Jaime Holland was having an infusion of Remicade, the biologic she had been receiving for over a year, when she began to feel faint. She felt other symptoms too, ones she had never experienced while receiving the drug: Her mouth was itching, her throat was tightening, her chest was heavy.
She knew something was wrong. Very wrong.
She pushed the emergency button on her infusion chair and threw (she thinks) a magazine to alert the infusion center staff.
"They came rushing over,” says Holland, 37, who lives in Tampa, FL. She was diagnosed with Crohn's disease in 2005 (she also has psoriasis, psoriatic arthritis, and Hashimoto's thyroiditis). "I pointed to my throat, I pointed to my chest. I was afraid to speak because I felt that if I couldn’t get my voice out, I would panic even more."
They stopped the infusion of the biologic, pumped Benadryl (diphenhydramine) into her IV over the course of several hours, and eventually she could swallow again. It's possible she’d been experiencing an allergic reaction—an uncommon side effect to the drug. The likely reason why?
Holland had developed antibodies to the biologic, which is a large protein molecule that is a type of antibody, too, one that targets the proteins causing your inflammatory bowel disease (IBD). Having a reaction like Holland's is one possible sign that your biologic has stopped working—but it's not the only one. (And one important thing to note: Just because she experienced this reaction, doesn't mean you might. Allergic reactions happen with biologics, but they're not frequent.)
Given how successful biologics can be in controlling and even eliminating symptoms, having yours not only stop working but also make you sick can feel like a blow. That’s why we went to the experts and combed through the research to learn the how, why, and what behind biologic treatment failure so you can be prepared with a plan B.
How Often Do Biologics Fail?
First, it's important to get the language right, says gastroenterologist David T. Rubin, M.D. He's a spokesperson for the American Gastroenterological Association as well as chief of gastroenterology, hepatology, and nutrition at University of Chicago Medicine and Biological Sciences.
Instead of viewing biologics in terms of success or failure, when you’re on treatment for Crohn's disease, you either have a response, which means you have some improvement, or you go into remission, which is your ultimate treatment destination, he says.
"In clinical trials and subsequent real world studies, about 60% of people will have a response, but 35% to 40% will get into remission. And that’s an important point, because remission is really the goal," Dr. Rubin explains.
There are two main types of remission for all IBD treatments: clinical (which means you no longer have symptoms) and deep (which means your doctor sees no signs of disease with an endoscope).
"Over the last decade, biologics have validated their role in the treatment of moderate-to-severe IBD, including Crohn's disease," notes Lina Velikova, M.D., Ph.D., who specializes in immunology and gastroenterology at University Hospital (Synevo Bulgaria) in Sofia, Bulgaria, and is a medical writer. "Many randomized controlled trials have supported their efficacy."
However: "Biologic therapy is not a panacea," she says.
Glenn H. Englander, M.D., a gastroenterologist at the GastroGroup of the Palm Beaches in West Palm Beach, FL, emphasizes the 60% response rate when telling people with Crohn's disease about treatment, while keeping in mind the lower remission rate. The reality is, not all patients will benefit from a biologic, he says. While drugs fail people—and not the other way around—there are things people can do to impact the effectiveness of these medications, like missing doses.
Not that staying of top of your injection schedule is always the easiest: A University of Virginia study found that over a two-year period, adherence (meaning, patients took it) to Humira (adalimumab) was 57%, and to Cimzia (certolizumab pegol) was 50%. Both biologics are given by injections, typically by yourself, at home.
By contrast, infusions, typically given at an infusion clinic by IV, had adherence rates of 83% (Entyvio, vedolizumab) and 70% (Remicade, infliximab). (Biologics not studied here but also available in the U.S. market for Crohn’s disease are Tysabri (natalizumab) and Stelara (ustekinumab).)
"We stress the need for compliance," Dr. Englander says. "Once you stop, restarting biologics does not always work as well."
According to Dr. Rubin, sticking to your biologic schedule is one of three factors that can make all the difference in achieving and staying in deep remission when you have Crohn's disease:
- Discuss with your doctor how the drug should be dosed.
- Be strictly adherent.
- Maintain regular follow-up visits with your doctors so they can assess your response.
"We have made great progress in understanding how to achieve deep remission and how to monitor and to prevent loss of response," he says.
Why Aren't You Experiencing a Response to Your Biologic?
Here's the kicker.
It could be that your biologic hasn't "failed" at all. If you have symptoms common to a Crohn’s flare, you could have an infection like Costridioides difficile, which can be common in IBD patients.
Or you could have irritable bowel syndrome (IBS), small-intestinal bacterial overgrowth, Celiac disease, scarring, strictures, or other issues related to previous surgery.
This is why your doctor will test you for infections and other disease-related issues before changing medications, says gastroenterologist Adam C. Ehrlich, M.D., co-medical director, Temple Inflammatory Bowel Disease Program in Philadelphia. He runs lab work for patients before considering what's behind a patient not responding to a biologic, which helps him determine the next step in treatment.
There are two main mechanisms for a not-so-positive response, he says:
- Primary non-response: You start a biologic, and it doesn't work for you during initial doses of the drug.
- Secondary non-response: You start a biologic and it works for a while—maybe even years—and then stops working.
Treatment changes are often determined depending on when, and why, a biologic doesn't put a Crohns patient into remission.
All About Primary Non-Response
Here's how Dr. Velikova explains this mechanism of non-response:
"In the primary absence of response, there is no effect from the therapy, although patients have adequate blood levels of the drug," she says. "Usually, no antibodies to the drug are detected. In this case, the patient needs to have the class of their medication changed."
Three classes of biologics are U.S. Food and Drug Administration (FDA)-approved for Crohn's disease:
- Anti-tumor necrosis factor (TNF) agents
- Integrin-receptor antagonists
- Interleukin-12 and -23 antagonist
Changing drug class gives you a fighting chance at success on biologics if your inflammatory response in IBD was due to a protein other than the one your biologic targeted. That was likely the case for Shawn Bethea, 27, who lives in Charlotte, NC, and was diagnosed with Crohn's disease as a senior in high school. Humira (an anti-TNF agent) never stopped her urgency, pain, and blood loss during the six months she took it from 2013 to 2014.
"I felt extremely disappointed," she says. "I knew deep down the medication wasn't working, but I didn't want to believe it. Instead I tried to convince myself that it just needed more time."
Her decline on Humira was so rapid, she had to stop the biologic and undergo J-pouch surgery. She wasn't sure she wanted to try another biologic, and didn't for the last five years because after surgery, she was doing well. But then familiar debilitating symptoms returned this year, and "the decline started to happen again."
Bethea began Stelara (an interleukin-12 and -23 antagonist) this April. She's feeling much better now—less urgency, less leakage, more energy.
All About Secondary Non-response
Here's Dr. Velikova on the actions your doctor will likely take with this type of non-response:
- If a patient's response to therapy stops, the patient's blood should be monitored for neutralizing antibodies.
- If antibodies against the drug are found, the doctor would change the patient's drug class.
- If antibodies aren't found, but blood levels of the drug are insufficient, then the therapy should be intensified by increasing the dose, reducing the interval between applications, or a combination of the two.
Dr. Rubin adds that a common type of secondary non-response is mechanistic escape, meaning the drug's mechanism fails. "Then you do need a different class of therapy or surgery," he says.
Developing new anti-drug antibodies that render your current biologic ineffective to stop inflammation is another (rare, but important) reason for secondary non-response. With this non-response, your body recognizes the biologic as foreign, just as it would a virus or bacteria, and therefore fights it off, Dr. Ehrlich explains. "The result is that your body clears the drug really fast, so you’re given the drug at whatever your dose is, and before you know it, your body is getting rid of it."
But if the drug had been previously working, you can try another in the same class, Dr. Rubin says. "The mechanism still will work," he explains. "The patient lost response because they became 'immune.'"
At first, Holland was switched from one anti-TNF to another: After failing Remicade (an anti-TNF agent) 15 months into taking the medication (her side effects included hives and deep shoulder pain), she was placed on Humira (an anti-TNF agent) in 2014. But by 2016, she was having varied symptoms, and "it felt like I was living in the bathroom again," she says.
When her antibody levels were tested, they were the highest her doctor had ever seen.
As a result, Holland was taken off anti-TNF agent class meds. She was placed on Stelara, which she's still on three years later, and it's working well for her.
Adding an immunomodulator to anti-TNF agents can reduce the chance of developing antibodies, says Dr. Erhlich, but this isn't an option for Holland. She's allergic to the medication.
But newer drugs, like Entyvio and Stelara, don't seem to have as much of an issue with developing antibodies as the older anti-TNF class, Dr. Ehrlich says, so combination therapy might not be as effective/required with those classes.
If you haven't developed antibodies to your biologic, yet don't have enough drug in your system when tested—called an assay—you can likely stay on the same class of drugs; your body initially responded well, and it now seems to be clearing the drug too quickly.
One possible reason? You could be losing the drug through your GI tract because of damage from IBD. Dr. Ehrlich describes it this way: "The inflammation and damage to the bowel wall actually allows the the medication to leak out into the stool. It's not supposed to be there. It's supposed to stay in the bloodstream and in the tissues."
Another reason you might not have enough drug in your system? Your unique biochemistry. The FDA has approved fixed levels of biologics, but not everyone's Crohn's disease responds to the same amount of drugs, Dr. Ehrlich says. You also may need more doses than typical.
This happened to Stephanie Hughes, 33, of Raleigh, NC, who was diagnosed with Crohn's disease 20 years ago. She tried three biologics in two classes over nearly eight years, but her urgency, stomach pain, and blood loss never eased enough to stay on the drugs long-term.
"Even when on the biologics, I struggled with being able to cope with the typical dose, and I usually was on a schedule that was half the length between doses," she says.
Hughes never learned why biologics didn't work for her. When she stopped biologics, she realized how truly sick she was, and decided to have a permanent ostomy. She's happy with her decision, she says.
"My doctor was always the one who told me that the medications were no longer working. It's not that I didn't already know it, but I was so opposed to having surgery, that to some extent I think I fooled myself into thinking that I was doing all right, even though I was really struggling," she says.
What Are the Signs You Aren't Responding to a Biologic?
- Your typical IBD symptoms don't stop (primary non-response)
- Your typical IBD symptoms return, and they're intolerable (secondary non-response)
However, as previously mentioned, your symptoms could be caused by an infection, IBS, or even those mussels you ate last night (food poisoning). So what should you be on the lookout for?
"You often hear people going off a biologic because they have an allergic reaction, or they have a terrible rash, or they get nauseous," says Natalie Hayden, 35, who lives St. Louis and was diagnosed with Crohn's disease in 2005. "Those things are not supposed to happen, so it's your body's way of saying this biologic might not be the right fit for you."
Hayden has been on Humira for 11 years, her first and only biologic. She's grateful for the medication, but since she's been on it, she hasn't been without symptoms and treatment: After several bowel obstructions, she had bowel resection in 2015, which involved removing 18 inches of her small intestine, appendix, and Meckel's diverticulum.
"There was never a question through those flare ups whether I needed to be off Humira," she says. "It definitely shortened my hospital visits. Prior to being on the biologic, I would maybe be in the hospital for seven to eight days," but after starting Humira and before having her first child, born two years ago, it was more like four or five days in the hospital, she says. Since having her son, she hasn't been hospitalized for IBD. She has been pregnant, carried her son (Reid) and daughter (Sophia) to full term, and been in clinical remission, all while on Humira.
However, she is prepared with a plan B in case her biologic fails. And it might benefit you, too, to have one, to help alleviate your concerns that one day, you just might have to make that switch.
"If Humira fails me, I know my next line of defense will be Stelera. That's what my GI has already talked about with me proactively, and I know many people how have great success on that, but I'm hoping I can stay with my current regime as long as possible," Hayden says.
Tracking Your Crohn's Disease Symptoms
Vern Laine, 51, who lives in Surrey, Canada, has been on his only biologic, Remicade, for seven years (he's had Crohn's disease since 1988). He says his doctor has told him to watch for symptoms like weight loss, pain, and fatigue. He tracks signs of his response to the medication—because having his biologic work is everything to him.
"My main concern if my Remicade fails is, 'What now?'" he says. "Will another biologic work? And now symptoms will be returning, and after years of relatively 'good' health, it's back to square one."
Hayden doesn't track her Crohn's disease symptoms, though she says a number of apps can be helpful for remembering when bad days happen.
"I've had this for 14 years," she says. "I know what my trigger foods are, when my body is not doing well, when I have more fatigue, when I have more abdominal pain. I'm very proactive now. That's the key—you have to stay ahead of it and not tackle it when it's got too out of control, when you need to be hospitalized."
Bethea watches out for the same symptoms she experienced while on Humira, or even before she was on biologics, typical IBD symptoms without pause.
"When you live with Crohn's, everything becomes a gamble," she says. "I accept the reality of living with an autoimmune disease. I know there's a chance Stelara will stop working, just as any other medication I try, but I try not to approach it with a negative outlook. Instead of worrying about the future, I choose to live in the present and appreciate the relief its brought me and the freedom it's given me."
See more helpful articles:
Treating Crohn’s Disease With Biologics: The Basics
How Well Is Your Crohn's Disease Being Managed?
Instagrammers With Crohn's Disease You'll Love