DMARDs
Disease Modifying Anti-Rheumatic Drugs.
Hydroxychloroquine
Standard therapy in lupus. Used with other agents in rheumatoid arthritis (RA).
The mechanism of action is unclear but is thought to alter the pH in lysosomes and/or affect toll-like receptor (TLR) signaling.
Side effects
- Retinal toxicity and vision loss
Sulfasalazine
Used in combination with other agents for RA.
The mechanism of action is unclear. There are frequent allergies to this drug due to the sulfa component.
Side effects
- Nausea
- Vomiting
- Loss of appetite
- Abdominal pain
Minocycline
Used for RA patients with (+) rheumatoid factor.
Thought to act at the level of metalloproteinases and may have some antimicrobial effects.
Side effects
- Dizziness
- Vestibular toxicity
- Nausea
- Hepatitis
Methotrexate
Major treatment for RA as it is well tolerated. It's discontinuation rate is lower than other drugs.
Blocks the folic acid synthesis pathway, so use includes folic acid and Leucovorin to reduce side effects.
Monitoring includes CBC and comprehensive metabolic panels, especially liver enzymes. Contraindicated in patients with renal insufficiency and pregnancy.
Azathioprine
Used more in lupus and vasculitis compared versus RA. Also has a role in transplant medicine to prevent rejection.
The prodrug of 6-mercaptopurine.
Side effects
- GI intolerance
- Bone marrow suppression
- Increased risk of viral infections
Leflunomide
Alternative to methotrexate to treat RA. Once a day tablet.
Works on dihydroorotate pathways. Does not induce bone marrow suppression or predisposition to opportunistic infections.
Very long half-life due to hepatobiliary secretion and reabsorption. Can be eliminated with the help of cholestyramine/bile salts.
Mycophenolate Mofetil
Used in lupus with corresponding kidney inflammation.
Reversible inhibitor of inosine monophosphate dehydrogenase which downregulates synthesis of guanosine nucleotides in T and B lymphocytes.
Tofacitinib
Used for RA.
JAK3 inhibitor. Absence of JAK3 causes SCID. Side effects include immune suppression and increased cholesterol.
Biologic Response Modifiers
Proteins derived from living material. 50% of people with RA can be treated with traditional oral agents, while biologics cover the other 50%.
TNF-alpha inhibitors
Metalloproteinases cleave membrane bound TNF receptors to bind soluble TNF which dampens the inflammatory signal. All anti-TNF drugs work well in RA.
Anti-TNF drugs also treat joint pain of ankylosing spondylitis.
Monoclonal antibodies assist with Crohn’s disease and uveitis. Monoclonals also work better on the skin in psoriasis. Both monoclonal antibodies and fusion receptors work well with inflammatory arthritis.
Lenercept
...
Infliximab
Used for Crohn’s disease. Stop-start dosing results in a higher development of antibodies to the drug. Co-administration of immunosuppressive drugs significantly reduce the anti-drug antibodies.
T-Cell Costimulatory Blockade
Blocks T-cell costimulatory signal.
Abatacept
Slow onset, well tolerated, moderately effective
Anti-CD20
Targets CD20 molecules on B cells, ultimately destroying them.
Rituximab
Works with RA and other autoimmune diseases. Works well in granulomatosis with polyangiitis (GPA).
Side effects include mild to severe infusion reactions, progressive multifocal leukoencephalopathy (through viral reactivation), Reactivation of Hepatitis B
Interleukin Receptor Antagonists
Reduction of IL-1 and IL-6 which drive the production of C reactive protein and other inflammatory conditions.
Anakinra
Recombinant IL-1 receptor antagonist. Moderately effective for RA. Effective at stopping gout.
Daily shot that causes uncomfortable welts. Other side effects include infections and neutropenia.
Tocilizumab
Anti-IL-6. Used for RA, JIA, and Castleman’s disease.
Side effects include infections, blood pressure elevation, and elevated liver enzymes.
B-Lymphocyte Stimulator (BLyS) inhibitors
Belimumab
Blocks BLyS, which normally helps to keep B cells alive. Somewhat effective in lupus.
Pegloticase
PEGylated to extend half-life and reduce immunogenicity. Dramatically reduces serum uric acid to prevent gout outbreaks. Add methotrexate when antibodies develop.
Treat To Target
Directed trial and error.
Diagnose → Treat → Measure → Monitor
Primary drug failure
When the drug does not work.
Solutions
- Choose another drug class
- Review diagnosis
Secondary drug failure
When a drug initially works but later loses effect.
Solutions
- Increase dose
- Shorten interval
- Choose another drug or target