Treatment of Major Rheumatic Diseases

1. Treatment of Major Rheumatic Diseases Dr Tanya Potter Consultant Rheumatologist

2. Aims • 1 To pass your exam • 2 Encourage safe prescribing (and remember that have an exam in this also)

3. Rheumatoid arthritis (RA) or osteoarthritis (OA) most common types seen in clinics (& exams) • Dramatically improved treatments in past 20 yrs

4. Osteoarthritis • most common • 75% people > 70 radiographic OA F: M 2.5:1

5. Osteoarthritis • Joint space narrowing • Osteophytes • Subchondral sclerosis • Bone cysts

6. Management • Pain relief is key • Seek improvement in joint mobility or walking time • e.g. how long it takes for pt to walk to end of corridor • Quality of life- can use functional measures to see how well person is doing. Use several simple questions: • How well can dress or wash? • Can make own meals everyday? • Gives good reliable data

7. OA - Goals of Treatment • No cure • Meds can improve function by reducing pain • Can limit final impairment • Non-pharmacological and pharmacological Non-pharmacological • Patient education (education leaflets/ websites) • Wt loss (10-15 lb weight loss can reduce pain 100%) • Every lb gained, X four across weight bearing joint • PT: Muscle strengthening important -esp. quads muscle • OT: Use devices for joint protection (canes, walkers etc)

8. Drugs • Mild to moderate • Paracetamol; • Topical agents: non steroidals, rubefacients • Moderate to severe • As above, plus • NSAIDs • combination analgesics (paracet +opiods) / Opiods/ Tramadol

9. Paracetamol • Analgesic/ antipyretic • Unknown mechanism of action • combo with opiods better response when can’t use NSAIDs (gu / du/ renal/ warfarin) • Doesn’t alter platelet function (bleeding/ surgery) • Safer for elderly • 1g qds max • Caution with chronic liver dz (hepatotoxicity, > 2 gm) • Thrombocytopaenia, neutropaenia rare

10. Tramadol • Centrally acting analgesic • Use in addition to NSAID • Effects mu receptors; Same potency as opiods • Can use as adjunctive therapy • Less opiod SE; esp constipation/ nausea/ vomiting • Balance problems • smaller potential of abuse or dose acceleration, (pt needs more drug in shorter time period) c.f. opiods

11. Strong opiods • Use in pt with limited options • loss of function due to pain • renal or heart disease preventing operation • Select pt carefully • Use during period of disease flare, then decrease use • Limitations • Nausea, vomiting, constipation, ***urinary retention • Chronic use leads to physical dependence • Can use with anti-inflammatory • Lots of choice (short or long acting, patches)

12. NSAIDS • 25 million NSAID prescriptions/ yr in UK • Non selective • Aspirin • Ibuprofen • Naproxen • Indomethacin • Piroxicam • Selective cox 2 inhibiters • Celecoxib • Etoricoxib • Meloxicam • etodolac

13. NSAID risk • How many GI bleed admissions annually in the uk? • What percentage are likely to due to NSAIDs? • How many deaths annually?

14. Upper GI complications • 65,000 emergency upper GI admissions p.a. in UK • 12,000 of these admissions (including 2,230 deaths) attributable to NSAID use • Further 330 attributable deaths occur in community • ~2% of NSAID users admitted annually for GI emergencies

16. GI event may be devoid of warning symptoms Many patients asymptomatic prior to serious NSAID-associated GI event (bleeding, perforation) n = 141 n = 1,921 19% 58% 42% 81% without symptoms with symptoms

17. prostoglandins

18. NSAIDs: Inhibit cox enzymes Asthma blocked

19. Action • Reduce prostaglandin production- less inflammatory mediators • Unopposed leukotrione action • Antipyretic effects – partly due to a decrease in prostaglandin that is responsible for elevating the hypothalamic set point for temp control in fever

20. COX enzyme • Cyclo-oxygenase (COX) has two forms • COX-1 : protects the stomach lining from harsh acids and digestive chemicals. It also helps maintain kidney function • COX-2 : is produced when joints are inflamed or injured

21. Action • Different NSAID’s inhibit the enzyme by different mechanisms • Aspirin – binds covalently with a serine residue of the enzyme (irreversible) • Ibuprofen/Piroxicam – reversible competitive inhibitors of COX non selective • Paracetamol – acts partly by reducing cytoplasmic peroxidase

22. Older nonselective NSAID’s (Ibuprofen, Naproxen) • Block both COX-1 and COX-2, GI upset, bleeding as well as decreasing inflammation • Advice patients to take them with food or a glass of milk and should avoid alcohol. • Pros: • OTC version of these drugs are inexpensive • Low doses of aspirin taken over long term helps to prevent heart attacks, strokes and bowel cancer • Cons: • GI upset ie nausea, ulcers • Kidney problems from overuse • Interacts with warfarin

24. COX-2 inhibitors (Celecoxib, meloxicam, etorocoxib) • Target only the COX-2 enzyme that stimulates the inflammatory response • Pros : • less likely to cause GI upset compared to the older NSAID’s • longer lasting drug – longer relief • do not thin the blood therefore can consider co-prescription with warfarin • Cons: • More expensive compared to traditional NSAID’s • Results not as good as endoscopic drug studies suggest

25. Indications • Commonest use – arthritis ie RA or OA and gout • Back pain, sciatica, sprains and strains and rheumatism • Dental pain • Post op pain • Period pain • Renal/ureteric colic • Fever • migraines

26. CAUTIONS • Elderly • Pregnancy- miscarriage, early closure of ductus arteriosus • Breast feeding • Coagulation defects • Renal, cardiac (heart failure/ hypertension/ IHD) or hepatic impairment

27. Contraindications • Severe heart failure • COX-2 : IHD, stroke, PVD and moderate to severe heart failure • CSM advice – previous or active peptic ulceration • hypersensitivity to aspirin or any NSAID – which includes those in whom attacks of asthma, angioedema, urticaria or rhinitis have been precipitated.

28. SIDE EFFECTS • GI – N&D, dyspepsia bleeding and ulceration, • Hypersensitivity • Headaches, dizziness, nervousness, depression, drowsiness, insomnia, hearing disturbances • Photosensitivity • Fluid retention (heart failure), raise blood pressure • Hepatic damage, pancreatitis • Eye and lung changes (alveolitis) • Stevens-Johnson syndrome & toxic epidermal necrolysis (rare)

29. GI • Similar anti inflammatory effects of selective and non selective NSAIDs • Non selective: • 15-40% dyspepsia, nausea, abdo pain • 10% discontinue • Severe GI toxicity 4.5/100pt years • Selective Cox 2 inhibiters • Similar GI symptoms • < 6% discontinue • Severe toxicity 2.1/100 pt years NNT 42 to prevent 1 serious GI event

30. Cardiovascular toxicity • Increased cardiovascular risk of selective NSAIDs is a problem • unopposed pro-thrombotic effects of COX-1-mediated production of thromboxane A2 • Also, coxibs effects on blood pressure and renal function could turn out to be more detrimental than those of conventional NSAIDs.

31. prostoglandins

32. CV risk • It is a real risk ‘APPROVE’ study • Data obscured by clinical trials not recruiting ‘normal pts’ • Data obscured by drug company manipulation of the results of clinical trials • Up to 42% higher risk of MI with selective • 0.6%/yr vs 0.3%/yr

33. All NSAID/ CVS • Rise in BP 3-5mm • Equate with an increase • CCF 10-20% • CVA 20% • Angina 12% Lowest risk of all with naproxen (aspirin like effects)

34. Naproxen • Pain and inflammation in rheumatic disorders • 0.5-1g / day in 1-3 divided doses • In high risk pts, give with PPI • Which one?

35. NSAIDs - past strategies • Enteric Coating • Pro-drugs; hepatic metabolism • Gastro-protective agents:PPIs, misoprostol, H2 blockade

36. OA- Adjunctive therapy • Intra articular steroids plus local anesthetic for joint inflammation • Decrease production of inflammatory mediators • Can last a 3-6 months; use with physio • Probably can be done safely up to four times a year • not too frequently; can effect the cartilage

37. Visco-supplementation • Crosslinked hyaluronic acid polymers • OA (knee) • Intra-articular injections X 3-5 • Change viscosity in joint • Pain relief with improved mobility • Success rate is 50-70% for up to 4-6 months • no systemic SE

38. Visco-supplementation • OA, where physio, weight loss, simple analgesia +/- NSAIDs insufficient • & IA steroids not helpful /not lasting • Awaiting/ unfit for surgery

39. Capcaisin cream • 0.025% preparation (Zacin) • Depletes Substance P from nerve endings • Slow to act (1/12 to max effect) • More effective than topical NSAIDs • May reduce analgesic requirement

40. What are the alternatives? • Cod liver oil & other fishy oils • Evening primrose oil • Borage or Starflower oil • Change in balance of cell membrane fatty acids

41. Alternatives? • Glucosamine 1.5 gram/day • substrate for glucosaminoglycans • Pain relief & mobility • Possible 10-25% analgesic effect • -disease modifier ? • ? Nutrition for cartilage • ? Stimulate metabolism • Vitamin C • Framingham study results show reduced pain OA of knee & hip • may improve integrity of cartilage

42. 0 of 120 Approximately how many upper GI admissions are attributable to NSAID use in the UK per annum? • 3000 • 6000 • 12000 • 24000

44. Gout • Joint inflammation caused by uric acid crystal deposits in the joint space

45. Gout • Primary • Over production (10%) • Under secretion (90%) • Enzyme mutations • Predominantly secondary • Overproduction (mutations, heavy exercise, obesity) • Under excretion severe renal diseases, drugs, alcohol, HBP

46. 2-17% of population are hyperuricaemic • The higher the uric acid the higher the chance of gout • Self reported adult prevalence of 8/1000 • 2-7M:1F • Increase in blacks may reflect increased rates of hypertension

47. Figure 4 Simplified diagram of uric acid production and excretion 1/3 2/3 2/3 1/3 Roddy E et al. (2007) The changing epidemiology of gout Nat Clin Pract Rheumatol3: 443–449 doi:10.1038/ncprheum0556

49. Epidemiology • Middle aged men • Dietary purine consumption • Alcohol • Drugs:Low dose aspirin, diuretics • Inherited metabolic abnormalities

50. Clinical features • Gouty Tophi on pinnae • Olecranon bursitis • Gouty tophi on hands • Gouty nephropathy& stones • Large joint oligoarthritis • 1st metatarsophalangeal joint arthritis‘podagra’