DMARDS

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.

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

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

Traditional DMARDs
HCQ Sulphasalazine Methotrexate Leflunomide Azothioprine Gold Minocycline Cyclosporin

Biologic response modifiers

Etanercept Infliximab Adalimumab Rituximab Abatcept

Choice
Empirical, Based on a balance between toxicity,

efficacy & prescriber's preference

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

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

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

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.

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

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.

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.

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

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

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

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.

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.

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

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.

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.

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

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.

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.

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.

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

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

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.

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.

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

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.

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

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

ADALIMUMAB
Recombinant human anti TNF monoclonal

antibody. Adm: subcutaneously, T 9-14 days Dose: 40 mg once in 2 wks. With Mtx it is action potentiated 30% reduced clearance, decreased formation of antibodies.

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.

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.

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.

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

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

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.

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.

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

responding to monotherapy.

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.

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

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

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.

THANK YOU