10/16/2020 Immunosuppressants - AMBOSS

Immunosuppressants
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Summary

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.

Overview

Immunosuppressant Common drugs Suppression

class of cell- Suppression
mediated of humoral
immune immune
Mechanism of action response response Main clinical uses

Glucocorticoids Prednisolone, Inhibition of ✓ ✓ Transplant rejection

hydrocortisone, intracellular NF-κB prophylaxis
dexamethasone → Multiple To suppress various
inflammatory and allergic, inflammatory,
immune mediators and autoimmune
are inhibited. reactions
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

Calcineurin Cyclosporine A Immunosuppression: ✓ – Transplant rejection

inhibitors binds cyclophilin → prophylaxis (in
(calcineurin = inhibition of combination with
calcium- and calcineurin → other
calmodulin- inhibition of NFAT immunosuppressants)
dependent serine- activation→ ↓ IL-2 Psoriasis
threonine transcription → ↓ Rheumatoid arthritis
phosphatase) activation of T cells
Cytostatic action:
binding to multidrug
resistance
glycoprotein P-170

Tacrolimus (also Binding to FK506 ✓ – Transplant rejection

FK-506 or binding protein prophylaxis
fujimycin) (FKBP) → inhibition
of calcineurin →
inhibition of NFAT
activation → ↓ IL-2
transcription → ↓
activation of T cells

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Immunosuppressant Common drugs Suppression

class of cell- Suppression
mediated of humoral
immune immune
Mechanism of action response response Main clinical uses

Pimecrolimus Atopic dermatitis

(topical use)

mTOR inhibitors Sirolimus (also Binds to FKBP → ✓ (✓) Renal transplant

known as inhibition of mTOR rejection prophylaxis
rapamycin) kinase→ inhibition of As a synergistic
the IL-2-mediated immunosuppressant
cell cycle → with cyclosporine
prevents response Also used in drug-
to IL-2 → blocks T- eluting stents.
cell activation and B-
cell differentiation →
Everolimus ↓ IgM, IgG, and IgA Rejection prophylaxis
production in liver and renal
transplant (in
combination with
other
immunosuppressants)

Purine analog Azathioprine Purine analog ✓ (✓) Prophylaxis against

(mercaptopurine) (antimetabolite renal transplant
precursor of 6- rejection
mercaptopurine Autoimmune disease
treatment (e.g.,
) → blocks rheumatoid arthritis,
nucleotide synthesis Crohn disease,
→ inhibits glomerulonephritis)
proliferation of To wean patients off
lymphocytes long-term steroid
Cytostatic effect at a therapy
high dosage via Steroid-refractory
inhibition of cell disease
proliferation
Immunosuppressive
effect at a low
dosage with
significant inhibition
of lymphocyte
proliferation

Protein drugs Antibodies Specific binding to ✓ ✓ See biological agents

relevant structure in for immunotherapy
the immune cascade below.
Other biological (detailed explanation
proteins below)

IMDH/IMPDH Mycophenolate Inhibition of inosine ✓ ✓ Lupus nephritis

inhibitors mofetil monophosphate Used in combination
dehydrogenase → with cyclosporin or
selective inhibition of tacrolimus as
lymphocyte transplant rejection
proliferation prophylaxis

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Immunosuppressant Common drugs Suppression

class of cell- Suppression
mediated of humoral
immune immune
Mechanism of action response response Main clinical uses

Other cytostatic and Methotrexate Folic acid antagonist ✓ ✓ Treatment of severe

antiproliferative (antimetabolite) psoriasis and
agents rheumatoid arthritis
: inhibition of In neoplastic diseases
dihydrofolate like gestational
reductase (DHFR) choriocarcinoma,
→ ↓ pyrimidine and chorioadenoma, and
purine nucleotide hydatidiform mole
synthesis → ↓ DNA
synthesis

Cyclophosphamide Alkylating agent: (✓) ✓ Autoimmune disease

alkylation of therapy (e.g., SLE,
DNA/RNA → cross- autoimmune
linking and strand hemolytic anemias)
breaks → impaired
DNA synthesis

✓ = Definite suppression

(✓) = Probable suppression (inconclusive research currently)

– = No suppression

References:[1][2][3][4][5][6]

Biological agents used in immunotherapy

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
Adalimumab Humanized Crohn disease, ulcerative colitis
Ankylosing spondylitis
Psoriatic arthritis
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 Colorectal cancer

receptor (EGFR inhibitor) Head and neck cancer

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Antibody
Type Target Indication

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 Antiplatelet agent, especially in patients undergoing

receptors percutaneous coronary intervention

Muromonab- Mouse CD3 from T cells Steroid-resistant acute rejection post-transplantation

CD3 antibody

Basiliximab Chimeric Alpha chain (CD25 Escalation therapy of multiple sclerosis

antigen) of the IL-2 Formerly used for the prevention of kidney rejection post-
receptor of T cells transplantation (in combination with cyclosporine and
Daclizumab Humanized glucocorticoids)

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.

Adverse effects

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

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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

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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.

Tips and Links

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Damiani D et al., Adjuvant treatment with cyclosporin A increases the toxicity of chemotherapy for remission induction in
acute non-lymphocytic leukemia, Leukemia 1998 Aug;12(8):1236-40

References

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