DMARDs are used to decrease pain, inflammation, and prevent joint damage in rheumatoid arthritis. They work by limiting inflammation early in the disease course before structural damage occurs. The traditional DMARDs include methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide, while biologic DMARDs target cytokines like TNF-α. Methotrexate is usually the first choice due to its efficacy and safety profile. DMARD therapy should be started aggressively within 3 months of diagnosis to prevent long-term disability. Combination therapy and treatment adherence are important to control symptoms and progression of rheumatoid arthritis.

1. DMARDS

2. Disease-modifying anti-rheumatic drugs
 decrease pain and inflammation, reduce or prevent joint
damage, and preserve the structure and function of the joints
Previously RA – Pyramidal approach
Now it is reversed.
early use of DMARDs is recommended before radiologically
damage develops.

3. Aim - aggressive approach is to limit inflammation and
prevent joint damage and subsequent disability.
firm diagnosis of rheumatoid arthritis
predictors of poor outcome
Positive RA factor, high disability scores and early
involvement of large joints
ACR-not to delay beyond 3 months

4. Rationale for DMARDs
NSAIDS – offer symptomatic relief.
No effect on cartilage or bone destruction.
Inflammation is maximal at an early stage.
If given early, DMARDs can stabilise joint function at a level
which is near to normal, rather than preserving the joint in a
state of disability

5. Traditional DMARDs
HCQ
Sulphasalazine
Methotrexate
Leflunomide
Azothioprine
Gold
Minocycline
Cyclosporin

6. Biologic response modifiers
Etanercept
Infliximab
Adalimumab
Rituximab
Abatcept

7. Choice
Empirical,
Based on a balance between toxicity,
efficacy & prescriber's preference

8. METHOTREXATE
DMARD of choice.
MOA: Inhibition of [AICAR] aminoimidazolecarboxamide
transformylase & thymidylate synthetase.
decrease the secretion of pro-inflammatory cytokines, such as
TNF, while increasing the secretion of the inhibitory cytokine IL-
10.
Decreases the rate of appearance of new erosions

9. Pharmacokinetics
Bioavailability -70%
Less active hydroxylated metabolite
Polyglutamated with in cells.
Serum T1/2 6-9 hrs
Excreted principally in urine.

10. Dosage
started at a dose of 7.5mg orally once weekly and this is
increased slowly to a maximum of 20mg once weekly
fail to respond to oral therapy - intramuscular route
Indicated in RA, PA, JCA, polymyositis.
onset of action: about one month

11. Adverse Effects
Nausea and stomatitis
hepatic toxicity
pneumonitis
teratogenic to ova and sperm
Recommended- contraception is taken during therapy and
that conception is avoided for at least six months after
stopping methotrexate.

12. Interactions
co-prescription of NSAIDs has been shown to increase the
toxicity
Conc increased by HCQ
GI & liver A/E, - reduced with leucovorin 24 hrs after each
wkly dose or folic acid daily.
C/I in pregnancy

13. Monitoring
FBC: Baseline, then fortnightly for one month (or until dose
stable) then monthly
RF:Baseline
LFT:Baseline, then fortnightly for one month (or until dose
stable) then monthly
CXR:Baseline.

14. Hydroxychloroquine
Antimalarials
suppression of lysosomal enzymes and inhibition of IL-1
release.
Suppression of T-cell lymphocyte response, leucocyte
chemotaxis, trapping of free radicals.
Clinical response 6 to 12 weeks.

15. Pharmacokinetics
Rapidly absorbed
Extensively tissue bound, esp melanin containing tissues-
eyes.
Eliminated in liver.
DOSAGE:
started at a dose of 400mg daily in two divided doses. The
maintenance dose is usually between 200mg and 400mg
daily .

16. Indications
RA
Not very effective. [bone damage]
Restricted to patients with mild, non-erosive disease or to
those in whom more powerful DMARD therapy is felt to be
too risky
used in combination with other agents

17. Adverse Effects
irreversible retinopathy
occurs rarely if daily dose of HCQ does not exceed
6.5mg/kg (or 400mg daily), the lifetime dose does not
exceed 200g
GI symptoms, rashes, nightmares
blood disorders
Relatively safe in pregnancy.
Eye: Baseline & six monthly follow-up

18. GOLD
Affect the function of B and T lymphocytes as well as PMN
leucocyte function
auranofin is less toxic but it is less efficacious
Time to response,oral:3-6months Parentral: 2-4 months.
Diarrhoea - frequent
Oral – less frequently used.

19. DOSAGE:
test dose of 10mg followed by weekly doses of 50mg until
there is definite evidence of remission
drug should be discontinued if no response after giving 1 gm
of gold.
Interval increased to 4 wks, continued up to 5 yrs after
complete remission.
Important to avoid complete relapse since second course of
gold are not usually effective.

20. Adverse Effects
Skin- eczematous reaction & M.U
Kidney- proteinuria
Blood: bone marrow suppression
 lungs and liver
limit the number of patients who can tolerate long-term
parenteral gold
Parenteral gold is still a useful option in patients who cannot
tolerate sulphasalazine or methotrexate

21. SULPHASALAZINE
anti-inflammatory (5aminosalicylic acid) and antibacterial
(sulphapyridine) moieties
onset of action 6 and 12 weeks
IgA & IgM RA factors decreased.
Suppresion of T-cell response to concanavalin.
Only 10-20% is absorbed.

22. Indication
Reduces the rate of new jt damage in RA
JCA, AS & its associated uveitis.
Dosage:starting dose of 500mg daily. Increased by 500mg at
weekly intervals to a maintenance dose of between 2g and 3g
daily in divided doses.

23. Adverse Effects
GI intolerance
Haematological abnormalities – serious
reversible male infertility
Not teratogenic
FBC:Baseline, monthly for three months, then every three
months
RF:Baseline
LFT:Baseline, monthly for three months, then every three
months

24. PENCILLAMINE
chelator of divalent cations structurally similar to cysteine
impair antigen presentation, diminish globulin synthesis, to
inhibit PMN leucocyte myeloperoxidase,
Rarely used today because of toxicity.

25. CYCLOSPORIN
Fungal peptide-impairs the function of B and T lymphocytes
by suppressing the synthesis and release of IL-1 & IL-2
Started at a dose of 2.5mg/kg daily in two divided doses.
Increased gradually after six weeks to a maximum of 4mg/kg
daily
Full response will take 12 wks.

26. Good efficiency
Less well tolerated because of hypertension and
nephrotoxicity which are common and dose related.
used in patients with severe disease who failed on other
treatments or unsuitable for other DMARDs
valuable when used together with methotrexate in patients
with very active early disease.

27. AZATHIOPRINE
oral purine analogue
inhibits lymphocyte proliferation, by disrupting the
incorporation of adenosine and guanine in DNA synthesis.
becomes biologically active after metabolism in the liver to
6-thioinosinic acid and 6-thioguanylic acid.
renally excreted

28. dose of 1.5 to 2.5mg/kg daily in divided doses
efficacy comparable to that of gold but greater toxicity.
potential for lymphoproliferative cancers
Used for progressive disease which is refractory to other
DMARDs of comparable potency or as a steroid-sparing
agent

29. LEFLUNOMIDE
immunomodulatory DMARD
Rapid conversion in to active metabolite A77-1726,
Isoxazole derivative.
Inhibit the dihydrooratate dehydrogenase  decrease in
RNA synthesis & arrest the stimulated cells in G1 phase of
cell growth.
Inhibit T cell proliferation & production of antibodies by B-
cells.

30. Increases IL-10 receptor m RNA
Decreases IL-8 receptor type A m RNA
P.Kinetics: completely absorbed.
Enterohepatic circulation.
Indicated in RA for inhibition of bone damage.

31. diarrhoea
reversible alopecia, hypertension, dizziness
teratogenic in mammals and is therefore not recommended
in women of childbearing age in the absence of reliable
contraception
Liver function should be monitored

32. Dosage
Daily dose of 10-20 mg
Loading dose of 100 mg once weekly for 3 wks in addition to
daily dose.
Complete effect takes 6-12 wks.

33. BIOLOGICALS – TNF-alpha blocking
agents
Cytokines –central role in immune response in RA.
TNF – alpha  heart of inflammatory process.
Two different approaches are available to decrease TNF
activity

34. anti-TNF alpha antibodies which cross link with TNF
receptor inhibit the endogenous cytokine
soluble TNF receptors – combining soluble TNF alpha.
Inhibit T –cell & macrophage function.
Avoid live vaccines

35. ADALIMUMAB
Recombinant human anti TNF monoclonal antibody.
Adm: subcutaneously,
T ½ 9-14 days
Dose: 40 mg once in 2 wks.
With Mtx it is action potentiated – 30% reduced clearance,
decreased formation of antibodies.

36. Reduces the formation of new erosions.
Monotherapy or in combination.
Indicated: RA, AS, PA,JCA.
Adv effects: risk macrophage dependent infections.
Screening for latent TB to be done before therapy.

37. INFLIXIMAB
Chimeric monoclonal antibody [25% mouse, 75% human]
Binds with both soluble & membrane bound TNF
IV infusions 3-5 mg/kg every 8 wks.
Antichimeric AB – 62% pts
Concurrent MTx adm, reduces.

38. Recommended to give along with MTx
Can be given with other DMARDs.
UTI ,opportunistic infections.
ANA & DS DNA antibodies occur but frank SLE rare.
Infusion site reaction.

39. ETANERCEPT
Recombinant fusion protein consists of two soluble TNF P75
receptor moieties linked to Fc portion of human IgG1.
Binds TNF & inhibits lymphotoxin alpha.
Adm: SC 25 mg twice wkly or 50 mg once wkly.
Peak conc 72 hrs after administration.
Used along with MTx

40. Incidence of inf is lower
Injection site reaction- 20-40%
Antibodies appear in 16% of Pts.

41. Newer biologicals
Rituximab –depletes B –cells by binding to cell surface
marker CD-20.
Abatecept – inhibits co-stimulatory molecule.
Anakinra -recombinant form of the naturally occurring
human IL-1 receptor antagonist.

42. Combination therapy
Complementry MOA
Non-overlapping pharmacokinetics
Non-overlapping toxicity.
With MTx back ground therapy, cyclosporin, HCQ, LFN,
infliximab adalimumab, etanercept shows improves
efficiency.
With auronofin, azothioprine, SS- no additional benefit.

43. Triple drug regimen: MTx, SS, HCQ.
Disadv: more toxicity [mostly not occurs]
C.T is becoming a rule for those not responding to
monotherapy.

44. Perioperative medication
recommendations
NSAIDS: Discontinue 5 half-lives before surgery.
Aspirin: discontinue 7-10 days before surgery.
Corticosteroids:Perioperative use depends on level of
potential surgical stress
MTx:Continue perioperatively for all procedures.

45. withholding 1 to 2 doses of MTx for patients with poorly
controlled diabetes; the elderly; and those with liver, kidney,
or lung disease
Leflunomide:Continue for minor procedures. Withhold 1-2
days before moderate and intensive procedures and restart 1-
2 weeks later.
Sulfasalazine, HCQ - Continue for all procedures

46. TNF antagonists:Continue for minor procedures. For
moderate to intensive procedures, withhold etanercept for1
week, and plan surgery for the end of the dosing interval for
adalumimab and infliximab.
Restart 10-14 days Postoperatively.
IL-1 antagonist:Continue for minor procedures. Withhold 1-
2 days before surgery and restart 10 days postoperatively for
moderate to intensive procedures

47. Suggestions
More aggressive therapy
Early institution of DMARDs with in 3 months
Consider NSAIDS
Consider local or low dose systemic steroids as bridge
therapy.
Maximization of MTx therapy.
Addition of TNF inhibitors for persistent activity.

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