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Gout

The right clinical information, right where it's needed

Last updated: Nov 13, 2017

Table of ContentsSummary 3

Basics 4

Definition 4

Epidemiology 4

Aetiology 4

Pathophysiology 5

Prevention 6

Primary prevention 6

Secondary prevention 6

Diagnosis 7

Case history 7

Step-by-step diagnostic approach 7

Risk factors 12

History & examination factors 13

Diagnostic tests 15

Differential diagnosis 16

Diagnostic criteria 17

Treatment 19

Step-by-step treatment approach 19

Treatment details overview 24

Treatment options 25

Emerging 39

Follow up 41

Recommendations 41

Complications 41

Prognosis 42

Guidelines 43

Diagnostic guidelines 43

Treatment guidelines 44

Online resources 46

Evidence scores 47

References 48

Images 55

Disclaimer 56

Summary

◊ Acute onset of severe joint pain.

◊ Swelling, effusion, warmth, erythema, and/or tenderness of the involved joint(s).

◊ Arthrocentesis with synovial fluid analysis shows strongly negative birefringent needle-shapedcrystals under polarised light.

◊ Non-steroidal anti-inflammatory drugs (NSAIDs), colchicine, or corticosteroids are used to treat acutedisease.

◊ Allopurinol, febuxostat, probenecid, lesinurad, or sulfinpyrazone may be used as uric acid-loweringdrugs when long-term prevention of crystal deposition is indicated.

◊ Complications include joint destruction, kidney disease, and urolithiasis.

Gout BasicsBA

SIC

S

DefinitionGout is a syndrome characterised by: hyperuricaemia and deposition of urate crystals causing attacks ofacute inflammatory arthritis; tophi around the joints and possible joint destruction; renal glomerular, tubularand interstitial disease; and uric acid urolithiasis. The disease most commonly affects the first toe (podagra),foot, ankle, knee, fingers, wrist, and elbow; however, it can affect any joint.

EpidemiologyThe annual incidence of gout in the US in people over 50 years of age is 1.6 per 1000 in men and 0.3 per1000 in women.[1] The incidence increases with age. The annual incidence of gout in men increases from 1per 1000 under 45 years of age, to 1.8 per 1000 at 55 to 64 years of age.[2] Gout is more common in menand is rare in pre-menopausal women.[3] The prevalence in the western world is about 1%, with a maleto female ratio of 7:1 to 9:1; in the UK and Germany the prevalence is 1.4%.[4] [5] The prevalence variesgeographically and racially. In New Zealanders with a European background, the prevalence is 3.6%. In theMaoris population, it is as high as 6.4%.[3] [6] [7] The incidence of gout that is not associated with diureticuse has doubled over the past 20 years.[8] This trend may be related to lifestyle changes and increasedobesity. Obesity was the most common comorbidity in the UK in 2000 to 2005 (27.7%), but in Germany themost common comorbidity was diabetes (25.9%). The prevalence of comorbidities tended to increase withserum uric acid (sUA) levels. There was a positive correlation between sUA level and the frequency of goutflares. Compared with those in whom sUA was <360 micromol/L (<6 mg/dL), odds ratios for a gout flare were1.33 and 1.37 at sUA 360 to 420 micromol/L (6-7 mg/dL), and 2.15 and 2.48 at sUA >530 micromol/L (>9mg/dL) in the UK and Germany, respectively (P <0.01).[5]

AetiologyThere is a causal relationship between hyperuricaemia (high urate level) and gout. Urate is a metabolite ofpurines and the ionised form of uric acid (a weak acid at a physiological pH); hence, uric acid exists mostlyas urate. Hyperuricaemia does not always lead to gout, but the incidence of gout increases with urate level.The annual incidence of gout in men is 0.4% for a urate level of 7 to 7.9 mg/dL, 0.8% for 8 to 8.9 mg/dL,4.3% for 9 to 9.9 mg/dL, and 7% for levels >10 mg/dL.[9]

Uric acid levels and cumulative incidence of first episodes of goutAdapted from Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia.

Risks and consequences in the Normative Aging Study. Am J Med. 1987;82:421-426

Hyperuricaemia is due to renal under-excretion of urate in 90% of cases and to over-production in 10%,although there is often an overlap of both.[10]

Risk factors for hyperuricaemia may eventually lead to gout and include dietary factors such as consumptionof seafood, meat, and alcohol, especially beer.[2] Another source of purines and urate is endogenousproduction due to high cell turnover, such as from haematological cancer and chemotherapy. A smallproportion of over-producers have a specific genetic enzymatic abnormality. Drugs such as diuretics canincrease urate levels. Other risk factors for gout include obesity, insulin resistance, and hypertension.[11] [12]

4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Nov 13, 2017.BMJ Best Practice topics are regularly updated and the most recent versionof the topics can be found on bestpractice.bmj.com . Use of this content is

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https://bestpractice.bmj.com

Gout Basics

PathophysiologyHumans and some other higher primates develop gout spontaneously. Humans no longer express the genefor the enzyme uricase, which degrades uric acid to the more soluble compound allantoin in animals. This,coupled with a high rate of renal re-absorption of urate, results in hyperuricaemia and gout.[13] [14] [15][16] Uric acid exists as urate at a physiological pH. High urate levels result in super-saturation and crystalformation, leading to gout. Urate levels directly correlate with the risk of the disease. Drugs that reduce uratelevels decrease the risk of recurrent attacks.[17]

The solubility of urate in the joints depends on temperature, pH, non-aggregated proteoglycans, andother factors. Gout more commonly affects the first metatarsophalangeal joint (cool part of the body) andosteoarthritic joints.[18]

Urate crystals in the joint interact with undifferentiated phagocytes and trigger an acute inflammatoryresponse by inducing TNF-alpha and activating signal pathways and endothelial cells.[19] TNF-alpha,interleukin (IL)-8, and other chemokines lead to neutrophil adhesion to endothelium, influx, and amplification,resulting in neutrophilic synovitis.

Colchicine works by intercepting the neutrophil-endothelial interaction.[10] [20] IL-8 accounts for 90%of the chemotactic activity of neutrophils in response to uric acid crystals; hence, inhibiting IL-8 mayhave therapeutic implications.[21] [22] In addition there is an evidence that urate crystals activateNALP3 inflammasome that induces the secretion of IL-1beta, which plays a role in the gout inflammatoryreaction.[23] This pathway has been the target of new therapeutic interventions in gout that inhibit theIL-1beta response.[24] [25] [26] [27]

Spontaneous resolution of gout attack results from clearance of urate crystals by differentiated phagocytes,coating of the crystals with proteins, neutrophilic apoptosis, and inactivation of inflammatory mediators.[10]Urate crystals can induce chronic inflammation, leading to synovitis, cartilage loss, and bone erosions. Theymay also induce chondrocytes to produce metalloproteinase and nitric oxide, which results in cartilage loss,and may cause bone damage by inhibiting osteoblasts.[28] [29]

BAS

ICS

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Nov 13, 2017.BMJ Best Practice topics are regularly updated and the most recent versionof the topics can be found on bestpractice.bmj.com . Use of this content is


5


Gout PreventionPR

EVEN

TIO

N

Primary preventionThere are no prospective studies or evidence regarding effective intervention for primary prevention of goutor hyperuricaemia.[30]

Secondary preventionHyperuricaemia does not always lead to gout, but the incidence of gout increases with urate level.[9]Patients with hyperuricaemia and gout should avoid risk factors that may precipitate gout such as excessivealcohol consumption, diuretic use, and weight gain, which will help reduce uric acid level and hence goutflares.[92] Patients with lymphoproliferative disorders requiring chemotherapy are given intravenous hydrationand allopurinol to prevent hyperuricaemia and complications such as acute renal failure due to uric acidnephropathy.[93]




Gout Diagnosis

Case historyCase history #1A 54-year-old man complains of severe pain and swelling in his right first toe that developed overnight.He is limping because of the pain and states that this is the most severe pain he has ever had ('evencovering my foot with the bed sheet hurts'). He has had no previous episodes. His only medication ishydrochlorothiazide for hypertension. He drinks 2 to 3 beers a day. On examination, he is obese. Thereis swelling, erythema, warmth, and tenderness of the right first toe. There is also tenderness and warmthwith mild swelling over the mid foot.

Case history #2An 85-year-old man presents with several days of swelling and severe pain in both hands limiting hisability to use his walking frame. He has a history of gout but has not experienced these symptoms before.On examination, he has a temperature of 37.8°C (100.1°F). There is diffuse warmth, mild erythema,and pitting oedema over the dorsum of both hands. There is tenderness and limited hand grip bilaterally.There are multiple nodules around several of the proximal interphalangeal and distal interphalangealjoints, and effusion and tenderness in his left olecranon bursa with palpable nodules.

Other presentationsGout may also present as acute bursitis, especially in the olecranon and prepatellar bursae. Chronictophaceous gout may cause inflammatory destructive polyarthritis. This usually occurs in people with along-standing history of attacks (mean 10 years) and with higher uric acid levels.[Fig-1]

[Fig-2]

Step-by-step diagnostic approachGout is clinically suspected in patients with typical history and examination findings. Diagnosis is confirmedby arthrocentesis showing monosodium urate crystals. Alternatively, diagnosis may be based upon fulfilmentof ≥6 of the following criteria from the American College of Rheumatology (ACR):[42]

• More than one attack of acute arthritis

• Maximum inflammation developed within 1 day

• Monoarthritis attack, redness observed over joints

• First metatarsophalangeal joint painful or swollen

• Unilateral first metatarsophalangeal joint attack

• Unilateral tarsal joint attack

• Tophus (confirmed or suspected)

DIAG

NO

SIS



7


Gout DiagnosisD

IAG

NO

SIS

• Hyperuricaemia

• Asymmetric swelling within a joint on x-ray film

• Subcortical cyst without erosions on x-ray film

• Joint culture negative for organism during attack.

However, the diagnosis can be made clinically with a good degree of certainty without the presence ofcrystals and without fulfilling the points suggested by the ACR criteria. For example, cases with a reliablehistory of recurrent acute monoarthritis of the first metatarsophalangeal joint (podagra).

In 2015 the ACR published new classification criteria; however, these criteria are intended for identifyingpeople who may be eligible for entry into a clinical study and they are not intended to be used to diagnosegout.[43] [44]

HistoryGout is more common in men and rare in pre-menopausal women. A history of previous attacks that areself-limiting (7-14 days) supports the diagnosis. Medications, dietary habits, and family history should beassessed.

The most common presentation is acute monoarticular arthritis characterised by sudden-onsetsevere pain and swelling. However, the disease may also be oligoarticular (<4 joints involved) or, toa lesser degree, polyarticular. The most commonly affected joints are the first metatarsophalangeal,tarsometatarsal, ankle, and knee joints, but almost any other joint may be affected.

In older people, the disease may be polyarticular and associated with marked oedema and swelling of thehands and feet.

Physical examinationInvolved joints are warm, red, and swollen. Usually, there is considerable tenderness and limited range ofmovement due to pain.

All joints should be examined, as others may be affected in a more subtle fashion.

Hard subcutaneous nodules (tophi) over the extensor surface of the joint, especially over the elbows,knees, and Achilles tendons, may be present. Tophi may also be evident over the dorsal aspects of handsand feet, and in the helix of the ears.[Fig-1]

[Fig-2]

Diagnostic testsArthrocentesis with synovial fluid analysis provides definitive diagnosis. The synovial fluid WCC countusually exceeds 2.0 x 10^9/L (2000/mm^3 or 2000/microlitre), and the cells are mostly PMNs type.Monosodium urate crystals (intracellular and/or extracellular needle-shaped crystals strongly negative forbirefringence under polarised light) confirm the diagnosis. Synovial fluid analysis should be consideredin most patients, but the diagnosis can often be made clinically. Aspiration and injection of the kneeanimated demonstrationEquipment needed




Gout Diagnosis

Prepare a sterile field using a non-touch technique with the following:

• Sterile gloves• Sterile antiseptic skin preparation (povidone-iodine or chlorhexidine are most suitable)• Surgical swabs• Sterile syringes and needles (21-gauge or 23-gauge)• Sterile specimen pots (if aspirating for diagnostic purpose)• Medication for injection (for therapeutic purpose)• Adhesive dressing• Local anaesthetic (optional).

Contraindications

• Joint replacement or prosthesis• Sepsis: local skin sepsis, bacteraemia, osteomyelitis, or septic arthritis (injection is contraindicated;

aspiration is indicated)• Cellulitis: cellulitis of the skin overlying the knee joint can result in distribution of bacteria directly

into a joint if you aspirate or inject it; this could result in iatrogenic septic arthritis, potentially leadingto joint damage and destruction

• Abnormal clotting (e.g., haemophilia or anticoagulation)• Haemarthrosis, osteochondral fracture, or suspected intra-articular fracture: do not perform a joint

injection if there is suspicion of an intra-articular fracture. Patients with intra-articular fractureswill need reduction and operative fixation to preserve joint function (injection is contraindicated;aspiration of haemarthrosis may be rarely indicated)

• Immunocompromised or poorly controlled diabetes• Patient refusal.

Indications

The indications for performing diagnostic aspiration of the knee joint include clinical suspicion of:

• Septic arthritis• Crystal arthropathy: gout and pseudogout• Inflammatory monoathropathy (e.g., osteoarthritis): symptoms of osteoarthritis can improve with

injection of corticosteroids into the affected joint, which can help reduce inflammation within thejoint and relieve painful symptoms

• Seronegative arthropathy (e.g., reactive arthritis, gonococcal arthropathy, ankylosing spondylitis)• Monoarthropathy, or joint effusion of unknown cause.

On rare occasions, aspirate the knee joint to provide symptomatic relief of a very tense and painfulhaemarthrosis or large tense effusion.

Complications

• Pain: should be short lived; after injection of medication there may be an initial flare of pain due toreactive arthralgia

• Haemorrhage• Infection: using an aseptic technique helps to reduce the risk of introducing infection into a

previously sterile joint space; further investigation and orthopaedic intervention may be necessary ifthere is suspicion of infection

DIAG

NO

SIS



9


Gout DiagnosisD

IAG

NO

SIS

• Recurrence of effusion or symptoms• Joint destruction: injecting a joint with corticosteroids may lead to osteonecrosis and destruction

of the joint surfaces. This should be weighed against the benefit of intermittent symptomatic relief.Injections should be limited to three per year per large joint.[45] [46]

Aftercare

• Send synovial fluid from the diagnostic aspirate to the lab for urgent microscopy, cell count, Gramstain and culture, and crystals (for gout and pseudogout)

• If the aspirate is frank pus, or if there is a clinical suspicion of septic arthritis, immediateorthopaedic assessment and intervention is necessary. Get blood cultures and start the patienton intravenous antibiotics following the local protocol. The patient will need to have a formal jointwashout in theatre as soon as possible

• For aspirates that are non-septic, base the management plan on clinical findings and the resultsfrom the analysis of the joint fluid.

Aspiration and injection of the shoulder animated demonstrationEquipment needed



Contraindications


aspiration is indicated)• Cellulitis: this is a bacterial infection and patients with cellulitis overlying the joint should not have

a joint aspiration and/or injection. There is a significant risk that bacteria causing the skin infectionmay be inoculated into the joint, causing iatrogenic septic arthritis. This may lead to severe jointdestruction and systemic illness

• Abnormal clotting (e.g., haemophilia) or anticoagulation: there is an increased risk of bleeding intothe joint, which would result in iatrogenic haemarthrosis

• Haemarthrosis, osteochondral fracture, or suspected intra-articular fracture (injection iscontraindicated; aspiration of haemarthrosis may be rarely indicated)

• Immunocompromised, including poorly controlled diabetes• Patient refusal.

Indications

The indications for performing diagnostic aspiration of the shoulder joint include clinical suspicion of:




Gout Diagnosis

• Septic arthritis• Crystal arthropathy: gout and pseudogout• Inflammatory monoarthropathy (e.g., osteoarthritis)• Seronegative arthropathy (e.g., reactive arthritis, gonococcal arthropathy, ankylosing spondylitis)• Seropositive arthropathy (e.g., rheumatoid arthritis)• Monoarthropathy or joint effusion of unknown cause• Adhesive capsulitis• Rotator cuff tendinopathy• Subacromial bursitis.

On rare occasions the shoulder joint can be aspirated to provide symptomatic relief of a very tense andpainful haemarthrosis or large tense effusion.

Patients with inflammatory arthropathies such as osteoarthritis can benefit from injection of intra-articularcorticosteroids, which can offer temporary relief of painful symptoms.

Complications

• Pain: should be short lived; after injection of medication there may be an initial flare of pain withreactive arthralgia


previously sterile joint space; further investigation and orthopaedic intervention is necessary if thereis a suspicion of infection

• Recurrence of effusion or symptoms• Joint destruction: injection of the joint with corticosteroids may lead to osteonecrosis and

destruction of the joint surfaces despite providing intermittent symptomatic relief. Injections shouldbe limited to three per year per large joint.[45] [46]

Aftercare

• Send synovial fluid from the diagnostic aspirate to the lab for urgent microscopy, cell count, Gramstain, culture, and crystals

• If the aspirate is frank pus, or there is a clinical suspicion of septic arthritis, immediate orthopaedicassessment and intervention is necessary. Get blood cultures and give the patient intravenousantibiotics. The patient will need to have a formal joint washout in theatre as soon as possible

• For aspirates that are non-septic, base the management plan on clinical findings and joint fluidanalysis

• Arrange follow-up to discuss the results of the procedure with the patient. Follow-up also enablesclinicians to check for any complications that may have occurred as a result of the procedure andestablish whether any intervention has been successful.

Serum uric acid level may be low, normal, or high during an acute gout attack. This test becomes morereliable when done at least 2 weeks after the attack resolves.

X-rays are not useful for diagnosis, but may differentiate between chronic gout and other jointconditions.[47] Ultrasound is more sensitive than x-rays in detecting erosions, tophi, and the gout-specificdouble contour sign (linear urate deposits over hyaline cartilage). Ultrasound and dual-energy computedtomography may be helpful, but the potential benefit of imaging over clinical diagnosis requires furtherstudy.[48]

DIAG

NO

SIS



11


Gout DiagnosisD

IAG

NO

SIS

Risk factorsStrongolder age• Incidence increases with age, peaking in men between 40 and 60 years and in women between 50

and 70 years.[2]

male sex• More common in men.[3]

menopausal status• Gout is especially rare in pre-menopausal women.[3] [30]

consumption of meat, seafood, alcohol• A prospective 12-year follow-up of 47,150 men reported a higher risk of gout among those in the

highest versus lowest quintiles of seafood and meat consumption, relative risks (RRs) 1.51 (95% CI1.17 to 1.95) and 1.41 (95% CI 1.07 to 1.86), respectively.

• Dairy consumption is associated with a lower risk, RR 0.56 (95% CI 0.42 to 0.74) comparing thehighest quintiles with the lowest quintile.[2]

• Consumption of alcohol, especially beer and spirits, is associated with a higher risk.[30] An additionaldaily serving of beer is associated with an RR of 1.49 (95% CI 1.32 to 1.70) and spirits with an RR of1.15 (95% CI 1.04 to 1.28). An additional daily serving of wine is not associated with increased risk,RR 1.04 (95% CI 0.88 to 1.22).[31]

use of diuretics• Thiazide and loop diuretics are associated with an increased risk of gout and of gout flares.[30]

use of ciclosporin (cyclosporine) or tacrolimus• Lead to increased tubular re-absorption of urate as well as decreased glomerular filtration and

interstitial nephropathy.

use of pyrazinamide• Increases urate re-absorption.

use of aspirin• Doses of ≤325 mg elevate urate levels, while higher doses have uricosuric effects and lead to lower

urate levels.[10]

genetic susceptibility• Some urate over-producers have specific genetic defects, such as hypoxanthine-guanine

phosphoribosyl transferase (HPRT) deficiency, 5-phosphoribosyl-l-pyrophosphate (PRPP) synthetasehyperactivity, and glucose-6-phosphate dehydrogenase (G6PD) deficiency.

• The most complete form of HPRT deficiency is associated with Lesch-Nyhan's syndrome (prematuregout and mental retardation in children). The partial deficit of the enzyme is associated with gout andhyperuricaemia without neurological manifestations.




Gout Diagnosis

• Both PRPP synthetase hyperactivity and HPRT deficiency are X-linked, while G6PD deficiency is anautosomal recessive condition. G6PD deficiency is associated with von Gierke's disease, a type-1glycogen storage disease.[32]

high cell turnover state• Conditions that lead to high endogenous purine metabolism include haematological malignancies,

myeloproliferative disorders, psoriasis, and chemotherapy-induced cell death.

Weakadiposity and insulin resistance• Associated with hyperuricaemia.[12] [33] [34] [35]• Small open-label studies show that weight loss is associated with lower urate level and risk of gout.[36]

[37]• Exogenous insulin can reduce the renal excretion of urate.[38] Also, insulin can enhance renal urate

re-absorption.[39]

hypertension• An independent risk factor for gout.[11] [30] Renal urate excretion is inappropriately low relative to

glomerular filtration rate.[40] This may reflect early nephrocalcinosis in hypertensive patients. Gout, inturn, may be associated with a higher incidence of hypertension and cardiovascular morbidity.[41]

renal insufficiency• Has been found to be associated with higher risk of incident gout or gout flares.[30]

diabetes mellitus• Has been found to be associated with a higher risk of incident gout and/or gout flares in

epidemiological studies.[30] However, there are many confounding factors that may have influencedthe findings. Variations in case definition, and the use of study populations from particulargeographical locations, should be borne in mind.

hyperlipidaemia• Hypertriglyceridaemia and hypercholesterolaemia have been found to be associated with a higher

risk of incident gout and/or gout flares in epidemiological studies.[30] However, there are manyconfounding factors that may have influenced the findings. Variations in case definition, and the use ofstudy populations from particular geographical locations, should be borne in mind.

History & examination factorsKey diagnostic factorspresence of risk factors (common)• Strong risk factors include: older age; male gender; use of drugs including aspirin, ciclosporin

(cyclosporine), tacrolimus, or pyrazinamide; consumption of meat, seafood, or alcohol; geneticsusceptibility; and conditions with a high cell turnover rate.

rapid-onset severe pain (common)

DIAG

NO

SIS



13


Gout DiagnosisD

IAG

NO

SIS

• Patients with an acute attack can often pinpoint the onset to the hour. They may describe the pain asthe most severe they have ever experienced.

joint stiffness (common)• Morning stiffness is prominent and reflects the underlying inflammatory mechanism. Function may be

limited because of pain and stiffness.

foot joint distribution (common)• Most commonly involved are joints in the feet, especially the first metatarsophalangeal,

tarsometatarsal, and ankle joints.

few affected joints (common)• Pattern is usually monoarticular or oligoarticular (<4 joints). Can be polyarticular, affecting multiple

joints in the hands and feet, especially in older people.

swelling and joint effusion (common)• Reflect the inflammatory nature of the disease.

tenderness (common)• Prominent diffuse joint tenderness usually exists.

tophi (common)• May be present over extensor surface joints, especially the elbows, knees, and Achilles tendons.• May also be evident over dorsal aspects of hands and feet, and in helix of the ears.

Other diagnostic factorserythema and warmth (common)• May be subtle at times, requiring careful examination.

family history of gout (uncommon)• Presence of family members with gout at a fairly young age may suggest a genetic defect in a specific

enzyme.




Gout Diagnosis

Diagnostic tests1st test to order

Test Resultarthrocentesis with synovial fluid analysis

• Should always be considered, but is not always necessary in patientsin whom a clinical diagnosis can be made confidently. Confirms thediagnosis, and will exclude septic arthritis and differentiate gout frompseudogout (calcium pyrophosphate deposition disease). At times,poor transportation conditions or a long lag time between obtainingthe synovial fluid and examining the specimen, makes it difficult toidentify the crystals.

• An expert, such as a rheumatologist or experienced technician,should examine the synovial fluid, as commercial laboratories maynot be reliable in detecting monosodium urate crystals.

• If the analysis fails to show these crystals or other aetiology for theacute inflammatory arthritis, repeating arthrocentesis during futureattacks should be considered. Aspiration and injection of the kneeanimated demonstrationEquipment needed


• Sterile gloves• Sterile antiseptic skin preparation (povidone-iodine or

chlorhexidine are most suitable)• Surgical swabs• Sterile syringes and needles (21-gauge or 23-gauge)• Sterile specimen pots (if aspirating for diagnostic purpose)• Medication for injection (for therapeutic purpose)• Adhesive dressing• Local anaesthetic (optional).

Contraindications

• Joint replacement or prosthesis• Sepsis: local skin sepsis, bacteraemia, osteomyelitis, or septic

arthritis (injection is contraindicated; aspiration is indicated)• Cellulitis: cellulitis of the skin overlying the knee joint can result

in distribution of bacteria directly into a joint if you aspirate orinject it; this could result in iatrogenic septic arthritis, potentiallyleading to joint damage and destruction

• Abnormal clotting (e.g., haemophilia or anticoagulation)• Haemarthrosis, osteochondral fracture, or suspected intra-

articular fracture: do not perform a joint injection if there issuspicion of an intra-articular fracture. Patients with intra-articular fractures will need reduction and operative fixation topreserve joint function (injection is contraindicated; aspirationof haemarthrosis may be rarely indicated)


Indications

The indications for performing diagnostic aspiration of the knee jointinclude clinical suspicion of:

• Septic arthritis• Crystal arthropathy: gout and pseudogout• Inflammatory monoathropathy (e.g., osteoarthritis): symptoms

of osteoarthritis can improve with injection of corticosteroidsinto the affected joint, which can help reduce inflammationwithin the joint and relieve painful symptoms

• Seronegative arthropathy (e.g., reactive arthritis, gonococcalarthropathy, ankylosing spondylitis)

• Monoarthropathy, or joint effusion of unknown cause.

On rare occasions, aspirate the knee joint to provide symptomaticrelief of a very tense and painful haemarthrosis or large tenseeffusion.

Complications

• Pain: should be short lived; after injection of medication theremay be an initial flare of pain due to reactive arthralgia

• Haemorrhage• Infection: using an aseptic technique helps to reduce the risk of

introducing infection into a previously sterile joint space; furtherinvestigation and orthopaedic intervention may be necessary ifthere is suspicion of infection

• Recurrence of effusion or symptoms• Joint destruction: injecting a joint with corticosteroids may

lead to osteonecrosis and destruction of the joint surfaces.This should be weighed against the benefit of intermittentsymptomatic relief. Injections should be limited to three peryear per large joint.[45] [46]

Aftercare

• Send synovial fluid from the diagnostic aspirate to the lab forurgent microscopy, cell count, Gram stain and culture, andcrystals (for gout and pseudogout)

• If the aspirate is frank pus, or if there is a clinical suspicionof septic arthritis, immediate orthopaedic assessment andintervention is necessary. Get blood cultures and start thepatient on intravenous antibiotics following the local protocol.The patient will need to have a formal joint washout in theatreas soon as possible

• For aspirates that are non-septic, base the management planon clinical findings and the results from the analysis of the jointfluid.



• Sterile gloves• Sterile antiseptic skin preparation (povidone-iodine or

chlorhexidine are most suitable)• Surgical swabs• Sterile syringes and needles (21-gauge or 23-gauge)• Sterile specimen pots (if aspirating for diagnostic purpose)• Medication for injection (for therapeutic purpose)• Adhesive dressing• Local anaesthetic (optional).

Contraindications

• Joint replacement or prosthesis• Sepsis: local skin sepsis, bacteraemia, osteomyelitis, or septic

arthritis (injection is contraindicated; aspiration is indicated)• Cellulitis: this is a bacterial infection and patients with cellulitis

overlying the joint should not have a joint aspiration and/or injection. There is a significant risk that bacteria causingthe skin infection may be inoculated into the joint, causingiatrogenic septic arthritis. This may lead to severe jointdestruction and systemic illness

• Abnormal clotting (e.g., haemophilia) or anticoagulation: thereis an increased risk of bleeding into the joint, which wouldresult in iatrogenic haemarthrosis

• Haemarthrosis, osteochondral fracture, or suspected intra-articular fracture (injection is contraindicated; aspiration ofhaemarthrosis may be rarely indicated)


Indications

The indications for performing diagnostic aspiration of the shoulderjoint include clinical suspicion of:

• Septic arthritis• Crystal arthropathy: gout and pseudogout• Inflammatory monoarthropathy (e.g., osteoarthritis)• Seronegative arthropathy (e.g., reactive arthritis, gonococcal

arthropathy, ankylosing spondylitis)• Seropositive arthropathy (e.g., rheumatoid arthritis)• Monoarthropathy or joint effusion of unknown cause• Adhesive capsulitis• Rotator cuff tendinopathy• Subacromial bursitis.

On rare occasions the shoulder joint can be aspirated to providesymptomatic relief of a very tense and painful haemarthrosis or largetense effusion.

Patients with inflammatory arthropathies such as osteoarthritis canbenefit from injection of intra-articular corticosteroids, which can offertemporary relief of painful symptoms.

Complications

• Pain: should be short lived; after injection of medication theremay be an initial flare of pain with reactive arthralgia

• Haemorrhage• Infection: using an aseptic technique helps to reduce the risk of

introducing infection into a previously sterile joint space; furtherinvestigation and orthopaedic intervention is necessary if thereis a suspicion of infection

• Recurrence of effusion or symptoms• Joint destruction: injection of the joint with corticosteroids may

lead to osteonecrosis and destruction of the joint surfacesdespite providing intermittent symptomatic relief. Injectionsshould be limited to three per year per large joint.[45] [46]

Aftercare

• Send synovial fluid from the diagnostic aspirate to the lab forurgent microscopy, cell count, Gram stain, culture, and crystals

• If the aspirate is frank pus, or there is a clinical suspicionof septic arthritis, immediate orthopaedic assessment andintervention is necessary. Get blood cultures and give thepatient intravenous antibiotics. The patient will need to have aformal joint washout in theatre as soon as possible

• For aspirates that are non-septic, base the management planon clinical findings and joint fluid analysis

• Arrange follow-up to discuss the results of the procedure withthe patient. Follow-up also enables clinicians to check forany complications that may have occurred as a result of theprocedure and establish whether any intervention has beensuccessful.

WCC count >2.0 x 10^9/L (2000/mm^3 or 2000/microlitre; mean,20,000/mm^3 or 20,000/microlitre); stronglynegative birefringentneedle-shaped crystalsunder polarised light

DIAG

NO

SIS



15


Gout DiagnosisD

IAG

NO

SIS

Other tests to consider

Test Resulturic acid level

• Should be obtained at least 2 weeks after the attack resolves, as itmay be falsely low or normal during the attack.

• Gout can develop with levels lower than the upper limit of normalvalues.

>416 micromol/L (7 mg/dL)in men; >360 micromol/L(6 mg/dL) in women

x-ray of affected joint• The hands are an optimal place to look for gouty erosions.

periarticular erosions(may have an overhangingedge or punched-outappearance)

ultrasound• Ultrasound-detected erosions are most commonly found in the first

metatarsophalangeal joint and the metacarpophalangeal joints.[49]

erosions, tophi, doublecontour line

Differential diagnosis

Condition Differentiating signs /symptoms

Differentiating tests

Pseudogout (calciumpyrophosphatedeposition disease)

• Presentation may beidentical to that of gout.

• Is less common in peopleyounger than 50 years ofage.

• Is more likely to affect wristand knee joints.

• Chondrocalcinosis(radiographic calcification ofcartilage in certain joints) isusually present.

• Ultrasound may helpto differentiate calciumpyrophosphate depositiondisease (CPPD) from gout.Calcium pyrophosphatedeposits are found deeperin the cartilage and are lesshomogenous (lumpy-bumpy)than the superficial doublecontour sign seen in gout.

• The definitive diagnosisis finding calciumpyrophosphate crystals inthe synovial fluid. Theseare rhomboid-shaped,weakly positively birefringentcrystals.

Septic arthritis • Presentation may beidentical to that of gout.

• Occurs in both sexes and atany age.

• Risk factors forinfection, such asintravenous drug use andimmunocompromise, may bepresent.

• Synovial fluid microscopyand culture may be Grampositive and show growth.

• Blood cultures may grow thecausal bacteria.

• Co-existence of crystals andinfection in the joint is notuncommon.




Gout Diagnosis

Condition Differentiating signs /symptoms

Differentiating tests

Trauma • A positive history is present.• Usually, there are fewer

inflammatory signs, such aserythema or warmth, on jointexamination than with gout.

• Synovial fluid is usuallybloody and has nomonosodium urate crystals.

Rheumatoid arthritis (RA) • Chronic tophaceous andpolyarticular gout maypresent like RA, and tophican be misdiagnosed asrheumatoid nodules.

• History of intermittent, acute,self-limited attacks of arthritisand podagra suggests gout.

• RA and gout appear tobe negatively correlated,as very few cases of co-existence have beenreported.

• Associated with positive RFin 70% to 78% of cases;however, 30% of patientswith gout have a positiveRF.[50]

• Anticyclic citrullinatedpeptide (anti-CCP) is a newdiagnostic test for RA. Ithas a high specificity, but alow sensitivity and it may beuseful in the early detectionof patients who will havesevere RA.[51]

• Synovial fluid is inflammatory(WCC count >2.0 x10^9/L or 2000/mm^3 or2000/microlitre), but nomonosodium urate crystalsare found.

Reactive arthritis • Recent infection withappropriate organism.

• Oligoarthritis present.• Commonly affects weight-

bearing joints.• May have tendon insertion

inflammation and dactylitis(whole digit inflammation).

• Conjunctivitis, urethritis, andstomatitis may be present.

• X-rays may show soft-tissueswelling.

Psoriatic arthritis • Patients usually have ahistory of psoriasis.

• Asymmetrical jointdistribution.

• Commonly affects the distalinterphalangeal joints.

• Presence of dactylitis.

• Typical radiographic findingsinclude joint erosions,joint space narrowing,bony proliferation includingperiarticular and shaftperiostitis, osteolysisincluding 'pencil in cup'deformity and acro-osteolysis, ankylosis,spur formation, andspondylitis.[52]

Diagnostic criteriaAmerican College of Rheumatology (ACR) preliminary criteria forthe classification of the acute arthritis of primary gout[42]

DIAG

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Diagnosis is satisfied by:

1. Characteristic monosodium urate crystals in joint fluid, or

2. Characteristic monosodium urate crystals from tophus, or

3. Fulfilment of ≥6 of the following criteria:

• More than one attack of acute arthritis• Maximum inflammation developed within 1 day• Monoarthritis attack, redness observed over joints• First metatarsophalangeal joint painful or swollen• Unilateral first metatarsophalangeal joint attack• Unilateral tarsal joint attack• Tophus (confirmed or suspected)• Hyperuricaemia• Asymmetric swelling within a joint on x-ray film• Subcortical cyst without erosions on x-ray film• Joint culture negative for organism during attack.

American College of Rheumatology/European League AgainstRheumatism (ACR-EULAR) gout classification criteria[43] [44]In 2015 the ACR published new classification criteria; however, these criteria are intended for identifyingpeople who may be eligible for entry into a clinical study and they are not intended to be used to diagnosegout.[43] [44]

• The sensitivity of the 2015 classification criteria is 92%, and the specificity is 89%.• The criteria include clinical, imaging, and laboratory-based features.• The maximum possible score in the final criteria is 23 and a threshold score of 8 classifies an

individual as having gout.• A unique aspect of these classification criteria is that there are 2 categories that elicit negative scores.

Specifically, if the synovial fluid is negative for monosodium urate, 2 points are subtracted from thetotal score. Similarly, if the serum urate level is <4 mg/dL (<0.24 mmol/L), 4 points are subtracted fromthe total score.

• Associated Web-based calculators are available. [ACR-EULAR gout classification criteria calculator]



http://goutclassificationcalculator.auckland.ac.nz/


Gout Treatment

Step-by-step treatment approachThe short-term treatment goal for acute gout is rapid resolution of pain and preservation of function. Long-term goals are to prevent recurrent attacks and chronic joint destruction. The earlier treatment is initiated, thebetter the clinical response.

Short-term managementNon-steroidal anti-inflammatory drug (NSAIDs) are first-line therapy for an acute attack if nocontraindications exist. It is common to use indometacin, although there is no evidence that it is moreefficacious than other NSAIDs and it is associated with more adverse effects.

An alternative to NSAIDs is colchicine.1[C]Evidence To avoid adverse effects, particularly diarrhoea, thetotal daily dose should not exceed 3 mg. One study showed that 1.2 mg of colchicine, followed by 0.6 mgafter 1 hour was better tolerated and as effective as taking total of 4.8 mg over 6 hours.[53] The effectthough was modest, with only approximately one third of patients reaching 50% reduction in pain within72 hours.

Corticosteroids are a possible alternative if both NSAIDs and colchicine are contraindicated (forinstance, in patients with renal insufficiency). They can be given either as an intra-articular injection formonoarticular acute gout or parenterally for oligoarticular or polyarticular acute gout. Potential seriousside effects of corticosteroids should be considered. Corticosteroids are probably more effective thancolchicine for acute gout, although there are no head-to-head comparison trials of these two types ofdrug.[54] 2[B]Evidence A randomised double-blinded controlled trial showed that oral prednisolone andindometacin were comparable in efficacy and adverse reactions when used for the treatment for acutegout in patients presenting to the emergency department.[55] Oral prednisolone could be considered asa first-line treatment for acute gout, as it is effective and associated with few adverse events, especiallywhen used for a short period of time.[55] Aspiration and injection of the knee animated demonstrationEquipment needed



Contraindications


aspiration is indicated)• Cellulitis: cellulitis of the skin overlying the knee joint can result in distribution of bacteria directly

into a joint if you aspirate or inject it; this could result in iatrogenic septic arthritis, potentially leadingto joint damage and destruction

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• Abnormal clotting (e.g., haemophilia or anticoagulation)• Haemarthrosis, osteochondral fracture, or suspected intra-articular fracture: do not perform a joint

injection if there is suspicion of an intra-articular fracture. Patients with intra-articular fractureswill need reduction and operative fixation to preserve joint function (injection is contraindicated;aspiration of haemarthrosis may be rarely indicated)


Indications

The indications for performing diagnostic aspiration of the knee joint include clinical suspicion of:

• Septic arthritis• Crystal arthropathy: gout and pseudogout• Inflammatory monoathropathy (e.g., osteoarthritis): symptoms of osteoarthritis can improve with

injection of corticosteroids into the affected joint, which can help reduce inflammation within thejoint and relieve painful symptoms

• Seronegative arthropathy (e.g., reactive arthritis, gonococcal arthropathy, ankylosing spondylitis)• Monoarthropathy, or joint effusion of unknown cause.

On rare occasions, aspirate the knee joint to provide symptomatic relief of a very tense and painfulhaemarthrosis or large tense effusion.

Complications

• Pain: should be short lived; after injection of medication there may be an initial flare of pain due toreactive arthralgia


previously sterile joint space; further investigation and orthopaedic intervention may be necessary ifthere is suspicion of infection

• Recurrence of effusion or symptoms• Joint destruction: injecting a joint with corticosteroids may lead to osteonecrosis and destruction

of the joint surfaces. This should be weighed against the benefit of intermittent symptomatic relief.Injections should be limited to three per year per large joint.[45] [46]

Aftercare

• Send synovial fluid from the diagnostic aspirate to the lab for urgent microscopy, cell count, Gramstain and culture, and crystals (for gout and pseudogout)

• If the aspirate is frank pus, or if there is a clinical suspicion of septic arthritis, immediateorthopaedic assessment and intervention is necessary. Get blood cultures and start the patienton intravenous antibiotics following the local protocol. The patient will need to have a formal jointwashout in theatre as soon as possible

• For aspirates that are non-septic, base the management plan on clinical findings and the resultsfrom the analysis of the joint fluid.






Gout Treatment


Contraindications


aspiration is indicated)• Cellulitis: this is a bacterial infection and patients with cellulitis overlying the joint should not have

a joint aspiration and/or injection. There is a significant risk that bacteria causing the skin infectionmay be inoculated into the joint, causing iatrogenic septic arthritis. This may lead to severe jointdestruction and systemic illness

• Abnormal clotting (e.g., haemophilia) or anticoagulation: there is an increased risk of bleeding intothe joint, which would result in iatrogenic haemarthrosis

• Haemarthrosis, osteochondral fracture, or suspected intra-articular fracture (injection iscontraindicated; aspiration of haemarthrosis may be rarely indicated)


Indications

The indications for performing diagnostic aspiration of the shoulder joint include clinical suspicion of:

• Septic arthritis• Crystal arthropathy: gout and pseudogout• Inflammatory monoarthropathy (e.g., osteoarthritis)• Seronegative arthropathy (e.g., reactive arthritis, gonococcal arthropathy, ankylosing spondylitis)• Seropositive arthropathy (e.g., rheumatoid arthritis)• Monoarthropathy or joint effusion of unknown cause• Adhesive capsulitis• Rotator cuff tendinopathy• Subacromial bursitis.

On rare occasions the shoulder joint can be aspirated to provide symptomatic relief of a very tense andpainful haemarthrosis or large tense effusion.

Patients with inflammatory arthropathies such as osteoarthritis can benefit from injection of intra-articularcorticosteroids, which can offer temporary relief of painful symptoms.

Complications

• Pain: should be short lived; after injection of medication there may be an initial flare of pain withreactive arthralgia

• Haemorrhage

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• Infection: using an aseptic technique helps to reduce the risk of introducing infection into apreviously sterile joint space; further investigation and orthopaedic intervention is necessary if thereis a suspicion of infection

• Recurrence of effusion or symptoms• Joint destruction: injection of the joint with corticosteroids may lead to osteonecrosis and

destruction of the joint surfaces despite providing intermittent symptomatic relief. Injections shouldbe limited to three per year per large joint.[45] [46]

Aftercare

• Send synovial fluid from the diagnostic aspirate to the lab for urgent microscopy, cell count, Gramstain, culture, and crystals

• If the aspirate is frank pus, or there is a clinical suspicion of septic arthritis, immediate orthopaedicassessment and intervention is necessary. Get blood cultures and give the patient intravenousantibiotics. The patient will need to have a formal joint washout in theatre as soon as possible

• For aspirates that are non-septic, base the management plan on clinical findings and joint fluidanalysis

• Arrange follow-up to discuss the results of the procedure with the patient. Follow-up also enablesclinicians to check for any complications that may have occurred as a result of the procedure andestablish whether any intervention has been successful.

Long-term managementThe long-term management for gout includes dietary modifications and weight loss (if indicated).[2] [11]Nonetheless, there is a paucity of high-quality evidence to either support or refute the use of lifestylemodifications for improving outcomes in people with chronic gout.[56]

Prophylactic drug therapy is indicated by presence of the following factors:

• Recurrent attacks (>2-3 per year)• Tophaceous gout• Radiographic changes and chronic destructive joint disease• Urate nephrolithiasis• Patient preference because of severe and debilitating polyarticular attacks.

Allopurinol reduces the production of uric acid. It should be started 2 weeks after the last exacerbationat a low dose of 100 mg/day. The dose should be increased over several weeks to months until the uricacid level is <360 micromol/L (<6 mg/dL). A retrospective case-controlled study suggested an increasedrisk of hypersensitivity to allopurinol when used at a dose >1.5 mg per mL of GFR.[57] This was reflectedin the 2012 American College of Rheumatology guidelines for gout management, which recommend aninitial dose of 100 mg/day, and lower starting dose in those with renal insufficiency.[58] It is safe to titrateuntil the goals of therapy have been reached, as long as it is tolerated and there is no evidence of adversereaction. There is a suggestion that allopurinol use might be associated with a modest decrease in therisk of death in subjects with hyperuricaemia.[59]

The American College of Physicians have not included a recommendation to lower serum uric acid levelsbelow <360 micromol/L (<6 mg/dL) in their 2016 guidelines on the management of acute and recurrentgout.[60] This is based on the lack of long-term clinical trial data. While there are no long-term clinicaltrial data concerning the long-term benefits and harms of this approach, there is evidence from populationdata about the long-term safety of uric acid lowering drugs, especially allopurinol, which the US Food and




Gout Treatment

Drug Administration (FDA) approved in 1966. The saturation threshold for urate is 404 micromol/L (6.8mg/dL), although uric acid levels fluctuate significantly as does the saturation threshold, which is lower insynovial fluid/joints. The standard practice of lowering serum uric acid levels to <360 micromol/L (<6 mg/dL) aims to buffer against those fluctuations.

In populations where HLA-B*5801 positive subjects are at high risk for severe allopurinol hypersensitivityreaction (e.g., Koreans with renal insufficiency, Han Chinese descent, and Thai descent), HLA-B*5801screening should be considered.[58] A large retrospective study conducted in Taiwan estimated theannual incidence of hypersensitivity reaction in new users of allopurinol at 4.68 per 1000, with mortalityof 0.39 per 1000.[61] The risk of hypersensitivity reaction was statistically significant among patients withrenal or cardiovascular disease who were prescribed allopurinol for asymptomatic hyperuricaemia.

Febuxostat is a non-purine selective xanthine oxidase inhibitor that reduces the production of uricacid. The goal is to reduce uric acid level to <360 micromol/L (<6 mg/dL) to prevent super-saturationand crystal formation.[62] The commonly reported adverse effects are elevated LFTs, headache,hypertension, diarrhoea, and arthralgia/stiffness.[63] [64] Two phase III clinical trials showed thatfebuxostat was more effective than allopurinol in reducing the uric acid level.[65] [66] An open extensiontrial for subjects up to 40 months from these 2 trials showed that a greater percentage of subjects onfebuxostat compared with subjects on allopurinol maintained this benefit.[67] However, caution is neededin interpreting the results of these studies. They all compared febuxostat to a maximum of 300 mg/dayof allopurinol. Recommendations and standard practices for rheumatologists are to titrate the dose ofallopurinol until the target of uric acid <360 micromol/L (<6 mg/dL) is reached, with a maximum dose of800 mg/day. Concluding that febuxostat is more effective or superior to allopurinol is inappropriate giventhe relatively low dose of allopurinol. The UK National Institute for Health and Care Excellence (NICE) hasrecommended that febuxostat be considered as an option for the management of chronic hyperuricaemiain gout only for people who are intolerant of allopurinol, or for whom allopurinol is contraindicated.[62]

If the patient cannot tolerate allopurinol, a uricosuric agent such as probenecid or sulfinpyrazone shouldbe considered. Uricosuric agents increase renal excretion of uric acid and are contraindicated in knownover-producers of uric acid. A 24-hour urine collection for uric acid should be obtained first. If it exceeds800 mg per 24 hours, probenecid or sulfinpyrazone are contraindicated as they increase the risk of uratenephrolithiasis. Probenecid and sulfinpyrazone are not effective in patients with renal insufficiency, butthey could be even considered as first-line options in patients with gout and normal renal function.

Lesinurad, a uricosuric agent that inhibits uric acid transporters (URAT1 and OAT4) in the proximal tubuleof the kidney, may be considered as an adjunctive therapy to allopurinol or febuxostat in patients whohave not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone. It is approved bythe US Food and Drug Administration (FDA) for use in combination with allopurinol or febuxostat only.In two phase III trials (CLEAR 1 and CLEAR 2), a combination of lesinurad and allopurinol modestlyincreased the proportion of people achieving serum uric acid <360 micromol/L (<6 mg/dL) at 6 monthscompared with allopurinol alone.[68] [69] Lesinurad was associated with ≥1.5 increase in serum creatinineand elevation in liver function tests. In addition, lesinurad (at a higher dose than approved) in combinationwith febuxostat has been found to be more effective in reducing the uric acid level to below 297 micromol/L (5 mg/dL) than febuxostat alone (76.1% vs 46.8% p<0.001), while lesinurad (at the approved dose)combined with febuxostat was not associated with a statistically significant difference.[70]

Combined treatment with allopurinol and benzbromarone, a potent uricosuric agent, appears to beeffective in non-responders to allopurinol who have moderate or severe renal insufficiency.[71] It may alsobe more effective than probenecid.[72] Benzbromarone was never approved in the US following reports

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of serious hepatotoxicity, and it has been withdrawn in many countries. Overall, there is a dearth of goodquality evidence regarding the safety and efficacy of uricosuric agents.

Intravenous pegloticase (a pegylated recombinant mammalian uricase) is an option for patients withrefractory tophaceous gout that is not responsive to treatment with other available conventional uric acid-lowering agents.[73] 3[A]Evidence

Urate-lowering agents should not be started until at least 2 weeks after the resolution of acute gout, assuch agents may increase the risk of recurrence or prolongation of the attacks by rapidly decreasingthe serum urate level. NSAIDs or low-dose colchicine should be considered as prophylaxis during theinitiation and titration of a urate-lowering agent. They should be continued for 3 to 12 months afterreaching the target level of uric acid. Once patients with gout start on urate-lowering agents, they need totake them permanently unless there is a serious adverse reaction; provided that the diagnosis of gout isaccurate.

Treatment details overviewConsult your local pharmaceutical database for comprehensive drug information including contraindications,drug interactions, and alternative dosing. ( see Disclaimer )

Acute ( summary )Patient group Tx line Treatment

acute gout 1st non-steroidal anti-inflammatory drug(NSAID)

2nd corticosteroid

3rd colchicine

Ongoing ( summary )Patient group Tx line Treatment

recurrent gout: 2 to 3 weeks postacute episode

1st xanthine oxidase inhibitor

plus suppressive therapy

adjunct lesinurad

2nd probenecid or sulfinpyrazone


3rd intravenous pegloticase





Gout Treatment

Treatment options

Acute

Patient group Tx line Treatment

acute gout 1st non-steroidal anti-inflammatory drug(NSAID)

» Halt the inflammatory cascade if they arestarted early. Also used to suppress goutyattacks when maintenance therapy with uricacid-lowering drugs is started.

» There is no evidence that indometacin issuperior to other NSAIDs. Two non-inferioritystudies showed indometacin was as efficaciousas etoricoxib and was associated with moreadverse effects.[75] [76]

» Should be used with preventive measures,such as proton-pump inhibitors or misoprostol, inpatients at high risk of GI complications.

» COX-2 inhibitors may be safer than traditionalNSAIDs in patients with a history of GI bleedingor comorbidities.

Primary options

» naproxen: 500 mg orally twice daily for10-14 days

OR

Primary options

» ibuprofen: 800 mg orally three to four timesdaily for 10-14 days

OR

Primary options

» diclofenac: 50 mg orally (immediate-release) three times daily for 10-14 days

OR

Primary options

» meloxicam: 7.5 to 15 mg orally once dailyfor 10-14 days

OR

Primary options

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Acute

Patient group Tx line Treatment» indometacin: 25-50 mg orally three timesdaily for 10-14 days

OR

Primary options

» celecoxib: 100-200 mg orally twice daily for10-14 days

2nd corticosteroid

» A possible alternative if both non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine arecontraindicated (for instance, in patients withrenal insufficiency). Probably more effective thancolchicine for acute gout, although there are nohead-to-head comparison trials of these twotypes of drug.[54] 2[B]Evidence

» A randomised controlled trial showed that oralprednisolone and indometacin were comparablein efficacy and adverse reactions when usedfor the treatment for acute gout in patientspresenting to the emergency department.[55]

» Used as an intra-articular injection formonoarticular gout and orally for oligo-articularand polyarticular gout.

» Potential serious side effects of corticosteroidsshould be considered. Should be avoidedif septic arthritis has not been excluded.Aspiration and injection of the knee animateddemonstrationEquipment needed

Prepare a sterile field using a non-touchtechnique with the following:

• Sterile gloves• Sterile antiseptic skin preparation

(povidone-iodine or chlorhexidine are mostsuitable)

• Surgical swabs• Sterile syringes and needles (21-gauge or

23-gauge)• Sterile specimen pots (if aspirating for

diagnostic purpose)• Medication for injection (for therapeutic

purpose)• Adhesive dressing• Local anaesthetic (optional).




Gout Treatment

Acute

Patient group Tx line TreatmentContraindications

• Joint replacement or prosthesis• Sepsis: local skin sepsis, bacteraemia,

osteomyelitis, or septic arthritis (injectionis contraindicated; aspiration is indicated)

• Cellulitis: cellulitis of the skin overlyingthe knee joint can result in distribution ofbacteria directly into a joint if you aspirateor inject it; this could result in iatrogenicseptic arthritis, potentially leading to jointdamage and destruction

• Abnormal clotting (e.g., haemophilia oranticoagulation)

• Haemarthrosis, osteochondral fracture,or suspected intra-articular fracture: donot perform a joint injection if there issuspicion of an intra-articular fracture.Patients with intra-articular fractureswill need reduction and operativefixation to preserve joint function(injection is contraindicated; aspiration ofhaemarthrosis may be rarely indicated)

• Immunocompromised or poorly controlleddiabetes

• Patient refusal.

Indications

The indications for performing diagnosticaspiration of the knee joint include clinicalsuspicion of:

• Septic arthritis• Crystal arthropathy: gout and pseudogout• Inflammatory monoathropathy

(e.g., osteoarthritis): symptoms ofosteoarthritis can improve with injectionof corticosteroids into the affected joint,which can help reduce inflammation withinthe joint and relieve painful symptoms

• Seronegative arthropathy (e.g., reactivearthritis, gonococcal arthropathy,ankylosing spondylitis)

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Acute

Patient group Tx line Treatment• Monoarthropathy, or joint effusion of

unknown cause.

On rare occasions, aspirate the knee joint toprovide symptomatic relief of a very tense andpainful haemarthrosis or large tense effusion.

Complications

• Pain: should be short lived; after injectionof medication there may be an initial flareof pain due to reactive arthralgia

• Haemorrhage• Infection: using an aseptic technique helps

to reduce the risk of introducing infectioninto a previously sterile joint space; furtherinvestigation and orthopaedic interventionmay be necessary if there is suspicion ofinfection

• Recurrence of effusion or symptoms• Joint destruction: injecting a joint with

corticosteroids may lead to osteonecrosisand destruction of the joint surfaces. Thisshould be weighed against the benefit ofintermittent symptomatic relief. Injectionsshould be limited to three per year perlarge joint.[45] [46]

Aftercare

• Send synovial fluid from the diagnosticaspirate to the lab for urgent microscopy,cell count, Gram stain and culture, andcrystals (for gout and pseudogout)

• If the aspirate is frank pus, or if thereis a clinical suspicion of septic arthritis,immediate orthopaedic assessmentand intervention is necessary. Getblood cultures and start the patient onintravenous antibiotics following the localprotocol. The patient will need to have aformal joint washout in theatre as soon aspossible

• For aspirates that are non-septic, base themanagement plan on clinical findings andthe results from the analysis of the jointfluid.




Gout Treatment

Acute

Patient group Tx line TreatmentAspiration and injection of the shoulder animateddemonstrationEquipment needed

Prepare a sterile field using a non-touchtechnique with the following:

• Sterile gloves• Sterile antiseptic skin preparation

(povidone-iodine or chlorhexidine are mostsuitable)

• Surgical swabs• Sterile syringes and needles (21-gauge or

23-gauge)• Sterile specimen pots (if aspirating for

diagnostic purpose)• Medication for injection (for therapeutic

purpose)• Adhesive dressing• Local anaesthetic (optional).

Contraindications

• Joint replacement or prosthesis• Sepsis: local skin sepsis, bacteraemia,

osteomyelitis, or septic arthritis (injectionis contraindicated; aspiration is indicated)

• Cellulitis: this is a bacterial infection andpatients with cellulitis overlying the jointshould not have a joint aspiration and/orinjection. There is a significant risk thatbacteria causing the skin infection may beinoculated into the joint, causing iatrogenicseptic arthritis. This may lead to severejoint destruction and systemic illness

• Abnormal clotting (e.g., haemophilia) oranticoagulation: there is an increased riskof bleeding into the joint, which wouldresult in iatrogenic haemarthrosis

• Haemarthrosis, osteochondral fracture,or suspected intra-articular fracture(injection is contraindicated; aspiration ofhaemarthrosis may be rarely indicated)

• Immunocompromised, including poorlycontrolled diabetes

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Acute

Patient group Tx line Treatment• Patient refusal.

Indications

The indications for performing diagnosticaspiration of the shoulder joint include clinicalsuspicion of:

• Septic arthritis• Crystal arthropathy: gout and pseudogout• Inflammatory monoarthropathy (e.g.,

osteoarthritis)• Seronegative arthropathy (e.g., reactive

arthritis, gonococcal arthropathy,ankylosing spondylitis)

• Seropositive arthropathy (e.g., rheumatoidarthritis)

• Monoarthropathy or joint effusion ofunknown cause

• Adhesive capsulitis• Rotator cuff tendinopathy• Subacromial bursitis.

On rare occasions the shoulder joint can beaspirated to provide symptomatic relief of a verytense and painful haemarthrosis or large tenseeffusion.

Patients with inflammatory arthropathies suchas osteoarthritis can benefit from injection ofintra-articular corticosteroids, which can offertemporary relief of painful symptoms.

Complications

• Pain: should be short lived; after injectionof medication there may be an initial flareof pain with reactive arthralgia

• Haemorrhage• Infection: using an aseptic technique helps

to reduce the risk of introducing infectioninto a previously sterile joint space; furtherinvestigation and orthopaedic interventionis necessary if there is a suspicion ofinfection

• Recurrence of effusion or symptoms




Gout Treatment

Acute

Patient group Tx line Treatment• Joint destruction: injection of the joint with

corticosteroids may lead to osteonecrosisand destruction of the joint surfacesdespite providing intermittent symptomaticrelief. Injections should be limited to threeper year per large joint.[45] [46]

Aftercare

• Send synovial fluid from the diagnosticaspirate to the lab for urgent microscopy,cell count, Gram stain, culture, andcrystals

• If the aspirate is frank pus, or there isa clinical suspicion of septic arthritis,immediate orthopaedic assessment andintervention is necessary. Get bloodcultures and give the patient intravenousantibiotics. The patient will need to have aformal joint washout in theatre as soon aspossible

• For aspirates that are non-septic, base themanagement plan on clinical findings andjoint fluid analysis

• Arrange follow-up to discuss the resultsof the procedure with the patient. Follow-up also enables clinicians to check for anycomplications that may have occurred asa result of the procedure and establishwhether any intervention has beensuccessful.

Primary options

» prednisolone: 1 mg/kg orally given as asingle doseThis regimen may be adequate if startedwithin 24 hours of attack.

OR

Primary options

» prednisolone: 20-40 mg orally once dailyinitially, decrease by 5-10 mg/day decrementsevery 3 days until discontinuation; or 30 mgorally once daily for 5 days

OR

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Acute

Patient group Tx line TreatmentPrimary options

» methylprednisolone: small joint: 4-10 mgintra-articularly as a single dose; mediumjoint: 10-40 mg intra-articularly as a singledose; large joint: 20-80 mg intra-articularly asa single dose

OR

Primary options

» triamcinolone acetonide: small joint: 2.5 to10 mg intra-articularly as a single dose; largerjoint: 5-40 mg intra-articularly as a singledose

3rd colchicine

» Used when non-steroidal anti-inflammatorydrugs (NSAIDs) and COX-2 inhibitors arecontraindicated because of a history of GIbleeding or comorbidities.

» Minimal effective dose should be usedbecause of the narrow benefit to risk index.Common adverse effects are diarrhoea, nausea,and vomiting.1[C]Evidence

» Intravenous use should be avoided because ofincreased toxicity.

» Give until relief, nausea/vomiting, diarrhoea,or maximum dose reached; diarrhoea likely willprecede pain relief; wait 3 days between courses

Primary options

» colchicine: 1.2 mg orally initially, followed by0.6 mg orally after 1 hour, maximum 1.8 mgtotal dose

Ongoing

Patient group Tx line Treatment

recurrent gout: 2 to 3 weeks postacute episode

1st xanthine oxidase inhibitor

» Allopurinol and febuxostat reduce theproduction of uric acid. Goal is to reduce uricacid level below 360 micromol/L (6 mg/dL) toprevent super-saturation and crystal formation.

» They should not be started during an acuteattack as they might prolong the attack or




Gout Treatment

Ongoing

Patient group Tx line Treatmentprecipitate more attacks.[62]Adjust doseaccording to serum urate target level of 360micromol/L (6 mg/dL).

» The starting dose of allopurinol should be lowto reduce the risk of hypersensitivity, a conditioncharacterised by eosinophilia, dermatitis,hepatitis, and renal failure, and associated with20% mortality.[77] In cases of hypersensitivityreaction where allopurinol is necessary and theonly treatment option, allopurinol desensitisationunder close monitoring should be considered.

» In populations where HLA-B*5801 positivesubjects are at high risk for severe allopurinolhypersensitivity reaction (e.g., Koreans withrenal insufficiency, Han Chinese descent, andThai descent), HLA-B*5801 screening should beconsidered.[58]

» Febuxostat is a non-purine selective xanthineoxidase inhibitor. The UK National Institutefor Health and Care Excellence (NICE) hasrecommended that febuxostat be consideredas an option for the management of chronichyperuricaemia in gout only for people who areintolerant to allopurinol, or for whom allopurinolis contraindicated.[62]

Primary options

» allopurinol: 100 mg orally once dailyinitially, increase by 100 mg/day incrementsevery week according to serum urate level,maximum 800 mg/day; a lower startingdose may be required in patients with renalimpairment

OR

Secondary options

» febuxostat: 40-80 mg orally once dailyplus suppressive therapy

» Suppressive (prophylactic) therapy such asnon-steroidal anti-inflammatory drugs (NSAIDs)or low-dose colchicine should be consideredduring initiation and tapering of a urate-loweringagent. They should be continued for 3 to 12months after reaching the target level of serumuric acid.

» Prednisolone may be considered if bothNSAIDs and colchicine are contraindicated, atthe lowest dose to prevent gout flares.

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Ongoing

Patient group Tx line TreatmentPrimary options

» naproxen: 250-500 mg orally twice daily

OR

Primary options

» ibuprofen: 400-800 mg orally three timesdaily

OR

Primary options

» diclofenac: 50 mg orally (immediate-release) two to three times daily

OR

Primary options

» meloxicam: 7.5 to 15 mg orally once daily

OR

Primary options

» indometacin: 25-50 mg orally three timesdaily

OR

Primary options

» celecoxib: 100-200 mg orally once to twicedaily

OR

Primary options

» colchicine: 0.6 mg orally once daily

OR

Secondary options

» prednisolone: 7.5 to 10 mg orally once dailyinitially, adjust to lowest dose that preventsgout flares

adjunct lesinurad

» A uricosuric agent that inhibits uric acidtransporters (URAT1 and OAT4) in the proximaltubule of the kidney.




Gout Treatment

Ongoing

Patient group Tx line Treatment» Approved by the US Food and DrugsAdminstration (FDA) to be used in combinationwith allopurinol or febuxostat only.

» May be considered as an adjunctive therapyto allopurinol or febuxostat in patients who havenot achieved target serum uric acid levels with axanthine oxidase inhibitor alone.

» In two phase III trials, a combination oflesinurad and allopurinol increased modestlythe proportion of people achieving serumuric acid <360 micromol/L (<6 mg/dL) at 6months compared with allopurinol alone.Lesinurad was associated with ≥1.5 increase inserum creatinine and elevation in liver functiontests.[68] [69]

Primary options

» lesinurad: 200 mg orally once daily2nd probenecid or sulfinpyrazone

» If the patient cannot tolerate allopurinol, auricosuric agent may be considered. Probenecidor sulfinpyrazone (uricosuric drugs) increasethe renal excretion of uric acid and arecontraindicated in known over-producers ofuric acid or when 24-hour uric acid >800 mgper 24 hours, as they increase the risk of uratenephrolithiasis.

» They should not be started during an acuteattack as they may prolong the attack orprecipitate more attacks.

» They are not effective in patients with renalinsufficiency and could be used in combinationwith allopurinol.

Primary options

» probenecid: 250-1000 mg orally twice daily

OR

Primary options

» sulfinpyrazone: 100-400 mg orally twicedaily


» Suppressive (prophylactic) therapy such asnon-steroidal anti-inflammatory drugs (NSAIDs)or low-dose colchicine should be consideredduring initiation and tapering of a urate-loweringagent. They should be continued for 3 to 12

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Patient group Tx line Treatmentmonths after reaching the target level of serumuric acid.


Primary options


OR

Primary options


OR

Primary options

» diclofenac: 50 mg orally (immediate-release) two to three times daily

OR

Primary options


OR

Primary options


OR

Primary options


OR

Primary options


OR

Secondary options

» prednisolone: 7.5 to 10 mg orally once dailyinitially, adjust to lowest dose to prevent goutflares

3rd intravenous pegloticase




Gout Treatment

Ongoing

Patient group Tx line Treatment» Intravenous pegloticase (PGL) (a pegylatedrecombinant mammalian uricase) may be anoption for patients with refractory tophaceousgout that is not responsive to treatment withother available conventional uric acid-loweringagents.[73]

» Gout flares may occur during initial treatment,and infusion reactions may be problematic.Anaphylaxis has occurred.

» Serum uric acid levels should be monitored 24to 72 hours before infusions and considerationgiven to stopping treatment if levels increase toabove 360 micromol/L (6 mg/dL), particularlywhen 2 consecutive levels above 360 micromol/Lare observed. Other urate-lowering drugs shouldnot be given concomitantly as this may makesuch changes harder to detect.

» Pre-medication with antihistamines andcorticosteroids should be given.

Primary options

» pegloticase: 8 mg intravenously every 2weeks


» Suppressive (prophylactic) therapy such asnon-steroidal anti-inflammatory drugs (NSAIDs)or low-dose colchicine should be consideredduring initiation and tapering of a urate-loweringagent. They should be continued for 3 to 12months after reaching the target level of serumuric acid.


Primary options


OR

Primary options


OR

Primary options

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Ongoing

Patient group Tx line Treatment» diclofenac: 50 mg orally (immediate-release) two to three times daily

OR

Primary options


OR

Primary options


OR

Primary options


OR

Primary options


OR

Secondary options

» prednisolone: 7.5 to 10 mg orally once dailyinitially, adjust to lowest dose to prevent goutflares




Gout Treatment

EmergingOxypurinolThis agent is a xanthine oxidase inhibitor that may be a substitute for allopurinol in patients with minorhypersensitivity to that drug. It is available in the US on compassionate use-only basis.

RilonaceptA phase II double-blind trial of gout flare prophylaxis during initiation of urate-lowering therapy randomised83 patients to subcutaneous rilonacept (a soluble IL-1 receptor-Fc fusion protein) or placebo.[78] At 12weeks, there were significantly fewer patients with one or more gout flare in the rilonacept group than in theplacebo group (15% vs. 45%, respectively). The results were replicated in a phase III, randomised, double-blind, placebo-controlled trial of rilonacept. The mean number of gout flares per patient over the 16 weekstudy period was significantly lower in both rilonacept arms relative to placebo (0.29 for rilonacept 80 mg;0.21 for rilonacept 160 mg; 1.06 for placebo). There were no safety signals during a four week extension ofthis trial.[79] The study was limited by comparing rilonacept with placebo rather than standard care, suchas colchicine or non-steroidal anti-inflammatory drugs (NSAIDs).[80] A double-blind randomised studyof treatment of acute gout attacks in 255 patients showed that adding rilonacept to indometacin was nomore effective than indometacin alone.[25] The study included a third arm of high-dose rilonacept that wasassociated with less pain reduction compared with the other 2 arms, but the study did not plan this analysis.

CanakinumabA fully humanised anti-interleukin-1 beta monoclonal antibody. In an 8-week, single-blind, double-dummy,dose-ranging study, patients with acute gout who did not respond or had contraindications to NSAIDs and/or colchicine were randomised to receive a single subcutaneous dose of canakinumab (various doses;n = 143) or an intramuscular dose of triamcinolone (n = 57). While canakinumab was associated withnumerically less pain (100-mm visual analogue score), only the highest dose was statistically superior totriamcinolone at 24, 48, and 72 hours. Canakinumab also prevented recurrent flares and did not appear toincrease the risk of serious adverse effects.[27] However, an oral corticosteroid or intra-articular injectionmay have been a more appropriate comparator. In a different analysis of the same study, treatment withcanakinumab was associated with significantly reduced tenderness and swelling at 72 hours comparedwith triamcinolone. Improvements in the SF-36 physical health scores were observed at 7 days post-dosein both treatment groups, but increases in scores were highest for canakinumab.[81] A 24-week double-blind study compared different doses of canakinumab with colchicine for the prevention of gout flares duringinitiation of treatment with allopurinol.[82] Patients taking canakinumab were significantly less likely toexperience gout flares than those taking colchicine. The colchicine dose was lower than that used in theUK or US. Two 12-week, randomised, double-blind studies with double-blind 12-week extensions comparedcanakinumab with triamcinolone in patients with gouty arthritis not suitable for NSAIDs and/or colchicine(beta-RELIEVED and beta-RELIEVED-II).[83] Pooled results of the studies showed that patients who tooka single dose of canakinumab during an acute flare experienced rapid and effective pain relief comparedwith patients receiving triamcinolone (mean 72-hour visual analogue scale pain score of 25.0 mm vs. 35.7mm, respectively; difference, -10.7 mm; p<0.0001), and a 56% reduction in risk of new flares over the 24-week period (HR: 0.44; p≤0.0001). It has been approved by the European Medicines Agency (EMA) for thesymptomatic treatment of adult patients with frequent gouty arthritis attacks (at least 3 attacks in the previous12 months) in whom NSAIDs and colchicine are contraindicated, are not tolerated, or do not provide anadequate response, and in whom repeated courses of corticosteroids are not appropriate. In the UK, theNational Institute of Health and Care Excellence (NICE) has stated that it was unable to recommend the usein the NHS of canakinumab for treating gouty arthritis attacks and reducing the frequency of subsequentattacks because no evidence submission was received from the manufacturer.[84] In June 2011, a US Foodand Drug Administration (FDA) panel rejected canakinumab as a treatment for gout because of the potentialrisk of infection, hypertriglyceridaemia, and elevated uric acid levels. [FDA Arthritis Advisory Committee:FDA briefing document on supplemental canakinumab]

Arhalofenate

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http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisDrugsAdvisoryCommittee/UCM259596.pdf



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A novel anti-inflammatory and a uricosuric agent that inhibits URAT1 and has anti-inflammatory featuresbased on mice data, inhibiting the release of interleukin-1 beta and other inflammatory mediators. A phaseIIB study randomised 248 subjects to receive one of two different doses of arhalofenate; allopurinol;allopurinol plus colchicine; or placebo. The primary outcome was gout flare prevention at 12 weeks.The higher dose of arhalofenate decreased gout flares by 46%, which was statistically significant only incomparison with allopurinol alone or placebo, and not in comparison with the allopurinol plus colchicine arm.The mean decrease in serum uric acid level was disappointing, only 12.5% ±16 (mean ± SD) with the lowerdose of arhalofenate and 16.5% ± 15 with the higher dose of arhalofenate, while the decrease was 24.9 ±-19.7 with allopurinol plus colchicine and 28.8% ± 20.3 in the allopurinol group. The study design did notfollow typical clinical practice, in having an arm initiating allopurinol 300 mg/day as opposed to 100 mg/day,and without a suppressive therapy (such as colchicine), which was used in only one arm of the comparisongroup. [85]

Purine nucleoside phosphorylase inhibitor (BCX4208)In a double-blind, placebo-controlled study, BCX4208 significantly reduced serum uric acid over a 3-weekperiod ( -2.7 mg/dL, -3.3 mg/dL, and -3.4 mg/dL in the 40 mg/day, 80 mg/day, and 120 mg/day dose groups,respectively, compared with -0.4 mg/dL for placebo).[86] Approximately one third of patients receivingBCX4208 achieved serum uric acid <360 micromol/L (<6 mg/dL), irrespective of dose. No subject in theplacebo group achieved serum uric acid <360 micromol/L. The drug produced moderate reductions inlymphocyte subsets, but was well tolerated.




Gout Follow up

RecommendationsMonitoringPatients should be monitored for recurrent attacks, the development of tophi and radiographic changes.

In patients taking uric acid-lowering agents, follow-up uric acid levels every 1 to 3 months initially, thenevery 6 months (target level <360 micromol/L or <6 mg/dL).

Patients should be monitored for adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs) andcolchicine, especially if they are used for prolonged periods. For NSAIDs, colchicine, and allopurinol,FBC, renal function tests, and liver function tests should be obtained every 3 to 6 months.

When initiating allopurinol, patients should be closely monitored for hypersensitivity syndrome(eosinophilia, dermatitis, and multisystem failure).

Long-term colchicine use may be associated with neuromyopathy. Probenecid may increase the risk ofnephrolithiasis.

Most of the above medications, and specifically allopurinol, have multiple drug interactions that mayrequire adjustments to medication dosages.

Patient instructionsFoods that have a high purine content (i.e., alcohol, seafood, and offal) are associated with higher risk ofelevated uric acid and gout.[2]

Reducing intake of alcohol, especially beer, lowers the risk of gout.[31]

Reducing seafood and meat intake helps to a lesser degree.

Reducing the intake of vegetables high in purines (i.e., asparagus, spinach, and mushrooms) does notseem to affect uric acid levels.

Dairy products reduce the risk of gout.

Complications

Complications Timeframe Likelihoodacute uric acid nephropathy short term low

Occurs most commonly in patients treated with cytotoxic agents, especially for lymphoproliferativedisorders and large tumour burdens (tumour lysis syndrome).

Usually occurs with very high uric acid levels exceeding 1190 micromol/L (20 mg/dL) and urine uric acid/creatinine ratio exceeding 1.

Patients may develop acute and oliguric renal failure. This is usually prevented with hydration andprophylaxis with allopurinol.

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Complications Timeframe Likelihoodnephrolithiasis variable medium

Uric acid calculi constitute 10% of the renal stones in the US. Their prevalence in patients with gout isvariable (10% to 42%) and increases with uric acid level.[91]

Prognosis

Gout attacks are painful and debilitating, but self-limiting. In patients untreated with uric acid-lowering drugs,the risk of recurrence after the first attack is 62%, 78%, and 84% during the first, second, and third year,respectively.[87]

In untreated gout, about 2% of patients developed severe debilitating arthritis typically 20 years after the firstattack.[88]

Among people with untreated gout, tophi occur in about 50% after 10 years and 72% after 20 years.[88]

Appropriate treatment can suppress gout attacks and their recurrence, and prevent long-term consequencesof the disease. There are currently few available uric acid-lowering agents, which is problematic in casesof medication intolerance or ineffectiveness. In addition, treatments for acute and chronic gout haveconsiderable risks and adverse events.

Gout and untreated hyperuricaemia may be associated with renal insufficiency. In a veteran population withgout, rates of incident kidney disease were lower in men with controlled serum urate levels than in those withhigh serum urate (2% vs. 4% at year 1, 3% vs. 6% at year 2, and 5% vs. 9% at year 3, respectively).[89] Highserum urate conferred a significant risk of kidney disease development (HR 1.43, 95% CI 1.20 to 1.70).

In a UK cohort study comprising individuals with a history of hyperuricaemia, allopurinol use was associatedwith a lower risk of all-cause mortality compared with non-use (HR 0.89, 95% CI 0.80 to 0.99).[59] Riskreduction was more pronounced when the analysis was limited to those with gout (HR 0.81, 95% CI 0.70to 0.92). Another study found no difference in mortality in subjects with incident gout who were treated withallopurinol compared with matched controls based on propensity scores.[90]




Gout Guidelines

Diagnostic guidelines

Europe

2011 recommendations for the diagnosis and management of gout andhyperuricemiaPublished by: European League Against Rheumatism Last published: 2011Summary: Update of the 2006 EULAR guidelines for gout. Includes recommendations for the diagnosisof gout and hyperuricaemia. Special attention is paid to the needs of primary care physicians, who managemost patients with gout. The management section of this 2011 guideline was updated in 2016.

EULAR evidence based recommendations for gout. Part I: diagnosisPublished by: European League Against Rheumatism Last published: 2006Summary: Ten key recommendations for diagnosis of gout were developed using a combination ofresearch-based evidence and expert consensus. The evidence for diagnostic tests, risk factors, andcomorbidities was evaluated and the strength of recommendation is provided.

North America

Diagnosis of acute gout: a clinical practice guideline from the AmericanCollege of PhysiciansPublished by: American College of Physicians Last published: 2016Summary: Presents the evidence and provides clinical recommendations on the diagnosis of gout.

Guidelines for the initial evaluation of the adult patient with acutemusculoskeletal symptomsPublished by: American College of Rheumatology Ad Hoc Committeeon Clinical Guidelines

Last published: 1996

Summary: Outlines the history, examination, and testing recommended for patients with acutemusculoskeletal pain. Highlights features that require urgent attention. Provides algorithms formonoarticular and polyarticular presentations.

Asia

Japanese guideline for the management of hyperuricemia and gout: secondeditionPublished by: Japanese Society of Gout and Nucleic Acid Metabolism Last published: 2011Summary: Second edition of the 'Japanese guideline for the management of hyperuricemia andgout', originally published in 2002. Key recommendations on the clinical management of gout andhyperuricaemia are presented together with the evidence level, consensus level, and strength of therecommendation.

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http://www.tandfonline.com/toc/ipgm20/123/sup1

http://www.tandfonline.com/toc/ipgm20/123/sup1

http://www.eular.org/Recommendations_classification_response_criteria_diagnostic.cfm

https://www.acponline.org/clinical-information/guidelines


http://onlinelibrary.wiley.com/doi/10.1002/art.v39:1/issuetoc

http://onlinelibrary.wiley.com/doi/10.1002/art.v39:1/issuetoc

http://www.tandfonline.com/toc/lncn20/30/12



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Treatment guidelines

Europe

2016 updated EULAR evidence-based recommendations for the managementof goutPublished by: European League Against Rheumatism Last published: 2016Summary: Includes 3 overarching principles and 11 key recommendations on the management of gout.

Febuxostat for the management of hyperuricaemia in people with goutPublished by: National Institute for Health and Care Excellence Last published: 2008

British Society for Rheumatology and British Health Professionals inRheumatology guideline for the management of goutPublished by: British Society for Rheumatology; British HealthProfessionals in Rheumatology

Last published: 2007

Summary: This guideline provides evidence-based recommendations for the management of gout fordoctors and allied health care professionals.

BSR & BHPR, BOA, RCGP and BSAC guidelines for management of the hotswollen joint in adults (re-affirmed 2012)Published by: British Society for Rheumatology Last published: 2006

North America

Management of acute and recurrent gout: a clinical practice guideline fromthe American College of PhysiciansPublished by: American College of Physicians Last published: 2016Summary: Presents the evidence and provides clinical recommendations on the management of gout.

2012 American College of Rheumatology guidelines for management of goutPublished by: American College of Rheumatology Last published: 2012

Asia

Japanese guideline for the management of hyperuricemia and gout: secondeditionPublished by: Japanese Society of Gout and Nucleic Acid Metabolism Last published: 2011Summary: Key recommendations on the clinical management of gout and hyperuricaemia are presentedtogether with the evidence level, consensus level, and strength of the recommendation.

Management of goutPublished by: HTA Unit, Ministry of Health, Malaysia Last published: 2008



http://ard.bmj.com/content/early/2016/07/25/annrheumdis-2016-209707.full

http://ard.bmj.com/content/early/2016/07/25/annrheumdis-2016-209707.full

http://guidance.nice.org.uk/TA164

https://www.rheumatology.org.uk/Knowledge/Excellence/Guidelines






http://www.rheumatology.org/Practice/Clinical/Guidelines/Clinical_Practice_Guidelines/



http://www.moh.gov.my/english.php/pages/view/224


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Online resources

1. ACR-EULAR gout classification criteria calculator (external link)

2. FDA Arthritis Advisory Committee: FDA briefing document on supplemental canakinumab (externallink)



http://goutclassificationcalculator.auckland.ac.nz/




Gout Evidence scores

Evidence scores

1. Reduction in pain: there is poor-quality evidence that colchicine may be more effective than placebo atreducing pain in people with gout.[53]Evidence level C: Poor quality observational (cohort) studies or methodologically flawed randomizedcontrolled trials (RCTs) of <200 participants.

2. Symptom resolution: there is moderate-quality evidence that corticosteroids are as effective as non-steroidal anti-inflammatory drugs (NSAIDs) in reducing symptoms in people with acute gout.Evidence level B: Randomized controlled trials (RCTs) of <200 participants, methodologicallyflawed RCTs of >200 participants, methodologically flawed systematic reviews (SRs) or good qualityobservational (cohort) studies.

3. Efficacy of pegloticase for refractory gout: there is good-quality evidence that intravenous pegloticasecan reduce serum urate levels in patients with gout refractory to treatment with allopurinol andfebuxostat.[73] [74]Evidence level A: Systematic reviews (SRs) or randomized controlled trials (RCTs) of >200participants.

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Key articles

• Choi HK, Atkinson K, Karlson EW, et al. Purine-rich foods, dairy and protein intake and the risk of goutin men. N Engl J Med. 2004;350:1093-1103. Full text Abstract

• Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann Intern Med. 2005;143:499-516. Abstract

• Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout. Part I:diagnosis. Report of a task force of the Standing Committee for International Clinical Studies IncludingTherapeutics (ESCISIT). Ann Rheum Dis. 2006;65:1301-1311. Abstract

References

1. Abbott RD, Brand FN, Kannel WB, et al. Gout and coronary heart disease: the Framingham Study. JClin Epidemiol. 1988;41:237-242. Abstract

2. Choi HK, Atkinson K, Karlson EW, et al. Purine-rich foods, dairy and protein intake and the risk of goutin men. N Engl J Med. 2004;350:1093-1103. Full text Abstract

3. Mikuls TR, Farrar JT, Bilker WB, et al. Gout epidemiology: results from the UK general practiceresearch database, 1990-1999. Ann Rheum Dis. 2005;64:267-272. Full text Abstract

4. Kramer HM, Curhan G. The association between gout and nephrolithiasis: the National Health andNutrition Examination Survey III, 1988-1994. Am J Kidney Dis. 2002;40:37-42. Abstract

5. Annemans L, Spaepen E, Gaskin M, et al. Gout in the UK and Germany: prevalence, comorbiditiesand management in general practice. Annals Rheum Dis. 2008;67:960-966. Full text Abstract

6. Bieber JD, Terkeltaub RA. Gout: on the brink of novel therapeutic options for an ancient disease.Arthritis Rheum. 2004;50:2004-2014. Abstract

7. Klemp P, Stansfield SA, Castle B, et al. Gout is on the increase in New Zealand. Ann Rheum Dis.997;56:22-26. Full text Abstract

8. Arromdee E, Michet CJ, Crowson CS, et al. Epidemiology of gout: is the incidence rising? JRheumatol. 2002;29:2403-2406. Abstract

9. Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia. Risks and consequences in theNormative Aging Study. Am J Med. 1987;82:421-426. Abstract

10. Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann Intern Med. 2005;143:499-516. Abstract

11. Choi HK, Atkinson K, Karlson EW, et al. Obesity, weight change, hypertension, diuretic use, and risk ofgout in men: the Health Professionals Follow-up Study. Arch Intern Med. 2005;165:742-748. Full text Abstract



http://www.nejm.org/doi/full/10.1056/NEJMoa035700#t=article

http://www.ncbi.nlm.nih.gov/pubmed/15014182?tool=bestpractice.bmj.com






http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1755343&blobtype=pdf



http://ard.bmj.com/cgi/content/full/67/7/960








http://archinte.ama-assn.org/cgi/content/full/165/7/742




Gout References

12. Lee J, Sparrow D, Vokonas PS, et al. Uric acid and coronary heart disease risk: evidence for a roleof uric acid in obesity-insulin resistance syndrome. The Normative Aging Study. Am J Epidemiol.1995;142:288-294. Abstract

13. Johnson RJ, Rideout BA. Uric acid and diet - insights into the epidemic of cardiovascular disease. NEngl J Med. 2004;350:1071-1073. Abstract

14. Wu XW, Lee CC, Muzny DM, et al. Urate oxidase: primary structure and evolutionary implications.Proc Natl Acad Sci USA. 1989;86:9412-9416. Full text Abstract

15. Wu XW, Muzny DM, Lee CC, et al. Two independent mutational events in the loss of urate oxidaseduring hominoid evolution. J Mol Evol. 1992;34:78-84. Abstract

16. Richette P, Bardin T. Gout. Lancet. 2010;375:318-328. Abstract

17. Shoji A, Yamanaka H, Kamatani N. A retrospective study of the relationship between serum uratelevel and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis withantihyperuricemic therapy. Arthritis Rheum. 2004;51:321-325. Full text Abstract

18. Fam AG, Stein J, Rubenstein J. Gouty arthritis in nodal osteoarthritis. J Rheumatol. 1996;23:684-689.Abstract

19. Yagnik DR, Hillyer P, Marshall D, et al. Noninflammatory phagocytosis of monosodium uratemonohydrate crystals by mouse macrophages. Implications for the control of joint inflammation in gout.Arthritis Rheum. 2000;43:1779-1789. Full text Abstract

20. Cronstein BN, Molad Y, Reibman J, et al. Colchicine alters the quantitative and qualitative display ofselectins on endothelial cells and neutrophils. J Clin Invest. 1995;96:994-1002. Full text Abstract

21. Terkeltaub R, Zachariae C, Santoro D, et al. Monocyte-derived neutrophil chemotacticfactor/interleukin-8 is a potential mediator of crystal-induced inflammation. Arthritis Rheum.1991;34:894-903. Abstract

22. Nishimura A, Akahoshi T, Takahashi M, et al. Attenuation of monosodium urate crystal-induced arthritisin rabbits by a neutralizing antibody against interleukin-8. J Leukoc Biol. 1997;62:444-449. Abstract

23. Martinon F, Pétrilli V, Mayor A, et al. Gout-associated uric acid crystals activate the NALP3inflammasome. Nature. 2006;440:237-241. Abstract

24. Terkeltaub R, Schumacher HR Jr, Saag KG, et al. Evaluation of rilonacept for prevention of gout flaresduring initiation of urate-lowering therapy: results of a phase 3, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2010;62(suppl):152. Full text

25. Terkeltaub R, Schumacher HR Jr, Curtis C, et al. Evaluation of rilonacept in patients with gouty arthritisexperiencing an acute gout attack. Arthritis Rheum. 2010;62(suppl):153. Full text

26. Schlesinger N, Lin HY, De Meulemeester M, et al. Efficacy of canakinumab (ACZ885), a fully humananti-interleukin (IL)-1beta monoclonal antibody, in the prevention of flares in gout patients initiatingallopurinol therapy. Arthritis Rheum. 2010;62(suppl):2087. Full text

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http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=2594778




http://www3.interscience.wiley.com/cgi-bin/fulltext/109062089/HTMLSTART




http://www3.interscience.wiley.com/cgi-bin/fulltext/78502428/PDFSTART


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http://www.blackwellpublishing.com/acrmeeting/abstract.asp?MeetingID=774&id=88807




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27. So A, De Meulemeester M, Pikhlak A, et al. Canakinumab for the treatment of acute flares in difficult-to-treat gouty arthritis: Results of a multicenter, phase II, dose-ranging study. Arthritis Rheum.2010;62:3064-3076. Abstract

28. Liu R, Liote F, Rose DM, et al. Proline-rich tyrosine kinase 2 and Src kinase signaling transducemonosodium urate crystal-induced nitric oxide production and matrix metalloproteinase 3 expression inchondrocytes. Arthritis Rheum. 2004;50:247-258. Full text Abstract

29. Bouchard L, de Medicis R, Lussier A, et al. Inflammatory microcrystals alter the functional phenotypeof human osteoblast-like cells in vitro: synergism with IL-1 to overexpress cyclooxygenase-2. JImmunol. 2002;168:5310-5317. Full text Abstract

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Gout Images

Images

Figure 1: Chronic tophaceous gout showing nodules in periarticular structures and arthritis

Adapted from BMJ Case Reports 2009 [doi:10.1136/bcr.03.2009.1668] Copyright © 2009 by the BMJ GroupLtd

Figure 2: Chronic tophaceous gout showing nodules in the hands, elbows, legs, buttocks, and abdominal wall(arrows)

Adapted from BMJ Case Reports 2009 [doi:10.1136/bcr.03.2009.1668] Copyright © 2009 by the BMJ GroupLtd

Figure 3: Uric acid levels and cumulative incidence of first episodes of gout

Adapted from Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia. Risks and consequencesin the Normative Aging Study. Am J Med. 1987;82:421-426

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Contributors:

// Authors:

Fadi Badlissi, MD, MScAssistant ProfessorHarvard Medical School, Attending Physician, Director of the Musculoskeletal Medicine Unit, Department ofOrthopedics & Division of Rheumatology, Beth Israel Deaconess Medical Center, Boston, MADISCLOSURES: FB declares that he has no competing interests.

// Peer Reviewers:

H. Ralph Schumacher, Jr., MDProfessor of MedicineVA Medical Center, Philadelphia, PADISCLOSURES: HRS has been a consultant for a number of pharmaceutical companies that produce drugsthat can be used for the treatment of gout. Some companies have supplied HRS with funding. HRS is anauthor of a number of references cited in this monograph.

Ade Adebajo, MDAssociate Director of Teaching and Honorary Senior Lecturer in RheumatologyAcademic Rheumatology Group, Faculty of Medicine, University of Sheffield, Sheffield, UKDISCLOSURES: AA declares that he has no competing interests.

Martin Underwood, MBBSProfessor of Primary Care ResearchWarwick Medical School, Coventry, UKDISCLOSURES: MU declares that he has no competing interests.

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