Rheumatoid arthritis, or RA, is an autoimmune disease that occurs when a person’s immune system
mistakenly attacks normal proteins within the body. The resulting chronic
inflammation primarily affects the synovium, or lining of the joints, leading to swelling,
stiffness, pain and deformation of the joints. In about 40% of individuals,
symptoms may also occur within the skin, lungs, muscles, and cardiovascular system. RA affects
about 1-1.5% of people within North America and is 3 times more prevalent in women than men.
According to CDC, the annual medical costs and earnings losses associated with arthritis
came in at 303.5 billion dollars in 2013, an amount equivalent to 1% of the gross domestic
product of the United States that year. The need for anti-rheumatic drugs is immense,
with a market size of 57 billion dollars in 2019 which is expected to grow to 63 billion by 2027.
Earlier in this series, we learned about NSAIDs, or non-steroidal anti-inflammatory drugs. These
drugs are common treatments for RA symptoms. However, they do not slow the progression of
the disease or limit joint deformation. Many patients, especially with moderate to severe RA,
are prescribed disease-modifying antirheumatic drugs, or DMARDs. These drugs limit the
underlying inflammation that causes RA, which not only decreases the pain associated with RA,
but also prevents further damage to the joints, preserving their function.
DMARDs consist of two different drug modalities: small molecule, and biologic. Small molecule drugs
are small compounds which bind to and either activate or deactivate a protein of interest.
They can be administered and readily absorbed through various routes that
we discussed earlier in the series. On the other hand, biologic DMARDs, or bDMARDs,
are antibodies, which are protein complexes that are significantly larger than small molecules.
While antibodies are normally generated by our immune system to guard us from invading organisms,
pharmacologists can hijack this biological response
to generate antibodies which target select proteins of interest with incredible specificity.
These two modalities differ greatly in their production, cost, administration,
and side effects. As proteins, biologic DMARDs must be made using biological processes
rather than by the significantly simpler and cheaper chemical processes
for small molecules. This also complicates their administration as large proteins can’t be absorbed
by normal routes of administration, and must be given by injection as often as once a week.
Production, storage, and dosing difficulties contribute to the high expense of bDMARDs.
As an example, Remicade, also known as infliximab, costs between 19 and 22 thousand dollars per year
for treatment. Conversely, a treatment regimen of 1 to 2 small molecule DMARDs can achieve disease
remission in many RA patients. Therefore, due to dosing difficulties and high costs,
biologic DMARDs are only prescribed for moderate to severe RA in cases when non-biologic DMARDs
fail to sufficiently relieve disease symptoms. Both modalities in this drug class are commonly
combined with NSAIDs for the treatment of the pain associated with inflammation.
Small molecule DMARDs are associated with a range of side effects.
Due to the highly specific nature of the antibody interaction with proteins, the side effects are
generally lower in this class however they have been associated with uncommon adverse events
including decreased white or red blood cell counts, lymphoma, demyelinating disease,
and heart failure. Both of these classes, however, are immunosuppressive and lead to an increased
risk for various opportunistic infections by bacterial, fungal, or viral agents that
would not cause infection in an individual with normal, uncompromised immune function. Though
DMARDs were originally classified for the treatment of RA, their immunosuppressive effects
make them efficacious treatments for many other immune disorders, including plaque psoriasis,
ankylosing spondylitis, Crohn’s disease, and ulcerative colitis. Let’s now move forward and
look at a specific antirheumatic drug, so we can better understand its mechanism of action.