Mechanism of Action of Mycophenolate in Interstitial Lung Disease with Autoimmune Features
Mycophenolate mofetil (MMF) acts primarily by inhibiting inosine monophosphate dehydrogenase (IMPDH), an enzyme critical for the de novo pathway of guanosine nucleotide synthesis, thereby selectively inhibiting T and B lymphocyte proliferation in interstitial lung disease with autoimmune features. 1, 2
Primary Mechanism of Action
- MMF is a prodrug that is hydrolyzed to mycophenolic acid (MPA), the active metabolite that selectively inhibits IMPDH 1
- This inhibition preferentially affects T and B lymphocytes because they are critically dependent on the de novo pathway for purine synthesis, unlike other cells that can use salvage pathways 2
- The mechanism creates a cytostatic and reversible effect on lymphocytes 1
Immunomodulatory Effects
- Decreases proliferative responses of T and B lymphocytes to both mitogenic and allo-antigenic stimulation 1
- Suppresses antibody production and cytokine release from lymphocytes and monocytes 1
- Modulates transcriptional activities in human CD4+ T-lymphocytes by suppressing the Akt/mTOR and STAT5 pathways 1, 3
- Enhances expression of negative co-stimulators (CD70, PD-1, CTLA-4) and transcription factor FoxP3 3
- Decreases expression of positive co-stimulators CD27 and CD28 3
- Induces T-cell anergy, making cells less responsive to antigenic stimulation 3
Anti-fibrotic Properties
- Beyond immunosuppression, MMF has important antiproliferative and antifibrotic effects that may be beneficial in interstitial lung disease 4
- Prevents the glycosylation of lymphocyte and monocyte glycoproteins involved in intercellular adhesion to endothelial cells 1
- May inhibit recruitment of leukocytes into sites of inflammation and fibrosis 1
Clinical Application in Interstitial Lung Disease
- MMF has been studied as a treatment option for various forms of interstitial lung disease, including those associated with autoimmune features 5
- In idiopathic pulmonary fibrosis (IPF), MMF has shown trends toward reduced annual FVC decline similar to approved antifibrotics 4
- MMF is considered a main alternative to cyclophosphamide as a first-line agent for rheumatic disease-related interstitial lung disease 5
Dosing in Interstitial Lung Disease
- Typical starting dose is 500 mg twice daily 6
- Dose is typically increased by 500 mg weekly to reach a target dose of 1000 mg twice daily (2 g/day) 6, 4
- In some cases, doses may be increased to 1500 mg twice daily (3 g/day) if tolerated 6
- Monitoring of MMF levels (glucuronide) may be performed to ensure therapeutic range 6
Safety Profile and Adverse Effects
- Common side effects include gastrointestinal disturbances (nausea, diarrhea) 6, 7
- Potential for leukopenia and transaminitis requiring laboratory monitoring 6
- Generally well-tolerated compared to other immunosuppressants like cyclophosphamide 5
- Contraindicated in pregnancy due to teratogenic effects 6
- Requires monitoring of complete blood count and liver function tests 7
Comparative Efficacy
- In a small retrospective study, MMF treatment was associated with trends toward reduced annual FVC decline (-76.3 mL, -2.4% of predicted) compared to no treatment (-239 mL, -11.5% of predicted) 4
- Another study showed no significant alterations in FVC, TLC, DLCO, and 6MWD after 12 months of treatment, though HRCT showed disease progression 8
- MMF may offer a safer alternative to traditional therapies with potentially similar efficacy in slowing disease progression 4