Edward V. Loftus Jr, MD, Editor

In their article, Drs Maneesh Dave, Konstantinos Papadakis, and William Faubion of Mayo Clinic review what is known about perturbations in the epithelial barrier, the innate immune system, and the adaptive immune system in patients with IBD. Although this basic work may seem a bit esoteric to the practicing clinician, these back-breaking efforts have led to the identification of multiple useful drug targets, such as tumor necrosis factor-α (TNF-α), other cytokines (both pro-inflammatory and anti-inflammatory), integrins, adhesion molecules, and kinases.

Drs Jennifer Jones and Juan-Nicholas Pena-Sanchez of the University of Saskatchewan then review our current thinking about which IBD patients are eligible for biologic therapy. In general, we are using biologic agents earlier in the disease course, especially in patients deemed to be at high risk of intestinal complications. They nicely document our shift from a reactive, symptom-based therapeutic approach to a more proactive one based on objective markers of inflammation such as endoscopy. In the following article, Drs Parambir Dulai and Corey Siegel from Dartmouth-Hitchcock Medical Center and Dr Laurent Peyrin-Biroulet from the Université de Lorraine review the rationale for using anti-TNF drugs in combination with thiopurines or methotrexate in most cases. The combination of an anti-TNF agent and a thiopurine seems to be our most efficacious combination of medication thus far. Most biologic agents are large protein molecules that are immunogenic, and it appears that combining them with a thiopurine reduces antidrug antibody formation and decreases clearance of the biologic. The authors remind us that we should be a little more wary of combination therapy in the elderly and in young men, but in certain high-risk patients in those demographics, combination therapy should still be considered.

In another article, Drs Siddarth Singh and Darrell Pardi of Mayo Clinic review the top-line efficacy results of infliximab, adalimumab, and certolizumab pegol in the treatment of Crohn disease. The authors also review data for secondary endpoints such as fistula healing, endoscopic improvement (“mucosal healing”), and health-related quality of life. Importantly, the use of these drugs is associated with statistically and clinically significant reductions in Crohn-related hospitalizations and surgeries. They also discuss the problems of primary nonresponse to anti-TNF therapy as well as secondary loss of response. Drs Mark Samaan, Preet Bagi, Niels Vande Casteele, and Geert D’Haens of the Amsterdam Medical Center and Dr Barrett Levesque of the University of California-San Diego review the efficacy of infliximab, adalimumab, and golimumab in the treatment of ulcerative colitis. The authors summarize not only the top-line efficacy data, such as clinical remission and response, but also important secondary endpoints, such as corticosteroid-free remission, mucosal healing, and reduction in ulcerative colitis–related hospitalizations and colectomies. The authors also compare the efficacy of infliximab and cyclosporine in the acute severe colitis setting. At the end of the article, the authors expand upon the concepts of “treat-to-target” and therapeutic drug monitoring, both of which are significantly altering the way we manage IBD patients.

Dr Sara Horst of Vanderbilt University Medical Center and Dr Sunanda Kane of Mayo Clinic provide an update on the use of biologic agents in pregnant women with IBD. They review how pregnancy impacts IBD and vice versa, the concept of placental transfer of biologic agents, and the safety of these agents in pregnant women with IBD and in mothers who are breastfeeding. The good news is that the anti-TNF agents appear to be safe for both the mother and the baby, and it may be wise to continue biologic therapy throughout the pregnancy.

Drs Uri Kopylov and Waqqas Afif of McGill University Health Center review infectious risks with biological agents, with specific emphasis on tuberculosis, granulomatous infections, fungal infections, and viral infections. The authors remind us of the small but real risk of progressive multifocal leukoencephalopathy in patients who are JC virus–positive and who have received the α-4 integrin antagonist, natalizumab, and that this serious neurologic complication has not been seen in patients treated with the gut-selective α-4 β-7 integrin antagonist, vedolizumab. They also discuss the role of keeping vaccinations up-to-date in our IBD patients, who are likely to receive immunosuppression at some point in their clinical course. In the article by Drs Dulai and Siegel of Dartmouth, they review what is known about the risk of cancer in IBD patients receiving biologic agents, with particular emphasis on the risk of lymphoma, nonmelanoma skin cancer, and melanoma. In contrast with the anti-TNF agents, no clearcut signal for increased malignancy risk has been detected with natalizumab or vedolizumab, but we probably need more person-years of observation on the drug to make any definite conclusions about this. Then, Drs Joseph Feuerstein and Adam Cheifetz of Beth Israel Deaconess Medical Center review what is known about other adverse events associated with these drugs, including infusion reactions (both acute and delayed), injection site reactions, autoimmune phenomena, such as drug-induced lupus, vasculitis, paradoxical arthritis, psoriasiform lesions, and demyelinating disorders.

Drs Kirk Lin and Uma Mahadevan of the University of California-San Francisco bring us up to speed on the current status of therapeutic drug monitoring of biologics. There are enormous interindividual differences in the pharmacokinetics of the biologics, and we can truly personalize our approach to each patient by periodically checking drug levels and the presence of antidrug antibodies and altering therapy accordingly. They present interesting data showing an inverse correlation between drug levels and objective markers of inflammation; in contrast, the presence of antidrug antibodies correlates with higher objective degrees of inflammation, loss of clinical response, and infusion reactions.

Dr Masayuki Saruta of the Jikei University School of Medicine and Dr Papadakis of Mayo Clinic review the lymphocyte trafficking pathway in intestinal inflammation and then provide us an update on drugs in this class, including the two already commercially available (natalizumab and vedolizumab), as well as a number of drugs in the development pipeline (including etrolizumab, PF-00547659, AMG181, and AJM300). Many of these drugs, including vedolizumab, etrolizumab, PF-00547659, and AMG181, appear to be gut-selective, and therefore, hold out the potential for a wider therapeutic window. Drs Brigid Boland, William Sandborn, and John Chang from the University of California-San Diego provide an update on Janus kinase inhibitors, including the one furthest along in drug development for IBD, tofacitinib. A phase 2 study of tofacitinib in ulcerative colitis was promising, leading to phase 3 trials. The authors also review potential side effects including opportunistic infections, dyslipidemia, and bone marrow suppression. In the final article, Drs Yvette Leung and Remo Panaccione of the University of Calgary review what is known about the efficacy and safety of the anti-IL-12/23 antibody, ustekinumab, for moderate to severe Crohn disease. Phase 2 trials of this drug in Crohn disease were promising, especially in the anti-TNF-exposed population, leading to ongoing phase 3 trials.

As you can see, considerable progress has been made in developing new therapies for our tough-to-treat IBD patients. We now have multiple drug targets and mechanisms of action. We are also beginning to better understand when to use the best drug in the best patient at the best time. More work needs to be done, however. We owe it to our patients.