- When Your Crohn’s Medication Stops Working
- Remicade (infliximab)
- How does infliximab work?
- How is infliximab used to treat inflammatory bowel disease?
- Who can take infliximab?
- What side effects can taking infliximab cause?
- Remicade not working anymore?
- What to expect when you’re starting HUMIRA—a Crohn’s disease medication.
- HUMIRA gives you the option to administer at home.
- Optimizing Management in IBD: The Rules of Stopping Biologics
- A European Perspective
- Treat-to-target approach
- Medical perspective
- Patient perspective
- Payor perspective
- TNF-α inhibitor discontinuation
- Reinitiation of TNF-α inhibitor therapy
- A North American Perspective
- Value of combination therapy
- Discontinuing therapy
- Lessons from discontinuation trials
- Safety considerations
- Case #1 presentation
- Case #2 presentation
- Is Leaky Gut Making You Sicker?
- TAKE THIS 3-MIN QUIZ NOW
- What to Expect
- Editorial: what can be done when infliximab stops working in ulcerative colitis? Authors’ reply
When Your Crohn’s Medication Stops Working
Crohn’s disease can change dramatically over time, and the condition is known to affect different people in different ways. There are a number of medications that can help people who have Crohn’s disease, but you may find that you must switch from medication to medication until you find one that gets your symptoms under control, or if a drug stops working for you.
In addition, because medications used to treat Crohn’s disease can be associated with certain risks and side effects, finding the right medication for you can take a few tries.
Getting Started With Crohn’s Meds
Your doctor will recommend a certain course of treatment for Cohn’s disease based on how severe your symptoms are and other factors. Anti-inflammatory medications and corticosteroids are common treatments for Crohn’s that have been around for a long time. There are also newer treatments that work differently from the older meds. Among them are Remicade (infliximab), Humira (adalimumab), and Cimzia (certolizumab pegol).
These medications belong to a group called anti-tumor necrosis factor (anti-TNF) medications, and they may be used in people with moderate to severe Crohn’s disease who are not responding to, or cannot tolerate, anti-inflammatory medications and corticosteroids.
Remicade, Humira, and Cimzia work by inhibiting the action of a protein called TNF-alpha, which can intensify inflammation in people who have Crohn’s disease. When the inflammation in your intestines is relieved, your body has time to heal, which can reduce Crohn’s disease symptoms such as fever, diarrhea, abdominal pain, and others.
The problem with anti-TNF medications is that they often become less effective over time, requiring you to switch medications in order to continue to keep your symptoms under control.
When It May Be Time to Switch Therapies
If symptoms like abdominal pain, diarrhea, bleeding, and fever don’t improve within a few weeks of starting a new medication, it may not be working as it should. Similarly, if your symptoms worsen after you’ve been taking a medication for a while, the drug may be losing its effectiveness.
When Crohn’s symptoms stop responding well to anti-inflammatory medications or corticosteroids, your doctor will probably first try Remicade. But because your condition may change over time, Remicade may eventually stop working as well. When you’re no longer benefiting from Remicade, the next option is Humira. And over time, if both Remicade and Humira stop working to relieve your Crohn’s symptoms, Cimzia, the most recent addition to the list of TNF inhibitors, is another possible option.
Finally, when anti-inflammatory medications, corticosteroids, or anti-TNF meds can no longer relieve your symptoms, your doctor may suggest you try a medication called called Tysabri (natalizumab). Tysabri, which is an antibody (basically, a protein that recognizes and helps fight infections) is sometimes used in people with Crohn’s disease who have not responded to or can’t tolerate conventional treatments or anti-TNF medications. (Due to the risk of a viral brain infection called PML (progressive multifocal leukoencephalopathy) and other serious side effects, Tysabri can only be given under a strict monitoring program developed by the drug’s maker, Biogen-Idec, in cooperation with the FDA.)
Most people feel better when they switch from a medication that has become less effective to a new one, but it’s important to call your doctor if your symptoms don’t improve or you experience any worrisome side effects while taking a new Crohn’s disease medication. Some of the potential side effects may include signs of infection, such as fever or chills; severe cough or flu-like symptoms; new or worsening signs of heart failure, such as shortness of breath or swelling in ankles or feet; bruising, bleeding, or pallor; and numbness, weakness, tingling, or problems with vision.
Are you doing everything you can to manage your Crohn’s? Find out with our interactive checkup.
Your doctor will monitor your response to your medications and help you determine when it may be time to adjust your dose, switch to a different medication, or try another kind of treatment.
Because all Crohn’s disease medications tend to stop controlling symptoms over time, up to two-thirds of people with Crohn’s disease eventually require surgery to remove the diseased section of their intestines, which helps relieve symptoms for some time. Even after surgery, some people may need to continue taking a medication to keep the disease under control, so it’s important to find one that works well for you.
Infliximab is a type of medication that can be used to treat people who have moderately or severely active inflammatory bowel disease (IBD), including Crohn’s disease (CD) or ulcerative colitis (UC).1,2 It can also be used to treat people who have fistulizing CD. Infliximab is a type of medication called a biologic therapy, and it is sold in the United States under the brand name Remicade.
Patients receive infliximab as an intravenous (IV) infusion, which takes around 2 to 4 hours for each dose. People usually have three infusions within the first 6 weeks of treatment, and then have one infusion every 8 weeks after that.
How does infliximab work?
Infliximab is a type of biologic therapy called an anti-tumor necrosis factor (anti-TNF) medicine.1,2,3 The active ingredients in anti-TNF medicines are special proteins called antibodies. These antibodies work by specifically targeting and interfering with the function of another kind of protein made by the immune system, called “tumor necrosis factor alpha.” These proteins are responsible for triggering inflammation to fight off infections in the body.
People with certain diseases, such as IBD, may have too much of this protein. Having too much of the protein can cause the immune system to attack parts of the body that are healthy. For people with IBD, these proteins can trigger the excessive inflammation in the digestive tract that causes IBD symptoms, as well as damaging the lining of the intestine. The antibodies in infliximab work by blocking the protein’s ability to cause this inflammation.
During the studies that were carried out to test the effectiveness of infliximab in treating IBD, more than 50% of patients had improvements in their symptoms after 2 weeks, although for other people it can take up to 8 weeks to start working.
How is infliximab used to treat inflammatory bowel disease?
For patients with moderate or severe CD or UC, infliximab’s ability to block these inflammation-causing proteins can:1-4
- Reduce the symptoms of IBD
- Help them to enter remission
- Help them to stay in remission longer
Infliximab can also help to heal the inside lining of the intestine, which can become damaged by inflammation due to IBD. New research suggests that because of this healing effect, people who have taken infliximab for a year tend to have fewer hospitalizations and a reduced need for surgery.
For adult patients who have fistulizing CD, taking infliximab can also help to:
- Reduce the number of draining fistulas between the digestive tract and the skin (enterocutaneous fistula) or between the rectum and the vagina (rectovaginal fistula)
- Maintain fistula closures
Infliximab can also be used to treat people with IBD who have symptoms that are located outside of the digestive tract, including:
- Ankylosing spondylitis
- Pyoderma gangrenosum
- Metastatic CD
For some people, infliximab does not work well enough to control their symptoms, or it may work at the beginning and then eventually stop working. In those cases, healthcare providers may recommend that they try another kind of biologic medicine, such as adalimumab.
Who can take infliximab?
Infliximab is approved for treating adults and children (over six years of age) with moderate to severe CD that has not responded well enough to other types of therapies, such as aminosalicylates, antibiotics, corticosteroids, or immunosuppressants. Infliximab is approved for treating adults with fistulizing CD and for treating children and teenagers between the ages of 6 and 17 years with CD who have not responded well to other kinds of treatment. Infliximab is also approved to treat ulcerative colitis, in those who have moderate to severe disease and who have not had a response to other therapies.3
Women who are pregnant, planning to become pregnant, or breastfeeding should let their healthcare providers know before starting treatment with infliximab. Anyone who is taking the medication should not receive any kind of live vaccine. Patients will be tested for TB before starting treatment.3
Before prescribing infliximab, healthcare providers need to know if the patient has, or has ever had:3
- Tuberculosis, or has been near someone with tuberculosis
- Recurring infections
- Immune system problems
- Any type of cancer
- Chronic obstructive pulmonary disease (COPD)
- Heart failure or other heart condition
- Hepatitis B
- Nervous system conditions, such as multiple sclerosis or Guillain-Barre syndrome
What side effects can taking infliximab cause?
The most common side effects experienced by people taking infliximab are respiratory infections, headache, rash, coughing, and stomach pain.3
Because of the way it affects the immune system, taking infliximab can reduce the body’s ability to fight off infections, including dangerous infections such as tuberculosis, pneumonia, and blood infections. For this reason, health care providers test patients for tuberculosis prior to starting treatment, and continue to monitor the patient throughout the treatment for signs of any infections.3
Taking infliximab can cause some very serious side effects. This is not a complete list of side effects. Patients should let their healthcare providers know about any new or worsened symptoms that they develop during treatment with the medicine. Healthcare providers will carefully monitor patients for signs or symptoms of the following conditions:3
- Skin cancer
- Heart failure
- Hepatitis B
- Liver injury
- Blood disorders
- Nervous system disorders
Patients should seek medical help immediately if they experience any signs of an allergic reaction during or after the infusion:3
- Trouble breathing
- Chest pain
- High or low blood pressure
- Swelling of the face and/or hands
- Fever or chills
Remicade not working anymore?
Are symptoms breaking through at a specific point in the cycle or is Remicade never making you feel better? If it works but only for a short while, it could be that your body is metabolizing the drug quickly. They can actually move infusions to as frequently as every 4 weeks and up to 10mg/kg…depending on what your insurance will approve. A good way to tell if increasing the dose or shortening interval will work is taking a levels test right before the next infusion. If your level is not at therapeutic levels then they just increase or shorten or both. They will also test for antibodies at the same time. If you are building antibodies they can add methotrexate but if the antibody level is high enough they will switch you to another biologic. If you have sufficient levels and no antibodies, you may have just lost response. This happens. My daughter has been on Remicade for 6 years, no antibodies and it is looking like she is losing response. It is just never working anymore. We are giving it one last ditch effort with 10mg/kg every 4 weeks for 4 months. If this doesn’t work we are moving on.
What to expect when you’re starting HUMIRA—a Crohn’s disease medication.
HUMIRA gives you the option to administer at home.
If your doctor decides that you are able to give your injections at home, you should receive training by a health care professional on the right way to prepare and inject HUMIRA. Do not try to inject HUMIRA yourself until you have been shown the right way to give the injections. Your first injection should be given under the supervision of a health care professional.
HUMIRA offers the independence of self-administration. You may not have to schedule an appointment in order to take your medication at a doctor’s office, because you can take HUMIRA in the comfort of your home. HUMIRA is typically taken every other week, after an initial starting dose, and requires refrigeration until administration. Your doctor will follow up with you on a regular basis. For more information, refer to the Patient Instructions for Use, and the Medication Guide located inside your HUMIRA carton, and within the Full Prescribing Information.
Common side effects of HUMIRA.
Common side effects of HUMIRA include injection site reactions (redness, rash, swelling, itching, or bruising), upper respiratory infections (sinus infections), headaches, rash, and nausea. These are not all of the possible side effects with HUMIRA. Tell your doctor if you have any side effect that bothers you or that does not go away.
Optimizing Management in IBD: The Rules of Stopping Biologics
Sep 6, 2016 – Classic Edition | IBD Dialogue | Volume 12 • 2016
Mentoring in IBD is an innovative and successful educational program for Canadian gastroenterologists that now includes an annual national meeting, regional satellites in both official languages, a website, an educational newsletter series, and regular electronic communications answering key clinical questions with new research. This issue is based on the presentation made by the contributing editors at the annual national meeting, Mentoring in IBD XVI: The Master Class, held November 6, 2015 in Toronto, Ontario.
A European Perspective
Alessandro Armuzzi, MD PhD
The treat-to-target approach to managing patients with inflammatory bowel disease (IBD) involves risk-stratifying patients, treating high-risk patients with combined immunosuppression that incorporates biologic therapy, selecting a treatment target, implementing regular objective monitoring, and adjusting therapy to maintain the target (Figure 1).(1,2) Prospective studies are required to determine how this approach changes outcomes and patient quality of life, and whether treatment needs to be continued indefinitely in patients in prolonged deep remission. This important unanswered question has led clinicians, patients, and regulators to contemplate treatment discontinuation in this situation.
TNF-α inhibitor benefits
The major benefit of tumour necrosis factor (TNF)-α inhibitors is their effectiveness in moderate-to-severe and immunomodulator-refractory inflammatory bowel disease (IBD), with their potential for achieving mucosal healing and preventing disease progression and complications, including hospitalization and surgery. TNF-α inhibitors can significantly improve quality of life for patients in whom they are effective. Early combined immunosuppression also has the potential to alter the natural history of Crohn’s disease (CD).(3) Several real-world studies with long-term follow-up indicate that about two-thirds of patients treated with TNF-α inhibitors experience a sustained benefit from these therapies.(4–7)
TNF-α inhibitor risks
Balanced against these benefits are the potential risks, including severe and opportunistic infections, malignancy, immune-mediated demyelinating neuropathies, cutaneous and allergic reactions, and infusion reactions. Concern is greatest for individuals at the extremes of age.
Data from the Therapy, Resource, Evaluation, and Assessment Tool (TREAT™) registry(8) and the Productivity, Safety and Efficacy: Long-Term Results in Adalimumab-Treated Patients with Crohn’s Disease (PYRAMID) registry(9) indicate an increased risk of serious and opportunistic infections with anti-TNF-α inhibitors in patients receiving triple immunosuppression that includes a corticosteroid, and with increasing age. A database study using the Food and Drug Administration Adverse Event Reporting System found an increased risk of lymphoma with TNF-α inhibitor use in combination with thiopurines.(10)
For many reasons—including inconvenience; dislike of taking drugs; fear of complications; and specific issues, such as pregnancy—patients may be reluctant to continue TNF-α inhibitor therapy indefinitely.
The Costs Of Inflammatory bowel disease in the Netherlands (COIN) study assessed the healthcare costs of IBD in a large cohort of patients (N=2252).(11) The study found that the overall cost of IBD is driven by medication costs, primarily by TNF-α inhibitor therapy, with hospitalization and surgery making up only a minority of healthcare costs. TNF-α inhibitors made up 64% of the cost of CD and 31% of the cost of UC. The cost of CD was almost three times higher than the cost of ulcerative colitis (UC).
TNF-α inhibitor discontinuation
The issues and unanswered questions described above have prompted an interest in the concept of de-escalating therapy or discontinuing TNF-α inhibitors in patients in remission, and several studies have addressed the impact of TNF-α inhibitor discontinuation on clinical status.
In the United Kingdom, regulators mandate reassessment of disease activity after 12 months of treatment with a TNF-α inhibitor and discontinuation in patients who have achieved clinical remission and mucosal healing. A retrospective audit of outcomes was performed in patients with IBD (N=160) in corticosteroid-free remission with a mean 25-month post-discontinuation follow-up.(12) Younger age at diagnosis (P=.003) and elevated white blood cell count (P=.044) predicted relapse, which was seen at 2 years in 56% of patients with CD and 50% of patients with UC or IBD unclassified. Reintroduction of TNF-α inhibitor therapy succeeded in recapturing response in 92% of patients.
A Spanish study evaluated outcomes in patients with IBD (N=1055) in clinical remission after discontinuing TNF-α inhibitor therapy.(13) Almost 50% of patients relapsed within 2 years. The risk of relapse was decreased in patients who continued an immunomodulator after relapse. The response rate to retreatment with the same agent was 88%.
The infliximab diSconTinuation in CrOhn’s disease patients in stable Remission on combined therapy with Immunosuppressors (STORI) trial evaluated outcomes and predictors of relapse after discontinuing infliximab in patients with CD (N=115) who continued immunomodulator therapy.(14) About 45% of patients relapsed after a median 28 months. Multivariate analysis found male sex, absence of surgical resection, white blood cell counts >6.0 x109/L, hemoglobin (Hb) ≤145 g/L, C-reactive protein (CRP) ≥5.0 mg/L, and fecal calprotectin ≥300 μg/g were predictors of relapse. Infliximab retreatment was effective in 88% of patients in the short term.
A systematic review of the impact of withdrawing biologic or immunomodulator therapy from patients with IBD in remission included 43 studies.(15) Analysis found that about 50% of patients who discontinued TNF-α inhibitor therapy after combination therapy relapsed after 2 years, with the proportion increasing over time.
A study investigating the effect of stopping TNF-α inhibitor therapy in patients (N=48) in long-term deep endoscopic remission included patients with detectable drug levels and those with undetectable drug levels.(16) During the first year after discontinuation, relapse occurred in 16 of 20 patients (80%) with detectable drug levels and in 9 of 28 patients (32%) with undetectable drug levels (P<.001). The finding of undetectable drug levels in patients with stable long-term remission may indicate that remission is no longer dependent on TNF-α inhibitor therapy.
A retrospective study evaluated outcomes in patients with CD (N=100) who discontinued infliximab after achieving clinical remission.(17) After a median 10-year follow-up, 52% of patients remained in sustained clinical remission. Most patients remained on immunomodulator therapy.
Reinitiation of TNF-α inhibitor therapy
A retrospective analysis of treatment outcomes in patients with IBD (N=128) who restarted infliximab after a median 15-month discontinuation found that 70% maintained response at 1 year and 61% maintained response at >4 years.(18) Higher trough levels were associated with response and undetectable antidrug antibody (ADA) levels were associated with a reduced risk of infusion reactions.
- Discontinuing biologic therapy may be justified in highly selected patients to optimize the benefit/risk ratio and the benefit/cost ratio, but it should never jeopardize tight disease control.
- The decision to discontinue biologic therapy should be made on a case-by-case basis, in conjunction with the patient, and considering the following factors:
- Patient demographics
- Disease features
- Treatment history
- Current clinical status: mucosal healing, clinical and biological remission, drug and ADA levels
- Approximately 50% of patients who stop biologics relapse within 2 years, but 50% maintain remission.
- The majority of patients retreated with biologics after discontinuation achieve clinical benefit.
- Peyrin-Biroulet L, Sandborn W, Sands BE, et al. Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining therapeutic goals for treat-to-target. Am J Gastroenterol. 2015;110:1324–38.
- Bouguen G, Levesque BG, Feagan BG, et al. Treat to target: a proposed new paradigm for the management of Crohn’s disease. Clin Gastroenterol Hepatol. 2015;13(6):1042–50.
- Louis E, Collard A, Oger AF, et al. Behaviour of Crohn’s disease according to the Vienna classification: changing pattern over the course of the disease.Gut. 2001;49(6):777–82.
- Schnitzler F, Fidder H, Ferrante M, et al. Long-term outcome of treatment with infliximab in 614 patients with Crohn’s disease: results from a single-centre cohort. Gut. 2009;58(4):492–
- Baert F, Glorieus E, Reenaers C, et al; BIRD (Belgian IBD Research and Development). Adalimumab dose escalation and dose de-escalation success rate and predictors in a large national cohort of Crohn’s patients. J Crohns Colitis. 2013;7(2):154–
- Italian Group for the Study of Inflammatory Bowel Disease, Armuzzi A, Biancone L, Daperno M, et al. Adalimumab in active ulcerative colitis: a “real-life” observational study. Dig Liver Dis. 2013;45(9):738–
- Armuzzi A, Pugliese D, Danese S, et al. Long-term combination therapy with infliximab plus azathioprine predicts sustained steroid-free clinical benefit in steroid-dependent ulcerative colitis. Inflamm Bowel Dis. 2014;20(8):1368–
- Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious infection and mortality in patients with Crohn’s disease: more than 5 years of follow-up in the TREAT™ registry. Am J Gastroenterol. 2012;107(9):1409–
- d‘Haens G, Reinisch W, Satsangi J, et al. PYRAMID registry: an observational study of adalimumab in Crohn’s disease: results at year 5. Presented October 15, 2013 at the 21st European United Gastroenterology Week; October 12–16, 2013: Berlin, Germany: OP214.
- Deepak P, Sifuentes H, Sherid M, et al. T-cell non-Hodgkin’s lymphomas reported to the FDA AERS with tumor necrosis factor-alpha (TNF-α) inhibitors: results of the REFURBISH study. Am J Gastroenterol. 2013;108(1):99–
- van der Valk ME, Mangen M-JJ, Leenders M, et al. Healthcare costs of inflammatory bowel disease have shifted from hospitalisation and surgery towards anti-TNFα therapy: results from the COIN study. Gut. 2014;63:72–9.
- Kennedy NA, Warner BD, Johnston E, et al. Anti-TNF withdrawal in IBD: relapse and recapture rates and predictive factors from 160 patients in a pan-UK study. Gastroenterology. 2015;148(4 Suppl 1):S-62: Abstract 288.
- Casanova González MJ, Chaparro M, García-Sánchez V, et al. Evolution after anti-TNF drug discontinuation in patients with inflammatory bowel disease (IBD): a multicenter long-term follow-up study. 23rd United European Gastroenterology Week; October 24–28, 2015: Barcelona, Spain: OP092.
- Louis E, Mary JY, Vernier-Massouille G, et al. Maintenance of remission among patients with Crohn’s disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology. 2012;142:63–
- Torres J, Boypati RK, Kennedy N, et al. Systematic review of effects of withdrawal of immunomodulators or biologic agents from patients with inflammatory bowel disease. Gastroenterology. 2015;149(7):1716–
- Ben Horin S, Chowers Y, Ungar B, et al. Undetectable anti-TNF drug levels in patients with long term remission predict successful drug withdrawal. Aliment pharmacol Ther. 2015;42:356–64.
- Papamichael K, Vande Casteele N, Gils A, et al. Long-term outcome of patients with Crohn’s disease who discontinued infliximab therapy upon clinical remission. Clin Gastroenterol Hepatol. 2015;13:1103–
- Baert F, Drobne D, Gils A, et al. Early trough levels and antibodies to infliximab predict safety and success of reinitiation of infliximab therapy. Clin Gastroenterol Hepatol. 2014;12(9):1474–
A North American Perspective
Brian G. Feagan, MD FRCPC
Arguments can be made for discontinuing biologic therapy in patients responding to combination therapy, but well-designed withdrawal studies have not been conducted. Discontinuation may eradicate the treatment benefit in the very patients who generate the greatest morbidity and healthcare costs. Whereas reinitiation of treatment may recapture response in some patients, immunogenicity is an important concern, and high-quality data to address this issue do not exist. In addition, safety concerns with biologic therapy have been overstated.
Value of combination therapy
Combination therapy with a TNF-α inhibitor and an immunomodulator is significantly more effective than immunomodulator therapy alone in patients with corticosteroid-dependent CD.(1) In addition, early use of combination therapy is significantly more effective than conventional therapy in inducing remission in patients with early CD.(2)
Data neither substantiate nor disprove the necessity of continued therapy for maintenance of remission, but several potential risks are associated with stopping therapy, including sensitization and the loss of an opportunity to change the natural history of the disease. Furthermore, stopping therapy may not necessarily be safer overall for the patient.
Lessons from discontinuation trials
An azathioprine withdrawal study in patients with CD in clinical remission on long-term azathioprine (N=83) randomized patients to continued azathioprine or placebo for 18 months.(3) Relapse occurred in 3 patients in the azathioprine group (8% ± 4%) and 9 patients in the placebo group (21% ± 6%). Factors predicting relapse were baseline CRP >20 mg/L, time without corticosteroids <50 months, and Hb <120 g/L.
An azathioprine withdrawal trial in patients with CD treated with combination therapy (N=80) followed patients who continued or discontinued azathioprine for 2 years.(4) A similar proportion of patients in both groups required changes in the infliximab dose or discontinued infliximab during follow-up. Low patient numbers, however, prevent definitive conclusions from being drawn. Median CRP was significantly higher in the group that discontinued azathioprine (2.8 mg/L) than in the group that continued immunomodulator therapy (1.6 mg/L, P<.005). In addition, 5 to 15% of patients who discontinued azathioprine had undetectable infliximab trough levels after 1 year, compared with no patients in the continuation group.
TNF-α inhibitor withdrawal
A study of remission induction with infliximab plus methotrexate in 20 patients with early poor-prognosis rheumatoid arthritis found significantly reduced synovitis and erosions at 1 year, at which time infliximab was withdrawn.(5) At 2 years, treatment benefits were sustained in 70% of patients. However, one-half of patients required reintroduction of treatment, which was unsuccessful in 25%.
The principal investigator of the STORI trial, described in A European perspective (reference 14), commented, “Currently there is no good medical reason to stop IFX in patients in stable remission.” It is also important to realize that the predictors of relapse in this trial are associations, not causative factors. Logically, there is no good reason to suppose that IBD disappears with time in patients who have discontinued therapy as a result of being in remission. IBD develops as a result of the interplay of environmental and genetic factors that are not altered with short-term therapy, and long-lived pathogenic T lymphocyte clones are not ablated with conventional treatments. As a result, there is no theoretical basis for stopping biologic therapy.
Causality is difficult to establish when evaluating the incidence of serious infection in patients with IBD receiving multidrug therapy.(6) A Mayo Clinic case-control study of 100 consecutive patients with opportunistic infections and 200 matched controls assessed associations between drug therapy and infection. Multivariate analysis found that single-drug therapy was associated with an odds ratio (OR) for infection of 2.9 (95% confidence interval : 1.5–5.3), whereas use of 2 or 3 of drugs was associated with an OR of 14.5 (95% CI: 4.9–43). The relative risk of opportunistic infection was greatest in patients >50 years of age (OR: 3.0; 95% CI: 1.2–7.2).
Analysis of the adverse events in the Study of Biologic and Immunomodulator Naive Patients in Crohn’s Disease (SONIC) trial by drug therapy found a similar incidence of adverse events in patients in each therapy group: azathioprine, infliximab, and combination therapy.(7)
A pooled analysis of adverse events in randomized controlled trials of infliximab in IBD found no significantly increased risks of serious infection in CD, UC, or IBD as a whole.(10)
A prospective observational cohort study of the lymphoma risk associated with thiopurine therapy from the CESAME group included 19,486 patients with IBD.(11) On multivariate analysis, the HR for lymphoproliferative disorder for patients receiving thiopurines and those who had never received them was 5.28 (95% CI: 2.01–13.9, P=.0007) (Figure 2).
Discontinuation of biologic therapy, the most effective therapy for CD, carries a cost of relapse in a proportion of patients. No high-quality randomized controlled trials have examined the question of discontinuation in CD, and the therapeutic index of stopping therapy is unknown. No good reason for discontinuing therapy exists, and it is appropriate to continue therapy until good evidence for stopping exists.
- Lémann M, Mary JY, Duclos B, et al; Groupe d’Etude Therapeutique des Affections Inflammatoires du Tube Digestif (GETAID). Infliximab plus azathioprine for steroid-dependent Crohn’s disease patients: a randomized placebo-controlled trial. Gastroenterology. 2006;130(4):1054–
- d’Haens G, Baert F, van Assche G, et al; Belgian Inflammatory Bowel Disease Research Group; North-Holland Gut Club. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet. 2008;371(9613):660–
- Lémann M, Mary JY, Colombel JF, et al. A randomized, double-blind, controlled withdrawal trial in Crohn’s disease patients in long-term remission on azathioprine. Gastroenterology. 2005;128(7):1812–
- Van Assche G, Magdelaine-Beuzelin C, D’Haens G, et al. Withdrawal of immunosuppression in Crohn’s disease treated with scheduled infliximab maintenance: a randomized trial. Gastroenterology. 2008;134(7):1861–
- Quinn MA, Conaghan PG, O’Connor PJ, et al. Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal: results from a twelve-month randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2005;52(1):27–
- Toruner M, Loftus EV Jr, Harmsen WS, et al. Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology. 2008;134(4):929–
- Sandborn W, Rutgeerts P, Reinisch W, et al. SONIC: a randomized, double-blind, controlled trial comparing infliximab and infliximab plus azathioprine to azathioprine in patients with Crohn’s disease naive to immunomodulators and biologic therapy. Presented at: American College of Gastroenterology Annual Scientific Meeting; October 3-8, 2008; Orlando, FL. Abstract 29.
- Lichtenstein GR, Cohen RD, Feagen BG, et al. Safety of infliximab and other Crohn’s disease therapies – TREAT registry data with nearly 15,000 patient-years of follow-up. Gastroenterology. 2006;130(4 Suppl 2):A71.
- Lichtenstein GR, Cohen RD, Feagan BG, et al. Safety of infliximab and other Crohn’s disease therapies — TREAT registry data with nearly 20,000 patient-years of follow up. Gastroenterology. 2007;132(4 Suppl 2):A178.
- Lichtenstein GR, Rutgeerts P, Sandborn WJ, et al. A pooled analysis of infections, malignancy, and mortality in infliximab- and immunomodulator-treated adult patients with inflammatory bowel disease. Am J Gastroenterol. 2012;107(7):1051–
- Beaugerie L, Brousse N, Bouvier AM, et al; CESAME Study Group. Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet. 2009;374(9701):1617–
Case #1 presentation
A 32-year-old female with proximal jejunal Crohn’s disease measuring over 30 cm and perianal fistulous disease has been receiving therapy with a tumour necrosis factor (TNF)-α inhibitor plus methotrexate for 6 years. Clinically and biochemically her disease is in remission. The most recent computed tomography enterography, performed 4 months ago, shows no active disease in either the jejunum or the perianal region. The patient has had 4 miscarriages in the past and wants to get pregnant. She tells you that she is going to stop both the TNF-α inhibitor and methotrexate 6 months before attempting conception and throughout the pregnancy. This decision, made by her and her partner, is firm. She is, however, concerned about the risk of antidrug antibodies (ADAs) developing and wonders whether she should take azathioprine or mesalamine during her pregnancy. She also wants to know whether she would be able to restart therapy after the pregnancy.
As she has high-risk disease, stopping therapy could threaten her clinical status. It is appropriate to stop methotrexate prior to conception, but there is no reason to stop the TNF-α inhibitor. This patient may have made her decision to discontinue all treatment without having all the relevant information. It is therefore critical that she understand the data and the potential consequences of stopping therapy: the data on TNF-α inhibitor efficacy, her individual risk of relapse (40–50% during the first year), TNF-α inhibitor safety in pregnancy, and the risk to the fetus of flare and how a flare during pregnancy could be treated. Mesalamine would be unlikely to have any clinical benefit in this patient.
If she continues to insist she wants to stop her therapy, it is important to ensure that she is in endoscopic remission. Close monitoring of her clinical status would be indicated, including laboratory investigations and ultrasound. However, it is only worth monitoring her status if she is willing to accept treatment if signs of disease are found. In that situation, it would be important to restart therapy before full-blown relapse develops. Low infliximab levels on therapeutic drug monitoring (TDM) would indicate a greater likelihood of maintaining remission than high drug levels. Similarly, low ADA levels would indicate a greater chance of successful reinitiation of therapy after the pregnancy. It would be important to restart infliximab after delivery, as it might not be possible to recapture response if she relapsed. Azathioprine does not appear to increase the risk of congenital malformation, but taking it during the pregnancy may reduce the risk of development of ADAs and infusion reactions when she restarts infliximab.
Case #2 presentation
A 52-year-old male with ulcerative colitis (UC) has been in remission on combination therapy with a TNF-α inhibitor and azathioprine for 6 years. He wants to stop the TNF-α inhibitor and is wondering about stopping all therapy. He asks you how long he is likely to stay in remission, if he would be able to restart the same TNF-α inhibitor if he had a flare, and if he needs any tests before stopping the TNF-α inhibitor.
Data are available to indicate relapse rates of approximately 18% per patient-year. After 1 year, 35 to 40% of patients relapse, and after 3 years, more than 50% relapse. No studies address relapse rates over longer time periods. No evidence addresses the risk of relapse for a patient with UC in long-term remission who stops all therapy. The severity of UC does, however decrease over time in some patients. Close monitoring would be appropriate, so that the TNF-α inhibitor could be restarted before a severe relapse developed.
Before stopping therapy, it would be appropriate to perform an endoscopy and biopsy to help gauge his risk of relapse. TDM would also be useful, as low drug levels could indicate a greater chance of maintaining remission. 6-thioguanine levels would also be useful. If he stops the TNF-α inhibitor, it would be wise to continue azathioprine, as this should help reduce ADA formation and the risk of infusion reactions when he needs to restart therapy. The best choice in that case would be the same TNF-α inhibitor he was originally taking.
John K. Marshall, MD MSc FRCPC AGAF, Chief of Gastroenterology Clinical Service, Hamilton Health Sciences; Professor of Medicine, Division of Gastroenterology, McMaster University , Hamilton, ON
Richard N. Fedorak, MD FRCPC FRCP (London) FRCS, Dean, Faculty of Medicine & Dentistry; Professor of Medicine, Division of Gastroenterology, University of Alberta, Edmonton, AB
Khursheed N. Jeejeebhoy, MD FRCPC PhD, Professor Emeritus, Department of Medicine, Department of Nutritional Sciences, University of Toronto, St. Michaels Hospital, Toronto, On
Mentoring in IBD Curriculum Steering Committee
Alain Bitton, MD FRCPC, McGill University, Montreal, QC
Brian Bressler, MD MS FRCPC, University of British Columbia, Vancouver, BC
Anne M. Griffiths, MC FRCPC, University of Toronto, Toronto, ON
Steven E. Gruchy, MD MSc FRCPC, Dalhousie University, Halifax, ON
Remo Panaccione, MD FRCPC, University of Calgary, Calgary, AB
Craig Render, MD FRPCP, University of British Columbia, University of Alberta, Kelowna, BC
Hillary Steinhart, MD MSc FRCPC, University of Toronto, Toronto, ON
Jennifer Stretton, ACNP MN BScN, St. Joseph’s Healthcare, Hamilton, ON
IBD Dialogue 2016·Volume 12 is made possible by unrestricted educational grants from…
1B-391 Berkeley Street, Toronto, ON M5A 2X8
Is Leaky Gut Making You Sicker?
Recently, this Cure Together survey of 1,327 Crohn’s Disease patients found the Specific Carbohydrate Diet to more effective at treating Crohn’s Disease than Humira…
In fact, SCD was only the 2nd most effective natural treatment option behind Cannabis… but how long does a good high possibly last anyway?
More and more, Crohn’s Disease patients are given Humira in their doctor’s office instead of a SCD quick start guide.
I wonder what would be possible if it was the other way around…
In light of that question, I want to share five reasons to try SCD instead of Humira to recover from the symptoms of Crohn’s Disease.
TAKE THIS 3-MIN QUIZ NOW
1. Diet Treats the Root Cause, Humira Treats the Sympstoms
What if I said to you, “Hey, my toilet is overflowing and every time I walk in the bathroom my socks get all wet!”?
Would you give me rubber boots so I could stop changing my socks every time I had to pee?
Or would you hit me upside the head and tell me to go turn off the water so we could fix the broken parts inside the toilet?
Humira is like those rubber boots… it turns off your immune system by blocking the production of TNF-alpha, an inflammatory cytokine your body produces as part of the inflammatory response, but believe me, the toilet is still overflowing. The drug doesn’t address the root cause leading to inflammation.
An anti-inflammatory diet like SCD does address the inflammation and helps prevent your bathroom floor from being wet for the rest of your life.
2. Humira Has Side Effects Like…
Reactions at the injection site, upper respiratory tract infections, sinus infections, nausea, urinary tract infections, flu symptoms, abdominal pain, high cholesterol, blood in the urine, back pain, high blood pressure, and more seriously: infections such as tuberculosis, sepsis (bacteria in the blood), and fungal infections… not to mention the whole increased chance of developing cancer thing.
A real food diet has side effects like: increased energy, mental clarity, reduced inflammation, reduced risk of cardiovascular disease, improved blood pressure, and increased nutritional uptake.
Both can help you get perfect poops… what more needs to be said?
3. Humira Is Expensive…
Estimates around the web show that Humira can cost more than $13,000 a year for patients who have no drug coverage. That’s over $1,000 a month.
Some of our Facebook Fans recently mentioned they are paying anywhere from $600-$800 a month for injections.
Even if you ate 100% organic food and grass-fed meat you would only spend about half that a month for one person!
If anything, changing your diet can save you money, especially in the long run. Think of it like this: instead of choosing expensive medication, you’re choosing high-quality healthy fuel for your body.
4. Humira Has Only Been Around for 10 Years…
Ever heard of the drug Fen-Phen?
It helped people when it was new too… until it started killing them. I’m not saying Humira is going to kill people, but the long-term risks of a drug can never be realized in such a short time period.
The FDA has been wrong before… know anyone that developed Crohn’s after taking Accutane?
Humans have been eating meat, fruits, nuts, and veggies for hundreds of thousands of years…
I’ll take hundreds of thousands of years of data please.
5. Humira Can Be a Crutch
But unlocking health through diet is empowering.
We all have to eat every day and the food we put in our mouth will either make inflammation worse or make it better. It’s either nourishing or harmful. Food can support us or hurt us… but we all have to eat. We all have a choice…
Choose your path wisely. I know which road I took… the healthier, less expensive, less risky road that ends up leading me to the healthy life I deserve… rather than taking me into a dark forest of illness, surgery, and more pills.
The bottom line is: it’s not healthy to rely on medicine to suppress your immune system and curb the symptoms of Crohn’s disease so that you can make it through the day.
Try SCD for 30 days as a part of a comprehensive healing plan to feel incredible and control the symptoms of the disease.
Empower yourself, take control of your health and break free of the medicine. It’s the only way to get your life back from the dark corners of digestive disease.
Diet versus Humira? Share your opinion in the comments…
Where do I even begin? It’s been a few weeks now since I was totally blindsided. I thought everything was going so well. Life was happy and truly felt worth living. Now, looking back over the past few months I feel like I really should have seen the signs. We all know that hindsight is 20/20… It really does feel like it came out of nowhere, though, ya know? I had so many explanations running through my head about what was going on under the surface, but I never expected this. This…my most painful break up.
Thankfully, I am not talking about my relationship with Alex. He is truly my rock and I don’t know how I’d deal with this without him.
I’m also not talking about #Brangelina (but, like, WHOA! Right?)
Remicade broke up with me. Suddenly. (Or so it felt).
Yes, Remicade, my miracle drug; the hero in this post, in fact. The one that well and truly saved my life last year decided that we just weren’t working together anymore and up and left me to deal with (dun dun DUN) drug-induced lupus.
*record scratch* *freeze frame* “Now, you’re probably wondering how I wound up in this situation…”
I realize that most of you reading this have either never heard of Remicade, or have only heard of it sparingly through me and just know that it’s a drug used to treat Ulcerative Colitis (and Crohn’s and Rheumatoid Arthritis). Remicade (drug name: Infliximab) is a chimeric monoclonal antibody biologic (literally WTF?) drug which basically (don’t kill me, science friends) means that it’s a drug that is extracted from a biological source, and in Remicade’s case, the biological source happens to be MICE. I can hear everyone who has seen me lose my shit around a mouse laughing in the background.
Anyway, when you start taking Remicade (or drugs like it) you’ll be warned about the fact that you could develop antibodies to the drug because your body just might notice that mouse protein is floating around in your body and that could render the drug useless because your immune system will try to fight it off like an infection. No bueno. I, like many other patients, took a supplementary immunosuppressant to try to ward off the development of antibodies.
I responded REALLY well to Remicade. I literally noticed an improvement in my UC symptoms the very same day of my first infusion. However, it took some time to get my dosing and frequency right. I would always start to get sick again around the 4 week mark at 5mg/kg. I was told I was a “fast metabolizer” (tell that to the jar of Nutella I had to make Alex hide, please). This was determined by somewhat regular blood tests. Eventually, we found that an infusion every 4 weeks at 10mg/kg worked for me. For reference, the average patient will get infused every 8 weeks with 5mg/kg (aka I was getting a hell of a lot of Remicade). The plan was to stick with this frequency and dosage to allow the drug to build up in my body enough that I could eventually start getting infused every 6 weeks, and then maybe every 8 weeks.
So how did this happen?
Shit luck? I was Hitler in a past life? I don’t know how, but it did. I’m writing about it because I know it will help me sort through this incredibly low point in my life and will hopefully help someone else. There are a number of internet forum posts on this topic, but I haven’t been able to find any blog posts or series about how you feel when you develop these antibodies or what happens next. That’s what I’m going to try to do.
On July 19th (I remember because it was the night before we left for Europe–posts coming! I know you’re all DYING 😉 ) my right ankle was in unbearable pain. My feet and legs had been hurting on and off in the days prior to this, but I chocked it up to wearing heels at a wedding the weekend before and not sitting down for almost 12 hours. We left on our flight to Amsterdam the next day and I was still in a lot of pain. Being cooped up on two different flights (one trans-atlantic and overnight) really didn’t help. The pain continued throughout our entire, nearly 3 week, trip. The pain didn’t just stay in my right ankle, though. It migrated through both knees, both ankles, my hips, my toes and even both hands and all of my fingers.
I attributed the persisting pain to our late nights and early mornings (which were actually not so early by the time we got going because I was hurting so badly), running to every train, walking an average of at least 10km per day on cobblestone streets, and clutching my purse with a death grip. Now I know…
I came home and was zonked and sore. Then I felt semi-ok for a few days. Then I got my first iron infusion in over a year with the highest dose I’d ever had. After the iron I felt worse than ever before. Some googling told me that sore and swollen joints could be a side effect of iron infusions, so I blamed it on that. A week later, I went home from work with my leg totally seized up. By 11pm that night (3 weeks ago today) I was bawling and writhing in pain. I could. not. move. Moving my fingers was enough to make me shriek. Alex basically carried me to the car and we headed to the emergency room. We were there until 7am, but nothing could really be determined. They suspected that maybe I had Rheumatoid Arthritis. It kind of made sense to me… another autoimmune disease? Why the f**** not?! My mom has it and was diagnosed at 24. This was 4 days before my 24th birthday so it seemed like it was right on time. For those few hours on that Friday morning, I’d nearly accepted that I now had RA too.
Then, the official break up happened. I went to my already scheduled Remicade appointment later that afternoon. I told my nurses at the infusion clinic what had transpired the night before. My nurse’s face totally fell. She said “It might be the Remicade.” I didn’t quite understand what she was getting at, at first. All this time I’d been very privy to the need to avoid antibodies. That I couldn’t go too long without Remicade, otherwise I’d develop them. I didn’t think it would be possible for me to develop them with my very high dosage and frequency, and truthfully I didn’t realize that any symptoms went along with their development. I just thought it would show up in a test result. I guess at first I thought she was just telling me it was a side effect.
My nurse got me set up in my recliner anyway and got me my pre-meds. I had the heat pack on my invisible veins and it seemed like business as usual. She said she was just going to make a phone call. (I should note that I left a message for my IBD team already that morning to let them know what was going on). She came back and had a blank look on her face. She’d been on the phone with my doctor and she said, “You have antibodies. We have to cancel your infusion. The test results came back two days ago.” (I mean, I guess I’m glad the break up was in person and not over the phone?!)
I burst into tears and my nurse started crying with me. She knew how sick I’d been a bit over a year ago, and how much Remicade had changed my life for the better. I cried and cried and she did her best to comfort me. It sunk in that not just this infusion was canceled, but I would not be able to take Remicade ever again. She told me that while this was devastating, it was really lucky that it was figured out before the drip started going. She told me how they’ve had to have people picked up at the clinic by ambulance while being infused because no one knew that they had antibodies (it can happen quickly and tests are only done every few months) and patients have stopped breathing or have gone in to shock. Really sobering stuff.
So where am I now?
I’m in the process of getting started on a brand new drug called Entyvio (or vedolizumab). It’s another infusion that wasn’t available to me when I started Remicade. It’s very new to patients like me, but has been in clinical trials for many years and it shows particularly good results for patients with Ulcerative Colitis. The potential side effects are also less nasty than Remicade (Remicade offered an increased risk of lymphoma, which, believe it or not is worth it when you honestly feel like you’re not living a real life when your IBD makes you so incredibly sick). There are a lot of first-hand accounts of Remicade posted online in the form of blog posts and videos, but hardly anything on Entyvio. I’m hoping to document my journey here and I hope to be a bit of a resource for anyone else who might be starting this new drug in the future.
And finally, what about that “drug-induced lupus” you mentioned above? Wtf?
WTF is right. My nurse practitioner evaluated all of my symptoms after Remicade broke up with me and determined that the antibody development is causing this drug-induced lupus. Basically, I’m experiencing many of the same symptoms as someone who has actual lupus. It’s HORRIBLE. I’m so incredibly grateful that this is not (or so I’m told; it is hard to believe) permanent and will dissipate with patience and time as the Remicade works its way out of my body. I can tell that my body is fighting incredibly hard because I’ve been experiencing:
- Persistent, excruciating joint pain. Every joint in my body hurts, but especially my fingers, thumbs, knees, toes, and ankles. Today it was nearly impossible to write with a pencil. As of this week I can get by pretty well all day at work with one dose each of advil and tylenol, but by mid-evening I’m back in excruciating pain town. A few weeks ago I was probably about to overdose on painkillers.
- Confusion. This has dissipated a lot over the past few months. On our vacation I was making a lot of really out of character, illogical mistakes. To the point where Alex remarked several times “What’s going on? This isn’t like you at all.” I also remarked a few times at work that I felt like I couldn’t access my normal vocabulary. Looking back now, it all makes sense.
- Fatigue. I am just so, so tired.
The worst “symptom” is well, I am very, very sad. Logically, I know this is a low point in my life and it won’t last forever. I have incredibly understanding colleagues and a great family, boyfriend, and friends. Heck, this all started while I was on a dream vacation in Europe with Alex–I have a lot to be thankful for! But it’s really hard to have the feeling of security Remicade provided ripped out from under me all while dealing with the worst pain of my life. It’s been six weeks since I last had Remicade and I’m scared about my colitis flaring up. I don’t ever want to be as sick as I was in 2015. It’s terrifying. I still haven’t started my Entyvio and unlike Remicade, it can take most patients longer to respond. The uncertainty is weighing on me.
Plus, I hate not being able to do anything. I haven’t been to barre class in over a month. Some days I can barely walk. My biggest stress reliever and one of my biggest pleasures over the past year has been working out, but I just can’t do it right now. I was even about to put my barre instructor certification to good use–I was offered a teaching position and the week before I was supposed to start, all of this came to a head and I had to give it up. It’s been incredibly disappointing and discouraging. All that said, it’s opened my eyes to how those of us with able bodies will take it for granted.
I feel like I’ve typed out my whole life story, but it really only covers a few months. I hope that in writing about what happens AFTER Remicade I’ll be able to help some other IBD patients and that I’ll look back and realize that this happened so that something better could fall into place.
Finally, to the people who have told me that my Instagram makes my life look perfect: now you know that it’s not. I’m just good at instagram 🙂 😉
*Edited to add*: I’m still an absolute supporter of Remicade. As mentioned, it worked incredibly well for me for over a year. It doesn’t work for everyone in the first place, and I am still very grateful to the ways it enhanced and improved my life, even if for a short time. I don’t want this post to discourage anyone from trying it. Some people can use Remicade for years and years without any trouble and I fully encourage you to give it a try if that’s what you and your healthcare team have decided might work for you. I’m hopeful that this post can provide some first-hand information about what to look for if you need to be aware of antibody development.
What to Expect
When your doctor first prescribes you a biologic, it’s usually an “anti-TNF” drug. These include:
If the first anti-TNF you try doesn’t work for you, your doctor will most likely try another one. If you still don’t get relief, he may switch you to another type of biologic. These include:
- Abatacept (Orencia), which blocks the immune system’s T cells to lower inflammation
- Anakinra (Kineret), which targets interleukin-1, a chemical your body makes that causes inflammation. Your doctor will call this type of drug an “IL-1 blocker.”
- Rituximab (Rituxan), which targets certain B cells, which are part of your immune system
- Tocilizumab (Actemra), which targets IL-6, a chemical your body makes that causes inflammation. Your doctor will call this type of drug an “IL-6 blocker.”
Sometimes, biologic drugs will help you for a while and then don’t work as well. It’s not clear why. If it happens to you, tell your doctor. He’ll probably switch you to another biologic or add another type of RA drug, like methotrexate or sulfasalazine, so your treatment works better.
Some people get more help from biologics than others. Experts can’t predict who’ll respond well and who won’t. But they know that people who get treatment in the earlier stages of RA tend to do better than those who’ve had the disease for many years.
Biologics also work best if you take them on a regular schedule. If you can’t do that due to side effects or the cost of the drugs, ask your doctor about your options.
Editorial: what can be done when infliximab stops working in ulcerative colitis? Authors’ reply
We thank Boyapati et al. for their interesting comments regarding our recent article.1, 2 Dealing with a loss of response to infliximab is often awkward, in terms or deciding whether to intensify infliximab therapy or to switch to an alternative.
While infliximab dose intensification restores clinical response in 60–90% of patients in the short term, only 35–47% of the responders will remained in remission at 12 months.3 In that setting, the economic burden of dose intensification could be useless since patients will have to switch to another treatment sooner or later. On the other hand, a significant proportion of patients who respond to dose intensification will be able to go back to a standard dose of 5 mg/kg (59% of the patients in our study).4Furthermore, the efficacy of a second anti‐TNF after secondary failure of infliximab has been shown to be poor in Crohn’s disease.5
We agree with Boyapati et al. that loss of response was not defined adequately. In our study, it was defined according to physician global assessment. However, the vast majority of patients presented with high partial Mayo score and all of them had active disease according to this previous score assessment.6, 7
We fully agree that therapeutic drug monitoring is a cornerstone in the management of patients who lose response to infliximab and is currently lacking in our study. Indeed, it has been shown that infliximab could be consumed by the inflammatory burden, immunogenicity of the drug, and faecal loss.8 However, time is not on our side when loss of response occurs, and it is often difficult to wait for the results of therapeutic drug monitoring to decide whether infliximab therapy should be intensified. New assays that provide a real‐time assessment of the anti‐TNF trough levels and the presence of anti‐drug antibodies are needed for a personalised drug optimisation strategy.