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.

48.
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