2. Introduction:
Rheumatoid arthritis (RA) is an autoimmune disease in which there is joint
inflammation, synovial proliferation and destruction of articular cartilage.
Immune complexes composed of IgM activate complement and release cytokines
(mainly TNF α and IL-1) which are chemotactic for neutrophils.
These inflammatory cells secrets lysosomal enzymes which damage cartilage and erode
bone, while PGs produced in the process cause vasodilation and pain.
RA is a chronic progressive, crippling disorder with a waxing and waning course.
Multiple small joints of hands and feet are preferentially affected; deformities are
produced as the disease progresses.
3. Cytokine release, chemotaxis, proliferation of immune cells
⬇️
Activation of T-cell and APC
⬇️
Release of IL-1,IL-4,IL-10, IL-11, IL-13,TNF-alpha
⬇️
Activation of macrophages, fibroblasts, chondrocytes and osteoclasts, proliferation of
synovial cell
⬇️
Arthritic condition
Pathophysiology :
4. Antirheumatic Drugs :
These are drugs which (except corticosteroids), can suppress the rheumatoid process,
bring about a remission and retard disease progression, but do not have nonspecific anti-
inflammatory or analgesic action.
They are used in rheumatoid arthritis (RA) in addition to NSAIDs, and are referred to as
disease modifying antirheumatic drugs (DMARDs) or slow acting antirheumatic drugs
(SAARDs).
They are used in rheumatoid arthritis (RA) in addition to NSAIDs, and are referred to as
disease modifying antirheumatic drugs (DMARDs) or slow acting antirheumatic drugs
(SAARDs).
The onset of benefit with DMARDs takes a few months of regular treatment, and
relapses occur at least a few months after cessation of therapy.
The onset of benefit with DMARDs takes a few months of regular treatment, and
relapses occur at least a few months after cessation of therapy.
5. Symptoms :
Weight loss
Fatigue
Swelling
Stiffness of joint
Joint tenderness
Numbness and tingling
Joint redness
Pain in joints
7. I) DMARDs :
A) Nonbiological drugs :
a) Immunosuppressant –
i) Methotrexate -(Mtx)
This dihydrofolate reductase inhibitor has prominent Immunosuppressant and anti-
inflammatory property.
MOA -
Act by inhibiting dihydrofolate reductase leading to inhibition of :
Cytokine production
8. Chemotaxis
Cell mediated immune reaction
Proliferation of immune cells
Uses –
① Methotrexate treats cancer by slowing the growth of cancer cells.
② Methotrexate treats psoriasis by slowing the growth of skin cells to stop scales from
forming.
③ Methotrexate may treat rheumatoid arthritis by decreasing the activity of the immune
system.
9. ii) Azathioprine –
MOA –
This purine synthase inhibitor acts after getting converting to 6-mercaptopurine by the enzyme
thiopurine methyl transferase(TPMT)
⬇️
Suppressed cell mediated immunity
⬇️
Selectively affect differentiation and function of T-cell and natural killer cells
⬇️
Suppresses inflammation and slow the progression of RA
Uses -
① Azathioprine is used to prevent organ rejection in people who have received a kidney
transplant.
② Azathioprine is also used to treat rheumatoid arthritis.
10. Contraindication -
① Pregnancy
② Breast feeding
③ Liver disease
④ Active infection
⑤ Leucopenia
⑥ Peptic ulcer
ADR -
① Oral ulceration
② Gastrointestinal upset
③ Dose dependent progressive liver damage
leading to cirrhosis
④ Predisposed to chest infection
11. b) Other immunomodulatory –
i) Sulfasalazine -
MOA –
Sulphapyridine split off in the colon by bacterial action and gets absorbed
⬇️
Suppressed generation of superoxide radicals and cytokine elaboration
⬇️
Relieve symptoms of RA
12. ii)Leflunomide –
Potent immunomodulator
MOA –
Leflunomide is rapidly converted in the active metabolites
⬇️
Inhibits dihydro-orotate dehydrogenase
⬇️
Inhibits pyrimidine synthesis which depressed cell proliferation
⬇️
Depressed antibody production by beta cells.
13. Contraindication –
① Pregnant women
② Active infection
③ Liver disease
④ Lactating mother
ADR –
① Diarrhea
② Headache
③ Nausea
④ Rashes
⑤ Thrombocytopenia
⑥ Leucopenia
⑦ Increased chance of chest infection
14. B) Biological agents :
a) TNF-α inhibitors –
MOA –
Binding to TNF-α cytokines and neutralize it
TNF-α not available to bind to TNF- receptors present on T-cells, Macrophages
Function of T-cells and macrophages suppressed
ADR -
i)Etanercept -
Pain, Redness, itching and swelling at injection site
ii) Infliximab -
Acute reaction (fever, bronchospasm), worsening of CHF.
15. b) Other biologicals –
i) Abatacept –
Binding to CD80 and CD86 molecules
Blocked the second signal for
Co-stimulation of T-cells.
Approved for moderate to severe active
RA not responding to Mtx.
Not to be combined with TNF-alpha
inhibitors.
Uses -
This medication is used to treat rheumatoid arthritis, a condition in which the body's own
defense system
16. (immune system) attack healthy tissue.
Abatacept works by weakening your immune system.
ii) Rituximab
Chimerized monoclonal Antibody
MOA -
Binding to CD20 beta cell antigen
Promotes apoptosis
Approved for active RA not responding to Mtx+TNF-α inhibitors.
ADR -
Infusion reaction, late onset neutropenia, depletion of beta lymphocytes, skin reactions.
17. II) Adjuvant drugs –
Prednisolone-
MOA –
As a glucocorticoid, the lipophilic structure of prednisolone allows for easy passage
through the cell membrane where it then binds to its respective glucocorticoid receptor
(GCR) located in the cytoplasm.
Upon binding, formation of the GC/GCR complex causes dissociation of chaperone
proteins from the glucocorticoid receptor enabling the GC/GCR complex to translocate
inside the nucleus.
This process occurs within 20 minutes of binding. Once inside the nucleus, the
homodimer GC/GCR complex binds to specific DNA binding-sites known as
glucocorticoid response elements (GREs) resulting in gene expression or inhibition.
Complex binding to positive GREs leads to synthesis of anti-inflammatory proteins while
binding to negative GREs blocks the transcription of inflammatory genes.
18. Contraindication -
Systemic infection, hypersensitivity to components.
ADR -
Nausea
vomiting
loss of appetite
heartburn
trouble sleeping
increased sweating, or acne may occur.
Uses -
It helps by reducing inflammation.