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Thank you for attending Rheumatoid Arthritis and Osteoarthritis Treatment A CHAMPS webcast presented by Dr. David Collier on Thursday, November 3rd, 2005 SUPPLEMENTARY INFORMATION PACKET I. Presentation Slide Text (Notes Pages) II. Biography of Dr. David Collier Pages 2-21 Page 22 III. Description of CHAMPS (Community Health Association of Mountain/Plains States) Page 22 IV. Description of the Arthritis Foundation Page 22 RA and OA Treatment Webcast, November 3, 2005 PRESENTATION SLIDE TEXT (NOTES PAGES) MANAGEMENT OF RHEUMATOID ARTHRITIS RA: Observations • RA affects 1% of the adult population • >70% of patients develop joint damage or erosions within 2 years of the onset of disease (chronic, polycyclic course) • >33% of patients are work disabled at 5 years • >50% of patients will be functional Class III or IV within 10 years of disease onset • If untreated, RA can result in joint destruction, deformity, disability, and premature death RA: Challenges • Preconceived notions that RA is a disease of lesser significance (“it’s just arthritis”) • Lack of appreciation of the potentially severe prognosis (disability and early mortality) may delay diagnosis, referral, and treatment • Delay in treatment may be due to lack of experience with prescribing and monitoring diseasemodifying antirheumatic drugs (DMARDs) • Primary care physicians are important members of the RA management team • Early recognition of the signs and symptoms of RA followed by expedited diagnosis and treatment results in more favorable patient outcomes ARA 1987 Criteria for RA (4 of 7 required) • Morning stiffness >1h, present for at least 6 wk • Swelling of 3 or more joint areas for at least 6 wk • Swelling of wrist, MCP, or PIP; >6wk • Symmetric joint swelling • Rheumatoid nodules • Serum rheumatoid factor (RF) • Hand radiographic changes: erosions Criteria were not intended for the diagnosis of RA in the clinical setting, particularly early disease Suspicion of an Inflammatory Arthritis • Spontaneous onset of 1 or more swollen joints • Morning stiffness lasting > 45 minutes • Diffuse joint pain and tenderness, particularly involving the MCPs and MTPs (forefoot pain can be the first and only small joint complaint) • Marked fatigue • Onset in women in the first year postpartum Screening Tool for Inflammatory Arthritis (RA) in Primary Care • Significant discomfort with squeezing the MCP and MTP joints • Presence of 3 or more swollen joints • More than 1 hour of morning stiffness Emery P et al. Ann Rheum Dis 2002;61:290-297. Anti-Cyclic Citrullinated Peptide Antibodies (Anti-CCP) • RF not very specific for RA • Autoantibodies reactive with synthetic peptides containing the unusual amino acid citrulline (modified arginine residue) are specifically present in the sera of RA patients: o Anti-CCP: sensitivity 56%, specificity 90% o IgM RF: sensitivity 73%, specificity 82% o RF and anti-CCP: sensitivity 48%, specificity 96% • The presence of RF with anti-CCP are associated with a higher probability of joint damage and disability Bas S et al. Rheumatology 2003;42:677-680. RA: Poor Prognostic Indicators • Earlier age at onset Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States 2 RA and OA Treatment Webcast, November 3, 2005 • • • • • • • Polyarticular synovitis (>20 joints) Rheumatoid nodules High titer rheumatoid factor, possibly anti-CCP Elevated ESR or CRP level Erosions or cartilage loss on x-ray HLA-DR4 or “shared epitope” Extraarticular manifestations Furst DE. Rheum Dis Clin North Am 1994;20:309-319. RA: Extraarticular Manifestations • Rheumatoid nodules • Sjögren’s syndrome • Episcleritis or scleritis • Interstitial lung disease • Pericardial disease • Systemic vasculitis • Felty’s: RA, neutropenia, splenomegaly RA: Important Lessons • Inflammation can be suppressed in early RA • When inflammation is suppressed, patients benefit • More therapy is not necessarily more toxic • Long-term benefits may be derived from early therapy RA: Initial Treatment • NSAIDs: reduce joint pain and swelling; improve function (cost, GI tolerance, half-life, patient preference) • Multidisciplinary care: o Rheumatology consultation o Physical and occupational therapy o Podiatry o Orthopaedics • Glucocorticoids ? • DMARDs: start within 2-3 months of diagnosis (shown to be the window of opportunity to prevent more joint destruction and preserve function) Lard LR et al. Am J Med 2001;111:446. RA: Glucocorticoids • Local injection: limited to a few joints • Low-dose oral (<10 mg prednisone): o “Bridge-therapy” until DMARD response (polyarticular synovitis) o Control of disease despite NSAIDs and adequate trials of DMARDs o Loss of independence or employment; flares; special events o Elderly - lower threshold for use o Toxicity (osteoporosis): dose and duration • Triamcinolone acetonide (Kenalog): 60 mg IM prn flare An • • • • • • • • Approach to Selecting DMARDs Patient compliance and convenience Cost of the DMARD and monitoring Time until expected benefit Potential for adverse reactions Comorbid diseases Response and toxicity to previous Rx Severity and prognosis of the disease Physician confidence in administering and monitoring the drug An Approach to Selecting DMARDs • Milder RA with no or few “poor prognostic indicators” consider: o Hydroxychloroquine (HCQ) o Sulfasalazine (SSZ) Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States 3 RA and OA Treatment Webcast, November 3, 2005 • • Severe RA with “poor prognostic indicators” consider: o Methotrexate (MTX) with rapid dose escalation o Combination DMARD therapy o New DMARDs and Biologics For women of childbearing age, effective contraception is required Methotrexate (MTX) • Fast acting: response in 3-6 weeks • Not remitting: RA flares if drug d/ced • Dosage: o Administer on a weekly basis, in one dose or cycled over 24 h o 5.0 or 7.5 mg po or SC/IM weekly, escalate rapidly to 15 mg/wk within 4-6 weeks and ideally to 20 mg/week by 8-12 weeks o Oral absorption is variable: if ineffective without rise in the MCV, try SC route MTX: Side Effects and Toxicity • Common: o Stomatitis, GI intolerance: try folate 1-2 mg/day o Myelosuppression: risks - use of antifolates, folate deficiency, renal insuff; use folate for rising MCV or MCV >100 o Transient LFT abn: hold or reduce dose for levels >2-3 x nl • Uncommon: o Hepatic fibrosis or cirrhosis (rare) o Pneumonitis: 2-6% o CNS reactions o Accelerated nodulosis o Fever, weight loss syndrome o Cutaneous vasculitis o Pneumocystis, fungal infections o ? Lymphoma association Methotrexate • Monitoring: o Baseline CXR, hepatitis B and C serologies o CBC, LFTs - 1 wk after 1st dose (idiosyncratic reaction) o CBC, Plt, AST/ALT, Alb, Cr q 4-8 weeks • Contraindications / Precautions: o Chronic renal insufficiency o Significant pulmonary disease o Alcohol abuse (no > few drinks/month), liver disease, obesity, diabetes o Concomitant antifolate therapy o Pregnancy and lactation RA: Monitoring Activity and Treatment • Each visit: o Degree of joint pain o Duration of morning stiffness o Severity of fatigue o Active synovitis on exam by joint count o Limitation of function o Extraarticular manifestations o Adverse drug reactions o Health Assessment Questionnaire (HAQ) can be used to score the patient’s function • Periodically: o Disease progression on PE: loss of motion, instability, malalignment, and/or deformity o ESR or CRP elevation o Progression of radiographic damage of involved joints (hands and feet) every 1 to 2 years (joint exam may not adequately reflect disease activity or structural damage); x-ray, possibly by ultrasound or portable MRI Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States 4 RA and OA Treatment Webcast, November 3, 2005 RA: Active or Progressive Disease Despite Current Treatment • Rheumatology consultation • Local glucocorticoid injection • Change drug regimen: o Increase DMARD dosage o Change the DMARD o Add a DMARD (combination therapy) o Start or increase glucocorticoids (eval and treat secondary osteoporosis) • Physical / Occupational Therapy • Surgical options for mechanical symptoms Refractory Rheumatoid Arthritis • Rheumatology consultation • Combination therapy: MTX/HCQ, MTX/SSZ, MTX/SSZ/HCQ, MTX/CSA, MTX/Leflunomide • Cyclosporine A (CSA)/Neoral: 2.5-4.0 mg/kg/day • Leflunomide (Arava) • Etanercept (Enbrel), Infliximab (Remicade), Adalimumab (Humira) • Anakinra (Kineret) • Mycophenolate (CellCept): 1000 mg bid • Cyclophosphamide, chorambucil • Investigational pharmacological or biological agents (anti-CD20, anti-CD40-L, CTLA4Ig) ACR-20/-50/-70 Response Criteria A 20%, 50%, or 70% improvement in: • Swollen joint count, AND • Tender joint count, AND • At least three of the following: o Patient’s global assessment of disease activity o Physician’s global assessment of disease activity o Patient’s assessment of pain o Acute-phase reactants (ESR or CRP) o Patient’s assessment of disability (HAQ) Efficacy of Triple Therapy in RA (2 year study, 171 patients, disease duration 6.9 ± 6.8 years) % Response Response % 90 80 70 60 50 40 MTX ++ SSZ SSZ 78 P = 0.005 60 55 49 40 30 20 10 00 MTX ++ HCQ HCQ MTX ++ HCQ HCQ ++ SSZ SSZ P = 0.05 P = 0.002 0.002 29 26 16 ACR-20 ACR-50 18 ACR-70 ACR-70 MTX MTX 7.5-17.5 7.5-17.5 mg/wk, mg/wk, HCQ 200 mg mg bid, bid, SSZ SSZ 500-1000 500-1000 mg mg bid. bid. O’Dell O’Dell JR, et al. al. Arthritis Arthritis Rheum. Rheum. 2002;46:1164–1170. 2002;46:1164–1170. II.34 II.34 Newer Agents for the Treatment of RA • Leflunomide (Arava) • Anti-TNF agents: o Etanercept (Enbrel), 1998 Soluble TNF receptor o Infliximab (Remicade), 2000 Chimeric anti-TNF antibody o Adalimumab (Humira), 2002 Human anti-TNF antibody • Anti-IL-1 agent: o Anakinra (Kineret), 2001 Modified IL-1 receptor antagonist (IL-1Ra) Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States 5 RA and OA Treatment Webcast, November 3, 2005 Leflunomide (Arava) • Mechanism of action: o Prodrug: metabolite inhibits dihydroorate dehydrogenase required for pyrimidine nucleotide synthesis o Antiproliferative effects on T cells and anti-inflammatory effects • Onset of action: o 4-12 wks, maximum effect by 4 months • Dosage: o Loading dose: 100 mg qd x 3 (optional) o Maintenance dose: 10-20 mg qd • Side Effects and Toxicity: o Increased LFTs/: usually < 2x increase and reversible; >3x (7%) increase requires discontinuation, dose reduction, cholestyramine if persistent o Hepatic failure: rare reports o Diarrhea (28%) o Rash (15%), reversible alopecia (9%) o Teratogenesis (Pregnancy Category X): Men or women who wish to have a child: stop leflunomide, cholestyramine 8 grams tid for 11 days, verify plasma (M1) levels < 0.02 mg/L by 2 separate tests 14 days apart (without cholestyramine - 2 yrs to eliminate drug) o Bone marrow suppression/aplasia: rare o Serious infection or lymphoma risk unknown • Monitoring: o LFTs, CBC, Cr q 4 wks x 6 months, then q 4-8 wks; baseline hepatitis serologies • Contraindications / Precautions: o Pregnancy and lactation o Renal or hepatic insufficiency o Severe uncontrolled infections or immunodeficiency o No vaccinations with live virus o Rifampin (40% ↑ M1 levels), MTX: possible hepatic toxicity o ↑ NSAID and tolbutamide levels in vitro Efficacy of Leflunomide in RA Pathogenesis of Rheumatoid Arthritis (6.3 years RA, 45% no prior DMARDs) ACR-20 Responders Over Two Years* % Responders Responders % 75 †† ‡‡ †† 45 IFNγ IFNγ and and HL A -DR Methotrexate (n = 101) other other cytokines cytokines Antigenpresenting cells Placebo (n = 36) 30 BB cell cell or or macrophage macrophage 15 Immune Immune complexes complexes T cell Leflunomide (n = 98) 60 Rheumatoid Rheumatoid factors factors BB cell cell Macrophage TNF IL-1 Synoviocytes Synoviocytes Pannus Pannus Chondrocytes Chondrocytes 0 Osteoclast Osteoclast 0 6 12 24 18 Month ACR-20 = * 20% improvement in response rates over time in ITT population; †P < 0.001 vs placebo; ‡P = 0.317 vs methotrexate For early withdrawals, the last observation carried forward (LOCF) is used. Cohen et al. Arthritis Rheum. 2001;44:1984–1992. Articular cartilage II.31 II.31 Characteristic Infliximab (REMICADE®®) (mean duration of disease 13 years) TNF MAb TNF MAb Construct Recombinant fusion protein Chimeric MAb Recombinant human MAb Half-life 4 days 8–10 days 10–20 days Binding target TNF/LTα TNF TNF Administration 25 mg SC 2x week or 50 mg mg SC SC once once weekly 3–10 mg/kg IV IV with with MTX MTX Every 4–8 weeks 40 mg SC SC Every other week* *Some *Some patients patients not not taking taking concomitant concomitant MTX MTX may may derive derive additional additional benefit benefit from from increasing increasing the the dosing dosing frequency frequency of of adalimumab adalimumab to to 40 40 mg mg every every week week * 71 Etanercept Etanercept 25 25 mg mg ++ MTX MTX (59) Placebo + MTX (30) 70 % of Patients sTNFR VI.4 VI.4 Etanercept + MTX: ACR Response Rates at 24 Weeks Adalimumab (HUMIRA™) 80 Class Bone Adapted from Arend WP, Dayer JM. Arthritis Rheum. 1990;33:305–315. Evolution of TNF Blocking Therapies Etanercept (ENBREL®®) Production of collagenase and other neutral proteases 60 50 * 39 40 30 27 † 15 20 10 3 0 ACR-50 ACR-70 0 ACR-20 IV.3 IV.3 MTX 15-25 mg/week, *P < 0.001; †P < 0.05 Weinblatt ME, et al. N Engl J Med. 1999;340:253–259. Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States IV.8 IV.8 6 RA and OA Treatment Webcast, November 3, 2005 Etanercept in Early RA (12 months disease): ACR Response Rates at Year 2 100 *† MTX MTX 20 20 mg mg (217) (217) P = NS 59 60 Patients (%) (%) Patients Etanercept 25 mg (154) P = 0.005 72 80 % of Patients TEMPO: ACR Response Rates at 52 Weeks Etanercept + Methotrexate (disease duration 6.0 ± 5.0 yrs) 49 42 P = NS 40 24 ACR-20 ACR-50 48 43 40 30 ACR-70 IV.18 IV.18 24 19 Oral MTX MTX (159) Etanercept (170) VII.24 VII.24 Klareskog L et al. Lancet 2004;363:675. ARMADA Patients Taking Concomitant MTX (16 ± 5 mg/week) (disease duration 12 ± 9 years) (duration of disease 9 years) Placebo (88 patients) Placebo (62 patients) Adalimumab 40 mg EOW 80 Infliximab 3 mg/kg q8wk (86 patients) 60 Responders (%) (%) Responders Responders (%) (%) Responders MTX + Etanercept (193) Adalimumab: Rapid ACR-20 Response Infliximab: Rapid ACR-20 Response Patients Taking Concomitant MTX (median dose 15 mg/wk) 60 ACR-70 *‡ *‡ 43 *P *P << 0.01 0.01 for for combination combination vs vs MTX; MTX; †P †P << 0.05 0.05 for for combination combination vs vs etanercept; etanercept; ‡P ‡P << 0.01 0.01 for for combination combination vs vs etanercept etanercept Etanercept Etanercept 25 25 mg mg SC SC twice/week; twice/week; Average Average dose dose of of MTX MTX was was 17.2 17.2 mg. mg. Analysis Analysis using using last last observation observation carried carried forward forward (LOCF) (LOCF) Genovese MC, et al. Arthritis Rheum. 2002;46:1443–1450. 80 *‡ 69 76 75 0 0 ACR-20 ACR-50 85 20 10 29 20 ATTRACT 90 80 70 60 50 40 20 * * (67 patients) * * * * * * 40 * 20 0 0 0 2 6 10 14 22 18 0 1 26 5 Maini R, et al. Lancet. 1999;354:1932–1939. VII.8 VII.8 20 24 Weinblatt ME, et al. Arthritis Rheum. 2003;48:35–45. Osteoclast Osteoclast precursor precursor TT cell cell Total Sharp TNF 3.5 JSN Joint Erosion 3.2 M-CSF M-CSF Median 3.0 Change From From Baseline Baseline Change RANK RANK OPG OPG Bone-lining Bone-lining cells cells VII.9 VII.9 Etanercept in Early RA: Change in Sharp Scores At 2 Years Effects of IL-1 and TNF on Bone Remodeling RANKL RANKL 15 *P *P << 0.05 0.05 vs vs placebo. placebo. Statistical Statistical comparisons comparisons were were not not performed performed at at these these time time points. points. IL-1 TNF 10 Weeks Weeks IL-1 Bone Bone Osteoclast Osteoclast MTX 20 mg Etanercept 25 mg 2.5 1.9 2.0 * 1.3 1.5 1.3 1.0 † 0.7 * 0.7 0.5 0 Adapted from Gravallese EM, Goldring SR. Arthritis Rheum. 2000;43:2143–2151. III.8 III.8 *P = 0.001; †P = NS TEMPO: Change in TSS From Baseline at 52 Weeks Infliximab + MTX (ATTRACT) Etanercept + Methotrexate Changes in Total Sharp Scores 14 Mean Change Change From From Baseline Baseline Mean Change in in TSS TSS (m (mean) ean) Change 3 2.8 2 1 * 0 (1.08, 4.51)‡‡ 0.52 (-1.00, (-1.00, -0.07)‡‡ (-0.10, 1.15)‡‡ -0.54 -1 Oral MTX (n = 212) Etanercept 25 mg BIW (n = 212) † ** Oral MTX + Etanercept (n = 219) 12.6 12.6 30 Weeks 12 54 Weeks 10 102 Weeks 8 6 77 4.8 4.8 4 P < 0.001 2 1.3 11 11 1.3 PP < 0.001 1.6 1.6 0.6 0.6 P < 0.001 P < 0.001 1.1 1.1 11 0.2 0.2 0 -0.5 -0.5 -2 TSS TSS == Total Total Sharp Sharp Score; Score; BIW BIW == twice twice per per week. week. Mean Mean dose dose of of MTX MTX was was 17.2 17.2 mg/week. mg/week. *P *P << 0.05 0.05 for for etanercept etanercept vs vs MTX; MTX; †P †P << 0.01 0.01 for for combination combination vs vs MTX; MTX; **P **P << 0.01 0.01 for for combination combination vs vs etanercept; etanercept; ‡(2-sided ‡(2-sided 95% 95% CI). CI). One One year year values values imputed imputed by by linear linear extrapolation extrapolation ifif needed. needed. Klareskog L et al. Lancet 2004;363:675. IV.30 IV.30 Genovese MC, et al. Arthritis Rheum. 2002;46:1443–1450. -0.3 -0.3 -0.7 -0.4 -0.7 -0.4 nn == 66 66 64 64 50 50 72 72 71 71 68 68 76 76 71 71 66 66 78 78 77 77 69 69 69 69 66 66 66 66 MTX MTX Alone Alone 33 mg/kg mg/kg q8w q8w 33 mg/kg mg/kg q4w q4w 10 10 mg/kg mg/kg q8w q8w 10 10 mg/kg mg/kg q4w q4w MTX + Infliximab VII.28 VII.28 P values are vs MTX alone Lipsky PE, et al. Arthritis Rheum. 2000;43(suppl):S269. Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States IV.23 IV.23 7 RA and OA Treatment Webcast, November 3, 2005 Adalimumab: Mean Change in Joint Erosions and Joint Space Narrowing in Patients With Early RA (< 2 Years) Placebo + MTX Adalimumab Adalimumab 40 mg mg EOW + MTX MTX Joint Erosions Joint Space Narrowing 2.6 2.6 3.0 3.0 2.5 2.5 Mean ean Change Change M Mean ean Change Change M 3.0 3.0 2.0 2.0 1.5 1.5 1.0 1.0 0.2 0.2 0.5 0.5 00 2.2 2.2 2.5 2.5 2.0 2.0 1.5 1.5 1.0 1.0 0.2 0.2 0.5 0.5 00 52 52 Weeks Weeks 52 52 Weeks Weeks EOW == every other week VII.30 VII.30 Keystone E, et al. Ann Rheum Dis. 2003; 62(suppl 1):170. Anakinra (Kineret) • Dosage: o 100 mg daily subcutaneous injection: half-life 4-6 hours o Predominantly cleared by the kidney: clearance ↓ in chronic renal insufficiency • Side Effects and Toxicity: o Injection-site reactions: 71%; placebo 28% o Serious infections: 2%; placebo <1% o Use with TNF blocking agents not recommended: serious infections 7%; neutropenia 3% o Rare hypersensitivity reactions Anakinra + MTX: ACR Response Rates at Week 24* (419 patients, had 6 months of prior MTX, 7.4 yrs of RA) 45 45 Anakinra Anakinra 1.0 1.0 mg/kg mg/kg SC SC qd qd + MTX MTX 35 35 35 35 % of Patients Placebo Placebo ++ MTX 42 42 40 40 Anakinra Anakinra 2.0 2.0 mg/kg mg/kg SC SC qd qd + MTX MTX 30 30 25 25 24 24 23 23 20 20 17 17 15 15 10 10 10 10 7 44 55 00 00 ACR-20 ACR-20 ACR-50 *Dose response; P = 0.003 vs placebo. Cohen S, et al. Arthritis Rheum. 2002;46:614–624. ACR-70 ACR-70 IV.6 IV.6 Anti-TNF Therapy: Adverse Effects • Injection site reactions, infusion reactions • Serious infections: d/c drug in the setting of an active infection • Atypical infections: o Tuberculosis: need pre-treatment PPD and CXR o Atypical mycobacterial infections o Candidiasis o Aspergillosis, Nocardiosis, Pneumocystis o CMV, Cryptococcosis, Coccidioidomycosis o Histoplasmosis: ? use in endemic areas o Listeria: avoid unpasteurized milk products, heat ready-to-eat meats • Demyelinating disease • Neoplasia: o Lymphoma: reported cases, difficult to ascertain increased drug risk over risk with RA alone (SIR 2.5) o Solid Tumors: limited data - risk unclear but does not appear to be increased, use with caution with h/o malignancy • Cytopenias • Heart failure • Antibody production: Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States 8 RA and OA Treatment Webcast, November 3, 2005 o o Non-neutralizing antibodies to the drug; incidence decreased with concomitant MTX therapy ANAs and anti-ds-DNA antibodies (10%-50%), rare cases of drug-induced lupus Average Costs of DMARDs Drug Dose AWP/ mos AWP/ year MTX 15mg/wk $72 $936 Leflunomide 20mg/day $422 $5,064 Etanercept 25mg twice weekly $1,370 $16,440 Infliximab 300mg infusion Adalumimab Anakinra 40mg qowk 100mg/day $16,660 (8 doses) $1,370 $1,303 RA: Health-Care Maintenance • Osteoporosis: o Calcium / Vit D: 1500 mg /400-800 U/day o Bisphosphonates o DEXA scans • Cardiovascular disease: assess risk / modify • Smoking cessation • Infection risk (particularly pulmonary infections): o Influenza vaccination yearly o Pneumococcal vaccination: before MTX $16,440 $15,636 ACR Treatment Algorithm Establish diagnosis of RA early R R hh ee uu m m aa tt oo ll oo gg ii ss tt PP C C PP Initiate therapy Periodically assess disease activity Adequate response Inadequate response Change/Add DMARDs MTX naive MTX Other mono Combination Suboptimal MTX response Combination Other Biologics mono Mono Combination Multiple Multiple DMARD DMARD failure failure Adapted Adapted from: ACR Subcommittee on RA Guidelines. Arthritis Arthritis Rheum. 2002;46:328–346. Symptomatic Symptomatic and/or and/or structural structural joint joint damage damage Rational Approach to DMARD Therapy in Severe RA • Start oral methotrexate (unless contraindicated) with rapid dose escalation, consider low-dose steroid “bridge therapy” • Inadequate response: consider parenteral (sq) methotrexate • Inadequate response: MTX combination DMARD therapy [SSZ, HCQ, or leflunomide (risk of hepatotoxicity)] or change to leflunomide • Inadequate response: add etanercept, infliximab, adalimumab, or anakinra RA: Unanswered Questions • How do we select the best DMARD for each patient (identify predictors)? • Should we step-up or step-down initial DMARD therapy (combo rx)? • Is there a role for induction therapy with steroids and/or anti-TNF / anti-IL-1 agents? TOPICS OF LECTURE OSTEOARTHRITIS • Definition • Laboratory Tests • Risk Factors • Management of OA OSTEOARTHRITIS Definition: Osteoarthritis is a heterogeneous disease representing a final common pathway of biochemical, metabolic, physiologic, and pathologic changes characterized by loss of articular cartilage and remodeling of subchondral and marginal bone. Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States 9 II.10 II.10 RA and OA Treatment Webcast, November 3, 2005 OA: LABORATORY TESTS No specific tests Synovial fluid analysis 1. Type 1 fluid, 200-1500 WBC, 20-50% polys. 2. Normal viscosity, glucose 3. Negative Crystal Exam Laboratory tests in secondary OA Investigational: Cartilage degradation products in serum and joint fluid. 1. Hyaluronic acid, fragments of aggrecan 2. Type II collagen 3. Cartilage oligomeric protein (COMP) OA: RADIOGRAPHIC FEATURES • Joint space narrowing • Bony sclerosis • Marginal osteophytes • Subchondral cysts • Altered shape of bone • Malalignment o Nails the diagnosis. Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States 10 RA and OA Treatment Webcast, November 3, 2005 OA: RISK FACTORS • Age: 75% of persons over age 70 have OA, uncommon under age 40. • Female sex • Obesity • Hereditary • Trauma • Neuromuscular dysfunction • Metabolic disorders OA: Clinical Syndromes - Six Types • Primary generalized OA • Inflammatory/erosive small joint OA • Isolated nodule OA • Unifocal large joint OA • Multifocal large joint OA • Unifocal small joint OA Management of OA • Establish the diagnosis of OA on the basis of history, physical and x-ray examinations o 1. Knee pain with radiographic OA can be due to patellofemoral disease, ligament strain, anserine bursitis, iliotibial band syndrome, referred from lumbosacral disease, etc. o 2. Hip pain could be trochanteric, iliopsoas, and ischial bursitis, referred back pain, sacroiliac disease, etc. TWO APPROACHES TO THE MEDICAL MANAGEMENT • Practical Guidelines-ACR Osteoarthritis Guidelines of OA of the Knee, the American Pain Society Guidelines to treat OA, or the EULAR 2003 Recommendations for Treating OA of the Knee o Based on evidence and expert opinion • Pathophysiological approach to OA WHAT IS IMPORTANT IN TREATING OSTEOARTHRITIS? • Biomechanical or Biochemical targets? • Primary Prevention? o Reduction of risk factors o 25% to 50% theoretically preventable by reducing obesity and repetitive activities. • Secondary Prevention? o Interventions that prevent progression o DMOADs • Tertiary Treatment? o Treatment of consequences of OA OA: FIT TREATMENT TO THE PATIENTS • Age • Comorbidity • Clinical Severity of OA • Individual preferences • Cost Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States 11 RA and OA Treatment Webcast, November 3, 2005 OA: FIT TREATMENT TO THE PATIENT • What are you treating-pain or limited motion? • Discuss the patients concerns - clear up misconceptions • Discuss what you can and cannot do for the patient • Monthly telephone call to patient on stable treatment reduced joint pain • Arthritis self-management education programs(1) (Self-help course of Arthritis Foundation) 1 Arthritis Rheum 2003; 48:2207-2213 OA: MODIFICATIONS • Weight loss if obese • Modify activities and occupations • Weight-bearing canes, braces and crutches • Assistive devices - door handles, toilet seat extenders, special chairs, etc. • Secondary fibromyalgia is common - correct sleep habits OA: PHYSICAL THERAPY • Heat (ultrasound, heat packs, wet heat) or ice • Gait instruction • Massage • Balneaotherapy • TENS1 • Exercise2 1 2 Clinical Rehabil 2002; 16:749-60 J Rheumatol 2002; 29:1737-45 OA: Exercise1,2 • Prescribe progressive exercise to: o Improve general health o Modify possible risk-factors in disease progression o Increase ROM and flexibility o Increase endurance and strength o Reduce fall risk o Chondroprotective 1 2 Current Rheumatology Reports 2001; 3:520-523 J Rheumatol 2002; 29:1737-45 STRENGTHENING AND RECONDITIONING EXERCISE PROGRAM FOR OA • Physical and Reconditioning Exercise Program for OA • General program for muscle strengthening o Warm up with ROM stretching o Lift body part against gravity - 6 to 10 reps. o Progressively increase resistance with weights or elastic bands o Cool-down with ROM stretching • Progress to aerobic exercise program ACR Osteoarthritis Guidelines OA of the Knee Nonpharmacologic Measures Topical Therapy Acetaminophen NSAIDS, COX-2 Inhibitors Nonselective NSAID plus misoprostol or PPI in high risk patients Intraarticular Therapy (hyaluronan or glucocorticoids) Nonacetylated salicylates Pure Analgesics (tramadol or opioids) ACR Subcommittee on OA Guidelines. Arthritis Rheum 2000; 43: 19051905-1915 Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States 12 RA and OA Treatment Webcast, November 3, 2005 PHARMACOLOGIC MANAGEMENT OF OA • Topical agents • Nonopioid analgesics • NSAIDs and COXIBs • Opioid analgesics • Nutraceuticals and alternative therapies • Intra-articular agents • Experimental TOPICAL AGENTS IN OA • Counter irritants - Ben-Gay, Flexall 454, Icy-Hot, Mineral Ice, etc. • Capsaicin - containing topicals o May paralyze C type pain fibers o Two studies support use in OA o Use daily, 4 times a day, for two weeks before benefit o Compliance poor without full instruction o Avoid contact with eyes • Topical NSAIDs – Aspercreme, diclofenac • Topical Glucosamine sulfate, chondroitin sulfate, and camphor o Recent blinded placebo controlled study showed improvement in knee OA in 4 weeks1 1 J Rheumatol 2003; 30:523 ACETAMINOPHEN 1. First-line pharmacological agent in the treatment of patients with OA 2. Low incidence of adverse events and low cost 3. Introduced in Europe in 1893 by von Mering 4. Rapidly and completely absorbed from GI tract 5. Peak plasma concentration in about 30 to 60 minutes 6. Plasma half-life is 2 hours 7. No specific precautions in the elderly 8. Metabolism altered by severe acute or chronic liver disease 9. Watch out for acetaminophen containing products ACETAMINOPHEN Mechanism of Action • Incompletely understood • Inhibitor of COX-3 in CNS • Does not inhibit neutrophile activation • In animal models inhibits substance P induced nociceptive response CLINICAL TRIALS IN OSTEOARTHRITIS ACETAMINOPHEN 1. 1991 NEJM study by Bradley, Brandt, et.al. – Randomized, double-blind, 4 week study with 184 patients with OA of knee – 3 Groups - 2400mg or 1200mg of ibuprofen or 4,000mg APAP – Outcome Variable (0-3) HAQ Pain Score Walking Pain Score Rest Pain Score Walking Distance Score APAP 4000mg 0.33 0.13 0.06 0.06 Ibuprofen 1200mg 0.30 0.31 0.33 0.01 Ibuprofen 2400mg 0.35 0.45 0.40 0.09 P value 0.93 0.10 0.05 0.77 OA: NSAIDs • Most widely prescribed drug class in country • 1 in 7 Americans use NSAIDs, 17 million regular users, 50% over age 60. • 111 million prescriptions annually. 3.9 billion dollars in annual costs. Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States 13 RA and OA Treatment Webcast, November 3, 2005 • Beneficial effects of NSAIDs o Analgesia o Antipyresis o Anti-inflammatory o Decreases platelet aggregation New Theory: Mechanism of Action of Nonspecific NSAIDs Arachidonic Acid COXCOX-1 “Constitutive” Constitutive” COXCOX-2 “Inducible” Inducible” Nonspecific NSAIDs Prostaglandins Protection of Gastric Mucosa Prostaglandins Hemostasis Mediate Pain, Inflammation, and Fever Donnelly et al. Aliment Pharmacol Ther. Ther. 1997;11:2271997;11:227-236. Pairet et al. Fundam Clin Pharmacol. Pharmacol. 1996:10:11996:10:1-15. NSAIDs - CLASSIFICATION • COX-1 specific - low dose aspirin • COX nonspecific - Ibuprofen, Naproxen, Indomethacin, Sulindac, Piroxicam • COX-2 preferential - Etodolac, Diclofenac, Nabumetone, Meloxicam • COX-2 specific - Celecoxib, Rofecoxib, Valdecoxib FACTORS AFFECTING THE CHOICE OF NSAIDs - THE DRUG 1. Efficacy 2. Tolerance / Safety 3. Dosage 4. Formulation 5. Cost NSAIDs - EFFICACY • No important differences with any NSAID • Individual variations in response • No correlation between amount of cyclooxygenase inhibition or plasma levels and efficacy • COX-2 Specific Inhibitors: Celecoxib and formerly Rofecoxib, Valdecoxib o Comparable to Ibuprofen, Naproxen and Diclofenac o Suppresses animal models of inflammation o Indicated for OA, RA and Pain TOXICITIES OF NSAIDS • Hypersensitivity • Gastrointestinal • Nephrotoxicity • Cardiotoxicity • Hepatotoxicity • Tinnitus / deafness • Central Nervous Systems • Cutaneous HYPERSENSITIVITY REACTION AND THE COX-2s HYPERSENSITIVITY Aspirin Sensitivity Normal Subjects Chronic Rhinitis Nasal Polyps Asthma Asthma w/ Nasal Polyps Incidence 0.09% 1.4% 14-23% 3.8-28% up to 78% Celecoxib and Rofecoxib have generic NSAID warning ( J Allergy Clin Immunol 2001; 108:47) Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States 14 RA and OA Treatment Webcast, November 3, 2005 FIVE MAIN CATEGORIES OF REACTIONS TO NSAIDs Underlying Reaction Mechanisms Reaction Type Diseases Cross-Reactions Cox-1 Inhibition Immunologic Cross-reacting Asthma, polyps respiratory Sinusitis, rhinitis Cross-reacting Chronic urticaria urticaria or none Urticaria/ anaphylaxis None Aseptic Meningitis None Hypersensitivity None ASA/NSAIDs ASA/NSAIDs None None None Yes None Yes None No No No IgE mediated DTH DTH Manifestation of NSAID-Induced Upper GI Toxicity • PUBs o perforations o ulcers o bleeds • POBs o perforations o obstructions o bleeds • Discomfort o dyspepsia o nausea o abdominal pain GASTROINTESTINAL • Gastritis, gastric ulcer, duodenal ulcers associated with NSAIDs o Endoscopic erosions in 10-30% of patients on NSAIDS o Ulcer complications 4%/year-most have no warning • Diarrhea-especially with meclomen • No protection from sucralfate and H-2 blockers • Protection from misoprostol and pump inhibitors • Poor PG inhibitors, such as sodium salicylate group (Disalcid, Trilisate) are easier on the stomach • Cox-2 inhibitors similar to placebo on stomach Effects of ASA on AntiAnti-inflammatory Drugs: SUCCESS Trial UGI Safety NSAIDs/ ASA NSAIDS Celecoxib/A SA Celecoxib (N=348) (N=4046) (N=697) (N=8103) 17.4 6.3 10 4.4 Ulcer complication 1.6 0.8 0.8 0.1 Ulcer complication/ Symptomatic ulcers 6.3 1.8 2.3 0.9 UGI events/100 pt-yrs Possible events Events were upper GI ulcer complications (perforation, gastric obstruction, bleeding), symptomatic upper GI ulcerations, or other GI events. Addition of ASA to NSAIDs and coxibs increases adverse events Singh et al. Available at: http://www.eular.org/eular2001/AbstractsOnline.cfm. David H. Collier - 11/03/05 HIGH RISK PATIENTS FOR NSAID INDUCED ULCER • Older Age • Hx of PUD, GI BLEED • Prior NSAID - related GI Intolerance • Chronic Diseases (CAD, RA, COPD) • Smoking, Ethanol USE • Corticosteroids (> 10 mg) Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States 15 RA and OA Treatment Webcast, November 3, 2005 • • Anticoagulant Therapy Possibly H. Pylori Infection CARDIOVASCULAR EFFECTS OF COX-2 INHIBITORS Effects of NSAIDs on Thromboxane and Prostacyclin JAMA Article - August 22, 2001 Endothelial cell Platelet COX-1 Nonspecific NSAIDs/ASA COX-1 Coxibs COX-2 Thromboxane (Tx) A2 Prostacyclin (PGI2) Vasoconstrictor Promotes platelet aggregation Vasodilator Inhibitor of platelet aggregation Hemostasis Thrombosis David H. Collier - 11/03/05 McAdam et al. Proc Natl Acad Sci USA. 1999;96:272. Celecoxib Long-term Arthritis Safety Study Vioxx® Gastrointestinal Outcomes Research Trial VIGOR Trial Design CLASS Trial • Randomized, double-blind • RA patients Design • Randomized, double-blind • OA/RA patients • Conduct based on clinical practice norms • Minimum 6 months’ exposure Treatments • Celecoxib 400 mg BID • Diclofenac 75 mg BID • Ibuprofen 800 mg TID • Median follow-up: 9.0 months Treatments • Rofecoxib 50 mg QD • Naproxen 500 mg BID • Low-dose aspirin excluded • Antacids and OTC H2-receptor antagonists allowed • Acetaminophen, non-NSAID analgesics, glucocorticoids, and DMARDs allowed Sample size • 8,076 patients (4,047 rofecoxib; 4,029 naproxen)David H. Collier - 11/03/05 Thromboembolic CV Adverse Events: VIGOR and CLASS Studies VIGOR Q R Silverstein, et al. JAMA. 2000;284:1247–1255. David H. Collier - 11/03/05 Risk of Cardiovascular Events Associated With Selective COX2 Inhibitors (JAMA. 2001;286:954-959) CLASS J P Rofecoxib 50 mg qd (n=4047) Naproxen 500 mg bid (n=4029) R R R R R R R RR R 1.5 R R R R R R RR R RR R P RR 1.0 RR PP RR R PP R RR R p < 0.05 PPP R P R 0.5 R P PP R R PP RR R P RP RP P R R PP P 0 PR P 0 40 80 120 160 200 240 280 320 360 2.0 Celecoxib 400 mg bid (n=3987) NSAIDs (n=3981) 2.5 % of Patients 2.5 % of Patients Sample size • 8,000 patients (4,000 celecoxib; 2,000 per NSAID); intent-to-treat analysis 2.0 J JP PJ PP J JPPJ J 1.5 J P P JJ P JJ P PPJ P JJ PJJP P J J 1.0 PP P JJ P P JJ PP JJ PJ J p = 0.973 P J PP JJ P 0.5 J PJ P PPJ J PJPJ P JJ J P J P JPP JP 0 JPPJ J 0 0 40 80 120 160 200 240 280 320 360 Days Days White et al. Am J Cardiol;2002:89:425Cardiol;2002:89:425-430 www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_6_cardio.doc David H. Collier - 11/03/05 Relative Risk of APTC End Point: Pooled Analysis Decreased risk on rofecoxib Increased risk on rofecoxib NSAIDs and Risk of Cardiovascular Thrombotic Events No Increased Risk with Celecoxib: All Patients Rofecoxib vs placebo 0.84 (0.51, 1.38) Pt-years = 3867 Celecoxib vs placebo Rofecoxib vs non-naproxen NSAIDs 0.79 (0.40, 1.55) Pt-years = 2918 Celecoxib vs non-naproxen NSAIDs Rofecoxib vs naproxen 1.69 (1.07, 2.69) Pt-years = 8364 0.2 0.5 1.0 2.0 5.0 Relative risk of rofecoxib to comparator David H. Collier - 11/03/05 Konstam et al. Circulation. 2001;104:2280. Increased risk on celecoxib Decreased risk on celecoxib 0.85 (0.23, 3.15) Pt-years=700 1.06 (0.70, 1.61) Pt-years=4,969 0.93 (0.32, 2.69) Pt-years=2,422 Celecoxib vs naproxen 0.0 0.2 0.5 Triangles represent relative risk, David and size of triangles represents patient-years of exposure. Bars indicate 95% CI. 1.0 2.0 H. Collier - 11/03/05 5.0 White WB et al. ACR 2002. Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States 16 RA and OA Treatment Webcast, November 3, 2005 Cardiovascular Problems with NSAIDS • APPROVe study-Vioxx vs placebo in patients with colonic polyp history o 2,600 pts, 25 mgs Vioxx, after 18 months o 45 pts CV events Vioxx, 25 pts CV events placebo • Adenoma Prevention Trial with Celecoxib or APC trial-NIH o >2,000 pts, 400 mg, 800 mg Celebrex, > 33 month o CV events, placebo-6, 400mg-15, 800mg-20 • Prevention of Spontaneous Adenomatous Polyps or PreSAP trial-Pfizer o >1,500 pts, 400mg, >33 months o 400mgs (n=993) 16 events (1.7%, Placebo (n=628)11 events (1.8%) • Alzheimer’s Disease Anti-inflammatory Prevention Trial (Adapt) o Naprosyn more CV events, Celebrex and placebo the same. FDA Kaiser Permanente Collaboration • Objectives o Determine if risk of AMI and SCD is increased with NSAID or COXIB use o Compare risk of AMI and SCD between COXIBS: celecoxib and rofecoxib • Study Population o California memebership of Kaiser Permanente (KP) o All patients age 18-84 treated with coxib or NSAIDs from 1/1/1999 through 12/31/2001 (N = 1.4 million) • Methods o Nested case-control study within this NSAID-exposed study cohort o Cases: All study cohort members with AMI or SCD during the study period o N=8,199 acute cardiac events (6,675 AMI: 1,524 SCD) o Controls: Risk-set matched 4:1 on event date, age, gender and health plan region AMI=acute myocardial infarction; SCD=sudden cardiac death Graham et al. Presented at ISPE 2004 Case-control Observational Study Risk of AMI and SCD With Current Use of COXCOX-2 Selective and NSNS-NSAIDs P<0.01 Adjusted† Odds Ratio (95% CI) 3.5 3.15 (1.14-8.75) 3.0 2.5 P=0.06 P=0.01 2.0 1.5 1.0 1.18 (1.04-1.35) 1.09 1.00 0.86 (0.99-1.21) (reference) (0.69-1.07) * P<0.01 1.29 (0.93-1.79) 1.16 (1.04-1.30) P=0.005 1.33 (1.09-1.63) 1.69 (0.97-2.93) 0.5 0.0 Control Celecoxib (remote use) Ibuprofen Naproxen Rofecoxib ≤25 mg Rofecoxib >25 mg Other Indomethacin Diclofenac NSAIDs AMI=acute myocardial infarction; SCD=sudden cardiac death. *P=0.04 compared with celecoxib. †Adjusted for age, gender, health plan region, medical history, smoking, and medication use. Adapted from Graham et al. Lancet. 2005;365:475-81. Platelet and Cardiovascular Effects of COX-2 Specific Inhibitors • COX-2 specific inhibitors spare platelets • COX-2 specific inhibitors do NOT decrease cardiovascular risk o If have cardiovascular risk, do not use COXIBs o Celebrex behaves differently than Vioxx or Bextra • Patients with cardiovascular risk need low-dose aspirin (≥ 81 mg/d) – use traditional NSAIDs with PPI • All NSAIDs possibly could increase CV risk RENAL EFFECTS OF COX-2 INHIBITORS Intrarenal Functional Role of COX-2 vs COX-1 • COX-2 appears to be a dominant contributor to sodium chloride and water homeostasis. • COX-1 appears to have a more dominant role in the maintenance of glomerular filtration rate. • Nonetheless, functions of both COX enzymes appear to overlap. Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States 17 RA and OA Treatment Webcast, November 3, 2005 Renal Syndromes Related to Use of Conventional NSAIDs Fluid and electrolyte abnormalities • Sodium chloride and water retention with edema formation (typically ≥ 5%) • Hyperkalemia Hypertension • Interaction with antihypertensive drugs and diuretics Congestive heart failure • Fluid retention and interaction with diuretic drug treatment Acute renal failure • Hemodynamically mediated during decreased renal perfusion Nephrotic syndrome • Minimal change glomerulonephritis and interstitial nephritis Papillary necrosis • Acute (usually single-drug pathogenesis) • Chronic (usually multi- drug pathogenesis) HIGH RISK PATIENTS FOR RENAL TOXICITIES • Older Age • ASHD • Renal Insufficiency • Renal hypoperfusion states: CHF, Cirrhosis, diuretics, hypovolemia, nephrotic syndrome • Risk factors for hyperkalemia: diabetes, renal insufficiency, ACE inhibitors, beta blockers, potassium sparing diuretics NSAIDs • Dosage - single and twice-a-day regimens have more compliance • Formulation o Enteric coated - Ecotrin, Easprin, Diclofenac o Liquid - Ibuprofen, Naproxen,Trilisate o Slow release - Indocin SR, Voltaren XR, Naprelan, Oruvail o Injectable – Ketorolac (soon to see Paracoxib) • Cost - use generic NSAIDs first if patient not at risk o COX-2 inhibitors more costly than traditional NSAID o Traditional NSAIDS plus H+ pump inhibitor may be less costly as pump inhibitors go generic. NSAIDs - COX-2 Inhibitors • Drug interactions o Can be used with warfarin o Increases methotrexate levels slightly o Have potential interactions with diuretics and ACE inhibitors, increase drug levels of lithium o Celecoxib contraindicated in sulfa allergic • COX-2 inhibitors are not “super” aspirin but are a safer aspirin NONOPIOID ANALGESICS IN OA • Tramadol (Ultram)1 • Tramadol and Acetaminophen (Ultracet)2 o Affects U-1 opioid and serotonin pathways o Non ulcerogenic o May be added to NSAIDs, acetaminophen o Both forms studied in OA and found beneficial o Side effects: Nausea, vomiting, dizziness, drowsiness, rash, constipation and may lower seizure threshold 1 2 J Rheumatol 2002;29:2196-9 Clin Ther 2002; 24:282-97 OPIOID ANALGESICS FOR OA • Use after most other medical interventions tried • Document decrease in pain level (VAS) and increase in function • Follow routinely-watch for addictive behavior Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States 18 RA and OA Treatment Webcast, November 3, 2005 • • • Contract your patients o State objectives for determining treatment success o You are exclusive supplier of drug o Can get urine-tox screen at any time Codeine, propoxyphene, hydrocodone, oxycodone, and long acting morphine all studied in OA o Only oxycodone and long acting morphine shown statistically better in blinded study than acetaminophen o Anticipate and prevent constipation o Watch for CNS effects in elderly o Long-acting oxycodone may have fewer CNS side effects Morphine and fentanyl patches for severe pain interfering with daily activity and sleep NUTRACENTICALS IN OA • Glucosamine and chondroitin sulfate marked in US as nutritional supplements for arthritis • Popularized by Jason Theodasakis, MD in two books, “The Arthritis Cure” and “Maximizing the Arthritis Cure” • www.Theo.com NUTRACEUTICALS IN OA - SUMMARY • Glucosamine and chondroitin sulfate are orally absorbed and preferentially distributed to the joints • Have analgesic effect in OA • Onset of analgesia slower than NSAIDs • Some evidence for “chondroprotection” • Very safe. Dose of glucosamine is 500 mg TID, Chondroctin Sulfate 400 mg TID. If respond in two months may decrease dose. INTRA-ARTICULAR AGENTS • Corticosteroids1 o Two year, double-blinded study of every 3 months injection of steroid or placebo o Significant pain relief o No difference in joint space width • Hyaluronate • IL-Ira (Kineret)2 o 14 patients injected with150mg of IL-1ra o Dramatic improvement in pain at one month o No side effects 1 2 Arthritis Rheum 2003; 48:370-77 ACR Annual Scientific Meeting - Late Breaking Abstract - 10/28/03 HYALURONAN OR VISCOSUPPLEMENTATION IN OA • Hyaluronic acid (HA) is polysaccharide made up of N-acetyl glucosamine and glucoronic acid and is core protein of proteoglycans • Exhibits elastic and viscous properties - slow movement HA is viscous, fast movement HA is elastic • When injected HA disappears from joint in less than a week • HA induces the formation of endogenous HA • HA has anti-inflammatory effects • Human and animal studies show prolonged analgesia after a series of HA injections Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States 19 RA and OA Treatment Webcast, November 3, 2005 Overall Response to Hylan G-F 20 Viscosupplementation Much Better 35.0% HA MW 700,000 hylan G-F 20 hylan A MW 6 million Better 42.2% Worse or Much Worse 1.3% David H. Collier - 11/03/05 Same 21.4% Reference: Lussier A, Cividino AA, McFarlane CA, et al. Viscosupplementation with hylan for the treatment of osteoarthritis: findings from clinical practice in Canada. J Rheumatol. 1996;23(9):1579-1585. David H. Collier - 11/03/05 CAVEATS ABOUT HYALURONAN IN OA • The cross linked product (Synvisc) has been reported to be associated with rare post injection flares • About 2.7% of patients develop local adverse reactions • Crystalline induced flares have been described post injection • Both products are isolated from rooster comb. Patients who are allergic to chickens or eggs should not receive therapy • No studies of repeated series of injections reported • Cost of therapy is $500-$800 (HA product, visit, injection) and is reserved for those who failed conventional therapy • Only approved for use in knee but studied in shoulder and ankle SURGICAL INTERVENTIONS IN OA • Tidal joint irrigation • Arthroscopic examination • Reparative • Reconstructive • Joint Replacement Complimentary and Alternative Therapy in Patients with OA • Use of Alternative Therapy is Common in OA1 o 4 Ethnic groups studied for use of alternative therapy (AT) o 83% of all patients used AT African-Americans – 85% Asian – 87% Caucasian – 79% Hispanic –81% o Dietary changes were the most common AT 1 Arthritis & Rheum 2003; 48(9Supp):S488 ALTERNATIVE THERAPIES IN OA • Leech therapy1 • S-adenosylmethionine (SAMe)2 • Ginger extract3 • Avocado/Soybean Unsaponifialbles4 • Acupuncture5,8 • Electromagnetic Fields6 • Magnets7 1 Ann Intern Med 2003; 193:724-730 J Fam Pract 2002; 51: 425-30 3 Arthritis Rheum 2001; 44:2531-8 4 Arthritis Care & Research 2002; 47:50-8 5 Acupuncture Med 2002; 2019-21 & BMC Complement Altern Med 2002;2:3 6 Cochrane Database Syst Rev 2002; 1:CD003523 7 Curr Med Res Opin 2001; 17:190-6 & Altern Ther Health Med 2002; 8:50-5 8 Arthritis & Rheum 2004;50(9supp);S644 2 Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States 20 RA and OA Treatment Webcast, November 3, 2005 Pulsed Electrical Stimulation (Bionicare Device) in Knee OA1 • Pulsed Electrical Stimulation (PES) is a low frequency, low amplitude, voltage source, Monphasic, spiked signal to the knee via skin surface electrodes. • Use for 6 or more hours per day • Showed mild but statistically significant improvement in physician’s global evaluation, patient’s evaluation of pain, and patient’s evaluation of function of the treated knee.1 • Mild skin reactions (thought to be to the gel) in 24% • The main author of the study was Thomas Zizic J Rheumatol 1995;22:1757-61 OA: MANAGEMENT SUMMARY • First be sure the pain is joint related • Discuss disease and concerns of patient • Initial treatment o Modifications - weight loss, modify activities and occupations, assistive equipment o Strengthening and reconditioning program o Topical agents and local heat or ice o Acetaminophen OA: MANAGEMENT SUMMARY • Second-line approach o NSAIDs o Nutraceuticals - glycosamine and chondroitin sulfate o Intra-articular agents or lavage Steroids Hyaluronan o Tramadol or Opioids o Alternative Therapies • Third-line o Arthroscopy o Osteotomy o Total joint replacement ADDITIONAL NOTES: Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States 21 RA and OA Treatment Webcast, November 3, 2005 Biography of Dr. David Collier Dr. David H. Collier is the Chief of the Division of Rheumatology at Denver Health Medical Center, and a Professor of Medicine at University of Colorado Health Sciences Center. He received a Bachelor of Science degree from California Institute of Technology in Pasadena, California, and his MD from the Washington University School of Medicine in St. Louis Missouri. Since his graduation, Dr. Collier has been a prolific researcher, writer, and presenter. He received an Excellence in Teaching Award from the Medical Student Council at the University of Colorado Health Sciences Center in 1998, received the 6th Annual Faculty Outstanding Clinician Award of the Year in 2000 by the Denver Health and Hospital Medical Staff, and was given the Rocky Mountain Chapter of the Arthritis Foundation Physician of the Year Award in 2005. Dr. Collier currently serves on the Board of Directors for the Rocky Mountain Chapter of the Arthritis Foundation, and acts as Chairman of their Patient Advocacy Committee. Description of CHAMPS CHAMPS, the Community Health Association of Mountain/Plains States, is a nonprofit organization dedicated to providing a coordinating structure of service to nonprofit primary health care programs whose primary purpose is to serve the medically indigent and medically underserved of Region VIII (CO, MT, ND, SD, UT, and WY). CHAMPS also serves the Region VIII State Primary Care Associations that assist those nonprofit primary health care programs. Currently, CHAMPS programs and services focus on education and training, collaboration and networking, policy and funding communications, and the collection and dissemination of regional data for Region VIII Community Health Centers and Primary Care Associations. For more information, please visit www.champsonline.org or call (303) 861-5165. Description of the Arthritis Foundation The Arthritis Foundation exists to help clinicians help their patients. The Arthritis Foundation supports research, and offers a wide variety of classes, presentations, and free lectures to provide information and instruction that can help people with arthritis take control and ensure high quality of life. The mission of the Arthritis Foundation is to improve lives through leadership in the prevention, control, and cure of arthritis and related diseases. The Foundation is the only organization in the country committed solely to helping find a cure for this disease which is the leading cause of disability in the US, and to making life easier for those who are faced with the challenges of arthritis. The Rocky Mountain chapter, located in Denver, Colorado, serves the more than 1 million people with arthritis in Colorado, Wyoming, and Montana. For more information, please visit www.arthritis.org or call 1-800-475-6447. Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States 22