Rheumatoid Arthritis: Constantly Evolving Treatment Approaches Jody Garry, Pharm.D. Primary Care Pharmacy Resident VA Medical Center - Iowa City Presentation Overview Pathophysiology & epidemiology Diagnostic criteria - American Rheumatism Association (ARA) Rheumatoid Arthritis (RA) management guidelines - American College of Rheumatology (ACR) Treatment options Number of People Affected by Arthritis Epidemiology 0.8% of adults worldwide U.S. 2.1 million 25/100,000 men 54/100,000 women 250,000 hospitalizations/year 9 million physician visits/year http://www.fda.gov/fdac/graphics/1996graphics/arthritis.jpeg Am Fam Physician 2005;72:1037-47,1049-50. Medical Costs $5 billion/year Cost Productivity Losses $20 billion/year 50% of potential earnings Etiology Environment/pathogenic organisms Parvovirus Rubella Epstein-Barr Family genetics Major Histocompatiblity Complex (MHC) HLA-DR1 HLA-DR4 http://www.remicade.com/global/hcp/hcp_ra.jsp Am Fam Physician 2005;72:1037-47,1049-50. 1
Boutonniere deformity of thumb www.medicinenet.com Swan-neck deformity of fingers Ulnar deviation of metacarpophalangeal joints Pathophysiology s & B- Pathophysiology Inflammation & IL-1 Metalloproteinases Cells Inflammation Collagen Degradation Bone & Cartilage Erosion Signs and Symptoms Typical presentation Pain Stiffness Prodromal Symptoms Fatigue/weakness Low-grade fever Anorexia Muscle aches Extra-articular articular Signs and Symptoms Dermatological nodules Pulmonary Fibrosis Effusions Pulmonary Sjogren s s Syndrome Neurological Peripheral neuropathy Carpal tunnel syndrome Neurological Pericarditis Am Fam Physician 2005;72:1037-47,1049-50. 2
Test ESR H/H CRP Platelets + WBC Laboratory Findings Description non-specific, with treatment response anemia of chronic disease inflammation thrombocytosis negative in 30% of patients turbid synovial fluid ESR = erythrocyte sedimentation rate, H/H = hemoglobin and hematocrit, CRP = C- reactive protein, = rheumatoid factor, WBC = white blood Rindfleisch, JA. Diagnosis and Management of Rheumatoid Arthritis Pharmacotherapy: A Pathophysiologic Approach. 5th ed. New York: McGraw-Hill, 2002: 1623-37. Criteria ARA Criteria for Classification Definition 1. Morning stiffness In and around the joints for at least 1 hour. 2. Arthritis of 3 or Joints must have soft tissue swelling or fluid (possible more joint areas joints: PIP, MCP, wrist, elbow, knee, ankle, & MTP). 3. Arthritis of hand At least 1 joint involving the wrist, MCP, or PIP joints. joints 4. Symmetrical Simultaneous involvement of the same joint areas on arthritis both sides of the body. 5. Rheumatoid SQ nodules, over bony prominences, extensor nodules surfaces, or in juxtaarticlar regions. 6. Serum Abnormal amounts of serum. rheumatoid factor 7. Radiographic Hand and wrist x-rays, including that show typical changes changes of erosion or loss of density adjacent to affected joints. Pharmacotherapy: A Pathophysiologic Approach. 5th ed. New York: McGraw-Hill, 2002: 1623-37. Treatment Goals ACR Improvement Criteria Early Diagnosis Early Treatment Limit Joint Destruction Remission ACR 20 20% improvement in tender/swollen joint count 20% improvement in 3/5: ACR 50 ACR 70 Patient s s global assessment Physician s s global assessment Patient s s assessment of pain Degree of disability Level of acute-phase reactant (CRP or ESR) Managed Care 2006; 15(Suppl 7):2-14. Treatment Options Traditional disease- modifying antirheumatic drugs (DMARDs) Biological agents Traditional DMARDs Hydroxychloroquine (HCQ) Mild/moderate disease Does not slow radiographic damage Retinal toxicity Sulfasalazine (SSZ) Mild/moderate disease Slows radiographic changes Nausea/abdominal pain Methotrexate (MTX) Moderate/severe disease Slows radiographic progression LFTs every 3-43 4 months 3
Traditional DMARDs Pros Improve signs and symptoms Reduce inflammation Some slow radiographic progression Inexpensive Well studied Cons Do not affect underlying disease Limited efficacy Bone erosions Pros Cons Biological ents Antagonists Etanercept Infliximab Adalimumab Mechanism Etanercept (Enbrel ) TNF-Fc Fc fusion protein Inactivates TNF 50 mg SQ once weekly or 25 mg SQ twice weekly Indicated alone or MTX combination Patient Information Refrigerate Injection sites Infliximab (Remicade ) Mechanism TNF antibody 3 mg/kg IV weeks 0, 2, and 6, then every 8 weeks Mechanism Indicated with MTX Lab Monitoring: LFTs Contraindications Class III/IV heart failure 4
Adalimumab (Humira ) Mechanism TNF antibody Mechanism 40 mg SQ every other week Indicated alone or with DMARD Not anakinra Efficacy of MTX and TNF Inhibitors TEMPO ASPIRE PREMIER RA 3 months 3 years Endpoints ACR 50 ACR 70 Disease Activity Score (DAS-28) Swollen joints Tender joints ESR Global health Trial TEMPO ASPIRE PREMIER n 229 1049 799 Regimen MTX + placebo Etanercept + placebo MTX + etanercept MTX + placebo MTX + 3mg/kg IFX MTX + 6mg/kg IFX MTX Adalimumab MTX + adalimumab ACR50 ACR70 (%) (%) 43 58 69 # 32 46* 50* 43 37 59 ## 23 33 44 # 21 33** 37* 28 27 47 ## Remission (DAS 28 <2.6) 19 34 43 15 21*** 31* 25 25 50 ## MTX = methotrexate, IFX = infliximab, DAS = Disease Activity Score * p<0.001 compared to MTX + placebo; ** p=0.002 compared to MTX + placebo; ***p=0.065 compared to MTX + placebo; # p<0.05 compared to MTX alone; ## p<0.001 compared to MTX alone and adalimumab alone Rheum Dis Clin N Am 2005;31:745-62. Efficacy of MTX and TNF Inhibitors Active infection Live vaccines Antagonists ADR Immunosuppression Injection site reaction Precautions Demyelination Lymphoma N Engl J Med 2004;350:2167-79. Baseline Evaluation Hepatitis B Tuberculosis Patient Education Benefit: days 12 weeks risk IL-1 Antagonist 5
Mechanism Anakinra (Kineret ) IL-1 1 receptor antagonist 100 mg SQ daily Renal dosing Indicated alone or combo DMARDs E. coli hypersensitivity TNF antagonists ADR Anakinra (Kineret ) ADR Injection site reaction /neutropenia Lab Monitoring CBC/Neutrophil counts Patient Information Refrigerate Injection sites risk N Engl J Med 2004;350:2167-79. N Engl J Med 2004;350:2167-79. Anakinra with MTX Randomized, double-blind, blind, placebo controlled Intervention Anakinra 100 mg SQ daily + MTX 10-25 mg/week (n=250) Placebo + MTX 10-25 mg/week (n=251) Patient population Currently active RA Radiographic bone erosion MTX x 24 weeks ADRs Injection site reaction (65% vs 24%) (33% vs 26%) Ann Rheum Dis 2004;63:1062-68. Patients (%) ACR Responses at Week 24 100 80 60 40 20 0 P=0.001 38 Anakinra 100 mg (n=250) 22 P <0.01 ACR 20 ACR 50 ACR 70 Ann Rheum Dis 2004;63:1062-68. 17 9 Placebo (n=251) P <0.05 6 2 T-Cell Inhibitor 6
Mechanism Abatacept (Orencia ) Inhibit T activation <60 kg: 500 mg 60-100 kg: 750 mg >100 kg: 1000mg IV at weeks 0, 2, and 4, then every 4 weeks Indicated alone or combo DMARDs Abatacept for RA Refractory to Inhibition Randomized, double-blind blind Patient population ACR criteria, RA x 1 year Inadequate response to anti-tnf therapy Intervention ADRs Abatacept (n=223) Placebo (n=99) (37.6% vs 32.3%) Infusion reaction (5.0% vs 3.0%) N Engl J Med 2005;353:1114-23. 100 80 60 Patients (%) 40 20 ACR Responses at Six Months 0 Abatacept (n=256) P <0.001 50.4 N Engl J Med 2005;353:1114-23. 19.5 P <0.001 20.3 3.8 Placebo (n=133) P=0.003 10.2 1.5 ACR 20 ACR 50 ACR 70 Abatacept (Orencia ) ADR TNF antagonists Live vaccines COPD exacerbation Headache Lymphoma Patient Information risk B-Cell Inhibitor 7
Mechanism Rituximab (Rituxan ) Mechanism B-cell depleting antibody 1000 mg, day 1 and 15 Premedicate with a corticosteroid Indicated with MTX, failed TNF agents Contraindications Anaphylactic reactions to mouse proteins Efficacy of B-CellB Cell-Targeted Therapy with Rituximab in Patients with RA Patient population ARA criteria RA with10 mg MTX/week Intervention ADRs MTX (> 9 mg/week) Rituximab (1000 mg days 1 & 15) Rituximab + cyclophosphamide (750 mg days 3 & 17) Rituximab + MTX Infusion reaction N Engl J Med 2004;350:2572-81. 100 80 60 Patients (%) 40 20 ACR Clinical Responses at Week 24 0 38 P=.025 65 N Engl J Med 2004;350:2572-81. P=.001 76 P=.003 73 MTX (n=40) Rituximab (n=40) Rituximab + cyclophosphamide (n=41) Rituximab + MTX (n=40) P=.005 P=.005 41 43 33 13 5 15 23 15 ACR 20 ACR 50 ACR 70 P=.048 Rituximab (Rituxan ) ADR Infusion reaction Mucocutaneous reaction Arrhythmias Renal toxicity Hepatitis B Monitoring Infusion reaction Hepatitis B CBC Patient information risk Risk of Malignancies and Infection in Anti-TNF Therapy ACR Treatment Algorithm Establish Diagnosis of RA Early Meta-analysis analysis of 9 randomized, placebo- controlled trials Infliximab or adalimumab for at least 12 weeks Malignancies Serious Infection Tx Group Placebo (n=3493) (n=1512) 29 126 3 26 Odds Ratio 3.3 2.0 Primary Care Physician Rheumatologist Initiate Therapy: 1. Patient Education 2. DMARD(s) 3. NSAIDs/Steroids 4. Physical Therapy Periodically Assess Disease Activity JAMA 2006;295:2275-2285. 8
ACR Treatment Algorithm Periodically Assess Disease Activity Adequate Response MTX Naive MTX Combo Rx Other Mono Rx Change/Add DMARDs Combo Rx Inadequate Response Suboptimal MTX Response Other Mono Rx Mono Biologics Combo Biologics Place in Therapy 1. Traditional DMARDs MTX 2. TNF antagonists Etanercept Infliximab Adalimumab 3. Other Biologics Anakinra Abatacept Rituximab Drug Etanercept (Enbrel ) Infliximab (Remicade ) Adalimumab (Humira ) Anakinra (Kineret ) Abatacept (Orencia ) Rituximab (Rituxan ) Biologicals for Treatment of RA FDA Approval Nov. 2, 1998 Aug. 24, 1998 Dec. 31, 2002 Nov. 14, 2001 Dec. 23, 2005 Feb. 28, 2006 Indication(s) Alone or combined with MTX In combination with MTX Alone or combined with other DMARDS Alone or combined with other DMARDS Inadequate response to DMARD; monotherapy or combined Combined with MTX; inadequate response to TNF antagonist Route SC IV SC SC IV IV Usual 25 mg 2X/week or 50 mg/week 3 mg/kg at 0, 2, 6 wks, then every 8 wks 40 mg every- other-week 100 mg daily Weight based dosing 1000 mg Cost of Biological and Traditional DMARDs Medication Etanercept Infliximab Adalimumab Anakinra Abatacept Rituximab Methotrexate Hydroxychloroquine Sulfasalazine www.drugstore.com Cost/year $19,496 $9,422 * $19,496 $18,640 $14,586 * $11,359 * $4,368 $218 $276 *Does not include infusion cost Summary Early pathologic changes Early treatment Medication Advancements Treatment shortfalls Limitations to ACR Guidelines 9