Pharmacotherapy of

rheumatoid arthritis

Contributed By:
Dr. Preethi G Pai MD
Department of Pharmacology
KMC, Mangalore
 Rheumatoid arthritis
• Chronic, systemic, inflammatory
disease predominantly affecting
joints & periarticular tissues
 etiology

• Autoimmune disease: autoantibodies to

Fc portion of IgG antibody are
produced by B lymphocytes
• High titres of serum RA factor
Pathophysiology

• Inflammation
• Synovial
proliferation
• Joint tissue
destruction
 Principles of management

• Rest to acutely inflamed joints

• Relief of pain & stiffness
• Reduction of inflammation
• Prevention of articular damage
• Preservation of joint function & muscle
strength
• Improve general well being of patient
PHARMACOTHERAPY OF
RHEUMATOID ARTHRITIS
 classification
• Symptomatic drugs: NSAIDs
• Disease modifying agents: Gold, d-
Penicillamine, Chloroquine or
Hydroxychloroquine, Sulfasalazine,
Leflunomide, Immunosuppressants-
Methotrexate, Azathioprine,
Cyclosporine
• Biologic response modifiers:Infliximab,
Adalimumab, Etanercept, Anakinra
• Adjuvant drugs: Corticosteroids
 methotrexate

• DMARD of first choice & standard drug

• Immunosuppressant & antiinflammatory
agent
• Dihydrofolate reductase inhibitor
• Inhibits cytokine production,
chemotaxis & cell mediated immune
reaction
 methotrexate

• Oral low dose (7.5-15 mg) weekly

regimen
• Rapid onset of action⇨ preferred
for initial treatment
• Sustained & predictable response
• Variable oral bioavailability;
affected by presence of food
 methotrexate
• Side effects: nodulosis, oral ulceration
& GI upset
– Prolonged courses: liver cirrhosis,⇪ chest
infections

• C/I: Pregnancy, lactation, liver

disease, kidney disease, active
infection, leucopenia & peptic ulcer
 azathioprine
• Purine antimetabolite
• Azathioprine ⇨ 6-mercaptopurine
Thiopurine methyl transferase
• Suppressant of cell mediated immunity &
inflammation
• Azathioprine + corticosteroids: Steroid
sparing effect
• Not combined with methotrexate
 Mycophenolate mofetil

• Semisynthetic fungal antibiotic

• Active metabolite: Mycophenolic acid
• Inhibits B & T cell proliferation
• Inhibits inosine monophosphate
dehydrogenase ⇨ reduces production of
cytotoxic T cells
• Also interferes with leucocyte adhesion
 sulfasalazine
• Sulfapyridine + 5-amino salicylic
acid
• Active moiety: sulfapyridine
• Suppresses generation of superoxide
radicals & cytokine elaboration
• Used as second line drug in milder
cases
• A/E: neutropenia/thrombocytopenia,
hepatitis
 Chloroquine
hydroxychloroquine
• Milder non erosive disease refractory
to methotrexate/sulfasalazine;
especially when only a few joints are
involved
• Reduce monocyte IL-1⇛inhibit B-
lymphocytes; also interfere with
antigen processing
 Hydroxychloroquine…

• HYDROXYCHlOROQUINE IS
PREFERRED OVER CHLOROQUINE
– As they are given for long periods in RA:
predominent toxicty⇛ retinal damage &
corneal opacity

• A/e: rashes, graying of hair, irritable

bowel syndrome, myopathy &
neuropathy
 leflunomide
• Similar in efficacy to Methotrexate
• Faster onset of action
• Symptomatic cure + retards
radiological progression of disease
• Used as alternative to methotrexate
• Leflunomide + Methotrexate
⇛⇪Hepatotoxicity
• Can be combined with Sulfasalazine
Leflunomide…

• Leflunomide ⇛active
metabolite ⇨ inhibits
dihydro-orotate
dehydrogenase & pyrimidine
synthesis in actively divided
cells
• Inhibits proliferation of
activated lymphocytes in
active RA
• Long t1/2= 2 weeks
 Adverse effects of Leflunomide

• Diarrhoea, headache, nausea,

rashes, loss of hair,
thrombocytopenia, leucopenia, chest
infections, hepatic transaminases

• C/I: Pregnant, Lactating & children

 gold
• Most effective agent to arrest
rheumatoid process
– Reduces
• chemotaxis
• Phagocytosis
• macrophage & lysosomal activity
• monocyte differentiation
– inhibits cell mediated immunity
– Prevents joint destruction; induces bone
healing
 Gold…
• Highly cumulative drug; high toxicity
• A/E: postural hypotension, dermatitis,
pruritic rashes, stomatitis, membranous
glomerulonephropathy (albuminuria),
hepatitis, peripheral neuritis,
encephalopathy, pulmonary fibrosis &
eosinophilia
• Salts used: Sodium aurothiomalate,
aurothiosulfate, aurothioglucose
 Auranofin
• Orally active
• Bioavailability: 25%
• Lower efficacy
• Lower toxicity to skin, mucous
membranes, kidney & bone marrow
• Main A/E: diarrhoea, abdominal
cramps
– Rarely pruritis, taste disturbances,
mild anaemia & alopecia
BIOLOGIC RESPONSE
MODIFIERS
 TNF-alpha blockers

• INFLIXIMAB
• ADALIMUMAB
• ETANERCEPT
 infliximab

• Chimeric monoclonal anti TNF antibody

• Binds to soluble + membrane bound

TNF-alpha ⇨ dose dependent
neutralisation ⇛down regulation of
macrophage & T cell functions⇛
prevents release of cytokines
 infliximab
• Distributed mostly in vascular
compartment
• Terminal t1/2= 8-12 days
• Not metabolised by hepatic cytochrome
P450 enzymes

• A/E: headache, nausea, rash & cough

– Can ppt URTI; activation of latent TB
– Antibodies may develop to infliximab
 Infliximab
• Given IV once in 2 months
• More beneficial when combined with
methotrexate
• Sustained & consistent benefit even
in DMARD & methotrexate resistant
cases

• Also approved for Crohn’s disease,

juvenile chronic arthritis, psoriatric
arthritis, wegener’s granulomatosis &
sarcoidosis
 adalimumab

• Recombinant human-anti-TNF
monoclonal antibody
• Given SC
• T1/2 = 9-14 days
• Similar actions as infliximab
• Lesser immunogenicity
 etanercept

• Genetically engineered fusion protein

• Dimer: TNF receptor+ Fc domain of
human IgG
• Binds to TNF alpha & also TNF beta
(cytokine lymphotoxin alpha)
• Given SC twice a week
• Useful in RA including juvenile RA
where infliximab is less effective
 Interleukin-1 blocker-
Anakinra
• Used in combination with
methotrexate in methotrexate
resistant cases
 Potential side effects
• Injection site reactions
• Infections & neutropenia
• Malignancy
• Immunogenicity

•Given Subcutaneously OD
•C/I: in case of infection
Never to be combined with
TNF alpha inhibitors
 Toclizumab

• Humanized anti-interleukin 6
receptor agent that blocks the
action of the inflammatory
cytokine.
• Phase III trials worldwide
• Licensed in Japan as an orphan drug
for treatment of Castleman's
disease.
STATUS OF NEWER
BIOLOGICS
• Rituximab: FDA-approved for lymphoma in
1997

- FDA-approved February, 2006 for

UPDATE

- patients with moderately severe RA

- inadequate response to >1 DMARDs
- use in combination with MTX

•Abatacept:
- FDA-approved December, 2005 for
- patients with moderately severe RA
- inadequate response to >1 DMARDs
- use as monotherapy or with DMARDs
other than TNF antagonists or anakinra
Rituximab: Mechanism of Action
 Abatacept: Mechanism of Action

Abatacept modulates the immune response by binding to CD80/CD86

on an antigen-presenting cell (APC), such as a dendritic cell, thus
preventing costimulatory binding of CD28 on naive T cells and
attenuating T-cell activation.
 Tenidap sodium

• IL-1 synthesis inhibitor

 corticosteroids
• Potent immunosuppressant &
antiinflammatory action
• Adjuvant drugs: symptomatic
improvement + arrest rheumatoid
process + delay bony erosions
• Low doses-Disadv: steroid
dependency
• High doses over short periods for
severe systemic manifestations
 Indications for local intra-
articular therapy

• One or two joints : resistant in

patients otherwise well
controlled on medical therapy
• Patients with one active joint in
whom oral NSAID are
contraindicated

Caution: Avoid injection more often than once in

3 months
 Choice of drug therapy
• Early treatment with DMARD ⇨
improves quality of life & long term
outcome
• Aspirin/NSAID given initially for quick
symptomatic relief
• Start concurrently DMARD-
methotrexate, hydroxychloroquine,
sulfasalazine
• If uncontrolled-combination of DMARD
 Drug therapy…
• Severe cases: steroids in large
doses ⇨ tapered to maintenance
doses
• Methotrexate (+folic acid) currently
favored
– Relative rapid onset of action
– Maintains sustained improvement
– Relative safety
– High level of patient compliance