Infliximab, a chimeric monoclonal antibody, sold under the brand name Remicade among others, is a medication used to treat a number of

autoimmune diseases 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 that ...

. This includes

Crohn's disease Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea, fever, abdominal distension, and weight loss. Complications outside of the ...

ulcerative colitis Ulcerative colitis (UC) is one of the two types of inflammatory bowel disease (IBD), with the other type being Crohn's disease. It is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary sympto ...

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 ...

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 ...

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 ...

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 ...

, and Behçet's disease. It is given by slow injection into a vein, typically at six- to eight-week intervals. Common side effects include infections, acute infusion reactions, and abdominal pain. Infliximab is a chimeric

monoclonal antibody A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodie ...

biologic. It seems to work by binding to and neutralizing TNF-α, preventing it from interacting with its receptors on the cell. TNF-α is a chemical messenger (

cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

) and a key part of the autoimmune reaction. Infliximab was originally developed in mice as a mouse antibody. Because humans have immune reactions to mouse proteins, the mouse common domains were replaced with similar human antibody domains. They are

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 ...

and have identical structures and affinities to the target. Because they are a combination of mouse and human antibody amino acid sequences, they are called a "chimeric monoclonal antibody". Infliximab was approved for medical use in the United States in 1998, and in the European Union in August 1999. Infliximab

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 ...

s have been approved in the EU (2013), in Japan (2014), and in the United States (2016, 2017, 2019). It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

Medical uses

Crohn's disease

Three

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...

s, or categories of disease, are present in

: stricturing disease (which causes narrowing of the bowel), penetrating disease (which causes

fistula In anatomy, a fistula (: fistulas or fistulae ; from Latin ''fistula'', "tube, pipe") is an abnormal connection (i.e. tube) joining two hollow spaces (technically, two epithelialized surfaces), such as blood vessels, intestines, or other h ...

e or abnormal connections of the bowel), and inflammatory disease (which primarily causes

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'', '' ...

Fistulizing disease

Infliximab was first used for closure of fistulae in Crohn's disease in 1999. In a 94-patient, phase II clinical trial, the researchers showed infliximab was effective in closing fistulae between the

skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different ...

and

bowel The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. T ...

in 56–68% of patients. A large, 296-patient Phase III clinical trial called the ACCENT 2 trial showed infliximab was additionally beneficial in maintaining closure of fistulae, with almost two-thirds of all patients treated with the three initial doses of infliximab having a fistula response after 14 weeks, and 36% of patients maintaining closure of fistulae after a year, compared with 19% who received

placebo A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials ...

therapy. This final trial resulted in the FDA approval of the drug to treat fistulizing disease.

Inflammatory disease

Infliximab has been used to induce and maintain remission in inflammatory Crohn's disease. The ACCENT 1 trial, a large, multicentre trial, found 39–45% of patients treated with infliximab, who had an initial response to it, maintained remission after 30 weeks, compared with 21% who received placebo treatment. It also showed a mean maintenance of remission from 38 to 54 weeks compared with 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

steroid A steroid is an organic compound with four fused compound, 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 t ...

medications to obtain remission, but steroids have many undesirable side effects, so some gastroenterologists are now advocating the use of infliximab as the first drug to try to get patients into remission. This has been called the top-down approach to treatment.

Ulcerative colitis

Infliximab targets TNF, thought to be more related to Th1 cytokines. Ulcerative colitis was thought to be a Th2 disease, and infliximab would be 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 Acute ulcerative Colitis Treatment trials (ACT1 and ACT2) to evaluate the utility of infliximab in ulcerative colitis showed 44–45% of patients treated with infliximab for a year maintained a response to the medication, compared with 21% of patients who were treated with placebo medication. At two months, the response was 61–69% for patients treated with infliximab, and 31% for those treated with placebo.

Psoriatic arthritis

(PsA), inhibitors of TNF, such as infliximab, improve the signs and symptoms. 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 Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, nephrotic syndrome, ecz ...

and infliximab. Based on studies in AS, the results suggest infliximab, etanercept, and

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' ...

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 infliximab is effective for the treatment of dactylitis in PsA.

Other

It was approved for treating

, psoriatic arthritis, psoriasis,

. Infliximab is also prescribed (out of indication) for the treatment of Behçet's disease. Infliximab is the most frequently used biological agent in treating relapsing polychondritis. Half of the patients saw benefit from this treatment, and a few other patients experienced infections that in some cases lead to death. There have been numerous case reports of the efficacy of infliximab in various inflammatory skin conditions diseases; the FDA approved infliximab for chronic severe

plaque 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 ...

in adults in September 2006. Infliximab has been used off-label in treating refractory

sarcoidosis Sarcoidosis (; also known as Besnier–Boeck–Schaumann disease) is a disease involving abnormal collections of White blood cell, inflammatory cells that form lumps known as granulomata. The disease usually begins in the lungs, skin, or lymph n ...

, where other treatments have not been effective. Infliximab has been tested in

chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by chronic respiratory symptoms and airflow limitation. GOLD defines COPD as a heterogeneous lung condition characterized by chronic respiratory s ...

(COPD) but there was no evidence of benefit with the possibility of harm. Infliximab is indicated for steroid refractory checkpoint inhibitor induced colitis, at a dose of 5 to 10 mg/kg. Infliximab has been found to be a safe alternative treatment to a second dose of

IVIG Immunoglobulin therapy is the use of a mixture of antibodies (normal human immunoglobulin) to treat several health conditions. These conditions include primary immunodeficiency, immune thrombocytopenic purpura, chronic inflammatory demyelin ...

for

Kawasaki Disease Kawasaki disease (also known as mucocutaneous lymph node syndrome) is a syndrome of unknown cause that results in a fever and mainly affects children under 5 years of age. It is a form of vasculitis, in which medium-sized blood vessels become in ...

resistant to initial IVIG therapy, showing better outcomes in fever resolution and fewer severe adverse effects such as

hemolytic anemia Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular). This most commonl ...

Adverse effects

Infliximab has adverse effects, some life-threatening, common to drugs in the class of TNF inhibiting

immunosuppressants Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system. Classification Immunosuppressive drugs can be classified ...

(which also includes etanercept (

Enbrel 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. I ...

) and adalimumab ( Humira)). Some of the most severe are: * serious

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 ...

s * reactivation of

hepatitis B Hepatitis B is an infectious disease caused by the '' hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection. Many people have no symptoms during an initial infection. ...

* reactivation of

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 ...

* lethal hepatosplenic T-cell lymphoma (generally only when combined with 6-mercaptopurine) * drug-induced lupus * demyelinating

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

disorders *

and psoriasiform skin lesions * new-onset

vitiligo Vitiligo (, ) is a chronic autoimmune disorder that causes patches of skin to lose pigment or color. The cause of vitiligo is unknown, but it may be related to immune system changes, genetic factors, stress, or sun exposure, and susceptibili ...

Cases of

leukopenia Leukopenia () is a decrease in the number of white blood cells (leukocytes). It places individuals at increased risk of infection as white blood cells are the body's primary defense against infections. Signs and symptoms Symptoms may include: * s ...

neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...

thrombocytopenia In hematology, thrombocytopenia is a condition characterized by abnormally low levels of platelets (also known as thrombocytes) in the blood. Low levels of platelets in turn may lead to prolonged or excessive bleeding. It is the most common coag ...

, and

pancytopenia Pancytopenia is a medical condition in which there is significant reduction in the number of almost all blood cells (red blood cells, white blood cells, platelets, monocytes, lymphocytes, etc.). If only two parameters from the complete blood cou ...

(some fatal) have been reported with infliximab. 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. The FDA issued a warning to doctors that there is an increased risk of lymphoma and other cancers associated with the use of infliximab and other tumor necrosis factor blockers in children and adolescents. 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

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 ...

(an antifolate 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 uses of these other immunosuppressants carry their own risks. Infliximab was studied in monotherapy (without concomitant immunosuppressants such as methotrexate or azathioprine) in

, and

Pharmacology

Infliximab is a purified, recombinant DNA-derived chimeric human-mouse IgG

that consists of mouse heavy and

light Light, visible light, or visible radiation is electromagnetic radiation that can be visual perception, perceived by the human eye. Visible light spans the visible spectrum and is usually defined as having wavelengths in the range of 400– ...

chain variable regions combined with human heavy and light chain constant regions. It has a serum half-life of 9.5 days and can be detected in serum 8 weeks after infusion treatment. Infliximab neutralizes the biological activity of TNF-α by binding with high

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

to the soluble (free floating in the blood) and transmembrane (located on the outer membranes of

T cells T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their ce ...

and similar immune cells) forms of TNF-α, and inhibits or prevents the effective binding of TNF-α with its receptors. Infliximab and

(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 A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently u ...

-, and

receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...

-bound) of TNF-α. Etanercept, a third TNF antagonist, is in a different subclass (receptor-construct fusion protein), and, because of its modified form, cannot neutralize receptor-bound TNF-α. Additionally, the anti-TNF antibodies

and infliximab have the capability of lysing cells involved in the inflammatory process, whereas the receptor fusion protein apparently lacks this capability. Other monoclonal antibodies targeting TNF-α are golimumab,

, and certolizumab pegol. Etanercept also binds and inhibits the action of TNF-α, but is not a monoclonal antibody (it is instead a fusion of TNF-receptor and an antibody constant region).

History

The importance of TNF in the development of

was originally demonstrated by George Kollias and colleagues in proof of principle studies in transgenic animal models. Infliximab was developed by Junming Le (b. 1940) and Jan Vilček (b. 1933) at

New York University School of Medicine The New York University Grossman School of Medicine is a medical school of New York University, a private research university in New York City. It was founded in 1841 and is one of two medical schools of the university, the other being the NYU G ...

and in collaboration with Centocor (now Janssen Biotech, Inc.).

Society and culture

Marketing

Remicade is marketed by Janssen Biotech, Inc. (formerly Centocor Biotech, Inc.) in the United States,

Mitsubishi Tanabe Pharma Mitsubishi Tanabe Pharma Corporation is a Japanese pharmaceuticals company from Osaka, a subsidiary of Mitsubishi Chemical Holdings Corporation. was formed in 2001 from the merger of Mitsubishi-Tokyo Pharmaceuticals and Welfide Corporation. On ...

in Japan, Xian Janssen in China, and

Schering-Plough Schering-Plough Corporation was an American pharmaceutical company. It was originally the U.S. subsidiary of the German company Schering AG, which was founded in 1851 by Ernst Christian Friedrich Schering. As a result of nationalization, it becam ...

(now part of

Merck & Co Merck & Co., Inc. is an American Multinational corporation, multinational pharmaceutical company headquartered in Rahway, New Jersey. The company does business as Merck Sharp & Dohme or MSD outside the United States and Canada. It is one of the ...

) elsewhere.

Biosimilars

In June 2013, two

versions (Inflectra and Remsima) were submitted for approval in the European Union, by Hospira and Celltrion Healthcare respectively. Both had a positive opinion from

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

's (EMA) Committee for Medicinal Products for Human Use (CHMP) for sale in the European Union (EU). Celltrion obtained marketing authorization approval (MAA) from 27 EU countries and 3 EEA (European Economic Area) countries by September 2013. Inflectra was approved for use in the European Union in September 2013, and Remsima was approved for use in the European Union in October 2013. In Japan, Celltrion received marketing authorization for Remsima from Japan's Ministry of Health, Labour and Welfare (MHLW) in July 2014. In India, Epirus Biopharmaceuticals obtained approval to produce biosimilar infliximab under the brand name "Infimab" (trail name BOW015). The US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) approved Celltrion/Hospira/Pfizer's Inflectra (infliximab-dyyb) in April 2016. The FDA approved Samsung Bioepis Co., Ltd.'s Renflexis (infliximab-abda) in April 2017.

Biogen Biogen Inc. is an American multinational biotechnology company based in Cambridge, Massachusetts, United States specializing in the discovery, development, and delivery of the treatment of neurological diseases to patients worldwide. Biogen ope ...

released another biosimilar, Flixabi, which was approved in Germany, the UK, and the Netherlands. Flixabi was approved for use in the European Union in May 2016. In December 2017, Ixifi (infliximab-qbtx) was approved in the United States. Zessly was approved for use in the European Union in May 2018. In December 2019, Avsola (infliximab-axxq) was approved in the United States. Avsola was approved for medical use in Canada in March 2020. In December 2021, Ixifi was approved for medical use in Canada.

Availability/affordability

Infliximab is supplied as a sterile, white, lyophilized (freeze-dried) powder, so must be reconstituted and administered by a health care professional, usually in a hospital or office setting. For this reason, it is usually covered under major medical insurance rather than prescription drug coverage. The loading regimen for all approved indications occurs at weeks 0, 2, and 6 at the above dosages. In the UK, infliximab is available from the NHS for

treatment provided three criteria are met. Patients should have severe active Crohn's disease with a CDAI score of 300 or more, have not responded to immunomodulating drugs and corticosteroids, and for whom surgery is inappropriate. Since February 2015, it is also approved for the treatment of

where other treatments have not worked. In Australia, infliximab is available through the PBS for Crohn's disease treatment provided the patient has not responded to conventional treatment and has a severe case of the condition. Johnson & Johnson reported in its 2013 annual report, "Remicade (infliximab), accounted for approximately 9.4% of the Company's total revenues for fiscal 2013."JNJ annual report, downloaded 22 April 2014. Zymfentra was approved for medical use in the United States in October 2023.

References

External links

* {{Authority control Engineered proteins Immunosuppressants Drugs developed by Johnson & Johnson Janssen Biotech Janssen Pharmaceutica Drugs developed by Merck & Co. Monoclonal antibodies Drugs developed by Schering-Plough TNF inhibitors World Health Organization essential medicines