This presentation contains extensive information on rheumatoid arthritis.

1. Rheumatoid Arthritis

2. What’s rheumatoid arthritis (RA)?
• Its is a chronic, autoimmune disease marked by inflammation
and pain in joints, synovial proliferation and destruction
articular cartilage.
• It is affecting 0.5-2% of the population.
• It affects 1.3 million of American population.
• It causes a joint damage on both side of body.
• Treatment works best if diagnosed in early phase of disease.
• Inflammatory features of RA were characterized by elevated
productions of cytokines of inflammatory biomarkers (IL-6,
CRP, and TNF etc.)

3. Contd..
• Immune complexes composed of IgM activate complement and
releases cytokines (Mainly TNF-α and IL-1) which are chemotactic
for neutrophils.
• Inflammatory cells secrete lysosomal enzymes which damage
cartilage and erode bone
• The prostaglandins produces causes vasodilation and pain.
• The long term RA may results in the poor psychological health,
especially depression, which affects 17% of the population.
• Cardiovascular disease (CVD) is the most common cause of death in
rheumatoid arthritis (RA) (3R1, 3R2) owed largely to a heightened
risk of coronary artery disease (CAD), stroke and heart failure (HF)
(3R3, 3R4).

4. Symptoms
• These symptoms and signs occur during periods known as flares or
exacerbations.
• Other times are known as periods of remission (when symptoms
disappear completely)
• The joint symptoms in RA mainly includes:
– joint pain
– joint swelling
– joint stiffness
– loss of joint function and deformities
• Symptoms may vary from mild to severe

5. Diagnosis
• Require multiple lab tests to confirm clinical examination findings.
• Physical exam of your joints.
– looking for swelling and redness
– examining joint function and range of motion
– touching the affected joints to check for warmth and
tenderness
– testing your reflexes and muscle strength
• Blood test for:- antibodies,
• Imaging test:- Ultrasound, X-ray or MRI

6. Blood tests for rheumatoid arthritis
• Rheumatoid factor test
• Anti-citrullinated protein antibody test (anti-CCP)
• Antinuclear antibody test.
• Erythrocyte sedimentation rate.
• C-reactive protein test

7. Treatment
• There’s no cure for RA, but there are treatments that can help you
manage it.
• Treat to Target RA is a treatment philosophy that rheumatologists use to
effectively manage this disease.
• Treatments may include:
– medications
– alternative or home remedies
– dietary changes
– specific types of exercise

8. Medications
• There are many types of medication for RA.
• Some of these medications help to reduce the pain and
inflammation of RA.
• Some help to reduce flares and limit the damage that RA does to
your joints.
• NSAIDS are the first line drugs and affords relief in pain, swelling,
morning stiffness, immobility, but do not arrest the disease
process.
• Goals of drug therapy
– Decrease pain, swelling and joint stiffness
– Prevent articular cartilage damage and bone erosions
– Prevent deformity and preserve joint function.

9. Drug classification
1. Disease modifying
antirheumatic drugs
(DMARDs)
2. Biologic response
Modifiers
3. Adjuvant Drugs
a) Immunosuppressant:
 Methotrexate,
 Azathioprine,
 Cyclosporine
a) Sulfasalazine
b) Chloroquine and
Hydroxychloroquine
c) Leflunomide
d) Gold sodium thiomalate,
Auranofin
e) d-Penicillamine
a) TNF-α inhibitors:
 Etanercept,
 Infliximab,
 Adalimumab
 Tocilizumab
 Sarilumab
 certolizumab
 pegol and
 golimumab
b) IL-1 antagonists:
 Anakira
C) Janus Kinase inhibitors
 Tofacitinib,
Baricitinib or
Upadacitinib
d) Non-TNF biologics:- rituximab,
abatacept, tocilizumab
a) Corticosteroids:
 Prednisolone and others

10. Methotrexate (MTX)
• Dihydrofolate reductase inhibitor
• Prominent Immunosuppressant and
• Anti-inflammatory property
• Inhibit cytokine production in RA
• Rapid onset of relief among DMARDs(4-6 weeks).
• First choice of DMARDs in RA
• Oral bioavailability affected by foods
• Excretion is hindered in renal disease hence not recommended
• Probencid and Aspirin Increase the MTX level and toxicity
• Trimethoprim addition inhibits DHFR and depress bone marrow.
• It is associated with the reduced risk of CVD
• SE:- Oral ulceration, Nodulosisi and G.I. upset of low MTX dose
• Prolonged therapy leads to liver damage and thus cause cirrhosis
• Contraindicated in: Pregnancy, Breast feeding, Liver disease, active infection,
leucopenia and peptic ulcer
• Brands:- Neotrexate, Biotrexate 2.5mg Tab.

11. Azathioprine
• Potent Suppressant of cell medicated
immunity.
• Selectively affect differentiation and
function of T-cells and natural killer cells
• Remission induced in smaller % of patients
• It is less commonly used
• Given along with corticosteroids
• Has steroid sparing affect
• It is not combined with MTX
• Brands:- IMURAN 50 mg tab
• Ciclosporin Chlorambucil and Cyclophosphamide are rarely used in RA.

12. Sulfasalazine
• Has Anti-inflammatory effect
• Primarily used for Ulcerative colitis
• Suppress the disease in significant number in RA
• Unknown mechanism of action
• Metabolised by bacteria in colon and absorbed systemically
• Efficacy in RA modest
• Second line of drug
• Brands: SALAZO PYRIN, SAZO-EN

13. Chloroquine and Hydroxychloroquine
• Antimalarial drug, induce 50% remission in RA, takes 3-6 months
• Low toxicity, low efficacy
• Do not prevent bone erosion
• Unknown MOA
• However found to
– Reduce monocyte IL-1
– Inhibit Lymphocyte B
– Interfere lysosome stabilization
– Free radical stabilization
• These drugs given for long periods in RA
• Accumulate in tissue and causes retinal damage and corneal opacity
• Which is less common in HCQ than CQ hence preferred
• AEs:- Rashes, Hair graying, IBS, myopathy, neuropathy.
• CQ/HCQ employed in milder non-erosive disease.
• The are combined with MTX/sulfasalazine.

14. Leflunomide
• Inhibits the proliferation of activated lymphocytes.
• Suppress the symptoms and retard the radiological progression.
• Efficacy comparable to MTX but onset is fast (4 weeks).
• Converted into active metabolite which inhibits dihydro-orate
dehydrogenase and pyrimidine synthesis in actively dividing cells.
• Suppress antibody production by B-cells
• Half life of active metabolite is 2 weeks
• Loading dose 100mg OD for 3 days followed by 20mg OD
• AEs:-Diarrhea, headache, nausea, rashes, loss of hair, thrombocytopenia,
leucopenia, increased chances of chest pain, raised hepatic transaminase
• Not used in children and Pregnant lactating women
• Alternative to MTX but can be added to it but combination is hepatotoxic
• Combi with Sulfasalazine improve benefits
• Brands:- Lefra 10mg, 20mg tabs
•

15. Gold
• Most effective agent for preventing rheumatoid process
• Std DMARD before advent of low-dose MTX
• Remission Rate:-50%
• Reduces chemotaxsis, phagocytosis, macrophage and lysosomal
activity, monocyte differentiation
• Inhibit cell-medicated immunity
• Lowers rheumatoid factor and ESR
• Prevents joint destruction
• Induce bone erosion healing
• Effective in psoriatic anthropathy
• Bounds to plasma & tissue proteins especially in kidney
• Stays in body for years
• Toxicity of Parenteral Gold salt:- Hypertension, dermatitis, stomatitis,
kidney liver damage, bone marrow deprresion
• Rarely used now

16. Auranofin
• Orally active gold compound containing 29% gold
• Bioavailability: 25%
• Lower plasma gold level and efficacy than injected gold sod
thiomalate
• Less toxic
• AEs:- diarrhoea (30% incidence), abdominal cramps
• Other AEs: Pruritus, taste distubabce, mild anemiaand
alopecia
• Used infrequently

17. d-Penicillamine
• Copper chelating agent with gold like action
• Less efficacious; do not heal bone erossion
• Not favoured
• Does not offer any advantage
• Toxicity similar to gold
• AEs:- Loss of taste, systemic lupus and myasthenia gravis
• Increase soluble collagen
• Preferred drug for stage I and II scleroderma
• Dose:-125-250 mg OD then 250 BD
• Brands:- Artin 150, 250 mg caps; Cilamin 250 mg cap

18. Biologic response Modifiers
• Several recombinant proteins/monoclonal antibodies that
binds and inhibit cytokines, especially TNF-α or IL-1
• Effective against autoimmune disease like RA, Inflammatory
bowel disease, Psoriasis, scleroderma.
a) TNF-α inhibitors:
 Etanercept,
 Infliximab,
 Adalimumbab
b) IL-1 antagonists:
 Anakira
•

19. TNF-α inhibitors:
• Plays an important role in inflammatory cascade of RA by activating
membrane bound receptors (TNFR1 and TNFR2 ) on the surface of
T-cells macrophage.
• Exogenously administered soluble TNF-receptor protein or antibody
can neutralize it and interrupt reaction mainly suppress T-cells and
macrophage.
• It slows inflammatory changes in joint regress and new erosions
• Quicker response than DMARDs
• Effective as Monotherapy
• Generally added to MTX
• Few SEs but susceptible to opportunistic infections tuberculosis and
pneumocystis pneumonia
• Very Expensive

20. Contd..
Etanercept Infliximab Adalimumab
 Recombinant protein of TNF-
receptor and Fc Portion of
Human IgG.
 SC, 50 mg weekly
 Pain redness itching and
swelling occur at injection site
 Chest infection may be
increased
 But immunogenicity is not a
clinical problem
 A chimeral monoclonal
antibody; Binds and neutralize
TNF-α
 3-5mg IV infusion every 4-8
weeks
 Acute reaction:- Fever, chills,
Urticaria, bronchospasm
 Combined with MTX which
improve response and
decreases antibody formation
against infliximab
 Recombinant anti-TNF-
antibody
 SC 40mg every 2 weeks
 Aes: Injection site reaction and
respiratory infections
 Combination with MTX
advised to improve response
to decrease antibody
formation

21. Janus Kinase Inhibitors
• Baricitinib
– Selective Janus kinase 1 and 2 inhibitor.
– approved for the treatment of adult patients with
moderately-to-severely active RA at the 2-mg dose in
Canada and the United States, and China at the 2-mg and
(recently) 4-mg doses.
– Administered orally and provides a convenient and
practical once-a-day treatment option for patients.

22. IL-1 Antagonist
• Anakira
– Recombinant human IL-1 receptor antagonist
– Clinically less effective than TNF- inhibitors
– Used in cases who have failed in one or more DMARDs
– Dose:- 100mg sc daily
– AEs: Local reaction and chest infection

23. Corticosteroids
• Have immunosuppressant and anti-inflammatory activity
• Can be used in any stage of RA with 1st line and 2nd line drugs
• Gives symptomatic relief
• Slows joint destruction and delays bone erosions
• Low dose given due to its serious AEs (Prednisolone 5-10mg)
• In case of severe symptoms, intra-articular injections of
soluble glucocorticoids given

24. Q&A
1. First choice of drug in RA?
 Methotrexate
2. Drugs increases the level of MTX?
 Probencid and Aspirin
3. Drugs are contraindicated in Pregnancy?
 MTX and Leflunomide
4. Drug has steroid sparing effect
 Azathioprine
5. Drugs have rapid onset of action?
 MTX (4-6 weeks) and Leflunamide (4 Weeks)
6. Prolonged use of drug causes liver cirrhosis?
 MTX

25. Contd..
7. Drugs cause retinal damage & corneal opacity?
 HCQ and CQ
8. Drug combination is hepatotoxic?
 MTX and Leflunomide
9. Drugs combined with MTX?
 HCQ and CQ
 TNF-α inhibitors
10. Drugs effective as monotherapy
 TNF-α inhibitors
11. Drugs combined with sulfasalazine?
 HCQ and CQ
 Leflunomide
12. Drug used in Ulcerative colitis
 Sulfasalazine

26. Contd..
13. Second line drug in RA
 Sulfasalazine
14. Drugs had copper chelating activity
 D-penicillamine
15. Drugs used in patients who have failed one or more
DMARDs?
 Anakira
16. Side effects of D-penicillamine
• Myasthenia gravis
• Loss of taste
• Systemic lupus

27. MCQs
1. Which of the following is a reserve drug but not a disease modifying drug
in rheumatoid arthritis:
A. Chloroquine
B. Sulfasalazine
C. Prednisolone
D. Methotrexate
2. Choose the correct statement about use of gold sod. thiomalate in
rheumatoid arthritis:
A. It affords more rapid symptomatic relief than NSAIDs
B. The NSAIDs therapy is discontinued when it is started
C. It is used as an alternative to corticosteroids
D. It is used only in severe cases when other diseases modifying
antirheumatic drugs have failed
1. C) 2. D)

28. Contd..
3. Choose the correct statement(s) about auranofin:
A. It is an orally active gold compound
B. It is equally effective but less toxic than
injected gold-sodium-thiomalate
C. Its major adverse effect is dermatitis
D. All of the above are correct
4. Used as a remission inducing agent in rheumatoid
arthritis, hydroxychloroquine:
A. Is more effective than chloroquine
B. Produces a lower incidence of retinal damage
than chloroquine
C. Is more effective and more toxic than gold
D. Both ‘A’ and ‘B’ are correct
3. A) 4. B)

29. Contd..
5. Sulfasalazine is used in the following disease(s):
A. Bacillary dysentery
B. Ulcerative colitis
C. Rheumatoid arthritis
D. Both ‘B’ and ‘C’ are correct
6. Disease modifying antirheumatic drugs are indicated
in rheumatoid arthritis:
A. In place of NSAIDs in patients who donot
tolerate the latter
B. Along with NSAIDs in patients with progressive disease
C. Only when NSAIDs fail to afford symptomatic
relief
D. In all patients irrespective of disease status/
concurrent medication
5. D) 6. B)

30. Contd..
7. What is true of disease modifying antirheumatic
drugs:
A. Their beneficial effect is manifest only after 1-3 months of therapy
B. The disease does not recurr once they induce remission
C. They are to be used life long
D. Concurrent use of more than one disease modifying drug is not
recommended
8. The following antirheumatic drug affords symptomatic
relief but does not bring about remission in rheumatoid
arthritis:
A. Gold sodium thiomalate
B. Prednisolone
C. Hydroxychloroquine
D. Leflunomide

31. Contd..
9. Which of the following is a disease modifying
antirheumatic drug whose active metabolite inhibits
the enzyme dihydro-orotate dehydrogenase:
A. Leflunomide
B. Nimesulide
C. Sulfasalazine
D. Colchicine
10. Which component of sulfasalazine is responsible for
the therapeutic effect in rheumatoid arthritis:
A. Intact sulfasalazine molecule
B. Sulfapyridine
C. 5–aminosalicylic acid
D. Both ‘B’ and ‘C’
9. A) 10. B)

32. Contd..
11. Among the disease modifying antirheumatic drugs,
fastest symptom relief is obtained with:
A. Auranofin
B. Hydroxychloroquine
C. Sulfasalazine
D. Methotrexate
11. D)

33. Thank you