Biological response modifiers (BRMs) are
substances that modify
immune responses. They can be
endogenous
Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell.
For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...
(produced naturally within the body) or
exogenous (as
pharmaceutical drug
Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the ...
s), and they can either enhance an immune response or
suppress it. Some of these substances arouse the body's response to an
infection
An infection is the invasion of tissue (biology), tissues by pathogens, their multiplication, and the reaction of host (biology), host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmis ...
, and others can keep the response from becoming excessive. Thus they serve as
immunomodulators
Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunothera ...
in
immunotherapy
Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...
(therapy that makes use of immune responses), which can be helpful in
treating cancer (where
targeted therapy
Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy (oncology), hormonal therapy and cytotoxic chemotherapy. As a form of molecular medici ...
often relies on
the immune system being used to attack cancer cells) and in treating
autoimmune
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease" ...
diseases (in which the immune system attacks the self), such as some kinds of
arthritis
Arthritis is a general medical term used to describe a disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, Joint effusion, swelling, and decreased range of motion of ...
and
dermatitis
Dermatitis is a term used for different types of skin inflammation, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened ...
. Most BRMs are
biopharmaceutical
A biopharmaceutical, also known as a biological medical product, or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semisynthesized from biological sources. Different from totally synthesized pharmaceuticals, t ...
s (biologics), including
monoclonal antibodies
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a Lineage (evolution), cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Mon ...
,
interleukin 2
Interleukin-2 (IL-2) is an interleukin, which is a type of cytokine signaling molecule forming part of the immune system. It is a 15.5–16 Dalton (unit), kDa protein that regulates the activities of white blood cells (leukocytes, often ...
,
interferon
Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten ...
s, and various types of
colony-stimulating factors (e.g., CSF, GM-CSF, G-CSF).
"Immunotherapy makes use of BRMs to ''enhance'' the activity of the immune system to increase the body's natural defense mechanisms against cancer", whereas BRMs for
rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...
aim to reduce
inflammation
Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
.
Some conditions which biologics are used to treat are
rheumatic disorders
such as
psoriatic arthritis
Psoriatic arthritis (PsA) is a long-term inflammatory arthritis that may occur in some people affected by the autoimmune disease psoriasis. The classic features of psoriatic arthritis include dactylitis (sausage-like swelling of the fingers ...
,
ankylosing spondylitis
Ankylosing spondylitis (AS) is a type of arthritis from the disease spectrum of axial spondyloarthritis. It is characterized by long-term inflammation of the joints of the spine, typically where the spine joins the pelvis. With AS, eye and bow ...
and
non-radiographic axial spondyloarthritis, and
inflammatory bowel disease
Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine, with Crohn's disease and ulcerative colitis (UC) being the principal types. Crohn's disease affects the small intestine and large intestine ...
.
Medical uses
Biologics provide
immunotherapy
Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...
and can function as
disease-modifying antirheumatic drugs
Disease-modifying antirheumatic drugs (DMARDs) comprise a category of otherwise unrelated disease-modifying drugs defined by their use in rheumatoid arthritis to slow down disease progression. The term is often used in contrast to nonsteroidal ...
.
Biologics can generally be grouped by their "class", that is, their specific
mechanism of action
In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...
and affected targets. Some classes are
TNF inhibitor
Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
s, anti-
IL-17A antibodies, and
IL-23 antibodies.
For people with moderate to severe
psoriatic arthritis
Psoriatic arthritis (PsA) is a long-term inflammatory arthritis that may occur in some people affected by the autoimmune disease psoriasis. The classic features of psoriatic arthritis include dactylitis (sausage-like swelling of the fingers ...
, biologics can provide some relief of the symptoms,
and even slow down or halt the progression of the disease. Classes of biologics typically used for psoriatic arthritis include TNF inhibitors, anti-IL17-A antibodies, IL-23 antibodies, and those that act on both
IL-12 and IL-23.
Biologics can treat
inflammatory bowel disease
Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine, with Crohn's disease and ulcerative colitis (UC) being the principal types. Crohn's disease affects the small intestine and large intestine ...
. Classes of biologics typically used for inflammatory bowel disease include TNF inhibitors, and anti-
CD28
CD28 (Cluster of Differentiation 28) is a protein expressed on T cells that provides essential co-stimulation, co-stimulatory signals required for T cell activation and survival. When T cells are stimulated through CD28 in conjunction with the T- ...
antibodies.
Contraindications
Biologics are generally used after considering other less invasive treatments.
Before using biologics to treat
psoriasis
Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by patches of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small localized patches to complete b ...
, treatment with topical
moisturizer
A moisturizer, or emollient, is a Cosmetics, cosmetic preparation used for protecting, moisturizing, and lubricating the Human skin, skin. These functions are normally performed by Sebaceous gland, sebum produced by healthy skin. The word "emollie ...
s or
steroids
A steroid is an organic compound with four fused rings (designated A, B, C, and D) arranged in a specific molecular configuration.
Steroids have two principal biological functions: as important components of cell membranes that alter mem ...
, or
light therapy
Light therapy, also called phototherapy or bright light therapy is the exposure to direct sunlight or artificial light at controlled wavelengths in order to treat a variety of medical disorders, including seasonal affective disorder (SAD), circ ...
may provide relief. Other drugs which may provide relief include
acitretin,
ciclosporin
Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is taken Oral administration, orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, nephr ...
, and
methotrexate
Methotrexate, formerly known as amethopterin, is a chemotherapy agent and immunosuppressive drug, immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancy, ectopic pregnancies. Types of cancers it is u ...
, but since these drugs have their own major side effects, doctors and patients should discuss whether to try one of these or a biologic first.
Most biologics are
injections so are not appropriate for use by someone with intense
fear of needles
Fear of needles, known in medical literature as needle phobia, is the extreme fear of medical procedures involving injections or hypodermic needles.
It is occasionally referred to as '' aichmophobia'', although this term may also refer to a more ...
.
A person with any
infection
An infection is the invasion of tissue (biology), tissues by pathogens, their multiplication, and the reaction of host (biology), host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmis ...
should not use biologics.
Other contraindications for biologics include cancer, certain neurologic disorders, being pregnant or breastfeeding, history of heart failure, or history of tuberculosis.
Adverse effects
Common adverse effects of biologic administration are
injection site reaction
Injection site reactions (ISRs) are reactions that occur at the site of injection of a drug. They may be mild or severe and may or may not require medical intervention. Some reactions may appear immediately after injection, and some may be delayed ...
s including
redness, pain, and
itching
An itch (also known as pruritus) is a sensation that causes a strong desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both ...
. Other adverse effects include headache, skin reactions,
respiratory tract infection
Respiratory tract infections (RTIs) are infectious diseases involving the lower or upper respiratory tract. An infection of this type usually is further classified as an upper respiratory tract infection (URI or URTI) or a lower respiratory tract ...
, and
urinary tract infection
A urinary tract infection (UTI) is an infection that affects a part of the urinary tract. Lower urinary tract infections may involve the bladder (cystitis) or urethra (urethritis) while upper urinary tract infections affect the kidney (pyel ...
.
Adverse effects may be class-dependent, and so switching to a biologic of another class may ameliorate those effects.
Potential serious adverse effects include
allergic reactions
Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, alle ...
, liver damage, cancer, and serious infections including
tuberculosis
Tuberculosis (TB), also known colloquially as the "white death", or historically as consumption, is a contagious disease usually caused by ''Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can al ...
,
pneumonia
Pneumonia is an Inflammation, inflammatory condition of the lung primarily affecting the small air sacs known as Pulmonary alveolus, alveoli. Symptoms typically include some combination of Cough#Classification, productive or dry cough, ches ...
,
staph infection, and
fungal infection
Fungal infection, also known as mycosis, is a disease caused by fungi. Different types are traditionally divided according to the part of the body affected: superficial, subcutaneous, and systemic. Superficial fungal infections include common ...
.
Patients with
systemic lupus erythematosus
Lupus, formally called systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Common ...
(SLE) who are treated with the standard of care, including biologic response modifiers, experience a higher risk of mortality and opportunistic infection compared to the general population.
Examples
Biopharmaceuticals
Biologics for immunosuppression include
adalimumab
Adalimumab, sold under the brand name Humira and others, is a disease-modifying antirheumatic drug and monoclonal antibody used to treat rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn' ...
,
certolizumab,
etanercept
Etanercept, sold under the brand name Enbrel among others, is a biologic medical product that is used to treat autoimmune diseases by interfering with tumor necrosis factor (TNF), a soluble inflammatory cytokine, by acting as a TNF inhibitor. ...
,
golimumab,
infliximab
Infliximab, a chimeric monoclonal antibody, sold under the brand name Remicade among others, is a medication used to treat a number of autoimmune diseases. This includes Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing ...
,
ixekizumab,
belimumab
Belimumab, sold under the brand name Benlysta, is a human monoclonal antibody that inhibits B-cell activating factor (BAFF), also known as B-lymphocyte stimulator (BLyS). It is approved in the United States and Canada, and the European Union to ...
, and
ustekinumab
Ustekinumab, sold under the brand name Stelara among others, is a monoclonal antibody medication used for the treatment of Crohn's disease, ulcerative colitis, Psoriasis, plaque psoriasis and psoriatic arthritis, targeting both IL-12 and IL-23. ...
.
Natural BRMs
Extracts from some
medicinal mushrooms are natural biological response modifiers.
Manufacturing
Genetically engineered cell cultures
Cell culture or tissue culture is the process by which cells are grown under controlled conditions, generally outside of their natural environment. After cells of interest have been isolated from living tissue, they can subsequently be main ...
in pharmaceutical labs produce the biologics.
History
Biologics are the second generation of
biopharmaceutical
A biopharmaceutical, also known as a biological medical product, or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semisynthesized from biological sources. Different from totally synthesized pharmaceuticals, t ...
products.
The first generation were the biopharmaceutical products which could be extracted from organisms without
biotechnology
Biotechnology is a multidisciplinary field that involves the integration of natural sciences and Engineering Science, engineering sciences in order to achieve the application of organisms and parts thereof for products and services. Specialists ...
from the
Information Age
The Information Age is a historical period that began in the mid-20th century. It is characterized by a rapid shift from traditional industries, as established during the Industrial Revolution, to an economy centered on information technology ...
,
such as blood for transfusion, early insulin extracted from animals, and vaccines from eggs.
When biologic drugs became available they led to significant changes in the management of various
autoimmune disease
An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...
s.
Society and culture
Term
The term "biologic therapy" is nonspecific, and can refer to any
biopharmaceutical
A biopharmaceutical, also known as a biological medical product, or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semisynthesized from biological sources. Different from totally synthesized pharmaceuticals, t ...
medication. However, many sources use the term to refer to
immunotherapy
Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...
treatments.
The explanation for this is that while "biologic" or "biopharmaceutical" refers to the chemical composition of medications which might be used to treat a range of medical conditions, when the term "biologic" became popular, many biologic medications available provided immunosuppression.
Legal status
Biosimilar
A biosimilar (also known as follow-on biologic or subsequent entry biologic) is a biologic medical product that is almost an identical copy of an original product that is manufactured by a different company. Biosimilars are officially approved ...
is a term used to describe a
biopharmaceutical
A biopharmaceutical, also known as a biological medical product, or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semisynthesized from biological sources. Different from totally synthesized pharmaceuticals, t ...
product which seems so close in composition and effect to another that they are functionally identical, analogous to
generic drug
A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
s. In this context, some publications describe "biologics" as "biosimilars".
Economics
Biologic drugs are expensive.
In the United States treatment with biologic drugs typically costs –6,000 per month,
compared to –600 per month for conventional (small-molecule)
DMARDs.
References
* Deepak A. Rao; Le, Tao; Bhushan, Vikas. First Aid for the USMLE Step 1 2008 (First Aid for the Usmle Step 1). McGraw-Hill Medical. {{ISBN, 0-07-149868-0.
Immune system
Immunotherapy
Disease-modifying antirheumatic drugs
Immunosuppressants
Monoclonal antibodies