Infliximab

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Overview
Infliximab (brand name Remicade) is a drug used to treat autoimmune disorders. Infliximab is known as a "chimeric monoclonal antibody" (the term "chimeric" refers to the use of both mouse (murine) and human components of the drug i.e. murine binding VK and VH domains and human constant Fc domains). The drug blocks the action of TNFα (tumour necrosis factor alpha) by binding to it and preventing it from signaling the receptors for TNFα on the surface of cells. TNFα is one of the key cytokines that triggers and sustains the inflammation response. Remicade was developed by Junming Le and Jan Vilcek at New York University School of Medicine and developed by Centocor, a biotechnology company later purchased by Johnson & Johnson.

Infliximab has been approved by the U.S. Food and Drug Administration for the treatment of psoriasis,Crohn's disease, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis. According to the manufacturer's websites, there are more patients world-wide who have been treated with Remicade (the first commercially available TNF antagonist) than Enbrel and Humira combined.

Remicade is administered by intravenous infusion, typically at 6-8 week intervals, and at a clinic or hospital. It cannot be administered orally, because the digestive system would destroy the drug.

Pharmacology
According to product labeling, Infliximab neutralizes the biological activity of TNFα by binding with high affinity 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 lymphotoxin α), a related but less inflammatory cytokine that utilizes the same receptors as TNFα. Biological activities that are attributed to TNFα include: induction of proinflammatory cytokines such as interleukin (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 phenotypes, or categories of disease presentation in Crohn's disease: stricturing disease (which causes narrowing of the bowel), penetrating disease (which causes fistulae or abnormal connections of the bowel), and inflammatory disease (which causes primarily inflammation).

Fistulizing disease
Infliximab was first used for closure of fistulae in Crohn's disease 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 skin 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 placebo 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 disease. 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 steroid 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 remission. This has been called the top-down approach to treatment.

Infliximab in ulcerative colitis
As infliximab targets TNF, thought to be more related to Th1 cytokines, it was initially thought to be of limited utility in ulcerative colitis, which was thought to be a Th2 disease. 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. After a number of studies and reports of adverse reactions in patients receiving anti-TNFα therapy (including serious and sometimes fatal blood disorders, infections, rare reports of lymphoma and solid tissue cancers, rare reports of serious liver injury, rare reports of drug induced lupus and rare reports of demyelinating central nervous system disorders), the FDA issued a warning to doctors appearing in the respective product labeling of these drugs instructing them to screen and monitor potential patients more carefully. Maintenance therapy with the drug (versus intermittent or sporadic therapy) lessens the likelihood of developing antibodies to infliximab which could reduce the efficacy of the drug. Combination treatment with methotrexate (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 liklihood 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 concommitant immunosuppressants such as methotrexate or azathioprine) in psoriasis, psoriatic arthritis, and ankylosing spondylitis, and only its use in rheumatoid arthritis requires the concomitant use of methotrexate by FDA product labeling. There are case reports of remicade infusions being associated with myocarditis.

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 spondylitis, Crohn's disease, fistulizing Crohn's disease, pediatric Crohn's disease, psoriatic arthritis, psoriasis, rheumatoid arthritis, and ulcerative colitis. 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, Remicade is an expensive medication, costing about $1000 for a 100mg dose, and is covered by almost every medical insurance plan. It is administered every 6-8 weeks, with an initial startup requiring smaller time frames between infusions. According to the labeling, the current posology is:
 * Ankylosing Spondylitis: 5mg per kg
 * Crohn's disease: 5mg per kg
 * Psoriatic Arthritis: 5mg per kg
 * Rheumatoid Arthritis: 3mg per kg
 * Psoriasis: 5mg per kg