Category: rheumatoid arthritis

Hydroxychloroquine – New Safety Advisory on Congenital Malformations, Phospholipidosis, and Myasthenia Gravis Aggravation

The Health Science Authority (HSA), Singapore, has announced that Sanofi-Aventis Pte Ltd has issued a “Dear Healthcare Professional Letter” to provide critical updates on the safety profile of Plaquenil® (Hydroxychloroquine sulphate). Healthcare professionals are urged to take note of these new findings, particularly in patients who are pregnant, those with myasthenia gravis, or individuals at risk of developing phospholipidosis.

Key Safety Update – Increased Risk of Major Congenital Malformations: A 2021 study by Huybrechts et al. has reported a small but significant increase in the relative risk of major congenital malformations linked to hydroxychloroquine when administered during the first trimester of pregnancy. The risk becomes more pronounced at higher daily dosages (≥ 400 mg/day).

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Why is hydroxychloroquine used for systemic lupus erythematosus (SLE)?

Why is an antimalarial drug, hydroxychloroquine, used as a rheumatological immunosuppressant in disorders such as systemic lupus erythematosus (SLE)?

Hydroxychloroquine (HCQ), originally developed as an antimalarial, has become a cornerstone in the treatment of autoimmune diseases, including systemic lupus erythematosus (SLE), primary Sjögren’s syndrome, and rheumatoid arthritis. How does this drug help address the challenges posed by these autoimmune diseases?

1. Interference with lysosomal activity and autophagy:
HCQ increases the pH within intracellular lysosomes, interrupting the autophagy of macromolecules and antigen processing in antigen-presenting cells. This leads to diminished T cell stimulation, providing an advantage in autoimmune conditions like SLE by modulating immune responses.

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Folate, folic acid or folinic acid to reduce adverse effects of methotrexate?

What is the difference between folate, folic acid, and folinic acid? And how do each of them contribute or are involved in the methotrexate pathway?

Folate is the naturally occurring salt form of vitamin B9. Folic acid is a synthetic water-soluble acid form of vitamin B9. Folate and folic acid are metabolised by dihydrofolate reductase, the enzyme inhibited by methotrexate, to FH2 and then FH4, which in turn is converted to N5, N10-methylene-FH4.

Folinic acid (also known as leucovorin) is N5-formyl-FH4 and can be converted rapidly to N5, N10-methylene-FH4 without the need for dihydrofolate reductase and so bypasses the inhibition of the pathway by methotrexate.

In the treatment of rheumatoid arthritis with methotrexate, adverse effects include nausea and vomiting, mouth and gastrointestinal ulcers, and hair loss are caused by the reduction in N5, N10-methylene-FH4, which is required for the synthesis of amino acids and nucleic acids necessary for cell proliferation.  Folic acid at high enough doses to overcome the methotrexate inhibition of dihydrofolate reductase or folinic acid is therefore used to reduce the adverse effects of methotrexate.

Paracetamol for osteoarthritis or rheumatoid arthritis?

Some guidelines say paracetamol is only suitable for osteoarthritis, not rheumatoid arthritis (RA), as it is a poor anti-inflammatory. However, further reading online indicates that paracetamol is still used for other inflammatory rheumatological disorders like gout and RA. May I seek further clarification on this point?

Paracetamol (acetaminophen) is no longer recommended as a first-line for the pain associated with osteoarthritis (OA) as it has only small, non-clinically significant effects on the pain and there are safety concerns over long-term use for osteoarthritis (e.g., Macahdo et al., 2015; Roberts et al., 2016). Previously, paracetamol alone was used for the pain associated with OA if there was no significant inflammation following the damage to the joints. However, paracetamol is rarely sufficient for the pain associated with gout or RA. As there is always inflammation in gout and RA, a drug that is both analgesic and anti-inflammatory, such as a non-steroidal anti-inflammatory drug (NSAID), is usually preferable. So you will typically find paracetamol in evidence-based medicine guidelines for OA but not for RA or gout.

However, paracetamol will still cause analgesia. Therefore, you will still find it used sometimes as a safer option in cases when the pain is mild or as an addon between doses of ibuprofen (which happens to have a similar dosing interval) to provide additional analgesia. In addition, for patients for whom NSAIDs are contraindicated, you will often find paracetamol used.

References:
Machado GC, Maher CG, Ferreira PH, Pinheiro MB, Lin CW, Day RO, McLachlan AJ, Ferreira ML. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials. BMJ. 2015;350:h1225.
Roberts E, Delgado Nunes V, Buckner S, Latchem S, Constanti M, Miller P, Doherty M, Zhang W, Birrell F, Porcheret M, Dziedzic K, Bernstein I, Wise E, Conaghan PG. Paracetamol: not as safe as we thought? A systematic literature review of observational studies. Ann Rheum Dis. 2016;75(3):552.

Does the 5-aminosalicylic acid metabolite of sulfasalazine play a role in management of rheumatoid arthritis

 Sulfasalazine is metabolized by gut microbiota into sulfapyridine, the active metabolite in the treatment of rheumatoid arthritis (RA), and 5-aminosalicylic acid. Does 5-aminosalicylic acid play any significant pharmacological role?

The mechanisms of action of sulfasalazine are not fully understood. However, it is unlikely that 5-aminosalicylic acid plays a role in the treatment of RA. But you will come across 5-aminosalicylic acid in the treatment of inflammatory bowel disease, where it is thought to be the active metabolite of sulfasalazine and is also administered as a drug itself.

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