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.

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.

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][6][7][8][9][10][11][12][13][14][15][16][17][18][19]}

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