. Arystals may be absent very early in a flare.

o @hile the sensitivity is inferior, urate crystals can be identified from synovial fluid aspirated from

previously inflamed joints that are not currently inflamed. Such crystals are generally e'tracellular.o Minute $uantities of fluid in the shaft or hub of the needle are sufficient for synovial fluid analysis.

o &nce a diagnosis of gout is established based on confirmation of crystals, joints do not need repeat

aspiration !ith subse$uent flares unless infection is suggested or the flare does not respond

appropriately to therapy for acute gout.o In patients !ith acute monoarticular arthritis, send synovial fluid for Gram stain and culture and

sensitivity. 0he culture also provides sensitivities for antibiotic management.o Synovial fluid should also be sent for cell count.

o Curing acute attac%s, the synovial fluid is inflammatory, !ith a @+A count greater than -;;;"F5 (class I

fluid) and possibly greater than 2;,;;;"F5, !ith a predominance of polymorphonuclear neutrophils.o Synovial fluid glucose levels are usually normal, !hereas they may be depressed in septic arthritis and

occasionally in rheumatoid arthritis. Measurement of synovial fluid protein has no clinical value.o Arystalline arthritis and infectious arthritis can coe'ist. Indeed, infectious arthritis is more common in

previously damaged joints, !hich may occur in patients !ith chronic gouty arthritis.

• Serum uric acid

o 0his is the most misused test in the diagnosis of gout. 0he presence of hyperuricemia in the absence of

symptoms is not diagnostic of gout. In addition, as many as ;> of patients !ith symptoms due to gout

may have normal serum uric acid levels at the time of their attac%. 0hus, the correct diagnosis of goutcan be missed if the joint is not aspirated. 7emember that situations that decrease uric acid levels cantrigger attac%s of gout. In such cases, the patientDs prior medical records may reveal prior elevations ofuric acid.

o ive to eight percent of the population has elevated serum uric acid levels (< mg"d5), but only 23-;>

of patients !ith hyperuricemia develop gout. 0hus, an elevated serum uric acid level does not indicateor predict gout. #s noted above, gout is diagnosed based on the discovery of urate crystals in thesynovial fluid or soft tissues. More importantly, some patients !ith infectious arthritis present !ith a hots!ollen joint and an elevated serum uric acid level and are at ris% of being mismanaged if their synoviafluid is not aspirated to rule out septic arthritis.

o #symptomatic hyperuricemia should generally not be treated. o!ever, patients !ith levels higher than

mg"d5 and overe'cretion of uric acid are at ris% for renal stones and renal impairment? thereforerenal function should be monitored in these individuals.2

o 0he level of serum uric acid correlates !ith ris% for developing gout. 0he 23year ris% for developing goutis appro'imately ;.9> if the level is less than <.= mg"d5, > if :3:.= mg"d5, and --> if higher than =mg"d5.

• Uric acid in -13hour urine sample

o # -13hour urinary uric acid evaluation is generally performed if uricosuric therapy is being considered.

o If patients e'crete more than :;; mg of uric acid in -1 hours on a regular diet, they are overe'cretors

and thus overproducers of uric acid. 0hese patients (appro'imately ;> of patients !ith gout) re$uireallopurinol instead of probenecid to reduce uric acid levels.



o 6atients !ho e'crete more than ;; mg in -1 hours should undergo close renal function monitoring

because of the ris% of stones and urate nephropathy.o In patients in !hom probenecid is contraindicated (eg, those !ith a history of renal stones or renal

insufficiency), a -13hour urine test of uric acid e'cretion does not need to be performed because thepatient clearly !ill need allopurinol.

• +lood chemistry

o &btaining an accurate measure of the patientDs renal function before deciding on therapy for gout isimportant, since the serum creatinine evaluation alone can underestimate renal dysfunction in elderlypatients or in patients !ith lo! muscle mass.

o 6atients !ith gout are at an increased ris% of developing diabetes mellitus.

o #bnormal liver function tests need to be considered !hen therapy is selected.

• A+A countE 0he @+A count may be elevated in patients during the acute gouty attac%, particularly if it is

polyarticular.

• 5ipidsE ypertriglyceridemia and lo! high3density lipoproteins are associated !ith gout.

• UrinalysisE 6atients !ith gout are at an increased ris% of renal stones? therefore, these patients may have a

history of hematuria.

I'aging Studies

•

7adiography• 6lain radiographs may sho! findings consistent !ith gout, but these findings are not diagnostic. 0he

most common radiographic findings early in the disease include soft3tissue s!elling or an absence ofabnormalities.

• aBiness suggestive of tophi can be seen in late gout, and tophi may calcify.

• *rosions that are not typical of rheumatoid arthritis may suggest gout.

• *rosions !ith maintenance of the joint space

• *rosions !ithout periarticular osteopenia

• *rosions outside the joint capsule

• *rosions !ith overhanging edges

• *rosions !ith sclerotic borders, sometimes called coo%ie3cutter or punched3out borders

• *rosions that are distributed asymmetrically among the joints, !ith strong predilection for dista

joints, especially in the lo!er e'tremities

Procedures

6erform arthrocentesis to rule out an infectious arthritis and to establish a crystal3proven diagnosis of gout. 0ophi alsomay be aspirated for crystal analysis under polariBing microscopy.

$istologic Findings

0ophi have been found in all tissues e'cept the brain. o!ever, monosodium urate dissolves in formalin? therefore, onlythe ghosts of urate crystals may be seen if formalin is used. #lcohol3fi'ed tissue is best for identification of uratecrystals.

Treat'ent



Medical #are

Gout is managed in / stagesE () treating the acute attac%, (-) providing prophyla'is to prevent acute flares, and (/)lo!ering e'cess stores of urate to prevent flares of gouty arthritis and to prevent tissue deposition of urate crystals.

#s mentioned above, asymptomatic hyperuricemia should generally not be treated. o!ever, patients !ith levels higher

than mg"d5 !ho overe'crete uric acid are at ris% for renal stones and renal impairment? therefore, renal functionshould be monitored in these individuals.2

"cute gout

&ptions for treatment of acute gout include nonsteroidal anti3inflammatory drugs (4S#ICs), corticosteroids, andcolchicine (a classic treatment that is no! rarely indicated). 0he choice is based primarily on any concomitant healthproblems (eg, renal insufficiency, peptic ulcer disease).

• 4onsteroidal anti3inflammatory drugs

o 4S#ICs are the drugs of choice in most patients !ith gout !ho do not have underlying health problems.

o #lthough indomethacin is the traditional 4S#IC of choice for acute gout (unless the patient is elderly

because of the potential for adverse A4S effects in this age group), most 4S#ICs can be used. Selectan agent !ith a $uic% onset of action, but do not use aspirin because it can alter uric acid levels andpotentially prolong and intensify an acute attac%. Aycloo'ygenase3- (A&H3-) inhibitors have been used!ith success.

o Start !ith the highest dose for -3/ days and taper do!n over appro'imately - !ee%s. Gout symptoms

should be absent for at least - days before the 4S#IC is discontinued.o #void 4S#ICs in patients !ho have a history of peptic ulcer disease or GI bleeding, patients !ith rena

insufficiency, patients !ith abnormal hepatic function, patients ta%ing !arfarin (selective A&H3-inhibitors can be used), and patients in the intensive care unit !ho are predisposed to gastritis. Use4S#ICs cautiously in patients !ith diabetes and those !ho are receiving concomitant angiotensin3converting enByme (#A*) inhibitors.

• Aorticosteroids

o Aorticosteroids can be given to patients !ith gout !ho cannot use 4S#ICs or colchicine. Some

rheumatologists recommend corticosteroids over 4S#ICs as the preferred choice for treatment of acutegout. Steroids can be given orally, intravenously, intramuscularly, intra3articularly, or indirectly viaadrenocorticotropic hormone (#A0).

o 6rednisone can be given at a dose of appro'imately 1; mg for 3/ days and then tapered over

appro'imately - !ee%s. 0apering more rapidly can result in a rebound flare.o Using parenteral corticosteroids confers no advantage unless the patient cannot ta%e oral medications.

o Intra3articular corticosteroids are particularly useful in patients !ith a monoarticular flare to help reduce

the systemic effects of oral steroids. *nsuring that the joint is not infected prior to injecting intra3articulacorticosteroids is particularly important.

o #A0 at 1; IU IM can be given to induce corticosteroid production by the patientDs o!n adrenal glands

Such a regimen does not depend on the patient to taper prednisone properly.

• Aolchicine

o Aolchicine in acute gout

•

#lthough colchicine !as once the treatment of choice for acute gout, it is no! a second3lineapproach because of its narro! therapeutic !indo! and ris% of to'icity.9 @hen used in classichourly dosing regimens in acute gout, colchicine causes adverse GI effects, particularlydiarrhea and vomiting, in :;> of patients.

• Cosing recommendations for colchicine in acute gout therapy have been modified in recent

years because of an increased a!areness of its to'icities. 0he most recent recommendationshave been trending to!ard lo!ered daily and cumulative doses. # tas% force of 0he *U5#7Standing Aommittee for International Alinical Studies has developed evidence3based guidelinesthat recommend colchicine dosing in acute gout of ;.2 mg tid (;.9 mg tid in the United States).

#n alternative regimen suggested by the 4e! ealand Medicines and Medical Cevices Safety



#uthority is as follo!sE mg loading dose follo!ed by ;.2 (;.9) mg every 9 hours, up to ama'imum of -.2 mg"-1 hours and 9 mg over 1 days. 9

• 6atients !ith gout may be able to abort an attac% by ta%ing a single colchicine tablet at the first

t!inge of an attac%.

• Aolchicine should not be used if the glomerular filtration rate (G7) is less than ; m5"min, and

the dose should be decreased by at least half if the G7 is less than 2; m5"min.

•Aolchicine should also be avoided in patients !ith hepatic dysfunction, biliary obstruction, or aninability to tolerate diarrhea.

• # clinical response to colchicine is not pathognomonic for gout and may occur in patients !ith

pseudogout, sarcoid arthropathy, psoriatic arthritis, or calcific tendonitis.

• In ebruary -;;:, the US ood and Crug #dministration (C#) ruled that intravenous colchicine

can no longer be produced or shipped in the United States because of its to'icities. +ecause ofthis, intravenous colchicine is no longer advocated for the treatment of acute gout in the UnitedStates.:

o Aolchicine as a prophyla'is against recurrence of acute flares

• 5o!ering uric acid !ith either allopurinol or probenecid can precipitate attac%s of gout. @hen

used prophylactically, colchicine can reduce such f lares by :2>.=

• 0he standard dose for prophyla'is is colchicine ;.9 mg bid. In patients !ith renal insufficiency

this dose may need to be decreased to daily or every3other3day administration.

• Aompared !ith the :;> ris% of adverse GI effects in patients using classic hourly colchicine forthe treatment of acute gout, the prophylactic dose of colchicine induces adverse GI effects inonly 1> of patients.

• 5ong3term use of colchicine can lead to a muscle !ea%ness associated !ith elevated levels of

creatine %inase due to a drug3induced neuromyopathy, particularly in patients !ith renainsufficiency.-;

• In patients !ho cannot ta%e colchicine, 4S#ICs, such as indomethacin at -2 mg bid, can be

used for prophyla'is. If 4S#ICs are contraindicated, lo! doses of prednisone can beconsidered.

• 6rophyla'is !ith colchicine can be started during an acute attac%.

#hronic gout

5ong3term management of gout is focused on lo!ering uric acid levels. 0he goal of therapy is to lo!er serum uric acidlevels to appro'imately 9 mg"d5 or less.

In many cases, patients !ho have a first attac% of gout should undergo therapy !ith agents that lo!er uric acid, giventhe high ris% for further inflammatory attac%s and the potential for destructive tophaceous deposition in the bone,synovium, and %idney, even !ithout episodes of acute inflammation. o!ever, some rheumatologists advocate !aitingfor the second attac% to initiate therapy to lo!er uric acid levels because not all patients e'perience a second attac% andbecause some patients may need to be convinced they need life3long therapy. 0he ris% of a second attac% of gout afterthe first attac% is 9-> after year, <:> after - years, and =/> after ; years. 0he decision to begin therapy dependspartly on the baseline serum uric acid levels (= mg"d5 denotes a higher ris% for recurrent gouty arthritis and tophi).

Monotherapy !ith colchicine may help prevent flares of inflammatory arthritis but does not prevent the accumulation of

uric acid in the joints, !hich can lead to further joint destruction. In all cases, the ris%s and benefits need to be judgedbased on the individual patient. or instance, in an elderly patient !ith multiple underlying medical problems and renainsufficiency, the ris%s of therapy to lo!er uric acid levels may out!eigh the benefits.

#gents that lo!er uric acid levels should not be initiated during an acute attac%. 0his may lead to a more intense andprolonged attac%. 0ypically, they should be started a fe! !ee%s after the attac% has resolved and !ith the protection of prophylactic colchicine to prevent another attac%. If the patient develops a gout flare after beginning therapy !ith a uricacid8lo!ering agent, the agent should not be discontinued because this !ill only cause another flu' in the uric acidlevel, !hich may prolong and intensify the attac%.



• 6robenecid

• Some rheumatologists prefer probenecid !henever possible because it has fe!er significant adverse

effects than allopurinol. 6robenecid can be used in most middle3aged patients !ith gout !ho areother!ise healthy.

• Indications for the use of allopurinol instead of probenecid include renal insufficiency (G7 J2;

m5"min), renal stones, use of aspirin (bloc%s the effect of probenecid), overproduction of uric acid, and

unresponsiveness to probenecid.• Crug interactions may occur !ith probenecid (see Medication).

• 6atients !ho use probenecid need to drin% - 5 of fluid daily at the inception of therapy in order to

reduce their urinary concentration and thereby reduce the ris% of renal stones.

• #llopurinol

• #llopurinol bloc%s 'anthine o'idase and thus reduces the generation of uric acid. 0herefore, it should be

used in patients !ho overproduce uric acid and in patients at ris% of tumor lysis syndrome to prevenrenal to'icity during therapy for malignancies. It is the most effective urate3lo!ering agent. o!ever,alcohol can interfere !ith the effectiveness of allopurinol.

• #ppro'imately /3;> of patients ta%ing allopurinol develop dyspepsia, headache, diarrhea, and"o

pruritic maculopapular rash. 5ess fre$uently, patients ta%ing allopurinol can develop allopurinohypersensitivity, !hich carries a mortality rate of -;3/;>. eatures of allopurinol hypersensitivity includefever, to'ic epidermal necrolysis, bone marro! suppression, eosinophilia, leu%ocytosis, renal failure

hepatic failure, and vasculitis. Aorticosteroids are often used to treat allopurinol hypersensitivity.• #llopurinol hypersensitivity is more li%ely to occur in patients !ith renal insufficiency, patients !ho are

ta%ing a diuretic, and patients begun on /;; mg of allopurinol. - #lthough allopurinol hypersensitivity ismore common (although still rare) in patients !ith renal insufficiency, this effect does not appear to bedose3related.-- 0hus, a slo! and careful titration of allopurinol dosing sufficient to achieve uric acidlevels of less than 9 mg"d5 is also recommended in these patients.-/

• #llopurinol should be discontinued in patients !ho develop a rash. In patients !ith a history of drug

eruptions due to allopurinol, both oral-1 and intravenous-2 desensitiBation regimens can be considered.

• In most patients, start at ;; mg per day (2; mg in patients !ith renal insufficiency) and adjust the dose

monthly according to the uric acid level until the goal of a uric acid level of 9 mg"d5 or less is achieved.

• +e!are of drug interactions. or e'ample, allopurinol prolongs the half3life of aBathioprine and 93

mercaptopurine. It enhances the bone marro! to'icity of cyclophosphamide. 6atients ta%ing

concomitant ampicillin are at an increased ris% of rash.• &nce the target uric acid level is achieved and maintained for 9 months, discontinue colchicine

prophyla'is.

• #voiding the use of medications that elevate uric acid in patients !ith gout is prudent. 0hus, other

agents are preferable to a thiaBide diuretic to treat hypertension. o!ever, if such a medication isneeded, it can be used !ith appropriate adjustments of allopurinol or probenecid.

• #llopurinol can be used in combination !ith probenecid. o!ever, note that allopurinol increases the

half3life of probenecid, !hereas probenecid increases the e'cretion of allopurinol.

Other therapeutic options

• 4onrecombinant urate3o'idase (uricase) is used in *urope to prevent severe hyperuricemia induced by

chemotherapy in patients !ith malignancies, as !ell as in selected patients !ith treatment3refractory gout.7ecently, the C# approved recombinant Aspergillus flavus uricase for the prevention of tumor lysis syndrome

o!ever, it is highly immunogenic and may cause anaphyla'is.-9 # polyethylene3glycol lin%ed uricase iscurrently being evaluated. In theory, short3term use of such agents in patients !ith severe tophaceous coulddebul% the total3body urate load, allo!ing for maintenance !ith probenecid or allopurinol.

• 6atients !ith allopurinol hypersensitivity can often tolerate o'ypurinol, !hich is a metabolite of allopurinol.-< It is

available on a Kcompassionate useK basis. Aross3reactivity !ith allopurinol can occur.

• +enBbromarone is an effective uricosuric agent that may eventually become available. o!ever, it can cause

fulminant hepatoto'icity.

• ebu'ostat, a nonpurine selective inhibitor of 'anthine o'idase, is a potential alternative to allopurinol in patients

!ith gout. ebu'ostat is administered orally and is metaboliBed mainly in the liver. In contrast, allopurinol and its

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metabolites are e'creted primarily by the %idney. 0herefore, febu'ostat can be administered in patents !ithrenal insufficiency, !ith no dosage adjustment. Its efficacy and side3effect profile other!ise appears similar tothat of allopurinol.-:

• 0he angiotensin receptor bloc%er losartan and the triglyceride3lo!ering agent microniBed fenofibrate have

moderately potent uricosuric effects. 0hey should therefore be considered in patients !ith gout !ho also re$uiretreatment for hypertension and hypertriglyceridemia.-9

•

Litamin A, !ith its uricosuric effect, may reduce the serum concentration of uric acid.-=

• In an open3label pilot study of ; patients !ith refractory acute gout treated !ith the I53 antagonist ana%inra,

pain !as substantially reduced in all patients !ithin t!o days, !ithout side effects. Alinical signs of inflammationhad disappeared in = of ; patients by the third day of treatment./;

Surgical #are

• In patients !ith gout that is diagnosed and treated early, orthopedic surgery is usually unnecessary. In patients

!ith untreated gout or gout that is treated late in the disease course, orthopedic repair may be necessary.

• 0ophi should not be surgically removed unless they are in a critical location or drain chronically.

• In patients undergoing arthroscopy, the presence of !hite lesions, sometimes on an erythematous base, should

prompt consideration of gout.

#onsultations

7heumatologists should be involved in the care of patients !ith gout. 0hey can establish the diagnosis !itharthrocentesis and synovial fluid analysis for crystals. 0hey also are s%illed in the management of this disorder.

%iet

• Ciet modifications can improve the serum uric acid levels by only mg"d5 and are rarely able to lo!er uric acid

levels sufficiently to prevent further attac%s and accumulation of urate.

• 6atients !ith gout should avoid beer and hard li$uor because they elevate levels of uric acid and therefore can

precipitate attac%s of gout. Indeed, heavy drin%ers are much more li%ely to have recurrent gout attac%s, even!ith allopurinol therapy. Moderate !ine inta%e is not associated !ith an increased gout flares./

• 6articularly because of the association of gout !ith atherosclerosis, the diagnosis of gout may be a good time to

advise a lo!3cholesterol, lo!3fat diet if other!ise appropriate for the patient. @hile such a diet may help uricacid levels, such advice should be given primarily to help prevent atherosclerosis.

• @eight reduction in patients !ho are obese can improve hyperuricemia.

"cti*ity

6atients !ith gout should avoid using the inflamed joint during an acute attac%. &ther!ise, they should be active.

Medication

#cute inflammation due to gout can be treated !ith 4S#ICs, corticosteroids, or, rarely, colchicine. 4S#ICs are generallythe drugs of choice unless the patient has a ris% factor that contraindicates these agents. Ultimately, gout is treated bydecreasing tissue stores of uric acid !ith allopurinol or probenecid. +ecause agents that lo!er uric acid can precipitate

attac%s of gout, lo!3dose colchicine is used as prophyla'is !hen such therapy is initiated.

+onsteroidal anti,in&la''atory drugs

0hese agents as a class are the drugs of choice to treat acute inflammation of gout in patients !ho can safely ta%ethese medications.





Indo'ethacin -Indocin.

The traditional NSAID used to treat acute inflammation in gout, although other NSAIDs can be used

effectively. These agents block cyclooxygenase and, thereby, the generation of prostaglandins. se maximum

level of NSAID and taper over approximately ! "eeks, depending on patient#s response.

Adult

2; mg 6& tid or $id for 3/ d, depending on response, and begin tapering

"nti,in&la''atory agents

Aolchicine is no! considered a second3line agent in the treatment of acute gout flares because of its narro! therapeutic!indo!. More often, it is used at a lo!er dose as a prophylactic agent to prevent flares of gout !hen adding agents thatlo!er uric acid.

#olchicine

Inhibits microtubules and thereby may inhibit phagocytosis, neutrophil mobility, and chemota'is. #lso may inhibigeneration of prostaglandins.

Adult

6& for acute flaresE ;.2 mg or ;.9 mg tidIL for acute flaresE 4o longer advocated6rophyla'isE ;.2 mg or ;.9 mg 6& bid? adjust dose for renal insufficiency

#orticosteroids

0hese agents are potent and effective anti3inflammatory drugs that can be used to treat acute gout in patients !ho

cannot tolerate 4S#ICs or colchicine. Steroids can be given 6&, IM, IL, intra3articularly, or indirectly via #A0. 0heshort3burst therapy of corticosteroids necessary to treat an acute flare of gout is generally !ell tolerated and notassociated !ith the chronic adverse effects associated !ith long3term steroid use. In many patients, a short course ofsteroids is a safer option than 4S#ICs and colchicine. In patients !ith only or - involved joints, intra3articularcorticosteroids are a safe and effective treatment option.

Prednisone -%eltasone Orasone Meticorten.

Aan be given 6& to abort an attac% of gout. 4o intrinsic advantage to treating !ith IL corticosteroids e'ists unless thepatient cannot ta%e medications 6&. 0he advantage of intra3articular steroids is that they reduce the systemic effects of6& steroids, but care must be ta%en to ma%e sure the joint is not infected. #A0 also can be used to induce thepatientDs o!n adrenal gland to produce corticosteroidsSteroid dose pac%s that clearly label the dose to be ta%en each day can be convenient for some pat

Adult

InitialE 1; mg 6& $d for 3/ d, depending on response, and tapered over appro'imately - !%

Uricosuric agents

Uricosuric agents lo!er uric acid levels by increasing net renal e'cretion of uric acid. 0hey are better tolerated thanallopurinol but are less effective and cannot be used in all circumstances. 0hese agents increase the ris% of renal



stones. 0hese agents should not be started during an attac% of acute gouty arthritis. 0he goal of therapy is to lo!erserum uric acid to appro'imately 239 mg"d5 !ithout causing renal stones.

Probenecid

Cesigned to lo!er tissue stores of uric acid by increasing net renal e'cretion of uric acid by inhibiting tubular

reabsorption. Some authorities recommend al%aliBing the urine !hen starting probenecid to reduce the ris% for renalstone formation.

Adult

-2; mg 6& bid for !%, then 2;; mg bid? can increase up to / g"d

Pediatric

4ot established

0anthine o!idase inhibitors

0hese agents prevent the generation of uric acid and thereby reduce the tissue stores of uric acid. #llopurinol is moreli%ely to be effective than uricosuric agents but carries an increased ris% for significant adverse effects. #llopurinoshould not be started during an attac% of acute gouty arthritis. 0he goal of therapy is to lo!er the serum uric acid level toappro'imately 239 mg"d5.

"llopurinol -1ylopri'.

7educes production of uric acid, thereby allo!ing body to dispose of e'cess uric acid stores. Most effective therapy tolo!er serum uric acid. Most patients achieve the target uric acid level of 2 mg"d5 at /;;31;; mg"d, less if renalinsufficiency is present.

Adult

InitialE ;; mg"d 6&? titrate monthly according to serum uric acid levelMaintenanceE /;;31;; mg"d 6&*ffective doses based on G7E 1;; mg 6& $d for 1; m5"min creatinine clearance? /;; mg for ;; m5"min creatinineclearance? -;; mg for 9; m5"min creatinine clearance? 2; mg for 1; m5"min creatinine clearance? ;; mg for -;m5"min or less

Febu!ostat -Uloric.

Hanthine o'idase inhibitor. 6revents uric acid production and lo!ers elevated serum uric acid levels. Indicated for long3term management of hyperuricemia associated !ith gout.

Adult

1; mg 6& $d initially? after - !%, if serum uric acid levels are not J9 mg"d5, increase to :; mg"d

Follo2,up



Further Outpatient #are

#fter diagnosis and treatment of an acute gouty arthritis episode, the patient should return for a follo!3up visit inappro'imately month to be evaluated for therapy to lo!er serum uric acid levels. If uric acid8lo!ering therapy isbegun, patients should be seen every 3- months !hile adjusting the dose of medications to achieve the target uric acidlevel of 239 mg"d5. &nce this level is achieved and maintained, patients can be seen every 93- months.

%eterrence/Pre*ention

• #voiding alcohol (beer and hard li$uor) and avoiding obesity may help deter or prevent gout.

#o'plications

• #lthough effective treatments for gout e'ist, failure of control can occur !ith inade$uate dosing of urate3lo!ering

medication, generally as a conse$uence of delayed treatment, inade$uate serum urate goals, patientnoncompliance, and"or medication intolerance.

• Untreated gout can lead to severe joint destruction and renal impairment.

• Septic arthritis can occur in a gouty joint, and draining tophi can become secondarily infected.

Prognosis

• Gout that is treated early and properly carries an e'cellent prognosis if patient compliance is good.

Patient 3ducation

• &nline information and pamphlets on gout are available from the #rthritis oundation. If appropriate, patients

should be counseled on the use of alcohol and a lo!3fat diet.

• or e'cellent patient education resources, visit eMedicineDs #rthritis Aenter . #lso, see eMedicineDs patien

education article Gout.

Medicolegal Pit&alls

• 0he major pitfall associated !ith gout is not establishing a crystal diagnosis. *stablishing a crystal diagnosis is

relatively easy and provides a clear reason to use life3long medications, such as allopurinol, !hich have

potentially serious adverse effects.• 6atients !ho present !ith acute inflammatory arthritis need to undergo arthrocentesis to e'clude septic arthritis

even if their serum uric acid level is elevated. 4ongonococcal infectious arthritis carries a ;> fatality rate andtherefore must be e'cluded.

• Under normal circumstances, patients should not be treated indefinitely !ith colchicine monotherapy. Synovia

tophi !ill continue to gro! and disrupt cartilage and bone. 0o prevent recurrent flares and tophus formationpatients should be given an agent that lo!ers uric acid, unless a contraindication e'ists.

• Co not start therapy !ith an agent that lo!ers uric acid during the acute attac% because doing so may intensify

and prolong the attac%.

• Aolchicine, even in prophylactic doses, can cause marro! to'icity and neuromyopathy in the setting of renal

insufficiency.

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