Infliximab (
Remicade) is a drug used to treat autoimmune diseases.
Infliximab has been approved by the U.S.
Food and Drug AdministrationThe Food and Drug Administration is a Government agency of the United States Department of Health and Human Services and is responsible for regulating and supervising the safety of foods, tobacco products, dietary supplements, Medication drugs, vaccines, Biopharmaceutical, blood transfusion,...
for the treatment of
psoriasisPsoriasis is a chronic, non-contagious autoimmune disease that affects the skin and joints. It commonly causes red, scaly patches to appear on the skin. The scaly patches caused by psoriasis, called psoriatic plaques, are areas of inflammation and excessive skin production. Skin rapidly...
,
Crohn's diseaseCrohn's disease is an inflammatory disease of the intestines that may affect any part of the gastrointestinal tract from anus to mouth, causing a wide variety of symptoms...
,
ankylosing spondylitisAnkylosing spondylitis , previously known as Bechterew's disease, Bechterew syndrome, and Marie Strümpell disease, a form of Spondyloarthritis, is a chronic, inflammatory arthritis and autoimmune disease...
,
psoriatic arthritisPsoriatic arthritis is a type of inflammatory arthritis that, according to the National Psoriasis Foundation, affects around 10-30% of people suffering from the chronic skin condition psoriasis...
,
rheumatoid arthritisRheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks the joints producing an inflammatory synovitis that often progresses to destruction of the articular cartilage and ankylosis of the joints...
and
ulcerative colitisUlcerative colitis is a form of inflammatory bowel disease . Ulcerative colitis is a form of colitis, a disease of the intestine, specifically the large intestine or colon, that includes characteristic ulcers, or open sores, in the colon. The main symptom of active disease is usually constant...
. Remicade won its initial approval by the FDA for the treatment of
Crohn's diseaseCrohn's disease is an inflammatory disease of the intestines that may affect any part of the gastrointestinal tract from anus to mouth, causing a wide variety of symptoms...
in August 1998.
Infliximab works by binding to tumour necrosis factor alpha (TNFα). TNFα is a chemical messenger (
cytokineCytokines are any of a number of substances that are secreted by specific cells of the immune system which carry signals locally between cells, and thus have an effect on other cells. They are a category of signaling molecules that are used extensively in cellular communication. They are proteins,...
) and a key part of the autoimmune reaction. Originally, it was assumed that Infliximab works by blocking the action of TNFα by preventing it from binding to its
receptorIn biochemistry, a receptor is a protein molecule, embedded in either the plasma membrane or cytoplasm of a cell, to which a mobile signaling molecule may attach...
in the cell, and for the action of infliximab in reumatoid arthritis this still seems to be true. Another TNFα-neutralizing medication,however, Enbrel is worse than a placebo in Crohn's disease and thus TNFα-neutralisation is not responsible for its powerful action in the latter disease . As infliximab causes programmed cell death of TNFα-expressing activated T lymphocytes, an important cell type mediating inflammation, but Enbrel does not have this activity, now it is generally assumed that resolution of activated T cells by Infliximab explains its efficacy in Crohn's disease.
Inflixmab is an artificial
antibodyAntibodies are gamma globulin proteins that are found in blood or other bodily fluids of vertebrates, and are used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses...
. It was originally developed in mice, as a mouse antibody. Because humans have immune reactions to mouse proteins, it was later developed into a human (humanized) antibody. Because the antibodies were produced from one cell that was grown into a clone of identical cells, it is called a monoclonal antibody. Because it is a combination of mouse and human antibody, it is called a chimeric monoclonal antibody.
Infliximab was developed by Junming Le and
Jan VilcekJán T. Vilček M.D., Ph.D. is a professor in the Department of Microbiology at the NYU School of Medicine. Vilcek, a native of Bratislava, Slovakia, received his M.D. degree from Comenius University Medical School, Bratislava, Czechoslovakia in 1957; and his Ph.D...
at
New York University School of MedicineThe New York University School of Medicine is one of the graduate schools of New York University. Founded in 1841 as the University Medical College....
and developed by
CentocorCentocor is a biotechnology company that was founded in Philadelphia in 1979 with an initial goal of developing new diagnostic assays using monoclonal antibody technology.In 1982 Centocor developed their first product approved by the U.S...
, a biotechnology company later purchased by
Johnson & JohnsonJohnson & Johnson is a global American pharmaceutical, medical devices and consumer packaged goods manufacturer founded in 1886. Its common stock is a component of the Dow Jones Industrial Average and the company is listed among the Fortune 500...
.
Infliximab can cost $19,000 to $22,000 a year per patient wholesale, according to Centocor.
Other monoclonal antibodies targeting TNFα are
golimumabGolimumab is a human monoclonal antibody which is used as an immunosuppressive drug and marketed under the brand name Simponi. Golimumab targets tumor necrosis factor alpha , a pro-inflammatory molecule and hence is a TNF inhibitor....
(Simponi) and
adalimumabAdalimumab is the third TNF inhibitor, after infliximab and etanercept, to be approved in the United States. Like infliximab and etanercept, adalimumab binds to TNFα, preventing it from activating TNF receptors; adalimumab was constructed from a fully human monoclonal antibody, while infliximab...
(Humira.)
EtanerceptEtanercept is a drug that treats autoimmune diseases by interfering with the TNF receptor by acting as a TNF inhibitor.Etanercept is a fusion protein produced through expression of recombinant DNA...
(Enbrel) also binds and inhibits the action of TNFα but is not, strictly speaking, a monoclonal antibody (it is instead a fusion of
TNF-receptorCD120 , also known as the tumor necrosis factor receptor . This protein is a member of the tumor necrosis factor receptor superfamily.- Receptor subtypes :...
and an antibody constant region).
Remicade is administered by
intravenous infusionIntravenous therapy or IV therapy is the giving of liquid substances directly into a vein. It can be intermittent or continuous; continuous administration is called an intravenous drip. The word intravenous simply means "within a vein", but is most commonly used to refer to IV therapy...
, typically at 6-8 week intervals, and at a clinic or hospital. It cannot be administered
orallyA route of administration in pharmacology and toxicology is the path by which a drug, fluid, poison, or other substance is brought into contact with the body....
, because the digestive system would destroy the drug.
Pharmacology
According to product labeling, Infliximab neutralizes the biological activity of TNFα by binding with high
affinityAffinity, in etymology affinity is the opposite of infinity . These two words have the same root coming from the Latin: finis = end. “Affinity” meaning is near to the “finis” e.g...
to the soluble (free floating in the blood) and transmembrane (located on the outer membranes of T cells and similar immune cells) forms of TNFα and inhibits or prevents the effective binding of TNFα with its receptors. Remicade and Humira (another TNF antagonist) are in the subclass of "anti-TNF antibodies" (they are in the form of naturally occurring antibodies), and are capable of neutralizing all forms (extracellular, transmembrane, and receptor-bound) of TNF alpha. Enbrel, a third TNF antagonist, is in a different subclass (receptor-construct fusion protein), and, because of its modified form, cannot neutralize receptor-bound TNFa. Additionally, the anti-TNF antibodies Humira and Remicade have the capability of lysing cells involved in the inflammatory process, whereas the receptor fusion protein apparently lacks this capability. Although the clinical significance of these differences have not been absolutely proven, they may account for the differential actions of these drugs in both efficacy and side effects.
Infliximab has high specificity for TNFα, and does not neutralize TNF beta (TNFβ, also called
lymphotoxinLymphotoxin is a lymphokine cytokine.It is a protein that is produced by "killer" CD8+ T cells that kill the virally infected cells by producing holes in the cell's cell membrane.-See also:...
α), an unrelated cytokine that uses different receptors from TNFα. Biological activities that are attributed to TNFα include: induction of proinflammatory
cytokineCytokines are any of a number of substances that are secreted by specific cells of the immune system which carry signals locally between cells, and thus have an effect on other cells. They are a category of signaling molecules that are used extensively in cellular communication. They are proteins,...
s such as
interleukinInterleukins are a group of cytokines that were first seen to be expressed by white blood cells , The term interleukine, as a means of communication, deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes...
(IL) 1 and IL 6, enhancement of leukocyte movement or migration from the blood vessels into the tissues by increasing the permeability of endothelial layer of blood vessels; and increasing the release of adhesion molecules. Infliximab prevents disease in transgenic mice (a special type of mice that are biologically engineered to produce a human form of TNFα and which are used to test the results of these drugs that might be expected in humans). These experimental mice develop arthritis as a
result of their production of human TNFα, and when administered after disease onset, infliximab allows eroded joints to heal.
Infliximab in Crohn's disease
There are three
phenotypeA phenotype is any observable characteristic or trait of an organism: such as its morphology, development, biochemical or physiological properties, or behavior. Phenotypes result from the expression of an organism's genes as well as the influence of environmental factors and possible interactions...
s, or categories of disease presentation in
Crohn's diseaseCrohn's disease is an inflammatory disease of the intestines that may affect any part of the gastrointestinal tract from anus to mouth, causing a wide variety of symptoms...
:
stricturing disease (which causes narrowing of the bowel),
penetrating disease (which causes
fistulaIn medicine, a fistula is an abnormal connection or passageway between two epithelium-lined organs or vessels that normally do not connect. It is generally a disease condition, but a fistula may be surgically created for therapeutic reasons.-Location of fistulas:Fistulas can develop in various...
e or abnormal connections of the bowel), and
inflammatory disease (which causes primarily
inflammationInflammation is the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. Inflammation is not a...
).
Fistulizing disease
Infliximab was first used for closure of fistulae in
Crohn's diseaseCrohn's disease is an inflammatory disease of the intestines that may affect any part of the gastrointestinal tract from anus to mouth, causing a wide variety of symptoms...
in 1999. In a 94 patient phase II clinical trial by
Present et al., the researchers showed that Infliximab was effective in closing fistulae between the
skinThe skin is the outer covering of the body. In humans, it is the largest organ of the integumentary system made up of multiple layers of mesodermal tissue, and guards the underlying muscles, bones, ligaments and internal organs. Skin of a different nature exists in amphibians, reptiles, birds...
and bowel in 56-68% of patients. A large 296 patient Phase III clinical trial conducted by Bruce Sands et al., called the ACCENT 2 trial, showed that infliximab was additionally beneficial in maintaining closure of fistulae, with almost two-thirds of all patients treated with the 3 initial doses REMICADE having a fistula response after 14 weeks, and 36% of patients maintaining closure of fistulae after a year, compared to 19% who received
placeboA placebo is a sham medical intervention. In one common placebo procedure, a patient is given an inert sugar pill, told that it may improve his/her condition, but not told that it is in fact inert...
therapy. This final trial resulted in the FDA approval of the drug to treat fistulizing disease.,
Inflammatory disease
Infliximab has also been used in order to induce and maintain remission in inflammatory
Crohn's diseaseCrohn's disease is an inflammatory disease of the intestines that may affect any part of the gastrointestinal tract from anus to mouth, causing a wide variety of symptoms...
. The ACCENT 1 trial was a large multicentre trial that showed that 39 to 45% patients treated with infliximab who had an initial response to it, maintained remission after 30 weeks, compared to 21% who received placebo treatment. It also showed a mean maintenance of remission from 38 to 54 weeks compared to 21 weeks for patients who received placebo treatment.
Crohn's patients have flares of their disease between periods of disease quiescence. Severe flares are usually treated with
steroidPrednisone is a synthetic corticosteroid drug that is particularly effective as an immunosuppressant, and affects virtually all of the immune system. It is used to treat certain inflammatory diseases and cancers, but has significant adverse effects. It is usually taken orally but can be delivered...
medications to obtain remission, but steroids have many undesirable side effects, and therefore some gastroenterologists are now advocating for the use of infliximab as the first drug to try to get patients into
remissionRemission may refer to:*Remission , the reflection or scattering of light by a material*Remission *Remission *Re-Mission, a video game for young people with cancer...
. This has been called the
top-down approach to treatment.
Infliximab in ulcerative colitis
Infliximab targets TNF, thought to be more related to Th1 cytokines. Ulcerative colitis was thought to be a Th2 disease, and Infliximab of limited use. However, patients with ulcerative colitis have begun to be treated with infliximab on the basis of two large clinical trials conducted in 2005 by Paul Rutgeerts and William Sandborn. The ACT 1 and ACT 2 (Acute ulcerative Colitis Treatment) trials evaluated the utility of infliximab in ulcerative colitis and showed that 44-45% of patients treated with infliximab for a year maintained a response to the medication, compared to 21% of patients who were treated with placebo medication. At 2 months, the response was 61-69% for patients treated with infliximab, and 31% for those who were treated with placebo.
Safety
According to the product labeling of infliximab, etanercept, and adalimumab, these drugs are in the class of immunosuppressants. A number of studies and reports of adverse and serious adverse reactions in patients receiving infliximab have been conducted. Risks include:
- serious and sometimes fatal blood disorders
- serious infection
An infection is the detrimental colonization of a host organism by a foreign species. In an infection, the infecting organism seeks to utilize the host's resources to multiply, usually at the expense of the host. The infecting organism, or pathogen, interferes with the normal functioning of the...
s
- lymphoma and solid tissue cancers
- reports of serious liver injury
- reactivation of hepatitis B
- reactivation of tuberculosis
- lethal hepatosplenic T-cell lymphoma
- drug induced lupus
- demyelinating central nervous system
The central nervous system is the part of the nervous system that functions to coordinate the activity of all parts of the bodies of bilaterian animals—that is, all animals more advanced than sponges or jellyfish. In vertebrates, the central nervous system is enclosed in the meninges. It contains...
disorders
Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia (some fatal) have been reported with infliximab.
http://www.remicade.com/remicade/global/hcp/healthcare_professionals.html The FDA issued a warning to doctors appearing in the respective product labeling of infliximab instructing them to screen and monitor potential patients more carefully
http://www.fda.gov/medwatch/safety/2006/May_PIs/Remicade_PI.pdf.
Maintenance therapy with the drug (versus intermittent or sporadic therapy) lessens the likelihood of developing antibodies to infliximab which are known to reduce the efficacy of the drug. Combination treatment with
methotrexateMethotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug used in treatment of cancer and autoimmune diseases. It acts by inhibiting the metabolism of folic acid...
(an anti-folate drug which suppresses the immune system) has been shown to reduce the formation of these antibodies in patients with rheumatoid arthritis and combination therapy with other immunosuppressants has been shown to reduce the likelihood of these antibodies being formed in Crohn's disease. The use of immunosuppressants may not be necessary in all diseases for which infliximab is indicated, and indiscriminant use of these other immunosuppressants carry their own risks. Infliximab was studied in monotherapy (without concomitant immunosuppressants such as methotrexate or
azathioprineAzathioprine is a drug that suppresses the immune system.Azathioprine is used in organ transplantation and autoimmune disease. Some of the autoimmune diseases are rheumatoid arthritis, pemphigus, Inflammatory Bowel Disease , multiple sclerosis, autoimmune hepatitis and restrictive lung...
) in psoriasis, psoriatic arthritis, and ankylosing spondylitis. Only its use in rheumatoid arthritis requires the concomitant use of methotrexate by FDA product labeling, however the concomitant use of methotrexate in other disease states may help to reduce the body's immune response to the infliximab and increase its duration of efficacy.
Other uses
Case studies have been done into other uses of infliximab, such as to treat skin diseases. Remicade (infliximab) has been approved for treating
ankylosing spondylitisAnkylosing spondylitis , previously known as Bechterew's disease, Bechterew syndrome, and Marie Strümpell disease, a form of Spondyloarthritis, is a chronic, inflammatory arthritis and autoimmune disease...
,
Crohn's diseaseCrohn's disease is an inflammatory disease of the intestines that may affect any part of the gastrointestinal tract from anus to mouth, causing a wide variety of symptoms...
, fistulizing Crohn's disease, pediatric Crohn's disease,
psoriatic arthritisPsoriatic arthritis is a type of inflammatory arthritis that, according to the National Psoriasis Foundation, affects around 10-30% of people suffering from the chronic skin condition psoriasis...
,
psoriasisPsoriasis is a chronic, non-contagious autoimmune disease that affects the skin and joints. It commonly causes red, scaly patches to appear on the skin. The scaly patches caused by psoriasis, called psoriatic plaques, are areas of inflammation and excessive skin production. Skin rapidly...
,
rheumatoid arthritisRheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks the joints producing an inflammatory synovitis that often progresses to destruction of the articular cartilage and ankylosis of the joints...
, and
ulcerative colitisUlcerative colitis is a form of inflammatory bowel disease . Ulcerative colitis is a form of colitis, a disease of the intestine, specifically the large intestine or colon, that includes characteristic ulcers, or open sores, in the colon. The main symptom of active disease is usually constant...
. Infliximab is also prescribed (out of indication) for the treatment of Behcet's disease and infusions of infliximab have been used successfully in the treatment of sciatica due to slipped discs.
There have been numerous case reports of the efficacy of infliximab in various inflammatory skin conditions diseases; psoriasis, in which increased TNFα has been demonstrated, is the most recent indication.
Psoriatic arthritis (PsA), a chronic systemic inflammatory disorder characterized by the association of arthritis and psoriasis, follows a heterogeneous and variable clinical course. Inhibitors of TNF, such as infliximab, substantially improve the signs and symptoms of psoriasis (level 1b, grade A). Several therapies with modest efficacy have been studied in nail psoriasis. Among available agents, higher quality data are available to support the efficacy of cyclosporine and infliximab, a TNF antagonist. Based on studies in AS, the results suggest that infliximab, etanercept, and adalimumab have the potential to reduce the signs and symptoms of moderate to severely active axial involvement in PsA in patients who have had an inadequate response to NSAID (level 1a, grade A).The anti-TNF agents (infliximab and etanercept; level 1b, grade A) are more effective for the treatment of enthesitis than traditional agents.Results suggest that infliximab is effective for the treatment of dactylitis in PsA (level 1b, grade B). KAVANAUGH et al., Systematic Review of Treatments for Psoriatic Arthritis: An Evidence Based Approach and Basis for Treatment Guidelines. 2006; J Rheumatol 2006;33:1417–21)
Availability/Affordability
Like all of the TNF inhibitors, infliximab is an expensive medication, costing about US$1650 for a 100 mg dose, and is covered by almost every medical insurance plan (though caps on many plans make it possible to be covered for only a subset of treatments in the course of a year).
According to the labeling, the current dosing is:
- Ankylosing spondylitis
Ankylosing spondylitis , previously known as Bechterew's disease, Bechterew syndrome, and Marie Strümpell disease, a form of Spondyloarthritis, is a chronic, inflammatory arthritis and autoimmune disease...
: 5 mg per kg
- Crohn's disease
Crohn's disease is an inflammatory disease of the intestines that may affect any part of the gastrointestinal tract from anus to mouth, causing a wide variety of symptoms...
: 5 mg per kg
- Psoriatic arthritis
Psoriatic arthritis is a type of inflammatory arthritis that, according to the National Psoriasis Foundation, affects around 10-30% of people suffering from the chronic skin condition psoriasis...
: 5 mg per kg
- Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks the joints producing an inflammatory synovitis that often progresses to destruction of the articular cartilage and ankylosis of the joints...
: 3 mg per kg
- Psoriasis
Psoriasis is a chronic, non-contagious autoimmune disease that affects the skin and joints. It commonly causes red, scaly patches to appear on the skin. The scaly patches caused by psoriasis, called psoriatic plaques, are areas of inflammation and excessive skin production. Skin rapidly...
: 5 mg per kg
See also
- Adalimumab
Adalimumab is the third TNF inhibitor, after infliximab and etanercept, to be approved in the United States. Like infliximab and etanercept, adalimumab binds to TNFα, preventing it from activating TNF receptors; adalimumab was constructed from a fully human monoclonal antibody, while infliximab...
- Biological therapy for inflammatory bowel disease
Biological therapy refers to the use of medication that is tailored to specifically target an immune or genetic mediator of disease. Even for diseases of unknown cause, molecules that are involved in the disease process have been identified, and can be targeted for biological therapy; many of...
- Etanercept
Etanercept is a drug that treats autoimmune diseases by interfering with the TNF receptor by acting as a TNF inhibitor.Etanercept is a fusion protein produced through expression of recombinant DNA...
- Monoclonal antibody
- Tumor necrosis factors
Tumor necrosis factors refers to a group of cytokines family that can cause cell death.-History:At the end of 19th century William Coley, a New York surgeon, described remission of tumors following bacterial infection...
External links