This document discusses disease modifying anti-rheumatic drugs (DMARDs) used to treat rheumatoid arthritis. It describes two main categories of DMARDs - synthetic DMARDs like methotrexate, sulfasalazine, and hydroxychloroquine, and biological DMARDs that target specific proteins in the immune system like TNF inhibitors etanercept and infliximab. It provides details on the mechanisms of action, dosages, and side effects of various DMARDs commonly used as first-line and subsequent options for treating rheumatoid arthritis.

1. DISEASE MODIFYING ANTI
-RHEUMATIC DRUGS
Faisal Ghafoor

2. WHAT IS RHEUMATOID ARTHRITIS
 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. 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).
 Also pertain many other diseases like,
.SLE
. Sjögren‘s syndrome.
. Myasthenia gravis etc etc.
 Reduce symptoms of RA
 Its effect take 6weeks- 6months
 slow acting as compared to NSAIDs

4. Classification
A. Synthetic DMARDs B. Biological DMARDs
1. Methotrexate a) TNF α antagonist
2. Azathioprine 1. Etanercept
3. Cyclophosphamide 2. Infliximab
4. Cyclosporine 3. adalimumab
5. Chloroquine b) IL-1 antagonist
6. Hydroxychloroquine 1. Anakinra
7. Sulphasalazine c) T-cell modulating agents
8. Leflunomide Abatacept
9. Gold salts d) B-lympho depletor
10. d-penicillamine 1. Rituximab
2. Methyl prednisolone

5. METHOTREXATE
 Considered first choice to treat RA
 MOA: it probably relates to inhibition of
aminoimidazolecarboxamide ribonucleotide
(AICAR) transformylase & thymidylate synthetase.
 It has secondary effects on PMN cells chemotaxis.
 It has direct inhibitory effects on proliferation
 and stimulates apoptosis in immune - inflammatory
cells.
 Orally 70% absorption.
 Metabolized to a less active hydroxylated metabolite,

6. (con. . . )
 Both parent cmpnd and metabolite
are Polyglutamated with in cells.
 Dose 15-25 mg weekly, starting with
7.5 mg
Adverse effects of Methotrexate:
 Nausea, mucosal ulcers.
 Dose related hepatotoxicity.
 Leucovorin used to reduce side
effects.
 Contraindicated in pregnancy, liver
disease, peptic ulcer.

8. Azathioprine
 Acts through major metabolite; 6 Thioguanine
 Which suppress;
Inosinic acid synthesis.
B-cell and T-cell function.
Ig production.
IL-2 production.
 production of 6 thioguanine is dependent on thiopurine methyl
transferase (TPMT), Pt with low TPMT or absent activity are at
High risk of of myelosuppression if the dosage is not adjusted.
Dosage; 2mg/kg/day.
Adverse effects  Bone marrow suppression
 GIT disturbance
 Increase infection risk
 Fever, rash, hepatoxicity

9. 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

10. 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.
 Reduces radiologic disease progression.
 Inhibit release of cytokines ( IL-1, IL-2,
IL-6, IL-12, TNFα)

11. (Con…)
 10%-20% of orally administered drug is absorbed.
 Sulfa pyridines well absorbed if 5aminosalicylclic acid
is unabsorbed.
Adverse effect
 Nausea
 Vomiting
 Rashes
 Hemolytic anemia etc.

12. 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
 DOSE : 20mg/day

13. Cyclosporine
 Acts through regulation of gene transcription.
 It inhibit IL-1 & IL-2 receptor production.
 Inhibit macrophage T-cell interaction
 Also inhibit T-cell responsiveness
 Its absorption is incomplete & some erratic
although micro emulsion formulation improves
its consistency & provide 20% - 30% bioavailability
 Grapefruit juice Inc. cyclosporine bioavailability by
as much as 62%.
 retards the appearance of bony erosion.
 Dosage : 3.5mg/kg/day.

14. Adverse effects
 Nephrotoxicity
 Hyper tension
 Hepatotoxicity
 Hyperkalemia
 Gingival hyperplasia
 Hirsutism.

15. Chloroquine & hydroxychloroquine
Mainly use in malaria and in rheumatic disease.
Mech : is unclear but
Proposed mech is:
 suppression of T lymphocytes response to mitogens.
Dec leukocytes chemotaxis.
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.
 Half life 45 days.

16. (Con…..)
 Dosage:
chloroquine = 200mg/day
hydroxychloroquine = 6.4mg/kg/day
 this drug is safe in pregnancy.
Adverse effect
Ocular toxicity
Dyspepsia
Nausea
Vomiting
Abd: pain
Rashes
Nightmares.

17. Gold salts
 Administered through,
a) parenterally : aurothiomalate
aurothioglucose
b) orally: auranofin
 They were used extensively
 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. These are
used when there is inadequate response with the
DMARDS
o Biologics are made through biotechnology and target very
specific proteins or cells that are involved in the
inflammatory process.
o Biologics have also been shown to help reduce the
progression of joint damage in RA.
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
 DOSE: 25 mg twice weekly given s.c.
A/E
- Opportunistic infections, Activation of latent TB

20. Infliximab
MOA: it is chimeric (25% mouse , 75%human) IgG1
monoclonal antibody that binds with TNFα
Mech : prevents TNFa interaction with cell surface
receptors causing down regulation of macrophages
and Tcell function.
DOSE: 3-10 mg/kg as an i.v. infusion every 8 weekly
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

21. 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.
Respiratory infection is a common a/e
Comb with MTX to improve response

22. Trans-Membrane
Bound TNF
Soluble TNF
Strategies for
Reducing
Effects of TNF
Macrophage
Monoclonal Antibody (Infliximab & Adalimumab)

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:
It is recombinant fusion protein.
MOA: inhibits activation of T cell
DOSE: depends on body wt it is given as i.v inj.
 <60 kg: 500mg
 60-100 kg: 750 mg
 >100kg: 1000mg.

25. Used when there is inadequate response to
DMARDS
A/e :
Risk of infections
Hypersensitivity reaction
Unfortunately not all patients respond
sufficiently to TNF blockade and some of the
patients become unresponsive to TNF-blocking
agents.
(Con….)

28. B-LYMPHOCYTES DEPLETOR
Targeting B-lymphocytes in these patients has opened a
new therapeutic window
Rituximab
 Chimeric monoclonal Ab, targets CD20 B cells
 Used in resistant RA .Benefit in treatment of RA
refractory to antiTNF agents
 Combination therapy with methotrexate
 Dose: 2ml IV infusions 2 wks apart
 ADRs: Mild infusion reactions (infrequent)

29. Rituximab in RA
B-Cell
CD-20
Rituximab: anti-CD-20

30. Thank you