cytokines and biologic treatment in arthritis susie d. averia, md, fpcp, dpra
TRANSCRIPT
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 Functions
TNFα 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 Neutroph i ls
Os teo c las ts
Bone
Cart ilage
Osteob 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 TNF
ActivatedMacrophage TNF
TM-TNF (transmembrane TNF)
TACE (TNF alpha converting enzyme)cleaves TM-TNFfrom the surface
ActivatedMacrophage
sTNFR
TNF 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 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-6 Receptor Antagonist
• Tocilizumab
Anti-TNFα AgentsEtanercept
Infliximab
Adalimumab
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 Psoriasis1. 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 days
Fixes 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 days
Fixes 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 Spondylitis5 mg/kg
0,2,6 then Q 6 weeks 40 mg q 1 to 2 wks; MTX not allowed
when given 1/wk
Psoriatic Arthritis5mg/kg
0,2,6, then Q 8 weeks40 mg q 1 to 2 wks; MTX not allowed
when given 1/wk
Plaque Psoriasis5mg/kg
0,2,6, then Q 8 weeks80 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 Colitis5mg/kg
0,2,6, 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
• 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
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
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
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 cells
B cells
T cells
Fibroblast – 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 TNF
TNF(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.
abatacept
Anakinra for RA
