Antirheumatic Drug Therapy J. Cush

Pain in Wrist l l l l l 54 yr. old woman c/o L > R wrist pain x 5 mos. Self treated with Tylenol or Advil (2 tabs bid) without help NO Hx of trauma, infection, fever, numbness, ∆BM PMHx: HTN, lymphedema, PUD age 34, TAHBSO Meds: HCTZ, omeperazole 20/d, ASA 81 qd, premarin EXAM: nl ROM, no pain over carpus; B/L CMC1 hypertrophy and tenderness. + crepitus in knees v 2+ BLE edema v Ecchymoses on arms v Left Thyroid nodule felt Pain in the Wrist l l l Additional Physical Exam? Laboratory Investigations? Radiographs? Initial Choice of Treatment? v NSAIDs vs. COX2 inhibitors v Analgesics: acetaminophen vs. tramadol v Ice or Heat v Wrist or CMC1 Splint v Topical: capsaicin qid v Local Steroid injection v Systemic steroids v Glucosamine History of NSAID Development Year 1898 1952 1964 1969 1972 1974 1984 1989 1999 2002 2005 Agent ASA Butazolidin Indomethacin Ibuprofen Naproxen Diclofenac Piroxicam Nabumetone/Oxaprozin Celecoxib/Rofecoxib Valdecoxib COX-2 withdrawn Comment Willow bark extract 1st synthetic NSAID Longest selling NSAID 1st approved for OTC use Rheumatology favored >20 yrs 1st to use DTC Ads 1st qd NSAID Better GI safety 1st COX-2 inhibitors 2nd generation COX-2 drug Rofecoxib, valdecoxibCVS Rise & Fall Vioxx W/D DTCA COX2 16K PGE2 death EGD NSAID ASA GI 1868 1898 1952 1965 1992 1994 1998 2002 2004 Available Rx NSAIDs NSAIDs SALICYLATES COX-2 INHIBITORS Diclofenac (Voltaren) Aspirina (Easprin) Celecoxib (Celebrex) Diclof/Misoprostol(Arthrotec)b Diflunisal (Dolobid) Valdecoxib (Bextra) Fenoprofen (Nalfon) Salsalate (Disalcid) Rofecoxib (Vioxx) Flurbiprofen (Ansaid) Choline salicylate (Trilisate) Ibuprofen (Motrin)a Magnesium salicylate Indomethacin (Indocin) Ketoprofen (Orudis)a In Development Meclofenamate Etoricoxib Mefenamic acid (Ponstel) Parecoxibc Nabumetone (Relafen) Lumiracoxib Naproxen (Naprosyn, Anaprox)a Oxaprozin (Daypro) a Also available as over-the-counter preparations in the U.S. Piroxicam (Feldene) b Combination tablet of NSAID/synthetic prostaglandin E 1 Sulindac (Clinoril) c Parenterally administered Tolmetin (Tolectin) 2004 Physician’s Desk Reference NSAID l l Action: reduces Pain, inflammation, Stiffness v anti-pyretic In Osteoarthritis clinical trials v NSAID > Tylenol > Placebo v NSAID = Analgesics in some patients NSAID Toxicity l l Renal: renal failure, interstitial nephritis,  HTN GI: Gastritis, GERD, Gastric > Duodenal ulcers v Risk Factors: » High dose (multiple) NSAIDs » Age > 60 yrs » Hx of Peptic Ulceration » Corticosteroid use » Anticoagulant use » Debility l Hematologic: impaired bleeding time, interacts w/ anticoagulants, anemia, cytopenias NSAID Gastropathy in USA Diagnosis RA Probable RA OA Total Exposed 2,000,000 3,000,000 8,000,000 13,000,000 Annual Estimates Hospitalization Deaths 30,000 4400 21,000 56,000 107,000 3300 8800 16,500 Total Cost (~$12,500/hospitalization) = $1,337,500,000 Singh. Am J Med 105:32S, 1998 In Vitro Selectivity: COX-2/COX-1 Ratio lumiracoxib etoricoxib rofecoxib valdecoxib etodolac nimesulide diclofenac celecoxib meloxicam > 50-fold COX-2 selective 5- 50-fold COX-2 selective fenoprofen < 5-fold COX-2 ibuprofen selective tolmetin naproxen aspirin indomethacin ketoprofen flurbiprofen ketorolac 0 1 2 Increasingly COX-1 Selective Warner et al. FASEB J. 2004:18:790-804 -3 -2 -1 Increasingly COX-2 Selective 3 Range of COX Selectivity for COX-1 and COX-2 (log10 IC50 COX-2/COX-1) NSAID Rx GUIDELINES (1) prescribe only one NSAID at a time; ask pts about OTC use (2) use the lowest effective dose; (3) educate the patient on their proper use (ie, take with meals or antacids) and cautionary symptoms (ie, nausea, melena, syncope from anemia/blood loss); (4) do not use NSAIDs when analgesic therapies, low dose corticosteroids or intraartcular steroids may be effective; (5) avoid NSAIDs in those with renal insufficiency, previous peptic ulceration and gastrointestinal bleed, those receiving anticoagulants or a possessing bleed diathesis and those with aspirin hypersensitivity (nasal polyps, rhinitis and asthma); and (6) in the elderly, NSAIDs should be used with extreme caution and at the lowest possible analgesic dose, only after other approaches have been tried. NSAID Rx GUIDELINES 7) Gastrointestinal toxicity is most likely in those receiving high dose NSAIDs, multiple NSAIDs, the elderly, previous hx of peptic ulcer disease and upper gastrointestinal bleeding, Steroids use, and Debility 8) Symptoms of dyspepsia, nausea may be effectively treated with H2 blockers (ie, ranitidine, cimetidine), but these agents do not protect against PUB 9) There is a poor correlation between symptoms and endoscopically proven ulceration or bleeding 10) Misoprostil and omerprazole may prevent NSAID-induced GI ulceration and bleeding, but should NOT routinely be used for ulcer prophylaxis. Cytoprotective therapy is reserved for patients who are at high risk for gastrointestinal ulceration and bleed, have failed alternative therapies (ie, analgesics) and must receive NSAID therapy. 11) COX-2 Inhibitors: preferred in high risk pts @ low CVS risk Cost Comparison of NSAIDs AWP 2004 – 30 day Rx Trade Rx Acetaminophen Salsalate Ibuprofen Naproxen Sulindac Piroxicam Diclofenac Etodolac Oxaprozin Tolmetin Nabumetone Mobic Celebrex Vioxx Bextra Max Dose 4000 mg/d 3750 mg/d 3200 mg/d 1250 mg/d 400 mg/d 20 mg/d 150 mg/d 1200 mg/d 1800 mg/d 1200 mg/d 2000 mg/d 15 mg/d 400 mg/d 50 mg/d 40 mg/d Generic $14 $42 $8 $10 $51 $61 $29 $17 $97 $47 $132 Brand $20 $239 $85 $173 $170 $96 $221 $158 $213 $121 $192 $105 $257 $125 $179 Disease Modifying OA Drugs (DMOADs) l l l l l l l Glucosamine NSAIDs Tetracyclines MMP inhibitors Diacerin Heparinoids MTX Acetaminophen l l l l l 325 mg; 500 mg; 650 mg (sustained release) Analgesic, antipyretic; not antiinflammtory MOA? May inhibit COX-2, CNS effects Avoid in liver disease, EtOH Adverse effects: allergy, rash v Rare: hepatotoxicity, hepatic failure (>10gr), renal impairment, agranulocytosis, anaphylaxis Surgery in Osteoarthritis l l Indications for TKR v Intractable pain v Disability v Advanced damage by Xray Joint Replacement 2001 v Knee 267,000 v Hip 168,000 New RA and Ongoing Care l l l l l l 37 yoWF w/ RA transfers her care to you. Doing well! RA x 6 years, dx based on polyarthritis, AM stiff=2 hrs, ESR 79 mm/hr, +RF 612 IU. Initial Rx with piroxicam, sulfasalazine. Now stable on MTX. Meds: MTX 15/wk, folate 1 mg/d, prednisone 7 mg/d Exam: no evidence of synovitis, tenderness, nodules v mild reducible swan neck changes in fingers Labs: H/H 13/38, W 5.6, ESR 22, AST 32. RF+ Plan: What would you do? v Wean off/down prednisone by 1 mg every 2-3wk New RA and Ongoing Care l l l 3 weeks later, pt. calls, now bothered by increasing pain, stiffness and fatigue x 2+ wks Current prednisone dose 4 mg/d What will you do? v Increase prednisone back to 6 mg qd v Increase prednisone to 10 mg qd v Decrease prednisone to 3 mg qd v Start Pt on COX2 inhibitor v Start Pt on analgesic v Have patient come in for urgent visit v Caution patient on steroid withdrawal symptoms Steroid Withdrawal Syndrome l l l Steroids decrease CRH, ACTH, and Cortisol HPA axis suppr, loss of diurnal rhythms w/ chronic steroids > 5 mg/d ?How much/how long to suppress HPA axis and how long it lasts? v Short term use < 4 weeks, show no suppression l Symptoms: fatigue, lethargy, flu-like feeling, arthralgia,myalgia, stiffness, nausea, anorexia, depression (fever?) Adrenal insufficiency: Hypotension, shock, hypoglycemia, hyponatremia>hyperkalemia Suggested weaning regimens v v v l l 80mg (decr 20-10mg) → 60 → 50 → 40 → 30 → 20 (q 2-4 weeks) 20mg (decr 5mg) →15 → 10 (q 2 – 4 weeks) 10mg: decrease by 1 mg every 2-4 weeks Prednisone l l l l l l Deltasone, Orasone Mechanism: powerful antiinflammatory, inhibition of PG, LPO, Cytokines, Proteases Clinical Responses: effective at low doses (2.5-10 mg/d) stiffness, pain, swelling v 10+ mg/d may protect against bone erosion v High doses (40-60 mg/d) for life-threatening disease v High doses=higher mortality & infections Doses: 5-10 mg/d (Tabs 1,2.5,5,10,20,50 mg) AE: HTN, BS, ↓Chol, Wt gain, acne, striae, bruises, weakness, osteoporosis, Fx, infection, cataracts, adrenal insufficiency, peptic ulcer Steroids are rapidly effective and chronically dangerous Early Rheumatoid Arthritis l l l l 55 yoWM Polyarthritis x 16wks, hands, feet, knees. AMStiff = all day Tender 34 Swollen28 (+erosions on XRAY) Labs initially neg RF, ESR 90, repeat shows +RF 14 IU l l Rx: Prednisone 10/d LOE What do you Rx next? Classifying Disease Activity Feature Swollen Joints ESR or CRP Erosions Nodules XtraArticular Serum RF Function SLOWLY PROGRESSIVE Few nl or modest Absent Absent Absent nl or modest Preserved AGGRESSIVE Many Very elevated May be present May be present May be present Very elevated Impaired Rx Slowly Progressive RA l Consider in NSAID nonresponsive patients: v Hydroxychloroquine v Methotrexate v Sulfasalazine v Auranofin v Minocycline v Fish Oils Rx of Aggressive RA v Consider early, NOT LATE, v v Methotrexate v v Intramuscular gold v Hydroxychloroquine v v Sulfasalazine v v Azathioprine v v D-Penicillamine v v Combination DMARD v Cyclophosphamide v Dapsone Cyclosporine Leflunomide Etanercept Infliximab Adalimumab Anakinra DMARD Survival 1.0 0.8 Azathioprine (n = 56) Hydroxychloroquine(n = 228) Estimated Continuation Methotrexate (n = 253) Oral gold (n = 84) Parenteral gold (n = 269) Penicillamine (n = 193) 0.6 0.4 0.2 0 0 10 20 30 Months 40 50 60 Pincus T, et al. J Rheumatol. 1992;19:1885–1894. Gold l l l l l l l Parenteral: Aurolate, Solganol ORAL: Ridura Mechanism: unknown, inhibits macrophages Clinical Responses: 30-50% (less than 40% still taking Au after 2 years) Formulations: 3 mg tabs; injectable vials Dose PO: 3 mg bid v IM: 10 mg, 25 mg, then 50 mg q wk (1 Gr) AE: Common - rash, itch, oral ulcers, proteinuria v Rare: thrombocytopenia, leukopenia, pneumonitis, colitis v (diarrhea common w/ PO) Gold is no longer the Gold Standard Hydroxychloroquine l l l l l l l Plaquenil (HCQ) Mechanism: unknown, inhibits lysosomal enzymes and macrophage function. Clinical responses: 30-40% Tabs: 200 mg Dose: 200 - 400 mg qd (qd or bid) AE: rash, itching, Nausea, diarrhea, retinopathy v must monitor w/ visual fields & SLE q 12 mos v Neuromyopathy is rare HCQ: May be the safest but weakest DMARD Sulfasalazine l l l l l l l Azulfidine (SSZ) Mechanism: unknown, inhibition of B cells and angiogenesis Clinical Response ~ 50% Tabs: 500 mg, EC coated Doses: 1000-4000 mg/d (3G/d), bid or tid AE: N/V, diarrhea, abdominal pain, rash, LFTs, oligospermia, Stevens-Johnson, anemia, leukopenia, thrombocytopenia SSZ: Higher dose associated w/Effect & GI Toxicity Methotrexate Use l l l l Indications: RA, psoriasis, mycosis fungoides, neoplasms MTX Mechanism of action v Dihydrofolate reductase inhibition  Toxicity > efficacy v Inhibition of purine pathway and release of adenosine Clinical Response Rates v Low dose weekly @ 7.5 mg/wk - Paulus 37??% v US301, US302 - ACR20 = 46-50% v Durable: > 65% still on MTX after 2 years Dose: 7.5 - 25 mg q week v Start 10 mg/wk (increase by 5 mg q month up to 20 mg) v Lower doses in elderly, renal insufficiency, intolerant v Daily folate 1 mg qd given to improve safety Methotrexate Use l l l l l Contraindications & Precautions: pregnancy or not using reliable contraception, active infection,decreased bone marrow function, hepatitis, hepatic dysfunction, alcohol abuse, renal insufficiency Common adverse events (AE): mucositis, painful oral ulcers, nausea, vomiting, diarrhea. Treat AW  IM or Vitamin A Uncommon AE: rash, alopecia, CNS (headache, dizzy, malaise). Treat CNS  DM Rare AE: leukopenia, hypersensitivity pneumonitis, hepatitis, hepatic cirrhosis Monitoring: Monthly CBC, LFTs x 3 mos; then q 6wk » Liver biopsy (only in psoriasis) done every 1500 mg. l Drug interactions: SMX/TMP; insignificant rxn w/ NSAIDs Leflunomide l l l l l l Mechanism of action v inhibits pyrimidine synthesis by blocking dihydroorotate dehydrogenase Clinical Response Rates v ACR 20%: ~ 50% v Durable? 2 year study results Dose: 100 mg x 3d; 10-20 mg qd maintenance Common AE: Diarrhea, nausea, alopecia, LFTs, rash Rare AE: Leukopenia, HTN, hyperuricemia Arava in News? 129 Hepatic rxns, 12 deaths, 56 hospitalizations? (see HOTLINE rheumatologogy.org) v EULAR 2002: AETNA Cohort study LEF < MTX, NSAID Cyclophosphamide l l l l l l Cytoxan (CTX) Mechanism of action: cytotoxic alkylating agent cross links DNA Indications: Chemo, mycosis fungoides, RA v SLE: III/IV GN, Cerebritis, severe hemolytic anemia v Vasculites: Polyarteritis nodosa, Wegeners Form: Pills 25, 50mg; IV Dose: varies PO 2 mg/kg; IV 500-750 gm/m2 Toxicity: Secondary malignancy, sterility, hemorrhagic cystitis, cytopenia, anorexia, N/V/D, HA, dark skin/nails DMARD Adverse Events & Safety Monitoring Drug Hydroxychloroquine Common AE rash, pruritis, nausea, diarrhea pruritic rash, oral ulcers, proteinuria, diarrhea, Diarrhea, pruritic rash, oral ulcers Rare/Serious AE Retinopathy, neuromyopathy thrombocytopenia, granulocytopenia, hypersensitivity pneumonitis, nitritoid reaction, chrysiasis Safety Monitoring Visual Sxs, Fundoscopy, slit lamp examin,visual field testing q 12 mos. Baseline: CBC, UA, creat. CBC, UA q 1-2 weeks x 20 weeks; then same at each injection IM Gold Auranofin (oral gold) thrombocytopenia, granulocytopenia, hypersensitivity pneumonitis hemolytic anemia, leukopenia, thrombocytopenia, Stevens-Johnson syndrome Baseline: CBC, UA, creatinine; then CBC and UA q 1-2 mos. Baseline: CBC, LFTs (& G6PDH for at risk pts). Then CBC q 2-4 weeks in 1st 3 mos, then q 3 mos. Baseline: CBC, creatinine, LFTs, Hepatitis B and C CBC LFTs q mo. X 6 mos; then q 1-2 mos. Sulfasalazine nausea, abdominal pain, diarrhea, rash, increased hepatic enzymes, oligospermia Leflunomide Nausea, diarrhea, alopecia, rash, increase LFTs Nausea, abdominal pain, hepatic abnormalities Hepatotoxicity, myelosuppresion, hypertension leukopenia, thrombocytopenia infection (eg, H. zoster), secondary neoplasia, pancreatitis Azathioprine Baseline: CBC, creatinine, LFTs CBC q 1-3 mos Infliximab and Etanercept: Structures Murine/Human Chimeric IgG1 Murine Light chain variable region Fab Murine Heavy chain variable region S S S S Human Heavy chain constant region sTNF-RII / Ig Human p75 TNF receptor S S SS 220 Hinge 235 region Hinge region 341 S S Human Heavy chain constant Fc region S S S S 341 Fc S S 446 COO 446 COO TNF Inhibitors l l l l l l l l l Infliximab: Chimeric IgG mAb Etanercept: Dimeric p75/IgG receptor construct Adalimumab: Human IgG mAb Binds/inhibits cell bound, circulating TNFα ½ life: 4-5d  2 weeks Indications: RA, early RA, AS, Psoriatic arthritis, Psoriasis Route: sc BIW, qWk, EOW; q 6-8 weeks IV Response: ACR20 = 50-80%!! Durable like MTX AE: ISR, Infusion rxn, infection, MS, ANA, DNA, Tbc, fungal infections, Cytopenias Who Should get Novel Therapies or Cytokine Inhibitors? Recommendations for the Treatment of RA* 1. Fundamental goal is elimination of synovitis & disease activity 2. Use the most effective DMARD (at optimal doses) first. 3. Methotrexate is the most common DMARD used to treat RA. 4. Early DMARD therapy is effective 5. All RA patients should be on DMARDs or biologic therapies 6. Prognostic factors should influence prescribed DMARD(s). 7. Biologic treatments are appropriate depending on disease activity and response to DMARD therapy 8. Anti-cytokine therapy should not be reserved for advanced or DMARD-resistant disease, but instead should be used in those with rapidly advancing aggressive disease. * Exerpted from Wolfe et al Evolving RA Treatment Paradigm Past Approach Evolving Paradigm • Early Diagnosis • Early Aggressive Rx • Evidenced based Combination regimen • Anti-Cytokine • Novel DMARDs • Combination for MTX non or partial responders • Possibly reduce or d/c Prednisone Initial treatment: Combo DMARD OR Combo Biologic MTX Etanercept Clinical Responses ACR20 80 70 75 70 71 ACR50 ACR70 Etanercept/Placebo (Moreland N Engl J Med 1997) % of Patients 60 50 59 Etanercept/Placebo 57 (Moreland Ann Intern Med 1999) Etanercept/Placebo 40 39 34 (European Etanercept Investigators Arthritis Rheum 1999) 40 30 Etanercept/Methotrexate (Weinblatt N Engl J Med 1999) 20 20 10 0 15 13 15 ACR responses at 6 months Global Safety/Efficacy of Etanercept in RA Klareskog, L, Moreland L, Cohen S. ACR 2002 Discontinuations 100 80 60 40 20 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Reason: Loss of efficacy Adverse event Patient decision Protocol issues Lost to follow up Other Total Early RA (U.S.) Advanced RA (U.S.) Advanced RA (Europe) % Remaining on Study 8% 9% 5% 2% 1% 3% 29% Months Withdrawal of Methotrexate and Prednisone Change at 3 Years *paired-rank sum` test (n=68) MTX 20 17.6 p<0.001* 10 Pred p<0.001 6.4 5 Mean MTX dose (mg/wk) 15 10 5 0 9.3 Mean Predinsone dose (mg/d) 2.3 0 Baseline Year 3 Baseline Year 3 Increased Decreased or D/C Discontinued Methotrexate 3% 68% 39% Prednisone 3% 85% 59% Rheumatoid Disease Progression Remicade: Xrays Week 102 Etanercept 25mg v Methotrexate 20 18 16 14 Total Sharp Score 12 10 8 6 4 2 0 0 1 2 Years Estimated Enbrel 25 DMARDs that Retard Radiographic Damage l l l l l l l l Cyclophosphamide Methotrexate Leflunomide Sulfasalazine Infliximab Etanercept Adalimumab Anakinra TNF Inhibitor: Adverse Events Etanercept Adalimumab Common Infliximab Infusion Rxn URI +ANA +dsDNA Drug-ind lupus M.Tbc Histo, fungal, etc MS/MS flare Injecion site Rxn URI +ANA +dsDNA Drug-ind lupus M.Tbc, fungal Aplastic anemia MS/MS flare Uncommon Rare Safety Issues With Biologic DMARDs l l l l l l l l Serious infections Opportunistic infections (eg, TB) Malignancies Demyelination Hematologic abnormalities Administration reactions Congestive heart failure Autoantibodies and lupus-like syndrome Algorithm for TB Testing New REMICADE® patient has office visit Administer PPD skin test Evaluate PPD test results Test Negative Test Positive Perform chest x-ray/Signs/Sxs Initiate REMICADE Normal CXR Initiate latent TB treatment Initiate REMICADE Active TB Treat active TB to resolution Initiate REMICADE PPD Positivity and Remicade 34 yr.old Korean female RA x 8 mos + PPD 19mm (no Sxs, neg CXR) IL-1 Blocking Therapy: Anakinra (KINERET®) Class IL-1 receptor antagonist Construct Half-life Binding Target Administration Recombinant, human 6 hours IL-1 receptor 100 mg SC daily Kineret (anakinra) + MTX in RA Week 24 45 40 35 30 25 20 15 10 5 0 ACR20 ACR50 Placebo ACR70 Kineret Withdrawls % responders Injection Site Rxn Week 2 Week 4 Goals of Therapy l l Prevention Remission v Completely suppress immune driven inflammation v Induce immunologic tolerance v Prevent damage, promote healing of tissues v Minimize untoward effects of treating agents Direct Costs of RA* Hospital admissions 51.7% Other expenses 7.5% Testing 4.7% AHP visits 1.4% Physician visits 8.6% Drugs 26.1% *Costs are shown for the pre-biologic DMARD era. AHP = allied health professional Yelin E, Wanke LA. Arthritis Rheum. 1999;42:1209–1218.