Rheumatoid Arthritis (RA)

• Rheumatoid arthritis (RA) is a chronic, systemic disorder.
• Primarily characterized by synovitis and destruction of articular tissue.
• RA is associated with pain, morning stiffness (>1hr), and inflammation, mainly in small synovial joints of the hands and feet.
• RA occurs more often in women than in men.
• The initiating factor in RA is unknown.
• A possible initiating factor is a virus or other infectious agent.
• This initiates an immune response involving mononuclear phagocytes, T lymphocytes, and B lymphocytes.
• These cells interact to produce inflammatory mediators, including cytokines like Tumor necrosis factor-alpha (TNF-α) and Interleukin-1 (IL-1).
• Eicosanoids (prostaglandins, leukotrienes) and destructive enzymes (proteases, collagenases) are also produced.
• These mediators induce destruction of articular cartilage and bone, leading to joint destruction in RA.
• Drug treatment of RA has two goals: decrease joint inflammation and arrest the progression of the disease.
• Three general categories of drugs are available: Nonsteroidal anti-inflammatory drugs (NSAIDs), Glucocorticoids (Steroids), and Disease-modifying antirheumatic drugs (DMARDs).
• NSAIDs and intra-articular glucocorticoids are used primarily to decrease joint inflammation.
• COX2-inhibitors are the most preferred NSAIDs.

Glucocorticoids

• Doses up to 10 mg of prednisone are usually used.
• Can produce harmful catabolic effects on supporting tissues (muscle, tendon, bone, skin) and joints already weakened by arthritic changes.
• High/long term doses can cause serious musculoskeletal problems.
• Timely dose reductions and cessation are necessary to avoid long-term adverse effects.
• The number of injections into an arthritic joint should be limited to no more than 4 injections in one joint within one year.
• DMARDs are used to slow the progress of RA by interfering with the immune response.

Methotrexate

• Methotrexate is an immunosuppressant and cytotoxic agent.
• Administered once a week.
• A response usually occurs within 3 to 6 weeks.
• Side effects include nausea, cytopenia, hepatotoxicity, and acute pneumonia-like syndrome.
• It is recommended to take folic acid the day after methotrexate injection.

Gold Salts

• Taken up by macrophages and will suppress phagocytosis and lysosomal enzyme activity.
• Retards the progression of bone and articular destruction.
• Beneficial effects may be seen in 3 to 6 months and are only effective in the early stages of RA.

Cyclophosphamide

• DNA alkylating agent that destroys DNA in T-lymphocytes.

Cyclosporin A

• Inhibits calcineurin in B- and T-lymphocytes.
• Inhibits important enzymes necessary for these immune cells.

Leflunomide

• Inhibits uridine monophosphate (UMP) synthesis.
• UMP is an important nucleotide for DNA and RNA synthesis in T- and B-lymphocytes.

Monoclonal Antibodies (MABs)

• Example: Infliximab.
• Binds to TNF-α, inhibiting its binding to its receptor, which reduces cartilage and joint destruction.
• Used in combination with methotrexate.

Etanercept

• A genetically engineered recombinant protein.
• Binds to TNF-α, thus blocking its interaction with its receptor.
• Approved for moderate to severe RA, either alone or in combination with methotrexate (more effective).
• Not used in viral hepatitis or leukemia, as it decreases the immune defense mechanism.

Anakinra

• An IL-1 receptor antagonist.
• Used in severe RA failing one or more DMARDs.
• May be used alone or in combination with DMARDs (other than TNF inhibitors).
• Can cause neutropenia, so absolute neutrophil counts should be monitored.