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ATTRACT BY DR/ SULTAN ALMOGAIRIN CONSULTANT IN RHEUMATOLOGY SERVICE HISTORY YOUNG LADY PRESENTED WITH TOW YEARS HISTORY OF SYMMETRICAL NON EROSIVE ARTHERITIS INVOLVING LARGE & SMALL JOINTS INCLUDING THE HANDS WITH POSITIVE R.F & NEGATIVE ANA Pt WAS STARTED INITIALLY ON HQ & SULFASALAZINE , BUT THERE WAS NO ADEQUATE RESPONSE AFTER TWO YEARS OF MAXIMUM DOSE OF ABOVE MEDICATIONS. LATER ON X.R OF JOINTS SHOWED ERROSIVE CHANGES & Pt WAS STARTED ON MTX HISTORY …cont Pt GOT SOME RESPONSE , BUT SHE CONT. TO HAVE ACTIVITY OF ABOUT 7 – 10 JOINTS OF HANDS IN THE FOLLOWING 14 MONTHS WE ADDED I.M GOLD , AGAIN THE Pt FELT RELATIVELY BETTER WITH LESS FREQUENCY FLARE UP & LESS ACTIVITY OF JOINTS BUT THERE IS STILL NO ADEQUATE RESPONSE NEXT THERAPY ?!!! Introduction to TNF Science & TNF Inhibition TNF "Family" Proteins Family of type II transmembrane proteins Single-binding domain Share 20%-30% amino acid homology Effects mediated through cell-cell contact – Exceptions – TNF – Lymphotoxin-a What Is Tumor Necrosis Factor? Purified in 1984 (cachectin, TNF) from mouse macrophages Cytolytic for tumor cells (in vitro) Necrosis of transplanted tumors (mice) Mediates endotoxic shock Catabolic hormone Highly toxic when given directly Tumor Necrosis Factor Member of TNF family of > 20 proteins 17 kd trimeric transmembrane protein Produced by macrophages/T cells Produced in response to IL-1/endotoxin/TNF Released from cell surface by TACE (TNF-alpha– cleaving enzyme) Flier JS. N Engl J Med. 1996. Effects of TNF Stimulates release of prostaglandins and chemokines Induces tumor lysis (mouse fibrosarcoma) Mediates shock (endothelium) Stimulates T-cell proliferation Causes apoptosis Activates neutrophils Suppresses lipoprotein lipase TNFa: Role in Host Defense Augments neutrophil microbicidal functions Promotes resistance against intracellular pathogens and parasites ? Promotes resistance against viruses Endotoxin (LPS) TNF Activated macrophage TACE TNF IL-1 TNF Family Receptors Transmembrane proteins Cysteine-rich amino acid domains Mediate effects via cytoplasmic signals Present on many cells (p55 and p75) Most remain cell-associated – Exceptions – Naturally occurring soluble p55 and p75 Cell-Bound TNF Receptors p75 p55 Extracellular region (TNF binding site) Transmembrane region Cytoplasmic tail (signaling) TNF Receptors Target cell TACE TNF and TNF Receptors Activated macrophage Target cell Signal TNF Events in Rheumatoid Arthritis B cell T cell Macrophage Synoviocyte Cytokines Increased cytokine production (IL-1, IL-6) Increased inflammation Increased adhesion molecules Increased production of MMP Cell migration into joints Tissue remodeling Events in Rheumatoid Arthritis B cell T cell Macrophage Synoviocyte TNF Increased cytokine production (IL-1, IL-6) Increased inflammation Endothelium Increased adhesion molecules Cell migration into joints Increased production of MMP Tissue remodeling Role of TNF in Arthritis Produced by synoviocytes/macrophages Increased levels in serum and synovial fluid Activates the endothelium (E-selectin/PGI2) Stimulates fibroblast proliferation Induces MMP production (synoviocytes) Stimulates production of IL-1 and IL-6 (+TNF) Activates osteoclasts via IL-1 stimulation SS S S S S Etanercept SS CH3 S S S S SS CH2 Fc region of human IgG1 Extracellular domain of human p75 TNF receptor TNF Inhibition: Etanercept Etanercept Activated macrophage Target cell Signal TNF Etanercept Summary: TNF in RA Binds and activates both p55 and p75 receptors Is an important inflammatory cytokine Can initiate events seen in joint inflammation Levels are increased in serum and synovial fluid Is an appropriate anti-inflammatory target قال النبى صلى هللا عليه وسلم : من ترك صالة العصر حتى خرج وقتها من غير عذر حبط عمله Treatment of Early RA: Clinical Response and Radiographic Progression (The ERA Trial) ERA Trial: Study Objectives Demonstrate in patients with early, active RA that etanercept: – Reduces the rate of joint damage – Is clinically effective in patients not previously treated with methotrexate – Is safe and well tolerated Finck B. Arthritis Rheum. 1999. Study Endpoints Prospectively Defined Primary – Change in Sharp score over 12 mo – Clinical improvement measured by area under the curve (AUC) of ACR-N over 6 mo Secondary – ACR20, ACR50, ACR70 at 6 mo Finck B. Arthritis Rheum. 1999. Eligibility Criteria Disease duration 3 yr No prior treatment with methotrexate Active disease: 10 swollen joints 12 tender joints Rheumatoid factor–positive or erosions on baseline x-rays Stable prednisone ( 10 mg/d) and NSAID Finck B. Arthritis Rheum. 1999. Study Design Randomized, multicenter, double-blind study 632 patients Three treatment groups – Etanercept 25 mg + placebo tablets – Etanercept 10 mg + placebo tablets – Methotrexate (7.5-20 mg) + placebo injections Analysis by intent-to-treat (patients followed and analyzed if study drug discontinued) Methotrexate Dose Escalation Rapid dose escalation of oral study drug required by protocol to optimize methotrexate treatment Escalated from initial dose of 7.5 mg/wk – To 15 mg/wk at wk 4 – To 20 mg/wk at wk 8 – If any active joints present Decrease of 5 mg allowed once Final mean methotrexate dose 18.3 mg/wk All patients on folic acid 1 mg qd Finck B. Arthritis Rheum. 1999. Mean Dose of Oral Tablets 8 No. of tablets/wk 7 Etanercept 25 mg 6 Etanercept 10 mg Methotrexate 5 4 3 2 0 Finck B. Arthritis Rheum. 1999. 2 4 6 Month 8 10 12 Demographics Etanercept Methotrexate (n = 217) 10 mg (n = 208) 25 mg (n = 207) 49 21-80 50 19-86 51 21-82 75 75 74 11.9 10.9 11.9 89 88 87 Age Mean Range Female (%) RA duration (mean mo) Rheumatoid factor–positive (%) Finck B. Arthritis Rheum. 1999. Mean Baseline Arthritis Activity Tender-joint count Swollen-joint count Physician global Patient global Pain (VAS) HAQ disability Disease activity score (DAS) AM stiffness (hr) CRP (mg/dL) Finck B. Arthritis Rheum. 1999. Methotrexate (n = 217) 30 24 6.0 6.1 5.6 1.4 5.2 3.7 3.7 Etanercept 10 mg 25 mg (n = 208) (n = 207) 31 31 24 24 6.3 6.2 6.1 6.1 5.6 5.9 1.4 1.5 5.2 5.2 3.7 3.8 4.4 3.3 Demographics Methotrexate (n = 217) Any prior DMARDs (%) Mean no. prior DMARDs DMARDs at washout (%) Any Hydroxychloroquine Concomitant therapy (%) NSAIDs Corticosteroids Mean daily dose (mg) Finck B. Arthritis Rheum. 1999. Etanercept 10 mg 25 mg (n = 208) (n = 207) 46 0.6 39 0.5 40 0.5 24 16 25 20 23 15 80 41 7 76 42 7 86 39 9 Study Drug Completion Status at 1 Year (%) Etanercept Methotrexate (n = 217) 10 mg (n = 208) 25 mg (n = 207) Completed 1 yr of study drug Oral dose reduced for AE 79 151 80 3 85 2 Discontinued study drug Adverse events Loss of efficacy Other 21 112 4 6 20 6 7 8 15 5 5 5 1. P < 0.001. 2. P = 0.03. Methotrexate vs etanercept 25 mg. Finck B. Arthritis Rheum. 1999. Modified Sharp Scoring Method1 Standardized method used in clinical trials 46 joints scored for erosion (grades 0-5) 42 joints scored for narrowing (grades 0-4) Total Sharp score = erosion score plus joint space narrowing score Modifications – Included feet (van der Heijde2) – Added percentage joint eroded or narrowed to grading method (Rau3) 1. Sharp. Arthritis Rheum. 1971. 2. van der Heijde. Br J Rheumatol. 1992. 3. Rau. J Rheumatol. 1995. Radiographic Methods Change in Sharp scores over 1 yr X-rays of hands/wrists and forefeet at baseline, 6 mo, and 1 yr Each case read by 2 of 6 qualified physicians trained in the modified Sharp reading method (inter-reader r=0.85) Sequence of films blinded to readers Finck B. Arthritis Rheum. 1999. Baseline Radiographic Features Methotrexate (n = 217) Total Sharp score Mean Calculated rate of annual progression Erosion score Mean Calculated rate of annual progression Joint space narrowing score Mean Calculated rate of annual progression Finck B. Arthritis Rheum. 1999. Etanercept 10 mg 25 mg (n = 208) (n = 207) 12.9 9.5 11.2 8.3 12.4 8.7 7.5 5.4 6.1 4.6 6.4 4.3 5.4 4.1 5.0 3.8 6.0 4.4 Predicted and Actual Annual Change in Total Sharp Score 10 Etanercept 25 mg Etanercept 10 mg Methotrexate 8.7 9.5 8.3 Mean change 8 6 4 2 0 1.4 0.8 Predicted Actual Predicted Actual 1.3 Predicted Actual Mean Change in Erosion and Joint Space Narrowing Scores Over 1 Year Mean change 2 Etanercept 25 mg Etanercept 10 mg Methotrexate 1 0.8 0.4 0.4* 0 * P < 0.05 vs methotrexate. Finck B. Arthritis Rheum. 1999. 0.9 Joint erosion 0.5 Joint space narrowing 0.4 Patients With No New Erosions at 1 Year All patients Patients with baseline erosions Patients with no baseline erosions Finck B. Arthritis Rheum. 1999. Methotrexate Etanercept 25 mg 57% (123/217) 75% (154/206) P < 0.001 52% 72% P < 0.001 (98/188) (130/181) 86% 96% (25/29) (24/25) P = 0.159 Methotrexate-Dose: Patients With No New Erosions Over 1 Year Methotrexate Methotrexate < 20 mg/wk 20 mg/wk Patients with no new erosions 48% (20/42) 59% (103/175) Etanercept 25 mg 75% (155/206) Definition of ACR20 Response 20% or greater improvement in – Tender-joint count – Swollen-joint count – Three of the following five Pain assessment Physician global assessment Patient global assessment Patient self-assessment of disability ESR or CRP Arthritis Rheum. 1995. ACR20 80 * % Patients 60 * * 40 * Etanercept 25 mg 20 0 Methotrexate 0 2 Max MTX dose *P < 0.05, methotrexate vs etanercept 25 mg. Finck B. Arthritis Rheum. 1999. 4 6 Months 8 10 12 ACR Responses 80 * % Patients 60 ACR20 * * 40 ACR50 * * * 20 * * * * 0 Max MTX dose * ACR70 Etanercept 25 mg Methotrexate * * 0 * 2 * P < 0.05. Finck B. Arthritis Rheum. 1999. 4 6 Months 8 10 12 Calculation of Numeric ACR (ACR-N) Compared to ACR20 ACR20 At least 20% improvement in: Swollen-joint count Tender-joint count Three of five remaining criteria: – – – – – MD global assessment Patient global assessment VAS for pain HAQ CRP or ESR ACR-N Least percent improvement in: Swollen-joint count Tender-joint count Third highest of five remaining criteria: – – – – – MD global assessment Patient global assessment VAS for pain HAQ CRP Calculation of Numeric ACR (ACR-N) Patient #1 Patient #2 Swollen-joint count Tender-joint count 28% 21% 48% 55% MD global assessment Pt global assessment VAS for pain HAQ CRP or ESR 40% 35% 26% 22% 47% 52% 51% 49% 22% 47% ACR20 ACR50 ACR70 ACR-N Yes Yes 21% 48% Criteria No No No No Numeric ACR (ACR-N) Over Time 50 Mean ACR-N 40 30 Etanercept 25 mg Methotrexate 20 10 0 0 2 4 6 Months Finck B. Arthritis Rheum. 1999. 8 10 12 AUC of Numeric ACR Etanercept 25 mg Methotrexate 50 Mean ACR-N 40 30 20 10 0 0 P = 0.002 over 6 mo. P = 0.009 over 12 mo. * Primary endpoint. Finck B. Arthritis Rheum. 1999. 2 4 6* Months 8 10 12 AUC of Numeric ACR AUC of Mean ACR-N 40 Etanercept 25 mg Methotrexate 34.9† 30 20 28.7 15.3* 11.5 10 0 *P = 0.002. †P = 0.009. Finck B. Arthritis Rheum. 1999. 0-6 mo 0-12 mo AUC of Improvement in Swollen-Joint Count Etanercept 25 mg Methotrexate Mean % improvement 60 40 20 0 0 P = 0.004. Finck B. Arthritis Rheum. 1999. 1 2 3 Months 4 5 6 AUC of Improvement in HAQ Etanercept 25 mg Methotrexate Mean % improvement 60 40 20 0 0 P = 0.002. Finck B. Arthritis Rheum. 1999. 1 2 3 Months 4 5 6 AUC of Improvement in CRP Etanercept 25 mg Methotrexate Mean % improvement 80 60 40 20 0 0 P < 0.001. Finck B. Arthritis Rheum. 1999. 1 2 3 Months 4 5 6 AUC of Improvement in ACR Criteria AUC of mean % improvement 30 Etanercept 25 mg Methotrexate * * * 20 * * * 10 0 Pain *P < 0.05. Finck B. Arthritis Rheum. 1999. HAQ Disability MD Global Pt Global Swollen Joints Tender Joints CRP Safety Noninfectious adverse events Infections Malignancies Laboratory abnormalities Antibodies to etanercept Finck B. Arthritis Rheum. 1999. Patients (%) With Noninfectious Adverse Events > 10% of Patients Injection-site reaction LFT elevation Headache Nausea Rash Rhinitis Diarrhea Asthenia Dizziness Dyspepsia Back pain Abdominal pain Alopecia Mouth ulcer Yellow = P < 0.05. Finck B. Arthritis Rheum. 1999. Etanercept Methotrexate (n = 217) 10 mg (n = 208) 25 mg (n = 207) 7 46 27 29 23 14 12 12 11 10 6 10 12 14 30 27 25 14 16 17 13 9 5 10 6 11 7 6 37 28 22 17 12 15 15 13 12 12 11 10 6 5 Infectious Adverse Events Etanercept Methotrexate (n = 217) (193 pt-yr) 10 mg (n = 208) (185 pt-yr) 25 mg (n = 207) (189 pt-yr) 72* 1.91* 61 1.54 67 1.54 No. infections per pt-yr 39 0.61 27 0.45 35 0.54 % of pts w/infections 60 1.30* 51 1.08 51 0.99 Infections by Type Any type: % of pts w/infections URI: * P <0.05. No. infections per pt-yr Finck. Arthritis Rheum. 1999. Non-URI: Malignancies Etanercept Methotrexate 10 mg Expected* 1.8 1.9 2.0 Observed 2 2 3 • Bladder • Colon * NCI SEER database. Finck B. Arthritis Rheum. 1999. • Breast • Lung 25 mg • Carcinoid (lung) • Hodgkin’s • Prostate Laboratory Abnormalities Routine laboratory testing and autoimmune testing performed at regular intervals No treatment emergent abnormalities detected with etanercept treatment Finck B. Arthritis Rheum. 1999. Antibodies to Etanercept Etanercept Assay Methotrexate (n = 207) N (%) 10 mg (n = 198) N (%) 25 mg (n = 202) N (%) ELISA 0 5 (2.5) 6 (3.0) Neutralizing 0 0/5 0/6 Finck B. Arthritis Rheum. 1999. Summary of Safety Rate of adverse events less in etanercept group compared to methotrexate group (P = 0.01) Fewer infections of any type seen in patients receiving etanercept compared to methotrexate (P < 0.01) AE-related withdrawals, including pneumonitis, more common in patients receiving methotrexate (P = 0.02) No treatment-associated laboratory abnormalities Finck B. Arthritis Rheum. 1999. Summary of Efficacy Etanercept – Has a clinical response in the first month that is sustained – Is effective as a single agent in reducing symptoms of early, active rheumatoid arthritis – Stopped erosion in 75% of patients and more effective than methotrexate (P < 0.001) Finck B. Arthritis Rheum. 1999. Summary of Efficacy (cont.) Etanercept and methotrexate are both effective DMARDs Etanercept is more efficient than methotrexate in slowing the rate of new erosions Etanercept stopped the development of new erosions in 75% of patients Finck B. Arthritis Rheum. 1999. Conclusions In patients with early, active rheumatoid arthritis, etanercept: – Reduces the rate of joint damage – Is clinically effective in patients not previously treated with methotrexate – Is safe and well tolerated Finck B. Arthritis Rheum. 1999. قال النبى صلى هللا عليه وسلم : من ترك صالة العصر حتى خرج وقتها من غير عذر حبط عمله