The Painful Gout - A Disease of The King

Introduction on Gout with outline of management of acute and chronic gout.

1. FARAH ADIBAH KASMIN MMED UITM RHEUMATOLOGY UNIT HOSPITAL SELAYANG MALAYSIA 14.6.2024

2. Case Study 51 years old Male, non alcoholic drinker Underlying 1. Hypertension 2. CKD V secondary to bilateral renal calculi 3. Gout First presentation in 2012, when he had sudden acute pain with redness at the right big toe. He seek treatment at GP and given analgesic. Since 2020, developed worsening pain with multiple tophi at bilateral UL and LL joint. He went to Klinik Kesihatan and started with T Allopurinol 100mg OD as the uric acid was high.

3. Presenting complaint: Fever x1/12 Joint pain and redness of the tophi of bilateral UL and LL x1/12 Pus discharge from the ruptured tophi of the 2 nd left toe x3/7 Further history, Gouty attack triggered by seafood and red meat.

4. On examination: Multiple tophi seen at: Left UL: Shoulder, elbow, forearm, wrist, 2 nd MCP joint, PIP joint of the thumb Right UL: Shoulder, elbow, wrist, IPJ 2nd-4th digit Right LL: Lateral and medial ankle, 1 st MTP joint Left LL: Knee, lateral and medial ankle, 1 ST MTP joint Redness, warm, tender and pus discharge over right elbow and left 2 nd toe. Right knee: Swollen, tender, limited ROM

5. Investigation: Hb 10. 1 WBC 18.7 Platelet 333 RP 122/5.3/23/731 Uric acid 530 Xray

6. Diagnosis: Acute flare of polyarticular gouty arthritis Sepsis secondary to infected tophi Chronic tophaceous gout

7. Further investigation: USG MSK of right knee Supratellar effusion with synovial thickening Double contour sign Proceeded with right knee tapping under aseptic technique 30cc chalky cream fluid aspirated 2cc Lignocaine administered - Sent for gram stain, culture and sensitivity

8. Management: Admit ward Septic work up IV Unasyn 3g OD T Prednisolone 30mg OD T Allopurinol 100mg OD IV Tramal 50mg TDS T Paracetamol 1g TDS

9. Point to discuss from this case: How do we treat acute flare of gout? What is the management of chronic gout? What are the urate lowering therapy(ULT) available? How do we select the ULT?

10. Discussion Introduction Definition and epidemiology Pathogenesis Clinical presentation Investigation Management

11. Introduction Gout is one of the oldest joint disease. Early record was dated back to 2640 before century (B.C) by the Egyptian. It is known as “Disease of Kings" because of the lavish diet and alcohol consumption of the wealthy, like King Henry VIII. Most common form of inflammatory arthritis in 21 st century

12. Definition and Epidemiology Gout is a disease caused by the deposition of monosodium urate crystals in articular and non-articular structures. It is a consequence of persistent hyperuricaemia . Men affected more than women From a hospital-based study in Malaysia, peak onset of gout is 30-60 years old. The gout prevalence increased from 2.7% to 6.7% in countries with a Western lifestyle.

13. Pathogenesis

14. 3 classic clinical stages Gout flare Intercritical gout Chronic gouthy arthritis Defined as a clinically evident episode of acute inflammation induced by MSU crystals. Occurs abruptly with joint pain peaking in intensity within 24 hours and resolves spontaneously within 1 - 2 week. Symptoms: Acute arthritis with joint pain, swelling, warmth, redness and movement difficulty. Systemic symptoms such as fever may present. Defined as asymptomatic period after or between gout flares, despite the persistence of MSU crystals. Defined as persistent joint inflammation induced by MSU crystals. Characterised by chronic arthritis, with or without tophi, chronic joint pain, functional disability, structural joint destruction, deformity and repeated flares.

15. Stages CPG Management of gout- Second Edition

16. Precipitants of acute gouty arthritis Joint trauma Surgery Initiation of urate- lowering therapy (ULT) Medication Acute illness CPG Management of gout- Second Edition

17. Comorbidities Comorbidities are common in people with gout which may complicate the disease management and outcomes. Risk of developing incident comorbidities was higher in patients with gout in the following diseases. - Congestive cardiac failure - Myocardial infarction - Hypertension - Hyperlipidaemia - Renal diseases - COPD - Urolithiasis -Diabetes Mellitus - Hypothyroidism -Liver disease CPG Management of gout- Second Edition

18. Lab investigation Gold standard: Demonstration of MSU (negative birefringent) crystals in SF or tophus aspirate.

19. Clinical features, lab investigations and imaging can be used if synovial fluid is not available. Diagnosis of gout should not be made based on hyperuricaemia alone. The cut off level of serum urate for hyperuricaemia is 408 μ mol/L. However, a normal or low serum urate during flare does not exclude gout. Other useful test include FBC, RP, LFT, UFEME.

20. Imaging Xray - Changes in plain radiograph take several years to develop. Bone erosions with overhanging edges and a sclerotic rim (A) Bone proliferation (B) Joint space narrowing (C) Soft tissue masses (tophi), which can be calcified (D)

21. Imaging Ultrasound - Useful in assisting the diagnosis of gout especially when the presentation is atypical and microscopic demonstration of MSU crystals is not feasible. Double- contour sign A deposition of monosodium urate crystals on the surface of hyaline articular cartilage.

22. Management Acute Gout Flare What is the mainstay of treatment? Pain relieve as early as possible

23. Pharmacological What is the choice of drug?

24. Colchicine A. For gout flare Must be taken within 12 hours onset of pain. Recommended dose: Loading dose of 1 mg, then 0.5mg 1 hour later for first day therapy. Subsequently, the dose may be reduced to 0.5 mg twice daily until 48 hours after the resolution of the flare. After completion of a course, another course should not be started for at least 3 days (72 hours) The AGREE trial showed colchicine taken within 12 hours of flare onset, self-administrated low-dose colchicine (1.8 mg) was as effective as high-dose colchicine (4.8 mg) but with a safety profile comparable to that of a placebo.

25. Colchicine B. For flare prophylaxis - Dispersion of MSU crystals during the initial phase of deposit dissolution may expose the patient to increased rate of acute flare. Recommended during the first 6 months of ULT. The dose is 0.5 mg OD or BD. C. For gout flare during prophylaxis - Do not exceed 1 mg at the first sign of flare, followed by 0.5mg 1 hour later. - Wait for 12 hours and then resume prophylactic dose.

26. Colchicine Possible AEs Contraindication/ Caution Common drug interaction* Common: • Gastrointestinal Nausea, vomiting, diarrhea Serious: • Hematologic Myelosuppression • Neuromuscular and skeletal Neuromuscular disease, neuromyotoxicity Contraindications: • Concomitant use of P- glycoprotein or CYP3A4 inhibitors in patients with renal or hepatic impairment • Patients with both renal and hepatic impairment • Blood dyscrasia • CYP3A4 inhibitor/P-GP inhibitor Increased risk of toxicity • Statin/fibrates/ digoxin/ ciclosporin Increased risk of myopathy and rhabdomyolysis

27. Colchicine Dosage Modification *Use of colchicine to treat gout flares is not recommended in patients with renal impairment ( CrCl <80 ml/min) already receiving prophylactic colchicine.

28. Colchicine Dosage Modification **Use of colchicine to treat gout flares is not recommended in patients with hepatic impairment already receiving prophylactic colchicine.

29. NSAIDS/COX-2i Most effective when treatment is initiated within 48 hours of the onset of symptoms.

30. NSAIDS/COX-2i In cases where patient contraindicated for NSAIDs/ COX-2 inhibitors tramadol can be considered .

31. Corticosteroid Several randomized trials comparing glucocorticoids with NSAIDs for gout flares demonstrate that glucocorticoids are at least as efficacious as NSAIDs and may be associated with fewer serious adverse outcomes. Recommended dose for treatment of gout flare: - Prednisolone 30 to 40 mg/day once daily or in 2 divided doses for 5 days. - If a longer duration is needed for more severe flare, a gradual taper over 7 to 10 days is an option. A slower taper (over 14 to 21 days) maybe required, particularly in patients with multiple recent flares. IV Hydrocortisone may be considered in severe polyarticular gouty arthritis.

32. Corticosteroid

33. Corticosteroid

34. Interleukin-1 inhibitor IL-1 is an important mediator of gouty inflammation and a therapeutic target in gout flares. Example of IL-1i is  Canakinumab. It has been ap proved by European and US for patients who have at least three flares annually that cannot be managed with other treatment options. However, Canakinumab is not readily accessible in Malaysia due to its cost.

35. Combination therapy The British Society for Rheumatology Guideline for the Management of Gout, 2017. CPG Management of Gout- Second Edition

36. Non pharmacological 1. Health education / behavioural intervention 2. Lifestyle modification Weight reduction L imitation of intake of purine-rich food except Omega-3 polyunsaturated fatty acids (PUFA). Limitation of all type alcohol consumption, high fructose corn syrup. Encourage cherry intake, stay well hydrated and cease smoking. 3. Topical ice

37. Ice pack Application of ice as adjuvant therapy. It should always be applied over a cloth and not directly onto the skin of the affected joint . The affected joints should be rested, elevated and exposed in a cool environment.

38. Can we start ULT during flare? Historically, i t has been recommended that ULT is commenced at least 2 weeks, often later, following complete resolution of a gout flare. Hill(2015): N: 37 Allopurinol (N:16) - 100mg OD for the first 14 days, then increased to 200mg daily for the next 14 days.  Placebo (N:19) Outcome:   S tatistically insignificant difference in days to resolution Taylor(2012): N: 57 Allopurinol (N:31) – Allopurinol 300mg OD for 10 days Placebo (N:26) – With indomethacin and colchicine Outcome:  Mean daily VAS pain scores did not differ significantly between study groups at any point between days 1 and 10. 

39. Treat to Target Strategy In two years RCT, treat to target (T2T) aiming for SU <360 umol /L in gout patient. A lower SU target of <5 mg/dl (<300 umol /L) for faster dissolution of crystals is recommended in severe gout (tophi, chronic arthropathy, frequent flares). Some studies suggested that urate might be protective against various neurodegenerative diseases, therefore prolonged SU <3 mg/dl (<180 umol /L) is not recommended. T2T target aiming SU less than 360 umol /L were also recommended by EULAR, ACR and BSR for all gout patients receiving ULT.

40. Management of Chronic Gout

41. What are the indications to start ULT? CPG Management of Gout- Second Edition 2020 ACR guideline for Gout

42. What are the urate lowering therapy?(ULT) Uricostatic First- line pharmacologic ULT Xanthine-oxidase inhibitor Allopurinol Febuxostat Uricosuric Contraindicated in urolithiasis and uric acid overproduction (elevated urine uric acid) Options Probenecid Benzbromarone Sulfinpyrazone Losartan Fenofibrate Uricolytics Recommended in severe gout disease burden and refractoriness to, or intolerance of, conventional and appropriately dose ULT Options Pegloticase Rasburicase Converts uric acid to allantoin, a water- soluble substance easily excreted by the body CPG Management of gout- Second Edition

43. Allopurinol Starts low and slow.

44. Characteristics Rash Eosinophilia Leucocytosis Fever Hepatitis Progressive kidney failure Risk factors Higher allopurinol starting dose Presence of renal impairment HLA- B*58:01 positivity Concomitant diuretics Mortality rates AHS: 9- 20% SJS/TEN: up to 34% DRESS: 10% Time from exposure Median: 30 days 90% occur during the first 8- 9 weeks (up to 180 days) Stamp, L. K., Day, R. O., & Yun, J. (2015). Allopurinol hypersensitivity: investigating the cause and minimizing the risk. Nature Reviews Rheumatology, 12(4), 235–242. doi:10.1038/nrrheum.2015.132 Allopurinol Hypersensitivity Syndrome (AHS) Prevalence of MPE: 2% Prevalence of AHS: 0.1%

45. HLA- B*58:01 screening ACR 2020 Background data Recommendations for screening Prevalence of HLA-B*58:01 Han Chinese, Thai, Japanese (7.4%) African Americans (3.8%) Whites/Hispanics (0.7%) Risk of AHS with HLA- B*58:01 positivity No renal impairment: <2.7% With renal impairment: 18% Stamp, L. K., Day, R. O., & Yun, J. (2015). Allopurinol hypersensitivity: investigating the cause and minimizing the risk. Nature Reviews Rheumatology, 12(4), 235–242. doi:10.1038/nrrheum.2015.132 ACR 2020 : Conditionally recommended for SE Asians EULAR 2016 : Prescriber’s discretion Malaysian CPG 2021 : Routine screening NOT recommended

46. Febuxostat Non purine XOI Indication to switch: Intolerance to Allopurinol Unable to achieve target SUA with Allopurinol Safe in those with: Mild to moderate renal impairment Liver impairment Child Pugh A-B

47. Febuxostat

48. Febuxostat vs Allopurinol? Primary outcome: 36.5% of participants treated with titrated dose allopurinol experienced one or more flares compared with 43.5% of participants treated with febuxostat; (P< 0.001 for noninferiority of allopurinol).

49. Febuxostat safety? Febuxostat is non-inferior to allopurinol for the primary cardiovascular endpoint, and its long-term use is not associated with an increased risk of death or serious adverse events.

50. Uricosuric agent Can be used in p atient intolerant to XOI. Used as combination wit XOI when SUA is not achieved. However, it is contraindicated in patients with urolithiasis and severe renal impairment .

51. Uricolytic Pegloticase ACR 2020 recommended to switch to Pegloticase in: Patients with gout where XOI, uricosurics, and other interventions have failed to achieve SU target and have frequent gout flares or non resolving subcutaneous tophi. IV 8mg in 250ml NS over 2hours every 2 weeks, pre-treatment with antihistamines and steroids. SUA measured before each infusion. Contraindicated in patients with G6PD deficiency because of the risk of haemolysis . Extra caution required in patients with CCF

52. What about in Asymptomatic Hyperuricemia? Definition: SUA >6.8mg/dL (404umol/L) No previous gout flare No subcutaneous tophi First flare in the absence of comorbidities – uncomplicated gout

53. Should they be treated with ULT? 24 patients would need to be treated with ULT for 3 years to prevent a single (incident) gout flare. Secondary outcome: I ncidence of gouty arthritis was significantly lower (P=0.007) in the Febuxostat group (0.91%) than in the placebo group (5.86%).

54. ACR recommended against initiating any pharmacologic ULT as the benefits would not outweigh the potential treatment cost or risk for the large number of patients unlikely to progress to gout.

55. When to make a referral?

56. Thank you.