Cytokines And Biologic Treatment in Arthritis

1. Cytokines And Biologic Treatment in Arthritis SUSIE D. AVERIA, MD, FPCP, DPRA

2. Objectives To define cytokines and discuss its role in the inflammatory cascade of arthritis To present cytokines and its equivalent biologic treatment in arthritis • To review the use of biologicals, clinical indications and its mechanism of action available locally

3. CYTOKINES • Hormonal messengers • Biological effects in the immune system • Cell mediated immunity • Allergic type responses • Divided into two groups: • Proinflammatory • Anti-inflammatory

4. CYTOKINES • T lymphocytes- major source • Antigen specific receptors on their cell surface • Recognition of foreign pathogens • Recognise normal tissue during episodes of autoimmune diseases

5. CYTOKINES • Two main subsets of T lymphocytes • CD4 • CD8 • CD4 -helper T cells are subdivided into • Th1-type cytokines • Th2-type cytokines

6. CYTOKINES Th-1 type cytokines Th-2 type cytokines Anti-inflammatory response IL-10 Promotion of IgE and eosinophilic responses IL- 4, 5, and 13 In excess counteracts the Th1 mediated microbicidal action • Proinflammatory responses • Kill intracellular parasites • Perpetuates autoimmune responses • Interferon gamma • In excess lead to uncontrolled tissue damage

7. Proinflammatory and anti-inflammatory cytokines in RA

8. CYTOKINES • One cytokine often influences the synthesis of other cytokines • Produce cascades, enhance or suppress production • Influence the action of other cytokines • Effects can be: • antagonistic • additive • synergistic

9. CYTOKINES • Bind to specific receptors on target cells with high affinity • Cells that respond to a cytokine: • Autocrine - same cell that secreted cytokine • Paracrine - a nearby cell • Endocrine- a distant cell reached through the circulation

10. Receptors for various cytokines

11. CYTOKINES Cytokines are currently being used clinically as biological response modifiers for the treatment of various disorders

12. Pathogenesis of Rheumatoid Arthritis

13. Pathogenesis of Rheumatoid Arthritis

14. Cellular Components of Synovial Lesion • T cells • B cells • Phagocytes • Neutrophils • Macrophage-like cells • Fibroblast-like cells

15. T-Cell Characteristics • HLA class II molecules present antigenic peptides to CD4 T cells • CD4 T cells become activated • Stimulates monocytes, macrophages, and synovial fibroblasts • These molecules in turn produce cytokines (IL-1, IL-6, TNF α) and secrete matrix metalloproteinases • Activated osteoclasts drive bone resorption

16. Interaction between CD4+ T cells and antigen-presenting cells δ

17. Cellular Components of Synovial Lesion • B cell • Express surface immunoglobulins • Provide cognate help for T-cells • T cells • B cells

18. Proinflammatory Cytokines

19. Proinflammatory and anti-inflammatory cytokines in RA

20. IL-1b and TNF-a: Proinflammatory Cytokines in the Rheumatoid Joint High endothelial venule B o n e O s t e o b l a s t s O s t e o c l a s t s Synovial membrane C a r t i l a g e IL-6 PGE2 IL-8 N e u t r o p h i l s TNF-α IL-1β Capsule Synovial space C h o n d r o c y t e s Pannus Osteoblasts Osteoclasts B o n e PGE2 = prostaglandin-E2 Dinarello C, Moldawer L. Proinflammatory and Anti-inflammatory Cytokines in Rheumatoid Arthritis: A Primer for Clinicians. 3rd ed. Thousand Oaks, Ca, USA: Amgen Inc.; 2001.

21. TACE (TNF alpha converting enzyme) cleaves TM-TNF from the surface TNF Production of TNF TM-TNF (transmembrane TNF) Activated Macrophage Activated Macrophage

22. Target Cell sTNFR Signal TNF TNF Mode of Action Activated Mf

24. Normal interaction Neutralization of cytokines Inflammatory cytokine Monoclonal antibody Cytokine receptor Soluble receptor Inflammatory signal No signal Activation ofanti-inflammatory pathways Receptor blockade Monoclonal antibody Anti-inflammatory cytokine Receptor antagonist Suppression of inflammatory cytokines No signal Inhibition of Cytokines Adapted with permission from Choy EH, Panayi GS. N Engl J Med. 2001;344:907–916.

25. What are Biologics? • A class of therapeutics (either approved or in development) that are produced by means of biological processes involving recombinant DNA technology

26. What are Biologics? • Usually one of three types: • Substances that are (nearly) identical to the body's own key signallingproteins. Eg: Erythropoetin • Monoclonal antibodies • Receptor constructs (fusion proteins), usually based on a naturally-occurring receptor linked to the immunoglobulin frame

27. Biologics in Non Rheumatologic Diseases • Cancer • Psoriasis • Inflammatory Bowel Diseases • Inflammatory Eye Diseases • Asthma

28. The Biologicals Inhibitors of Tumor Necrosis Factors • Infliximab • Etanercept • Adalimumab B Cell Targeted Therapies • Rituximab (Rituximab) • Belimumab • Interleukin-1 ReceptorAntagonist and Interleukin-1 Receptor • Anakinra • Interleukin-6 ReceptorAntagonist • Tocilizumab

29. Anti-TNFα Agents Etanercept Infliximab Adalimumab

30. TNF Inhibition: Mechanisms of Action • Soluble TNF receptors • Human TNF receptor linked to Fc portion of IgG • Bind soluble and cell-bound TNF • Do not fix complement or lyse immune cells (in vitro)

31. TNF Inhibition: Mechanisms of Action • TNF monoclonal antibodies • Variable (Fab) region binds to soluble and cell-bound TNF • Chimeric and human versions • Can fix complement leading to cell lysis (in vitro)

32. Effects TNF-α Inhibitors • Down regulation of local and systemic proinflammatory cytokine production • Reduction of lymphocyte migration into the joint • Reduction of angiogenesis in the joints

33. Effects TNF-α Inhibitors • Reduction of serum levels of IL-6 and IL-1 significantly • Reduction in the synthesis of MMP and production of other enzymes • Dose-dependent decrease in soluble forms of intracellular adhesion molecule-1 (ICAM-1) and E-selectin • Reduction of vascular endothelial growth factor (VEGF) serum levels

34. Soluble portion of the Human p75 chain TNFareceptor (binds extracellular TNF) Fragment crystallizable (Fc) portion of Human IgG1 (prolongs its circulating half-life) Etanercept (Enbrel)

35. sTNFR:Fc sTNFR:Fc Activated Activated M Etanercept Mode of Action Target Target M f Cell f Cell TNFR TNFR Signal Signal sTNFR TNF TNF sTNFR:Fc

36. Etanercept • ENBREL® Package Insert

37. Characteristics • ENBREL® Package Insert

38. Etanercept • ENBREL® Package Insert

39. Mouse IgG1 Infliximab Human Human IgG1 Adalimumab

40. Activated Activated Target Target M M f Cell f Cell TNFR TNFR Signal Signal TNF TNF Infliximab/AdalimumabMode of Action

41. Characteristics • Remicade® Package Insert 2. HumiraTM Package Insert

42. Infliximab/Adalimumab*

43. Dosages • Remicade® Package Insert 2. HumiraTM Package Insert

44. Drug Interactions • Abatacept • Anakinra • Azathioprine • Etanercept • "Live" vaccinations • Mercaptopurine • Tocilizumab

45. Toxicity: in Clinical Trials • Injection site reaction in 35% • Rate of infections < MTX • Serious infections • Malignancy as per normal • Haematological sfx < MTX • No SLE/demyelination • No neutralising antibodies • Anaphylaxis/infusion reaction • Rate of infections ~MTX • Serious infections • Malignancy as per normal • Haematological sfx ~MTX • No SLE/demyelination • Autoantibodies Etanercept Infliximab

46. Toxicity: Real Life • Injection site reaction in 35% • Rate of infections > MTX • Conventional bacterial, TB • No dose adjustment • Malignancy? • Haematological sx ~ MTX • No neutralising antibodies Infliximab Etanercept • Anaphylaxis/infusion reaction • Rate of infections > MTX • Frequency of TB etc • Dose adjustment • Malignancy? • Haematological sx ~MTX • Autoantibodies; lupus-like syndrome

47. Absolute Contraindications • ONGOING INFECTIONS: pneumonia, cellulitis, sepsis, skin ulceration, UTI and abscess • TUBERCULOSIS (screen patients with PPD and CXR)

48. Philippine Guidelines on the Screening for TB prior to the use of Biologic Agents JJ Lichauco, S. Tanke Torres, S. Navarra, L. Dans Philippine guidelines on the screening for TB prior to the use of biologic agents APLAR J of Rheumatol 2006; 9: 184-192

49. EVALUATE PATIENT History and PE EVALUATE CONTACTS Hx and PE CXR (PA/APL view) CXR (PA/APL view) Perform TST Currently active TB? <8mm >8mm NO YES Interpret according to risk of latent TB infection and/or state of immunosuppression 1. Multidrug TB tx 2. Provide TB prophylaxis to candidate patient for biologic tx Active TB ? Full diagnostic work up? NEGATIVE POSITIVE NO YES Proceed with anti TNF tx but with awareness of: 1. non-specific TB manifestations 2. Extrapulmonary TB 1. Tx latent TB infection 2. Delay TNF blockade 1. Multidrug TB tx 2. Postpone anti-TNF tx until TB therapy is completed

50. Other Considerations • Monitoring during Anti-TNF- α Therapy • CBC • Sign of demyelinating disease and malignancy • Pregnancy and breast feeding • Not recommended during pregnancy • Relative rates of live births, miscarriages, and therapeutic termination were relatively comparable to healthy women • Not also use in nursing mothers • Anti-TNF- α therapy for other diseases • Assessed its used in JIA, psoriasis, PsA, ankylosing spondylitis and Wegener’s Granulomatosis • Open-labeled study: use in Bechet’s Syndrome, Still’s dse, uveitis, Scleroderma, Sjogren’s syndrome, sarcoidosis,pyodermagranulomatosum, and polymyositis or dermatomyositis