How to Pick & Choose: Which Patient & Agent in Biologic-Naive Patients
The past decade has seen increased use of TNF antagonists for the treatment of inflammatory bowel disease.
Brian G. Feagan, MD, FACG
The past decade has seen increased use of TNF antagonists for the treatment of inflammatory bowel disease. The most useful information comes from randomized controlled trials in Crohn’s disease; less information is available regarding the use of these agents in the management of ulcerative colitis.
Currently, three TNF antagonists are FDA approved for the treatment f Crohn’s disease. Infliximab, adalimumab, and certolizumab pegol appeared to have similar efficacy and safety. Structurally, these agents are quite different, having evolved out of the concept that increasing the similarity of a therapeutic antibody to a human immunoglobulin structure would result in less immunogenicity and better long-term efficacy. Although theoretically attractive, this concept has not been validated in human experiments. All three monoclonals have similar rates of sensitization. Recent data have demonstrated that co-administration of immunosuppressive antimetabolites (purine antimetabolites, methotrexate) Reduces the prevalence of antibody formation and result in greater efficacy.
All three TNF antagonists have similar rates of secondary loss or response in Crohn’s disease. Although multiple factors may contribute to failure in a give patient, formation of antibodies to the drug, increase metabolism and clearance, and development of mechanistic override through non-TNF dependent pathways are the most important causes. Co-administration of either azathioprine or methotrexate could reduce the risk of failure mediated by and of these mechanisms.
The notion that combination therapy is more effective than monotherapy with either a TNF antagonist or an antimetabolite became well-established in rheumatoid arthritis where the combination of methotrexate and any of the TNF antagonists was shown to be synergistically effective with a reduced rate of anti-drug antibody formation. For example, in the PREMIER trial,1 patients with early rheumatoid arthritis treated with combination therapy had almost complete blunting of progressive joint damage that was observed with either adalimumab or methotrexate monotherapy. These observations were extended by the BeST trial2 results, which showed that the early introduction of combined infliximab and methotrexate was superior to monotherapy-based “step up” strategies.
Until recently, very few trials had examined combination therapy in CD. One of the first studies, published by the GETAID group, demonstrated that combined azathiprine/infliximab was more effective than azathioprine monotherapy in steroid-dependent Crohn’s disease.3 However, large subgroup analyses of the pivotal ACCENT I,4 CHARM,5 and PRECISE-26 trials failed to confirm this benefit. This led many experts to conclude that combination therapy was not indicated.
Subsequent studies have clearly demonstrated a benefit of combination therapy for the treatment of active Crohn’s disease. The first trial, performed by D’Haens and colleagues7 randomly assigned newly diagnosed CD patients to conventional “step up” treatment or early combined immunosuppression with infliximab/azathioprine (if azathioprine was not tolerated, methotrexate was substituted). Episodic treatment with infliximab was utilized in both groups according to pre-specified criteria. At the end of both 6 months and 12 months, the proportion of patients who were in corticosteroid-free remission was substantially higher in patients assigned to early combined immunosuppression. Strikingly, complete ulcer disappearance at 2 years was observed in 73% of patients assigned to early combined immunosuppression as compared with 30% o those who were treated according to the conventional approach.
Similar results were obtained in the SONIC trial,8 which randomly assigned over 500 patients who had not previously received treatment with azathioprine or biologics to induction therapy with azathioprine, infliximab, or the combination. Patients who received combination therapy were significantly more likely to be in corticosteroid-free remission at the end of the 6 months that those who received infliximab monotherapy, which in turn was superior to azathioprine monotherapy. Patients who received combination therapy had higher trough drug concentrations and were significantly less likely to develop antibodies to infliximab.
A third trial (COMMIT)9 compared triple therapy with corticosteroids, methotrexate, and infliximab to corticosteroids and infliximab. The trial did not show superiority of triple therapy; however, both group had very high rates of successful corticosteroid-free remission at week 14, suggesting that the combination of corticosteroids and infliximab might be synergistically effective. Similar results to those obtained with azathioprine in SONIC were observed in the methotrexate arm; patients who received the combination had higher trough infliximab concentrations and were significantly less likely to form anti-drug antibodies.
Who to TreatOn the basis of these three studies, a strong case can be made that patients should receive combination therapy in most situations. However, important concerns have been raised regarding safety. A case-control study originating from the Mayo Clinic10 suggested a large increase in risk associated with the use of multidrug regimens. However, such a relationship was not evident in any of the previously describe clinical trials, the large experience in rheumatoid arthritis, or two prospective safety registries (TREAT,11 ENCORE12). Thus, the available prospective data do not suggest that combination therapy is less safe than monotherapy.
Collectively, these observations have changed my approach to induction therapy. High-risk patients (complex fistula, deep ulceration on endoscopy, extensive disease, high-risk disease location [ie, gastroduodenal, rectal], young age at onset, systemically unwell) receive early combined immunosuppression. All other patients are treated with corticosteroids (prednisone for more severe patients or those with extensive colonic disease, budesonide for milder disease with appropriate anatomy) and followed closely. Patients who show steroid resistance or dependence within a 6-8-week period are escalated to combination therapy, patients who successfully tape from corticosteroids are observed. This “accelerated step care approach” holds out the possibility of directing the most effective therapy to the patients who are highest risk of complications.
In summary, although many questions remain regarding the long-term use of combined immunosuppression in inflammatory bowel disease, the role of this approach in the management of Crohn’s disease is now well-established.
References
1. http://onlinelibrary.wiley.com/doi/10.1002/art.21519/pdf
2. http://onlinelibrary.wiley.com/doi/10.1002/art.21405/abstract
3. http://www.gastrojournal.org/article/S0016-5085%2806%2900276-9/abstract
4. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2802%2908512-4/abstract
5. http://www.gastrojournal.org/article/S0016-5085%2806%2902522-4/abstract
6. http://www.nejm.org/doi/pdf/10.1056/NEJMoa062897
7. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2808%2960304-9/abstract
8. Sandborn WJ, Rutgeerts PJ, Reinisch W, Mantzaris GJ, Kornbluth A, et al. One Year Data from the Sonic Study: A Randomized, Double-Blind Trial Comparing Infliximab and Infliximab Plus Azathioprine to Azathioprine in Patients with Crohn's Disease Nave to Immunomodulators and Biologic Therapy. Gastroenterology 136[5 Suppl 1)]. 2009
9. http://www.gastrojournal.org/article/S0016-5085%2808%2900909-8/fulltext
10. http://www.gastrojournal.org/article/S0016-5085%2808%2900051-6/abstract
11. http://www.cghjournal.org/article/S1542-3565%2806%2900228-X/abstract
Adapted from materials provided in the American College of Gastroenterology 2010 Annual Scientific Meeting Breakfast Sessions guide.
