Gout PDF

Gout Clinical Pharmacy and Therapeutics 3 Dr Yasaman Malekizadeh [email protected]  Learning objectives ❖ What is gout? ❖ Learn about different stages of gout ❖ Pathophysiology ❖ Clinical symptoms ❖ Biosynthesis ❖ Risk factors ❖ Diagnos...

Gout Clinical Pharmacy and Therapeutics 3 Dr Yasaman Malekizadeh [email protected]  Learning objectives ❖ What is gout? ❖ Learn about different stages of gout ❖ Pathophysiology ❖ Clinical symptoms ❖ Biosynthesis ❖ Risk factors ❖ Diagnostic tests ❖ Available treatment  History of gout https://encrypted-tbn1.gstatic.com/images?q=tbn:ANd9GcTBtt25-JvQmnaTG_6epe5KuW8IlP7TXVrwtgMrCZWJMcyE5vKl ❖ The disease of kings due to its association with high consumption of alcohol and rich food ❖ Rich food such as wine and meat contribute to increased uric acid levels ❖ Gout is linked to The Gout, James Gillray, 1799 hyperuricaemia  Define gout ❖ An arthritis caused by a build up of uric acid crystals in the joints (especially big toe, but also hands) ❖ Claudius Galenus was the most famous physician of the Greco-Romans who described “tophi”, the crystalised monosodium urate deposits, leading to hyperuricaemia for the first time ❖ Men (3-6%) > women (1-2%) ❖ Age of onset: 30- 50 in men and after menopause in women ❖ Very treatable (early acute stage) ❖ If not treated can develop into chronic tophaceous gout Stages of the disease  Pathogenesis of acute gout ❖ The pathogenesis of gouty arthritis involves initial activation of monocytes and mast cells followed by neutrophils in connective tissues and bone marrow ❖ Before the first attack of gout and in the inter-critical period, differentiated macrophages engulf UA crystals without inducing an inflammatory response ❖ Less-differentiated monocytes produce abundant amounts of TNF (Tumor Necrosis Factor), IL-1 (Interleukin), IL-6 and IL-8 following phagocytosis of urate crystals ❖ Mast cells are key players by producing histamine and IL-1 ❖ This results in increasing vascular permeability and vasodilatation ❖ The acute attack of gout is usually self-limited and resolves within hours to few days of -> This occurs by removal and phagocytosis of crystals by macrophages -> suppression of cellular and chemokine activation ❖ Macrophages clear the cellular apoptosis and eliminate IL-1 to stop the inflammatory cascade Ragab et al., 2017  Clinical diagnosis of acute gout ❖ Acute gouty attack is usually monoarthritic that peaks within hours ❖ Cardinal signs of inflammation including redness, hotness, tenderness, swelling and loss of function ❖ In large joints such as knees and ankles, skin signs are infrequent, but swelling and pain can be intense ❖ Gout has a predilection for lower extremities such as the first metatarsophalangeal joint, which is the most common site for acute gout known as “podagra” ❖ Other effected joints include ankles, knees, wrists and metacarpophalangeal joint of the hands ❖ Constitutional symptoms such as fever, headache, and malaise can be present ❖ Gouty attack can be mild with low-grade inflammation  Pathogenesis of chronic gout ❖ Recurrent attacks of gout leads to chronic inflammation ❖ Chronic gout manifests by cartilage damage and tophi formation ❖ Presence of urate crystals in the synovium (connective tissue that lines the inside of the joint capsule) leads to stimulation of chondrocytes (important for cartilage formation) to produce inflammatory cytokines and nitric oxide as a result of cartilage damage ❖ On the bone level, IL-1β activation and release of pro-inflammatory cytokines from osteoblasts (cells that form bone tissue) are responsible for the formation of bone erosions and destruction. ❖ The same cytokines responsible for the acute gout, can also be found at lower concentrations inbetween attacks. ❖ The incident of progression into chronic gout can be decreased by long-term use of low dose anti- inflammatory agents. Uric acid levels excreted into blood and urine can be used to calculate fractional excretion of uric acid and identify the disease stage Pathogenesis of chronic gouty arthritis  Clinical diagnosis of chronic gout ❖ Untreated disease progresses into destruction of joints with formation of palpable tophi ❖ Tophi can be present around the joints in the ears, the subcutaneous tissue or the skin ❖ Tophi may lead to joint destruction, deformity and bony erosions ❖ In atypical presentation of gout such as in multiple joint affection or atypical joint distribution, identification of monosodium urate is mandatory to differentiate gout from other diagnoses ❖ Synovial fluid analysis is advised to exclude other causes mainly septic arthritis ❖ Formation of tophi is a late clinical manifestation of gout, though it may develop early in the disease course Symptoms  Uric acid biosynthesis Dietary intake Purine bases Cell breakdown Hypoxanthine xanthine oxidase Xanthine xanthine oxidase Uric acid EXCRETION BY KIDNEY  Predisposition ❖ Gender: M >F ❖ Family history ❖ Body size: L >S ❖ Diet (purine rich) ❖ Alcohol ❖ Diuretics (hypertension treatment)- Diuretics induce hyperuricaemia by increasing urate reabsorption ❖ Disease or treatment that cause high cell turnover (psoriasis and chemotherapy) ❖ Renal impairment  Diagnostic tests ❖ Joint aspiration and polarised light microscopy to detect crystals ❖ Full blood count: high level of white blood cells due to inflammation ❖ Erythrocyte sedimentation rate: measures how quickly erythrocytes settle at the bottom of a test tube that contains a blood sample. Normally, red blood cells settle relatively slowly, a faster-than-normal rate may indicate inflammation in the body ❖ X-ray (normal with acute gout) ❖ Serum uric acid elevated of > 10mg/l (normal level: < 7 mg/l) ❖ High level of serum uric acid doesn’t necessarily represent gout disease  Gout management ❖ Life style and diet has a major impact on the risk of gout and controlling metabolic syndrome and cardiovascular diseases associated with gout ❖ Weight loss in obese patients ❖ Avoidance of beer (including non-alcoholic), spirit and sugar containing drinks; and increased intake of skimmed-milk products ❖ Restriction of meat and seafood intake ❖ Reduced intake of carbohydrates, increased proportion of proteins and unsalted fats ❖ Regular exercise ❖ All these factors have been shown to be beneficial in controlling lipoprotein levels and lowering serum urate ❖ Targeting serum uric acid levels is key in gout management and treatment, in addition to disappearing of gout features  Gout treatment ❖ Consumption of urate lowering drugs ❖ NSAIDS Maximum authorised dose Diclofenac, indomethacin NOT Aspirin (it can alter uric acid levels and potentially prolong and intensify an acute attack) Inhibits prostaglandin production involved in inflammatory responses Analgesia like ibuprofen or naproxen ❖ COX-2 inhibitors (if suffering from GI problems and CAN’T take NSAIDS): etoricoxib  Gout treatment ❖ Colchicine: blocks neutrophil migration and production of inflammatory glycoproteins Very effective when taken within 12 h after gout onset, but less efficient when given long after the flare onset Narrow therapeutic toxicity window and can be very toxic when used inappropriately Gastrointestinal intolerance (diarrhea, nausea, or vomiting) is usually the first feature of colchicine toxicity and should lead to dose reduction or interruption Renal failure decreases colchicine excretion, so doses should be closely monitored and minimised in patients with moderate renal insufficiency Nerve and muscle toxicity can be observed in long term low dose colchicine users who have kidney transplant or chronic kidney disease, toxicity is usually slowly reversible after drug cessation and requires Doses should also be reduced in patients with hepatic failure, the drug is predominantly eliminated through the hepato-biliary system Inhibitors of cytochrome P4503A4 or P-glycoprotein increase plasma concentration and toxicity of colchicine  Gout treatment ❖ Allopurinol: An analogue of hypoxanthine It is a purine which can be metabolised to its active form, oxypurinol by xanthine oxidase enzyme Reduces synthesis of uric acid by inhibiting xanthine oxidase Lowers amount of uric acid crystals in tissues Inhibits formation of renal stones Ideal only for treatment of chronic gout Excretion through kidney -> reduced excretion if suffering from renal failure Cutaneous side effects such as Steven Johnson syndrome may develop during the 2 or 3 first months of treatment and should lead to immediate, life-long, allopurinol cessation  Gout treatment ❖ Febuxostat: A non-purine xanthine oxidase Inhibits xanthine oxidase More potent than allopurinol Reduces levels of uric acid Contraindicated with some chemotherapeutic drugs Because of its mixed renal and hepatic metabolism, the drug can be prescribed with no dose reduction in patients with moderate renal failure Skin reactions to febuxostat is more frequent in patients with previous cutaneous intolerance to allopurinol Phase 3 studies showed an increased number of cases with cardiovascular side effects and mortality compared to the allopurinol-treated patients -> prescribed with caution in patients with a history of cardiovascular diseases Other side effects: nausea, vomiting, joint stiffness, headaches  Gout treatment ❖ Uricosuric agents: Probenecid, benzbromarone and sulfinpyrazone Reduce URAT1 (an urate transporter) activity and uric acid reabsorption in renal proximal tubular cells Lower uricemia by increasing uric acid output in the urine, exposing the patients to the risk of uric acid stone, which is worse at the onset of treatment Should not be prescribed as monotherapy in patients with a history of uric acid stone or hyperuricuria and should be taken with abundant water intake ❖ Lesinurad: Selective URAT1 inhibitor recently approved as an add-on therapy to xanthine oxidase inhibitors when these failed to lower uricemia down to the suitable target ❖ P2X7R receptors: ATP promotes the pathogenesis of gouty arthritis via increasing the secretion of IL-1 β, and its receptor (P2X7R) function associated single nucleotide polymorphisms may be related to gouty arthritis -> ATP-P2X7R signalling pathway plays a significant regulatory role in the pathogenesis of gout  Renal excretion ❖ Renal excretion of uric acid is the end result of 4 phases ❖ The first phase is the passage of UA across the Bowman’s capsule (glomerular filtration); followed by reabsorption of almost all urates passing in the proximal tubules ❖ The third phase involves secretion of part of the reabsorbed UA ending with another reabsorption phase in the proximal tubules ❖ The excreted UA is almost 10% of the filtered urate through Bowman’s capsule and the rest Bobulescu et al.,2012 is reabsorbed in the body  Conclusion…. ❖ Gout is caused by deposition of uric acid crystals in joints leading to inflammation ❖ Diagnosis is by family history and clinical testing (polarised microscopy of synovial fluid) ❖ Gout is a very treatable arthritic condition ❖ Treat acute attacks and consider drug therapy to prevent further episodes ❖ Untreated acute gout develops into chronic tophaceous gout ❖ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512152/ ❖ https://www.sciencedirect.com/science/article/pii/S2589936821000244?via%3Dihub  Case study part 1 ❖ Mr B is 58 year old who has been admitted to hospital for knee replacement ❖ Mr B is a Smoker and drinks (35u per week) with BMI=27 Kg/m2 ❖ He has hypertension, but no other comorbidities ❖ During his stay at the hospital, he develops excruciating pain in big toe of right foot, which is very swollen ❖ He is diagnosed with gout  Case study 1 assessment ❖ Q1: what is gout? ❖ Q2: List three ways gout can develop ❖ Q3: Risk factors for gout ❖ Q4: Symptoms of gout ❖ Q5: What investigations can be carried out by medical team ❖ Q6: Advice on avoidance of recurrent attacks ❖ Q7: Treatment options for acute attack of gout  Assessment 1 answers ❖ Q1: What is gout? Inflammatory arthritis that is characterised by the deposition of monosodium urate crystals in synovial fluid and other tissues ❖ Q2: List three ways gout can develop Overactive PRPP enzyme which leads to increased Purine production Acute illness which increases ATP metabolism Renal failure ❖ Q3: Risk factors for gout Alcohol (Mr B drinks a lot) Weight (Mr B is overweight with BMI 27 kg/m2) Gender (he is male) Purine rich diet Diuretics (he has BP so he is most probably on diuretics) Renal impairment Family history  Assessment 1 answers ❖ Q4: Symptoms of gout Pain that rapidly worsens in the big toe Pain in knees, ankles, wrists and elbows Kidney stones Lumps around joints ❖ Q5: What investigations can be carried out by medical team Blood test (Erythrocyte sedimentation rate, WBC, uric acid levels) X ray to look for erosions joint aspiration to look for urate crystals ❖ Q6: Advice on avoidance of recurrent attacks Reduce weight, reduce alcohol, reduce intake of purine reach food  Assessment 1 answers ❖ Q7: Treatment options for acute attack of gout NSAIDs if can be tolerated, start RAPIDLY after symptoms start COX-2 inhibitor (etoricoxib) Colchicine (slow onset of action), considering Mr B’s medical history this would be the most likely drug used Steroid injection (but must make sure that patient has acute gout and not septic arthritis, since steroids can exacerbate the infection Systemic steroids, useful for polyarticular gout If patient has renal disease, colchicine must be prescribed (colchicine is mostly eliminated through liver)  Case study part 2 ❖ Mr B’s attack resolves and he is sent home ❖ Mr B has a second attack several months after his discharge from hospital ❖ GP decides to place him on long-term prophylaxis against further attacks  Case study 2 assessment ❖ Q1: Why wasn’t Mr B put on prophylactic treatment after his first attack? ❖ Q2: What options are available to Mr B and which one is the usual drug of choice in these situations? ❖ Q3: State two similarities between gout and rheumatoid arthritis and compare drug treatment options for the two diseases  Assessment 2 answers ❖ Q1: Why wasn’t Mr B put on prophylactic treatment after his first attack? Patient hadn’t reached the threshold for prophylactic use (>2 gouty attacks per year) Cannot use prophylactic use for acute attack since lowering uric acid levels will mobilise urate stores in response to decreased serum levels and this may prolong the attack or precipitate another gouty arthritic attack ❖ Q2: What options are available to Mr B and which one is the usual drug of choice in these situations? Xanthine oxidase inhibitors (allopurinol & febuxostat ) Allopurinol (1st line agent) Sulfinpyrazone Colchicine may be used upon commencement of allopurinol to prevent attack ❖ Q3: State two similarities between gout and rheumatoid arthritis and compare drug treatment options for the two diseases Both are arthropathies and need rapid treatment to avoid development of chronic problems Different pathophysiology highlight different drug treatments, although steroids and NSAIDs do form a common feature of both diseases