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