NSAIDs

1st line of therapy in the medical management of RA

• Control the symptoms and signs of local inflammatory process

• Minimal effect on the progression of the disease

• i.e. Diclofenac sodium, naproxen sodium, etc.

• COX-2 inhibitors– Suppresses COX that is involved in inflammation– Less damaging to the stomach– Associated with increased risk of cardiovascular

events

GLUCOCORTICOIDS

2nd line of therapy

• Systemic GC therapy– Provide effective symptomatic therapy in patients

with RA– Low dose PREDNISONE (<7.5 mg/dl)

• Useful additive therapy to control symptoms• May retard the progression of bone erosions• Initial course of low dose GC may have a long term

protective effect against bone damage • LOW DOSE GC + DMARD therapy (i.e. Methotrexate) can

be beneficial in controlling sins and symptoms rapidly and affording long term retardation of bone erosion

Source: Harrison’s Principles of Internal Medicine 17th ed.

DMARDS(Disease-Modifying Anti-rheumatic Drugs)

3rd line of therapy

• Slows down the progression of joint destruction

• Slow acting because it may take 6 weeks to 6 months for it to become evident

• Methotrexate, azathioprine, penicillamine, hydroxychloroquine and chloroquine, organic gold compounds, sulfasalazine

Methotrexate

• DMARD of FIRST choice to treat RA• Individuals with RF for development of bone

erosions or persistent synovitis or >3months

• MOA:– Inhibition of aminoimidazolecarboxamide

ribonucleotide (AICAR) transformylase and thymidylate synthetase, with secondary effects on polymorphonuclear chemotaxis

• Pharmacokinetics– 70% absorbed after oral administration– Metabolized to a less active hydroxylated

metabolite and both the parent compound and the metabolite are polyglutamated within cells where they stay for prolonged periods

– Half-life: 6-9 hours– Increased in the presence of hydroxychloroquine– Excreted primarily in the urine

• Indications– Dosing regimen: 15-25 mg weekly, 30 or 35 mg

weekly has an increased effect– Decreases the rate of appearance of new erosions– Juvenile chronic arthritis, ankylosing spondylitis,

polymyositis, dermatomyositis, Wegener’s granulomatosis, giant cell arteritis, SLE and vasculitis

• Maximal improvement is observed after 6 months of therapy

• Adverse Effects– Nausea and mucosal ulcers – most common– GI upset– Progressive dose-related hepatotoxicity (enzyme

elevation) occurs frequently– Contraindicated in pregnancy

Source: Basic and Clinical Pharmacology 10th edition, 2007 by Katzung

BIOLOGICS

4th line of therapy

• Slows down progression of damage to articular structures

• Major impact on the signs and symptoms of RA

• TNG-neutralizing agents– Infliximab, etanercept and adalimumab

• IL-1 neutralizing agents– Anakinra

• B-cell inhibitors– Rituximab

• Inhibition of T cell activation– Abatacept

ABATACEPT

• MOA:– Costimulation modulator that inhibits the

activation of T cells.

• Pharmacokinetics– IV infusion – 3 doses (day 0, week 2 and week 4) initially– Followed by monthly infusions– Dose is based on body weight

• <60kg – 500mg• 60-100kg – 750mg• >100kg – 1000g

– Half-life: 13-16 days– Coadministration with methotrexate, NSAIDs and

corticosteroids does not influence clearance of abatacept

• Indications– Can be used as monotherapy or in combination

with other DMARDs in patients with moderate to severe rheumatoid arthritis who have had an inadequate response to DMARDs or TNF antagonists.

– Reduces the clinical signs and symptoms of rhematoid arthritis, slows the progression of damage to the joints, and improves the physical function of patients

• Adverse Effects– Increased risk of upper respiratory tract– concomitant use with TNF antagonists is NOT

recommended due to increased risk of infection

Source: Basic and Clinical Pharmacology 10th edition, 2007 by Katzung

IMMUNOSUPPRESSIVE THERAPY

5th line of therapy

• Azathioprine, leflunomide, cyclosporine and cyclophosphamide

• Effective in the treatment of RA and exerts therapeutic effects similar to DMARDs

• DMARDs > immunosuppressive agents• Increase toxicities• Reserved for patients who have failed DMARDs

and biologics therapy

Source: Harrison’s Principles of Internal Medicine 17th ed.