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.
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
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
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
15.
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/
29.
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
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
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
+ve In about 80% of cases
- Also present in about 5% of normal individuals
- when it appears in patients with arthritic pain on both sides of the body, it is a strong indicator of RA.
The higher the ES
High levels of C-reactive protein (CRP) are also indicators of active inflammation..R the greater the inflammation., help determine how active the condition is.
The presence of antibodies to cyclic citrullinated peptides (CCP) can identify RA years before symptoms develop.
COMPUTED TOMOGRAPHY (CT)
* The criteria are aimed at classification of newly presenting patients. In addition, patients with erosive disease typical of rheumatoid arthritis (RA) with a history compatible with prior fulfillment of the 2010 criteria should be classified as having RA. Patients with longstanding disease, including those whose disease is inactive (with or without treatment) who, based on retrospectively available data, have previously fulfilled the 2010 criteria should be classified as having RA. † Differential diagnoses vary among patients with different presentations, but may include conditions such as systemic lupus erythematosus, psoriatic arthritis, and gout. If it is unclear about the relevant differential diagnoses to consider, an expert rheumatologist should be consulted. ‡ Although patients with a score of 6/10 are not classifiable as having RA, their status can be reassessed and the criteria might be fulfilled cumulatively over time. § Joint involvement refers to any swollen or tender joint on examination, which may be confirmed by imaging evidence of synovitis. Distal interphalangeal joints, first carpometacarpal joints, and first metatarsophalangeal joints are excluded from assessment. Categories of joint distribution are classified according to the location and number of involved joints, with placement into the highest category possible based on the pattern of joint involvement. ¶ “Large joints” refers to shoulders, elbows, hips, knees, and ankles. # “Small joints” refers to the metacarpophalangeal joints, proximal interphalangeal joints, second through fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists. ** In this category, at least 1 of the involved joints must be a small joint; the other joints can include any combination of large and additional small joints, as well as other joints not specifically listed elsewhere (e.g., temporomandibular, acromioclavicular, sternoclavicular, etc.). †† Negative refers to IU values that are less than or equal to the upper limit of normal (ULN) for the laboratory and assay; low-positive refers to IU values that are higher than the ULN but 3 times the ULN for the laboratory and assay; high-positive refers to IU values that are 3 times the ULN for the laboratory and assay. Where rheumatoid factor (RF) information is only available as positive or negative, a positive result should be scored as low-positive for RF. ACPA anticitrullinated protein antibody. ‡‡ Normal/abnormal is determined by local laboratory standards. CRP C-reactive protein; ESR erythrocyte sedimentation rate. §§ Duration of symptoms refers to patient self-report of the duration of signs or symptoms of synovitis (e.g., pain, swelling, tenderness) of joints that are clinically involved at the time of assessment, regardless of treatment status. 2
The ACR (American College of Rheumatology) Response Criteria.
A method for measuring response to RA therapy.
Biologics are genetically-engineered proteins derived from human genes. They are designed to inhibit specific components of the immune system that play pivotal roles in fueling inflammation, which is a central feature of rheumatoid arthritis.
Biosimiliar is a biologic medical product which is a copy of an original product that is manufactured by a different company. Biosimiliar are officially approved versions of original &quot;innovator&quot; products, and can be manufactured when the original product&apos;s patent expires.
http://www.everydayhealth.com/hs/rheumatoid-arthritis-treatment-management/biologics-facts
Currently, the law provides at least 12 years of regulatory data protection for innovative biological products through the biosimilar pathway, which was created as part of the Biologics Price Competition and Innovation Act. The data exclusivity period for biologic medicines regularly mentioned in the 2015 White House budget, however, refers to a seven-year exclusivity period. In the budget proposal, released in 2014 by United States Department of Health and Human Services, the number of years that a drug company has exclusivity or “monopoly pricing power” for a medication was reduced from 12 to seven years in order to foster biosimilar competition. As a result, there is some talk about whether or not seven years is the timeframe that the TPP will secure for patent protection.
Biologic DMARDs Included in the Comparative Effectiveness Review
The biologic disease-modifying anti-rheumatic drugs (DMARDs) that have been studied for treatment of rheumatoid arthritis and were included in the comparative effectiveness review are:
The biologic DMARDs that target tumor necrosis factor-alpha (TNF-α) include adalimumab (Humira), certolizumab pegol (Cimzia), etanercept (Enbrel), golimumab (Simponi), and infliximab (Remicade).
Other biologic DMARDs included in the review target immune system components other than TNF-α. They are:
Abatacept (Orencia): Its target of activity is CD28.
Anakinra (Kineret): Its target of activity is interleukin 1.
Rituximab (Rituxan): Its target of activity is CD20.
Tocilizumab (Actemra, RoActemra): Its target of activity is the interleukin-6 receptor.
Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
an infusion reaction includes any signs or symptoms experienced by a patient during the infusion of pharmacologic or biologic agents or any events occurring on the first day of drug administration. Infusion reactions can be acute (occurring within two hours of infusion) or delayed (occurring up to 14 days after an infusion).
Dyspnoea : difficulty in breathing
“tickle in the throat.”: I constantly feel the need to cough to clear my throat. It is not particularly full of mucus but I always feel that there&apos;s a little something there.
sepsis (a bacterial infection that spreads throughout the body)