The human gastrointestinal tract can be a hostile place for visitors. It’s filled with digestive acids and microorganisms that rapidly break down swallowed bits of food, and it can be just as rough on non-food molecules. That includes some of the latest drugs for the treatment of inflammatory bowel disease (IBD). “Some medications that target the immune system don’t work if they’re swallowed because your gut would digest them like a piece of steak,” says Dr. Gilaad Kaplan, a gastroenterologist, IBD researcher, and professor of medicine at the University of Calgary in Canada. “You have to deliver these medications to the immune system in a way that bypasses the GI tract.” One method of bypassing the gut is known as an infusion, which is essentially a drawn-out intravenous injection.
Infusion therapies for IBD have long been used in patients who need rapid, high-doses of a drug, or who are too unwell to swallow pills. For example, Kaplan says people with IBD who are very sick and hospitalized are sometimes administered systemic corticosteroids via intravenous infusion. However, infusions have become a more common method of delivering IBD drugs thanks to the emergence of biologics. Biologics are medicines made from living cells that are designed to locate and alter the activity of immune system proteins that promote inflammation, and many of them have to be administered via infusion.
“Traditional chemical drugs bind to receptors on cells, which can lead to a whole cascade of things happening on a cellular level,” Kaplan explains. While this cascade can be helpful, it can also give rise to negative side effects. “The cool thing about biologics is that they usually only block a single protein,” he says. As a result, these drugs are often capable of altering immune functioning or inflammation very narrowly. Put another way, the medication’s effects are often more “targeted” and less likely to result in unwanted side effects, he says.
Here, Kaplan and other experts describe some of the most common infusion therapies for IBD. They explain how they’re administered, their risks and benefits, and who is an appropriate candidate for these treatments.
How infusion therapies work
Many types of IBD therapy involve needle injections. But infusions aren’t the same as a simple shot. “There are some subcutaneous shots that the patient can administer themselves at home,” says Dr. Bruce Sands, chief of the division of gastroenterology and a professor of medicine at the Icahn School of Medicine at Mount Sinai. “With an infusion, the drug is usually diluted with something like salt water and given in greater volume via an intravenous catheter.” The infusion can last anywhere from 30 minutes to a couple of hours, he says, and therefore self-administration is not an option. Most people have to visit a hospital or clinic to receive the treatment, which can be time-consuming and inconvenient—especially for those who don’t live near a medical facility.
On the other hand, while most oral drugs (and some injectable treatments) are taken on a daily basis, infusion therapies are usually more spread out. “The biological half-life of infused drugs tends to be much longer than an oral pill,” Kaplan says. This means it takes the human body more time to clear out the drug, and so the therapeutic effect of an infusion therapy can last for weeks or even months, as opposed to mere hours for an oral drug. After the initial “loading doses” of a biologic infusion therapy are completed—something that can take six to 12 weeks—later maintenance doses tend to be required only once every two months. “The relative infrequency can be a benefit,” Sands says. Also, because these therapies are administered in a medical setting, nurses or other providers are on-hand to monitor and address potential adverse reactions. “These are very rare, but might include things like shortness of breath or a rash, or a sudden drop in blood pressure,” he says.
Infusion therapies, like most other IBD treatments, are usually taken indefinitely. “These drugs are not cures—they only suppress the immune or inflammatory state,” Sands says. “Patients usually relapse if we stop the treatment.” Infusion therapies also tend to be expensive. Annual costs of biologics, for example, run between $20,000 and $30,000, and insurance usually covers the tab only for people with severe IBD who haven’t responded well to less-expensive treatments.
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The newest infusion therapies
Infusions of biologics have been a mainstay of treatment for moderate and severe IBD for the past 20 years. But a lot has changed during those two decades—and especially during the past seven years.
“We’ve been using infliximab since the early 2000s, and in 2005 adalimumab came along,” Kaplan says. Both of these biologics began as treatments for other immune disorders, but were eventually shown to benefit people with IBD. Both of these drugs work by interfering with an immune system molecule called tumor necrosis factor, or TNF. “TNF is basically a messenger molecule that calls on an inflammatory response,” he explains. “With Crohn’s disease and ulcerative colitis and other immune diseases, TNF is perpetually being expressed and telling the immune system to effectively attack ‘ghost’ pathogens that aren’t really there.” Infusions of TNF blockers can stop those inappropriate attacks by binding to TNF receptors, which limits the molecule’s ability to stoke inflammation.
While anti-TNF infusion therapies are effective, they can in some cases impair the immune system’s ability to fend off infections. These drugs are also associated with a small increase in risk for blood malignancies such as lymphoma, he says. TNF blockers are still used today (they can be especially useful for people who have IBD and other common immune conditions, such as rheumatoid arthritis), but the latest infusion therapies are more targeted and less likely to cause side effects. “The immune system is like a tree with all these branches coming out of it,” Kaplan says. “We really want to prune the branches that are causing the problems while leaving the rest of the tree alone.” Some of the newest biologics accomplish this by manipulating the activity of immune system molecules known as integrins. These diverse molecules are akin to small branches on the outskirts of the immune-system tree. Turning them off leaves most of the immune system intact. “They’re targeting a very finite area while leaving the rest of this complex network alone, which has been a huge breakthrough,” he says. For example, vedolizumab is an anti-integrin infusion therapy that selectively blocks the immune response in the gut and is used in the treatment of IBD.
In medical science, new advancements often reveal new challenges. And that has proved true for the development of IBD infusions. “As we’re doing more immune-system analyses, what we’re finding is that different IBD patients have different cytokine profiles,” says Dr. Karen Madsen, an IBD researcher and professor in the division of Ggastroenterology at the University of Alberta in Canada. “We’re learning that no matter how good the drug is, only a subset of patients will actively respond.”
Even if a person does respond well to a drug, there’s no assurance that this response will continue indefinitely. “Another thing we’ve learned is that this disease has escape mechanisms,” Kaplan says. “It finds ways to bypass the immune system, and so we sometimes need to use another drug to recover the good response.” Biologic infusion therapies are sometimes combined with oral medications. “The immune system is so complex that sometimes blocking one of these proteins is not enough,” he explains.
Who is a candidate for infusion therapy?
Answering that question is tricky. Experts say that no two IBD patients are the same. Medical science is getting much better at identifying immune system “markers,” or biological indicators, that can predict a person’s response to an infusion therapy. (This is one of the hottest areas of IBD research.) But at this point, it can still be difficult to predict how well a person with IBD will react to an infusion therapy. “Right now, these are usually reserved for people with moderate-to-severe disease who are not doing well on other treatments,” Kaplan says. “We usually don’t start with biologic infusion therapies; we escalate up to them.”
Because of the cost and logistical burden of administering infusion therapies, many people who might benefit aren’t on them. “It’s safe to say that a higher proportion of patients are good candidates than are actually getting them,” Sands says. When it comes to biologics, he says that—for reasons that are unclear—people with Crohn’s disease are more likely to receive these drugs than people with ulcerative colitis. “We see more widespread use in Crohn’s,” he says. “Estimates are that somewhere around 30% of people with Crohn’s may be getting a biologic therapy, and that’s maybe 15% or at most 20% in people with ulcerative colitis.”
Sands and other IBD experts agree that these drugs have been truly revolutionary. But like all medications, they come with side effects. Again, these are more commonplace among the older anti-TNF drugs, which can raise a person’s risks for skin symptoms (rashes, mostly), infections, and some blood cancers. Sands says the newer biologic medications have a much improved safety profile.
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The future of infusion therapy
There are efforts to help move these treatments out of the clinic. Recent advances in the equipment and techniques required to administer these drugs have made at-home use possible for some patients. Down the road, many people who need these drugs may be able to take them outside of a medical setting.
Meanwhile, the number of effective IBD infusion therapies is growing quickly. “Since around 2015, we’ve seen an explosion of different biologics working on different mechanisms of action, and I think in the next year or two we’ll see a bunch of new therapies for IBD coming to market,” Kaplan says.
The need for newer and more convenient IBD drugs is urgent. For reasons that aren’t well understood, IBD is increasingly common across much of the world. It’s also becoming more prevalent in younger people. Kaplan says that changes in the composition of the gut microbiome—the community of organisms that resides in the human GI tract—are likely a major contributor to the rising prevalence of IBD. But there’s no simple answer to the question of what’s going wrong with our guts. A mix of inherited and environmental factors is likely at play.
While experts are sorting that out, the latest infusion therapies are providing durable relief for people with IBD. “Our ability to treat these conditions has really improved,” Kaplan says.
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Contributor: Markham Heid