Non-Glucocorticoid Immunosuppressants
The primary non-glucocorticoid immunosuppressive agents used in clinical practice include azathioprine, cyclophosphamide, methotrexate, and mycophenolate mofetil, as defined by the American College of Rheumatology. 1
Conventional Immunosuppressive Agents
Antimetabolites
- Azathioprine is an antimetabolite that inhibits both de novo and salvage pathways of purine synthesis, resulting in lymphocyte suppression 2, 3
- Methotrexate functions as an antimetabolite and is frequently used as a first-line steroid-sparing agent, particularly well-tolerated in pediatric populations 1
- Mycophenolate mofetil (MMF) selectively inhibits the de novo purine synthesis pathway, offering a more targeted mechanism than azathioprine 4, 3
Alkylating Agents
- Cyclophosphamide is the preferred agent for severe, life-threatening or organ-threatening disease manifestations 1
- Chlorambucil represents another alkylating agent option, though less commonly used in current practice 5
Calcineurin Inhibitors
T-Cell Suppression Agents
- Cyclosporine prevents IL-2 transcription by binding calcineurin and blocking its nuclear translocation, though it carries significant nephrotoxicity risk 3, 5
- Tacrolimus operates through a similar calcineurin inhibition mechanism and has emerged as an effective option, particularly for lupus nephritis with nephrotic-range proteinuria 6, 3
mTOR Inhibitors
- Sirolimus (Rapamycin) inhibits IL-2 expression through interaction with the mammalian Target of Rapamycin (mTOR) protein, offering an alternative mechanism to calcineurin inhibitors 3, 5
Biologic Agents
Monoclonal Antibodies
- Rituximab achieves B-cell depletion, though its efficacy in certain conditions like polyarteritis nodosa remains uncertain due to limited comparative data 1, 7
- Daclizumab and basiliximab are humanized/chimeric monoclonal antibodies providing effective induction therapy with minimal adverse effects 3
TNF Inhibitors
- Tumor necrosis factor inhibitors are recommended for Takayasu arteritis refractory to glucocorticoids and serve as first-line therapy for deficiency of adenosine deaminase 2 (DADA2) 1, 8
IL-6 Inhibitors
- Tocilizumab blocks interleukin-6 signaling, though it is not recommended as initial therapy for Takayasu arteritis due to unproven efficacy in this condition 1
Clinical Context and Selection
Disease-Specific Considerations
The choice of non-glucocorticoid immunosuppressant depends heavily on disease severity and organ involvement 1:
- For severe disease (renal insufficiency, mononeuritis multiplex, mesenteric ischemia): Cyclophosphamide is the preferred first-line agent when combined with glucocorticoids 1
- For non-severe disease: Azathioprine or methotrexate are typically used as first-line agents 1
- For cyclophosphamide intolerance: Alternative agents such as azathioprine or methotrexate should be used rather than glucocorticoid monotherapy 1
Mechanism-Based Classification
These agents can be categorized by their primary mechanism 3, 5:
- Alkylating agents: Cyclophosphamide, chlorambucil
- Antimetabolites: Azathioprine, methotrexate, mycophenolate mofetil
- Calcineurin inhibitors: Cyclosporine, tacrolimus
- mTOR inhibitors: Sirolimus
- Biologics: Rituximab, TNF inhibitors, tocilizumab
Important Caveats
All immunosuppressive agents increase infection risk, requiring screening for tuberculosis, hepatitis B, Strongyloides stercoralis, and consideration of Pneumocystis jirovecii pneumonia (PJP) prophylaxis when combined with moderate-to-high dose corticosteroids 9
Azathioprine and mycophenolate carry specific risks for progressive multifocal leukoencephalopathy (PML), necessitating urgent neurological evaluation for any new neurological symptoms 9
Cyclophosphamide-induced myelosuppression requires PJP prophylaxis when combined with corticosteroids until prednisone-equivalent doses reach ≤5 mg/day 9