Non-biologic disease modifying anti-rheumatic drugs (DMARDs)

Disease-modifying anti-rheumatic drugs, or DMARDs for short, are a group of medications primarily used to modify or slow down the progression of rheumatoid arthritis. Now, there are two types of DMARDs, biologic DMARDs, which are developed from microorganisms, animals, or humans, and non-biologic DMARDs, which are chemically synthesized in the laboratory. In this video, we’ll particularly focus on the non-biologic DMARDs.

Alright, first let’s talk about physiology eal quick. During the S phase of the cell cycle, the cell performs DNA replication. DNA is composed of a sequence of deoxyribonucleotides and each deoxyribonucleotide is made out of a phosphate group, a five-carbon sugar like deoxyribose, and a nucleobase, which can be either a pyrimidine like cytosine, or thymidine, or a purine like adenine or guanine. Now, pyrimidine synthesis starts when folic acid, or vitamin B9, from our diet, is converted into dihydrofolate or DHF. DHF then gets converted by an enzyme called dihydrofolate reductase or DHFR into tetrahydrofolate, or THF.

THF acts as a mediator and accepts a methyl group from the amino acid serine, becoming 5,10-methyl-THF. This methyl group is then used by an enzyme called thymidylate synthetase, which transfers it to dUMP or deoxyuridine monophosphate, turning it to dTMP or deoxythymidine monophosphate. dTMP then through a series of reactions eventually turns into thymine. And at that point, we’re all set to make DNA.

At the same time, purine synthesis starts with the amino acids glutamine, aspartate, and glycine, together with bicarbonate and formate, which is the anion derived from formic acid. These undergo a ten-step pathway and the result is inosine monophosphate, or IMP, which is a precursor to adenine and guanine. And at that point, we’re all set to make DNA.

Okay, now, rheumatoid arthritis or RA for short is a chronic, progressive, inflammatory disorder that affects synovial joints and, sometimes, other parts of the body like the skin and the lungs. It is thought to be an autoimmune reaction, however, the exact cause is unknown. Generally speaking, it seems to be associated with environmental risk factors like infections and smoking, and with a genetic predisposition like having the alleles HLA-DR1 and HLA–DR4.

So basically, cells of the immune system, including T-cells, and macrophages, enter the joint space and start releasing inflammatory cytokines, like tumor necrosis factor, or TNF-α, interleukin- 1 or IL-1, and interleukin- 6, or IL-6. These cytokines stimulate synovial cells to proliferate and create a pannus, which is a thick, swollen synovial membrane with granulation or scar tissue, made up of fibroblasts, myofibroblasts, and inflammatory cells. Over time, the cytokines released in the pannus start to break down the articular cartilage, eventually leading to bone erosion.

The good news is that we can slow down this process by using non-biologic DMARDs. These mainly include methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine. Note though that non-biologic DMARDs can also be used in other conditions, such as inflammatory bowel disease, or IBD, and various cancers, like leukemia.