RA and gout treatment overview
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This document discusses rheumatoid arthritis and gout. It provides information on the pathogenesis, clinical presentation, diagnosis and management of these conditions. It lists various disease-modifying antirheumatic drugs and biological agents used to treat rheumatoid arthritis, along with their mechanisms of action, dosing and side effects. It also discusses the evaluation and treatment of acute and chronic gout, including use of colchicine, NSAIDs, allopurinol and febuxostat.
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RA and gout treatment overview
- 1. Rheumatoid arthritisRheumatoid arthritis and goutand gout . Prof Dr Lokendra SharmaProf Dr Lokendra Sharma Department of Pharmacology, SMS Medical College Jaipur
- 2. Early RA: First few months of symptoms
- 4. Rheumatoid Arthritis: Hands 5 Months of Disease 5 Years of Disease
- 5. Rheumatoid Arthritis: 10 Years Later
- 7. Rheumatoid Arthritis: A systemic autoimmune disease unknown cause Synovial tissues proliferate erosions of bone.
- 9. RA Epidemiology: 2x4 time women child-bearing age ‘Rare’ in men < 45 years On the Terrace, 1878
- 10. DMARDs Conventional Methotrexate Hydrochloroquine Sulfasalazine Leflunomide Gold Azathioprine Minocycline Cyclophasphamide – severe RA Biologicals Etanercept Infliximab Anakinra Adalimumab Abatacept Rituximab Prosorba column- severe RA,Psoriatic A
- 11. DMARDS Mechanism AE & Risk Approximate time to benefit Month/weak Dose Comments/ MCQ Diet Glucosemene & condrotin Pain relief Methotrexate Antimetobolite DNA Synthsis Cell division Hepatoxicity, Myelotoxioity fibrosing alveolitis 1-2M 5- 25mg/ wk Ist line Sulfasalazine Antimetabolite & Antimalarial Hepatoxicity, myelotoxicity Hypersensitivi ty reactions 1-3M 2- 4g/day Oligospermia, Pro drug
- 12. DMARDS AE & Risk Appoxim ate time to benefit Month/w eak Dose Comment/ MCQ Antimalarial (Hydrochloro quine) Interfere with Antigen processing Retinopathy Macular damage (HCQ) 2-6 M 200-400 mg/day Leflunamide Blocks T- Cell division Hepatotoxicity, Myelotoxicity, Hypertension 4-12 wk 10- 20mg/day Gold salt (Parentral) unknown Hypersensitivity, Nephritis fibrosing alveolitis 3-6M 50mg/mon th 1m Auranofin (Oral Gold) unknown Diarrhoea, Hypersencentivity reaction 4-6m 3mg twice a day Cyclosporin T-cell activity intibitor Nephrotoxicity, Hypertension 6-12wk 150- 300mg/day Severe active RA not responde MTX
- 13. DMARDS AE & Risk Appoximate time to benefit Month/wea k Doge MCQ Azathioprime Cytostatic Hapatotoxicity, Myelotoxicle Gastrointestinal 2-3m 50- 150mg/ day Not1st line, active RA, with SLA Bucillamine Proteinuria, Hepatotoxic, Mylosupression 1-3m 100- 200mg/ day Tacrolimus Renal insuff, HT, Anemia, Impaired glucose tolerance 6-12 wk 3mg/da y D- Penicillamine Unknown alter T-cell function Myelosuph, proteinurea, Nephrotoxic 3-6m 250- 750mg/ day Persistent active disease Minocycline Hyperpigmintation, dizziness,vaginal yeast infection 1-3m 100mg BD
- 14. Biological DMARDS Anti – TNFx Dose Command Structure Use Anti TNFx SE Etanercept Infliximab Adalimumab Certolizumab Golimumab 50mg/wk/sc 3mg/kg/8wk 40mg/2wk sc 200 mg/2wk sc 50mg/4wk sc Decoy (R) for TNFx RA & Crohns dz antibody to TNF given with MTX Human fusion protein Mouse/hum an MaB Fully human MaB RA, JRA, Psoritic arthritis ankylosing spondelyti s crohns disease Infection CHF Neurological Malignancy Autoimmunity Hematological Hypersencitivity Anti-B-cell therapy Rituximab 1000mg/repea t after 2 wk Premedication Methylprednis olone Chlorphenara mine PCM
- 15. Biological DMARDSAnti – TNFx Dose Command Structure Inhibitory of T-cell activation abatacept 125mg sc/wk Favorable safety profile Anti-1L6 Tocilizumab 8mg/kg/4wk More effective than anti TNF in MTx intolerant patients Anti 1L-1 blocking agent Anakinra IL-1 trap 100 mg /sc /daily Phase I Less effective Recombinant form of human 1L-1 Ra
- 16. Extra-articular RA • Subcutaneous nodules • Pleural/Pericardial Disease • Sjogren’s Syndrome • Felty’s Syndrome • Vasculitis
- 17. Joint Distribution: RA Compared to OA Rheumatoid Arthritis Osteoarthritis
- 18. Stevens-Johnson syndrome target skin lesions mucous membrane erosions epidermal necrosis with skin detachment
- 19. Redness and Swelling of Acute Gouty Attack http://medicine.ucsd.edu/clinicalimg/extremities-gout.jpg
- 20. Tophaceous Deposits of Urate http://arthritis.about.com/od/goutdiag/
- 21. Gout - acute arthritis acute synovitis, ankle & first MTP joints
- 22. Gout - acute bursitis acute olecranon bursitis
- 23. Gout - acute arthritis acute synovitis, ankle & first MTP joints Arthrocentesis
- 24. Chronic tophaceous gout tophus = localized deposit of monosodium urate crystals
- 25. Gout - tophus Classic location of tophi on helix of ear
- 26. Gout - X-ray changes DIP joint destruction phalangeal bone cysts
- 27. Gout - X-ray changes bony erosions
- 29. Drugs Used for Therapy of GoutDrugs Used for Therapy of Gout N N NH N OH HO O N N NH N OH HO OH pKa 5.6
- 30. DMARDS Mechanism AE & Risk Use Colchicine Interfere with PMN Gastrointestinal Hamatological (agran& apla)Muscle weekness High dose acute gout with allopurinol and probenacid Low dose prevent recurence NSAID Inhibit PG Probenacid Inhibit urate excretion Induce acute attach Decrese secretion of anionic drugs Allopurinol 100 &300mg Inhibit xanthine oxidase Rash ,abn liver function,GIT ,marrow supp,vasculitis,Toxic epi nec Chronic Gout With chemotherapy Recurrent renal Ca oxalate stone Febuxostat Oral xanthine oxidase inhibitors Minimal ADR use in renal patient
- 31. Drugs Increasing Risk of Toxicity Macrolide antibiotic Azole antifungals Calcium channel blockers Amiodarone Cyclosporin Statins
- 33. Estimation of 24-hr Urinary Uric Acid Indications: Gout in –men less than 25 years –premenopausal women
- 34. Urate Lowering Therapy: Indications… >3 attacks per year 2/yr if disabling, prolonged, interferes with ADL Clinical or radiographic signs of chronic gouty joint disease Gout with renal insufficiency Urinary uric acid excretion >1100 mg/day (6.5 mmol)
- 35. Urate Lowering Therapy: Indications Serum uric acid persistently >10.1 Tophi in soft tissues or subchondral bone Recurrent urate urolithiasis ? Strong family history of gout
- 36. Goals of Therapy Serum urate <6 mg/dL (<357 µmol/L) <5 mg/dL (<297 µmol/L) in patients with tophi A fall of <0.6 mg/mo ensures recurrence free achievement of target
- 37. General Principles Should not be initiated during an attack Conventional interval: 4 wk Exceptions: Inter-critical interval <4 wk Chronic tophaceous gout Titrated against serum urate at 3 to 4 wks Treatment should be Continuous Duration: indefinite
- 38. Choice of Drugs Xanthine oxidase inhibitors: allopurinol, febuxostat Uricosuric drugs: probenecid, sulfinpyrazone, benzbromarone Uricase: pegloticase (porcine), rasburicase (recombinant)
- 39. Allopurinol Urate-lowering drug of general choice Particularly suitable for overproducers Started with 100 mg/day single dose after meals with plenty of fluid Doses >300 mg divided Increased at 2 to 3 wks by 100 mg till target reached Maximum: 900 mg/day Monitoring parameters CBC, serum uric acid, ALT, S Cr, at start of therapy
- 40. Allopurinol: Adverse Effects Diarrhea, and drug fever Rashes, rarely TEN and Steven Johnsons Association: HLA- B*5801 Leukopenia or thrombocytopenia Interstitial nephritis, vasculitis Allopurinol hypersensitivity syndrome (AHS): erythematous rash, fever, eosinophilia, hepatitis, and acute renal failure Rare but life-threatening, mortality 25%
- 41. Starting Dose and Titration of Allopurinol on eGFR eGFR Starting dose Titration ≥60 ml/min 100 mg/day 100 mg every 2-3 wk 30-59 ml/min 100 mg/day 50 mg every 2-3 wk 10-29 ml/min 50 mg/day 50 mg every 2-3 wk
- 42. Rational Treatment in Two Phases:Rational Treatment in Two Phases: Phase I – control pain and inflammation: NSAIDs (ibuprofen – may use indomethacin) or colchicine Phase II – decrease the serum urate (< 4.0 mg/dL) > 800 mg in 24 hr urine suggests overproduction – use allopurinol < 500 mg in 24 hr urine suggests decreased renal clearance – use probenecid
- 43. Febuxostat investigational agent (NDA 12/2004) oral xanthine oxidase inhibitor chemically distinct from allopurinol 94% of patients reached urate < 6.0 mg/dl minimal adverse events can be used in patients with renal disease
- 44. Febuxostat… Indications: Intolerance/allergy to allopurinol Mild to moderate CKD 40 mg produces a reduction equivalent to 300 mg allopurinol Started at 40 mg/day Increased to 80 mg if target not reached after 2 wks Maximum recommended dose 120 mg
- 46. Uricosuric Drugs Indication: Intolerance to allopurinol Requisite: 24-hr urinary uric acid <800 mg Contra-indications: Nephrolithiasis or uric acid nephropathy Uric acid overproduction Renal insufficiency Extensive tophi
- 52. 6. All of the following drugs can produce hyperuricemia EXCEPT a. Ethambutol b. Pyrazinamide c. Sulfinpyrazone d. Hydrochlorothiazide ©
- 53. 7. Drug of choice for acute gout is a. Colchicine b. Indomethacin c. Allopurinol d. Dexamethasone (b)
- 54. 8. Most common dose limiting adverse effect of colchicine is a. Sedation b. Kidney damage c. Diarrhea d. Muscle paralysis ©
- 55. 9. Which of the following drugs is useful in chronic gout but is NOT a uricosuric agent? a. Probenecid b. Phenylbutazone c. Sulfinpyrazone d. Allopurinol (d)
- 56. 10. Allopurinol is useful in all of the following conditions EXCEPT a. Cancer chemotherapy induced hyperuricemia b. Hydrochlorothiazide induced hyperuricemia c. Acute gouty arthritis d. Kala –azar ©
- 57. 11. Rasburicase is a newer drug used in gout. It act by a. Decreasing urate synthesis b. Increasing urate oxidation c. Decreasing intestinal absorption of uric acid d. Increasing renal excretion of uric acid (b)
- 58. 12. A drug that is effective for rheumatoid arthritis but is not appropriate for osteoarthritis is a. Acetaminophen b. Infliximab c. Keterolac d. Rofecoxib (b)
- 59. 13. Among NSAIDs aspirin is unique because it a. Irreversibly inhibits its target enzyme b. Reduces the risk of colon cancer c. Reduces fever d. Selectively inhibits COX-2 enzyme (a)
- 60. 14. Most specific drug for the treatment of peptic ulcer caused due to chronic use of NSAIDs is a. Rabeprazole b. Loxatidine c. Misoprostol d. Esomeprazole ©
- 61. 15. A drug X is useful in the treatment of rheumatoid arthritis. It is available only in parenteral formulation and its mechanism of action is antagonism of tumor necrosis factor. Which of the following can be X? a. Cyclosporine b. Penicillamine c. Phenylbutazone d. Etanercept (d)
- 62. 16. Which of the following increases uric acid excretion? a. Allopurinol b. Aspirin c. Colchicine d. Probenecid (d)
- 63. 17. True about COX-2 are all EXCEPT a. Furosemide b. Sulfinpyrazone c. Allopurinol d. Piroxicam (d)
- 64. 18. Allopurinol potentiates the action of a. Corticosteroids b. Probenecid c. 6-Mercaptopurine d. Ampicillin ©
- 65. 19. Probenecid interacts with a. Streptomycin b. Ampicillin c. Vancomycin d. Erythromycin (b)
- 66. 20. Drug useful for gout a. Pyrazinamide b. Rifampicin c. Allopurinol d. Naloxone ©
- 67. 21. Loading dose of leflunomide in rheumatoid arthritis is a. 20 mg b. 10 mg c. 100 mg d. 400 mg (c)
- 68. Thanks
Editor's Notes
- Rheumatoid arthritis (chronic progressive crippling dz) and gout
- Small lumps, called rheumatoid nodules, may form under your skin at pressure points, and can occur at your elbows, hands, feet and Achilles tendons. Rheumatoid nodules may also occur elsewhere, including the back of your scalp, over your knee or even in your lungs. These nodules can range in size — from as small as a pea to as large as a walnut. Usually these lumps aren&apos;t painful.
- A systemic autoimmune disease of unknown cause with its primary manifestation in synovial tissues. Synovial tissues proliferate in an uncontrolled fashion resulting in stretching of tendon and ligaments and erosions of bone.
- Two to four times more common in women Highest incidence in women of child-bearing age ‘Rare’ in men &lt; 45 years Role of sex hormones… Remission in pregnancy Increased risk in postpartum Oral contraceptives
- Drugs that have the ability to slow or halt progression of RA; including radiographic progression