presentation on pathophysiology and management of RA

1. Rheumatoid arthritis
Pharmacology and therapeutics I
Pawan Maharjan

2. Introduction
• Rheumatoid arthritis (RA) is
an autoimmune disease in
which there is joint
inflammation, synovial
proliferation and
destruction of articular
cartilage.
• Immune system
identifies the synovial
membrane as "foreign"
and begins attacking it.
• It is chronic and progressive
disorder.

3. Cont..

4. Pathogenesis/pathophysiology overview
Immune complexes composed of IgM
activate complement and release cytokines activate
complement and release cytokines
(mainly TNFa and IL-l)
These cytokines attract
neutrophils.
Neutrophils phagocyte the immune complex cause synovitis and release
lysozome and prostaglandins
Lysozome damage cartilage and erode bone.
Prostaglandin cause pain and vasodilation
Joint instability, decrease range of motion, systemic
complication.

5. Sign and symptoms
• Initially Malaise, anorexia, tender and swollen
joint.
• Decrease in range of motion, stiffness
• Chronic: joint deformities
Extra articular effect: anemia, neuropathy,
kidney disease, pulmonary disease,
cardiovascular, osteoporosis., fever, weight loss.

6. Sign and symptom

7. Goal of therapy
• To manage pain, swelling and joint stiffness,
• Prevent articular cartilage damage and bony
erosions
• Prevent deformity and preserve joint function

8. Drug used in RA
1) NSAID: Aspirin, diclofenac, Ibuprofen etc.
2) Steroids ( Prendisolne, methylprednisolone, hydrocortisone,)
3) Disease-Modifying Antirheumatic Drugs (DMARDs)
i) Immunosuppressants: Methotrexate, Azathioprine, Cyclosporine
ii) Antimalarials: Chloroquine or Hydroxychloroquine
iii) Gold-containing compounds: Gold sod. thiomalate, Auranofin,
iv) Sulfasalazine
V) d-Penicillamine
VI) Lefunomide (immunomodulator)
4) Biological response modifiers:
i) TNF α inhibitors: Etanercept, Infliximab
ii) IL 1 antagonist: Anakinra

9. Cont..
• NSAIDs:
• These are only use for symptomatic relief to reduce pain ,
inflammation.
• Does not have any role progression of bone and cartilage
destruction.
Adjuvant therapy : Corticosteroids
• Use in form of oral tablet and articular injection as well.
• It act by inhibitiy both COX(cycloxygenase() and LOX
(lipoxygenase)pathway .
• They are also use for symptomatic relief.
• They have potent immunosuppressant and anti inflammatory
activity.
• They do not arrest the rheumatoid process ,though joint
destruction may be slowed and bony erosions may be delayed.

10. DMARDs
• Methotrexate
• Azathioprine
• D-penicillamine

11. D-Penicillamine
• It is drug of choice for younger patient.
• M.O.A: It depress circulating IgM rheumatoid
factors and T-cell. Hence it slows the progress
of bone destruction and RA.
• Other pharmacological action: It also form
chelate with heavy metal such as copper,
mercury, arsencic.

12. D-penicllamine
• Pharmacokinetics:
– Absorption: 40-70%
– Plasma protein bound: 80%
– Metabolized via liver enzyme
– Excretion: Urine
• Indication/clinical use: Rheumatiod arthritis, as
antidote in heavy metal poisoning
• Dose and dosage form: Tablet 250 mg, 125 mg
• Start with 125-250 mg OD . Later may increase up
to 250 mg BD/TDS.

13. D-penicillamine
• Adverse effect:
– Nausea, anorexia, loss taste, skin rashes,
thrombocytopenia, nephritic syndrome,
proteinuria.
• Precaution: Renal impairment patient, clotting
disorder
• Contraindication: Hypersensitivity, aplastic
anemia, pregnancy , lactation, lupus
erythematous.

14. Methotrexate
• It is immunosuppressant and anti folate drug.
• M.O.A: Its exact mechanism in treatment of
RA is unknown. It suppress the immune
system hence retard the inflammatory process
of Rheumatoid arthritis.
• Other pharmacological action: It also inhibit
dihydrofolic acid reductase enzyme hence
inhibit folic acid synthesis, also inhibit DNA
synthesis and cell reproduction.

15. methotrexate
• Pharmacokinetics
– Bioavailabitly; 50%
– Protein bound: around 50%
– Metabolize via liver enzyme
– Excretion via urine
• Indications/clinical uses: RA, psoriasis, leukemia,
breast carcinoma.
• Dosage form: Tablet, injection
• Dose; For RA: 5-7.5 mg weekly, when response is
obtained dose should be decreased.

16. Methotrexate
• ADR: GI disturbances, bone marrow depression,
hepatotoxicity, skin rashes, blurred vision,
alopecia
• Precaution:
– Patient with renal and hepatic impairment.
– Bone marrow depression
– Peptic ulcer, elderly, neonates
• Contraindications: Pregnancy, lactation, severe
renal and hepatic failure
–

17. Azathioprine
• M.O.A: Its exact mechanism in treatment of
RA is unknown. It suppress the immune
system hence retard the inflammatory process
of Rheumatoid arthritis
• Other pharmacological action: It inhibit
protein, DNA and RNA synthesis. It is purine
antimetabolite and inhibit purine synthesize
also.

18. Azathioprine
• Pharmacokinetic:
– Well absorbed orally
– Protein bound: 30%
– Metabolize by liver enzyme
– Excretion via urine
• Indication: RA, as immunosuppressant in organ
transplant, antineoplastic agent.
• Dosage form: Tablet, injection
• Dose: For RA: initially 1mg/kg/day for 6-8 weeks.
Can increase by 0.5 mg/kg weekly until response.
Max dose: 2.5mg/kg/day.

19. azathioprine
• Adverse effect: Bone marrow depression,
anorexia, , N/V, skin rashes, alopecia,
hepatotoxicity, diarrhea , arthralgia.
• Precaution: Renal and hepatic impairment.
• Contraindication: Hypersensitivity, pregnancy,
lactation, severe renal and hepatic disease ,
severe blood dyscrasias.

20. Surgical treatment
• Considered when pain is severe, loss in range
of motion ,
• Poor joint function and joint damage.

21. Non Pharmacological treatment
• Tobacco and smoking cessation.
• Regular physiotherapy to protect range of
motion.
• Decrease stress
• Avoid heavy physical work

22. Thank you