Long-term data on a biologic for Crohn's

Testing a new blog format

So... I have been realizing that my goal to try and pick a Crohn's-related topic that seems interesting (to me), and then produce an unbiased review on that subject, may have been a bit overambitious.  Thus, I am going to try a new format for most of my blog posts.  I am going to start with an interesting article, and then base my post around that particular article (more journal club style... and way more manageable).  I hope that this will allow me to post more frequently and enable me to more thoroughly discuss the article theme.  I still plan to do larger "review" articles, but more intermittently, as time permits.

Today's featured article:

Seminerio et al. 2012. Infliximab for Crohn’s Disease: The First 500 Patients Followed up Through 2009. Digestive Diseases Science DOI 10.1007/s10620-012-2405-z.

Although I am not on… nor have I yet tried… infliximab (better known by its brand name of Remicade), I thought this would be a great article for the IBD community because there is finally some long-term data regarding the use of this biologic therapy for Crohn's patients.  We are now starting to get information about the durability of the clinical response to a biologic agent, as well as results about long-term side effects of biologic therapies.

Infliximab: the background

Infliximab is of the class of therapies called biologics (please see my previous post for a summary of Crohn’s therapies), and this particular drug is an antibody that targets the molecule TNF (short for tumor necrosis factor).  TNF is one of the nasty players mediating overaggressive immune responses… in Crohn’s disease and other autoimmune conditions.  Thus, the objective is for the infliximab antibodies to bind to the excess TNF, neutralize it, and inhibit its activity.

In 1998, infliximab became the first-approved biologic therapy for Crohn’s disease in the US.  It was initially approved only for short-term induction therapy in Crohn’s patients with moderate to severe disease, for whom other therapies had failed (Targan et al. 1997., Present et al. 1999.).  The FDA approval was extended to include long-term maintenance therapy in 2002 (Hanauer et al. 2002., Sands et al. 2004.)  Following the introduction of infliximab, a couple of other similar TNF-targeting medications were introduced, including adalimumab (Humira) and certolizumab pegol (Cimzia).  Once these biologic agents started to gain greater clinical use, more adverse effects of these medications were recognized... including tuberculosis, certain types of fungal infections, and, in rare cases, even lymphoma (Brown et al. 2002., Keane et al. 2001., Lee et al. 2002., Mackey et al. 2007.).  Thus, long-term evaluation of the risks and benefits of these medications has been needed... and now has finally been published.

Study patients, infliximab treatment regimen, & measurement of response

The investigators identified 512 Crohn's patients that were treated with infliximab between 1998 and 2002 and who were followed-up through 2009.  Of those patients, 496 gave consent to review of their medical records and were included in the study.  Patients initially received an infliximab dose of 5 mg/kg body weight by two-hour intravenous infusion and were given one to three doses within three weeks as induction therapy.  Some patients continued to receive maintenance therapy with infliximab, but the dosing regimens were variable depending on patient response and physician treatment strategies.  Of the initial patient population, 37% (182 patients) received maintenance therapy with infliximab at some point.

Patients' response to therapy was assessed by looking at overall symptomatic resolution during the treatment period... e.g. decreasing diarrhea (reduction in frequency > 90%), relief of abdominal pain or cramping, fistula healing, etc.  More rigorous quantitative measures, such as the Crohn's Disease Activity Index (CDAI), were not used because this was a retrospective study*, and CDAI measures were not routinely taken at doctors' visits.

Short- and long-term response to therapy

The majority of patients demonstrated at least some response to infliximab induction therapy... with 20% having a partial response (response lasting < 3 weeks) and 61% having a complete response.  The rest of the patients in the study either had no response (13%) or were considered lost to follow-up (5%).

As for the long-term data, what seems to be the good news is that 97 (20%) of the patients were still using infliximab at the final evaluation point (presumably because they were still having clinical benefit and not experiencing significant adverse effects) and another 64 (13%) had discontinued the medication because they had achieved remission of the disease.  Thus, even after > 10 years of follow-up after initial infliximab treatment, a sizable proportion of patients had continued benefit.  Not unexpectedly, the majority of patients (57%) did need dose escalation or shortening of the interval between infusions at some point during the follow-up.  The dose escalation/interval change over time did also parallel the discontinuation of the drug over time... indicating that there is loss of response to infliximab in the long term.

The less-good (but not entirely surprising) news is that a relatively high proportion (39%) of patients experienced at least one adverse event during the follow-up period, and the longer the follow-up, the more likely these events were to occur.  Now, adverse events could either be minor or major, and included all infections, malignancy, hypersensitivity reactions, autoimmune reactions, and death.  The most prevalent adverse events seemed to be infusion or hypersensitivity reactions (17% of patients), a single abscess (10% of patients), or minor bacterial infections (14% of patients).  Pre-cancerous lesions (dysplasia) occurred in 17 patients (3%), and cancer developed in 26 patients (5%).  Although the cancer incidence is increased from the general population, it is hard to say that this is due to infliximab therapy... there could be referral bias in the patient population or an increased risk of cancer due to Crohn's disease.

Concluding thoughts

 
Infliximab therapy seems to be a good long-term option for a proportion of Crohn's patients, but could potentially cause serious complications in others if used for many years.  Although, major adverse events that are clearly caused by infliximab therapy are relatively rare, even after 10-year follow-up, they do indicate the need for watchful evaluation in patients on this drug.

Currently, we don't have any research to suggest for which patients infliximab (or any other therapy for that matter) will work wonders or for which other patients it will cause problems.  This is a major issue that needs to be addressed by more research.  For example, in my own care, I feel that we are just throwing random drugs at the disease to see what sticks.  If we had more individualized data to suggest what drugs to use for which patients, treatment strategies for Crohn's disease could be less haphazard than they are now.  We do have some good medications now (although we do still need more), but they are not applied optimally... leading to waste and poor outcomes.

*Terminology explanation:

Retrospective study: This is a type of study design in which the investigators look back at events that have already taken place.  While not the most rigorous type of study, because there often isn't good control data to match the treatment group, this type of study does allow potentially useful information to be extracted from existing records.  Also, these type of studies can usually be done more quickly than a prospective (watching individuals going forward) study.  In the case of this particular article, a similar prospective study would have taken greater than 10 years to complete, from inception to end.

Bibliography:

Brown et al. 2002. Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the food and drug administration. Arthritis & Rheumatism 46:3151–3158.

Hanauer et al. 2002. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 359:1541–1549.

Keane et al. 2001. Tuberculosis associated with infliximab, a tumor necrosis factor alpha- neutralizing agent. New England Journal of Medicine 345:1098–1104.

Lee et al. 2002. Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept. Arthritis & Rheumatism 46:2565–2570.

Mackey et al. 2007. Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease. Journal of Pediatric Gastroenterology & Nutrition 44:265–267.

Sands et al. 2004. Infliximab main- tenance therapy for fistulizing Crohn’s disease. New England Journal of Medicine 350:876–885.