1. GOUTY ARHTRITIS

2. GOUTY ARHTRITIS Definition:
Gout is a disease that causes acute joint inflammation and pain secondary to the deposition of monosodium urate (MSU) crystals within the synovial fluid and lining.
Clinically, acute gout presents as monoarticular inflammation in 85% to 90% of patients with the first metatarsophalangeal joint (great toe) typically affected; this is called podagra.

5. PATHOPHYSIOLOGY
Uric acid is the end product of purine degradation.
Purines originate from dietary purine, conversion of tissue nucleic acid to purine nucleotides, and denovo synthesis of purine bases.
An increased urate pool in individuals with gout may result from
1.over-production of uric acid
2.under-excretion of uric acid

6. Pathophysiology
Purine precursors come from exogenous sources or endogenous metabolism (synthesis and cell turnover)
Crystallization of MSU occurs when uric acid levels exceed the saturation point, through inefficient elimination or excessive production of uric acid. The multiple risk factors for the formation of urate crystals are shown in yellow boxes at their sites of action. Abbreviation: MSU, monosodium urate.
Amount of urate in the body depends on the balance between dietary intake, synthesis and excretion. 1/3 eliminated in GI tract and 2/3 by kidneys
Rees, F. et al. (2014) Optimizing current treatment of gout
Nat. Rev. Rheumatol. doi: /nrrheum
Rees, F. et al. (2014) Optimizing current treatment of gout
Nat. Rev. Rheumatol. doi: /nrrheum

7. PATHOPHYSIOLOGY 1.Over production of uric acid May result from:
A. Abnormalities in enzyme systems that regulate purine metabolism such as
Increased activity of phospho-ribosyl pyro-phosphate[PRPP] synthetase.
Deficiency of hypo-xanthine-­guanine phospho-ribosyl transferase[HGPRT].

8. PATHOPHYSIOLOGY
UNDEREXCRETION
Uric acid is filtered in the renal glomerulus and is almost completely (98%–100%) reabsorbed in the proximal tubule.
Uric acid is then secreted distal to the proximal tubular reabsorption site , and most is reabsorbed again.

9. PATHOPHYSIOLOGY
UNDEREXCRETION
In normal patients, homeostasis between reabsorption and secretion of urate is maintained.
Renal impairment, certain drugs(H.W), alcohol excess, metabolic syndrome, hypertension [HTN],coronary heart disease [CHD]) can cause this balance to fail, resulting in excess serum concentrations of uric acid and tissue deposition.

10. PATHOPHYSIOLOGY
Deposition of urate crystals in synovial fluid results in inflammation, vasodilation, increased vascular permeability, complement activation, and chemotactic activity for polymorpho-nuclearleukocytes.
Phagocytosis of urate crystals by leukocytes results in rapid lysis of cells and discharge of proteolytic enzymes into cytoplasm.

11. PATHOPHYSIOLOGY
The ensuing inflammatory reaction causes intense joint pain erythema, warmth, and swelling.
Uric acid nephrolithiasis occurs in 10%to25% of patients with gout.
Predisposing factors include excessive urinary excretion of uric acid, acidic urine, and highly concentrated urine.

13. Epidemiology
The risk of gouty arthritis is approximately the same for both men and women at any given SUA concentration.
The onset of gout is uncommon in prepubertal children, premenopausal women,

14. Symptoms Signs and symptoms
There is severe pain accompanied by erythema, swelling, and warmth in the affected joint(s).
The attack is usually mono-articular
the most common sites are the metatarsophalangeal joint and knee joints.
( the onset of pain during the night is typical of gout)

15. Signs and symptoms Signs
Affected joint(s) are warm, erythematous, and swollen.
Mild fever may be present.
Tophi(usually on hands, wrists, elbows, or knees) may be present in chronic, severe disease.

16. Tophi in Gout

17. Laboratory dignosis
Microscopic examination of aspiration from the synovial joint will show monosodium urate crystal deposits.
The peripheral WBC count may be only mildly elevated.
The serum uric acid level often is elevated but may be normal during an acute attack.
Other laboratory markers of inflammation (e.g., increased erythrocyte sedimentation rate) are often present.

18. Laboratory dignosis
A 24-hour urine collection can be obtained to determine whether the patient is an overproducer or an under-excretor of uric acid.
Individuals who excrete more than 800 mg of uric acid in this collection are considered overproducer.
Patients with hyperuricemia who excrete less than 600 mg/day (3.57 mmol/day) are classified as under-excretors of uric acid.

19. TREATMENT OF ACUTE GOUT:

20. TREATMENT OF ACUTE GOUT:
Goals of Treatment:
Terminate the acute attack
prevent recurrent attacks and
pre­vent complications associated with chronic deposition of urate crystals in tissues.

21. TREATMENT OF ACUTE GOUT
1.Non-steroidal anti-inflammatory drugs 2. CORTICOSTEROIDS 3.COLCHICINE

22. 1. Non-steroidal anti-inflammatory drugs:
NSAIDs have excellent efficacy and minimal toxicity with short­ term use.
Indomethacin, naproxen, and sulindac have Food and Drug Administration (FDA) approval for gout, but others are likely to be effective.
Start therapy within 24 hours of attack onset and continue until complete resolution (usually 5–8 days).

23. 1.Non-steroidal anti-inflammatory drugs:
SE GI tract (gastritis, bleeding, perforation), kidneys (renal papillary necrosis, reduced creatinine CL, cardiovascular system (increased blood pressure, sodium and fluid retention), and `central nervous system (CNS) (impaired cognitive function, headache, dizziness).

24. 1.Non-steroidal anti-inflammatory drugs:
Selective cyclooxygenase­2 (COX­2) inhibitors (eg, celecoxib) may be an option for patients unable to take nonselective NSAIDs, but the risk­ to ­benefit ratio in acute gout is unclear, and cardiovascular risk must be considered.

25. 2. CORTICOSTEROIDS
Corticosteroid efficacy is equivalent to NSAIDs; they can be used systemically or by intra­-articular (IA) injection.
Systemic therapy is necessary if an attack is poly-articular.

26. 2. CORTICOSTEROIDS Prednisone or prednisolone oral dosing strategies:
(1) 0.5 mg/kg daily for 5 to 10 days followed by abrupt discontinuation; or
(2) 0.5 mg/kg daily for 2 to 5 days fol­lowed by tapering for7 to 10 days.
Tapering is often used to reduce the steroid withdrawal.

27. 2. CORTICOSTEROIDS
IA corticosteroids should generally be used with oral
NSAID, colchicine, or corticosteroid therapy.

28. 3. CORTICOSTEROIDS
Methylprednisolone (a long­ acting corticosteroid) given by a single (IM) injection followed by oral corticosteroid therapy is another reasonable approach.
Alternatively, IM corticosteroid mono-therapy may be considered in patients with multiple affected joints who cannot take oral therapy.

29. 2. CORTICOSTEROIDS
Short-term corticosteroid use is generally well tolerated.
Use with caution in patients with diabetes, GI problems, bleeding disorders, cardiovascular disease, and psychiatric disorders.
Avoid long­ term use because of risk for osteoporosis, hypothalamic–pituitary–adrenal axis suppression, cataracts,

30. 3. COLCHICINE
Colchicine is highly effective in relieving acute gout attacks; when it is started within the first 24 hours of onset, about two thirds of patients respond within hours.
Use only within 36 hours .
SE (nausea, vomiting, and diarrhea, neutropenia and neuro-myopathy, which may be wors­ened in patients taking other myopathic drugs (eg, statins) or in renal insufficiency.

31. 3. COLCHICINE
Do not use concurrently with P­-glycoprotein or strong CYP450 3A4 inhibitors (eg, clarithromycin) because reduced biliary excretion may lead to increased plasma colchicine levels and toxicity.
Use with caution in renal or hepatic insufficiency.

32. HYPERURICEMIA IN GOUT
Recurrent gout attacks can be prevented by maintaining low uric acid levels.
Pharmacologic Therapy
After the first attack of acute gout, prophylactic pharmacotherapy is recommended if patients have two or more attacks per year, even if serum uric acid is normal or only minimally elevated, chronic kidney disease Urolithiasis, and presence of tophi.

33. Pharmacologic Therapy
Urate ­lowering therapy can be started during an acute attack if anti-inflammatory prophylaxis has been initiated.
The goal of urate ­lowering therapy is to achieve and maintain serum uric acid less than 6 mg/dL and preferably less than 5 mg/dL if signs and symptoms of gout persist.

34. Pharmacologic Therapy
Serum urate can be reduced by decreasing synthesis of uric acid (xanthine oxidase inhibitors) or by increasing renal excretion of uric acid (uricosurics).
Xanthine oxidase inhibi­tors are recommended first­line therapy; the uricosuric agent probenecid is recom­mended as alternative therapy.
In refractory cases, combination therapy is suggested.

35. XANTHINE OXIDASE INHIBITORS
Xanthine oxidase inhibitors reduce uric acid by impairing conversion of hypoxan­thine to xanthine and xanthine to uric acid.
Due to rapid mobilization of urate deposits during initiation, give concomitant therapy with colchicine or an NSAID for at least the first 8 weeks of therapy to prevent acute gout flares
Examples (Allopurinol and Febuxostat).

36. XANTHINE OXIDASE INHIBITORS

37. Allopurinol
A starting dose no greater than 100 mg daily and then gradually titrating every 2 to 5 weeks up to a maximum dose of 800 mg/day until the serum urate target is achieved.
Patients with chronic kidney disease (stage 4 or worse) should start at a dose no greater than 50 mg per day. .

38. Febuxostat
Febuxostat also lowers serum uric acid in a dose ­dependent manner.
The recommended starting dose is 40 mg once daily.
Increase the dose to 80 mg once daily for patients who do not achieve target serum uric acid concentrations after 2 weeks of therapy.

39. SE : nausea, arthralgias, and minor hepatic transaminase elevations.
Febuxostat
SE : nausea, arthralgias, and minor hepatic transaminase elevations.
Febuxostat does not require dose adjustment in mild to moderate hepatic or renal dysfunction.

40. URICOSURICS
Probenecid increases renal clearance of uric acid by inhibiting the post secretory renal proximal tubular reabsorption of uric acid.
Start therapy with uricosurics at a low dose to avoid marked uricosuria and possible stone formation.
Maintaining adequate urine flow and alkalinization of the urine during the first several days of therapy may also decrease likelihood of uric acid stone formation.

41. Pegloticase
Pegloticase is a pegylated recombinant uricase that reduces serum uric acid by converting uric acid to allantoin, which is water soluble.
Pegloticase is indicated for antihyper-uricemic therapy in adults refractory to conventional therapy.
The dose is 8mg by IV infusion over at least 2 hours every 2 weeks.

42. Pegloticase
Because of potential infusion related allergic reactions, patients must be pretreated with anti­histamines and corticosteroids.
Pegloticase is substantially more expensive than first line urate lowering therapies.
The ideal duration of Pegloticase therapy is unknown.
Development of Pegloticase antibodies resulting in loss of efficacy may limit the duration of effective therapy.

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