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

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Introduction0:00–0:34

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.

Physiology0:34–2:31

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.

Pathology2:31–3:46

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.

Pharmacology3:46–4:10

Over time, the cytokines released in the pannus start to break down the articular cartilage, eventually leading to bone erosion.

Methotrexate4:10–7:50

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.
Okay, starting with methotrexate, this is the first-line medication for individuals with moderate to severe rheumatoid arthritis and it’s important to get it started as soon as possible after the diagnosis.
Now, methotrexate is a folic acid analog that works by inhibiting nucleotide synthesis. Specifically, methotrexate has a higher affinity for DHFR, than DHF and so it binds and irreversibly inhibits the enzyme resulting in decreased levels of THF.
Low THF means low thymidylate production. At the same time, methotrexate inhibits an enzyme involved in purine synthesis.
This leads to a decrease in DNA synthesis, which in turn inhibits the cell cycle from progressing to the S phase. This mainly affects rapidly dividing cells in our body, including cells of the immune system.
So, in rheumatoid arthritis, this can help reduce joint inflammation and injury. Now, let’s move on to side effects.
The major side effect of methotrexate is bone marrow suppression, where white blood cells or WBCs, red blood cells or RBCs, and platelet production slows down, resulting in low WBC count or leukopenia, low RBC count or anemia, and low platelets, or thrombocytopenia.
Now, the type of anemia caused is megaloblastic, meaning that megaloblasts or large, immature red blood cells are produced.
That’s because the cytoplasm develops normally, but the DNA synthesis is impaired. In addition, as methotrexate arrests the cell division, all rapidly dividing cells in the body like those lining the gastrointestinal tract also get affected.
This results in frequent oral ulcers, gum bleeding, peptic ulcers, and hemorrhagic enteritis. Delay in the cell division also affects the hair cells, resulting in alopecia.
Another important side effect of methotrexate is liver toxicity or hepatotoxicity, which manifests as macrovesicular fatty change, a severe form of hepatic steatosis where fat vesicles displace the nucleus to the periphery of the hepatocyte, and pulmonary toxicity which manifests as pulmonary fibrosis.
Finally, methotrexate is teratogenic, meaning that its use during pregnancy can lead to neural tube defects and congenital heart defects.
So, methotrexate is contraindicated in pregnancy and characterized as category X. Using its teratogenic effect, methotrexate is often used to end the fetus in unruptured ectopic pregnancies where continuation of the pregnancy becomes hazardous for the mother.The good news is that the incidence of side effects of methotrexate can be reduced with folic acid supplementation, without affecting its efficacy.
Folic acid, in high concentrations, can displace the methotrexate from the active site of DHFR and restore nucleotide synthesis.
But this process is slow and takes time to show its effect. So in case immediate action is needed, folinic acid or leucovorin is used as an antidote.

Leflunomide7:50–9:16

This strategy is called “leucovorin rescue”, and is often used to reverse bone marrow suppression. Leucovorin is already a reduced form of folic acid and thus, it doesn’t require DHFR to get activated.
So, after entering the cell, it can be readily converted into 5,10-methyl-THF, which is then used for nucleotide synthesis.When methotrexate monotherapy doesn’t work or it’s contraindicated, the person should take another DMARD.
There’s leflunomide, which is a prodrug that, after taken orally and going into the intestine, enters the enterohepatic circulation to reach the liver.
That’s where it gets metabolized into its active form, known as teriflunomide. Teriflunomide reversibly inhibits a mitochondrial enzyme called dihydroorotate dehydrogenase or simply DHODH, arresting the cell in the G1 phase of growth.
In activated T-cells, DHODH plays an important role in pyrimidine synthesis, which is needed to make new DNA. So, when DHODH is inhibited, the proliferation of T-cells gets suppressed, decreasing further damage to the joints.

Hydroxychloroquine9:16–10:20

In terms of side effects, leflunomide mainly causes bone marrow suppression and hepatotoxicity. Other side effects include gastrointestinal disturbances like nausea, vomiting, and diarrhea, as well as peripheral neuropathy, and alopecia.
Finally, leflunomide, just like methotrexate, is teratogenic, so it should be avoided in pregnant individuals. If someone becomes pregnant while on leflunomide, it should be stopped immediately and a medication named cholestyramine can be given to “wash out” any leflunomide from the body.
Next in line is an old anti-malarial medication known as hydroxychloroquine or HCQ for short. Typically, it takes almost 3 to 6 months for hydroxychloroquine to start showing its effect on individuals with RA.

Sulfasalazine10:20–11:18

Now, the exact mechanism of action of hydroxychloroquine is yet to be understood, but it is thought that it inhibits the release of TNF-α and IL-1 by macrophages.
This can help prevent synovial cell proliferation and pannus formation, slowing down joint destruction. As for side effects, these are usually milder than other DMARDs.
Note that hydroxychloroquine is also safe to use during pregnancy. However, long term use of hydroxychloroquine can lead to the accumulation of the medication in melanin-rich tissues such as the skin and retina.
This can manifest as skin hyperpigmentation, as well as retinal damage or retinopathy. Other side effects include muscle weakness due to myopathy, premature greying of hair, and gastrointestinal disturbances.

Review11:18–12:13

Finally, there’s sulfasalazine, which is a combination of sulfapyridine, and 5-aminosalicylic acid, attached together through an azo bond.
This is also a prodrug that's taken orally. And as soon as it reaches the colon, the gut flora breaks down the azo bond and releases the two molecules- sulfapyridine and 5 ASA.