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Adalimumab Induces Deep Remission in Patients With Crohn's Disease

      Background & Aims

      Patients with moderate to severe ileocolonic Crohn's disease (CD) who received adalimumab induction and maintenance therapy had greater rates of mucosal healing than patients who received placebo after adalimumab induction therapy in a 52-week trial (EXTend the Safety and Efficacy of Adalimumab Through ENDoscopic Healing). We investigated whether this treatment also induced deep remission—a composite clinical and endoscopic end point.

      Methods

      Rates of deep remission, defined as the absence of mucosal ulceration and CD Activity Index scores less than 150, were compared between patients given continuous adalimumab and those given only induction therapy followed by placebo. We assessed the relationships between deep remission and other outcomes among patients who received adalimumab. The outcomes of patients with deep remission were compared with those of patients with only the absence of mucosal ulceration or only clinical remission.

      Results

      Rates of deep remission were 16% in patients given adalimumab vs 10% in those given placebo (P = .34) at week 12, and 19% vs 0% (P < .001) at week 52. Rates of deep remission were greatest among patients who received adalimumab and had CD for 2 years or less (33% at weeks 12 and 52). At week 52, patients who achieved deep remission at week 12 required significantly fewer adalimumab treatment adjustments, hospitalizations, and CD-related surgeries; had significantly less activity impairment; and had better quality of life and physical function compared with patients not achieving deep remission. Deep remission generally was associated with better outcomes than only an absence of mucosal ulceration; outcomes of patients with deep remission vs only clinical remission were similar. Deep remission was associated with estimated total cost savings of $10,360 (from weeks 12 through 52) compared with lack of deep remission.

      Conclusions

      In an exploratory study of patients with moderate to severe ileocolonic CD who received adalimumab induction and maintenance therapy, patients achieving deep remission appeared to have better 1-year outcomes than those not achieving deep remission. These findings should be validated in large, prospective trials. ClinicalTrials.gov number: NCT00348283.

      Keywords

      Abbreviations used in this paper:

      CD (Crohn’s disease), CDAI (Crohn’s Disease Activity Index), DR (deep remission), EOW (every other week), EXTEND (EXTend the Safety and Efficacy of Adalimumab Through ENDoscopic Healing), HRQOL (health-related quality of life), IBDQ (Inflammatory Bowel Disease Questionnaire), ITT (intention-to-treat), MCS (Mental Component Summary), PCS (Physical Component Summary), SES-CD (Simple Endoscopic Score for Crohn’s Disease), SF-36 (Short Form 36 Health Survey), TNF (tumor necrosis factor), TWPI (total work productivity impairment), WPAI (work productivity and activity impairment)
      See related article, Feagan BG et al, on page 681 in Gastroenterology; see related article, Colombel JF et al, on page 423 of this issue; see editorial on page 432.
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      Although pivotal clinical trials of anti-TNF agents for CD used the CD Activity Index (CDAI) to evaluate efficacy via clinical symptom improvements, mucosal healing is now viewed as an important end point in clinical trials.
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      suggests the need for a new end point that combines these outcomes. Similarly, the widely accepted treatment target in rheumatoid arthritis requires a composite measure of disease activity that includes assessment of the affected organ (ie, the joints), with the goal of preserving long-term function.
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      Although the concept is still evolving and a consensus definition has not yet been established for CD, this new desired goal could be a state of deep remission (DR), defined as a composite of clinical and endoscopic remission.
      • Colombel J.F.
      • Louis E.
      • Peyrin-Biroulet L.
      • et al.
      Deep remission: a new concept?.
      • Panaccione R.
      • Hibi T.
      • Peyrin-Biroulet L.
      • et al.
      Implementing changes in clinical practice to improve the management of Crohn’s disease.
      • Sandborn W.J.
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      • Travis S.
      • Feagan B.G.
      • Rutgeerts P.
      • et al.
      The future of inflammatory bowel disease management: combining progress in trial design with advances in targeted therapy.
      By assessing both clinical remission and mucosal healing, the randomized, double-blind EXTend the Safety and Efficacy of Adalimumab Through ENDoscopic Healing (EXTEND) trial provided an opportunity to examine the ability of adalimumab treatment to produce DR, which was a secondary outcome.
      • Rutgeerts P.
      • Van Assche G.
      • Sandborn W.J.
      • et al.
      Adalimumab induces and maintains mucosal healing in patients with Crohn’s disease: data from the EXTEND trial.
      In EXTEND, adalimumab was more effective than placebo for healing the intestinal mucosa at 1 year (24% and 0%, respectively; P < .001) in patients with moderate to severe ileocolonic CD.
      • Rutgeerts P.
      • Van Assche G.
      • Sandborn W.J.
      • et al.
      Adalimumab induces and maintains mucosal healing in patients with Crohn’s disease: data from the EXTEND trial.
      Mucosal healing rates at week 12 (primary end point) were 27% for continuous adalimumab vs 13% for placebo-treated patients who received adalimumab induction therapy (P = .06). Here, we compared DR rates between adalimumab- and placebo-treated patients and evaluated the impact of achieving early DR on long-term clinical, health-related quality of life (HRQOL), and economic end points.

      Materials and Methods

       Study Design

      EXTEND (Clinicaltrials.gov number: NCT00348283) was a 52-week, randomized, double-blind, placebo-controlled trial of adalimumab for inducing and maintaining mucosal healing in 135 adults aged 18 to 75 years with moderate to severe ileocolonic CD for at least 4 months (CDAI, 220–450 at baseline) and evidence of mucosal disease (Supplementary Figures 1 and 2).
      • Rutgeerts P.
      • Van Assche G.
      • Sandborn W.J.
      • et al.
      Adalimumab induces and maintains mucosal healing in patients with Crohn’s disease: data from the EXTEND trial.
      All patients received open-label adalimumab (160/80 mg at weeks 0/2) during the 4-week induction phase and were randomized at week 4 to receive adalimumab 40 mg every other week (EOW) or placebo as maintenance therapy. At or after week 8, patients with flares or nonresponse could receive open-label adalimumab (40 mg EOW and subsequently weekly, if needed). All participating sites received ethics approval of the protocol, and all patients provided written informed consent. All authors had full access to the data and reviewed and approved the final manuscript.

       Ileocolonoscopies

      Mucosal ulceration status was determined by ileocolonoscopy. Baseline mucosal ulceration was defined by a score of 2 or 3 on the ulcerated surface subscore of the Simple Endoscopic Score for CD (SES-CD) in 1 or more of the 5 ileocolonic segments.
      • Daperno M.
      • D’Haens G.
      • Van Assche G.
      • et al.
      Development and validation of a new, simplified endoscopic activity score for Crohn’s disease: the SES-CD.
      All patients had baseline mucosal ulceration per the study site’s initial ileocolonoscopy assessment; in some cases, baseline ulceration was judged to be absent by the independent blinded central reviewer/central review committee. Ileocolonoscopies were performed and recorded at baseline, week 12, week 52 (or early termination), and before receiving open-label adalimumab EOW in patients with flares or loss of response.

       Clinical Outcomes and Statistical Analysis

      DR, defined as the absence of mucosal ulceration plus clinical remission (CDAI <150), was a prespecified secondary outcome. DR rates between the continuous adalimumab and induction-only/placebo groups were compared at weeks 12 and 52. To evaluate the efficacy of adalimumab on both components of the DR end point, the analysis population was limited to all patients with baseline mucosal ulceration, per central review, and baseline CDAI of 220 to 450. DR also was analyzed by disease duration (≤2 y, >2–5 y, and >5 y).
      Statistical comparisons between treatment groups were performed using the Cochran–Mantel–Haenszel test with an increase of 70 points or more from baseline in CDAI responder status (CR-70) at week 4 as the stratification factor. Analyses involving mucosal healing and clinical remission used nonresponder imputation, whereby patients with missing data were considered to have mucosal ulceration or to be nonremitters, respectively. Blinded ileocolonoscopy data collected between weeks 8 and 12 (for patients receiving open-label adalimumab) were carried forward to week 12.
      The analysis population for exploring relationships between DR and hospitalization and surgery rates, HRQOL outcomes, and work productivity included only adalimumab-treated patients (intention-to-treat [ITT] population). Comparisons were between patients who achieved DR at week 12 and those who did not. These analyses included all patients regardless of baseline ileocolonoscopic/clinical status and used a modified nonresponder imputation approach to define patients in DR at week 12, whereby patients with missing data or escalating to weekly adalimumab therapy were considered nonresponders. For analysis of categoric variables at week 52 (Inflammatory Bowel Disease Questionnaire [IBDQ] remission, and Short Form 36 Health Survey [SF-36] Mental Component Summary [MCS] and Physical Component Summary [PCS] status), patients with missing week-52 data or escalating to weekly adalimumab were considered nonresponders. For continuous variables (work productivity and activity impairment [WPAI]), least-squares means were calculated from an analysis of covariance model with the last observation carried forward to week 52 and were adjusted for baseline WPAI score.
      All-cause and CD-related hospitalization and surgery rates from weeks 12 through 52 were summarized descriptively. All-cause hospitalizations were defined as hospital admissions for any reason. CD-related hospitalizations were those resulting from adverse events or CD-related treatment or complications, including the following: (1) CD-related surgery; (2) hospitalizations for nonsurgical CD-related events, such as CD-related flares; (3) hospitalizations for CD treatment-related adverse events; and (4) hospitalizations related to complications/extraintestinal manifestations of CD. Similar to the approach by Feagan et al,
      • Feagan B.G.
      • Panaccione R.
      • Sandborn W.J.
      • et al.
      Effects of adalimumab therapy on incidence of hospitalization and surgery in Crohn’s disease: results from the CHARM study.
      CD-related hospitalizations were identified from a list of the Medical Dictionary for Regulatory Activities codes. At least one author confirmed the CD-related hospitalizations and surgeries by reviewing serious adverse event reports and narratives, respectively.
      Relationships between DR at week 12 and IBDQ remission status and normal status for the SF-36 MCS and PCS at week 52 were analyzed. IBDQ remission is defined as an IBDQ score of 170 points or greater,
      • Hlavaty T.
      • Persoons P.
      • Vermeire S.
      • et al.
      Evaluation of short-term responsiveness and cutoff values of inflammatory bowel disease questionnaire in Crohn’s disease.
      which correlates with clinical remission.
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      • et al.
      Quality of life: a valid and reliable measure of therapeutic efficacy in the treatment of inflammatory bowel disease. Canadian Crohn’s Relapse Prevention Trial Study Group.
      Normal status for the SF-36 MCS and PCS is defined as a score of 50 or greater.

      Ware JE. SF-36® Health Survey update. Available: http://www.sf-36.org/tools/SF36.shtml. Accessed: April 22, 2011.

      Logistic regression was performed with control for the respective baseline HRQOL score.
      To assess work productivity, mean week-52 WPAI Questionnaire scores were evaluated. The WPAI is a validated, reliable, and responsive instrument for evaluating the impact of therapy on CD-related absenteeism (time missed from work), presenteeism (decreased productivity at work), total work productivity impairment (TWPI; composite of absenteeism and presenteeism), and total activity impairment (impairment of daily nonwork activities).
      • Reilly M.C.
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      • et al.
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      Multiple linear regressions were conducted with control for baseline WPAI scores.
      Rates of moving to open-label EOW and weekly dosing through week 52 were compared between adalimumab ITT patients who achieved week-12 DR and those who did not, using the Fisher exact test. Outcomes for patients achieving DR vs absence of mucosal ulceration only or clinical remission only also were compared.
      Costs components for analysis of the economic impact of DR were CD-related hospitalizations during weeks 12 to 52; other direct medical costs estimated per percentage of time spent in remission, moderate disease, or severe disease as measured on a biweekly basis; and indirect work loss costs calculated biweekly as the percentage of work time impaired based on the WPAI. The study population included adalimumab ITT patients only. For patients with no observations for WPAI, sample averages at weeks 12, 28, and 52 were carried forward for all midpoints. The last WPAI observation before discontinuation was carried forward for patients who discontinued before week 52. Costs were adjusted to 2009 US$ using the medical care component of the Consumer Price Index; no discounting was performed. The 40-week time span from determination of DR (week 12) to the end of the study was analyzed. A Monte Carlo simulation was used to generate 95% confidence intervals for costs and cost differences between subgroups.
      CD-related hospitalization costs were calculated by multiplying per-patient hospitalization rates by a cost of $36,159 per hospitalization.
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      • Larson L.R.
      • Roth J.M.
      • et al.
      The cost of hospitalization in Crohn’s disease.
      To assess costs related to disease severity, the percentage of time spent in remission, with moderate CD, and with severe CD (biweekly assessments), was multiplied by costs of $277, $506, and $580, respectively.
      • Feagan B.G.
      • Vreeland M.G.
      • Larson L.R.
      • et al.
      Annual cost of care for Crohn’s disease: a payor perspective.
      Cost estimates for productivity loss were calculated by multiplying the percentage of work time impairment per patient using a biweekly average salary estimate of $1496.

      US Bureau of Labor Statistics. Household data annual averages: median weekly earnings of full-time wage and salary workers by selected characteristics. Available: http://www.bls.gov/cps/cpsaat37.pdf. Accessed: February 2, 2012.

      Results

       Demographics, Clinical Characteristics, and Crohn's Disease–Related Medications

      Approximately half of the patients in each ITT group (N = 65 induction-only/placebo; N = 64 continuous adalimumab) previously had received anti-TNF therapy (Table 1). The induction-only/placebo group had significantly greater baseline aminosalicylates (29% vs 14%) and corticosteroid (38% vs 14%) use than the continuous adalimumab group. Baseline immunosuppressant use and baseline CDAI and SES-CD scores were similar between groups.
      Table 1Baseline Demographics, Clinical Characteristics, and Concomitant Medication Use: ITT Population (N = 129)
      Adalimumab induction-only/placebo (n = 65)Continuous adalimumab (n = 64)
      Demographics
       Women, n (%)41 (63.1)40 (62.5)
       White, n (%)60 (92.3)59 (92.2)
       Age (y), mean (±SD)37.2 (12.6)37.1 (11.1)
      Clinical characteristics
       CRP ≥1.0 mg/dL, n (%)
      Two patients in the continuous adalimumab group did not have a baseline C-reactive protein (CRP) measurement.
      28 (43.1)31 (50.0)
       CD duration (y), mean (±SD)9.8 (8.4)10.4 (8.0)
       CDAI score, mean (±SD)321.1 (72.1)318.7 (68.6)
       SES-CD score, mean (±SD)13.3 (8.4)11.8 (8.2)
       Prior anti-TNF agent, n (%)37 (56.9)30 (46.9)
      Concomitant medications, n (%)
       Aminosalicylates
      P < .05 for adalimumab induction-only vs continuous adalimumab therapy (chi-square test).
      19 (29.2)9 (14.1)
       Immunomodulators25 (38.5)28 (43.8)
       Corticosteroids
      P < .05 for adalimumab induction-only vs continuous adalimumab therapy (chi-square test).
      25 (38.5)9 (14.1)
       CD-related antibiotics7 (10.8)7 (10.9)
      IBDQ, mean (±SD)117.1 (29.1)116.5 (33.3)
      WPAI components, mean (±SD)
       Absenteeism30.5 (36.9)35.9 (36.1)
       Presenteeism46.3 (33.1)57.5 (23.7)
       TWPI57.0 (34.1)70.5 (24.1)
       Total activity impairment64.6 (26.7)68.1 (21.2)
      SD, standard deviation.
      a Two patients in the continuous adalimumab group did not have a baseline C-reactive protein (CRP) measurement.
      b P < .05 for adalimumab induction-only vs continuous adalimumab therapy (chi-square test).

       Deep Remission Rates at Weeks 12 and 52: Overall and by Disease Duration (Deep Remission Analysis Population)

      In the DR analysis population, which excluded patients lacking baseline mucosal ulceration per blinded/central review (n = 2 for continuous adalimumab, n = 4 for induction-only placebo), DR rates at week 12 were numerically greater for the continuous adalimumab group (16%; 10 of 62 patients) compared with the induction-only/placebo group (10%; 6 of 61 patients), but did not reach statistical significance (P = .34) (Figure 1A). Continuous adalimumab therapy (19%; 12 of 62 patients) was significantly more effective than induction-only/placebo therapy (0%; 0 of 61 patients) for producing DR at week 52 (P < .001) (Figure 1A). Adalimumab-treated patients with a disease duration of 2 years or less had the highest DR rates at weeks 12 and 52 (Figure 1B).
      Figure thumbnail gr1
      Figure 1DR at weeks 12 and week 52 (A) overall and (B) by disease duration. Patients with baseline mucosal ulceration per blinded/central review (N = 61 for induction-only/placebo; N = 62 for continuous adalimumab). aCochran–Mantel–Haenszel test for adalimumab vs placebo. bP = .19 for adalimumab vs placebo, adjusted for baseline disease duration (Cochran–Mantel–Haenszel test). cP < .001 for adalimumab vs placebo, adjusted for baseline disease duration (Cochran–Mantel–Haenszel test). dFisher exact test for adalimumab vs placebo within disease duration group.

       Impact of Early Deep Remission on Long-term Outcomes for Adalimumab-Treated Patients (Adalimumab Intention-to-Treat Population)

      Eleven patients in the adalimumab ITT population achieved DR by week 12. No patients who achieved early DR were hospitalized or underwent a CD-related surgery. Nine patients (17%) in the non–DR group were hospitalized; 5 (9%) of these hospitalizations were CD-related (Supplementary Table 1). Three patients in the non–DR group required CD-related surgeries.
      At week 52, significantly more patients in the DR group achieved IBDQ remission (64% vs 26%; P < .05) and normal SF-36 PCS status (55% vs 19%; P < .05) than patients without DR (Figure 2A) . Patients with early DR were approximately 5 times more likely to achieve IBDQ remission (odds ratio, 5.0) as well as a normal SF-36 PCS score (odds ratio, 4.7) at week 52 (both P < .05).
      Figure thumbnail gr2
      Figure 2Quality of life and productivity at week 52: adalimumab-treated patients with and without week-12 DR. (A) IBDQ remission and normal SF-36 MCS/PCS. (B) Mean WPAI component scores. N = 64 ITT adalimumab patients regardless of baseline mucosal healing status; 11 patients achieved DR at week 12, according to site assessment. aIBDQ score of 170 points or greater. bSF-36 MCS/PCS score of 50 or greater. cLower absenteeism scores indicate fewer work days missed. dLower presenteeism scores indicate less work productivity impairment. eLower TWPI scores indicate greater work productivity. fLower total activity impairment (TAI) scores indicate less daily nonwork activity impairment.
      Adalimumab-treated patients with early DR had significantly less impairment in daily nonwork activities (ie, lower total activity impairment score) at week 52 than patients without DR (P < .05; Figure 2B). DR also was associated with improved work productivity (ie, lower TWPI, absenteeism, and presenteeism scores). Although results were not statistically significant, the degree of the difference between the DR group and the non–DR group met the criterion for clinical significance on absenteeism and TWPI (≥7 percentage points).
      • Reilly M.C.
      • Brown M.C.
      • Brahant Y.
      • et al.
      Defining the minimally important difference for WPAI: CD scores: what is a relevant impact on work productivity in active Crohn’s disease?.
      Patients with early DR were significantly less likely to receive open-label EOW therapy over 1 year (9%; 1 of 11 patients) than patients without early DR (49%; 26 of 53 patients; P = .02). For patients without DR at week 12, the average time to transition from blinded to open-label EOW therapy was 206 days (Supplementary Figure 3A). No patients achieving early DR required open-label weekly therapy compared with 28% of patients without DR. The average time from blinded EOW therapy to dosage adjustment to weekly open-label therapy was 264 days (Supplementary Figure 3B).

       Deep Remission vs Absence of Mucosal Ulceration or Clinical Remission Only

      Of 53 adalimumab-treated ITT patients without DR, 8 had an absence of mucosal ulceration without clinical remission and 19 had clinical remission with persistent mucosal ulceration. DR generally was associated with better outcomes compared with an absence of mucosal ulceration only; results for patients with clinical remission only were similar to those for patients with DR (Figure 3) .
      Figure thumbnail gr3
      Figure 3Comparison of outcomes for patients achieving DR (N = 11) vs absence of mucosal ulceration only (N = 8) or clinical remission only (N = 19). (A) Quality-of-life scores at week 52, hospitalization, and treatment adjustment. (B) Work productivity scores at week 52. aFor each end point except CD-related hospitalization, P < .05 for patients achieving DR vs absence of mucosal ulceration only; there were no statistically significant differences for patients with DR vs clinical remission only. bIBDQ score of 170 points or greater. cSF-36 MCS/PCS score of 50 or greater. dLower TWPI and total activity impairment (TAI) scores indicate less impairment. OL, open label.

       Economic Benefit of Deep Remission

      Supplementary Figure 4 summarizes costs associated with hospitalization, the percentage of time spent in the 3 disease severity states, and work productivity impairment. During the 40 weeks after early DR achievement, estimated savings were $6117 for direct medical costs and $4243 for indirect costs related to improved productivity compared with patients without DR. Total cost savings associated with DR amounted to $10,360 (Figure 4) .
      Figure thumbnail gr4
      Figure 4Cost estimates at week 52: adalimumab-treated patients with and without week-12 DR. aTotal costs (indirect + direct); difference between groups = $10,360. bTotal direct costs; difference between groups = $6117. cIndirect costs; difference between groups = $4243.

      Discussion

      In this preliminary exploration of DR as a new treatment goal in CD, nearly 1 in 5 adalimumab-treated patients in the EXTEND trial achieved the composite end point of clinical remission plus complete absence of mucosal ulceration at week 52, compared with none who received induction-only/placebo therapy. Results for DR at week 12 were not statistically significant, possibly because a carryover effect of adalimumab induction therapy in patients randomized to placebo may have confounded the results at this time point. Patients with early DR had fewer hospitalizations and CD-related surgeries, lower rates of dosage adjustment, better HRQOL, less productivity and activity impairment, and lower medical costs than patients without early DR. In addition, the current data suggest that anti-TNF agent therapy earlier in the disease course increases the probability of achieving DR. One other study using clinical remission and a less stringent endoscopic component (SES-CD score, 0–2) to define DR found that 43% of patients achieved DR after an average of 23 months of anti-TNF maintenance therapy.
      • Molander P.
      • Sipponen T.
      • Kemppainen H.
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      Achievement of deep remission during scheduled maintenance therapy with TNFα-blocking agents in IBD.
      The majority of these patients also had histologic remission; however, the study did not assess long-term patient outcomes.
      This treatment target in CD, which combines symptom control with an objective indicator of inflammatory disease activity, still is evolving.
      • Colombel J.F.
      • Louis E.
      • Peyrin-Biroulet L.
      • et al.
      Deep remission: a new concept?.
      • Panaccione R.
      • Hibi T.
      • Peyrin-Biroulet L.
      • et al.
      Implementing changes in clinical practice to improve the management of Crohn’s disease.
      • Sandborn W.J.
      The future of inflammatory bowel disease therapy: where do we go from here?.
      • Travis S.
      • Feagan B.G.
      • Rutgeerts P.
      • et al.
      The future of inflammatory bowel disease management: combining progress in trial design with advances in targeted therapy.
      • Zallot C.
      • Peyrin-Biroulet L.
      Deep remission in inflammatory bowel disease: looking beyond symptoms.
      Although the current analysis provides preliminary evidence that early DR is achievable and may be a useful treatment target, the definition of DR applied here was exploratory; a consensus definition that can be validated in prospective trials has yet to be established. For example, ileocolonoscopy achieved a strong endorsement as the best method to evaluate mucosal healing in a recent expert consensus report
      • Feagan B.G.
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      • et al.
      Recommendations for the treatment of Crohn’s disease with tumor necrosis factor antagonists: an expert consensus report.
      and was used in the current DR definition; however, ileocolonoscopy use in daily practice is limited because it is invasive and expensive. Exploration of biomarkers and other patient characteristics as mucosal healing surrogates may be an option to refine the definition and enhance the practicality of assessing DR. Before any recommendation to adopt DR as a treatment target, establishing a clear association between achievement of DR and better long-term prognosis is necessary. To our knowledge, no prior studies have compared long-term outcomes between DR and mucosal healing or clinical remission alone. It is unclear why the present study does not show an advantage of DR in improving patient outcomes compared with clinical remission alone. Small sample size, lack of sensitivity of the chosen outcome variables to detect differences, or the lack of an actual difference could explain this finding. For hospitalization and surgery rates specifically, too few events attributable to disease progression may have occurred during the 52-week study to show a difference. Although the present analysis estimated lower medical costs for patients with DR than those without DR, it did not address the important issue of costs in patients with DR vs clinical remission. More studies are needed to examine the comparison between DR vs clinical remission alone.
      Further, these analyses could not address whether a particular threshold of mucosal healing can be associated with improved long-term outcomes or whether the definition of DR should be uniform for all patients or vary depending on disease duration and degree of baseline damage. Other issues such as drug escalation in patients who do not achieve DR and the potential for a relapse-free disease course after withdrawal of anti-TNF therapy require additional studies to be clarified. Larger prospective studies evaluating various treatment algorithms to achieve DR and the utility of DR to predict important outcomes related to disease progression and disability currently are ongoing or planned (Clinicaltrials.gov numbers: NCT01235689 and NCT01698307). Such studies will provide valuable insight regarding the optimal definition of DR and clarify its role as a treatment target in CD.

      Acknowledgements

      The authors thank Kathleen G. Lomax, MD, formerly of AbbVie, Inc, for reviewing the manuscript. Medical writing services were provided by Cathryn M. Carter, MS, of Arbor Communications, Inc, and was funded by AbbVie, Inc.

      Supplementary Material

      Figure thumbnail fx1
      Supplementary Figure 1EXTEND study design. The study was conducted from August 2006 to September 2008 at 19 sites (Europe, the United States, and Canada). The primary efficacy end point was mucosal healing (ie, absence of mucosal ulceration in patients with baseline ulceration) as determined by the review committee’s visual assessment of the week-12 ileocolonoscopies.
      • Rutgeerts P.
      • Van Assche G.
      • Sandborn W.J.
      • et al.
      Adalimumab induces and maintains mucosal healing in patients with Crohn’s disease: data from the EXTEND trial.
      Starting at week 8, patients with symptomatic flare (increase in the CDAI of ≥70 points compared with week 4 and a CDAI of >220) or nonresponse (failure to achieve a CDAI decrease of ≥70 points compared with baseline [CR-70]) could receive open-label adalimumab 40 mg EOW with subsequent adjustment to open-label adalimumab 40 mg weekly at or after week 10 for ongoing flare/nonresponse. CD-related concomitant medications were permitted, provided that patients were receiving stable dosages before baseline as specified in the protocol. Patients could have received prior anti-TNF therapy for CD, provided that the other agent was discontinued at least 8 weeks before baseline and the reason for discontinuation was not primary nonresponse. Patients who continued on blinded therapy for the full duration of the trial or who moved to open-label therapy before week 12 had 3 ileocolonoscopies (baseline, week 12/move to open-label, and week 52/termination). Patients who remained on their randomized treatment until week 12 and subsequently moved to open-label therapy had 4 ileocolonoscopies (baseline, week 12, move to open-label EOW, and week 52/termination). aAdalimumab induction-only with placebo maintenance; reinitiation of adalimumab for flare/nonresponse.
      Figure thumbnail fx2
      Supplementary Figure 2EXTEND patient disposition. A total of 135 patients entered the induction phase and received adalimumab 160 mg at baseline/week 0 and 80 mg at week 2; 129 patients were randomized at week 4 (65 to induction only/placebo and 64 to continuous adalimumab). Five (8%) patients randomized to induction only/placebo and 10 (16%) patients randomized to continuous adalimumab discontinued from the study during the double-blind phase.
      Figure thumbnail fx3
      Supplementary Figure 3Kaplan-Meier analysis of time to open-label dosing: patients with and without early DR. There were 64 ITT adalimumab patients regardless of baseline mucosal ulceration status. Eleven patients had achieved DR at week 12, according to site assessment. Patients were censored if they dropped out of the study early or completed the study without moving to open-label EOW or weekly dosing. (A) Moved to open-label EOW therapy within 1 year. Cumulative probability of moving to open-label EOW therapy within 1 year was significantly lower for patients who achieved DR at week 12 (10%) vs patients who did not (54%; P < .02 from log-rank test). For patients not in DR at week 12, the average time to transition from blinded to open-label EOW therapy was 206 days; the 1 patient who achieved week-12 DR and moved to open-label EOW therapy did so on day 325. (B) Moved to open-label weekly therapy within 1 year. The cumulative probability of a dosage increase to weekly therapy within 1 year was 33% for patients who did not achieve DR at week 12 (P < .05 from log-rank test). The average time from blinded EOW therapy to dosage adjustment to weekly open-label therapy was 264 days. aN = number of patients remaining in the respective group at each time point.
      Figure thumbnail fx4
      Supplementary Figure 4Cost calculations during the 40 weeks from determination of early DR at week 12 to end of study. There were 64 ITT adalimumab patients (N = 11 in DR; N = 53 not in DR), regardless of baseline mucosal healing status; of the 11 patients with DR at week 12, there was 1 patient who had baseline mucosal ulceration based on the site’s assessment, but not the central review of the ileocolonoscopy.
      Supplementary Table 1Description of Hospitalizations and Surgeries: Patients Who Did Not Achieve Early DR
      EventCD-relatedSurgery
      CD stricture of ileumYY (ileocecostomy)
      Enteroenteric fistula and intrafascicular fistulaYY (resection)
      Abdominal pain, ovarian cyst torsion considered related to prior CD-related surgeriesYY
      Vulvar abscessYN
      CD flare (fistula, abscess)YN
      Coronary heart disease (dyspnea on exertion, shortness of breath, left arm pain), underwent angiography and stentingNN
      TonsillitisNN
      ZosterNN
      FibromyalgiaNN
      NOTE. No patients who achieved early DR had a CD-related hospitalization or surgery.

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      Linked Article

      • Deep Remission in Crohn's Disease: Is It the End of the Placebo Effect?
        Clinical Gastroenterology and HepatologyVol. 12Issue 2
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          I have read with great interest the article by Colombel et al1 showing that in moderate-to-severe ileocolonic Crohn's disease (CD) patients who received adalimumab induction and maintenance therapy, patients achieving deep remission appeared to have better 1-year outcomes than those not achieving deep remission. Deep remission was empirically defined as the absence of mucosal ulceration and CD Activity Index scores below 150.1
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