anti ra drugs

7/28/2019 Anti RA Drugs

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รศ.ดร. บญเกด คงย งยศ ภาควชาเภสัชวทยา คณะแพทยศาสตร

มหาวทยาลัยขอนแกน 2555

DISEASE-MODIFYING

ANTIRHEUMATIC DRUGSDMARDs

DISEASE-MODIFYING

ANTIRHEUMATIC DRUGSDMARDs



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• Purpose of drug therapy in rheumatoid arthritis

OBJECTIVES : DMARDs

• Notes on important drug groups:

- Hydroxychloroquine, chloroquine - Sulfasalazine

- Immunosuppressants:- Methotrexate, tacrolimus,

- Leflunomide

- Biologic agents:

- Anti-TNF: Infliximab, Adalimumab, Etanercept

- IL-1 inhibitor : Anakinra

- Immunomodulators: Abatacept, Rituximab Mechanism of action Adverse effects



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• Rheumatoid Arthritis (RA)

Incidence increases with age Female : Male = 3 : 1 1% of world population Aged 40-70 years

incomplete known causes & unclear pathogenesis

• Genetic influence •

Autoimmune disease

A systemic inflammatory disorder movable joints

• Environmental factors: smoking?



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Symptoms: pain, stiffness, swelling of peripheral joints Variable clinical course: remission continuing progression

joint deformity functional disability increased mortality

20% Mild RA 5% Disabilty

75% Continue havingInflammed joint

• Rheumatoid Arthritis (RA)



• Therapy of RA

• Main purpose of using DMARDs in RA

- Slow /stop the course of disease progression

2. Pharmacological :

no known cure pain & prevent destruction

definite diagnosis :

- DMARD initiation - immediate use- monotherapy- if poor response add DMARD Biologic DMARDs

NSAIDs, corticosteroids:

- before DMARD onset, during DMARD therapy

1. Non-pharmacological :

rest, weight, light & regular exercise

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Improvement of symptoms & reduce disease activity reduce rheumatoid factor, anti CCP in serum

Unclear mechanism of action except biologic agents

some effective in other chronic inflammatory diseases

e.g. SLE, psoriasis, atopic dermatitis, Crohn’s disease, etc.

Effective as monotherapy, more effective in combination (2-3)

remission is possible (Individualization) Efficacy loss over time

tDMARDs

Slow onset (after 6 weeks – 6 months)

The use must be weighed against serious adverse effects

toxicity limits dose/duration of therapy

No general anti-inflammatory action



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Hypothesized(auto) antigen

triggering events

Geneticpredisposition

Biologic DMARDRituximab

Biologic DMARDAbatacept

TraditionalDMARDs

MethotrexateLeflunomideSulfasalazine

Biologic DMARDs

Infliximab, AdalimumabEtanercept, Anakinra

Mechanism of action of drugs in RA

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Sulfasalazine

Adverse effects: nausea, diarrhea, headache, folate absorption

Serious toxicities: granulocytopenia, hemolytic anemia (G6PD def.),

anaphylactic reactions 30% discontinue

Monitoring: CBC, LFT, G6PD level

Chloroquine, Hydroxychloroquine

Mechanism ?

- pH in lysosomes immune cell function

- stimulation of TLR (innate immune sys.)

Few side effects: nausea, diarrhea, headache, rashes

Serious toxicities: irreversible retinopathy dose & duration

- hydroxychloroquine < chloroquine

- ophthalmologic test every 6-12 months

colon bacteria sulfapyridine + 5-amino salicylic acid, poor absorbed

Mechanism ? - scavenge toxic oxygen metabolites of neutrophils



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Tacrolimus: Macrolide (fungus)

• Calcineurin inhibitor ciclosporin but more potent

- T-cell proliferation ( IL-2 syn & IL-2-Rc), B-cell response• po, iv, ointment, 99% metabolized by liver , t1/2 7 h

• Adverse effects: ciclosporin but more severe

- higher nephrotoxicity & neurotoxicity, lower incidence of

hirsutism, GI effects, hyperglycemia

Leflunomide intestine, plasma active A77-1726

• inhibits dihydroorotate dehydrogenase (pyrimidine syn.)

• specific inhibitory effect on activated T-cells,

B-cell-autoAb production• oral active, well absorbed (80%), t1/2-19 days

• efficacy methotrexate

• Adverse effects: alopecia, diarrhea (25%)

- serious: hepatotoxicity, BM suppression

Immunosuppressants



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Other DMARDs

• Minocycline

• Gold compounds

• Penicillamine

• Other immunosuppressants:

- Azathioprine- cyclosporine

In RA : variable success, unfavorable toxicities

rarely use now



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Biologic agents

Infliximab

- chimeric mouse-human IgG1 monoclonal Ab TNF-a- binds both soluble & membrane bound TNF-a; iv, q8w, t1/2 9-12 d

macrophage, T-cell function

• recombinant engineered Ab or receptor

targeted at specific cytokines

• difficult and expensive to produce

• for inadequate response to tDMARD

Anti-cytokine: TNF-a, IL-1

Adalimumab - human IgG1 monoclonal Ab, sc, q2w

- similar to infliximab, t1/2 10-20 d,

Infliximab Adalimumab

Golimumab, Certolizumab



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- a recombinant protein- two TNF p75 (sol.) Rc fused to Fc-IgG1

binds TNF-a (soluble & cell bound), sc, twice a week, t1/2 4.5 d

- efficacy comparable to methotrexate with earlier onset

Etanercept

Biologic agents

Adverse effects:

- risks of bacterial, fungal infection (URI)

- reactivation of latent TB

- rare leucopenia, hepatitis, SLE,neurologic deficits

- increase in Ab against the drugs

by + methotrexate

- injection site reactions antihistamines

- initial PPD skin test - a recombinant human IL-1 receptor antagonist (E. coli), sc, od

- Adverse effects: bacterial, viral infection, TB reactive, neutropenia

- Not with anti-TNF-a, not use live-virus vaccine

Anakinra



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Immunomodulators in RA refractory to anti-TNF

Rituximab

- a chimeric monoclonal Ab against CD20 B-lymphocytes

- 2 i.v. infusion separated by 2 weeks, repeated after 6-9 m

- Adverse effects:

1st infusion reactions (urticaria, HT, angioedema) stop

IgG & IgM - gradually decrease, bacterial, viral infections

hepatitis B reactivation

Biologic agents

Abatacept : a costimulation modulator - A soluble recombinant fusion protein

competes with CD28 for binding on CD80/86 protein on APC

inhibits the activation of T cells

- i.v. infusion in 3 doses (d 0, w 2, & w 4) monthly infusions,

- Adverse effects: headache, infection (URI), nausea, Ab,not + anti-TNF, anakinra



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ADCC = Ab-dependent cell-mediated cytotoxicity



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anti ra drugs

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