Pharmacotherapy of

rheumatoid arthritis
Contributed
Dr. Preethi
Department
KMC,

By:
G Pai MD
of Pharmacology
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, dPenicillamine, Chloroquine or
Hydroxychloroquine, Sulfasalazine,
Leflunomide, ImmunosuppressantsMethotrexate, 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-1inhibit Blymphocytes; 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 Crohns disease, juvenile chronic
arthritis, psoriatric arthritis, wegeners 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 blockerAnakinra
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

UPDATE

1997
- FDA-approved February, 2006 for
- 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 intraarticular 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 DMARDmethotrexate, 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