1. NSAIDs, Rheumatoid Arthritis, & Osteoarthritis: A Case Approach Bobo Tanner MD Rheumatology & Allergy Monday Feb 19, 2007 VMS IV

2. AGENDA Differentiate RA & OA Therapeutic Choices Case based examples Treat Early & Monitor Monitor for Benefit & Side Effects

3. Case 1 65-year-old man: knee pain that began insidiously about a year ago. No other rheumatic symptoms. PMHx: PUD, ischemic heart dz, sulfa allergy What further questions should you ask? What are the pertinent physical findings? Which diagnostic studies are appropriate?

4. Inflammatory vs. Mechanical RA History & PE AM stiffness >1 hr. Symmetrical swelling, tenderness: wrists, MCPs, PIPs Labs 45-85% +RF, +CCP Ab ESR,C-RP, Hct X-rays JSN erosions OA History & PE Worse pain w/activity DIPs, 1st CMC, wt.bearing jts. Labs Medication monitoring CBC,BMP,UA X-rays Osteophytes, asymmetry, sclerosis

5. Therapeutic Options RA NSAIDs Corticosteroids DMARDs Biologic DMARDs Also: Joint Injections PT/OT Surgery SLE Steroids Anti-malarial Immunosuppressive OA Analgesics NSAIDs Also: Joint injections PT/OT Surgery Nutritional supplements

8. Case 1: Radiographic Features Asymmetric joint space narrowing Marginal osteophytes Subchondral cysts Bony sclerosis Malalignment NAILS THE DIAGNOSIS

9. OA: Risk Factors Why did this patient develop osteoarthritis?

10. OA: Risk Factors (cont’d) Age: 75% of persons over age 70 have OA Female sex Obesity Hereditary Trauma Neuromuscular dysfunction Metabolic disorders

11. Case 1: Cause of Knee OA On further questioning, patient recalls a serious knee injury during high school football Therefore, posttraumatic OA is most likely diagnosis

12. Pharmacologic Management of OA NSAIDs Non-opioid analgesics Topical agents Opioid analgesics Intra-articular agents Unconventional therapies

13. NSAIDs Inhibit prostaglandin synthesis & other Account for ½ the Rx in the elderly If no response to one may respond to another Lower doses may be effective Do not retard disease progression

15. NSAIDs (cont’d) Side effects: GI, renal, cardiac, edema Severe side effects <5%, but large numbers of users Gastroprotection increases expense Antiplatelet effects may be hazardous GI tolerance much better with COX-2 C-V events overshadow COX-2

16. Non-opioid Analgesic Therapy Acetaminophen Pain relief comparable to NSAIDs, less toxicity Beware of toxicity from use of multiple acetaminophen-containing products Maximum safe dose = 4 grams/day Lifetime dose & toxicity?

17. * P<.05 Bradley, et al. N Engl J Med. 1991;325:87–91. Ibuprofen vs Acetaminophen for Knee OA—Equivalent Benefit

18. Celecoxcib vs Acetaminophen for Hip & Knee OA—Pincus data PACES trial Patient preferences: 53% celecoxib (200mg) vs 24% acetaminophen(4 gm) PACES-a (p<0.001) 37% acetaminophen v 28% placebo in PACES-a (p = 0.340) Ann Rheum Dis. 2004 Aug;63(8):931-9

19. OA: Nutritional Supplements Polysulfated glycosaminoglycans— nutriceuticals Glucosamine +/- chondroitin sulfate: Symptomatic benefit, no known side effects, long-term controlled trials pending

20. Knee Injection Knee fully extended Junction upper third and lower two thirds of the patella Insert needle under patella and aim superiorly © ACR

21. OA: Intra-articular Therapy Intra-articular steroids Pain relief Up to q 3 mo Risks: infection, worsening diabetes, or CHF Joint lavage Symptomatic benefit demonstrated Hyaluronate injections* Synvisc ®, Hylgan® Symptomatic relief Improved function $$$$$$$ Series of injections, fail steroids first? No evidence of long- term benefit Knees, other? * Altman, et al. J Rheumatol. 1998;25:2203.

22. Physical Therapy Prescribe progressive exercise to Increase function Increase endurance and strength Reduce fall risk Patient education: Self-Help Course Weight loss Heat/cold modalities Rogind, et al. Arch Phys Med Rehabil. 1998;79:1421–1427. Jette, et al. Am J Public Health. 1999;89:66–72

23. Strengthening Exercise for OA Decreases pain and increases function Physical training rather than passive therapy General program for muscle strengthening Warm-up with ROM stretching Step 1:Lift the body part against gravity, begin with 6 to 10 repetitions Step 2:Progressively increase resistance with free weights or elastic bands Cool-down with ROM stretching Rogind, et al. Arch Phys Med Rehabil. 1998;79:1421–1427. Jette, et al. Am J Public Health. 1999;89:66–72.

24. Surgical Therapy for OA Arthroscopy May reveal unsuspected focal abnormalities Results in tidal lavage Expensive, complications possible Osteotomy: May delay need for TKR for 2 to 3 years Total joint replacement: for severe pain and function significantly limited

26. Case 2: Rheumatoid Arthritis 53-year-old woman with 6 months history of RA sx Morning stiffness = 30 minutes Synovitis: 1+ swelling of MCP, PIP, wrist, and MTP joints Normal joint alignment Rheumatoid factor positive, anti-CCP + No erosions seen on x-rays

27. Rheumatoid Arthritis: Treat Early & Prevent Damage & Dysfunction Ulnar deviation of R hand MCP & PIP swelling synovitis of left wrist Joint space narrowing & erosions on x-ray Synovial thickening feels like a firm sponge

28. Case 2 (cont’d) Assessment Rheumatoid Arthritis No sign of damage Treatment NSAID, steroid, DMARD Education + ROM, conditioning, and strengthening exercises Which DMARD would you choose?

29. Rheumatoid Arthritis: Drug Treatment Options NSAIDs –Symptomatic relief, improved function –No change in disease progression Low-dose prednisone (  10 mg qd) –If used long term, consider prophylactic treatment for osteoporosis Intra-articular steroids –Useful for flares Paget. Primer on Rheum Dis. 11th edition. 1997:168.

30. Rheumatoid Arthritis: Disease modifying drugs (DMARDs) –Hydroxychloroquine (Plaquenil®) Modest effect, low toxicity –Sulfasalazine Moderate effect, monitor like MTX –Methotrexate Most effective single DMARD Good benefit-to-risk ratio –Leflunomide (Arava®) Effect & side effects similar to MTX Combinations Alarcon. Rheum Dis Clin North Am. 1998;24:489–499. Paget. Primer on Rheum Dis. 11th edition. 1997:168.

31. Rheumatoid Arthritis: Monitoring Treatment With DMARDs These drugs need frequent monitoring Blood, liver, lung, kidney,skin are frequent sites of adverse effects √ CBC,LFTs, creatinine, urine Lab intervals: 4 to 12 weeks commonly Most patients need to be seen 3 to 6 times a year

32. Biologic DMARDs Anti-TNF –Etanercept (Enbrel®) 50mg SQ weekly –Infliximab (Remicade®) IV q 8 weeks –Adalimumab (Humira®) 40mg SQ QOW –Rapid onset, effective in refractory patients with and w/o MTX, halts bone erosions –Screen for Tb, infections, expensive Also –Anakinra (Kineret®), daily SQ, inj. anti-IL-1 –Abatacept (Orencia®), IV monthly, T cell 2 nd sig. –Rituximab ( Rituxan®) IV x 2, TNF failure, B cells Fleischmann. Rheum Dis Clin North Am. 2006;32(1):21-28.

33. Early Intervention Is Effective in RA Early Intervention Is Effective in RA Several studies collectively provide clear evidence that delayed use of DMARD therapy in RA may adversely affect clinical and radiographic outcomes Treatment should be initiated within months of the diagnosis, not years

34. Short Delay of Therapy Affected Joint Damage Lard LR, et al. Am J Med. 2001;111:446-451. Time (months) 0 2 4 6 8 10 12 14 06121824 Early Treatment = median 15 days Delayed Treatment = median 123 days JointDamage

35. Percentage improvement Percentage deterioration Ritchie articular index Morning stiffness Radiological score VAS = 10 cm visual analogue scale. Hemoglobin Pain VAS Grip strength Sedimentation rate 75 50 25 0 –25 –50 –75 Mulherin D, et al. Br J Rheumatol. 1996;35:1263-1268. Clinical Parameters Don’t Correlate with Bone Damage

36. Case 2 Which DMARD would you choose? Monitor : Clinically Labs X-rays

37. Case 3 68-year-old woman, 3-years of RA, squeezed into your schedule as a new patient 4 weeks of increasing fatigue, dizziness, dyspnea, and anorexia Joint pain and stiffness: mild & unchanged Meds: flare up 4 mos. ago,switched to naproxen and prednisone

38. Case 3 (cont’d) Past history: Peptic ulcer 10 years ago, mild hypertension Exam: thin, pale apathetic woman with Temp 98.4ºF, BP 110/65, pulse 110 bpm Symmetrical 1+ synovitis of the wrist, MCP, PIP, and MTP joints Heart, lungs, and abdomen: unremarkable

39. Case 3 (cont’d) The doctor is falling behind in the schedule What system must you inquire more about today? A. Cardiovascular B. Neuropsychological C. Endocrine D. Gastrointestinal

40. Case 3 (cont’d) Clues of impending disaster High risk for NSAID gastropathy Presentation suggestive of blood loss Pale, dizzy, weak Tachycardia, low blood pressure No evidence of flare in RA to explain recent symptoms of increased fatigue

41. Case 3 (cont’d) NSAID gastropathy is sneaky and can be fatal Don’t Miss It

42. Singh. Am J Med. 1998;105(suppl B):31S–38S. NSAID Gastropathy Gastric ulcers are more common than duodenal ulcers No reliable warning signs 80% of occur without prior symptoms Ulcers in RA 2.5- 5.5 times more than general population 107,000 hospitalized & 16,000 deaths annually due to NSAID-GI complications

44. NSAID Gastropathy: Key Points Know the risk factors The best way to treat it is to prevent it Avoid it: Use acetaminophen, salsalate, (or ? selective COX-2 inhibitor) Counteract it: PPI or prostaglandin analogue Antacids and H2 blockers are not the answer May mask symptoms but do not prevent serious events

45. Singh. Am J Med. 1998;105(suppl B):31S–38S. GI Risk Factors : NSAID Ulcers Older age Prior history of peptic ulcer or GI symptoms with NSAIDs Concomitant use of prednisone NSAID dose Disability level: The sicker the patient the higher the risk

46. Balancing NSAID Efficacy and Safety Is NSAID therapy indicated? Can low dose relieve symptoms? Risk of complications ? Consider NSAID therapy with reduced GI toxicity or combination Rx with GI med Antiinflammatory activity Analgesia GI toxicity Renal toxicity Platelet effects

47. Selective COX-2 Medications VIOXX® :withdrawn from market 9/30/04 Celebrex® Bextra® withdrawn 2005 also associated with cardiovascular dz, hypertension, edema and sulfa & skin rxns

48. COX-2 Selective NSAIDs A replacement for non-selective NSAIDs? Pain relief equivalent to older NSAIDs Less GI toxicity (rofecoxcib) No effect on platelet aggregation or bleeding time Cost similar to generic NSAIDs plus proton pump inhibitor or misoprostol Side effects: Cardio-Vascular,BP,edema Medical Letter. 1999;41:11–12.

49. COX-2 : CV events (rofecoxcib) Time in study WSJ 10/1/04

50. Case 4 52-year-old man with destructive RA Rx NSAID & low-dose prednisone MTX & Remicade( anti-TNF) started 4 months ago 3-week history of fever, dry cough, and increasing shortness of breath Exam: Low-grade fever, fine rales in both lungs, Labs: normal CBC,LFTs, low alb Chest xray: bilat.interstitial infiltrates

51. Case 4 (cont’d) What should be done? A. Culture, treat with antibiotic for bacterial pneumonia B. Place PPD, sputum for AFB C. Give steroids for hypersensitivity pneumonitis and stop methotrexate D. Give a high-dose steroids and increase methotrexate for rheumatoid lung

52. DMARDs & Biologics Have a Dark Side Don’t Miss It Methotrexate may cause serious problems Lung Liver Bone marrow Anti-TNF (Remicade, Enbrel, Humira) assoc. with TB reactivation and other infections

53. Case 5 A pre-op physical has been ordered for a routine cholecystectomy on a 43-year-old woman with RA since age 20 PMH: bilateral THR,left TKR Meds: NSAID, 5 mg/d prednisone, MTX General physical exam normal MS exam, extensive deformities, mild synovitis In addition to routine tests, what test should be ordered before surgery?

54. Don’t Miss It Subluxation of C1 on C2 RA can cause asymptomatic instability of the neck Manipulation under anesthesia can cause spinal cord injury

55. Clues for C1-C2 Subluxation Long-standing rheumatoid arthritis or JRA May have NO symptoms C2-C3 radicular pain in the neck and occiput Spinal cord compression Quadriparesis or paraparesis Sphincter dysfunction Sensory deficits TIAs secondary to compromise of the vertebral arteries Anderson. Primer on Rheum Dis. 11th edition. 1997:161.

56. Summary Distinguish Inflammatory Disease (RA) from mechanical (OA) Treat RA early Know the medication side effects Know the complications of the disease

57. One Last Word: Unconventional Therapies Keep in touch with current information. The unconventional may become conventional www.quackwatch.com ACR Website (www.rheumatology.org) Arthritis Foundation Website (www.arthritis.org)