Cytokines And Biologic Treatment in Arthritis

SUSIE D. AVERIA, MD, FPCP, DPRA

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

CYTOKINES

• Hormonal messengers

• Biological effects in the immune system• Cell mediated immunity • Allergic type responses

• Divided into two groups: • Proinflammatory • Anti-inflammatory

CYTOKINES

• T lymphocytes- major source

• Antigen specific receptors on their cell surface

• Recognition of foreign pathogens

• Recognise normal tissue during episodes of autoimmune diseases

CYTOKINES

• Two main subsets of T lymphocytes• CD4 • CD8

• CD4 -helper T cells are subdivided into • Th1-type cytokines• Th2-type cytokines

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

Proinflammatory and anti-inflammatory cytokines in RA

• 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

• 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

Receptors for various cytokines

CYTOKINES

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

Pathogenesis of Rheumatoid Arthritis

Pathogenesis of Rheumatoid Arthritis

Cellular Components of Synovial Lesion

• T cells• B cells• Phagocytes• Neutrophils• Macrophage-like cells• Fibroblast-like cells

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

Interaction between CD4+ T cells and antigen-presenting cells

δ

Cellular Components of Synovial Lesion

• T cells• B cells

• B cell• Express surface immunoglobulins• Provide cognate help for T-cells

Proinflammatory Cytokines

Cytokines Cell sources FunctionsTNFα Macrophages,

lymphocytes, fibroblasts

Inflammation, fever, bone and cartilage resorption

IL-1α Macrophages, monocytes

Targets thymocytes and neutrophils

IL-1β Fibroblasts, epithelial cells

Targets B and T cells and tissue cells

IL-6 Macrophages, T cells, fibroblasts, some B cells

Differentiation, bone resorption

Proinflammatory and anti-inflammatory cytokines in RA

IL-1b and TNF-a: Proinflammatory Cytokines in the Rheumatoid Joint

TNF-α IL-1β Neutro ph i ls

Os teo c las ts

Bone

Cart ilage

Osteo b las ts

Chondrocytes

Bone

Synovial space

IL-6

PGE2

IL-8

High endothelial venule

Synovial membrane

Capsule

PannusOsteoblasts Osteoclasts

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.

Production of TNFa

ActivatedMacrophage TNFa

TM-TNF (transmembrane TNF)

TACE (TNF alpha converting enzyme)cleaves TM-TNFfrom the surface

ActivatedMacrophage

sTNFR

TNFa Mode of Action

TargetCell

Signal

ActivatedMf

TNF

Adapted with permission from Choy EH, Panayi GS. N Engl J Med. 2001;344:907–916.

Inhibition of Cytokines

Activation ofanti-inflammatory pathways

Anti-inflammatorycytokine

Suppression ofinflammatorycytokines

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

What are Biologics?

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

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

Biologics in Non Rheumatologic Diseases

• Cancer• Psoriasis• Inflammatory Bowel Diseases• Inflammatory Eye Diseases• Asthma

The BiologicalsInhibitors of Tumor

Necrosis Factors• Infliximab• Etanercept • Adalimumab

B Cell Targeted Therapies• Rituximab (Rituximab)• Belimumab

Interleukin-1 Receptor Antagonist and Interleukin-1 Receptor

• Anakinra

Interleukin-6 Receptor Antagonist

• Tocilizumab

Anti-TNFα AgentsEtanercept InfliximabAdalimumab

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)

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)

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

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

Etanercept (Enbrel)

Soluble portion of theHuman p75 chain TNFareceptor (binds extracellular TNF)

Fragment crystallizable (Fc) portion of Human IgG1 (prolongs its circulating half-life)

Etanercept Mode of Action

sTNFR:FcsTNFR:FcActivatedActivated

MMffTargetTarget

CellCell

SignalSignalsTNFR

TNF

TNF

TNFRTNFR

sTNFR:Fc

Etanercept

INDICATIONS:

Rheumatoid Arthritis (RA)

Juvenile Idiopathic Arthritis (JIA)

Psoriatic Arthritis (PsA)

Ankylosing Spondylitis (AS)Plaque Psoriasis

1. ENBREL® Package Insert

CharacteristicsEtanercept1

Structure Human fusion protein receptor

Administration 25 mg SC biweeklyJIA 0.4 mg/kg SC biweekly

Half-life 3 to 4.8 daysFixes complement

(in vitro) No

Lyses TNF-expressing cells (in vitro) No

Antibodies < 5% (non-neutralizing)

1. ENBREL® Package Insert

Etanercept

Most common side effects Injection site reactions (redness, rash, swelling, itching, or bruising)

37 %

Sinus infection 35%

Headache 17%Runny nose 12%

1. ENBREL® Package Insert

Constant (Fc)

Variable

Murine

Constant (Fc)

Variable

Human

Human

Infliximab

Mouse

IgG1

Adalimumab

HumanIgG1

Infliximab/AdalimumabMode of Action

ActivatedActivatedMMff

TargetTargetCellCell

SignalSignal

TNFTNF

TNFRTNFR

Characteristics

Infliximab1 Adalimumab2

Structure Chimeric MAb (mouse/human) Human MAb

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 8 to 9.5 days 10-14 daysFixes complement

(in vitro)

Yes Yes2

Lyses TNF-expressing cells (in

vitro)Yes Yes2

Antibodies 13% (HACA) 1-12% antibodies; 5% neutralizing

1. Remicade ® Package Insert

2. HumiraTM Package Insert

Infliximab/Adalimumab*

INDICATIONS:

Rheumatoid Arthritis (RA) *Juvenile Idiopathic Arthritis (JIA)*

Psoriatic Arthritis (PsA)*Ankylosing Spondylitis (AS)*

Plaque Psoriasis*Crohn’s Disease*Ulcerative Colitis

DosagesInfliximab1 Adalimumab2

Rheumatoid Arthritis5mg/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 5mg/kg0,2,6, then Q 8 weeks

40 mg q 1 to 2 wks; MTX not allowed when given 1/wk

Plaque Psoriasis 5mg/kg0,2,6, then Q 8 weeks

80 mg then 40mg Q 2 wks starting the week after the 1st dose

Crohn’s Disease5mg/kg

0,2,6, then Q 8 weeksMay 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/kg0,2,6, then Q 8 weeks

JIA33 to 66 pounds- 20 mg Q other wk. 66 pounds or heavier-40 mg Q other

wk.

1. Remicade ® Package Insert

2. HumiraTM Package Insert

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

Etanercept Infliximab

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

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

Etanercept Infliximab• Anaphylaxis/infusion

reaction• Rate of infections > MTX• Frequency of TB etc• Dose adjustment • Malignancy?• Haematological sx ~MTX• Autoantibodies; lupus-like

syndrome

Absolute Contraindications

ONGOING INFECTIONS: pneumonia, cellulitis, sepsis, skin ulceration, UTI and abscess

TUBERCULOSIS (screen patients with PPD and CXR)

JJ Lichauco, S. Tanke Torres, S. Navarra, L. DansPhilippine guidelines on the screening for TB prior to the use of biologic

agentsAPLAR J of Rheumatol 2006; 9: 184-192

Recommendations1. 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

EVALUATE PATIENTHistory and PE

EVALUATE CONTACTSHx and PE

CXR (PA/APL view)

Perform TSTCXR

(PA/APL view)Currently active TB?

NO YES

1. Multidrug TB tx2. Provide TB prophylaxis to candidate patient for biologic tx

>8mm<8mm

Interpret according to risk of latent TB infection and/or state of immunosuppression

NEGATIVE POSITIVE

Proceed with anti TNF tx but with awareness of:1. non-specific TB manifestations2. Extrapulmonary TB

Active TB ?Full diagnostic work up?

NO YES

1. Tx latent TB infection2. Delay TNF blockade

1. Multidrug TB tx2. Postpone anti-TNF tx until TB therapy is completed

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

Anakinra

Interleukin-1 Receptor Antagonist

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

Interleukin-1Ra (Anakinra)

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

Tocilizumab

Interleukin-6 Receptor Antagonist

IL-6

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.

IL-6 Receptor Antagonist

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

Frequently reported AE’s

• URTI• Headache• Nasopharyngitis• RA worsening• ALT increase

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

Rituximab Belimumab

B Cell Targeted Therapies

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 1994-80

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

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

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

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.

Other Biologics: No Human Trial• Adhesion Molecule• Chemokines

IL-8; ENA-78; CTAP-III; MCP-1

• Inflammatory cellsB cellsT cellsFibroblast – like synoviocytes

• Trimolecular complex of T cell Receptor-Antigen-MHC

• Costimulatory Molecules

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."

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

Active Biologic Therapy by Drug Class FDA Approval Date2 No. of Studies Selecteda

B-cell depletor

      Rituximab November 26, 1997 1

IL-1 receptor antagonist

      Anakinra November 14, 2001 3

Costimulatory blocker

      Abatacept December 23, 2005 3

Tumor necrosis

   factor-α antagonist

      Infliximab August 24, 1998 4

      Etanercept November 2, 1998 5

      Adalimumab December 31, 2002 6

      Certolizumab April 22, 2008 3

      Golimumab April 24, 2009 1

IL-6 receptor antagonist

      Tocilizumab January 8, 2010 4

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.

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

• 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

• 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:

• 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.

• 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.

• 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.

Key Actions Attributed to TNFa

TNFa(VEGF)

• 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.

• Golimumab (Simponi). Approved in April 2009 for: moderate-to-severe rheumatoid arthritis, active psoriatic arthritis, and active ankylosing spondylitis.

• 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.

http://www.cimzia.com/crohns-disease/hcp/chartpopup.html?image=/crohns-disease/hcp/images/chart-3-1_lg.jpg

abatacept

Anakinra for RA