Immunosuppressants

Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. There are multiple targets in the immune system, as well as varied mechanisms in inhibiting inappropriate immune activity. Biologic agents are medications derived from living organisms that target particular components of the immune system. The targets can be tumor necrosis factor Tumor necrosis factor Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) ( TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF)), interleukins Interleukins Interleukins are a type of cytokines (signaling proteins) that communicate messages between different parts of the immune system. The majority of interleukins are synthesized by helper CD4 T lymphocytes along with other cells such as monocytes, macrophages, and endothelial cells. Interleukins (ILs), or B- or T-cell activity. Calcineurin inhibitors halt the activity of calcineurin, a phosphatase involved in T-cell activation. Corticosteroids interfere with the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle of inflammatory cells and modify the activity of other immune components. mTOR inhibitors are proliferation signal inhibitors, reducing immune-cell proliferation. Some immunosuppressants, such as cytotoxic agents, have antineoplastic activity; these are used in rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Rheumatoid Arthritis, as prophylaxis for transplant rejection, and for malignant diseases.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Immunosuppressants are a class of drugs that decrease the activity of the immune system in conditions such as autoimmune diseases, organ transplantation Organ Transplantation Transplantation is a procedure that involves the removal of an organ or living tissue and placing it into a different part of the body or into a different person. Organ transplantations have become the therapeutic option of choice for many individuals with end-stage organ failure. Organ Transplantation, and malignancies.

Immune system

  • The immune system provides defense (immunity) against invading pathogens, discriminating self from nonself to protect the host.
  • 2 lines of defense (that overlap):
    • Innate immunity (which is nonspecific), including:
      • Phagocytes
      • Cytokines (e.g., interleukins Interleukins Interleukins are a type of cytokines (signaling proteins) that communicate messages between different parts of the immune system. The majority of interleukins are synthesized by helper CD4 T lymphocytes along with other cells such as monocytes, macrophages, and endothelial cells. Interleukins)
    • Adaptive immunity (based on specific antigen recognition), including:
      • T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells (helper, cytolytic, and regulatory (suppressor) cells)
      • B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells (which make antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins)
  • These components are targets for the different agents of immunosuppression.

Classification

Immunosuppressants can be classified into various categories of drugs with different targets in the immune system and varying mechanisms of action:

  • Biologic agents
  • Calcineurin inhibitors
  • Corticosteroids
  • mTOR inhibitors
  • Cytotoxic agents and other immunomodulating agents

Biologic Agents

Definition

Biologic agents are derived from living organisms (e.g., humans, animals, or microorganisms) and engineered to suppress specific components or pathways of the immune system.

Nomenclature

Names of drugs are based on their structure:

  • “-cept”:  fused receptor and the Fc part of human IgG1
  • “-mab”: a monoclonal antibody (mAb)
  • “-ximab”:  a chimeric mAb
  • “-zumab”: a humanized mAb
  • “-umab”: a fully human mAb

Drugs

  • B-cell inhibitors:
    • Belimumab
    • Ocrelizumab 
    • Rituximab 
  • Interleukin inhibitors:
    • IL-1 inhibition:
      • Anakinra
      • Canakinumab
      • Rilonacept
    • IL-6 inhibition:
      • Sarilumab 
      • Tocilizumab
    • IL-17 inhibition:
      • Ixekizumab 
      • Secukinumab 
    • IL-12/23 blockade: 
      • Guselkumab 
      • Ustekinumab
  • Tumor necrosis factor ( TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF)) inhibitors:
    • Adalimumab
    • Certolizumab
    • Etanercept
    • Golimumab
    • Infliximab 
  • T-cell inhibition:
    • Abatacept

B-cell inhibitors

  • Inhibition of B-cell activity reduces inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and decreases immune response by:
    • ↓ Antibody production
    • ↓ Antigen presentation by B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells to T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells 
    • ↓ T-cell activation by B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells
    • ↓ Production of proinflammatory cytokines
  • These drugs are available in IV form, with belimumab also administered SC.
Table: Biologic agents against B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells
Belimumab Ocrelizumab Rituximab
Mechanism of action mAb prevents binding of B-lymphocyte stimulator protein to B-lymphocyte receptor → ↓ survival of B lymphocytes B lymphocytes B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells mAb binds to the cell-surface antigen CD20 of B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells, facilitating cell killing through:
  • Antibody-dependent cell-mediated phagocytosis and cytotoxicity
  • Complement-mediated cytolysis
Indications
  • Lupus nephritis
  • SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus
Multiple sclerosis Multiple Sclerosis Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease that leads to demyelination of the nerves in the CNS. Young women are more predominantly affected by this most common demyelinating condition. Multiple Sclerosis
  • CLL CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia
  • Granulomatosis with polyangiitis Granulomatosis with Polyangiitis Granulomatosis with polyangiitis (GPA) is a rare autoimmune disease of unknown etiology. It leads to a necrotizing granulomatous inflammation of small and medium-sized blood vessels of the nose, sinuses, throat, lungs, and kidneys. Granulomatosis with Polyangiitis
  • Microscopic polyangiitis
  • NHL
  • Pemphigus vulgaris Pemphigus vulgaris Bullous pemphigoid and pemphigus vulgaris are two different blistering autoimmune diseases. In pemphigus vulgaris, autoantibodies attack the desmosomal proteins, which connect the keratinocytes to one another. This attack results in a more severe, potentially fatal condition with fragile, flaccid blisters, usually with significant mucosal involvement. Bullous Pemphigoid and Pemphigus Vulgaris
  • RA
Adverse effects
  • Anaphylactic reaction
  • Cardiovascular effects (e.g., MI MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction, VF)
  • Cytopenias
  • Infections (e.g., hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus reactivation)
  • Nephrotoxicity
  • Secondary malignancy
  • PML associated with JC virus JC Virus JC virus (JCV) is a small, nonenveloped, single-stranded DNA virus belonging to the Polyomaviridae family, which are ubiquitous in the human population. While the primary infection is usually asymptomatic, the infection leads to lifelong latency in the kidneys and lymphoid organs. JC Virus and BK Virus
  • Tumor lysis syndrome Tumor lysis syndrome Tumor lysis syndrome is a potentially lethal group of metabolic disturbances that occurs when large numbers of cancer cells are killed rapidly. The lysed cells release their intracellular contents into the bloodstream, resulting in the development of hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, and acute kidney injury. Tumor Lysis Syndrome
Contraindications
  • Hypersensitivity to drugs or their components
  • Individuals with a previous history or current history of PML
  • Severely immunocompromised state
  • Individuals with severe and active infections (e.g., hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus infection)
Drug interactions
  • Vaccines: ↓ therapeutic effects of inactivated vaccines and ↑ adverse effects of live vaccines
  • Use with other immunosuppressants: ↑ immunosuppression
NHL: non- Hodgkin lymphoma Hodgkin lymphoma Hodgkin lymphoma (HL) is a malignancy of B lymphocytes originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, fever, splenomegaly and hepatomegaly. Hodgkin Lymphoma
PML: progressive multifocal leukoencephalopathy
RA: rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Rheumatoid Arthritis
SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus: systemic lupus erythematosus Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus

Interleukin inhibitors

  • Interleukin inhibitors target cytokines that transmit chemical signals between leukocytes to prepare them to attack against infections.
  • Suppression of the action of cytokines causes immune system suppression and reduces inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation.
  • Administered IV and SC
Table: Biologic agents targeting IL-1 and IL-6
IL-1 inhibitors IL-6 inhibitors
Mechanism of action
  • Anakinra: IL1 receptor antagonist
  • Canakinumab: IgG1 mAb against IL-1beta
  • Rilonacept: IL-1 fused to a human IgG1 Fc domain
Sarilumab and tocilizumab:
  • IgG1 mAb against IL-6R
  • IL-6R antagonist
Indications
  • Anakinra: RA, neonatal-onset multisystem inflammatory disease
  • Canakinumab: FMF, Still disease, CAPS, other periodic fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever syndromes
  • Rilonacept: CAPS, recurrent pericarditis Pericarditis Pericarditis is an inflammation of the pericardium, often with fluid accumulation. It can be caused by infection (often viral), myocardial infarction, drugs, malignancies, metabolic disorders, autoimmune disorders, or trauma. Acute, subacute, and chronic forms exist. Pericarditis
  • Sarilumab and tocilizumab: RA
  • Tocilizumab:
    • SS-associated ILD ILD Interstitial lung diseases are a heterogeneous group of disorders characterized by the inflammation and fibrosis of lung parenchyma, especially the pulmonary connective tissue in the alveolar walls. It may be idiopathic (e.g., idiopathic pulmonary fibrosis) or secondary to connective tissue diseases, medications, malignancies, occupational exposure, or allergens. Interstitial Lung Diseases
    • Polyarticular juvenile idiopathic arthritis Juvenile Idiopathic Arthritis Juvenile idiopathic arthritis (JIA), formerly known as juvenile rheumatoid arthritis, is a heterogeneous group of inflammatory diseases characterized by inflammation of 1 or more joints and is the most common pediatric rheumatic disease. Juvenile Idiopathic Arthritis
    • Cytokine release syndrome
    • Giant-cell arteritis
Adverse effects
  • ↓ WBCs, platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets
  • Infections
  • Malignancy
  • Hypersensitivity reactions
Contraindications
  • Hypersensitivity to the drug or components
  • Active infections (e.g., TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis)
Drug interactions
  • Vaccines: ↓ therapeutic effects of inactivated vaccines and ↑ adverse effects of live vaccines
  • Use with other immunosuppressants: ↑ immunosuppression
CAPS: cryopyrin-associated periodic syndromes
FMF: familial Mediterranean fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
SS-associated ILD ILD Interstitial lung diseases are a heterogeneous group of disorders characterized by the inflammation and fibrosis of lung parenchyma, especially the pulmonary connective tissue in the alveolar walls. It may be idiopathic (e.g., idiopathic pulmonary fibrosis) or secondary to connective tissue diseases, medications, malignancies, occupational exposure, or allergens. Interstitial Lung Diseases: systemic sclerosis Systemic sclerosis Scleroderma (systemic sclerosis) is an autoimmune condition characterized by diffuse collagen deposition and fibrosis. The clinical presentation varies from limited skin involvement to diffuse involvement of internal organs. Scleroderma–associated interstitial lung disease
Table: Biologic agents targeting IL-17 and IL-23
IL-17 inhibitors IL-17/23 inhibitors
Mechanism of action Secukinumab and ixekizumab: mAb against IL-17
  • Ustekinumab: mAb binding p40 of IL-17 and IL-23
  • Guselkumab: mAb binding p19 of IL-23
Indications
  • Ankylosing spondylitis Ankylosing spondylitis Ankylosing spondylitis (also known as Bechterew's disease or Marie-Strümpell disease) is a seronegative spondyloarthropathy characterized by chronic and indolent inflammation of the axial skeleton. Severe disease can lead to fusion and rigidity of the spine. Ankylosing Spondylitis
  • Plaque psoriasis Psoriasis Psoriasis is a common T-cell-mediated inflammatory skin condition. The etiology is unknown, but is thought to be due to genetic inheritance and environmental triggers. There are 4 major subtypes, with the most common form being chronic plaque psoriasis. Psoriasis
  • Psoriatic arthritis
  • Nr-axSpA
  • Psoriatic arthritis
  • Plaque psoriasis Psoriasis Psoriasis is a common T-cell-mediated inflammatory skin condition. The etiology is unknown, but is thought to be due to genetic inheritance and environmental triggers. There are 4 major subtypes, with the most common form being chronic plaque psoriasis. Psoriasis
  • Crohn’s disease and UC UC Ulcerative colitis (UC) is an idiopathic inflammatory condition that involves the mucosal surface of the colon. It is a type of inflammatory bowel disease (IBD), along with Crohn's disease (CD). The rectum is always involved, and inflammation may extend proximally through the colon. Ulcerative Colitis (ustekinumab only)
Adverse effects
  • Infections
  • Hypersensitivity reactions
Contraindications Hypersensitivity to the drug or components
Drug interactions
  • Vaccines: ↓ therapeutic effects of inactivated vaccines and ↑ adverse effects of live vaccines
  • Use with other immunosuppressants: ↑ immunosuppression
Nr-axSpA: nonradiographic axial spondyloarthritis
UC UC Ulcerative colitis (UC) is an idiopathic inflammatory condition that involves the mucosal surface of the colon. It is a type of inflammatory bowel disease (IBD), along with Crohn's disease (CD). The rectum is always involved, and inflammation may extend proximally through the colon. Ulcerative Colitis: ulcerative colitis Ulcerative colitis Ulcerative colitis (UC) is an idiopathic inflammatory condition that involves the mucosal surface of the colon. It is a type of inflammatory bowel disease (IBD), along with Crohn's disease (CD). The rectum is always involved, and inflammation may extend proximally through the colon. Ulcerative Colitis

Tumor necrosis factor inhibitors

  • Agents bind to tumor necrosis factor Tumor necrosis factor Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) ( TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF)) and block its interaction with TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) receptors.
  • All drugs approved for treatment of RA
Table: Biologic agents against TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF)
Adalimumab Certolizumab Infliximab Etarnecept
Mechanism of action Fully human mAb against TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) Humanized mAb against TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) Chimeric mAb against TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) p75 TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) receptor fusion protein
Indications
  • RA
  • Plaque psoriasis Psoriasis Psoriasis is a common T-cell-mediated inflammatory skin condition. The etiology is unknown, but is thought to be due to genetic inheritance and environmental triggers. There are 4 major subtypes, with the most common form being chronic plaque psoriasis. Psoriasis
  • Psoriatic arthritis
  • AS
  • Juvenile idiopathic arthritis
  • UC UC Ulcerative colitis (UC) is an idiopathic inflammatory condition that involves the mucosal surface of the colon. It is a type of inflammatory bowel disease (IBD), along with Crohn's disease (CD). The rectum is always involved, and inflammation may extend proximally through the colon. Ulcerative Colitis
  • HS
  • RA
  • Plaque psoriasis Psoriasis Psoriasis is a common T-cell-mediated inflammatory skin condition. The etiology is unknown, but is thought to be due to genetic inheritance and environmental triggers. There are 4 major subtypes, with the most common form being chronic plaque psoriasis. Psoriasis
  • Psoriatic arthritis
  • AS
  • Crohn’s disease
  • Nr-axSpA
  • RA
  • Plaque psoriasis Psoriasis Psoriasis is a common T-cell-mediated inflammatory skin condition. The etiology is unknown, but is thought to be due to genetic inheritance and environmental triggers. There are 4 major subtypes, with the most common form being chronic plaque psoriasis. Psoriasis
  • Psoriatic arthritis
  • AS
  • Crohn’s disease
  • UC UC Ulcerative colitis (UC) is an idiopathic inflammatory condition that involves the mucosal surface of the colon. It is a type of inflammatory bowel disease (IBD), along with Crohn's disease (CD). The rectum is always involved, and inflammation may extend proximally through the colon. Ulcerative Colitis
  • RA
  • Plaque psoriasis Psoriasis Psoriasis is a common T-cell-mediated inflammatory skin condition. The etiology is unknown, but is thought to be due to genetic inheritance and environmental triggers. There are 4 major subtypes, with the most common form being chronic plaque psoriasis. Psoriasis
  • Psoriatic arthritis
  • AS
  • Juvenile idiopathic arthritis
Adverse effects
  • Infections (including TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis, hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus reactivation)
  • Malignancy
  • Heart failure
  • Demyelinating disease
  • Antibody formation
  • Cytopenias
  • Infliximab: hepatic impairment
Contraindications
  • Hypersensitivity to the drug
  • Severe infections
  • Moderate to severe heart failure
Drug interactions
  • Vaccines: ↓ therapeutic effects of inactivated vaccines and ↑ adverse effects of live vaccines
  • Use with other immunosuppressants: ↑ immunosuppression
AS: ankylosing spondylitis
HS: hidradenitis suppurativa Hidradenitis suppurativa Hidradenitis suppurativa (HS) is a chronic skin condition due to the inflammation of apocrine sweat glands and hair follicles. Most commonly, it occurs due to occlusion of the follicular component of pilosebaceous units (PSUs). Hidradenitis Suppurativa

T-cell inhibitor

  • Targets pathway for T-cell activation
  • Drug: abatacept
    • Fusion protein composed of cytotoxic T-lymphocyte associated protein 4 (CTLA4) and the Fc portion of IgG1 
    • A selective costimulation modulator
  • Mechanism of action:
    • Normally, CD80 and CD86 (B7 proteins present on antigen-presenting cells (APCs)) interact with costimulatory receptors in T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells (costimulation).
    • Activation of T cell is inhibited by binding to CD80 and CD86 on APCs → blocking CD28 interaction between APCs and T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells
  • Pharmacokinetics:
    • IV, SC
    • Half-life: 13 days (IV)
  • Indications:
    • RA
    • Juvenile idiopathic arthritis
    • Psoriatic arthritis
  • Adverse effects:
    • Chronic obstructive pulmonary disease Chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD) ( COPD COPD Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD)) exacerbation
    • Infections
    • Malignancy
    • Hypersensitivity reactions
  • Contraindications:
    • Hypersensitivity to the drug
    • Active TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis infection
  • Drug interactions:
    • Vaccines: ↓ therapeutic effects of inactivated vaccines and ↑ adverse effects of live vaccines
    • Use with other immunosuppressants: ↑ immunosuppression

Calcineurin Inhibitors

Definition

Calcineurin inhibitors are immunosuppressive agents that target calcineurin, a signaling phosphatase important in T-cell activation. 

Drugs

  • Cyclosporine
  • Pimecrolimus
  • Tacrolimus

Pharmacodynamics

Mechanism of action:

  • Binds to an intracellular protein, FKBP-12, and forms a complex with calcineurin-dependent proteins → ↓ calcineurin phosphatase activity → ↓ cellular immunity 
  • Also blocks transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription of cytokines (e.g., IL-2, interferon gamma (IFN-γ)) transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription, resulting in inhibition of T-cell activation
  • In vitro prevention of the release of inflammatory cytokines and mediators from mast cells

Pharmacokinetics

  • Cyclosporine:
    • Dosage forms:
      • Systemic: oral, IV
      • Ophthalmic
    • Systemic forms:
      • > 90% protein-binding
      • Hepatic metabolism (cytochrome P450 or CYP)
      • Excretion: mostly in feces
  • Pimecrolimus:
    • Topical
    • Low systemic absorption
    • Hepatic metabolism (CYP)
    • Excretion: feces
  • Tacrolimus:
    • Dosage forms:
      • Systemic: oral, IV
      • Topical
    • Systemic forms:
      • Variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables absorption with oral form
      • Approximately 99% protein-binding
      • Hepatic metabolism (CYP)
      • Excretion: feces

Indications

  • Transplant rejection prophylaxis and long-term treatment (e.g., graft-versus-host disease)
  • RA
  • Psoriasis
  • Atopic dermatitis Atopic Dermatitis Atopic dermatitis, also known as eczema, is a chronic, relapsing, pruritic, inflammatory skin disease that occurs more frequently in children, although adults can also be affected. The condition is often associated with elevated serum levels of IgE and a personal or family history of atopy. Skin dryness, erythema, oozing, crusting, and lichenification are present. Atopic Dermatitis (Eczema) 

Adverse effects

  • Diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus (new onset, after transplantation)
  • Electrolyte disturbance ( hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia, hyperuricemia, hypomagnesemia)
  • Hepatotoxicity
  • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
  • Infections
  • Myocardial hypertrophy
  • Nephrotoxicity
  • Neurotoxicity
  • Prolonged QT
  • Red-cell aplasia
  • Secondary malignancy (e.g., lymphoma)

Contraindications

  • Sensitivity to the drug or its components 
  • Hypersensitivity to polyoxyethylated castor oil (IV preparations)
  • Individuals with arthritis and psoriasis Psoriasis Psoriasis is a common T-cell-mediated inflammatory skin condition. The etiology is unknown, but is thought to be due to genetic inheritance and environmental triggers. There are 4 major subtypes, with the most common form being chronic plaque psoriasis. Psoriasis with primary or secondary immunodeficiency
  • Uncontrolled hypertension Uncontrolled hypertension Although hypertension is defined as a blood pressure of > 130/80 mm Hg, individuals can present with comorbidities of severe asymptomatic or "uncontrolled" hypertension (≥ 180 mm Hg systolic and/or ≥ 120 mm Hg diastolic) that carries with it a significant risk of morbidity and mortality. Uncontrolled Hypertension
  • Uncontrolled severe infection

Drug interactions

  • CYP3A4 inducers: ↓ serum concentration of calcineurin inhibitors 
  • CYP3A4 inhibitors: ↑ serum concentration of calcineurin inhibitors 
  • Grapefruit juice: increases the serum concentration of calcineurin inhibitors
  • Live vaccines: Calcineurin inhibitors enhance the adverse effects of live vaccines. 
  • Statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins: Cyclosporine increases serum concentration of statins.

Corticosteroids

Definition

Corticosteroids have a role in the immune response, inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation, and metabolism. These hormonal agents interfere with the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle of inflammatory cells and other inflammatory components (e.g., cytokines, enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes, proteins). 

Drugs

Include (but not limited to):

  • Hydrocortisone
  • Methylprednisolone
  • Prednisolone 
  • Prednisone

Pharmacodynamics and pharmacokinetics

  • Mechanism of action:
    • The glucocorticoid receptor is within the cytoplasm, and with glucocorticoid binding, gene transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription and translation Translation Translation is the process of synthesizing a protein from a messenger RNA (mRNA) transcript. This process is divided into three primary stages: initiation, elongation, and termination. Translation is catalyzed by structures known as ribosomes, which are large complexes of proteins and ribosomal RNA (rRNA). Stages and Regulation of Translation for inflammatory leukocytes and structural cells are inhibited. 
    • ↓ In proinflammatory cytokines, chemokines, cell adhesion molecules, and other components involved in the inflammatory response
  • Pharmacokinetics vary with type of corticosteroids.

Indications

Conditions include the following:

  • Allergic/respiratory: 
    • Anaphylaxis
    • Asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma and COPD COPD Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD) exacerbation
    • Urticaria Urticaria Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives) and angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema
    • Sarcoidosis Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. Sarcoidosis
    • Interstitial lung disease
  • Dermatologic: 
    • Contact dermatitis
    • Pemphigus vulgaris Pemphigus vulgaris Bullous pemphigoid and pemphigus vulgaris are two different blistering autoimmune diseases. In pemphigus vulgaris, autoantibodies attack the desmosomal proteins, which connect the keratinocytes to one another. This attack results in a more severe, potentially fatal condition with fragile, flaccid blisters, usually with significant mucosal involvement. Bullous Pemphigoid and Pemphigus Vulgaris
  • Endocrinologic: 
    • Adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease
    • Congenital adrenal hyperplasia Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) consists of a group of autosomal recessive disorders that cause a deficiency of an enzyme needed in cortisol, aldosterone, and androgen synthesis. The most common subform of CAH is 21-hydroxylase deficiency, followed by 11β-hydroxylase deficiency. Congenital Adrenal Hyperplasia
  • Gastroenterologic: 
    • Autoimmune hepatitis Autoimmune hepatitis Autoimmune hepatitis (AIH) is a rare form of chronic liver disease in which the immune system attacks the liver causing inflammation. It predominantly affects women. Clinical presentation ranges from asymptomatic cases to patients that present with symptoms of acute liver failure (jaundice, right upper quadrant pain). Autoimmune Hepatitis
    • Inflammatory bowel disease
  • Hematologic: 
    • Hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia
    • Idiopathic thrombocytopenic purpura
    • Leukemia
    • Lymphoma
  • Ophthalmologic: 
    • Uveitis Uveitis Uveitis is the inflammation of the uvea, the pigmented middle layer of the eye, which comprises the iris, ciliary body, and choroid. The condition is categorized based on the site of disease; anterior uveitis is the most common. Diseases of the Uvea
    • Keratoconjunctivitis
  • Rheumatologic: 
    • Dermatomyositis
    • RA
    • Polymyalgia rheumatica
    • Polymyositis Polymyositis Polymyositis (PM) is an autoimmune inflammatory myopathy caused by T cell-mediated muscle injury. The etiology of PM is unclear, but there are several genetic and environmental associations. Polymyositis is most common in middle-aged women and rarely affects children. Polymyositis
    • SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus
  • Others: 
    • Antenatal lung maturation
    • Cerebral edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
    • Multiple sclerosis Multiple Sclerosis Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease that leads to demyelination of the nerves in the CNS. Young women are more predominantly affected by this most common demyelinating condition. Multiple Sclerosis
    • Nephrotic syndrome Nephrotic syndrome Nephrotic syndrome is characterized by severe proteinuria, hypoalbuminemia, and peripheral edema. In contrast, the nephritic syndromes present with hematuria, variable loss of renal function, and hypertension, although there is sometimes overlap of > 1 glomerular disease in the same individual. Nephrotic Syndrome
    • Organ transplantation

Adverse effects

  • Cardiovascular:
    • Cardiac arrhythmias
    • Cardiac failure (predisposition of cardiac diseases) 
    • Edema
    • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
  • Dermatologic:
    • Skin atrophy
    • Skin rash
    • Hypopigmentation or hyperpigmentation
  • Endocrine and metabolic:
    • Hyperglycemia
    • Diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
    • Adrenal suppression
    • Cushingoid features
    • Growth suppression in children
  • GI: peptic ulcer Peptic ulcer Peptic ulcer disease (PUD) refers to the full-thickness ulcerations of duodenal or gastric mucosa. The ulcerations form when exposure to acid and digestive enzymes overcomes mucosal defense mechanisms. The most common etiologies include Helicobacter pylori (H. pylori) infection and prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs). Peptic Ulcer Disease
  • Genitourinary: menstrual irregularities
  • Musculoskeletal:
    • Aseptic necrosis of the humeral head/femoral head
    • Susceptibility to fractures
    • Myopathy
    • Osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis
  • Neurologic and psychiatric:
    • Headache
    • Idiopathic intracranial hypertension Idiopathic Intracranial Hypertension Idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri, is a clinical disorder that presents with symptoms due to increased intracranial pressure (ICP; ≥ 20 mm Hg) or CSF pressure (> 250 mm H2O), with no structural changes or other attributable causes. Idiopathic Intracranial Hypertension
    • Paresthesia
    • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
    • Vertigo Vertigo Vertigo is defined as the perceived sensation of rotational motion while remaining still. A very common complaint in primary care and the ER, vertigo is more frequently experienced by women and its prevalence increases with age. Vertigo is classified into peripheral or central based on its etiology. Vertigo
    • Psychosis
    • Agitation 
    • Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia
  • Ophthalmic:
    • Glaucoma Glaucoma Glaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP). Glaucoma
    • Cataracts
  • Others: impaired wound healing Wound healing Wound healing is a physiological process involving tissue repair in response to injury. It involves a complex interaction of various cell types, cytokines, and inflammatory mediators. Wound healing stages include hemostasis, inflammation, granulation, and remodeling. Wound Healing

Contraindications

  • Hypersensitivity to the drug or its components
  • Recent administration of live or live attenuated vaccines
  • Uncontrolled active infections (e.g., bacterial, viral, or fungal)
  • Uncontrolled diabetes
  • Uncontrolled psychotic states
  • Uncontrolled hypertension Uncontrolled hypertension Although hypertension is defined as a blood pressure of > 130/80 mm Hg, individuals can present with comorbidities of severe asymptomatic or "uncontrolled" hypertension (≥ 180 mm Hg systolic and/or ≥ 120 mm Hg diastolic) that carries with it a significant risk of morbidity and mortality. Uncontrolled Hypertension
  • Peptic ulcer

Drug interactions

  • Live and inactivated vaccines: Corticosteroids enhance the adverse effects of vaccines. 
  • Use with NSAIDs: ↑ risk of GI ulcers and bleeding
  • Warfarin: corticosteroids ↑ anticoagulant effects
  • Antihyperglycemic agents: corticosteroids may ↓ effects

mTOR inhibitors

Definition

  • Medications that reduce the activity of mTOR serine/threonine kinase involved in cell growth, metabolism, and immune cell proliferation
  • The mTOR signaling pathway is abnormally activated in some tumors.
    • By inhibiting mTOR serine/threonine kinase activity, there is a halt in the progression of the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle, decreasing proliferation.
    • Agents also have antiangiogenic effects.
  • Class of drugs also called proliferation signal inhibitors

Drugs

  • Everolimus
  • Temsirolimus
  • Sirolimus

Pharmacodynamics

Mechanism of action:

  • Form 2 complexes:
    • mTORC1: important in lipid, glucose, protein, and nucleotide metabolism
    • mTORC2: involved in insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin signaling pathway, regulating lipid and glucose metabolism
  • Change the activity of mTOR, leading to:
    • Disruption of normal myeloid and lymphoid development
    • Cell cycle arrest in the G1–S phase, preventing cell-cycle progression and cell proliferation 
    • Antiproliferative and antiangiogenic effects

Pharmacokinetics

  • Everolimus:
    • Oral, with rapid absorption
    • 74% protein-binding
    • Half-life: approximately 30 hours
    • Hepatic metabolism
    • Excretion: mostly in feces
  • Temsirolimus:
    • IV
    • Half-life: approximately 17 hours
    • Hepatic metabolism
    • Excretion: mostly in feces
  • Sirolimus: 
    • Oral, with rapid absorption
    • Half-life: approximately 55 hours
    • Intestinal and hepatic metabolism
    • Excretion: feces

Indications

Related agents (rapamycin analogs (rapalogs)) and indications:

  • Everolimus:
    • Renal cell carcinoma Renal cell carcinoma Renal cell carcinoma (RCC) is a tumor that arises from the lining of the renal tubular system within the renal cortex. Renal cell carcinoma is responsible for 80%-85% of all primary renal neoplasms. Most RCCs arise sporadically, but smoking, hypertension, and obesity are linked to its development. Renal Cell Carcinoma
    • Prevention of transplant rejection
    • Tuberous sclerosis Tuberous sclerosis Tuberous sclerosis or tuberous sclerosis complex (TSC) is an autosomal dominant disorder with mainly neurocutaneous symptoms. Mutation in the TSC genes causes excessive tumor-like growths in the brain, eyes, heart, kidney, and lungs. Cutaneous manifestations include hypopigmentation (i.e., ash leaf spots, confetti lesions) or excessive growth (i.e., angiofibroma, shagreen patch). Tuberous Sclerosis complex–associated partial-onset seizures, renal angiomyolipoma, and subependymal giant-cell astrocytoma Astrocytoma Astrocytomas are neuroepithelial tumors that arise from astrocytes, which are star-shaped glial cells (supporting tissues of the CNS). Astrocytomas are a type of glioma. There are 4 grades of astrocytomas. Astrocytoma 
    • Neuroendocrine tumors
    • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
  • Temsirolimus: renal cell carcinoma
  • Sirolimus 
    • Lymphangioleiomyomatosis 
    • Prevention of transplant rejection

Adverse effects

  • Serious infections
  • Pulmonary toxicity
  • Angioedema
  • ↑ Lipid
  • Secondary malignancy

Contraindications

  • Hypersensitivity to the drug or its components 
  • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Bilirubin > 1.5 times of the upper limit of normal value

Drug interactions

  • CYP3A4 inducers: ↓ serum concentration of mTOR inhibitors
  • CYP3A4 inhibitors: ↑ serum concentration of mTOR inhibitors
  • Live vaccines: mTOR inhibitors increase the adverse effects of live vaccines. 
  • Tacrolimus: mTOR inhibitors enhance the adverse effects of tacrolimus.
  • St. John’s wort decreases the serum concentration of mTOR inhibitors.

Other Cytotoxic and Immunomodulating Agents

Drugs

  • Some medications have both immunosuppressive and antineoplastic activities and are thus used for malignancies as well.
  • Some of these are cytotoxic agents, interfering with the nucleic acid and protein synthesis of cells, and others interrupt normal immune response.
  • As medications have varying mechanisms and belong to different classes, pharmacology of these agents will be discussed individually.
    • Azathioprine 
    • Cyclophosphamide 
    • Hydroxychloroquine 
    • Leflunomide 
    • Methotrexate 
    • Mycophenolate 
    • Thalidomide

Azathioprine

  • Prodrug of mercaptopurine
  • Mechanism of action:
    • Cleaved to 6-mercaptopurine → metabolized by hypoxanthine–guanine phosphoribosyltransferase (HGPRT) into a metabolite thioinosine monophosphate (TIMP)
    • TIMP outcompetes purine derivatives and inhibits enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes of purine synthesis.
    • Triphosphate forms of TIMP are incorporated into the DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure → ↓ cell proliferation and lymphocyte function
  • Pharmacokinetics:
    • Oral, well-absorbed
    • Hepatic metabolism
    • Half-life: approximately 2 hours
    • Excretion: renal
  • Indications:
    • Prevention of transplant rejection (e.g., kidney transplant)
    • RA
    • Also used in off-label indications such as Crohn’s disease, psoriasis Psoriasis Psoriasis is a common T-cell-mediated inflammatory skin condition. The etiology is unknown, but is thought to be due to genetic inheritance and environmental triggers. There are 4 major subtypes, with the most common form being chronic plaque psoriasis. Psoriasis
  • Adverse effects:
    • Alopecia Alopecia Alopecia is the loss of hair in areas anywhere on the body where hair normally grows. Alopecia may be defined as scarring or non-scarring, localized or diffuse, congenital or acquired, reversible or permanent, or confined to the scalp or universal; however, alopecia is usually classified using the 1st 3 factors. Alopecia
    • Myelosuppression
    • GI toxicity
    • Hepatotoxicity
    • ↑ Infections (especially varicella and herpes simplex viruses)
    • ↑ Risk of malignancy (e.g., posttransplantation lymphoma)
  • Contraindications:
    • Hypersensitivity to the drug
    • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
    • Those with RA and prior use of alkylating agents (↑ malignancy)
  • Drug interactions:
    • Allopurinol: blocks xanthine oxidase (enzyme important in the catabolism of azathioprine metabolites) → ↑ active metabolites of azathioprine
    • ACE inhibitors and other myelosuppressive agents: ↑ myelosuppressive effects of azathioprine

Cyclophosphamide

  • Belongs to the group of nitrogen mustards, alkylating agents that work primarily by binding alkyl groups to various parts of DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure
  • Antineoplastic and immunosuppressive properties
  • Indications (non-oncologic): nephrotic syndrome

Hydroxychloroquine

  • Antimalarial agent and a disease-modifying antirheumatic drug ( DMARD DMARD Disease-modifying antirheumatic drugs are antiinflammatory medications used to manage rheumatoid arthritis. The medications slow, but do not cure, the progression of the disease. The medications are classified as either synthetic or biologic agents and each has unique mechanisms of action and side effects. Disease-modifying Antirheumatic Drugs)
  • An immunomodulatory agent:
    • Inhibits nucleic acid sensors, including toll-like receptor 9 and cyclic GMP–AMP synthase
    • ↑ Lysosomal pH, disrupting processing of antigens (endolysosomal pathway)
    • Inhibits proinflammatory cytokine production, such as tumor necrosis factor Tumor necrosis factor Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) α ( TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF)-α), IFN-γ, and IL-6 
  • Indications (nonmalarial):
    • SLR
    • RA

Leflunomide

  • Pyrimidine synthesis inhibitor
  • Antiinflammatory and immunomodulatory
  • Mechanism of action: inhibits dihydroorotate dehydrogenase (mitochondrial enzyme), which is important in pyrimidine synthesis → ↓ lymphocyte activation
  • Pharmacokinetics:
    • Oral
    • Active metabolite with long half-life
    • Hepatic metabolism
    • Excretion: feces and urine
  • Indications: RA
  • Adverse effects:
    • Dermatologic reactions (e.g., Stevens-Johnson syndrome Stevens-Johnson syndrome Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome)
    • Hematologic toxicities: pancytopenia, agranulocytosis, and thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia
    • Hepatotoxicity
    • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
    • Infections
    • Nephrotoxicity
    • Secondary malignancy
  • Contraindications:
    • Hypersensitivity to the drug
    • Immunodeficiency
    • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
    • Severe hepatic and renal impairment
  • Drug interactions: 
    • Activated charcoal and cholestyramine ↓ leflunomide
    • Immunosuppressive drugs enhance immunosuppressive effects of leflunomide.
    • Vaccines: ↓ therapeutic effects of inactivated vaccines and ↑ adverse effects of live vaccines

Methotrexate

  • Folic acid analog, belonging to antimetabolite agents, which block folic acid activity to inhibit cell division
  •  Mechanism of action:
    • Binds to dihydrofolate reductase (DHFR) → inhibits the formation of tetrahydrofolate (FH4) → ↓ DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure synthesis
    • Folylpolyglutamate synthetase (FPGS) adds glutamyl residues to the molecule, making the molecule unable to cross cell membranes.
    • This mechanism of ion trapping permits prolonged retention of MTX in the cell.
  • Indications (nonneoplastic): 
    • RA
    • Psoriasis
    • Juvenile idiopathic arthritis

Mycophenolate

  • Mycophenolate mofetil (MMF) → hydrolyzed to mycophenolic acid (MPA), the active immunosuppressive agent
  • Mechanism of action:
    • MPA reversibly inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme in the de novo pathway of guanine nucleotide synthesis.
    • T and B lymphocytes B lymphocytes B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells depend on this pathway for proliferation.
  • Pharmacokinetics:
    • Oral, rapid absorption
    • Half-life: approximately 16 hours
    • Metabolism: hepatic, GI tract
    • Excretion: urine
  • Indications: to prevent organ transplant rejection
  • Adverse effects:
    • Infections
    • CNS depression
    • Lymphoma and skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin malignancy
    • Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia
    • Red-cell aplasia
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, vomiting
    • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
  • Contraindications:
    • Hypersensitivity to the drug
    • Allergy to polysorbate 80 (IV formulation)
    • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
  • Drug interactions:
    • Cholestyramine resin: ↓ serum concentration of mycophenolate 
    • Tacrolimus: ↑ activation of polyomaviruses such as BK virus BK Virus BK virus (BKV) is a small, nonenveloped, single-stranded DNA virus belonging to the Polyomaviridae family, which are ubiquitous in the human population. While the primary infection is usually asymptomatic, the infection leads to lifelong latency in the kidneys and lymphoid organs. JC Virus and BK Virus (can cause interstitial nephritis)
    • Vaccines: ↓ therapeutic effects of inactivated vaccines and ↑ adverse effects of live vaccines

Thalidomide

  • Immunomodulator
  • Mechanism of action:
    • TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF)-α, ↑ natural killer cells, and IL-2 
    • Alters expression of cellular adhesion molecules
    • Antiangiogenic effects 
  • Pharmacokinetics:
    • Oral
    • Half-life: 7 hours
    • Minimal metabolism
    • Excretion: urine
  • Indications:
    • Multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma
    • Erythema nodosum Erythema nodosum Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum leprosum
  • Adverse effects:
    • Bradycardia
    • Dizziness, drowsiness
    • Dermatologic reactions
    • Hepatotoxicity
    • Myelosuppression
    • Orthostatic hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
    • Secondary malignancy
    • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
    • Teratogenicity
    • Thromboembolic events
  • Contraindications:
    • Hypersensitivity to the drug
    • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
  • Drug interactions:
    • Hormonal contraceptives Hormonal contraceptives Hormonal contraceptives (HCs) contain synthetic analogs of the reproductive hormones estrogen and progesterone, which may be used either in combination or in progestin-only formulations for contraception. Hormonal Contraceptives: ↑ thrombogenic effects of thalidomide
    • CNS depressants: ↑ CNS effects of thalidomide

Comparison of Immunosuppressive Agents

Table: General overview of the different immunosuppressive agents
Mechanism Common indications
Biologic agents Inhibition of B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells/ T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells, interleukin, or TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF)
  • RA and other rheumatologic conditions
  • IBD
Calcineurin inhibitors Blocks calcineurin, a signaling phosphatase essential in T-cell activation
  • Transplant rejection
  • RA
  • Psoriasis
Corticosteroids Suppress cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle and activity of inflammatory cells and other components Multisystem indications (e.g., respiratory, hematologic, musculoskeletal conditions)
mTOR inhibitors Inhibition of proliferation signal transduction
  • Malignancies (e.g., breast cancer)
  • Lymphangioleiomyomatosis
  • Transplant rejection
Immunomodulators Thalidomide: antiangiogenesis, ↓ immune components (e.g., IL-2)
  • Multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma
  • Erythema nodosum Erythema nodosum Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum leprosum
Hydroxychloroquine: disrupts endolysosomal pathway, inhibits cytokine production and nucleic acid sensors
  • SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus
  • RA
Cytotoxic agents Interfere with the nucleic acid and protein synthesis of cells
  • Malignancies
  • RA
  • Transplant rejection
IBD: inflammatory bowel disease

References

  1. Beaugerie, L. (2013) Use of immunosuppressants and biologicals in patients with previous cancer. Dig Dis 31:254–259. https://doi.org/10.1159/000353382
  2. Burmester, G. (2021) Overview of biologic agents and kinase inhibitors in the rheumatic diseases. UpToDate. Retrieved October 16, 2021, from https://www.uptodate.com/contents/overview-of-biologic-agents-and-kinase-inhibitors-in-the-rheumatic-diseases
  3. Hedstrom, L. (2009). IMP dehydrogenase: structure, mechanism, and inhibition. Chemical Reviews 109:2903–2928. https://doi.org/10.1021/cr900021w
  4. Hodgens, A., Sharman, T. (2021). Corticosteroids. StatPearls. Retrieved October 16, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK554612/
  5. Lake, D. F., & Briggs, A. D. (2021). Immunopharmacology. Chapter 55 of Katzung, B. G., Vanderah, T. W. (Eds.),  Basic & Clinical Pharmacology, 15th ed. McGraw=Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2988&sectionid=250603682
  6. Pande, A., Culver, D. A. (2020) Knowing when to use steroids, immunosuppressants or biologics for the treatment of sarcoidosis. Exp Rev Respir Med 14:285–298. https://doi.org/10.1080/17476348.2020.1707672
  7. Safarini, O. A., Patel, J. (2021). Calcineurin inhibitors. StatPearls. Retrieved October 19, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK558995/
  8. Saxton, R. A., Sabatini, D. M. (2017). mTOR signaling in growth, metabolism, and disease. Cell 168:960–976. https://doi.org/10.1016/j.cell.2017.02.004
  9. Zheng, Y., Jiang, Y. (2015). mTOR inhibitors at a glance. Molecular and Cellular Pharmacology 7:15–20.

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