1. The Biologic therapies Dr. R MUSA SPR rheumatology

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. TNF secreted 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 therapy Anakinra Infliximab Etanercept Adalimumab Human Chimeric Human Recombinant construct Type I IL-1R TNF-  TNF-  Primary binding target 4–6 hours 8–10 days 4.3 days Half-life Human TNF-  10–1 3.6 days IL-1Ra TNF-  mAb sTNFR construct Class TNF-  mAb 100 mg/d sc 3–10 mg/kg 4–8 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 cytokine Normal interaction Neutralization of cytokines Receptor blockade Activation of anti-inflammatory pathways Cytokine receptor 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

12. Infliximab in Crohn’s Disease Influence of Immunogenicity on Duration 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 <0.001

13. The incidence of lymphomas is increased in RA, but. The apparent increase in lymphomas in patients treated with TNF inhibitors may be due to confounding by indication — that is, that patients with severe disease who are (historically) most likely to develop lymphomas are also the ones most likely to receive TNF inhibitors. TNF-alpha plays an important role in tumor surveillance, particularly lymphoma. Because of this, Using TNF-alpha blocking agents in the treatment of rheumatoid arthritis (RA) may increase the risk of developing malignancies. Clinical trials of TNF inhibitors have not identified an increase in tumor (including lymphoma) risk, but are limited by short observation intervals and small cohorts. Here, Geborek et al Bladstrom, Jacobsson 2003 Lymphoma With TNF Antagonists

14. Lymphoma With TNF Antagonists 5.4 (2.6 – 10.0) 6.4 (1.7 – 16.3) 2.31  3.47 (1.59 – 6.59) SIR Lymphoma (95% conf interval) 18 mo (2.0 – 42.0) 10-19 mo (6.4) 21 mo (0.1 – 4.6) Mean Time to Onset (range) 1/9 1/3 3/6 Hodgkin's/ Non-Hodgkin's † 10 4 6  9 Total No. 2468 (4870) 1298 (2458) 3389 (8336) Treated/Exposure Pt-No. Pt-Yr Adalimumab Infliximab Etanercept † Majority diffuse large B cell SIR=standardized incidence ratio

15. Spondyloarthropathy family of disorders Inflammatory condition primarily affecting the spine which have in common the presence of sacroilitis, the presence of the HLA B27 gene and characteristic extra-articular manifestation. example: Ankylosing spondylitis Psoriatic arthritis Reactive arthritis Reiter syndrome Enteropathic arthritis (IBD associated arthritis) Undifferentiated Spondyloarthropathy

21. Sacroilitis by MRI Normal SI - SE T1 Fused SI - SE T1

22. Modified new York criteria 1984 (Van der Linden) Radiological criterion sacroilitis, Grade=/>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

24. 2- BASDAI= Bath Ankylosing Spondylitis Disease Activity Index

25. 3-Global Assessment: PtGA

27. life impact of AS Suffer pain and disability Socio-economic impact because onset at early age Unemployment (>50%) and high insurance 50% develop hip arthritis at early age and require Hip replacement which more often require reoperation due to heterotopic ossification of the hip prosthesis Mortality higher 1.5 than general population due to Cardiac valvular disease Amyloidosis Osteoporosis occurs 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

30. Sacroiliac Biopsy In Ankylosing Spondylitis Bollow M, Braun J. Ann Rheum Dis. 2000.

36. Biologic Audit Rheumatology Department Watford G Hospital Dr R MUSA Dr A Hayee Margaret Brown

38. Age & sex distribution On therapy - 13 female all Rheumatoid arthritis patients 9 male six Rheumatoid arthritis and three AS All the six suspended patients are female Age range RhA(35 - 80) and AS(22 - 69)

39. Data available on 15 patients with Rh A

40. Data available on 15 patients with Rh A

41. Change in BASDI & BASFI score after 6 months Etanercept therapy in 3 patients with AS

49. Thank you for attending