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.
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
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
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.
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.
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.