Immunosuppressive drugs

IMMUNOSUPPRESSIVE DRUGS
Pairach Supsongserm
Allergy and Clinical Immunology Fellow
King Chulalongkorn Memorial Hospital
12 June 2020

OUTLINE
• Introduction
• Role of immunosuppressive drugs
• Classification
• Immunosuppressive drugs
> Glucocorticoid
> Cytostatics
> Antibodies
> Drugs acting on immunophilins
> Other drugs
• Drug monitoring
• Drug summary

INTRODUCTION
• Immunosuppression involves an act that reduces the activation or efficacy
of the immune system
• Immunosuppressants are used to control severe manifestations of allergic,
autoimmune and transplant-related diseases
• Immunosuppression is typically done using drugs, but may involve surgery
(splenectomy), plasmapharesis, or radiation
• Clinically they are used to
> Prevent the rejection of transplanted organs and tissues
> Treatment of autoimmune diseases or diseases that are most likely of
autoimmune origin
> Treatment of some other non-autoimmune inflammatory diseases
RATHEE P, ET AL. IMMUNOSUPPRESSANTS: A REVIEW. THE PHARMA INNOVATION – JOURNAL 2012;1(12):90-101.

ROLE OF IMMUNOSUPPRESSIVE DRUGS:
AUTOIMMUNE DISEASES
• Arteritis
• Autoimmune diseases
• Behcet's disease
• Chronic inflammatory demyelinating
polyneuropathy
• Collagenous colitis
• Crohn's disease
• Dermatomyositis
• Eczema
• Endocarditis
• Glomerulonephritis
• Goodpasture syndrome
• Lupus
• Myasthenia gravis
• Pemphigus
• Polyarteritis nodosa
• Reiter’s syndrome
• Rheumatoid arthritis
• Schilder's disease
• Scleritis
• Sjogren's syndrome
• Sympathetic ophthalmitis
• Temporal arteritis
• Thrombocytopenia

AUTOIMMUNE DISEASES
KOVARIK J. FROM IMMUNOSUPPRESSION TO IMMUNOMODULATION: CURRENT PRINCIPLES AND FUTURE STRATEGIES. PATHOBIOLOGY 2013;80:275–281.

ORGAN TRANSPLANTATION
ABBAS AK, ET AL. TRANSPLANTATION IMMUNOLOGY. CELLULAR AND MOLECULAR IMMUNOLOGY (9TH ED) 2018.

• Patterns of allograft rejection
> Hyperacute rejection
> Acute rejection
> Chronic rejection and graft vasculopathy

• Hyperacute rejection is
characterized by thrombotic
occlusion of the graft vasculature
• Begins within minutes to hours after
host blood vessels are anastomosed
to graft vessels
• Mediated by preexisting antibodies
in the host circulation that bind to
donor endothelial antigens

• Acute rejection is a process of injury to the graft parenchyma and blood
vessels
> Acute cellular injection
> Acute antibody mediated rejection
• Mediated by alloreactive T cells and antibodies
• Before modern immunosuppression, acute rejection would often begin
several days to a few weeks after transplantation
• In current clinical practice, it may occur at much later times, even years
after transplantation

• A dominant lesion of chronic
rejection in vascularized grafts is
arterial occlusion as a result of the
proliferation of intimal smooth muscle
cells
• The grafts eventually fail mainly
because of the resulting ischemic
damage

HALLORAN PF. IMMUNOSUPPRESSIVE DRUGS FOR KIDNEY TRANSPLANTATION. N ENGL J MED 2004;351:2715-29.

CLASSIFICATION
• Glucocorticoid
• Drugs acting on immunophilins
> Calcineurin inhibitors: cyclosporine,
tacrolimus
> Target-of-rapamycin inhibitors: sirolimus
• Cytostatics
> Alkylating agents: cyclophosphamide
> Inhibitors of nucleotide synthesis:
mycophenolate mofetil, leflunomide
> Antimetabolites: azathioprine,
methotrexate
• Antibodies
> Polyclonal antibodies
> T-cell receptor directed antibodies:
muromonab
> B-cell receptor directed antibodies:
rituximab
> IL-2 receptor directed antibodies:
basiliximab, daclizumab
• Other drugs
> Interferons: IFN-ß
> TNF binding proteins: infliximab,
adalimumab, etanercept

CLASSIFICATION
VAN LAAR JM. IMMUNOSUPPRESSIVE DRUGS. KELLEY AND FIRESTEIN'S TEXTBOOK OF RHEUMATOLOGY (10TH ED) 2017.

GLUCOCORTICOID
• Corticosteroids are the mainstay of most immunosuppressive regimens in
both the induction and maintenance phases
• In high intravenous pulse doses, they are directly lymphocytotoxic
• In smaller doses, they are immunosuppressive and anti-inflammatory by
limiting cytokine production
• The required dose and duration of treatment therefore tends to be disease
specific

GLUCOCORTICOID
BUTTGEREIT F, ET AL. GLUCOCORTICOIDS IN THE TREATMENT OF RHEUMATIC DISEASES. ARTHRITIS & RHEUMATISM 2004.
STAHN C, ET AL. GENOMIC AND NONGENOMIC EFFECTS OF GLUCOCORTICOIDS. NATURE CLINICAL PRACTICE RHEUMATOLOGY 2008.

GLUCOCORTICOID
BUTTGEREIT F, ET AL. GLUCOCORTICOIDS IN THE TREATMENT OF RHEUMATIC DISEASES. ARTHRITIS & RHEUMATISM 2004.

GLUCOCORTICOID
STAHN C, ET AL. GENOMIC AND NONGENOMIC EFFECTS OF GLUCOCORTICOIDS. NATURE CLINICAL PRACTICE RHEUMATOLOGY 2008.

DRUGS ACTING ON IMMUNOPHILINS:
CALCINEURIN INHIBITORS >
CYCLOSPORINE
• Brand names: Neoral, Sandimmune, Gengraf
• A lipophilic endecapeptide derived from a fungus (Tolypocladium inflatum)
• Two formulations of cyclosporine are available for oral use
> Oil-based Sandimmune formulation (No longer available)
> Microemulsion Neoral formulation (Better bioavailability and less
variability)
• It is effective in refractory RA, psoriatic arthritis, SLE, autoimmune eye disease
included prophylaxis and treatment of graft rejection following solid organ
transplantation

CYCLOSPORINE

CYCLOSPORINE
• The starting dosage of cyclosporine is
2.5 mg/kg/day, usually administered in
divided doses
• To improve efficacy, the dosage can be
increased by 0.5 mg/kg/day at 4- to 8-
week intervals to a maximal dosage of 4
mg/kg/day of the microemulsion
formulation
• In patients whose disease is well
controlled, the dosage of cyclosporine
can be decreased by 0.5 mg/kg/day at
4- to 8-week intervals to determine the
minimal effective dose for the individual
patient

CYCLOSPORINE
CLINICAL GUIDELINES FOR TRANSPLANT MEDICATIONS 2019.

CALCINEURIN INHIBITORS >
TACROLIMUS
• Brand names: : Prograf, Envarsus XR, Astagraf XL, Hecoria
• Previously known as FK506
• A macrolide derived from an actinomycete and is widely used in organ
transplantation (Heart, liver, kidney) as an alternative to cyclosporine
• Second-line therapy for the short-term and non-continuous chronic
treatment of moderate to severe atopic dermatitis
• Studies in rheumatic autoimmune disease are less advanced

TACROLIMUS

TACROLIMUS
• Adverse effects experienced by patients receiving tacrolimus are similar to
those experienced by patients receiving cyclosporine
• The principal adverse effects of tacrolimus are tremor, headache, nausea,
diarrhea, hypertension, and renal impairment
• Anaphylactic reactions have been reported in animals and humans
following intravenous administration, most likely due to the polyoxyl-60-
hydrogenated castor oil vehicle

TARGET-OF-RAPAMYCIN INHIBITORS >
SIROLIMUS
• Brand name: Rapamune
• Sirolimus (Rapamycin) is a macrolide lactone
• Produced by the actinomycetes (Streptomyces hygroscopicus)
• It is used to prevent rejection reactions
• Although it is a structural analogue of tacrolimus, it acts somewhat differently

SIROLIMUS
IMMUNOSUPPRESSIVE DRUGS. MEDBULLETS STEP 1 2019.

SIROLIMUS
• Side effects
> Nephrotoxicity
> Neurotoxicity
> Hirsutism
> Gingival hyperplasia
> Hypertension
> Hyperlipidemia
IMMUNOSUPPRESSIVE DRUGS. MEDBULLETS STEP 1 2019.

DRUG INTERACTION WITH
CALCINEURIN INHIBITORS AND
TARGET-OF-RAPAMYCIN INHIBITORS
WHAT’S NEW IN KIDNEY TRANSPLANTATION. CONSULT QD 2018.

CYTOSTATICS:
ALKYLATING AGENTS >
CYCLOPHOSPHAMIDE
• Brand names: Cytoxan, Neosar, Cytoxan Lyophilized
• Cyclophosphamide was introduced as a cytotoxic agent in 1958
• In combination with glucocorticoids, cyclophosphamide is particular
effective as a remission induction agent in severe SLE and necrotizing
vasculitis

CYCLOPHOSPHAMIDE

CYCLOPHOSPHAMIDE
• Indications
> Autoimmune diseases
>> Organ-threatening SLE
>> Systemic necrotizing vasculitis
>> Goodpasture’s syndrome
>> Autoimmune disease–associated interstitial lung disease
>> Inflammatory eye disease
> Malignancy
>> Lymphoma
>> Multiple myeloma
>> Leukemias
>> Breast carcinoma
>> Adenocarcinoma of ovary

CYCLOPHOSPHAMIDE
• Dosages for IV pulse therapy with
cyclophosphamide range from 0.5
to 1 g/m2
• The dosage for oral therapy is 2
mg/kg

CYCLOPHOSPHAMIDE
• Side effects
> Nausea and vomiting
> Alopecia
> Myelosuppression
> Mucositis
> Enteritis
> Hemorrhagic cystitis
> Pericardial effusion and tamponade (Rare)

CYTOSTATICS:
INHIBITORS OF NUCLEOTIDE SYNTHESIS >
MYCOPHENOLATE MOFETIL
• Brand name: Cellcept
• Mycophenolate mofetil (MMF), a
prodrug, is the inactive 2-
morpholinoester of mycophenolic
acid, which is hydrolyzed to the
active mycophenolic acid (MPA),
an antibiotic with
immunosuppressive effects
• Purine synthesis inhibitors

ALLISON AC, ET AL. MYCOPHENOLATE MOFETIL AND ITS MECHANISMS OF ACTION. IMMUNOPHARMACOLOGY 2000.

• MMF is used as a safer alternative to cytostatic agents in the treatment of several
rheumatic diseases
> SLE
> Systemic sclerosis
> Vasculitis
> Inflammatory muscle disease
• Effective daily dosages of MMF range from 0.5 to 1.5 g twice a day
• Side effects
> MMF is generally well tolerated
> The most common adverse effects are gastrointestinal, such as diarrhea, nausea,
abdominal pain, and vomiting
> Occasional infections, leukopenia, lymphocytopenia, and elevated liver enzymes

CYTOSTATICS:
INHIBITORS OF NUCLEOTIDE SYNTHESIS >
LEFLUNOMIDE
• Brand name: Arava
• Leflunomide is an immunosuppressive disease-modifying antirheumatic drug
(DMARD)
• Used in active moderate-to-severe rheumatoid arthritis and psoriatic arthritis
• It is a pyrimidine synthesis inhibitor that works by inhibiting dihydroorotate
dehydrogenase

LEFLUNOMIDE

LEFLUNOMIDE
LEFLUNOMIDE. ARTHRITIS AUSTRALIA 2017.

CYTOSTATICS:
ANTIMETABOLITES >
AZATHIOPRINE
• Brand names: Imuran, Azasan
• Azathioprine is a prodrug that is converted to 6-mercaptopurine (6-MP)
• 6-MP is a purine analogue that acts as a cycle-specific antimetabolite
chemotherapeutic agent and interferes with the synthesis of nucleotides,
thereby inhibiting proliferation of lymphocytes

AZATHIOPRINE

AZATHIOPRINE
• Azathioprine is often started at a
dose of 1 mg/kg daily, and if this
dose is tolerated, it is increased to 2
to 2.5 mg/kg after 2 to 4 weeks
• A gradual increase in dose is often
better tolerated
• The onset of immunosuppressive
effects is relatively slow, over several
weeks

AZATHIOPRINE

AZATHIOPRINE
• Drug interaction
> Xanthine oxidase inhibitors (Allopurinol and febuxostat)
>> Azathioprine is metabolized by xanthine oxidase
>> Xanthine oxidase inhibitors may inhibit azathioprine metabolism, thus
resulting in increased azathioprine activity and toxicity
> Angiotensin-converting enzyme inhibitors (Captopril, enalapril)
>> ACEIs may induce anemia and severe leukopenia
> Warfarin
>> Azathioprine may inhibit the anticoagulant effect of warfarin

CYTOSTATICS:
ANTIMETABOLITES >
METHOTREXATE
• Brand names: Trexall, Rasuvo, Otrexup, Methotrexate LPF Sodium
• Methotrexate (Analog of folic acid) is commonly used in the treatment of a wide
range of malignant and non-malignant diseases
• Indications
> Rheumatoid arthritis
> Juvenile idiopathic arthritis
> Psoriasis
> Inflammatory bowel diseases
> Multiple sclerosis
> Vasculitis
> Systemic lupus erythematosus
> Transplantation
BEDOUI Y, ET AL. METHOTREXATE AN OLD DRUG WITH NEW TRICKS. INT. J. MOL. SCI. 2019.

METHOTREXATE
BEDOUI Y, ET AL. METHOTREXATE AN OLD DRUG WITH NEW TRICKS. INT. J. MOL. SCI. 2019.

ANTIBODIES:
POLYCLONAL ANTIBODIES
• Polyclonal antibodies inhibit T lymphocytes and cause their lysis, which is both
complement mediated cytolysis and cell-mediated opsonization followed by
removal of reticuloendothelial cells from the circulation in the spleen and liver
• Polyclonal antibodies inhibit cell-mediated immune reactions
> Graft rejection
> Delayed hypersensitivity: tuberculin skin reaction
> Graft-versus-host disease (GVHD)
• Side effects
> Infections: CMV
> Serum sickness
> Post-transplant lymphoproliferative disorders (PTLD)

ANTIBODIES:
T-CELL RECEPTOR DIRECTED ANTIBODIES >
MUROMONAB
• Brand name: Orthoclone OKT3
• OKT3 (R) is presently the only approved anti-CD3 antibody
• It is a mouse anti-CD3 monoclonal antibody of the IgG2a type
• It prevents T-cell activation and proliferation by binding the T-cell receptor
complex present on all differentiated T cells
• Clinically used to control the steroid and/or polyclonal antibodies resistant
acute rejection episodes
• Side effects
> Excessive immunosuppression
> Neutralizing antibodies against the drug

ANTIBODIES:
B-CELL RECEPTOR DIRECTED ANTIBODIES >
RITUXIMAB
PIERPONT TM, ET AL. PAST, PRESENT, AND FUTURE OF RITUXIMAB—THE WORLD’S FIRST ONCOLOGY MONOCLONAL ANTIBODY THERAPY. FRONTIERS IN ONCOLOGY 2018.
• Brand names: Rituxan, Truxima,
Ruxience, Mebthera
• Rituximab is a chimeric mouse/human
monoclonal antibody (mAb) therapy
with binding specificity to CD20
• Indications
> Rheumatoid Arthritis
> Granulomatosis with polyangiitis
(Wegener’s granulomatosis)
> Microscopic polyangiitis
> Non–Hodgkin’s lymphoma
> Chronic lymphocytic leukemia

RITUXIMAB

RITUXIMAB
• Side effects
> Nausea
> Hives
> Headache
> Itching
> A sensation of swelling of the tongue or throat
> Irregular heart rhythms
> Severe decreases in red or white blood cells and platelets
> Infections: hepatitis B or C, shingles

ANTIBODIES:
IL-2 RECEPTOR DIRECTED ANTIBODIES >
BASILIXIMAB, DACLIZUMAB
• Brand names: Simulect (Basiliximab),
Zenapax (Daclizumab)
• The IL-2a (CD25, T-cell activation antigen,
TAC) is expressed only by the already
activated T lymphocytes
• Basiliximab and daclizumab are
mouse/human anti-Tac antibodies
• These drugs act by binding the IL-2a
receptor's α chain, preventing the IL-2
induced clonal expansion of activated
lymphocytes and shortening their survival
• They are used in the prophylaxis of the
acute organ rejection after the bilateral
kidney transplantation
Basiliximab
Daclizumab

OTHER DRUGS:
INTERFERONS >
IFN-ß
• Brand names: Avonex, Rebif, Avonex Prefilled Syringe, Avonex Pen
• IFN-β suppresses the production of Th1 cytokines and the activation of
monocytes
• It is used to slow down the progression of multiple sclerosis

OTHER DRUGS:
TNF BINDING PROTEINS >
INFLIXIMAB, ADALIMUMAB,
ETANERCEPT
• Brand names: Remicade (Infliximab), Humira (Adalimumab), Enbrel
(Etanercept)
• A TNF-α binding protein is a monoclonal antibody (Infliximab, adalimumab)
or a circulating receptor (Etanercept) that binds to TNF-α and prevent it from
inducing the synthesis of IL-1 and IL-6 and the adhesion of lymphocyte
activating molecules
• They are used in the treatment of rheumatoid arthritis, ankylosing spondylitis,
Crohn's disease and psoriasis

INFLIXIMAB, ADALIMUMAB, ETANERCEPT

INFLIXIMAB, ADALIMUMAB, ETANERCEPT
STEELAND S, ET AL. A NEW VENUE OF TNF TARGETING. INT. J. MOL. SCI. 2018.

DRUG MONITORING
HSU DC, ET AL. LONG-TERM MANAGEMENT OF PATIENTS TAKING IMMUNOSUPPRESSIVE DRUGS. AUSTRALIAN PRESCRIBER 2009.

DRUG SUMMARY
TOMKINS- NETZER O, ET AL. CORTICOSTEROID- SPARING AGENTS: NEW TREATMENT OPTIONS. DEV OPHTHALMOL 2012.

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