RHEUMATOID ARTHRITIS

Rheumatoid arthritis is an autoimmune disease in which there is joint

inflammation, synovial proliferation and destruction of articular cartilage.
Immune complexes composed of IgM activate complement and release
cytokines mainly TNFα and IL-1 which are chemotactic for neutrophils.
These inflammatory cells secrete lysosomal enzymes which damage cartilage
and erode bone, while PGs produced in the process cause vasodilatation and
pain.
Rheumatoid arthritis is a ­chroni­c inflammatory disease that affe­ts primarily the
joints but may involve extraarti­ular tissues su­h as the skin, blood vessels, lungs
and heart. Affected joints become swollen, painful, deformed and immobile
PATHOPHYSIOLOGY OF RA
• As in other autoimmune diseases, genetic predisposition and
environmental factors contribute to the development, progression,
and chronicity of the disease.
• The pathologic changes are mediated by antibodies against self-
antigens and cytokine-mediated inflammation,predominantly
secreted by T-cells .
• T helper (TH) cells may initiate the autoimmune response in RA by
reacting with an arthritogenic agent, perhaps microbial or a self-
antigen. The T cells produce cytokines that stimulate other
inflammatory cells to effect tissue injury.
• Although a large number of cytokines can be isolated from inflamed
joints, the most important ones include:
• IFN-γ from TH1 cells activates macrophages and resident synovial cells.
• IL-17 from TH17 cells recruits neutrophils and monocytes.
• TNF and IL-1 from macrophages stimulates resident synovial cells to
secrete proteases that destroy hyaline cartilage.
• RANKL expressed on activated T cells stimulates bone resorption
TNF has been most firmly implicated in the pathogenesis of RA and TNF
antagonists have proved to be remarkable effective therapies for the
disease
TREATMENT OF RHEUMATOID
ARTHRITIS
 DISEASE-MODIFYING ANTIRHEUMATIC
DRUGS
• The DMARDs are chemically diverse class of agents, all of which have
varying capacities to slow the progression of joint erosion.
• Their actions manifest over the course of weeks to months; they are
usually employed in combination with NSAIDs and sometimes other
DMARDs.
• Recent therapies employ certain DMARDs early in the treatment of
disease, since they are effective in slowing the joint deterioration that
occurs at this stage.
Methotrexate
• It is an immunosuppressant which is widely prescribed in treatment
of RA and psoriatic arthritis.
• It slows the progression of new erosion within the involved joints
• It can also be used as anticancer and immunosuppressive agents
Mechanism of action
• Methotrexate is a folate antimetabolite that inhibits dihydrofolate
reductase and other folate-dependent enzymes in cells.
• Methotrexate inhibits folate-dependent enzymes involved in
adenosine degradation leading to increased concentration of
extracellular adenosine
• Adenosine acts via cell surface receptors to inhibit the production of
inflammatory cytokines such as TNF-α and IFN-γ
• Methotrexate also decreases the production of inflammatory
prostaglandins and proteases
Adverse effects of methotrexate

• Gastric irritation and stomatitis (most common)

• Pancytopenia
• Hepatotoxicity with fibrosis and cirrhosis
• Interstitial pneumonitis (Hypersensitivity reaction)
• Teratogenicity
• Increased risk of B-cell lymphomas
Contraindications and Drug Interactions
• Methotrexate is teratogenic and is contraindicated during pregnancy and
breast-feeding
• contraindications to methotrexate administration include kidney, liver, and
lung disease;moderate to high alcohol use; immunodeficiency; blood
dyscrasias; and hypersensitivity.
• Elderly persons may beat increased risk for toxicity because of decreased
renal and hepatic function.
• Methotrexate clearance can be decreased by the coadministration of NSAIDs
• Methotrexate can be displaced from plasma protein binding sites by
phenylbutazone, phenytoin sulfonylureas, and sulfonamides and certain
other antibiotics.
Sulfasalazine
• Sulfasalazine (Azulfidine) is approved for the treatment of rheumatoid
arthritis and ulcerative colitis. It is also used to treat ankylosing
spondylitis and Crohn’s disease.
• Comparisons of sulfasalazine with other DMARDs suggest that it is
more effective than hydroxychloroquine azathioprine, and oral gold
compounds.
• Sulfasalazine is a prodrug of which 70% is converted by colon bacteria
to two active metabolites, sulfapyridine and -aminosalicylic acid
(mesalamine).
• sulfapyridine is the active moiety in Rheumatoid arthritis and 5-
aminosalicylic acid is useful for ulcerative colitis.
• Sulfasalazine is used in patients when methotrexate is
contraindicated.
• Sulfasalazine has ability to increase adenosine levels,which has its
inhibitory effects on IL-1 and TNF-α release,
Adverse Effects
• Mild to moderate side effects, including nausea, vomiting,abdominal
pain, diarrhea, anorexia, and headache,
• Skin rash and discoloration, fever, reversible male infertility,and liver
enzyme elevation occur less frequently
• Rare hematological abnormalities, such as agranulocytosis,aplastic
anemia, hemolytic anemia, neutropenia, or other blood dyscrasias,
can be fatal.
Contraindications and Drug Interactions
• Sulfasalazine is contraindicated in infants and children under 2 years
of age.
• Sulfasalazine passes into breast milk and is therefore contraindicated
for nursing mothers and pregnant women near term should not use
this drug
• Sulfasalazine can inhibit the absorption of cardiac glycosides and folic
acid
• It may displace certain drugs,including warfarin, phenytoin,
methotrexate, tolbutamide chlorpropamide, and oral sulfonylureas,
from their protein binding sites.
Leflunomide
• It is used mainly to treat RA and prevent transplant rejection.
• It has relatively specific inhibitoryeffect on activated T cells
• It is transformed to active metabolite that inhibits de novo synthesis
of pyrimidine by inhibiting dihydro-orotate dehydrogenase which
causes cell arrest
• It is orally active and well absorbed from the GI tract.
Adverse Effects
• Diarrhea occurs in approximately one-third of patients taking this
drug; indigestion, nausea, and vomiting occur in about 10%.
• Other common adverse effects include weight changes, headache,
skin rashes, pruritus, and reversible alopecia and hepatic enzyme
elevation.
Contraindications and Drug Interactions
• Leflunomide is teratogenic in animal models; it is absolutely
contraindicated in pregnancy, in women who may become pregnant,
and in breast-feeding women.
• Because of its long half-life, the active metabolite of leflunomide may
remain in the body for up to 2 years; therefore, a drug elimination
procedure using cholestyramine should be used before any attempt at
pregnancy
• This drug is not recommended for use in children
Antimalarials
• Hydroxychloroquine (Plaquenil) and chloroquine (Aralen) are 4
aminoquinoline antimalarial drugs that possess modest DMARD
activity.
• They are indicated for the treatment of rheumatoid arthritis and
systemic lupus erythematosus
• The onset of action of these drugs is longer than that of other
DMARDs, and their side effects are relatively mild.
• Hydroxychloroquine and chloroquine are similar in activity; however,
hydroxychloroquine has a lower incidence of ocular side effects and is
used more frequently
• These drugs are weak bases that enter and interfere with the
functioning of lysosomes and other subcellular compartments of T-
and B-lymphocytes, monocytes, and macrophages.
• This in turn inhibits the ability of these cells to produce and release
inflammatory cytokines and hydrolytic enzymes.
Adverse Effects
• Skin rashes and pruritus are common adverse effects of the 4-
aminoquinoline antimalarials
• Irreversible retinopathy with resultant blindness, is dose related and
can be minimized by maintaining a daily dose of hydroxychloroquine
less than 6.5 mg/kg or chloroquine less than 4 mg/kg.
• Severe hematological toxicity (neutropenia thrombocytopenia,
aplastic anemia) is rare.
Contraindications and Drug Interactions
• The aminoquinolines accumulate in lung, kidney, and liver; thus, any
preexisting pathology in these tissues contraindicates their use.
• Aminoquinolines can increase plasma concentrations of penicillamine,
hence the potential for serious hematological or renal toxicity.
• Gold and an aminoquinoline probably should not be administered
concurrently because of the propensity of each to produce dermatitis.