biologics in rheumatoid arthritis
TRANSCRIPT
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BIOLOGICS IN RHEUMATOID ARTHRITIS
Sachin KumarDepartment of Pharmacology
AIIMS, New Delhi
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Rheumatoid arthritis (RA) is the most common type of arthritis. It is triggered by a faulty immune system and affects the wrist and small joints of the hand, including the knuckles and the middle joints of the fingers.
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INTRODUCTION
• Rheumatoid arthritis is a autoimmune disease.
• Most commonly wrist and hands involved with typically the same joints involved on both sides of the body.
• Rheumatoid arthritis affects approximately 1% of world population, with women developing the condition three times more than men.
• Prevalence of RA in India is 0.20-0.75%
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Etiology: Cause is unknown .
HLA DR4, Dw16, DR10, DR9, DR3 associated with rheumatoid arthritis.
Cigarette smoking – triggering factor.
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• Fatigue
• Joint pain
• Joint
tenderness
• Joint swelling
• Joint redness
• Joint warmth
• Joint stiffness
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Diagnosis Blood test X-ray
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• Rheumatoid Factor• ESR• C-Reactive Protein• Anti-CCP Antibody Test• Tests for Anemia
INVESTIGATIONS
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• X-Rays• Ultrasound. • Magnetic Resonance Imaging
(MRI) / CT SCAN
• Above lab findings plus clinical features are important to make the diagnosis
IMAGING TECHNIQES
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30 NOVEMBER 2009 10
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DIAGNOSIS [ACR Criteria (1987)]
•Morning stiffness 1h
•Three or more joints involved
•Arthritis of hand joints
•Symmetric arthritis
•Rheumatoid nodules
•Rheumatoid factor (positive < 5% normal subjects)
•Radiographic changes (must show erosion/decalcification)
Present for 6wk
Any 4 of the following must be present to allow diagnosis of RA (Patients with 2 or more clinical diagnoses are not excluded)
Reference: Arnett et al. The American Rheumatism Association1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315-324
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2010 ACR/EULAR Classification Criteria• A score of ≥6/10 is needed for classification of a patient as having definite RAA. Joint involvement
SCORE• 1 large joint 0• 2−10 large joints 1
1−3 small joints (with or without involvement of large joints) 2
• 4−10 small joints (with or without involvement of large joints) 3• >10 joints (at least 1 small joint)†† 5 B. Serology (at least 1 test result is needed for classification)• Negative RF and negative ACPA 0• Low-positive RF or low-positive ACPA 2• High-positive RF or high-positive ACP 3
C. Acute-phase reactants (at least 1 test result is needed for classification)• Normal CRP and normal ESR 0• Abnormal CRP or normal ESR 1
D. Duration of symptoms• <6 weeks 0• ≥6 weeks 1
ARTHRITIS & RHEUMATISM Vol. 62, No. 9, September 2010, pp 2569–2581 DOI 10.1002/art.27584 © 2010, American College of Rheumatology
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ACR Response Criteria≥ 20% / 50% / 70% Improvement in:
• Number of swollen joints (SJC)
• Number of tender joints (TJC)
• Improvement of at least three of the following:
• Patient Global Assessment
• Physician Global Assessment
• Patient Pain Scale
• Health Assessment Questionnaire (HAQ)
• ESR or CRP
Felson DT et al. Arthritis Rheum. 1993; 41: 1564-1570
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• Disease Activity Score of 28 joints (DAS28). It is widely used as an indicator of RA disease activity and response to treatment The joints included in DAS28 are PIP ,MCP joints ,wrists, elbows , shoulders and knees
• When looking at these joints, both the number of joints with tenderness upon touching (TEN28) and swelling (SW28) are counted.
• In addition, the ESR is measured.• Score less than 3.2 means pt is inactive• 3.2-5.1 means moderately active patient • more than 5.1 means pt is active
Monitoring progression
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Therapeutic Strategies
• Use of early DMARDs• Combinations of Conventional DMARDs
• Three studies have confirmed the use of “triple therapy” in early RA is more effective than a single agent. (Clin Exp Rheumatol 17:699-704, 1999, Arthritis Rheum 50:2072-81, 2004, Arthritis Rheum 46:1164-70, 2002).
• Combinations of Methotrexate plus Biologic agents
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-Current recommendation is to add DMARDs as soon as the diagnosis is confirmed
-Slow acting, take 6weeks to 6 months to show the effects.
-They modify/ alter disease progression Commonly used DMARDs are -: - Methotrexate - Sulphasalazine - Hydroxychloroquine - Leflunomide - cyclosporine - Azathioprine
Disease modifying anti rheumatic drugs (DMARDs):
MANAGEMENT
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Advantages of DMARDs • Slow disease progression• Improve functional disability• Decrease pain• Interfere with inflammatory processes• Retard development of joint erosions
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Limitations of conventional DMARDs
1) The onset of action takes several months.
2) The remission induced in many cases is partial.
3) There may be substantial toxicity which requires careful monitoring.
4) DMARDs have a tendency to lose effectiveness with time.
These drawbacks have made researchers look for alternative treatment strategies for RA- The Biologic Response Modifiers.
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• Biologics are medications genetically engineered
from a living organism, such as a virus, gene or
protein, to simulate the body’s natural response to
infection and disease.
•Biologics are typically reserved for people whose
arthritis has not responded adequately to traditional
disease-modifying anti rheumatic drugs (DMARDs).
Biologics
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Important points
•Biologics are effective
•Biologics may be your only medication or part
of a combination approach
•Biologics may increase your risk for infection
•Biologics are usually given by Injection or IV
•Biologics have safety issues
•Biologics require a strict follow-up schedule
• Biologics are expensive
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What’s important to know about the drug class?
•All biologics increase risk of infection.
•Patients should be screened for
tuberculosis and other infections before
starting a biologic.
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How Do Biologics Treat Rheumatoid Arthritis
• They inhibit specific components of the immune system that play pivotal roles in inflammation
• Biologics are used to treat moderate to severe rheumatoid arthritis that has not responded adequately to other treatments.
• Slow down the progression of rheumatoid arthritis when 1st line drugs have failed.
• Aggressive treatment is known to help prevent long-term disability from RA.
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BIOLOGICS IN RA
• Cytokines such as TNF-α ,IL-1,IL-6 etc. are key mediators of immune function in RA and have been major targets of therapeutic manipulations in RA.
• Various biologicals approved in RA are:- Anti TNF agents : Infliximab, Etanercept,
Adalimumab IL-1 receptor antagonist : Anakinra IL-6 receptor antagonist : Tocilizumab Anti CD20 antibody : Rituximab T cell co-stimulatory inhibitor : Abatacept
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Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
Biologic Disease-Modifying anti-rheumatic Drugs
Name Trade Name Target of ActivityAdalimumab Humira® TNF-α
Certolizumab pegol Cimzia® TNF-α
Etanercept Enbrel® TNF-α
Golimumab Simponi® TNF-α
Infliximab Remicade® TNF-α
Abatacept Orencia® CD28
Anakinra Kineret® IL-1
Rituximab Rituxan® CD20
Tocilizumab Actemra®
RoActemra®IL-6 receptor
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Biologics• The currently available biologic therapies for RA
must either be injected under the skin [Etanercept, Adalimumab, Anakinra] or infused [Infliximab, Abatacept, and Rituximab]).
Available TNF alpha inhibitors
• Etanercept (Enbrel) • Infliximab (Remicade) • Adalimumab (HUMIRA)• Golimumab (Simponi)• Certolizumab (Cimizia)
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TNF alpha Approved year
• TNF alpha, a key cytokine for the development of the inflammatory response
• The first approved TNF alpha blocker was Etanercept (Enbrel) in May 1998
• Infliximab (Remicade) in November 1999
• Adalimumab (HUMIRA) was approved in December 2002
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Cont…
• 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.
http://pharmacologycorner.com/mechanism-of-action-indications-and-adverse-effects-of-etanercept-infliximab-and-adalimumab/
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TNFα inhibitors
• Etanercept (Enbrel) :• MOA: It is recombinant fusion protein consisting of
two soluble TNF p75 receptor moieties linked to Fc
portion of human IgG1, it binds TNFα molecule
• It decreases rate of formation of new erosion
• DOSE: 25 mg twice weekly given s.c.
• SIDE EFFECTS : “Injection site reactions, Increased
risk of infections (Tuberculosis (TB) and fungal
infections)
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Adalimumab
• MOA: It is fully human IgG1 anti TNF monoclonal
antibody complexes with soluble TNFα and prevents
its interaction with cell surface receptors causing
down regulation of macrophages and T-cell function
• DOSE: 40 mg given every 2 weekly given s.c.
• Common side effect : Redness, itching, pain,
or swelling at the injection site, Respiratory infection
• Combination with MTX to improve response
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Infliximab• MOA: It is chimeral IgG1 monoclonal antibody that
binds with TNFα
• DOSE:3 mg/kg IV infusion, Weeks 0, 2 and 6;
then every 8 weeks Combine with Methotrexate
• SIDE EFFECT: URTI, nausea, headache, sinusitis,
activation of latent , severe allergic reaction with
swelling of the lips, difficulty breathing and low
blood pressure
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TNF- blocking agentsS.NO AGENT CLASS DOSE FREQUENCY
1 INFLIXIMAB TNF-alpha inhibitor
3 mg/kg IV infusion
Weeks 0, 2 and 6; then every 8 weeks Combine with Methotrexate
2 ETANERCEPT TNF-alpha inhibitor
50 mg SC; 25 mg SC
Weekly; twice weekly
3 ADALIMUMAB TNF-alpha inhibitor
40 mg SC Every 14 days May increase dose to 40 mg every week in patients not taking Methotrexate
4 CERTOLIZUMAB TNF-alpha inhibitor
400 mg SC, followed by 200 mg SC
400 mg SC weeks 0, 2, and 4, followed by 200 mg SC every 2 weeks
5 GOLIMUMAB TNF-alpha inhibitor
50 mg SC Monthly Combine with Methotrexate
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• Anakinra (Kineret)- It is recombinant human IL-1 receptor antagonist.
• Used in cases who have failed on others drugs.
• Side effects: local reaction on s/c inj. & chest infection
S.NO AGENT CLASS DOSE FREQUENCY
1 Anakinra IL-1 receptor antagonist
100 mg SC Daily
IL-1 RECEPTOR ANTAGONIST
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IL-1R antagonists: ANAKINRA (Kineret)
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IL-6 RECEPTOR ANTAGONIST : TOCILIZUMAB (Actmera)
• Tocilizumab is a Humanized anti IL-6 monoclonal Ab that specifically inhibits the action of 1L-6
• It is reserved for Resistant RA • Side effects : Infusion related reaction (flushing,
headache, fever, nausea, fatigue)
S.NO AGENT CLASS DOSE FREQUENCY
1 Tocilizumab IL-6 receptor antagonist
IV: 4 mg/kg; may increase to 8 mg/kg
Every 4 weeks
SC: 162 mg < 100 kg: every other week; increase to every week based on clinical response ≥ 100 kg: every week
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• It is recombinant fusion protein.• MOA: inhibits activation of T cell• Used when there is inadequate response to DMARDSA/e :• Risk of infections• Hypersensitivity reaction
S.NO AGENT CLASS DOSE FREQUENCY
1 Abatacept T-Cell co-stimulation inhibitor
IV: < 60 kg: 500 mg 60–100 kg: 750 mg > 100 kg: 1000 mg
Weeks 0, 2, 4, then monthly
SC: 125 mg Weekly May be initiated with or without single IV loading dose If using loading dose, use weight-based dose above and start SC injection within 24 hours of the initial IV infusion
T-Cell co-stimulation inhibitor : Abatacept (Orencia)
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RITUXIMAB (RITUXAN OR MABTHERA)B CELL DEPLETION THERAPY
• Targeting B-lymphocytes in these patients has opened a new therapeutic window
• Chimeric monoclonal Ab, targets CD20 B cells
• Used in resistant RA .
• Combination therapy with Methotrexate
• Dose: 2 IV infusions 2 wks apart • Side effects: Mild infusion reactions (flushing,
headache, fever, nausea, fatigue)
S.NO
AGENT CLASS DOSE FREQUENCY
1 Rituximab Anti-CD 20 1000 mg IV plus 2 IV infusions 2 wks apart Combine with Methotrexate
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Janus Kinase enzyme inhibitor/ SYK inhibitor
S.NO AGENT CLASS DOSE FREQUENCY1 Tofacitinib Janus Kinase
enzyme inhibitor5 mg PO Days 1 and 15 may retreat
every 24 weeks (no sooner than every 16 weeks) Combine with Methotrexate
• Tofacitinib (Xeljanz) JAK inhibitor• USE: Similar to biologics in effectiveness and side effects• Mechanism: Oral disease modifying medication Targets inflammation signaling pathway• Oral agents (Biosimiliar): Tofacitinib (Pfizer) Baricitinib (Eli lilly)• SYK inhibitor (spleen tyrosine kinase (Syk)
inhibitors): Fostamatinib
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BIOLOGICS : FUNCTION AT A GLANCE
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Adverse Effects of Biologics
Infusion related reactions : Dyspnoea , chest pain ,
headache, high blood pressure, dizziness, rash,
flushing, hypotension or a “tickle in the throat.” Serious Infections
• Tuberculosis and sepsis Malignancy : Lymphoma ?, Solid Tumors ?
OTHERS: Optic neuritis, Increase LFT
Severe allergic reaction
Numbness and Tingling
• Pregnancy: stop before 3 months
• No live vaccines should be given
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• Treatment should start early and aggressively to prevent functional limitations and structural damage
• Methotrexate is the first line drug, but in high risk patients early combination of Methotrexate with prednisone or a tumour necrosis factor inhibitor improves outcomes
• The goal of treatment today is remission, which has been defined in several ways, including the DAS28 score, SDAI, CDAI, and a provisional ACR/EULAR definition
Summary
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• There are currently five TNF inhibitors on the market, which vary in mode and frequency of administration. The drugs are generally similar in efficacy and side effect profiles
• A safety concern with the biologic drugs is the potential for serious infections, so monitoring is needed
Summary
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Thank you.