Immunosuppressants

Immunosuppressants use heterogeneous mechanisms of action to suppress the body's cell-mediated and humoral immune response. They may be used as transplant rejection prophylaxis or to treat autoimmune disorders such as lupus, psoriasis, and rheumatoid arthritis. Commonly used immunosuppressants include cyclosporine A, tacrolimus, glucocorticoids, methotrexate, and biological agents (like rituximab). A common side effect of immunosuppressants is an increased susceptibility to infection and malignancy.

Glucocorticoids are discussed in detail in another article.

Immunosuppressant class	Common drugs			Mechanism of action	Suppression of cell-mediated immune response	Suppression of humoral immune response	Main clinical uses
Glucocorticoids	Prednisolone, hydrocortisone, dexamethasone			Inhibition of intracellular NF-κB → Multiple inflammatory and immune mediators are inhibited. Acute effect (occurs within minutes) → While the mechanism is not entirely clear, a membrane stabilizing effect is hypothesized. Long-term effects (in hours) → direct influence on gene expression	✓	✓	Transplant rejection prophylaxis To suppress various allergic, inflammatory, and autoimmune reactions
Calcineurin inhibitors (calcineurin = calcium- and calmodulin-dependent serine-threonine phosphatase)	Cyclosporine A			Immunosuppression: binds cyclophilin → inhibition of calcineurin → inhibition of NFAT activation→ ↓ IL-2 transcription → ↓ activation of T cells Cytostatic action: binding to multidrug resistance glycoprotein P-170	✓	–	Transplant rejection prophylaxis (in combination with other immunosuppressants) Psoriasis Rheumatoid arthritis
	Tacrolimus (also FK-506 or fujimycin)			Binding to FK506 binding protein (FKBP) → inhibition of calcineurin → inhibition of NFAT activation → ↓ IL-2 transcription → ↓ activation of T cells	✓	–	Transplant rejection prophylaxis
	Pimecrolimus						Atopic dermatitis (topical use)
mTOR inhibitors	Sirolimus (also known as rapamycin)			Binds to FKBP → inhibition of mTOR kinase→ inhibition of the IL-2-mediated cell cycle → prevents response to IL-2 → blocks T-cell activation and B-cell differentiation → ↓ IgM, IgG, and IgA production	✓	(✓)	Renal transplant rejection prophylaxis As a synergistic immunosuppressant with cyclosporine Also used in drug-eluting stents.
	Everolimus						Rejection prophylaxis in liver and renal transplant (in combination with other immunosuppressants)
Purine analog	Azathioprine (mercaptopurine)			Purine analog (antimetabolite precursor of 6-mercaptopurine ) → blocks nucleotide synthesis → inhibits proliferation of lymphocytes Cytostatic effect at a high dosage via inhibition of cell proliferation Immunosuppressive effect at a low dosage with significant inhibition of lymphocyte proliferation	✓	(✓)	Prophylaxis against renal transplant rejection Autoimmune disease treatment (e.g., rheumatoid arthritis, Crohn disease, glomerulonephritis) To wean patients off long-term steroid therapy Steroid-refractory disease
Protein drugs	Antibodies			Specific binding to relevant structure in the immune cascade (detailed explanation below)	✓	✓	See biological agents for immunotherapy below.
	Other biological proteins
IMDH/IMPDH inhibitors	Mycophenolate mofetil			Inhibition of inosine monophosphate dehydrogenase → selective inhibition of lymphocyte proliferation	✓	✓	Lupus nephritis Used in combination with cyclosporin or tacrolimus as transplant rejection prophylaxis
Other cytostatic and antiproliferative agents	Methotrexate			Folic acid antagonist (antimetabolite) : inhibition of dihydrofolate reductase (DHFR) → ↓ pyrimidine and purine nucleotide synthesis → ↓ DNA synthesis	✓	✓	Treatment of severe psoriasis and rheumatoid arthritis In neoplastic diseases like gestational choriocarcinoma, chorioadenoma, and hydatidiform mole
	Cyclophosphamide			Alkylating agent: alkylation of DNA/RNA → cross-linking and strand breaks → impaired DNA synthesis	(✓)	✓	Autoimmune disease therapy (e.g., SLE, autoimmune hemolytic anemias)
✓ = Definite suppression (✓) = Probable suppression (inconclusive research currently) – = No suppression

References:^{[1][2][3][4][5][6]}

• Biological agents are recombinant proteins that intervene in immunological processes.
• Used in autoimmune diseases and malignancies
• Although complex and costly, they can significantly improve the success of treatment in some cases.

Antibody	Type	Target	Indication
Infliximab	Chimeric	TNF-α inhibition	Refractory-therapy for chronic inflammatory systemic diseases Rheumatoid arthritis Crohn disease, ulcerative colitis Ankylosing spondylitis Psoriatic arthritis
Adalimumab	Humanized
Etanercept	Fusion protein
Golimumab	Humanized
Certolizumab	Humanized
Rituximab	Chimeric	CD20	Rheumatoid arthritis ITP CLL, B-cell non-Hodgkin lymphoma (NHL) Symptomatic Waldenstrom macroglobulinemia
Cetuximab	Chimeric	Epidermal growth factor receptor (EGFR inhibitor)	Colorectal cancer Head and neck cancer
Alemtuzumab	Humanized	CD52	Chronic lymphoid leukemia (CLL) Escalation therapy of multiple sclerosis (see subsection “Disease-modifying therapy”, under Treatment section of multiple sclerosis)
Natalizumab	Humanized	Alpha-4 integrin	Escalation therapy of multiple sclerosis (see subsection “Disease-modifying therapy”, under Treatment section of multiple sclerosis) Crohn disease
Omalizumab	Humanized	IgE	Severe allergic asthma (stage V)
Abciximab	Chimeric	Antagonist of GP IIb/IIIa receptors	Antiplatelet agent, especially in patients undergoing percutaneous coronary intervention
Muromonab-CD3	Mouse antibody	CD3 from T cells	Steroid-resistant acute rejection post-transplantation
Basiliximab	Chimeric	Alpha chain (CD25 antigen) of the IL-2 receptor of T cells	Escalation therapy of multiple sclerosis Formerly used for the prevention of kidney rejection post-transplantation (in combination with cyclosporine and glucocorticoids)
Daclizumab	Humanized
Trastuzumab	Humanized	HER2/neu	HER2/neu-positive breast cancer Stomach cancer with overexpression of HER2/neu
Bevacizumab	Humanized	VEGF	Neovascular age-related macular degeneration (off-label use in the US) Colorectal cancer, renal cell carcinoma
Eculizumab	Humanized	Complement protein C5	Paroxysmal nocturnal hemoglobinuria
Ustekinumab	Human	IL-12, IL-23	Psoriasis, psoriatic arthritis, Crohn disease
Tocilizumab	Humanized	IL-6 receptor	Giant cell arteritis, juvenile idiopathic arthritis, rheumatoid arthritis.

Calcineurin inhibitors

Cyclosporine A

• Nephrotoxic
• Neurotoxic
• Gingival hyperplasia
• Tremors
• Hypertension
• Hypertrichosis and hirsutism
• Hyperkalemia
• Nausea and diarrhea
• Diabetogenic effect (particularly after organ transplantation). This can lead to:
  • Hyperuricemia
  • Hyperlipidemia
  • Elevated liver enzymes
• Increase in malignancies and infectious diseases

Tacrolimus

• Nephrotoxic; : monitor for oliguria
• Neurotoxic
• Nausea and diarrhea
• Hypertension
• Hair loss
• Headache
• Insomnia
• Hyperglycemia
• Abdominal discomfort
• Hyperkalemia
• Hypophosphatemia
• Hypomagnesemia

Many side effects of tacrolimus are similar to cyclosporine A, but tacrolimus does not cause gingival hyperplasia or hypertrichosis!

Tacrolimus and cyclosporine A should not be combined because together they could have nephro- and neurotoxic effects!

Purine analog (Azathioprine/Mercaptopurine)

• Pancytopenia (leukopenia, macrocytic anemia, thrombocytopenia)
  • Increased by interaction with allopurinol
• Acute pancreatitis
• Hepatotoxicity
• Malignancies: e.g., cervical cancer, lymphoma, squamous cell carcinoma, melanoma (rare)
• Nausea, vomiting, and dose-related diarrhea

Allopurinol causes toxic accumulation of azathioprine! In cases in which concomitant treatment is unavoidable, a dose reduction of azathioprine is necessary!

mTOR inhibitors (Sirolimus, Everolimus)

• Infection (e.g., respiratory or urinary tract)
• Peripheral edema
• Hypertension
• Insulin resistance
• Pancytopenia
• Stomatitis
• Hyperlipidemia

Mycophenolate mofetil

• Pancytopenia
• Infection (e.g., respiratory or urinary tract)
• Vomiting and diarrhea
• Peripheral edema
• Hyperglycemia
• ↑ Blood urea nitrogen
• Hypercholesterolemia
• Hypertension
• Back pain
• Cough

Methotrexate

• Pancytopenia and/or macrocytic anemia
• Mucositis (particularly stomatitis, enteritis), susceptibility to infection
• Hepatotoxicity
• Nephrotoxicity
• Nausea and vomiting
• Diarrhea
• Pulmonary fibrosis and toxicity
• Hair loss

Salvage therapy (leucovorin rescue therapy)

• The side effects of methotrexate can be reduced by administering salvage therapy.
• Salvage therapy involves the administration of folic acid and folinic acid (active folic acid = leucovorin = calcium folinate).
• Indications
  • Methotrexate (MTX) intoxication (inadvertent overdosage or impaired elimination): administered every 6 hours until methotrexate level < 10 mol
  • Prophylactic therapy: within 24–48 h of starting high dose MTX

Biologics (e.g., daclizumab)

• General side effects
  • Rash, dermatitis
  • Flu-like symptoms
  • Lymphadenopathy
  • Infections (e.g., nasopharyngitis)
  • Gastrointestinal symptoms (e.g., diarrhea)
  • Leukocytosis or leukopenia, thrombocytopenia, anemia
  • ↑ ALT, AST
  • Depression
  • Formation of anti-drug antibodies (especially for adalimumab and infliximab); : can manifest with a decrease in clinical response (e.g., recurrence of symptoms); , low drug levels, and/or allergic reactions.
• Rituximab and Natalizumab:
  • Reactivation of a latent JC virus infection resulting in PML.
• Bevacizumab:
  • Gastrointestinal perforation
  • Hemorrhages (e.g., GI bleeding)
  • Wound healing complications
• Contraindications to anti-TNF-α treatment (infliximab, adalimumab, etanercept)
  • Pregnancy
  • Immunosuppressed individuals
  • Systemic or localized infections
  • Chronic infections (particularly tuberculosis; rule out latent tuberculosis before starting therapy )
  • Multiple sclerosis
  • Malignancy
  • Moderate to severe heart failure (NYHA class III/IV)

Both calcineurin inhibitors (cyclosporine and tacrolimus) are highly nephrotoxic.

Perform testing for latent tuberculosis before initiating anti-TNF-α treatment!

References:^{[5][7][8][6][9][10][11][12][13][14][15][16][17][18][19]}

We list the most important adverse effects. The selection is not exhaustive.