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

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Presentation on theme: "Cytokines And Biologic Treatment in Arthritis SUSIE D. AVERIA, MD, FPCP, DPRA."— Presentation transcript:

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 Th-1 type cytokines Proinflammatory responses Kill intracellular parasites Perpetuates autoimmune responses Interferon gamma In excess lead to uncontrolled tissue damage 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 CYTOKINES

7 Proinflammatory and anti-inflammatory cytokines in RA

8 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 CYTOKINES

9 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 CYTOKINES

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 Normal Synovium Composed primarily of type II collagen and proteoglycans Enable low friction, high velocity movement between bones Absorbs considerable impact and stress Collagen fibrils comprises 90% of the fibrillar network Provides tensile strength and provides the framework in which proteoglycan and chondrocytes are embedded Aggrecan is the major proteoglycan that imparts elasticity to articular cartilage The synovium serves as a source of nutrients for cartilage These constitutes the structural framework of the synovial interstitium Synovial cells synthesize joint lubricant such as hyaluronic acid, collagens and fibronectin Chonsynthesize proteases and their inhibitors docytes secrete and in matrix turnover Synovial Cavity 1-2.5ml of highly viscous fluid

14 Pathogenesis of Rheumatoid Arthritis

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16 Cellular Components of Synovial Lesion T cells B cells Phagocytes Neutrophils Macrophage-like cells Fibroblast-like cells

17 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

18 Interaction between CD4 + T cells and antigen- presenting cells δ

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

20 Proinflammatory Cytokines CytokinesCell sourcesFunctions TNFαMacrophages, lymphocytes, fibroblasts Inflammation, fever, bone and cartilage resorption IL-1αMacrophages, monocytes Targets thymocytes and neutrophils IL-1βFibroblasts, epithelial cells Targets B and T cells and tissue cells IL-6Macrophages, T cells, fibroblasts, some B cells Differentiation, bone resorption

21 Proinflammatory and anti-inflammatory cytokines in RA

22 IL-1  and TNF-  : Proinflammatory Cytokines in the Rheumatoid Joint TNF-α IL-1β Neutrophils Osteoclasts Bone Cartilage Osteoblasts Chondrocytes Bone Synovial space IL-6 PGE 2 IL-8 High endothelial venule Synovial membrane Capsule Pannus OsteoblastsOsteoclasts PGE 2 = prostaglandin-E 2 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.

23 Production of TNF  ActivatedMacrophage TNF  TM-TNF (transmembrane TNF) TACE (TNF alpha converting enzyme) cleaves TM-TNF from the surface ActivatedMacrophage

24 sTNFR TNF  Mode of Action Activated M  TNF

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

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

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

29 Biologics in Non Rheumatologic Diseases Cancer Psoriasis Inflammatory Bowel Diseases Inflammatory Eye Diseases Asthma

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

31 Anti-TNFα Agents Etanercept Infliximab Adalimumab

32 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)

33 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)

34 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

35 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

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

37 Etanercept Mode of Action M   Target Cell Signal sTNFR TNF TNFR sTNFR:Fc

38 Etanercept INDICATIONS: Rheumatoid Arthritis (RA) Juvenile Idiopathic Arthritis (JIA) Psoriatic Arthritis (PsA) Ankylosing Spondylitis (AS) Plaque Psoriasis 1.ENBREL ® Package Insert

39 Characteristics Etanercept 1 Structure Structure Human fusion protein receptor Administration Administration 25 mg SC biweekly JIA 0.4 mg/kg SC biweekly Half-life Half-life 3 to 4.8 days Fixes complement (in vitro) No Lyses TNF-expressing cells (in vitro) No Antibodies < 5% (non-neutralizing) 1.ENBREL ® Package Insert

40 Etanercept Most common side effects Injection site reactions (redness, rash, swelling, itching, or bruising) 37 % Sinus infection35% Headache17% Runny nose12% 1.ENBREL ® Package Insert

41 Human Infliximab Mouse IgG1 Adalimumab Human IgG1

42 Infliximab/Adalimumab Mode of Action Activated M M   Target Cell Signal TNF TNFR

43 Characteristics Infliximab 1 Adalimumab 2 Structure Structure Chimeric MAb (mouse/human) Human MAb Administration Administration 3 –10 mg/kg Q 4-8 weeks intravenous 40 mg q 1 to 2 wks; MTX not allowed when given 1/wk Half-life Half-life 8 to 9.5 days days Fixes complement (in vitro) Yes Yes 2 Lyses TNF-expressing cells (in vitro) Yes Yes 2 Antibodies 13% (HACA) 1-12% antibodies; 5% neutralizing 1.Remicade ® Package Insert 2. HumiraTM Package Insert

44 Infliximab/Adalimumab* INDICATIONS: Rheumatoid Arthritis (RA) * Juvenile Idiopathic Arthritis (JIA)* Psoriatic Arthritis (PsA)* Ankylosing Spondylitis (AS)* Plaque Psoriasis* Crohn’s Disease* Ulcerative Colitis

45 Dosages Infliximab 1 Adalimumab 2 Rheumatoid Arthritis 5mg/kg 0,2,6, then Q 8 weeks IV (may increase to 10mg) 40 mg q 1 to 2 wks; MTX not allowed when given 1/wk Ankylosing Spondylitis 5 mg/kg 0,2,6 then Q 6 weeks 40 mg q 1 to 2 wks; MTX not allowed when given 1/wk Psoriatic Arthritis Psoriatic Arthritis5mg/kg 0,2,6, then Q 8 weeks 40 mg q 1 to 2 wks; MTX not allowed when given 1/wk Plaque Psoriasis 5mg/kg 0,2,6, then Q 8 weeks 80 mg then 40mg Q 2 wks starting the week after the 1 st dose Crohn’s Disease 5mg/kg 0,2,6, then Q 8 weeks May increase to 10mg) 160 mg for the first dose (taken as four separate injections over one or two days), 80 mg two weeks later, then 40 mg Q other wk. Ulerative Colitis 5mg/kg 0,2,6, then Q 8 weeks JIA 33 to 66 pounds- 20 mg Q other wk. 66 pounds or heavier-40 mg Q other wk. 66 pounds or heavier-40 mg Q other wk. 1.Remicade ® Package Insert 2. HumiraTM Package Insert

46 Drug Interactions Abatacept Anakinra Azathioprine Etanercept "Live" vaccinations Mercaptopurine Tocilizumab

47 EtanerceptInfliximab 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

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

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

50 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: Recommendations 1. Patients for biologic therapy should be screened for latent and active TB prior to initiating tx 2.. All patients who are candidates for biologic agents should be screened by tuberculin skin test TB, a chest radiograph for active TB 3.. Household and close contacts of candidate patients should be screened for active TB 4. All household and close contacts of candidate patients should be screened for active TB using CXR 5. Treat latent and active TB according to local guidelines 6. Delay tx with biologic agents in patients with latent and active TB 7. Administer TB prophylaxis to the patient for biologic therapy exposed to household contacts with active TB Philippine Guidelines on the Screening for TB prior to the use of Biologic Agents

51 EVALUATE PATIENT History and PE EVALUATE CONTACTS Hx and PE CXR (PA/APL view) Perform TST CXR (PA/APL view) Currently active TB? NOYES 1. Multidrug TB tx 2. Provide TB prophylaxis to candidate patient for biologic tx >8mm<8mm Interpret according to risk of latent TB infection and/or state of immunosuppression NEGATIVEPOSITIVE Proceed with anti TNF tx but with awareness of: 1. non-specific TB manifestations 2. Extrapulmonary TB Active TB ? Full diagnostic work up? NOYES 1. Tx latent TB infection 2. Delay TNF blockade 1. Multidrug TB tx 2. Postpone anti-TNF tx until TB therapy is completed

52 Safety Issues with Biologic Serious infections Opportunistic infection Malignancies Demyelination Congestive heart failure Autoantibodies and lupus-like syndrome Administration reactions

53 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,pyoderma granulomatosum, and polymyositis or dermatomyositis

54 Anakinra Interleukin-1 Receptor Antagonist

55 Interleukin 1

56 IL-1Ra (Anakinra) Approved in 2002 Targets interleukin-1 (IL-1) Another type of immune factor MOA: blocks the activity of IL-1 by competitively inhibiting IL-1 binding to the IL-1RI receptor

57 Interleukin-1Ra (Anakinra)

58 Anakinra Human recombinant anti-IL-1 receptor antagonist Daily 100mg subcutaneous injection ACR 20 response rates were only 38% Modest reductions in radiographic progression of joint disease Clinical benefits of anakinra are less than those of the TNF blockers Limited to selective patients with refractory disease

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60 Tocilizumab Interleukin-6 Receptor Antagonist

61 IL-6

62 IL-6 Receptor Antagonist (Tocilizumab) Humanised anti-IL-6 receptor antibody Indication: Moderate to severe active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.

63 IL-6 Receptor Antagonist

64 Tocilizumab Given IV Monotherapy or concomitantly with mtx or other DMARDs Recommended dose: Starting dose: 4mg/kg followed by an increase to 8mg/kg once every 4 weeks as a 60-minute single intravenous drip infusion

65 Frequently reported AE’s URTI Headache Nasopharyngitis RA worsening ALT increase

66 Adverse events Infusions generally well tolerated Low incidence of adverse GI events (1 peridiverticular abscess, 1 gastroenteritis) Transient ALT elevation- no evidence of clinical hepatitis or hepatic failure Lipid levels initially increased and subsequently stabilized at the upper level of normal-no relevant change in atherogenic risk index Slight increase in infections (including serious infections) over placebo- no occurrence of TB

67 Rituximab Belimumab B Cell Targeted Therapies

68 B cells Produce antibodies against target antigens Present antigen to T lymphocytes Produce cytokines that support mononuclear cells Regulate and organize inflammatory response Direct infiltration of end organs (kidneys and joints) Ref: B cells in autoimmunity ; J of Exp Medicine

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70 Rituximab Anti-CD20 Chimeric murine/human monoclonal antibody Indication: Moderately- to severely- active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies In combination with methotrexate

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74 Recommended Dose for Rheumatoid Arthritis (RA) Administer as two-1000 mg intravenous infusions separated by 2 weeks. Glucocorticoids administered as methylprednisolone 100 mg intravenous or its equivalent 30 minutes prior to each infusion are recommended to reduce the incidence and severity of infusion reactions. Subsequent courses should be administered every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks. Given in combination with methotrexate. Premedicate before each infusion with acetaminophen and an antihistamine

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78 Belimumab (Benlysta) Human monoclonal antibody that recognizes and inhibits the biological activity of B- lymphocyte stimulator (Blys) FDA approved the use in March 9, 2011 First drug approved for the treatment of lupus in 56 years

79 Belimumab (Benlysta) Indication: Active, antibody-positive SLE who are receiving other treatments for SLE Recommended dose: 10 mg/kg at two-week intervals for the first three doses and at four-week intervals thereafter, administered intravenously over a one-hour period.

80 Other Biologics: No Human Trial Adhesion Molecule Chemokines IL-8; ENA-78; CTAP-III; MCP-1 Inflammatory cells B cells T cells Fibroblast – like synoviocytes Trimolecular complex of T cell Receptor-Antigen- MHC Costimulatory Molecules

81 Quote of the Day  "Continuous attention span, or the amount of time a human can focus on an object without any lapse at all, is very brief and may be as short as 8 seconds. “  “After this amount of time, it is likely that an individual's eyes will shift focus, or that a stray thought will briefly enter consciousness."  "Continuous attention span, or the amount of time a human can focus on an object without any lapse at all, is very brief and may be as short as 8 seconds. “  “After this amount of time, it is likely that an individual's eyes will shift focus, or that a stray thought will briefly enter consciousness."

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83 Other Biologics Abatacept (Orencia) Tocilizumab (Actemra) AMG-714 HuMax-CD20 Belimumab (Lymphostat-B) Golimumab (CNTO 148) > T-cell co-stimulator modulator > IL-6 receptor > IL-15 receptor > regulates CD20 B cell activity > B cell depletion > tumor necrosis factor alpha

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86 Clinical Study P: treatment of active RA (24wks) I: 30mg, 75mg, 150mg, and placebo : extension of 55weeks (placebo grp) O: ACR 20 Radiographic changes: decrease in the rate of progressive joint damage M: 24 week placebo control study P: RA patients I: Anakinra + MTX vs (0; 0.04; 0.1; 1.0; 2.0 mg/kg) MTX alone O: ACR 20 response 24wks - 42% (optimum dose MTX) - 23% (placebo + MTX) P: 24 wk randomized, double-blind placebo controlled study

87 Rituximab (Mabthera) Approved in 2006 Targets CD20-positive B cells and blocks their activation Used in combination with methotrexate for patients with moderate-to-severe RA who have not responded to anti-TNF therapies.

88 Toxicity and Monitoring Injection site reaction (ISR): mild and transient Infections: cellulitis; pneumonia and bone & joint infection Headache Nausea; Diarrhea; abdominal pain Sinusitis; Influenza like syndrome Malignancy Signs & symptoms of infection Neutrophils counts at baseline and monthly for 3mos and every 4 mos up to 1 yr Pregnancy & breastfeeding: Used only if it is clearly needed and discontinued in nursing mothers

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96 Rilonacept-IL-1 Trap, is a dimeric fusion protein consisting of the extracellular domain of human interleukin (IL)-1 receptor and the FC domain of human immunoglobulin G-1 (IgG1) that binds and neutralizes IL-1. Rilonacept is currently approved for use in cryopyrin-associated periodic syndromes

97 Recombinant DNA biologics As indicated the term "biologics" can be used to refer to a wide range of biological products in medicine. However, in most cases, the term "biologics" is used more restrictively for a class of medications (either approved or in development) that are produced by means of biological processes involving recombinant DNA technology. These medications are usually one of three types: recombinant DNA Substances that are (nearly) identical to the body's own key signalling proteins. Examples are the blood-production stimulating protein erythropoetin, or the growth-stimulating hormone named (simply) "growth hormone" or biosynthetic human insulin and its analogues.erythropoetingrowth hormoneinsulin Monoclonal antibodies. These are similar to the antibodies that the human immune system uses to fight off bacteria and viruses, but they are "custom- designed" (using hybridoma technology or other methods) and can therefore be made specifically to counteract or block any given substance in the body, or to target any specific cell type; examples of such monoclonal antibodies for use in various diseases are given in the table below.Monoclonal antibodieshybridoma Receptor constructs (fusion proteins), usually based on a naturally-occurring receptor linked to the immunoglobulin frame. In this case, the receptor provides the construct with detailed specificity, whereas the immunoglobulin- structure imparts stability and other useful features in terms of pharmacology. Some examples are listed in the table below.fusion proteinsimmunoglobulinpharmacology

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99 Key Actions Attributed to TNF  TNF  (VEGF)

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102 Newer TNF alpha blockers Certolizumab pegol (Cimzia): pegylated humanized Fab’ fragment that binds tumor necrosis factor alpha. FDA approved it in April 2008 for the treatment of Crohn’s disease.FDA approved it in April 2008 for the treatment of Crohn’s disease. Golimumab (Simponi). Approved in April 2009 for: moderate-to-severe rheumatoid arthritis, active psoriatic arthritis, and active ankylosing spondylitis.

103 TNF blockers adverse effects: risks of tuberculosis reactivation and invasive fungal infections TNF inhibitors have a number of known side effects, mainly related to their immunosuppressant activity. Since TNF is a important cytokine when fighting against tuberculosis, these drugs can reactivate a latent tuberculosis infection. The official FDA presentation below discusses adverse effects associated with TNF blockers: infections (tuberculosis, histoplasmosis and other invasive fungal infections), congestive heart failure, neurologic events, malignancies and autoimmunity.

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112 abatacept

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114 Anakinra for RA

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