MSK pharm – Rheumatoid arthritis drugs

Methotrexate, a competitive and reversible inhibitor of dihydrofolate reductase (DHFR), is the well-established first-line DMARD used to treat rheumatoid arthritis (RA). As soon as a diagnosis of RA is made, it is recommended that DMARD therapy is commenced.¹ 

NSAIDs, such as ibuprofen, and glucocorticoids may be used for symptomatic relief only, but they do not halt progression of the disease.² Glucocorticoids are generally implemented as a short taper while the initial DMARD is being commenced (or if DMARDs are being switched).¹ 

Methotrexate causes pulmonary fibrosis³, hepatotoxicity (↑ ALT, AST)⁴, and mucositis (due to agranulocytosis).⁵

Inhibition of soluble TNF-α refers to infliximab, adalimumab, etanercept (a recombinant receptor), golimumab, and certolizumab pegol.⁶

The above three bold TNF-α agents are exceedingly HY for the USMLE. The latter two agents are lower yield but newer. And anything new is fair game.

Inhibition of dihydroorotate dehydrogenase refers to leflunomide.⁷

Inhibition of interleukin-6 (IL-6) receptor refers to tocilizumab.⁸

Inhibition of CD80/86 refers to abatacept, a fusion protein that prevents B cell activation by T cells.⁹

Treatment of RA:¹  

Early, symptomatic RA

• Methotrexate is first-line DMARD. Commence as soon as diagnosis of RA is made.
• If methotrexate monotherapy is insufficient, add leflunomide or sulfasalazine (i.e., combination DMARD therapy), OR commence TNF-α agent monotherapy.

Established RA

• Methotrexate is first-line DMARD. Commence as soon as diagnosis of RA is made.
• If methotrexate therapy fails, add an TNF-α agent.

The USMLE Step 1 and 2CK will not make you differentiate between early and established RA. However they want you to know that methotrexate is used first and to merely be aware of the other available treatments.

Bottom line: Methotrexate is a competitive, reversible inhibitor of DHFR. It causes pulmonary fibrosis, hepatotoxicity, and mucositis (due to neutropenia). Depending on the severity and progression of RA, anti-TNF-α agents are frequently used as a step-up after methotrexate. NSAIDs and steroids do not slow progression of disease; they are used for symptomatic management only.

1) https://www.rheumatology.org/Portals/0/Files/ACR%202015%20RA%20

2) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527878/

3) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814259/

4) https://www.ncbi.nlm.nih.gov/books/NBK548219/

5) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4851368/

6) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877629/

7) https://www.ncbi.nlm.nih.gov/pubmed/7575649

8) https://www.ncbi.nlm.nih.gov/pubmed/30427250

9) https://pubmed.ncbi.nlm.nih.gov/19228144/

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1. What’s the MOA of methotrexate?

Dihydrofolate reductase inhibitor

2. What’s the MOA of leflunomide?

Dihydroorotate dehydrogenase inhibitor

3. What’s the MOA of tocilizumab?

Monoclonal antibody against interleukin-6 (IL-6) receptor

4. a) Name five anti-TNF-alpha drugs.

b) Which is the odd one out and why?

a) Infliximab, adalimumab, etanercept, golimumab, certolizumab pegol.

b) Etanercept is the odd one out. It is a recombinant receptor that mops up soluble TNF-alpha. The others are all monoclonal antibodies that target soluble TNF-alpha.

 

5. Three highest yield side-effects of methotrexate?

Pulmonary fibrosis, hepatotoxicity, neutropenia (causes mouth ulcers, aka mucositis).

6. 32F with recently diagnoses RA. What do we give her to manage pain?

NSAIDs first. If sufficient, don’t need steroids. If insufficient, add corticosteroids.

7. 34F + recently diagnoses RA + NSAIDs work well for her pain when she takes them; currently not taking NSAIDs and in pain; what drug should be added to her regimen (NSAIDs not listed)?

Slightly weird question but asked on the USMLE.

Methotrexate. Steroids are the wrong answer.

NSAIDs + steroids are for symptoms (pain) only. But methotrexate needs to be commenced at the onset of disease.

The Q says that insofar as she takes NSAIDs they are sufficient for pain. So she has no reason to commence steroids. But she needs to start methotrexate regardless.

Once again, slightly weird question, but asked on USMLE.

8. What’s the MOA of infliximab?

 Monoclonal antibody against TNF-alpha

 Monoclonal antibody against TNF-alpha receptor

Infliximab, adalimumab, certolizumab pegol, and golimumab are all monoclonal antibodies against soluble TNF-alpha, not TNF-alpha receptor.

This distinction is on USMLE.

9. How is osteoarthritis treated?

(Important to contrast with RA, so I threw this Q in here)

Weight loss is always first answer if listed (obesity greatest risk factor).

For pharmacologic Tx, choose acetaminophen before NSAIDs.

The pain will never go away because OA is degenerative joint disease (non-inflammatory), so taking NSAIDs long term will kill the kidney.

Steroids have no role. Answers regarding steroid injections, GAGs, capsaicin, etc., are always wrong on USMLE. They are essentially placebos that can be tried in patients with refractory pain in an attempt to hold off surgical management.

10. Which drug for RA is a dihydrofolate reductase inhibitor?

Methotrexate

11. Which drug for RA inhibits dihydroorotate dehydrogenase?

Leflunomide

12. Which drug for RA inhibits IL-6 receptor?

Tocilizumab

13. MOA of abatacept?

Fusion protein that targets CD80/86, thereby preventing B cell activation by T cells.

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