FREEDOM FROM RHEUMATOLOGICAL DISORDERS

Gout Gout

An elevated serum urate concentration An elevated serum urate concentration Recurrent attacks of acute arthritis in which Recurrent attacks of acute arthritis in which MSU( monosodium urate) crystals are seen in MSU( monosodium urate) crystals are seen in synovial fluidsynovial fluidAggregates of MSU crystals (tophi) are Aggregates of MSU crystals (tophi) are deposited in & around joints leading to deposited in & around joints leading to deformity & cripplingdeformity & crippling

HyperuricemiaHyperuricemia An elevated level of urate in the blood > An elevated level of urate in the blood > 7mg/dl in males and >6.5mg/dl in females7mg/dl in males and >6.5mg/dl in females

EpidemiologyEpidemiology

The incidence of gout varies in population with an The incidence of gout varies in population with an

overall prevalence of less than 1 to 15.3% overall prevalence of less than 1 to 15.3%

PathophysiologyPathophysiology

Uric acid is the end product of the degradation of Uric acid is the end product of the degradation of

purines. purines. The accumulation may result from either The accumulation may result from either

overproduction or underexecreation.overproduction or underexecreation.

The purines from which uric acid is produced The purines from which uric acid is produced originate from three sources: dietary originate from three sources: dietary purine,conversion of tissue nucleic acid to purine,conversion of tissue nucleic acid to purine nucleotides and de novo synthesis of purine nucleotides and de novo synthesis of purine bases.purine bases.Overproduction of uric acid result from:Overproduction of uric acid result from:

1.1. Abnormalities in the enzyme system that Abnormalities in the enzyme system that regulate purine metabolism.regulate purine metabolism.

2.2. An increase in the activity of phosphribosyl An increase in the activity of phosphribosyl pyrophosphate(PRPP) synthatase, a key pyrophosphate(PRPP) synthatase, a key determinant in purine synthesis and thus uric determinant in purine synthesis and thus uric acid overproduction. acid overproduction.

3. A deficiency of hypoxanthine-guanine 3. A deficiency of hypoxanthine-guanine phosphoribosyl transferase (HGPRT) may phosphoribosyl transferase (HGPRT) may also result in the overproduction of uric also result in the overproduction of uric acid.acid.

4. Increased breakdown of tissue nucleic 4. Increased breakdown of tissue nucleic acids, as with myeloproliferative and acids, as with myeloproliferative and lymphoproliferative disorders.lymphoproliferative disorders.Drugs that decrease renal clearance:Drugs that decrease renal clearance:

Diuretics, salicylate<2g\d, ethanol, L-dopa, Diuretics, salicylate<2g\d, ethanol, L-dopa, cyclosporine, ethambutol……..cyclosporine, ethambutol……..

Normal individual produce 600-800mg of Normal individual produce 600-800mg of uric acid daily and excrete less than 600 uric acid daily and excrete less than 600 mg in urine. Individual who excrete more mg in urine. Individual who excrete more than 600 mg on a purine-free diet are than 600 mg on a purine-free diet are considered overproducers.considered overproducers.Hyperuricemic individuals who excrete Hyperuricemic individuals who excrete less than 600mg per 24 hours on purine-less than 600mg per 24 hours on purine-free diet are defined as underexcretors of free diet are defined as underexcretors of uric acid.uric acid.On regular diet, excretion of >1000 mg per On regular diet, excretion of >1000 mg per 24 hours reflect overproduction , less than 24 hours reflect overproduction , less than this is probably normalthis is probably normal. .

Gout once called the “Disease of Kings”

is also seen in Women,

Especially After

Menopause

M:F - 7:1 to 9:1M:F - 7:1 to 9:1

Women before menopause- F Women before menopause- F < M< M

In ages younger than 65- M:F- 4:1 ratio In ages younger than 65- M:F- 4:1 ratio

In the older age groups > 65- M:F-3:1 In the older age groups > 65- M:F-3:1 ratioratio

After 80 years of age-F >After 80 years of age-F > M M

URIC ACID METABOLISMURIC ACID METABOLISM MEN Vs WOMENMEN Vs WOMEN

Estrogen have a mild uricosuric effect; therefore, Estrogen have a mild uricosuric effect; therefore, gout is unusual in premenopausal women gout is unusual in premenopausal women

Higher renal clearance of urate in women Higher renal clearance of urate in women possibly due to their higher plasma estrogen possibly due to their higher plasma estrogen levels levels The declining use of HRT may further increase The declining use of HRT may further increase the frequency of gout in women at an earlier age the frequency of gout in women at an earlier age

Pathogenesis of GoutPathogenesis of Gout

Hyperuricemia results from urate Hyperuricemia results from urate overproduction (10%), under excretion overproduction (10%), under excretion (90%) or often a combination of two (90%) or often a combination of two

Gout is mediated by supersaturation and Gout is mediated by supersaturation and crystallization of uric acid within joints crystallization of uric acid within joints ultimately, the formation of tophi ultimately, the formation of tophi

Interactions of MSU crystals with the Interactions of MSU crystals with the components of the innate immune system components of the innate immune system trigger acute gouty inflammationtrigger acute gouty inflammation

Triggering Factors-Acute Attack

Alchol ingestionAlchol ingestionDietary excess of purineDietary excess of purineHemorrhageHemorrhageAcute medical illnessAcute medical illnessInfectionsInfectionsExercise Exercise TraumaTraumaSurgery Surgery Drugs: Drugs: cyclosporine, furosemide, ethambutol, cyclosporine, furosemide, ethambutol, aspirin (Low dose), pyrazinamide, thiazides, nicotinic aspirin (Low dose), pyrazinamide, thiazides, nicotinic acids etcacids etc

Asymptomatic Hyperuricemia

Acute Gouty Arthritis - Acute monoarticular arthritis - The attacks begin abruptly and reach maximum

intensity in 8-12 hours - The joints are red, hot, and exquisitely tender - Untreated, the first attacks resolve spontaneously in less than 2 weeks. - Gout can initially present as a polyarticular arthritis in 10% of patients

Clinical Features in Gout patient

Intercritical gout

Chronic tophaceous Gout - Attacks become more polyarticular

- Inflammation may become less intense - Proximal and upper-extremity joints involved - Attacks occur more frequently and last longer - Tophi in the soft tissues (helix of the ear, fingers, toes……………)

Clinical FeaturesClinical FeaturesMEN Vs WOMENMEN Vs WOMEN

In women, polyarticular/tophaceous disease is In women, polyarticular/tophaceous disease is often the first manifestation of goutoften the first manifestation of gout

A preceding recurrent mono-arthritis is found A preceding recurrent mono-arthritis is found in joints other than the big toein joints other than the big toe

The duration of disease before tophi is shorterThe duration of disease before tophi is shorter

The prevalence of tophi is higher and its The prevalence of tophi is higher and its localization different in female than in male localization different in female than in male patients patients

Tophi are usually indolent and show little Tophi are usually indolent and show little

surrounding inflammation surrounding inflammation

Gout in women has higher frequency of Gout in women has higher frequency of

upper limb joint involvement in comparison to upper limb joint involvement in comparison to

menmen

The articular features of gout are usually The articular features of gout are usually

similar similar

Definitive diagnosis is best established by• Aspiration of joint and identification of urate crystal • The triad of acute monoarticular arthritis, hyperuricemia and dramatic response to colchicines• Presence of 6 of the below mentioned 12 clinical, laboratory and radiographic criteria Criteria of Acute Gouty Arthritis

► More than one attack of arthritis ► Maximum inflammation in one day ►Monoarticular arthritis ►Joint redness ► First metatarsophalangeal joint involvement ► Unilateral attack ► Unilateral attack involving tarsal joint ► Suspected tophus ►Hyperuricemia ► Asymmetric swelling within joint (radiograph) ► Subcortical cyst without erosion (radiograph) ►Negative culture of joint fluid for microorganism

Renal stones Urate nephropathy & chronic kidney failureHypertensionDiabetesEndothelial dysfunction ObesityInsulin resistance syndromeAtherosclerosis Cardiovascular disease related mortalityCerebrovascular diseaseHypothyroidism

Co morbid Conditions

Treatment of GoutTreatment of Gout

Treat acute arthritic attack promptlyTreat acute arthritic attack promptlyPrevent recurrence of acute gouty arthritisPrevent recurrence of acute gouty arthritisLower urate levelsLower urate levelsPrevent or reverse complications of the Prevent or reverse complications of the disease resulting from deposition of MSU disease resulting from deposition of MSU crystal in joint, kidney, or other sitescrystal in joint, kidney, or other sitesPrevent or reverse co-morbid conditions Prevent or reverse co-morbid conditions like obesity, HT & triglycerdemia & renal like obesity, HT & triglycerdemia & renal complicationscomplications

Treatment of Acute Gouty ArthritisTreatment of Acute Gouty Arthritis NSAIDs NSAIDs are preferred in patients with uncomplicated are preferred in patients with uncomplicated

gout gout

Intraarticular corticosteroidIntraarticular corticosteroid for gout affecting one or for gout affecting one or two large jointstwo large joints

ColchicineColchicine is preferred for patients in whom the is preferred for patients in whom the

diagnosis of gout is not confirmeddiagnosis of gout is not confirmed

It is most effective during the first 12-24 hours of an It is most effective during the first 12-24 hours of an

attack, effectiveness declines with the duration of attack, effectiveness declines with the duration of

inflammationinflammation

Long-Term or Prophylactic TherapyLong-Term or Prophylactic Therapy Lowering uric acid with either allopurinol or probenecid can Lowering uric acid with either allopurinol or probenecid can precipitate attacks of gout precipitate attacks of gout NSAIDs and colchicine are frequently used as prophylaxis NSAIDs and colchicine are frequently used as prophylaxis against recurrent acute goutagainst recurrent acute goutA standard practice is to use low-dose oral colchicine (0.6 mg A standard practice is to use low-dose oral colchicine (0.6 mg orally twice a day in patients with intact renal function) for the first orally twice a day in patients with intact renal function) for the first six months of antihyperuricemic therapysix months of antihyperuricemic therapyLong-term use of colchicine can lead to a muscle weakness with Long-term use of colchicine can lead to a muscle weakness with elevated levels of creatine kinase particularly in patients with elevated levels of creatine kinase particularly in patients with renal insufficiency renal insufficiency NSAIDs can be used for prophylaxis, such as indomethacin at 25 NSAIDs can be used for prophylaxis, such as indomethacin at 25 mg bidmg bid

Approaches to Lowering Uric Acid LevelsApproaches to Lowering Uric Acid Levels Asymptomatic HyperuricemiaAsymptomatic Hyperuricemia Rarely an indication for specific drug therapy Rarely an indication for specific drug therapy

Symptomatic HyperuricemiaSymptomatic Hyperuricemia Life long therapy with anti-hyperuricemic Life long therapy with anti-hyperuricemic

therapy is indicated in following situationtherapy is indicated in following situation>2 or 3 acute attacks>2 or 3 acute attacksRenal stonesRenal stonesTophaceous goutTophaceous goutChronic gouty arthritis with bony erosions.Chronic gouty arthritis with bony erosions.

Antihyperuricemic TherapyAntihyperuricemic Therapy

In many cases, patients who have a first attack of In many cases, patients who have a first attack of gout should undergo therapy with agents that gout should undergo therapy with agents that lower uric acidlower uric acidSome rheumatologists advocate waiting for the Some rheumatologists advocate waiting for the second attack to begin therapy to lower uric acid second attack to begin therapy to lower uric acid levels because not all patients have a second levels because not all patients have a second attack attack Antihyperuricemic therapy should be started a few Antihyperuricemic therapy should be started a few weeks after the attack has resolved and with the weeks after the attack has resolved and with the institution of colchicine to prevent another attackinstitution of colchicine to prevent another attack

Indications for Allopurinol(Xanthine Oxidase inhibitor)

Hyperuricemia associated overproducers of uric acidIn patients at risk of tumor lysis syndrome to prevent renal toxicity during therapy for malignancies Uric acid excretion of 1000mg or more in 24 hoursHyperuricemia associated with HGPRT deficiency or PRPP synthetase over activityUric acid nephropathyNephrolithiasis

Intolerance or reduced efficacy of space uricosuric agentsGout with renal insufficiency (GFR<60ml/min)Allergy to uricosurics

Candidates for uricosuric drugsCandidates for uricosuric drugs

Who is younger than 60 years of age and Who is younger than 60 years of age and normal renal function (creatinine clearance normal renal function (creatinine clearance greater than 80ml/min)greater than 80ml/min)

Uric acid excretion of less than 800 mg/24 Uric acid excretion of less than 800 mg/24 hours on a general diethours on a general diet

No h/o of renal calculiNo h/o of renal calculi

ProbenecidProbenecid

Reduce serum urate levels by enhancing the renal Reduce serum urate levels by enhancing the renal excretion of UAexcretion of UA

Fewer significant adverse effects than allopurinol Fewer significant adverse effects than allopurinol

Can be used in the majority of middle-agedCan be used in the majority of middle-aged

Maintenance dose ranges from 500 mg to 3 g per day Maintenance dose ranges from 500 mg to 3 g per day & is administered on twice daily or thrice daily schedule& is administered on twice daily or thrice daily schedule

Precipitation of gout, urolithiasis, and impairment of Precipitation of gout, urolithiasis, and impairment of renal function are common side effectsrenal function are common side effects

SulfinpyrazoneSulfinpyrazoneSulfinpyrazone is an alternative uricosuric agent that Sulfinpyrazone is an alternative uricosuric agent that

has antiplatelet activity but is seldom used because has antiplatelet activity but is seldom used because

of the added risk of bone marrow suppression of the added risk of bone marrow suppression

Starting dose, 50 mg orally twice daily; gradually Starting dose, 50 mg orally twice daily; gradually

increased to 100-400 mg dailyincreased to 100-400 mg daily

Precipitation of gout, urolithiasis, and impairment of Precipitation of gout, urolithiasis, and impairment of

renal function are common side effects renal function are common side effects

Dietary Management of HyperuricemiaDietary Management of Hyperuricemia Alcohol consumption must be avoidedAlcohol consumption must be avoided

Diets like butter, red meat, pasta sweets, white rice, Diets like butter, red meat, pasta sweets, white rice, potatoes, white bread, wine beer, liquor, fish poultry potatoes, white bread, wine beer, liquor, fish poultry and sea food increase the risk of gout and sea food increase the risk of gout

Higher level of consumption of dairy products is Higher level of consumption of dairy products is associated with a decreased risk associated with a decreased risk

Moderate intake of purine-rich vegetables or protein Moderate intake of purine-rich vegetables or protein is not associated with an increased risk of goutis not associated with an increased risk of gout

Those who consumes milk 1 or more times per day Those who consumes milk 1 or more times per day have a lower serum uric acid level have a lower serum uric acid level

Recent Advances in TreatmentRecent Advances in Treatment

Recombinant uricaseRecombinant uricase can promote accelerated can promote accelerated tophus dissolutiontophus dissolution

OxipurinolOxipurinol is the active metabolite of allopurinol. is the active metabolite of allopurinol. Patients with allopurinol hypersensitivity can often Patients with allopurinol hypersensitivity can often tolerate oxypurinoltolerate oxypurinol

FebuxostatFebuxostat is an orally administered selective is an orally administered selective inhibitor of xanthine oxidase. It inhibits both the inhibitor of xanthine oxidase. It inhibits both the oxidized and reduced forms of xanthine oxidase. It is a oxidized and reduced forms of xanthine oxidase. It is a potential alternative to allopurinol for patients with potential alternative to allopurinol for patients with gout. gout.

Anti-tumour necrosis factorAnti-tumour necrosis factor as a new therapeutic as a new therapeutic optionoption

Treatment of Co morbid conditionsTreatment of Co morbid conditions

The ARBs like The ARBs like losartan, Amlodipinelosartan, Amlodipine & the triglyceride- & the triglyceride-lowering agent lowering agent fenofibratefenofibrate - Uricosuric effects - Uricosuric effects

Weight loss is protectiveWeight loss is protective

The amelioration of insulin resistance by either a low-The amelioration of insulin resistance by either a low-energy diet or energy diet or troglitazone & Metformintroglitazone & Metformin therapy can also therapy can also lower uric acid and attenuate the articular syndromelower uric acid and attenuate the articular syndrome

Role of HRT in GoutRole of HRT in GoutThe effect of exogenously administered The effect of exogenously administered oestrogens, produce a fall in plasma uric oestrogens, produce a fall in plasma uric acid concentration through a uricosuric effectacid concentration through a uricosuric effect

However, there is no conclusive evidence is However, there is no conclusive evidence is available for the use of estrogen available for the use of estrogen replacement for such cases; however it replacement for such cases; however it remains the potential area of research remains the potential area of research

Good luckGood luck