Biological Therapy for Rheumatoid Arthritis

Biological Therapy for Rheumatoid Arthritis Michael Maricic, M.D. Catalina Pointe Rheumatology Rheumatoid arthritis Is often an aggressive disease May have potentially devastating consequences Early, aggressive management can lead to successful control and remission • • • Morbidity & Mortality of Rheumatoid Arthritis Average life expectancy shortened by 5-15 years. Twice as likely to have MI or CVA Increased risk of infection Risk of lymphoma 3 times greater than general population Brown SL, et al. Arthritis Rheum. 2002;46:3151–3158; Bjornadal L, et al. J Rheumatol. 2002;29:906–912; Wolfe F, et al. J Rheumatol. 2003;30:36–40; Doran MF, et al. Arthritis Rheum. 2002;46:2287–2293; Asten P, et al. J Rheumatol. 1999;26:1705–1714; Jones M, et al. Br J Rheumatol. 1996;35:738–745; Baecklund E, et al. BMJ. 1998;317:180–181; Isomaki HA, et al. J Chronic Dis. 1978;31:691–696; Solomon DH, et al. Circulation. 2003;107:1303–1307. Disability in Rheumatoid Arthritis Average lifetime earnings loss = 50% 40%-85% of RA patients will be unable to work within 8-10 years of disease onset Pathogenesis of Rheumatoid Arthritis Current Treatment Targets B cell T cell IFN-γ & γ Neutrophil Antigenpresenting cells B cell or macrophage Pannus other cytokines Macrophage Rheumatoid Factors, anti-CCP Immune complexes Complement Synoviocytes Mast cell TNFα IL-1 Chondrocytes Osteoclast Articular cartilage Production of collagenase and other neutral proteases Bone Adapted from Arend WP, Dayer JM. Arthritis Rheum. 1990;33:305–15 Chronic Inflammation: Imbalance Between Mediators IL-10 TGFβ β IFNγ γ IL-6 IL-8 IL-1β β TNFα α IL-4/IL-13 IL-1Ra Functional Decline Begins Early in RA Moderate loss of function* Severe loss of function* Very severe loss of function* 0 2 5 Years from Symptom Onset 10 * 50% rates of loss of function based on HAQ scores Wolfe F, Cathey MA. J Rheumatol. 1991;18:1298-1306. Most RA Patients Develop Bone Erosions During First 2 Years of Disease 100 90 80 70 60 50 40 30 20 10 0 Baseline 1 2 3 Years of Follow-Up Patients with RA < 1 year underwent annual radiologic assessment of hands and feet. Hulsmans HM et al. Arthritis Rheum. 2000;43:1927-1940. Cumulative Percentage of Patients with Erosions Hands Feet Hands or Feet Hands and Feet 4 5 American College of Rheumatology Diagnostic Criteria for RA Must have at least 4 of the following 7 criteria: - Morning stiffness in joint for at least 1 hour.* Arthritis in 3 or more joint areas (PIP, MCP, wrist, elbow, ankle, MTP)* Arthritis of the hand (wrist, MCP, PIP)* Symmetric arthritis* Rheumatoid nodules Rheumatoid factor Radiographic changes *Must be present at least 6 weeks - Anti-Cyclic Citrullinated Peptide Antibody Specificity RF + Anti-CCP + Anti-CCP + RF + 75% 96% 99% Sensitivity 60% 75% 80% * High titer anti-CCP may predict aggressive erosive disease. Linn-Rasker SP, et al. Ann Rheum Dis 2006;65:366-71 Factors Suggesting Poor Prognosis >20 swollen joints High RF titer Elevated anti-CCPs Elevated Sed Rate Elevated CRP Late implementation of treatment Joint erosions Presence of rheumatoid nodules Socioeconomic characteristics Smoking Poor functional status The Treatment of Rheumatoid Arthritis Therapeutic Window of Opportunity Erosive changes occur early in disease Even a brief delay of therapy can have a significant impact on disease parameters years later Early DMARD treatment appears to reset the rate of progression for years to come O’Dell JR. Arthritis Rheum. 2002;46:283-285. Van der Heijde DM. Br J Rheum. 1995;34 (suppl 2):74-78. Treatment: The Earlier the Better Delayed Treatment Early Treatment 12 Change in Sharp Scores 10 8 6 4 2 0 0 6 12 Months 18 24 (median treatment lag time = 123 days; n = 109) (median treatment lag time = 15 days; n = 97) Patients were treated with chloroquine or azathioprine Lard LR, et al. Am J Med. 2001;111:446–451. Traditional DMARD’s Methotrexate (Rheumatrex) Hydroxychloroquine (Plaquenil) Sulfasalazine (Azulfidine) D-penicillamine Leflunomide (Arava) Azathioprine (Imuran) Gold (Solganol, Ridaura) Cyclosporine (Neoral) Minocycline (Minocin)* *Not FDA approved for RA Conventional DMARD Safety Considerations Hematologic Host Defense Hepatic Gastro-intestinal Malignancy & Lymphoma Reproductive Pulmonary Allergic Cutaneous Renal Ocular Problems with Old Approach Damage can occur early. Risk of morbidity and mortality potentially increases when disease is poorly controlled. Toxicity References: 1. Mulherin D, et al. Br J Rheumatol. 1996;35:1263-1268. 2. McGonagle D, et al. Arthritis Rheum. 1999;42: 1706-1711. 3. Gabriel SE, et al. Arthritis Rheum. 2003;48:54-58. 4. Anderson JJ, et al. Arthritis Rheum. 2000;43:22-29. Evolving RA Treatment Paradigm Current Approach Evolving Paradigm Initial treatment: traditional DMARDs • Early aggressive treatment • Biologics • Combination therapy Biologic DMARD’s – Genetically Engineered Targeted Molecules Similar or Identical to Naturally Occurring Molecules TNFα antagonists: Adalimumab (Humira) Etanercept (Enbrel) Infliximab (Remicade) Interleukin-1 antagonist Anakinra (Kineret) Suppress T-Cell activation Abatacept (Orencia) Anti B-Cell monoclonal antibody Rituximab (Rituxan) Characteristics of Biologics Etanercept Enbrel Target Half Life Construct TNF 3-5 Days Human Once Biweeklyweekly Sub-Cut Infliximab Remicade TNF 8-10 Days Chimeric Once every 4-8 weeks I.V. Adalimumab Humira TNF 10-20 Days Human Once every 1-2 weeks Sub-Cut Anakinra Kineret IL-1 Receptor 4-6 Hrs Human Once Daily Sub-Cut Abatacept Orencia T-Cell Activation 13-16 Days Human Once Monthly I.V. Rituximab Rituxan B-Cell 19 Days Chimeric Twice every 6-12 months I.V. Dosing Route Anti-TNF Monotherapy Improves Clinical Signs & Symptoms 70 60 50 59* Placebo (n = 30) Etanercept 25 mg (n = 78) 40* 40 30 20 15* 11 5 1 10 0 ACR20 * p ≤ 0.001. ACR50 ACR70 Moreland LW et al. Ann Intern Med. 1999;130:478-486. Better Outcomes in Patients Receiving Combination Therapy of MTX & Anti TNFα ACR50 Response Mean Change TSS 70 60 50 40 30 20 10 0 Mean Change in Total Sharp Score 61 46 42 43 37 59 12 10 8 6 4 2 0 5.7 3 1.3 10.4 Patients (%) 5.5 1.9 year 1 year 2 MTX Adalimumab MTX + Adalimumab year 1 year 2 Breedveld FC Arthritis Rheum 2006; 54(1): 26-37 Half of Patients on Anti TNFα+MTX Achieve Clinical Remission by DAS28<2.6: 2-year Data 60 50 % of Patients 40 30 20 10 0 Adalimumab + MTX Adalimumab MTX 23 25 21 25 49* 43* Week 52 Week 104 *p<0.001 vs adalimumab alone and MTX alone Breedveld FC Arthritis Rheum 2006; 54(1): 26-37 Anti TNF + MTX Combination Slows Radiographic Progression 14 12 Mean Change in Total Sharp Score 12.6 N = 428 30 Weeks 54 Weeks 102 Weeks 10 8 6 4 2 0 -2 Placebo + MTX 4.8 7 p < 0.001 1 1.3 1 p < 0.001 1.6 0.6 1 p < 0.001 1.1 -0.5 0.2 p < 0.001 -0.3 -0.7 -0.4 Infliximab + MTX 3 mg/kg q8w 3 mg/kg q4w 10 mg/kg q8w 10 mg/kg q4w p values are versus placebo + MTX. Maini R et al. Lancet. 1999;354:1932-1939; Lipsky PE et al. N Engl J Med. 2000;343:1594-1602 Patients Treated Early Will Respond: Change in Total Sharp Score at 2 Years Mean Change in Total Sharp Score From Baseline Disease Duration ≤ 3 Years 8 7 6 5 4 3 2 1 0 -1 Methotrexate Etanercept Etanercept + Methotrexate 0.4 2.8 7.0 8 7 6 5 4 3 2 1 0 -1 Methotrexate Etanercept -0.6* Etanercept + Methotrexate † All Patients 3.3 1.1* (n=72) *p<0.05 vs. MTX vs. etanercept (n=76) (n=74) (n=206) (n=202) (n=212) †p<0.05 Bathon et al NEJM 2000;343(1):1586-1593 Rituximab: Mechanism of Action Rituximab initiates complement-mediated B-cell lysis Rituximab initiates cellmediated cytotoxicity via macrophages and natural killer (NK) cells Rituximab induces apoptosis caspase-3,-9 CD20 Rituximab Macrophage B cell B cell Complement cascade B-cell lysis Apoptosis Clynes RA et al. Nat Med. 2000;6:373-374; Reff ME et al. Blood. 1994;83:435-445. B Cell Depleting Therapy in RA Patients Refractory to Anti TNFα Therapy: ACR Responses at 6 Months 60 50 % Patients 40 30 20 10 0 ACR20 ACR50 ACR70 Placebo (N=201) Cohen S, et al. Arthritis and Rheumatism 2006:54(9):2793-2806 p < 0.0001 51 p < 0.0001 27 18 5 p < 0.0001 12 1 Rituximab (N=298) B Cell Depleting Therapy in RA Patients Refractory to Anti TNFα Therapy: Radiographic Endpoints at 6 Months 1.5 Mean Change p=0.1693 1.2 p=0.2358 1 0.6 0.5 p=0.0156* 0.8 0.4 0.5 0.2 0 Total Genant-Modified Sharp Score Joint Space Narrowing Score Erosion Score Placebo (N=177) *Statistically significant Rituximab (N=268) 24 Placebo and 30 rituximab patients were missing x-rays at week 24 Cohen S, et al. Arthritis and Rheumatism 2006:54(9):2793-2806 Abatacept for RA Abatacept Fusion protein First in the new class of “costimulation blockers” for treatment of RA Prevents T-cell activation via binding CD80 and CD86 on antigen-presenting cells Kremer JM et al. N Engl J Med. 2003;349:1907-1915. CTLA4lg (Abatacept) Effectively Blocks CD28 Dependent Costimulatory Signals Antigen Presenting Cell T Lymphocyte Costimulation CD80 CD86 CD28 CD28 Clonal Proliferation Cytokine Production IL-2 IL-4 IL-5 TNF-α Full Activation CTLA4lg MHC II TCR Antigen specific Inhibition of T-Cell Activation by CoStimulatory Pathway Blockade in RA Patients With Inadequate MTX Response 100 90 80 70 68 73 ACR Response Placebo + MTX Abatacept + MTX Patients (%) 60 50 40 30 20 10 0 6 Mos 12 Mos 6 Mos 12 Mos 6 Mos 12 Mos 48 40 40 40 29 17 18 7 20 6 ACR 20 ACR 50 ACR 70 1. Kremer et al. Annals of Internal Medicine: 2006; 144:865-876 Safety Considerations with Biologic DMARD’s Serious Infections Opportunistic infections (TB) Malignancies/lymphoma Demyelination Hematologic abnormalities Administration reactions Congestive heart failure Hepatic Autoantibodies and drug induced lupus Vaccination Biologics: Relative Contraindications Active Hepatitis B Infection Multiple sclerosis, optic neuritis Active serious infections Chronic or recurrent infections Current neoplasia History of TB or positive PPD (untreated) Congestive heart failure (Class III or IV) Treatment Summary Early appropriately aggressive intervention in patients with inflammatory arthritis: critical to best possible outcome. The combination of a biologic plus MTX is frequently more effective than either agent alone. Conclusion Rheumatoid Arthritis is a serious disease Early diagnosis is key to good outcomes Advent of new therapies have major impact in altering disease progression