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  • 1.The Biologic therapiesDr. R MUSA SPR rheumatology

2. TNF Antagonists :licensed indicationsandfuture use

  • Confirmed in Trials
  • Crohns disease
  • Rheumatoid arthritis
  • Spondyloarthropathies
    • Psoriatic arthritis
    • Psoriasis
    • Ankylosing spondylitis
    • Reactive arthritis
  • Juvenile RA
  • Adult Stills disease
  • Under Investigation
  • Vasculitis: Wegeners disease, giant cell arteritis
  • Scleroderma
  • Graft-versus-host disease
  • Inflammatory myositis
  • Interstitial lung disease
  • Sjogrens syndrome
  • Inflammatory eye and ear disease
  • Asthma
  • Hepatitis
  • Sarcoidosis
  • Behcets disease
  • Pyoderma gangrenosum

Cush J.Rheumatology . 2003. In press. 3. Cytokine Signaling Pathways &TNF Adapted from Choy EHS, Panayi GS.N Engl J Med . 2001;344:907-916. Copyright 2001 Massachusetts Medical Society. All rights reserved. TNFsecreted by macrophage TNF- IL-1 IL-6 IFN- IL-12 IL-4 IL-10 Macrophage RF IL-4 IL-6 IL-10 Plasma cell B cell Interferon- Th0 Th2 Synovium OPGL CD4 + T cell CD69 CD11 CD11 CD69 Osteoclast Fibroblast Chondrocyte Production of metalloproteinases and other effector molecules Migration of polymorphonuclear cells Erosion of bone and cartilage 4. Biologic therapyAnakinra Infliximab Etanercept Adalimumab Human Chimeric Human Recombinant construct Type I IL-1R TNF- TNF- Primary binding target 46 hours 810 days 4.3 days Half-life Human TNF- 101 3.6days IL-1Ra TNF- mAb sTNFR construct Class TNF- mAb 100 mg/d sc 310 mg/kg 48 wk iv+ MTX 25 mg sc 2x/wk Administration 40 mg sc eow 5. Inhibition of Cytokines Adapted with permission from Choy EHS, Panayi GS.N Engl J Med . 2001;344:907-916. Copyright 2001 Massachusetts Medical Society. All rights reserved. Inflammatory cytokineNormal interaction Neutralization of cytokines Receptor blockade Activation of anti-inflammatory pathways Cytokinereceptor Soluble receptor Monoclonal antibody Monoclonal antibody Receptor antagonist Anti-inflammatory cytokine Suppression of inflammatory cytokines No signal No signal Inflammatory signals 6. PRE-INFUSION 2 WEEKS POST POST-GD SE T1 7. Baseline 2 weeks One year SACROILIAC JOINT INFLAMMATION 8. Baeten et al Arthritis Rheum 2001 the effect of 3 infusions infliximab on the synovium evaluated between baseline on the left and at 12 weeks on the right 9. BASELINE 2 DAYS 2 WEEKS SPINAL INFLAMMATION 10. TB and Anti-TNF Recommendations

  • Purified protein derivative (PPD) and chest x-ray (CXR) in all patients on biologics
  • PPD 0.1 mL is neither 100% sensitive or 100% specific, because there are as many as 25% false negatives
  • Sensitivity varies with cutoff 5 vs 10 vs 15
  • Low cutoff for those at high risk
  • Treatment with isoniazid (INH) for 9 months for all PPD > 5 mm
  • Delay anti-TNF therapy if possible, avoid infliximab

11. Antibody Formation With TNF Inhibitors

  • Monoclonal antibodies appear to form neutralizing antibodies in a portion of the population, regardless of whether they are human- or mouse-based
  • This may affect long-term efficacy

5% neutralizing (Range 1% on MTX; 12% on monotherapy) 10% (HACA) < 5% (non-neutralizing) Adalimumab Infliximab Etanercept 12. Infliximab in Crohns DiseaseInfluence of Immunogenicity onDuration of Clinical Response (N=125) Baert F, et al.N Engl J Med.2003;348:601-608. 65 38.5 0 10 20 30 40 50 60 70 Days of Clinical Response Patients With Infusion Reactions* Patients Without Infusion Reactions *Infliximab antibodies detected (61%); cumulative incidence of infusion rxs (27%). P 2 bilat / Grade3/4 unilat Clinical criterion(2 out of the following 3) 1-Low back pain and stiffness for >3months improve with exercise but not rest 2-Limitation of motion of lumber spine in both the sagital and frontal planes 3-Limitation of chest expansion relative to normal value for age and sex 23. Instruments for assessment of AS1-BASFI=Bath Ankylosing Spondylitis Functional Index

  • Used to evaluate functional abilityBASFIis scored as follows:
    • 8 VAS regarding function scored:
    • Easy0 1 2 3 4 5 6 7 8 9 10Impossible
    • 2 questions regarding ability to cope with daily life scored:
    • Easy0 1 2 3 4 5 6 7 8 9 10Impossible

24. 2- BASDAI= Bath Ankylosing Spondylitis Disease Activity Index 25. 3-Global Assessment: PtGA 26. 4-BASMI:SPINAL MOBILITY

  • Lateral bending
  • Intermalleolar distance
  • Occiput to wall
  • Modified schober index

27. life impact of AS Sufferpain anddisability Socio-economic impactbecause onset at early age Unemployment (>50%) and high insurance 50% develophip arthritis at early ageand requireHip replacementwhich more often requirereoperationdue to heterotopic ossification of the hip prosthesis Mortality higher 1.5than general population due to Cardiac valvular diseaseAmyloidosis Osteoporosisoccurs early in disease increase fracture Annual health cost of one patient=6720$ 28. Conventional therapy for AS Aim: relieve pain and stiffness Regular physiotherapy Hydrotherapy NSAIDs (improvement within 24 hours if there is failure to response Probability of suffering from AS is as low as 3%)long term use do not alters structural progression of the disease(use mainly as symptomatic relieve of pain and stiffness) Risk of GI upset use Naprxone / Use COX2 inhibitor ?celebrex support in the NASS and OPD rheumatology clinic NOTES:Treatment of peripheral and axial disease are different May be spontaneous remission later in life 29. Rationale for TNF blockade

  • TNF- in AS
    • Over-expression of TNF in mouse model produces AS like disease
    • Abundant TNF- mRna in Sacroiliac joint biopsy specimens from inflamed sacroiliac joints
  • Good therapeutic effect in other autoimmune disease, IBD, RA
    • 60% AS patients have sub clinical colitis

30. Sacroiliac Biopsy In Ankylosing Spondylitis Bollow M, BraunJ. Ann Rheum Dis.2000. 31. TNF mRNA In Sacroiliac Biopsy In AS

  • Inflamed sacroiliac joint of a young, female patient with AS
  • 3 years diseaseduration
  • In situ hybridization

Braun J et al.Arthritis Rheum.1995. 32. BSR Guideline on Eligability for anti TNF therapy ( the same as ASAS Consensus) AS sessments inASworking group

  • Initiation of therapy
    • 1-Ankylosing Spondylitispatient satisfies modified New York
    • criteria
    • 2-Failed conventional therapy (2 or > NSAID each taken sequentially at maximum tolerated dose for 4 weeks
    • 3-Active disease for at least 4 weeks
      • BASDAI =/> 4 and
      • Physician global (specialist) yes/no
    • Refractory disease
      • Failed at least 2 NSAIDS at max tolerated doses during 3 month period and I/A steroids/SSZ if indicated
  • ASAS workshop, Berlin January 2003

33. Contraindication

  • Pregnancy or breast feeding
  • Active significant infection
  • Septic arthritis of prosthetic joint within last 12/12 or indefinitely if joint remain in site
  • Precautions TB and positive PPD test
  • Congestive heart failure (NYHA grade )
  • Demyelination
  • adverse events
  • Major:Reactivation of TB, shingle, Sepsis, anaphylactic shock
  • Minor:Injection site reactions, infusion reactions, autoantibodies formation and lupus, Abnormal liver function tests

34. BSR definition of response to treatment (the same as ASAS consensus guidelines)

  • Response
      • Time of evaluation at 6-12 weeks
      • BASDAI >50% improvement and absolute improvement >2 units and Physician global assessment of response to treatment
  • Infusions every 6-8 weeks
  • patient pain and patient global assessment, spinal mobility, CRP and BASDAI assessed in follow up on all patients

35. NASS

  • Welcome to The Norwich Branch of The National Ankylosing Spondylitis Society (NASS). Run by Patients for Patients. We offer Support, Advice, and Exercise Sessions with Professional Supervision 36. Biologic AuditRheumatology Department Watford G Hospital Dr R MUSA Dr A Hayee Margaret Brown 37. Total of 22 Patients currently on biologic therapy for Rheumatology indication at WGH

  • 23 rheumatoid arthritis patients ( 11 )adalimumab (Humira)
  • ( 3 )infliximab (Remicade)
  • ( 5 )Etanercept (Enbrel)
  • SixRhA Patients their therapy suspended
  • (11)Patients waiting to start near further