RHEUMATOID ARTHRITIS AND NEWER BIOLOGICS

1. BIOLOGICS IN
RHEUMATOID ARTHRITIS
Sachin Kumar
Department of Pharmacology
AIIMS, New Delhi

2. 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.

3. 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%

4. Etiology:
 Cause is unknown .
 HLA DR4, Dw16, DR10, DR9, DR3
associated with rheumatoid arthritis.
 Cigarette smoking – triggering factor.

6. • Fatigue
• Joint pain
• Joint
tenderness
• Joint swelling
• Joint redness
• Joint warmth

7. Diagnosis
Blood test X-ray

8. • Rheumatoid Factor
• ESR
• C-Reactive Protein
• Anti-CCP Antibody Test
• Tests for Anemia
INVESTIGATIONS

9. • X-Rays
• Ultrasound.
• Magnetic Resonance Imaging
(MRI) / CT SCAN
• Above lab findings plus clinical
features are important to make
the diagnosis
IMAGING TECHNIQES

10. 30 NOVEMBER 2009 10

11. 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

12. 2010 ACR/EULAR Classification Criteria
• A score of ≥6/10 is needed for classification of a patient as having definite RA
A. 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

13. 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

14. • 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

16. 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

17. -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

18. Advantages of DMARDs
• Slow disease progression
• Improve functional disability
• Decrease pain
• Interfere with inflammatory processes
• Retard development of joint erosions

19. 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.

20. • 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

21. 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

22. 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.

23. 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.

24. 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

25. 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 Activity
Adalimumab 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

26. 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)

27. 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

28. Cont…
• Certolizumab pegol (Cimzia): pegylated
humanized Fab’ fragment that binds tumor
necrosis factor alpha.
FDA approved it in April 2008 for the treatment o
• 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/

30. 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)

31. 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

32. 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

33. TNF-α blocking agents
S.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

34. • 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

35. IL-1R antagonists: ANAKINRA (Kineret)

36. 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

37. • It is recombinant fusion protein.
• MOA: inhibits activation of T cell
• Used when there is inadequate response to DMARDS
A/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)

38. 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.N
O
AGENT CLASS DOSE FREQUENCY
1 Rituximab Anti-CD 20 1000 mg IV plus 2 IV infusions 2 wks apart
Combine with Methotrexate

39. Janus Kinase enzyme inhibitor/ SYK inhibitor
S.NO AGENT CLASS DOSE FREQUENCY
1 Tofacitinib Janus Kinase
enzyme inhibitor
5 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

40. BIOLOGICS : FUNCTION AT A GLANCE

41. 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

42. • 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

43. • 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

44. Thank you.