New IBD Drug Entyvio Is Not for the Faint of Immune System

Possible adverse effect of Entyvio concerns physicians.

Crohn's Disease.

Primum non nocere.  An aphorism that encapsulates the enduring spirit of medicine: "First, do no harm."  We live in a world where physicians are expected to do something, do anything to treat disease.  But sometimes the repercussions of action outweigh the benefit of inaction.  For example, physicians don't perform surgery on nonsurgical candidates; physicians don't give high-dose chemo to people ravaged by deadly metastatic cancer; and physicians try to avoid treating patients with medications with life-threatening adverse effects.

Entyvio is a new drug aimed at helping people with inflammatory bowel disease (IBD), a debilitating illness which erodes the quality of life in those affected.  Its maker (Takeda Pharmaceuticals), the FDA and gastroenterologists everywhere worry, however, that people who take Entyvio may open themselves up to infection with progressive multifocal leukoencephalopathy (PML). 

PML is a rare infection of the central nervous system usually only experienced by those with severely compromised immune systems (think people with AIDS).  So far, Entyvio hasn't yet caused PML in any people taking it, but its chemical cousin, another integrin receptor antagonist called natalizumab, causes PML in about 1 person per 1000 receiving treatment.  In sum, the possible adverse effects of Entyvio may outweigh its clinical utility in people with IBD and weakened immune systems.

What is IBD?

Your gut is a dirty place.

It's filled with bacteria that help us digest our food.  Remember that bacteria are bugs, and, anywhere outside the gut, such bacteria would cause a mega-immune reaction.  (To quote Bill Murray's character from Ghostbusters, "human sacrifice, dogs, and cats living together, mass hysteria!") Consequently, the immune cells in our gut are on constant guard, and "physiological inflammation" is the status quo.

Fortunately, through complex mechanisms, our body dampens the full-on activation of gut-associated lymphoid tissue.  Granted all this postulating is just consensus hypothesis, and we all know, some consensus hypotheses turn out to be crap (pun totally intended); nevertheless, knowing what we know about IBD, all this makes sense.

As is evident from its name, inflammatory bowel disease is a condition whose hallmark is inflammation. It has a bimodal distribution with peak ages of onset between 15 and 30 and 60 and 80 with an increased prevalence in Ashkenazi Jews. The clinical symptoms of IBD are nasty: abdominal pain, diarrhea, bleeding, anemia, and weight loss. It can also manifest in anatomic locations outside the gut and cause arthritis, eye problems (uveitis and iritis), rash (erythema nodosum) and more. 

IBD comes in two terrible flavors; ulcerative colitis and Crohn's disease.  Although similar in many ways, there are some key differences between these two types of IBD.  Ulcerative colitis is confined to the colon and hits confluent or contiguous portions of the bowel; whereas Crohn's disease can affect any part of the GI tract (from mouth to anus) and is patchy in its pathology, tending to skip areas of the GI tract.

Most commonly, Crohn's disease messes up the real estate adjacent to the ileocecal valve.  Crohn's disease also causes transmural lesions which affect the entire thickness of the bowel resulting in strictures or even fistulas (unwelcome passageways between parts of the intestine).

With respect to IBD, physicians aim to control acute exacerbations or flare-ups, maintain remission from such flare-ups and treat fistulas and obstructions (caused by strictures) and provide other measures of symptomatic treatment.  Most people with IBD end up having surgery at some point in their lives.  (On a personal note, one of the saddest things that I've ever witnessed was a young newlywed with IBD crying after a bowel resection that left him with a colectomy bag.  His honeymoon was cut short by an acute flare-up of Crohn's disease.)

The mainstay of most medical treatment of IBD includes immunosuppressant drugs such as glucocorticoids, sulfasalazine, and 5-aminosalicylic acid.  Azathioprine and cyclosporine are other anti-inflammatory and immunosuppressant drugs that are useful in treating IBD.  Most recently, biologic agents such as the aforementioned natalizumab and vedolizumab (Entyvio) have been used to treat IBD.

Entyvio and Progressive Multifocal Leukoencephalopathy (PML)

According to the FDA:

Entyvio is an integrin receptor antagonist. Integrin receptors are proteins expressed on the surface of certain cells. Integrin receptors function as bridges for cell-cell interactions. Entyvio blocks the interaction of a specific integrin receptor (expressed on circulating inflammatory cells) with a specific protein (expressed on cells in the interior wall of blood vessels), and thereby blocks the migration of those circulating inflammatory cells across those blood vessels and into areas of inflammation in the gastrointestinal tract.

Furthermore, according to the FDA:

Results showed that a greater percentage of participants treated with Entyvio compared to a placebo achieved and maintained clinical response, achieved and maintained clinical remission, achieved corticosteroid-free clinical remission, and as seen during endoscopy, had improved appearance of the colon

In other words, Entyvio works by mitigating inflammation in the GI tract and has proven effective when treating flare-ups and maintaining steroid-free remission.  Of note, a meta-analysis of Entyvio and other biologic agents showed that Entyvio was equally effective at maintaining remission in people with ulcerative colitis as other types of biologic agents.  Of note, entyvio is intended for people who are unresponsive to or intolerant of other medications used to treat IBD (like steroids or biologic agents).

So far, documented adverse reactions caused by Entyvio were mostly limited to headache, joint pain, nausea, and fever.  More serious reactions included allergy and hepatotoxicity (liver toxicity).  But physicians, the feds, and the drug's maker are on the lookout for a much more serious adverse effect that has yet to rear its ugly head: progressive multifocal leukoencephalopathy (PML).

PML is a neurological disease that results from infection with the JC virus  Most of us have antibodies to this virus and infection in healthy people is exceedingly rare.  But in people whose immune systems are leveled by HIV, cancer, sarcoidosis, and other diseases, PML can take hold. 

In people with PML, the JC virus demyelinates oligodendrocytes or nerve cells primarily in the cerebral hemispheres but also brain stem or cerebellum.  In other words, this virus strips our white matter of myelin needed for nerve conduction.  Symptoms include dementia, vision problems, paralysis (hemiparesis), trouble speaking (aphasia) and sensory impairment.

Within 3 to 6 months, PML kills about 50 percent of those infected.  Prognosis for those who develop PML on account of natalizumab therapy for multiple sclerosis is a bit better; only 20 percent die.  But even for those who end up living with PML, disability is profound.  According to Harrison's Principles of Internal Medicine, as of its 2012 publication date, 104 people treated with natalizumab for multiple sclerosis developed PML, and only one person treated for Crohn's developed the disease.

What do worries about Entyvio causing PML mean to you?

If you or a loved one suffers from IBD--especially IBD that is unresponsive to steroids and other immunomodulators--Entyvio looks like promising treatment.  However, before beginning treatment with Entyvio, it's imperative that you disclose any current infections or infections that "don't go away" and may suggest a weakened immune system.  Moreover, if you were recently vaccinated, you shouldn't be taking Entyvio either.  (Of note, you shouldn't take Entyvio if you have liver problems, allergic reactions, and so forth.)  If you do develop neurological problems (or really any significant problems) while on Entyvio, it's imperative that you immediately contact your health care provider.

On a final note, it's important to remember that we have yet to observe PML in people taking Entyvio.  Furthermore, the FDA and Entyvio's maker are closely watching for cases of PML secondary to Entyvio administration and are currently conducting post-marketing studies and facilitating advanced and expedited reporting of adverse effects.

Selected Sources

Friedman S, Blumberg RS. Chapter 295. Inflammatory Bowel Disease. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 18e. New York, NY: McGraw-Hill; 2012.  Accessed November 15, 2014.

Greenberg DA, Aminoff MJ, Simon RP. Chapter 5. Dementia & Amnestic Disorders. In: Greenberg DA, Aminoff MJ, Simon RP. eds. Clinical Neurology, 8e. New York, NY: McGraw-Hill; 2012.  Accessed November 15, 2014.

"Vedolizumab (Entyvio) for Inflammatory Bowel Disease" from The Medical Letter on Drugs and Therapeutics published on 9/15/2014.  Accessed from PubMed on 11/15/2014.

Wallace JL, Sharkey KA. Chapter 47. Pharmacotherapy of Inflammatory Bowel Disease. In: Brunton LL, Chabner BA, Knollmann BC. eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e. New York, NY: McGraw-Hill; 2011. Accessed November 15, 2014.

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