2. WHATIS RHEUMATOIDARTHRITIS
A long lasting autoimmune disorder.
Primarily affects joints.
Result in warm, swollen and painful joints.
Wrist and hands are more commonly involved.
Cause is not clear but believed to involve
genetic and environmental factors.
Affects bone and cartilage
3.
4. DMARDS
A category of unrelated drugs defined by their use in
rheumatoid arthritis
Also called Remission Inducing Drugs (RIDs)
OR Slow Acting Anti Rheumatic Drugs (SAARDs)
Reduce symptoms of RA
Its effect take 6weeks- 6months
Slow acting as compared to NSAIDs
6. METHOTREXATE (MTX)
Considered first choice to treat RA
MOA: Methotrexate inhibits purine and pyrimidine
synthesis, which accounts for its efficacy in the
therapy of cancer as well as for some of its
toxicities & thymidylate synthetase.
It has secondary effects on PMN cells chemotaxis.
It has direct inhibitory effects on proliferation and
stimulates apoptosis in immune - inflammatory
cells.
Metabolized to a less active hydroxylated
metabolite.
7.
8. Adverse effects of Methotrexate
Nausea, mucosal ulcers.
Dose related hepatotoxicity.
Leucovorin used to reduce side effects.
Contraindicated in pregnancy, liver
disease, peptic ulcer.
9.
10. Cyclophoshamide
MOA; its major metabolite is: Phosphoramide
mustard
Which;
.cross link DNA and prevent cell replication
. Suppress T-cell & B-cell function.
Dosage: 2mg/kg/day orally.
Adverse effect;
Nausea
vomiting
11. Sulfasalazine
It is metabolized to sulfa pyridine & 5- amino
salicylic acid.
In treated arthritis patients, IgA & IgM rheumatoid
factor production are decreased.
Suppression of T cell responses to concanavalin
(glycoprotein that play role in cell interaction in
inflammatory cell).
Inhibition of in vitro B cell proliferation.
Inhibit release of cytokines ( IL-1, IL-2, IL-6, IL-12, TNFα)
12. 10%-20% of orally administered drug is absorbed.
Its mechanism of action in treating RA is unclear. The
onset of activity is 1 to 3 months, and it is associated
with GI adverse effects (nausea, vomiting, anorexia)
and leukopenia.
Adverse effect
Nausea
Vomiting
Rashes
Hemolytic anemia etc.
13. Leflunomide
MOA: its active metabolite (A77-1726) inhibits
dihydroorotate dehydrogenase and causes arrest of
dividing T cells and inhibition of production of
autoantibodies by B cells
In RA it is as effective as MTX
Inhibits bony damage
A/e : diarrhoea, Hepatitis, alopecia, wt gain, HTN
C/I : pregnancy
14.
15. Chloroquine & hydroxychloroquine
Mainly use in malaria and in rheumatic disease.
Mechanism is unclear but
Suppression of T lymphocytes
Stabilization of lysosomal enzymes.
Inhibition of DNA & RNA synthesis.
Trapping of free radical.
Rapidly absorb & about 50% protein bound in
plasma
very extensively tissue bound sp: melanin-
containing tissue i.e Eye
Deaminated in liver.
17. Gold salts
Administered through,
a) parenterally : aurothiomalate, aurothioglucose
b)orally: auranofin
But are no longer recommended b/c of significant
toxicities & questionable efficacy.
D-penicillamine
Metabolite of penicillin
Rarely use now b/c of toxicity.
18. Biologic therapies, or biologics
o Newer drugs that reduce RA inflammation in a
more highly targeted manner than the
sDMARDs.
o Biologics are made through biotechnology and
target very specific proteins or cells that are
involved in the inflammatory process.
o The currently available biologic therapies for RA
must either be injected under the skin
[etanercept, adalimumab, anakinra] or infused
[infliximab, abatacept, and rituxumab]).
19. TNFα inhibitors
Etanercept
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
A/E
- Opportunistic infections, Activation of latent TB
20. TNFα inhibitors
Etanercept
The combination of etanercept and methotrexate is more effective
than methotrexate or etanercept alone in hindering the RA disease
process, improving function, and achieving remission. Etanercept is
given subcutaneously once weekly and is generally well tolerated.
21. Infliximab
MOA : prevents TNFa interaction with cell surface
receptors causing down regulation of macrophages
and Tcell function.
Comb with MTX improves response and decreases
rate of formtion of new erosions more than MTX
alone
A/E: URTI, nausea, headache, sinusitis, rash,
activation of latent TB
C/I: multiple sclerosis as demyelinating syndromes
have been reported
22. 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
Respiratory infection is a common a/e
Comb with MTX to improve response
23. IL-1 ANTAGONIST
Anakinra
It is recombinant human IL-1 receptor antagonist.
Used in cases who have failed on others drugs.
A/e local reaction on s/c inj. & chest infection
Do not use in combination with TNF-alpha
antagonists
24. T-cell modulating agent
Abatacept
Abatacept is a recombinant fusion protein and
costimulation modulator that competes with CD28
for binding on CD80/CD86 protein, thereby
preventing full Tcell activation and reducing the
inflammatory response.
Common adverse effects include infusion-related
reactions, headache, upper respiratory infections,
and nausea.
25.
26.
27. B-LYMPHOCYTES DEPLETOR
Targeting B-lymphocytes in these patients has opened a new
therapeutic window
Rituximab
Used in resistant RA .Benefit in treatment of RA refractory
to antiTNF agents
Combination therapy with methotrexate
ADRs: Mild infusion reactions (infrequent)
29. Janus kinases are intracellular enzymes that modulate immune
cell activity in response to the binding of inflammatory mediators to
the cellular membrane.
Tofacitinib is a synthetic small molecule that is an oral inhibitor of
Janus kinases. It is indicated for the treatment of moderate to severe
established RA in patients who have had an inadequate response or
intolerance to methotrexate.
Tofacitinib treatment may also increase the risk for new primary
malignancy and opportunistic infections.
