Alimentary Pharmacology and Therapeutics
Review article: why, when and how to de-escalate therapy in inﬂammatory bowel diseases B. Pariente* & D. Laharie†
*Service d’hepato-gastroenterologie, H^opital Saint-Louis, Universite Paris VII, Paris, France. † Service d’Hepato-gastroenterologie – Univ. Bordeaux, Laboratoire de bacteriologie, CHU de Bordeaux, H^opital Haut-Lev^eque, Pessac, France.
Correspondence to: Dr D. Laharie, CHU de Bordeaux, H^opital Haut-Leveque Hospital, Service d’Hepato-gastroenterologie, Pessac F-33600, France. E-mail: [email protected]
Publication data Submitted 10 November 2013 First decision 1 December 2013 Resubmitted 14 March 2014 Resubmitted 14 May 2014 Resubmitted 24 May 2014 Accepted 25 May 2014 EV Pub Online 23 June 2014 This commissioned review article was subject to full peer-review and the authors received an honorarium from Wiley, on behalf of AP&T.
SUMMARY Background Therapeutic objectives are currently evolving in inﬂammatory bowel diseases (IBD) from control of symptoms towards improvement of long-term disease outcomes. In patients achieving remission, safety concerns – infections or neoplasia – and economic issues are prompting de-escalation strategies.
Aim To give a complete overview of studies on de-escalating therapy in IBD.
Methods A structured search in Pubmed, the Cochrane Library and EMBASE was performed using deﬁned key words (inﬂammatory bowel diseases, Crohn’s disease, ulcerative colitis, immunosuppressants, azathioprine, methotrexate, anti-TNF, inﬂiximab, adalimumab, de-escalation, dose reduction, cessation, stopping, withdrawal), including full text articles and abstracts in English language.
Results Eleven studies were identiﬁed, investigating cessation of immunosuppressants (IS) and/or anti-TNF treatments. Patients exposed to a combination of IS and anti-TNF have an increased risk for infections, especially due to opportunistic agent, without any clear signal for associated cancers when compared to those receiving single therapy. In patients receiving IS alone, relapse rate at 12 months following IS cessation is close to 20% and 30% in Crohn’s disease (CD) and ulcerative colitis (UC) respectively. There is no study speciﬁcally evaluating anti-TNF treatment withdrawal in case of scheduled anti-TNF monotherapy in IBD. In patients receiving combination therapy with IS and inﬂiximab (IFX) for at least 6 months, relapse rate of IFX failure following IS cessation is near to 20% at 24 months and seems to be similar in patients who maintained combination therapy. In case of antiTNF therapy, cessation in CD patients in combo-therapy proportion of relapse is high, close to 40% and 50% over 1 year and 2 years respectively. Regarding higher risk of adverse events, some special situations – young males, pregnancy and elderly – should be managed speciﬁcally and de-escalating treatment considered.
Conclusions De-escalating treatment strategy should be mainly considered in patients with high risk of severe adverse events and low relapse risk (patients in deep remission) after drug withdrawal. For these reasons, cessation of anti-TNF treatment and/or immunosuppressants should be a case by case decision in highly selected patients.
Aliment Pharmacol Ther 2014; 40: 338–353
ª 2014 John Wiley & Sons Ltd doi:10.1111/apt.12838
Review: de-escalation of therapy in IBD INTRODUCTION Inﬂammatory bowel diseases (IBD) are chronic destructive diseases that lead to digestive damage, loss of function and disability.1–3 Therapeutic objectives are therefore currently evolving from mere control of symptoms towards ‘deep’ remission and consequent improvement of long-term disease outcomes.3 Deep remission that could be deﬁned as a composite of symptom control and mucosal healing may currently be a realistic target in IBD.4 Of note in Crohn’s disease (CD), higher rates of deep remission may be able to be achieved in patients with early disease, who have no irreversible transmural disease (strictures or ﬁstula) and who have not required surgical treatment. While it remains to be clearly proven that treating to the point of deep remission will affect the natural course of the disease, it has been reported that providing greater levels of mucosal healing and resolution of clinical symptoms may modify the disease course.5 This will often necessitate long-term therapy with immunosuppressants (IS) or newer biological therapies such as anti-TNF antibodies. Both these classes of drugs are associated with side effects and the latter are also very expensive. Both these factors have led clinicians to seek ways of safely de-escalating therapy once a sustained remission has been obtained. Here, we describe a systematic review of the evidence from clinical trials that have assessed the safety of de-escalation strategies and also consider speciﬁc situations such as the management of patients in pregnancy, who are elderly or with ﬁstulas, all of which may impact on relative risks for continuation or de-escalation of therapy. EFFICACY OF COMBINATION IMMUNOSUPPRESSIVE AND ANTI-TNF THERAPY COMPARED WITH MONOTHERAPY Two large randomised, double-blind, controlled studies have demonstrated that CD and ulcerative colitis (UC) patients receiving inﬂiximab (IFX) plus azathioprine (AZA) have signiﬁcantly higher rates of corticosteroid-free clinical remission and mucosal healing as compared to those receiving AZA or IFX alone.6, 7 In CD, 57% of patients receiving combination therapy were in corticosteroid-free clinical remission and 44% achieved mucosal healing at week 26, as compared to 44% and 30% respectively in patients receiving IFX alone and 30% and 16% respectively of patients receiving AZA alone.6 In UC, corticosteroid-free remission at week 16 was achieved by 40% of patients receiving combination therapy, compared with 22% receiving IFX alone and 24% receiving AZA alone; mucosal healing occurred in Aliment Pharmacol Ther 2014; 40: 338-353 ª 2014 John Wiley & Sons Ltd
63% of patients receiving combination therapy, compared with 55% receiving IFX and 37% receiving AZA.7 However, such a result has not been observed with methotrexate (MTX) in a recent double-blind, placebo-controlled trial showing that combination with IFX was not more effective than IFX alone in patients with CD.8 In IBD patients refractory to conventional IS, the clinical beneﬁts of continuing a drug that has previously failed when starting an anti-TNF therapy is still a matter of debate. Data from three cohort studies of patients treated with IFX suggested that an IS co-treatment (especially with thiopurines) was associated with reduced disease activity, less risk of needing to switch to another anti-TNF treatment (1% and 5% in patients with IS than in those without IS respectively),9, 10 and more ano-perineal ﬁstula closure (hazard ratio = 2.6).11 Evidence supporting combinations of IS with adalimumab (ADA) is weaker. No additional beneﬁt was observed in a recent abstract reported a meta-analysis of individual data from patients recruited in the pivotal trials conducted with anti-TNF in CD.12 This conﬁrms results in a cohort of 207 CD patients from two European reference centres, that showed modest beneﬁt for the combination ADA and IS only within the ﬁrst semester of treatment when compared to ADA alone.13 Mechanisms of combination therapy efﬁcacy still remain unclear and several hypotheses have been proposed including that concomitant IS could reduce anti-IFX antibodies (ATI) formation and improve the pharmacokinetics of the drug.14 In UC, beneﬁt of IS co-treatment in case of anti-TNF maintenance therapy has not been assessed.
CONCERNS REGARDING COMBINATION THERAPY Infection risk Infection risk is a crucial issue in IBD patients receiving immunomodulators. Indeed, there is an increased rate of mortality in both CD and UC and infections are one of the most important speciﬁc causes of death in IBD patients.15 According to the TREAT registry which evaluated the long-term safety of IFX in a large cohort of 6273 CD patients, factors independently associated with serious infections were moderate-to-severe disease activity, narcotic analgesic treatment, prednisone therapy and IFX treatment.16 Importantly, only treatments with prednisone or narcotic analgesics increased the mortality risk. Opportunistic infections are speciﬁc complications associated with all immunomodulators, such as corticosteroids, IS and anti-TNF. In a case–control study from the 339
B. Pariente and D. Laharie Mayo Clinic, each of these three agents predisposed to opportunistic infection with speciﬁc pathogens: corticosteroids with Candida species, thiopurines with virus and IFX with fungi and mycobacteria. Moreover, association of immunomodulators treatments is associated with a three-fold increased risk for opportunistic infections.17 Nevertheless, this increased infectious risk related to combination therapy remains controversial. In a recent meta-analysis comparing safety and efﬁcacy of combination therapy to anti-TNF monotherapy, no increased risk of total adverse event, including infection and severe infection, could be identiﬁed.18 All studies assessing infection risk with combination therapy that have included more than 100 patients are presented in Table 1.19, 20 An Italian case–control study comparing 95 IBD patients more than 65 years old exposed to anti-TNF to younger controls showed that infectious risk related to anti-TNF agents was higher in the elderly (11% and 2.6% developed severe infections respectively).21 Anti-TNF dosage may also impact on infections as observed in a controlled trial in rheumatoid arthritis (RA).22 When compared to a placebo group, relative risks of developing a serious infection were respectively 1.0 and 3.1 in patients receiving 3 mg/kg and 10 mg/kg of IFX as maintenance therapy. In IBD, no dedicated study explored the impact of anti-TNF dosage. However, no increase risk associated with high doses has been reported.17, 23, 24
Cancer and lymphoma risk The risk of neoplasm in IBD patients receiving anti-TNF therapy is controversial. In an Italian multicentre, matched-pair study aiming to determine long-term risk of neoplasm in CD patients treated with IFX,25 404 IFX-treated and 404 controls never exposed to IFX were included and followed-up for 4 years. Frequency of neoplasm was similar in patients treated with IFX and controls (P = 0.95). Recent data from the TREAT registry assessing potential associations between malignancy and anti-TNF therapy in patients with CD, demonstrated that baseline age, disease duration and smoking were independently associated with the risk of malignancy, but that no increased risk associated with immunosuppressive therapy alone, IFX therapy alone nor their combination.26 Other reassuring data from rheumatology cohorts did not observe an increased risk of malignancy, including lymphoma associated with anti-TNF.27 A different message however comes from recently reported retrospective cohort and nested case–control studies 340
comprising 108 579 patients with IBD, and evaluating the risk of melanoma and nonmelanoma skin cancer in IBD.28 Incidences of melanoma and nonmelanoma skin cancer increased among patients with IBD (incidence rate ratio = 1.29 and 1.46 respectively) and only therapy with biologics were associated with an increased risk of melanoma (odds ratio = 1.88). It has also been clearly demonstrated that IBD patients exposed to thiopurines have higher risks of developing nonmelanoma skin cancer (ongoing thiopurine treatment, hazard ratio = 5.9 and past thiopurine exposure, hazard ratio = 3.9) or lymphoproliferative disorders (hazard ratio = 5.28 between patients receiving and those who had never received thiopurine), including Epstein–Barr Virus-related post-transplant like lymphoma, hepatosplenic T-cell lymphoma and post-mononucleosis lymphoproliferation.28–31 Notably, it has been shown that old age (>65 years old) is associated with risk of incident lymphoproliferative disorder.29 It follows that the combination of an anti-TNF agent with a thiopurine may promote cancer risk, especially lymphoma. This has been ﬁrstly suspected for hepatosplenic T-cell lymphoma (HSTCL), when 36 cases have been declared including 20 receiving IFX with a thiopurine.32 Even though extremely rare, the risk of HSTCL, mainly observed in young males, needs to be considered because of its very bad prognosis. In a recent Food and Drug Administration registry including 91 IBD patients who developed T-cell lymphoma, risk for HSTCL was related to thiopurine alone and not to anti-TNF or combination therapy.33 Relevant studies assessing cancer and lymphoma risk with anti-TNF and/or immunosupressants are summarised in Table 2.
Pregnancy Except MTX, most IBD therapies are considered to be of low risk during pregnancy.34 MTX exposure during pregnancy, particularly during the ﬁrst trimester, may result in abortions, growth retardation, foetal loss and congenital malformations, including craniofacial anomalies, limb defects and central nervous system abnormalities.35 Consequently, MTX should be withdrawn in female before conception. For male, recent data suggest that paternal MTX exposure at the time of conception does not seem to raise any major concern for offspring.36 Concerning thiopurines and corticosteroids, no increased risk of malformations in the newborn have been observed and they can be used during pregnancy.34, 37 Management of anti-TNF therapy during pregnancy is not straightforward.38, 39 On the one hand, these Aliment Pharmacol Ther 2014; 40: 338-353 ª 2014 John Wiley & Sons Ltd
Review: de-escalation of therapy in IBD Table 1 | Relevant studies assessing infection risk with combination therapy Author
Case–control study assessing risk of opportunistic infection in IBD patients receiving corticosteroids, thiopurines, and/or IFX
100 consecutive IBD patients with opportunistic infections matched with 200 IBD patients with no history of opportunistic infection
6.0 9 10(9)/L, levels of haemoglobin ≤145 g/L, Creactive protein ≥5.0 mg/L, faecal calprotectin ≥300 lg/g (patients with no more than 2 of these risk factors had a 15% risk of relapse within 1 year) Effective re-treatment with IFX and well tolerated in 88% of patients who relapsed Relapse rate: 50% within 477 days after IFX discontinuation (35% of patients remained without clinical relapse up to the end of the follow-up and 73% of patients without relapse received concomitant IS therapy at time of IFX withdrawal) Relapse rates at 1 year: 39% in CD and 25% in UC Predictors of relapse: none (including concomitant IS)
Aliment Pharmacol Ther 2014; 40: 338-353 ª 2014 John Wiley & Sons Ltd
Review: de-escalation of therapy in IBD Table 3 | (Continued) Author
Molnar Combination et al. 2013 IS–anti-TNF: Anti-TNF discontinuation
while in steroid-free remission. Prospective observational study 121 CD patients (87 IFX and 34 ADA) assessing frequency of relapse in CD patients in clinical remission following 1 year of anti-TNF therapy who discontinued anti-TNF
Relapse rate: 45% within 1 year Predictors of relapse: previous biological therapy (P = 0.011), dose intensiﬁcation during the 1-year course of biological therapy (P = 0.024) (use of concomitant thiopurines not associated with prolonged remission)
IBD, inﬂammatory bowel disease; CD, Crohn’s disease; IFX, inﬂiximab; ADA, adalimumab; IS, immunosupressants; AZA, azathioprine; CRP, C-reactive protein; HR, hazard ratio.
Table 4 | Risk level of relapse in case of treatment de-escalation according to disease and therapeutic factors Low risk Deep remission: clinical remission with biomarker normalisation and complete mucosal healing Long duration of combination therapy (immunosupressant and anti-TNF agent)
Clinical remission and biomarker normalisation or low elevated inﬂammation parameters and nonsevere endoscopic lesions Short treatment duration
Complicated disease: stenosis and/or ﬁstula (in case of CD)
groups: 8 4% in patients continuing AZA and 21 6% in those who stopped the drug. The statistical hypothesis that placebo was inferior to AZA was not rejected (P = 0.195). Notably, presence of any endoscopic CD activity (CDEIS >0) or ulcerations at baseline were not predictive of relapse. These results suggest continuing AZA as maintenance therapy beyond 3.5 years. With a prolonged follow-up of 54.5 months, nearly half of the patients experienced clinical relapse. Cumulative probabilities of relapse at 1, 3 and 5 years were respectively 14%, 53% and 63%.76 Out of notice, among the 23 patients who relapsed and were re-treated by AZA alone, and all but one achieved remission. Recently, French et al. conducted a meta-analysis on relapse rate following AZA withdrawal in maintaining remission for CD.77 AZA discontinuation was found to signiﬁcantly increase the risk of relapse at 6, 12 and 18 months with pooled odds ratios
Aliment Pharmacol Ther 2014; 40: 338-353 ª 2014 John Wiley & Sons Ltd
Perianal disease (in case of CD) Extensive disease Clinical symptoms Elevated biomarkers Severe endoscopic lesions Treatment with monotherapy
of 0.22 (95% CI: 0.09–0.53), 0.25 (95% CI: 0.11–0.56) and 0.35 (95% CI: 0.21–0.6) respectively. No study looking at relapse rates beyond 5 years was available. Relevant trials assessing relapse rate after IS discontinuation in IBD patients under IS alone are summarised in Table 5. There is no study speciﬁcally evaluating anti-TNF treatment withdrawal in case of scheduled anti-TNF monotherapy neither in IBD nor in RA. Nevertheless, important messages were provided by several randomised controlled trials assessing beneﬁt of maintenance anti-TNF therapy vs. placebo in patients with active disease who have responded to induction. In the ACCENT 1 trial, 335 patients with active CD who have responded to a single IFX infusion, including 27% receiving an IS, were randomly assigned for placebo or IFX infusions at weeks 2 and 6 and then every 8 weeks thereafter until week 46. Patients receiving IFX were more likely to sus-
B. Pariente and D. Laharie
Table 5 | Relevant trials assessing relapse rate after IS discontinuation in IBD patients under IS alone Author IS discontinuation in UC
IS discontinuation in UC
IS discontinuation in CD
Hawthorne et al. 199273
Cassinotti et al. 200974
Lemann et al. 200575
Multicentre, controlled, randomised, double-blind trial of withdrawal or continuation of AZA in UC patients under AZA for at least 6 months
79 patients in remission or with mild disease activity taking AZA for at least 6 months were randomised to receive AZA (33) or placebo (34).
HR = 0.5 (95% CI: 0.25–1.0) for risk of relapse in patients continuing AZA compared those taking placebo. In the subgroup of 54 patients in long-term remission (>6 months), the one year rate of relapse was 31% (8/26) for patients continuing AZA and 61% (17/28) for those taking placebo. For the small group of patients with chronic stable colitis no beneﬁt was found from continued azathioprine therapy. HR 2.350 (CI 95% 1.434-3.852) for risk of relapse after drug withdrawal in patients with lack of sustained remission during AZA maintenance. HR 1.793 (CI 95% 1.064 –3.023) for risk of relapse after drug withdrawal in patients extensive colitis vs. left-sided colitis. HR 2.783 (CI 95% 1.267–6.114) for risk of relapse after drug withdrawal in patients with short treatments (3–6 months) more disadvantaged than >48-month treatments. Concomitant aminosalicylates were the only predictors of sustained remission during AZA therapy. Relapse rates at 18 months were 8 4% in patients continuing AZA and 21 6% in those who stopped AZA. The statistical
Multicentre observational retrospective study assessing clinical outcomes and predictive factors after withdrawal of AZA in UC patients
Multicentre, double-blind, non-inferiority withdrawal study in CD patients in clinical remission with AZA
127 UC patients, who were in steroid-free remission at the time of withdrawal of AZA, were followed-up for a median of 55 months or until relapse
83 patients in clinical remission with AZA for at least 3.5 years were randomly assigned to receive AZA (40) and to receive placebo (43).
20 mg/L, time without steroids