3EpidemiologyAncient disease : “the king of diseases and the disease of kings”first identified by the Egyptians5thcentury BC: Hippocrates referred to gout as “unwalkable disease” and noted links between gout & lifestyle, demographics & other variables
4Crystals from tophi were first described during the 18th and 19th centuries In the mid 20th century the role of excess urate production and impaired excretion in the pathogenesis of hyperuricemia were reported.Finally, McCarty and Hollander showed that crystals from the synovial fluid of patients with gout were composed of MSU
5Rates of gout in USA increased during the 1990s—especially for men older than 75 years in whom rates nearly doubled from 2.1% in to 4.1% in 1999.In USA 2.6 million in 2005, projected to increase to 3.6 million in 2025The prevalence of gout is much higher in men than in women and rises with age.Wallace K, Riedel A, Joseph-Ridge N, Wortmann R. J Rheumatol 2004; 31: 1582–87.
7Asymptomatic hyperuricemia Clinical laboratories define hyperuricemia as > mg/dlIn physiologic terms , any levels > 6.8 mg/dl because it exceeds the soluble concentration of MSU in body fluidIncidence of gout increases with age as well as degree of hyperuricemia
8Over time, high serum urate levels lead to gout Normative Aging Study:1858 previously healthy men (average initial age 42) followed for yearsCampion et al. Am J Med. 1987;82:
9However vast majority of people with hyperuricemia never develop symptoms associated with uric acid excess .
10Acute intermittent gout Decades of untreated, chronic hyperuricemia increases body urate stores, advancing the severity of the disease:Flares last longerFlares occur more oftenIntercritical segments (flare free periods) decreasePersistent pain and stiffness occur
11Primer on the Rheumatic Diseases. 12th ed Primer on the Rheumatic Diseases. 12th ed. Arthritis Foundation; 2001:313.
12Description of acute attack: The night is spent in torture !Description of acute attack:The victim goes to bed and sleeps in good health. About 2 am he is awakened by a severe pain in the great toe; more rarely in the heel , ankle, or instep. The pain is like that of a dislocation, and yet the parts feel as if cold water were poured over them…..Now it is a violent stretching and tearing of the ligaments…. So exquisite and lively meanwhile is the feeling of the part affected , that it cannot bear the weight of bedclothes nor the jar of a person walking in the room.Primer on the Rheumatic Diseases. 12th ed. Arthritis Foundation; 2001:313.Thomas Sydenham, 17th century
13In Their Own Words“It is by far the most horrendous pain one should have to endure.”“I can’t believe how much this hurts.”“I've broken legs, arms, ribs, all nothing compared to my big toe. Even a bed sheet hurts.”“There’s worse things, but they don’t hurt as much as gout.”
14A typical attack of gout: Rapid development of warmth, swelling, erythema and pain in the affected jointPain escalates to most intense level in 8-12 hrsInitial attack is usually monoarticular and >50% cases involve the 1st MTP joint.Other joints involved in early stage: midfoot, ankles, heels and knees. Less commonly wrists , fingers and elbows.
16Systemic symptoms such as fever > 38 C can be seen in 30% of patients with acute gout attacks, chills, and malaise.It also triggers a systemic inflammatory response manifesting with leukocytosis, elevated ESR and CRP.
17Solubility of urate in joint fluids depends on: the articular hydration stateTemperaturepH, concentration of cations, and presence of extracellular matrix proteins such as proteoglycans, collagens, and chondroitin sulphate.
18these factors might explain: The 1st MTP joint involvement (a peripheral joint with low temperature)Osteoarthritic joints (joints with decreased collagen and proteoglycan content)The nocturnal onset of pain (because of intra-articular dehydration)Choi HK, Mount DB, Reginato AM. Ann Intern Med 2005; 143: 499–516.Roddy E, Zhang W, Doherty M. Ann Rheum Dis 2007; 66: 1374–77.
19Intervals between 1st and 2nd acute flares: Yu et al. Ann IntMed. 1961;55:
20Acute attacks can be precipitated: Increased alcohol consumption (especially beer)TraumaUse of diureticsDehydrationCyclosporineDiet (organ meat, shellfish)Drugs that can lead to sudden changes (increase or decrease) in urate levels, such as hypouricemic agents
21If left untreated , acute gout varies from episodes of mild pain “petits attacks” to several attacks that last 1 to 2 weeks.Over time, attacks typically become more frequent, longer in duration, and involve more joints, and spread to the upper limbs.
22Intercritical period: Previously involved joints are virtually free of symptomsDespite this, MSU crystals often can be identified in the synovial fluid of previously inflamed joints which reflect ongoing subclinical inflammation
24Advanced goutIt is characterized by chronic destructive polyarticular involvement with low-grade joint inflammation, joint deformity, and tophiTophaceous gout develops within 5 years of onset of gout in 30% of untreated patientsTophi are painless and rarely become infected but function and health-related QoL can be severely affected with chronic gout
25PatientSociety↓QOL with gout progression, worse QOL scores with >1 tophi vs no tophiEstimated 2.6 million (2005) with estimate of 3.6 million (2025)Inter-critical periods:25% report pain when not experiencing flare$27.4 million = estimated annual direct cost for new cases of acute gout in USNearly half of all gout pts have difficulty in recreation & other QOL activities, but some will also have difficulty with even basic activities of daily livingNear doubling of claims cost for Rx, sick leave, short term disability and workman’s comp in gout vs non-gout pts ($6970 vs $3705)Higher rate of all-cause mortality in those with gout vs withoutMore absence days per year and lower mean annual productivity
26Tophi are frequently seen in: Helix of the earOver the olecranon processesOn the Achilles tendonsWithin and around the toe or finger jointsAround the knees, and within the pre-patellar bursaeSpinal involvement can lead to nerve root or cord compression and might also mimic epidural infectionMedian nerve, which leads to carpal tunnel syndromeRare locations: eyes, breast, vocal cords, heart, and colon
27Lancet. 2010 Jan 23;375(9711):318-28. doi: 10.1016/S0140-6736(09)60883-7
28Bycontrast, patients who have had years of intermittentepisodic arthritis and those with chronic gout mightshow characteristic features, mainly the consequences oftophus infi ltration into bone, on radiography.86 Eccentricnodular soft-tissue prominence accompanies soft-tissuedeposition of urate and is usually visible late in theevolution of disease.
29Diagnosis (EULAR recs) A typical presentation of gout is highly suggestive of crystal inflammation, although not specific for goutIdentification of MSU crystals in synovial fluid or tophus aspirates allows a definitive diagnosis of goutGout and sepsis can coexist, so gram stain and culture of synovial fluid should still be done when septic arthritis is even if MSU crystals are identifiedSerum uric acid concentrations do not confirm or exclude gout because many people with hyperuricemia do not develop gout, and during acute attacks serum concentrations might be within the normal range in a third of patients
30Radiographs useful for differential diagnosis and might show typical features in chronic gout, but are not useful for confirmation of diagnosis of early or acute goutRisk factors for gout and associated comorbidity should be assessed, including features of metabolic syndrome (obesity, hyperglycemia, hyperlipidemia, and hypertension)Lancet Jan 23;375(9711): doi: /S (09)
31Lancet. 2010 Jan 23;375(9711):318-28. doi: 10.1016/S0140-6736(09)60883-7
32They are typically punched out, occurring along the long axis of the bone, withoverhanging edges and sclerotic rims (fi gure 5).87 Thejoint space is very well preserved until late in the courseof disease.Lancet Jan 23;375(9711): doi: /S (09)
33Treatment Lifestyle modifications: Obesity is the commonest comorbid risk factor for gout ->address over- weightProtective food: coffee, dairy products, and vitamin CCausative (beer but not wine, meat and seafood, and fructose)Adhering to lifestyle advice alone can have a small urate lowering effect but carry additional benefits in terms of overall health, with regard to the metabolic syndrome.Further treatment is divided into acute and chronic gout treatment
34Acute treatment:Main aim of acute treatment is to provide rapid relief of pain and inflammation and exclude joint sepsisAffected joints should be rested and treated with ice, which has a significant anti-inflammatory effect
35NSAIDs are the most commonly used first-line treatment Head-to-head studies show few differences between drugsFull doses of NSAID should be initiated immediately and tapered after resolution of symptomsKelsey Jordan.Curr Opin Rheumatol 2012, 24:145–151
36Co-administration of a proton pump inhibitor should be considered Avoid NSAIDs:G-I ulcerBleeding or perforationRenal insufficiencyHeart failureUse of oral anticoagulantsCo-administration of a proton pump inhibitor should be considered
37Colchicine:Blocks microtubule assembly in neutrophils reducing phagocytosis and transport of MSU crystals.Affects neutrophil migration into joints by reducing adhesion molecules on endothelial cells and neutrophils in response to IL-1 or TNF-a.Reduces NALP3 inflammasome-driven caspase-1 activation by microtubule inhibition which decreases MSU delivery
38Adverse events of colchicine: low-dose colchicine (1.8 mg over 1 hour) can be utilized effectively and safely in acute gout flareAdverse events of colchicine:Abdominal crampsNausea, vomitingBone marrow suppressionNeuropathy and myopathyIV colchicine is no longer as it has a 2% mortality rate.Kelsey Jordan.Curr Opin Rheumatol 2012, 24:145–151
39Reduced dosing in elderly or those with renal or hepatic impairment Toxicity can be caused by drugs interacting with its metabolism and clearance, which include macrolides, cyclosporine and protease inhibitorsNo trials have directly compared NSAIDs and colchicine.
40Corticosteroids:Intraarticularly (preferred route if one or two joints affected)OrallyIntramuscularly or intravenously.Corticosteroids are a good alternative where NSAID and colchicine cannot be used or in refractory casesStudies showed equal efficacy between corticosteroid and NSAIDs, with no reported side-effects with short-term use of corticosteroidKelsey Jordan.Curr Opin Rheumatol 2012, 24:145–151
41The anti-IL-1 drugs: anakinra Subcutaneous injections of anakinra 100mg daily for 3 days is well tolerated and efficacious treatment of flares.Used in case gout is refractory to other available options, or NSAIDs , colchicine or steroids cannot be usedExpensiveNot for preventive useKelsey Jordan.Curr Opin Rheumatol 2012, 24:145–151
42In certain cases narcotics are only options for treatment of acute gout flares (neutropenia, advanced renal failure, infection, malignancy)
43Chronic treatment:Prevent recurrent attacks and alleviate complications of chronic gouty arthritis‘Treat to target’ to prevent MSU crystal saturation and dissolve crystals already deposited in joints and soft tissue (goal serum urate < 6 mg/dl)Assess and modify contributing risk factors (HTN, DM type 2, DLP, CHF, obesity, OA, drugs (diuretics and ciclosporin)Provide long-term follow-up and monitoring of gout including serum urate checks
44It has long been advocated that urate-lowering therapy (ULT) should not be initiated until after an acute gout flare has resolvedThe absolute risks of these complications have not been established , and some experts have suggested that ULT can occasionally be started together with anti-inflammatory therapy during an acute attackTaylor TH, et al Am J Med Nov;125(11):
45Uricostatic agents: xanthine oxidase inhibitors Allopurinol: The most commonly used dose is 300mg daily, with the maximum dose of 900mg daily.Introducing at a dose of 100mg daily and increased by 100mg ,may reduce flare on initiationCommencing at a low dose and slowly incrementing can reduce the risk of allopurinol hypersensitivity reaction .
46Adverse events of allopurinol: Rash (2%)VasculitisEosinophiliaLife-threatening hypersensitivity reactionHepatitisDecreased renal function and bone-marrow suppression.
47In transplant patients be aware of the dangerous drug interaction between allopurinol and azathioprine, because xanthine oxidase is related to metabolism of azathioprine (and 6-mercaptopurine).Mycophenolate mofetil, which is not metabolised by xanthine oxidase, can be substituted for azathioprine to ensure safe use of allopurinol.
48Febuxostat (Uloric):new nonpurine selective xanthine oxidase inhibitor.It is primarily metabolized in the liver and therefore no dose reduction in moderate renal function is required.Efficacy: at 52 weeks s uric acid < 6 mg/dl -> 53% of the patients on 80mg of febuxostat, 62% on 120mg of febuxostat and only 21% in those receiving allopurinol 300 mg daily.
49Its place in treatment should be as a second-line agent where allopurinol has failed to reduce s uric acid or contraindicated.
50Uricosuric agents :These drugs enhance the renal clearance of urate Probenicid: Can be effective as an add-in therapy when allopurinol alone is insufficient, contraindicated in nephrolithiasis and inefficient in renal failure
51Oral colchicine can reduce the frequency of recurrent episodes of acute gouty arthritis (0.6 mg orally once or twice daily for patients with normal renal function)colchicine is continued for six months after normal serum urate values have been obtained in patients without tophiOther interventions: discontinuation of diuretics and use of the uricosuric drugs losartan and fenofibrate for HTN and DLP.
52Studies have shown only 30–60% of patients are still prescribed allopurinol 1 year after initiation of therapy and that management of gout is frequently inappropriate.Patient education:Disease natureTargets and practicalities of drug therapyHow to prevent and handle flaresImportance of lifestyle and dietary factors
53Pseudogoutcalcium pyrophosphate dehydrate (CPPD) crystals deposit in joints and soft tissue, resulting in inflammation and tissue damageIt is not commonly encountered at a younger age without a previous history of trauma or surgery, is seen more commonly after age 50 years, and it has no definite ethnic or gender predilection
54Clinical manifestations: Ranges from asymptomatic to gout like (pseudogout)Rheumatoid arthritis–like (pseudo-rheumatoid arthritis)Osteoarthritis-like (pseudo-osteoarthritis)PMR-like (pseudo-PMR)
55Acute or subacute attacks can involve one or multiple joints Systemic features such as fever, malaise, leukocytosis, and elevated ESR and CRP can be presentPseudogout and gout can share similar joint predilection, but pseudogout affects larger joints more commonly than gout (knee joints, wrists, elbows, shoulders)It is often difficult to differentiate gout and pseudogout without a synovial fluid analysis
56Diagnosis: Synovial fluid analysis: Radiographs: CPPD crystals might not be as evident as MSU crystals.Detection might not be as accurate if fluid analysis is delayed.In addition, because pseudogout and gout can coexist, MSU crystals might also be observedRadiographs:Chondrocalcinosis in the joint involved and other more typical joints even if pseudogout is not clinically active at the time of presentationThey are not required to make the diagnosis once CPPD crystals are seen under polarized light
61Treatment: Acute: Chronic: If one or two joints: joint aspiration and IA steroid injectionIf more than two joints are involved treatment is directed more toward systemic therapy (NSAIDs, corticosteroids, colchicine)Chronic:In patients with three or more attacks a year colchicine at a dose of 0.6 mg once or twice daily to reduce the number of attacks in a year.There are no hypouricemic equivalents to improve the long-term control of pseudogout and to prevent or reverse CPPD crystal deposit disease.
63Milwaukee shoulder: Seen mainly in older females with advanced DJD Severe destructive shoulder arthropathyFluid is non inflammatory, and is due to basic calcium phosphate crystals (hydroxyapatite)
64Steroid induced arthritis: Iatrogenic crystal arthritisDevelop within few hours after IA cortisteroid injectionSeptic arthritis takes longer to developShort livedSymptomatic treatment: rest and ice application