FREEDOM FROM RHEUMATOLOGICAL DISORDERS

Gout An elevated serum urate concentration Recurrent attacks of acute arthritis in which MSU( monosodium urate) crystals are seen in synovial fluid Aggregates of MSU crystals (tophi) are deposited in & around joints leading to deformity & crippling Hyperuricemia An elevated level of urate in the blood > 7mg/dl in males and >6.5mg/dl in females

Epidemiology The incidence of gout varies in population with an overall prevalence of less than 1 to 15.3% Pathophysiology Uric acid is the end product of the degradation of purines. The accumulation may result from either overproduction or underexecreation.

The purines from which uric acid is produced originate from three sources: dietary purine,conversion of tissue nucleic acid to purine nucleotides and de novo synthesis of purine bases. Overproduction of uric acid result from: Abnormalities in the enzyme system that regulate purine metabolism. An increase in the activity of phosphribosyl pyrophosphate(PRPP) synthatase, a key determinant in purine synthesis and thus uric acid overproduction.

3. A deficiency of hypoxanthine-guanine phosphoribosyl transferase (HGPRT) may also result in the overproduction of uric acid. 4. Increased breakdown of tissue nucleic acids, as with myeloproliferative and lymphoproliferative disorders. Drugs that decrease renal clearance: Diuretics, salicylate<2g\d, ethanol, L-dopa, cyclosporine, ethambutol……..

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

Gout once called the “Disease of Kings” is also seen in Women, Especially After Menopause

M:F - 7:1 to 9:1 Women before menopause- F < M In ages younger than 65- M:F- 4:1 ratio In the older age groups > 65- M:F-3:1 ratio After 80 years of age-F > M

URIC ACID METABOLISM MEN Vs WOMEN Estrogen have a mild uricosuric effect; therefore, gout is unusual in premenopausal women Higher renal clearance of urate in women possibly due to their higher plasma estrogen levels The declining use of HRT may further increase the frequency of gout in women at an earlier age

Pathogenesis of Gout Hyperuricemia results from urate overproduction (10%), under excretion (90%) or often a combination of two Gout is mediated by supersaturation and crystallization of uric acid within joints ultimately, the formation of tophi Interactions of MSU crystals with the components of the innate immune system trigger acute gouty inflammation

Triggering Factors-Acute Attack Alchol ingestion Dietary excess of purine Hemorrhage Acute medical illness Infections Exercise Trauma Surgery Drugs: cyclosporine, furosemide, ethambutol, aspirin (Low dose), pyrazinamide, thiazides, nicotinic acids etc

Clinical Features in Gout patient 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

Chronic tophaceous Gout 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 Features MEN Vs WOMEN In women, polyarticular/tophaceous disease is often the first manifestation of gout A preceding recurrent mono-arthritis is found in joints other than the big toe The duration of disease before tophi is shorter The prevalence of tophi is higher and its localization different in female than in male patients

Tophi are usually indolent and show little surrounding inflammation Gout in women has higher frequency of upper limb joint involvement in comparison to men The articular features of gout are usually 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

Co morbid Conditions Renal stones Urate nephropathy & chronic kidney failure Hypertension Diabetes Endothelial dysfunction Obesity Insulin resistance syndrome Atherosclerosis Cardiovascular disease related mortality Cerebrovascular disease Hypothyroidism

Treatment of Gout Treat acute arthritic attack promptly Prevent recurrence of acute gouty arthritis Lower urate levels Prevent or reverse complications of the disease resulting from deposition of MSU crystal in joint, kidney, or other sites Prevent or reverse co-morbid conditions like obesity, HT & triglycerdemia & renal complications

Treatment of Acute Gouty Arthritis NSAIDs are preferred in patients with uncomplicated gout Intraarticular corticosteroid for gout affecting one or two large joints Colchicine is preferred for patients in whom the diagnosis of gout is not confirmed It is most effective during the first 12-24 hours of an attack, effectiveness declines with the duration of inflammation

Long-Term or Prophylactic Therapy Lowering uric acid with either allopurinol or probenecid can precipitate attacks of gout NSAIDs and colchicine are frequently used as prophylaxis against recurrent acute gout 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 six months of antihyperuricemic therapy Long-term use of colchicine can lead to a muscle weakness with elevated levels of creatine kinase particularly in patients with renal insufficiency NSAIDs can be used for prophylaxis, such as indomethacin at 25 mg bid

Approaches to Lowering Uric Acid Levels Asymptomatic Hyperuricemia Rarely an indication for specific drug therapy Symptomatic Hyperuricemia Life long therapy with anti-hyperuricemic therapy is indicated in following situation >2 or 3 acute attacks Renal stones Tophaceous gout Chronic gouty arthritis with bony erosions.

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

Indications for Allopurinol (Xanthine Oxidase inhibitor) Hyperuricemia associated overproducers of uric acid In patients at risk of tumor lysis syndrome to prevent renal toxicity during therapy for malignancies Uric acid excretion of 1000mg or more in 24 hours Hyperuricemia associated with HGPRT deficiency or PRPP synthetase over activity Uric acid nephropathy Nephrolithiasis Intolerance or reduced efficacy of space uricosuric agents Gout with renal insufficiency (GFR<60ml/min) Allergy to uricosurics

Candidates for uricosuric drugs Who is younger than 60 years of age and normal renal function (creatinine clearance greater than 80ml/min) Uric acid excretion of less than 800 mg/24 hours on a general diet No h/o of renal calculi

Probenecid Reduce serum urate levels by enhancing the renal excretion of UA Fewer significant adverse effects than allopurinol Can be used in the majority of middle-aged Maintenance dose ranges from 500 mg to 3 g per day & is administered on twice daily or thrice daily schedule Precipitation of gout, urolithiasis, and impairment of renal function are common side effects

Sulfinpyrazone Sulfinpyrazone is an alternative uricosuric agent that has antiplatelet activity but is seldom used because of the added risk of bone marrow suppression Starting dose, 50 mg orally twice daily; gradually increased to 100-400 mg daily Precipitation of gout, urolithiasis, and impairment of renal function are common side effects

Dietary Management of Hyperuricemia Alcohol consumption must be avoided Diets like butter, red meat, pasta sweets, white rice, potatoes, white bread, wine beer, liquor, fish poultry and sea food increase the risk of gout Higher level of consumption of dairy products is associated with a decreased risk Moderate intake of purine-rich vegetables or protein is not associated with an increased risk of gout Those who consumes milk 1 or more times per day have a lower serum uric acid level

Recent Advances in Treatment Recombinant uricase can promote accelerated tophus dissolution Oxipurinol is the active metabolite of allopurinol. Patients with allopurinol hypersensitivity can often tolerate oxypurinol Febuxostat is an orally administered selective inhibitor of xanthine oxidase. It inhibits both the oxidized and reduced forms of xanthine oxidase. It is a potential alternative to allopurinol for patients with gout. Anti-tumour necrosis factor as a new therapeutic option

Treatment of Co morbid conditions The ARBs like losartan, Amlodipine & the triglyceride-lowering agent fenofibrate - Uricosuric effects Weight loss is protective The amelioration of insulin resistance by either a low-energy diet or troglitazone & Metformin therapy can also lower uric acid and attenuate the articular syndrome

Role of HRT in Gout The effect of exogenously administered oestrogens, produce a fall in plasma uric acid concentration through a uricosuric effect However, there is no conclusive evidence is available for the use of estrogen replacement for such cases; however it remains the potential area of research

Good luck