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.
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
Rheumatoid Factors, anti-CCP Immune complexes B cell T cell IFN- & HLA Neutrophil -DR other cytokines Antigen- presenting cells Macrophage Mast cell B cell or macrophage Synoviocytes Chondrocytes TNF IL-1 Pannus Articular cartilage Production of collagenase and other neutral proteases Pathogenesis of Rheumatoid Arthritis Current Treatment Targets Complement Osteoclast Bone Adapted from Arend WP, Dayer JM. Arthritis Rheum. 1990;33:305–15
Chronic Inflammation: Imbalance Between Mediators IL-10 TGF IL-1Ra IFN IL-4/IL-13 IL-6 IL-8 IL-1 TNF Anti-inflammatory Proinflammatory
Functional Decline Begins Early in RA Very severe loss of function* Moderate loss of function* Severe loss of function* 10 0 2 5 Years from Symptom Onset * 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 Patients with RA < 1 year underwent annual radiologic assessment of hands and feet. Hulsmans HM et al. Arthritis Rheum. 2000;43:1927-1940.
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 * High titer anti-CCP may predict aggressive erosive disease. Linn-Rasker SP, et al. Ann Rheum Dis 2006;65:366-71
>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 Factors Suggesting Poor Prognosis
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 (median treatment lag time = 123 days; n = 109) Early Treatment (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.
Methotrexate (Rheumatrex) Hydroxychloroquine (Plaquenil) Sulfasalazine (Azulfidine) D-penicillamine Leflunomide (Arava) Azathioprine (Imuran) Gold (Solganol, Ridaura) Cyclosporine (Neoral) Minocycline (Minocin)* *Not FDA approved for RA Traditional DMARD’s
Hematologic Host Defense Hepatic Gastro-intestinal Malignancy & Lymphoma Reproductive Pulmonary Allergic Cutaneous Renal Ocular Conventional DMARD Safety Considerations
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.
Initial treatment: traditional DMARDs Evolving RA Treatment Paradigm Evolving Paradigm Current Approach • 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)
Anti-TNF Monotherapy Improves Clinical Signs & Symptoms Placebo (n = 30) 59* Etanercept 25 mg (n = 78) 40* % of Patients 15* 11 5 1 ACR20 ACR50 ACR70 * p 0.001. Moreland LW et al. Ann Intern Med. 1999;130:478-486.
MTX Adalimumab MTX + Adalimumab Better Outcomes in Patients Receiving Combination Therapy of MTX & Anti TNFα ACR50 Response Mean Change TSS Mean Change in Total Sharp Score Patients (%) Breedveld FC Arthritis Rheum 2006; 54(1): 26-37
60 Week 52 * Week 104 49 50 * 43 40 % of Patients 30 25 25 23 21 20 10 0 Adalimumab + MTX Adalimumab MTX Half of Patients on Anti TNFα+MTX Achieve Clinical Remission by DAS28<2.6: 2-year Data *p<0.001 vs adalimumab alone and MTX alone Breedveld FC Arthritis Rheum 2006; 54(1): 26-37
14 12.6 12 10 8 7 6 4.8 4 1.6 2 1.3 1.1 1 1 1 0.6 -0.5 0.2 -0.4 -0.3 -0.7 0 -2 Anti TNF + MTX Combination Slows Radiographic Progression N = 428 30 Weeks 54 Weeks 102 Weeks Mean Change in Total Sharp Score p < 0.001 p < 0.001 p < 0.001 p < 0.001 Placebo + MTX Infliximab + MTX 3 mg/kg 3 mg/kg 10 mg/kg 10 mg/kg q8w q4w q8w 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
(n=72) (n=76) (n=74) (n=206) (n=202) (n=212) 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 All Patients *p<0.05 vs. MTX †p<0.05 vs. etanercept Bathon et al NEJM 2000;343(1):1586-1593
Rituximab initiates complement-mediated B-cell lysis Rituximab initiates cell-mediated cytotoxicity via macrophages and natural killer (NK) cells Rituximab induces apoptosis caspase-3,-9 Rituximab: Mechanism of Action Macrophage Complement cascade B cell B cell B-cell lysis Apoptosis CD20 Rituximab 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 p < 0.0001 60 51 50 40 p < 0.0001 % Patients 27 30 p < 0.0001 18 20 12 10 5 1 0 ACR20 ACR50 ACR70 Placebo (N=201) Rituximab (N=298) Cohen S, et al. Arthritis and Rheumatism 2006:54(9):2793-2806
B Cell Depleting Therapy in RA Patients Refractory to Anti TNFα Therapy: Radiographic Endpoints at 6 Months p=0.1693 1.5 1.2 p=0.2358 1 Mean Change 0.8 p=0.0156* 0.6 0.5 0.4 0.5 0.2 0 Total Genant-Modified Joint Space Erosion Score Sharp Score Narrowing Score Placebo (N=177) Rituximab (N=268) *Statistically significant 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.
ClonalProliferation Signal 2 CytokineProduction IL-2 IL-4 IL-5 TNF- Costimulation Signal 1 CD80 CD28 CD86 CD28 Full Activation CTLA4lg MHC II TCR Antigen specific CTLA4lg (Abatacept) Effectively Blocks CD28 Dependent Costimulatory Signals Antigen Presenting Cell T Lymphocyte
Inhibition of T-Cell Activation by Co-Stimulatory Pathway Blockade in RA Patients With Inadequate MTX Response ACR Response Placebo + MTX Abatacept + MTX ACR 20 ACR 50 ACR 70 1. Kremer et al. Annals of Internal Medicine: 2006; 144:865-876
Serious Infections Opportunistic infections (TB) Malignancies/lymphoma Demyelination Hematologic abnormalities Administration reactions Congestive heart failure Hepatic Autoantibodies and drug induced lupus Vaccination Safety Considerations with Biologic DMARD’s
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