Transcript
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 approachNow 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 jointsACR-not to delay beyond 3 months
Rationale for DMARDsNSAIDS – 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 DMARDsHCQSulphasalazineMethotrexateLeflunomideAzothioprineGoldMinocyclineCyclosporin
Biologic response modifiers
EtanerceptInfliximabAdalimumabRituximabAbatcept
ChoiceEmpirical, Based on a balance between toxicity,
efficacy & prescriber's preference
METHOTREXATEDMARD 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
PharmacokineticsBioavailability -70% Less active hydroxylated metabolitePolyglutamated with in cells.Serum T1/2 6-9 hrsExcreted principally in urine.
Dosagestarted 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 spermRecommended- contraception is taken
during therapy and that conception is avoided for at least six months after stopping methotrexate.
Interactionsco-prescription of NSAIDs has been shown
to increase the toxicity Conc increased by HCQGI & 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.
HydroxychloroquineAntimalarialssuppression 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.
PharmacokineticsRapidly absorbedExtensively 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.
IndicationsRANot 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 Effectsirreversible retinopathyoccurs 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, nightmaresblood disorders Relatively safe in pregnancy.Eye: Baseline & six monthly follow-up
GOLDAffect the function of B and T lymphocytes
as well as PMN leucocyte functionauranofin is less toxic but it is less
efficaciousTime to response,oral:3-6months Parentral:
2-4 months.Diarrhoea - frequentOral – 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 EffectsSkin- eczematous reaction & M.U Kidney- proteinuria Blood: bone marrow suppression lungs and liverlimit the number of patients who can
tolerate long-term parenteral goldParenteral gold is still a useful option in
patients who cannot tolerate sulphasalazine or methotrexate
SULPHASALAZINEanti-inflammatory (5aminosalicylic acid)
and antibacterial (sulphapyridine) moietiesonset of action 6 and 12 weeksIgA & 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 RAJCA, 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 intoleranceHaematological abnormalities – serious reversible male infertilityNot teratogenicFBC:Baseline, monthly for three months,
then every three months RF:Baseline LFT:Baseline, monthly for three months,
then every three months
PENCILLAMINEchelator of divalent cations structurally
similar to cysteineimpair 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 efficiencyLess 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.
AZATHIOPRINEoral 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
LEFLUNOMIDEimmunomodulatory 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 RNADecreases IL-8 receptor type A m RNAP.Kinetics: completely absorbed.Enterohepatic circulation.Indicated in RA for inhibition of bone
damage.
diarrhoeareversible 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
DosageDaily dose of 10-20 mgLoading dose of 100 mg once weekly for 3
wks in addition to daily dose.Complete effect takes 6-12 wks.
BIOLOGICALS – TNF-alpha blocking agentsCytokines –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
ADALIMUMABRecombinant human anti TNF monoclonal
antibody.Adm: subcutaneously, T ½ 9-14 daysDose: 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 MTxCan be given with other DMARDs.UTI ,opportunistic infections.ANA & DS DNA antibodies occur but frank
SLE rare.Infusion site reaction.
ETANERCEPTRecombinant 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 biologicalsRituximab –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 therapyComplementry MOANon-overlapping pharmacokineticsNon-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 recommendationsNSAIDS: Discontinue 5 half-lives before
surgery.Aspirin: discontinue 7-10 days before
surgery.Corticosteroids:Perioperative use depends
on level of potential surgical stressMTx: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 therapyEarly institution of DMARDs with in 3
monthsConsider NSAIDSConsider local or low dose systemic
steroids as bridge therapy.Maximization of MTx therapy.Addition of TNF inhibitors for persistent
activity.
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