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ScienceDirect Drug resistance in inflammatory bowel diseases Jacques Moreau1 and Emmanuel Mas2,3,4,5 The management of patients with moderate to severe inflammatory bowel diseases, that is, Crohn’s disease and ulcerative colitis, remains challenging. In recent years, therapeutic goal evolved from clinical remission to mucosal healing and deep remission. In order to achieve remission, it is important to appropriately choose and use available drugs. Therefore, anti-TNFa treatment should be rapidly used for severe and at-risk patients, sometimes in association with thiopurines or methotrexate. The monitoring of through levels and antibodies to anti-TNFa is relevant to optimize the treatment and to reduce drug inefficacy. However, the development of new drugs is required to offer alternative tools to severe and refractory patients. Addresses 1 De´partement de Gastroente´rologie, Hoˆpital Rangueil, CHU de Toulouse, Toulouse, France 2 Unite´ de Gastroente´rologie, He´patologie, Nutrition, Diabe´tologie et Maladies He´re´ditaires du Me´tabolisme, Hoˆpital des Enfants, CHU de Toulouse, F-31300, France 3 INSERM U1043, Toulouse F-31300, France 4 CNRS, U5282, Toulouse F-31300, France 5 Universite´ de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse F-31300, France Corresponding author: Mas, Emmanuel ([email protected]
Current Opinion in Pharmacology 2015, 25:56–61 This review comes from a themed issue on Gastrointestinal Edited by Nathalie Vergnolle
http://dx.doi.org/10.1016/j.coph.2015.11.003 1471-4892/Published by Elsevier Ltd.
Introduction Crohn disease (CD) and ulcerative colitis (UC) are two chronic disabling and progressive inflammatory bowel diseases. Their treatment is based on standard medication, immunosuppressive drugs and anti-TNFa therapies. During the last two decades, the strategies used to manage these patients were called step-up and topdown; anti-TNFa treatment, which is the most effective drugs in IBD, is used during the follow-up (step-up) or at the diagnosis (top-down). The dilemma of these approaches is in the one hand to effectively treat severe patients, but in the other hand to not over-treat mild-tomoderate patients. In order to choose an appropriate therapy, it is required to assess the severity of CD or Current Opinion in Pharmacology 2015, 25:56–61
UC with clinical and endoscopic scores. It is also important to follow the efficacy of the treatment with the evolution of these clinical scores and the inflammatory markers, C-reactive protein (CRP) and fecal calprotectin. Moreover, the main goal of the treatment seems to achieve a mucosal healing .
Drug resistance definition It can be defined as the reduction of drug effectiveness to cure IBD. We will discuss the mechanisms of resistance of corticosteroids, azathioprine (AZA) and 6-mercaptopurine (6-MP), and anti-TNFa, but also the effectiveness of the drugs used in IBD. In 2015, drug efficacy should be a deep remission, which means mucosal healing and improvement of inflammatory markers, in order to change the course of the disease. Indeed, half of the patients with CD in clinical remission have endoscopic and/or CRP evidence of residual activity in the SONIC trial . In this trial, 20.2% of the patients achieved clinical remission plus mucosal healing plus CRP normalization .
Corticosteroid resistance Conventional therapy of IBD has included corticosteroids, which inhibit T cell activation and pro-inflammatory cytokines . However, 50% of CD and 20% of UC patients fail to respond to glucocorticoid treatment . Several mechanisms of glucocorticoid resistance have been identified: activation of mitogen-activated protein kinase pathways, excessive activation of transcription factor activator protein 1, reduced histone deacetylase2 expression, raised macrophage migration inhibitory factor, and increased P-glycoprotein-mediated drug efflux . Thus, we believe that corticosteroid should be used at diagnosis in mild or moderate CD patients, in association during 2–3 months with thiopurine analogues, which will be effective to maintain remission by that time. However, in CD children, exclusive enteral nutrition (EEN) is an excellent alternative to corticosteroid and EEN should be proposed alone or in association with thiopurine analogues.
Azathioprine and 6-mercaptourine management Thiopurine analogues, AZA and 6-MP, are used as a maintenance therapy in IBD. These pro-drugs are transformed into active metabolites, 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine ribonucleotides (6MMPR) . The key enzyme of individual variations in www.sciencedirect.com
Drug resistance in IBD Moreau and Mas 57
this metabolism is the thiopurine methyltransferase (TPMT). In the general population, three sub-groups of persons can be separated according to their level of TPMT activity: normal to high (89%), intermediate (11%), and low to absent activity (<1%) [7,8]. A low to absent TPMT activity is associated to an increased 6-TGN concentration and to an increased risk of bone marrow suppression while a very high TPMT activity, which is present in 10% of IBD patients is associated to thiopurine hepatotoxicity and pharmacoresistance . Response to thiopurine analogues appears optimized at 6-TGN levels > 235–250 pmol/ 8 108 erythrocytes [7,8]. A prospective study included 55 IBD patients with steroid-dependency or active disease despite 6 months of AZA treatment; all of them had a normal TPMT activity . AZA dose were increased and metabolites levels were recorded. The authors found that a 6-TGN level > 400 pmol/8 108 erythrocytes may predict AZA resistance, with a 100% predictive value. Steroidfree remission was achieved in 43.6% of these patients. Recently, a same level of 6-TGN (405 pmol/8 108 erythrocytes) was also predictor of AZA resistance in pediatric IBD patients . Dose escalation should be stopped when this 6-TGN level is reached, because of drug resistance and increased adverse events. In CD, thiopurine analogues seem more effective in children  than in adults . An early administration of AZA within 6 months after CD diagnosis did not improve its efficacy compared to AZA use in cases of corticosteroid dependency, chronic active disease with frequent flares, poor response to corticosteroids, or development of severe perianal disease . Physicians should be aware of the increase of malignancies in IBD patients treated by thiopurine analogues, that is, lymphoproliferative disorders and non-melanoma skin cancer .
Methotrexate In IBD, methotrexate is used when patients fail to respond or are intolerant to thiopurine analogues. In a retrospective study, 60–78% of CD and UC patients had a clinical response (steroid withdrawal, CRP normalization or clinical improvement) at 6 months on methotrexate . Nowadays, in a single-centre prospective study of CD patients in clinical remission within at least 3 months, mucosal healing was achieved in only 2/18 (11%) with methotrexate, in 9/18 (50%) with AZA, and in 9/15 (60%) with infliximab .
Anti-TNFa treatment These drugs are used at the onset of the disease in moderate to severe patients or in refractory patients. The results of ACCENT I study have shown that CD patients with a CDAI 220 who responded to the initial dose of infliximab 5 mg/kg (58%) were more likely to be in remission at week 30 (around 40%) and week 54, to www.sciencedirect.com
discontinue corticosteroids, and to maintain their response, with repeated infusions at weeks 2, 6 and every 8 weeks . In the CHARM trial, 499/854 CD patients (58%) responded to adalimumab induction, that is, clinical remission (CDAI decrease 70) . Around 40% of them remained in remission at week 56, either in the adalimumab 40 mg eow (36%) or 40 mg weekly (41%) . In the EXTEND trial, the authors found a 19% rate of deep remission, defined by the absence of mucosal ulceration plus clinical remission (CDAI < 150), in the adalimumab 40 mg group versus 0% in the placebo group at week 52 . To note, this rate of deep remission was greatest when adalimumab was used in patients who had CD for less than 2 years (33%) . In the PRECISE 2 trial, 64% of patients with moderateto-severe CD had a clinical response after induction with 400 mg certolizumab pegol injections at weeks 0, 2, and 4 . When this dose was continued every 4 weeks, initial responders were more likely to be in clinical remission at week 26, compared to placebo, 48% versus 29% respectively . As shown in a randomized controlled trial, infliximab was as effective than ciclosporin in patients with acute severe UC . Treatment failure occurred in 31 (54%) and in 35 (60%) patients respectively given infliximab and ciclosporin respectively. Some patients generate antibodies to these drugs. Thus, 53/90 (59%) patients developed antibodies to infliximab (ATI) . ATI were transient in 15/53 (28%) patients. The risk to discontinue infliximab treatment was greater in patients with sustained versus transient ATI (relative risk 5.1) . Ungar et al. found that 42% of CD and UC patients remained ATI-free by 4 years of treatment . ATI were generally developed within the first 12 months. This incidence was reduced by combined immunosuppressive treatment. ATI development often preceded clinical flare. A combination of infliximab and AZA was more effective than conventional treatment with corticosteroids AZA for induction of remission and reduction of corticosteroid use in newly diagnosed CD patients who had not previously received corticosteroids, antimetabolites, or biological agents . At week 26, 60% patients of the combined immunosuppression group were in remission (CDAI < 150) without corticosteroid and without surgical resection, versus 35.9% in the conventional group ( p = 0.0062); this difference remained significant at week 52, 61.5% versus 42.2% ( p = 0.0278). In the SONIC trial, a randomized, double-blind trial, combination therapy with infliximab and AZA was more effective to achieve corticosteroid free clinical remission in moderate-to-severe Current Opinion in Pharmacology 2015, 25:56–61
CD patients than infliximab alone or AZA alone, in 56.8%, 44.4%, and 30% of patients respectively, at week 26 . Mucosal healing occurred in 43.9%, 30.1%, and 16.5% of these groups respectively. In a SONIC post hoc analysis, Colombel et al. found that a combination therapy with infliximab and AZA was more effective than AZA or infliximab monotherapy in achieving composite remission (clinical remission and/or mucosal healing and/or CRP normalization) at week 26 . Moreover, median serum through infliximab concentrations were greater among patients who achieved mucosal healing (clinical remission). In severe CD children, we believe that a combination therapy of infliximab and AZA should be used, at least for 6 months when penetrating perianal lesions are present. Finally, several factors have been identified as a cause of failure of anti-TNF therapy: high inflammatory process with massive production of TNF (i.e.: severe UC), low albumin level, high BMI, high drug clearance including stool loss, early production of permanent neutralizing antibodies, irregular (episodic) administration and/or bad patient adherence, and other inflammatory process non-TNF dependent. Efforts have been made to optimize their efficacy by increasing induction doses, by scheduling maintenance therapy, by adding immunomodulators such as thiopurines or methotrexate, by changing the route (IV vs. SC), the dosage and the delay between two injections, by monitoring the trough levels of the drug (infliximab 3–7 mg/ml and adalimumab 6–9 mg/ml), and by detecting the presence of neutralizing antibodies [25,26]. Biosimilars of infliximab were used since few years and available in clinical practice since few months. These drugs demonstrated their efficacy and safety in IBD [27– 29]. We started to use them for IBD patients who are naı¨ve of infliximab .
Choosing the optimal window to treat a wellclassified IBD patient It was shown by several studies that the response to treatment is increased in CD patients during the first years after diagnosis. In 2012, an expert panel defined the Paris criteria of early CD for use in disease-modification trials . It was composed by disease duration 18 months after diagnosis and no previous or current use of immunomodulators and/or biologics, while previous or current use of 5-aminosalicylate and/or corticosteroids is permitted. In addition to these components, the experts added covariates for consideration: endoscopic or radiologic evidence of active disease, CDAI > 150, bowel damage (fistula, abscess or stricture) . The results of a large CD cohort of 736 patients with 87.0% of B1 (non-stenosing, non-penetrating) phenotype at diagnosis revealed that AZA monotherapy or AZA plus Current Opinion in Pharmacology 2015, 25:56–61
anti-TNFa could delay disease progression to B2 (stenosing) or B3 (penetrating) phenotype when it was started prior to phenotype progression . Risk factors for disease progression were upper gastrointestinal tract involvement, male gender, and steroid use. In patients with CD who have complicated disease or bowel damage, and with poor prognosis factors and/or severe disease, anti-TNFa treatment should be considered as first-line therapy . Thus, it is important to select these patients in a timely and appropriate manner. Conversely, a step-up approach, based on corticosteroids, EEN and thiopurine analogues should remain the firstline of treatment in patients with mild-to-moderate CD without poor prognosis factors . Meanwhile, it is important to monitor their efficacy in order to change to anti-TNFa with a rapid step-up approach in order to avoid thiopurine analogues’ adverse events and to improve the disease course of patients . In CD children, a recent study revealed that anti-TNFa treatment (<3 months after diagnosis) was superior to that of an immunomodulator to obtain clinical remission at oneyear, 85.3% versus 60.3% respectively ( p = 0.0003) . Clinical remission was defined as corticosteroid free and PCDAI 10. To note, an improvement of the mean height z-score was only found in the anti-TNFa group. The authors were not able to identify clinical or laboratory marker of response to a particular approach. In UC children, Hyams et al. evaluated the efficacy and safety of infliximab for patients who failed to respond or had complications or side effects with 5-aminoslicylates, thiopurine analogues, or corticosteroids . After induction, main results were clinical response (73.3%), clinical remission (40%) and mucosal healing (68.3%) at week 8 in infliximab-treated patients. During the maintenance phase, infliximab therapy was more effective every 8 weeks than every 12 weeks. At week 54, the overall remission rate was 28.6%. We could speculate that new techniques, like 3D organoids culture, will enable pharmacological study and help physicians to accurately choose the best drug for a patient . Finally, we chose not to discuss 5-aminosalicylates indications because we believe that they are not useful in CD , although they are useful in mild UC, alone or in association with other drugs [38,39]. We also have to keep in mind that EEN is an excellent option to obtain remission in CD involving at least the small bowel; it should be encouraged in children with failure to thrive [40,41].
Need for new drug development The resistance to standard medication, to immunosuppressive drugs and to a less degree to anti-TNFa treatment, www.sciencedirect.com
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justifies the need for commercialization of new drugs. Such drugs could target the innate immune system or the intestinal barrier in addition to the acquired immune system, as described by Peyrin-Biroulet et al. in a review on CD few years ago . There is also a breakdown in the balance between proteases and protease inhibitors in humans and mice, which was restored by the overexpression of elafin in a mouse model of colitis [43,44]. Another approach could be to reverse glucocorticoid resistance by blocking its underlying mechanisms . Granulocytapheresis has shown some efficacy in open trials, mainly in UC. This technique was used in steroid-dependent and steroid-resistant CD and UC patients in a prospective observational study . One session was performed each week for 5 weeks. Mesalazine was permitted but immunosuppressive drugs and biological agents were not. Clinical remission was achieved in 71% of UC and 63% of CD patients at the end of granulocytapheresis. It was maintained by 66% and 54% of UC and CD patients respectively at 6 months, and by 48% and 43% at 12 months. In another trial, the authors found that an early introduction of granulocytapheresis in the management of newly diagnosed and moderate UC patients reduced steroid administration and steroid dependency during a 5-year follow-up . However, in a randomized, double-blind, sham-controlled trial in patients with active moderate-to-severe UC, granulocytapheresis did not demonstrate efficacy for induction of clinical remission or response .
Conclusion The treatment of CD and UC remains challenging and should be based on severity scores. The aim of this treatment evolves from clinical remission towards mucosal healing and even more to a deep remission. To achieve this aim, an early intervention, with or without combination therapy, can be justify to improve anti-TNFa efficacy. We believe that an early therapy with anti-TNFa is indicated for severe patients and a rapid step-up approach with thiopurine analogues can be used for moderate patients. However, the development of new drugs is required to offer alternative tools to severe and refractory patients.
Conflict of interest statement Emmanuel Mas has no conflict of interest to disclose.
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