Published: 1 September 2022

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Paradoxical acute inflammatory syndrome with mycophenolate mofetil

Prescriber Update 43(3): 41–42
September 2022

The New Zealand data sheet for CellCept (mycophenolate mofetil) was updated in January 2021 to include de novo purine synthesis inhibitor-associated acute inflammatory syndrome as a newly described paradoxical pro-inflammatory reaction.¹ This article provides information about this adverse reaction.

De novo purine synthesis inhibitors

Purines are the building blocks of DNA and RNA molecules and provide energy and cofactors to promote cell survival and proliferation.² They are involved in many biological processes, including immune responses and host–tumour interaction.² The de novo synthetic pathway is essential to replenish the purine pool.² De novo purine synthesis inhibitors interrupt this pathway and are therefore used as immunosuppressant medicines.

Mycophenolate mofetil (MPM) is a pro-drug that is rapidly metabolised to mycophenolic acid (MPA). MPA is an inhibitor of inosine monophosphate dehydrogenase, which inhibits the de novo pathway for guanosine nucleotide synthesis and subsequent proliferation of T- and B-lymphocytes.¹

CellCept is the only MPM product available in New Zealand. It is indicated for the prophylaxis of solid organ rejection in adults receiving allogeneic organ transplants and in paediatric patients receiving allogeneic renal transplants.¹ There are no MPA products available in New Zealand.

De novo purine synthesis inhibitors-associated acute inflammatory syndrome

Acute inflammatory syndrome is a paradoxical pro-inflammatory adverse reaction associated with MPM and MPA.³ The post-market frequency of this adverse reaction is uncommon (≥1/1,000 to <1/1000). Case reports describe a close temporal relationship between medicine use and the onset of acute inflammatory syndrome. Positive medicine de-challenge and re-challenge suggests a causal relationship.^3,4

The mechanism behind acute inflammatory syndrome is not completely understood. Systemic pro-inflammatory cytokine release induced by MPA-acyl glucuronide (a metabolite of MPA) may contribute to syndrome onset.⁵

Patients with acute inflammatory syndrome may present with fever, arthralgias, arthritis, muscle pain and elevated inflammatory markers. Discontinuation of the medicine can lead to a rapid improvement in symptoms.¹

To date, the syndrome has only been described with MPM and MPA, but it may occur with other purine synthesis inhibitors.

New Zealand information

As of 7 July 2022, the Centre for Adverse Reactions Monitoring had not received any reports of de novo purine synthesis inhibitors-associated acute inflammatory syndrome.

Advice for prescribers

• Be aware of the risk of acute inflammatory syndrome when prescribing mycophenolate mofetil.
• Consider acute inflammatory syndrome if patients show signs and symptoms of pyrexia, arthritis, arthralgia, myalgia and elevated inflammatory markers.
• If clinically appropriate, discontinue treatment. The available information suggests symptoms rapidly improve following treatment discontinuation.¹

References

1. Roche Products (New Zealand) Limited. 2021. CellCept New Zealand Data Sheet 29 January 2021. URL: medsafe.govt.nz/profs/Datasheet/c/Cellceptcapsuspinf.pdf (accessed 13 June 2022).
2. Yin J, Ren W, Huang X, et al. 2018. Potential mechanisms connecting purine metabolism and cancer therapy. Frontiers in Immunology 9(Jul 30): 1697. DOI: 10.3389/fimmu.2018.01697 (accessed 22 July 2022).
3. Maruyama Y, Sadahira T, Mitsui Y, et al. 2018. Acute inflammatory syndrome paradoxically induced by de novo purine inhibitors synthesis before renal transplantation: a case report and review of the literature. Transplantation Proceedings 50(3): 895–7. DOI: 10.1016/j.transproceed.2017.12.030 (accessed 13 June 2022).
4. Konon I, Cronin ME, Ryan LM. 2008. Acute inflammatory syndrome following introduction of mycophenolate mofetil in a patient with systemic lupus erythematosus. Arthritis & Rheumatism (Arthritis Care & Research) 59(5): 754–6. DOI: 10.1002/art.23574 (accessed 13 June 2022).
5. Maes B, Oellerich M, Ceuppens JL, et al. 2002. A new acute inflammatory syndrome related to the introduction of mycophenolate mofetil in patients with Wegener's granulomatosis. Nephrology Dialysis Transplantation 17(5): 923–6. DOI: 10.1093/ndt/17.5.923 (accessed 12 June 2022).