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Biological Therapy for Rheumatoid Arthritis : 

Biological Therapy for Rheumatoid Arthritis Michael Maricic, M.D. Catalina Pointe Rheumatology

Rheumatoid arthritis : 

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 : 

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 : 

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 : 

Pathogenesis of Rheumatoid Arthritis Osteoclast Bone Complement Adapted from Arend WP, Dayer JM. Arthritis Rheum. 1990;33:305–15 Current Treatment Targets

Chronic Inflammation: Imbalance Between Mediators : 

Chronic Inflammation: Imbalance Between Mediators Proinflammatory Anti-inflammatory TNF IL-1 IL-8 IL-6 IFN IL-4/IL-13 IL-1Ra TGF IL-10

Functional Decline Begins Early in RA : 

Wolfe F, Cathey MA. J Rheumatol. 1991;18:1298-1306. Functional Decline Begins Early in RA 10 5 0 2 Moderate loss of function* Severe loss of function* Very severe loss of function* Years from Symptom Onset * 50% rates of loss of function based on HAQ scores

Most RA Patients Develop Bone Erosions During First 2 Years of Disease : 

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 : 

American College of Rheumatology Diagnostic Criteria for RA - 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 Must have at least 4 of the following 7 criteria:

Anti-Cyclic Citrullinated Peptide Antibody : 

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

Factors Suggesting Poor Prognosis : 

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 : 

The Treatment of Rheumatoid Arthritis

Therapeutic Window of Opportunity : 

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 : 

Treatment: The Earlier the Better Patients were treated with chloroquine or azathioprine Lard LR, et al. Am J Med. 2001;111:446–451. Delayed Treatment (median treatment lag time = 123 days; n = 109) Early Treatment (median treatment lag time = 15 days; n = 97)

Traditional DMARD’s : 

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 : 

Conventional DMARD Safety Considerations Hematologic Host Defense Hepatic Gastro-intestinal Malignancy & Lymphoma Reproductive Pulmonary Allergic Cutaneous Renal Ocular

Problems with Old Approach : 

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 : 

Evolving RA Treatment Paradigm Early aggressive treatment Biologics Combination therapy Current Approach Evolving Paradigm

Biologic DMARD’s – Genetically Engineered Targeted Molecules Similar or Identical to Naturally Occurring Molecules : 

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 : 

Characteristics of Biologics

Anti-TNF Monotherapy Improves Clinical Signs & Symptoms : 

Anti-TNF Monotherapy Improves Clinical Signs & Symptoms Moreland LW et al. Ann Intern Med. 1999;130:478-486. ACR20 ACR50 ACR70 % of Patients 59* 11 40* 5 15* 1 * p  0.001. Etanercept 25 mg (n = 78) Placebo (n = 30)

Better Outcomes in Patients Receiving Combination Therapy of MTX & Anti TNFα : 

Breedveld FC Arthritis Rheum 2006; 54(1): 26-37 Better Outcomes in Patients Receiving Combination Therapy of MTX & Anti TNFα ACR50 Response Mean Change TSS Patients (%) Mean Change in Total Sharp Score

Half of Patients on Anti TNFα+MTX Achieve Clinical Remission by DAS28<2.6: 2-year Data : 

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

Anti TNF + MTX Combination Slows Radiographic Progression : 

Anti TNF + MTX Combination Slows Radiographic Progression 30 Weeks 54 Weeks 102 Weeks 3 mg/kg 3 mg/kg 10 mg/kg 10 mg/kg q8w q4w q8w q4w Placebo + MTX Infliximab + MTX p < 0.001 p < 0.001 p < 0.001 p < 0.001 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 = 428 Mean Change in Total Sharp Score

Patients Treated Early Will Respond: Change in Total Sharp Score at 2 Years : 

Patients Treated Early Will Respond: Change in Total Sharp Score at 2 Years Bathon et al NEJM 2000;343(1):1586-1593 *p<0.05 vs. MTX †p<0.05 vs. etanercept Mean Change in Total Sharp Score From Baseline Disease Duration  3 Years All Patients

Rituximab: Mechanism of Action : 

Rituximab: Mechanism of Action 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 CD20 Rituximab Clynes RA et al. Nat Med. 2000;6:373-374; Reff ME et al. Blood. 1994;83:435-445. B cell B-cell lysis Apoptosis Complement cascade Macrophage B cell

B Cell Depleting Therapy in RA Patients Refractory to Anti TNFα Therapy: ACR Responses at 6 Months : 

B Cell Depleting Therapy in RA Patients Refractory to Anti TNFα Therapy: ACR Responses at 6 Months 18 5 1 51 27 12 0 10 20 30 40 50 60 ACR20 ACR50 ACR70 % Patients Placebo (N=201) Rituximab (N=298) p < 0.0001 p < 0.0001 p < 0.0001 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 : 

B Cell Depleting Therapy in RA Patients Refractory to Anti TNFα Therapy: Radiographic Endpoints at 6 Months 1.2 0.5 0.8 0.6 0.4 0.2 0 0.5 1 1.5 Total Genant-Modified Sharp Score Joint Space Narrowing Score Erosion Score Mean Change Placebo (N=177) Rituximab (N=268) p=0.0156* p=0.1693 p=0.2358 *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 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 : 

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 : 

Inhibition of T-Cell Activation by Co-Stimulatory Pathway Blockade in RA Patients With Inadequate MTX Response 1. Kremer et al. Annals of Internal Medicine: 2006; 144:865-876 ACR 20 ACR 50 ACR 70 Placebo + MTX Abatacept + MTX ACR Response

Safety Considerations with Biologic DMARD’s : 

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

Slide 33: 

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)

ACR Algorithm for Management of RA : 

ACR Algorithm for Management of RA ACR Subcommittee on RA Guidelines. Arthritis Rheum. 2002;46:328-346. Diagnosis Establish early diagnosis of RA Document baseline disease activity and damage Estimate prognosis of patient Initiate therapy Patient education Start disease-modifying agent within 3 months Consider NSAID and/or local or low-dose steroids Physical/occupational therapy Subjective criteria Physical exam Laboratory tests Radiography DMARDs Biologics Periodically assess disease activity

ACR Algorithm for Management of RA : 

ACR Algorithm for Management of RA ACR Subcommittee on RA Guidelines. Arthritis Rheum. 2002;46:328-346.

Treatment Summary : 

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 : 

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

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