What Are Immunomodulators?
Immunomodulators are medications that alter the immune system's function by either suppressing or enhancing immune responses, and in the context of inflammatory bowel disease and other immune-mediated conditions, they primarily include corticosteroids, thiopurines (azathioprine, mercaptopurine), methotrexate, calcineurin inhibitors, anti-TNF agents, and other biologics. 1
Classification and Mechanism
Immunomodulators fall into two broad categories:
Immunosuppressants
These agents reduce or suppress immune activity and include:
- Corticosteroids (prednisone, prednisolone)
- Thiopurines (azathioprine at 2-2.5 mg/kg/day, mercaptopurine at 1-1.5 mg/kg/day) 2
- Methotrexate (typically 25 mg weekly for induction, 15 mg weekly for maintenance with daily folic acid) 2
- Calcineurin inhibitors (cyclosporine, tacrolimus) 1, 3
- Anti-TNF biologics (infliximab, adalimumab)
- Other biologics (vedolizumab, ustekinumab, risankizumab) 2
Immunostimulants
These agents enhance immune function, though they are less commonly used in inflammatory conditions 4, 5
How They Work
Each immunomodulator compromises the immune response through different mechanisms, but all share the common effect of altering immune competence to varying degrees. 1 There is currently no single biological method to accurately quantify the degree of immunosuppression these agents produce in individual patients 1.
Clinical Context and Risks
Infection Risk
Immunomodulators significantly increase the risk of opportunistic infections 1:
- Corticosteroids: Risk increases with doses ≥20 mg prednisolone daily for ≥2 weeks 1
- Combination therapy: Using multiple immunomodulators together creates an incremental (threefold) increase in infection risk compared to monotherapy 1
- Anti-TNF agents: Associated with increased rates of serious bacterial, fungal, and mycobacterial infections 1
Important Clinical Considerations
When combining immunomodulators with biologics:
- Thiopurines combined with infliximab increase infliximab trough concentrations and reduce anti-drug antibody formation 2
- This pharmacokinetic benefit does NOT apply to non-TNF biologics like vedolizumab or ustekinumab, where anti-drug antibody prevalence is <1% regardless of immunomodulator use 2
- JAK inhibitors have no immunogenicity risk, so adding immunomodulators provides no pharmacokinetic benefit 2
Monitoring Requirements
Routine monitoring of complete blood counts and liver function tests is mandatory when using thiopurines and methotrexate 2
Common Pitfalls
Assuming all biologics benefit from combination therapy: Only TNF antagonists show clear pharmacokinetic advantages when combined with immunomodulators 2
Underestimating infection risk: Age, malnutrition, and combination therapy exponentially increase opportunistic infection risk 1
Ignoring contraindications: Methotrexate is absolutely contraindicated in women considering pregnancy or who are pregnant 2
Continuing unnecessary combination therapy: After 6 months of remission on TNF antagonist plus immunomodulator, the immunomodulator can typically be withdrawn to reduce long-term risks of malignancy and infection 2