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Journal of Crohn's and Colitis: 10 (8)

Editor-in-Chief

Laurence J. Egan, Ireland

Associate Editors

Shomron Ben-Horin, IsraelSilvio Danese, ItalyPeter Lakatos, HungaryMiles Parkes, UKJesús Rivera-Nieves, USABritta Siegmund, GermanyGijs van den Brink, NLSéverine Vermeire, Belgium

6.585
5.586

Published on behalf of

Exploring the use of adalimumab for patients with moderate Crohn's disease: Subanalyses from induction and maintenance trials

Abstract

BackgroundAnti-TNF agents are often reserved for patients with severe Crohn's disease (CD).

AimsWe explored the predictive value of baseline disease activity and C-reactive protein (CRP) for disease course, adalimumab efficacy for remission (induction and maintenance) in patients with moderate and severe CD, and adalimumab efficacy in moderate CD by CRP category.

MethodsPost hoc analyses of remission data were performed for all randomized patients from induction (CLASSIC I) and maintenance (CHARM, EXTEND) adalimumab trials in patients with moderate (CDAI = 300) or severe (CDAI > 300) CD, and in high (= 10 mg/L) or low (< 10 mg/L) CRP moderate CD subgroups. Placebo-treated CHARM patients were evaluated for disease activity over time and time to CD-related hospitalization, by baseline disease severity and CRP.

ResultsModerate CD patients had the highest clinical remission rate and largest treatment effect size compared with placebo at week 4 after 160/80 mg induction (46.3% adalimumab, 17.4% placebo; versus 22.9%, 3.6% for severe patients). Moderate-CD/high-CRP patients had the most pronounced efficacy (57.1% adalimumab, 6.7% placebo; versus 40.7%, 20.0% for lower CRP group). Adalimumab maintenance treatment (40 mg every-other-week) achieved superior remission versus placebo at one year in moderate (32.9% versus 13.7%) and severe (27.2% versus 7.5%) cohorts. Among moderate patients, efficacy was similar by CRP category. Moderate-CD/high-CRP placebo-treated patients experienced disease activity and hospitalization rates at week 56 of CHARM approaching those of severe CD patients.

ConclusionsThis analysis suggests that moderate CD patients can be treated effectively with adalimumab, and supports using CRP to identify moderate CD patients at greatest risk of disease progression.

Keywords
  • Crohn's disease;
  • C-reactive protein;
  • Adalimumab;
  • Anti-tumor necrosis factor therapy;
  • Inflammatory bowel disease

1 Introduction

Crohn's disease (CD) is a chronic condition characterized by a pattern of relapsing and remitting symptoms. Conventional treatments for Crohn's disease, including corticosteroids and immunosuppressants such as thiopurines or methotrexate, do not adequately control the disease in all patients. The biologic anti-tumor necrosis factor (TNF) agents adalimumab, infliximab, and certolizumab pegol are effective for treating patients with moderate to severe Crohn's disease15 and have expanded the available treatment strategies for CD.

Though not routinely used in clinical practice, the Crohn's disease activity index (CDAI) is currently the gold standard for quantifying Crohn's disease activity in clinical trials of patients with luminal disease, and is the basis of regulatory approval of treatments for CD.6,7 While the definition of clinical remission (CDAI < 150 points) is well accepted, the categorization of disease severity based on the CDAI is not as clear. The investigators who developed the CDAI arbitrarily designated a value of 150–219 as “mildly active” disease, 220–450 as “moderately active” disease and values greater than 450 as “very severe disease”.6,7 A CDAI range of 220–450 was used as the enrollment criteria for the pivotal clinical trials for adalimumab, certolizumab pegol, and infliximab (infliximab trials used a maximum CDAI of 400).15 In the United States, the prescribing information for all three agents specifies use in patients with “moderate to severe” CD who have failed conventional therapy.810 In Europe, the prescribing information for adalimumab and, until recently, infliximab, was limited to patients with “severe” CD11,12 (certolizumab pegol is not approved in Europe). The European indication for infliximab was recently expanded to include “moderate” CD.13

In clinical practice anti-TNF agents are often reserved for patients with more severe symptoms, because of symptom-based “step up” treatment strategies, benefit/risk concerns in patients with less severe disease, approved indication, and cost.14,15 Recent position statements regarding the treatment of CD have advocated earlier introduction of biological or immunosuppressant therapy in patients with a poor disease prognosis defined by demographic, genotypic, serological, or immunological factors, including elevated C-reactive protein (CRP).16 These recommendations are based at least in part on the desire to quickly introduce effective therapy in patients who will eventually experience disease progression, but also on an increasing recognition of the limited correlation between clinical symptoms and inflammation.16,17

CRP is a widely used biomarker of inflammation in Crohn's disease.1820 Measurement of CRP could be useful in identifying patients with moderate symptoms for whom biologic therapy may be appropriate, while minimizing the use of these agents in patients who are less likely to benefit.

In this post hoc analysis of clinical trial data, we explored the efficacy and safety of adalimumab treatment for induction and maintenance of remission in patients with moderate (CDAI = 300) versus severe (CDAI > 300) Crohn's disease. The CDAI threshold was selected based upon the European regulatory approval for adalimumab and infliximab, which define severe CD as a CDAI > 300.12,13 To provide information about the quality of life in patients with moderate CD, we evaluated baseline Inflammatory Bowel Disease Questionnaire (IBDQ)21,22 scores according to baseline disease severity. To help provide guidance for selection of patients for adalimumab treatment with consideration of the benefit/risk balance, we also explored the predictive value of CRP, a serum biomarker of inflammation, for disease course and adalimumab efficacy in patients with moderate CD.

2 Methods

2.1 Induction and maintenance trials

Data from the CLASSIC 1 trial3 was used to explore the efficacy and safety of adalimumab for induction of remission in patients with moderate to severe CD. The eligibility criteria and design of CLASSIC I have been published.3 Briefly, patients with a diagnosis of CD for at least 4 months prior to screening and a baseline CDAI of 220–450 were included in the trial. Concomitant treatment with stable doses of corticosteroids, 5-aminosalicylates, and immunosuppressants (azathioprine, mercaptopurine, methotrexate) was permitted, but previous exposure to anti-TNF agents was not allowed. Eligible patients were randomized (1:1:1:1) to one of four induction regimens: subcutaneous adalimumab 40 mg at week 0, 20 mg at week 2; 80 mg at week 0, 40 mg at week 2; 160 mg at week 0, 80 mg at week 2; or placebo at week 0 and week 2.

Maintenance of clinical remission in patients with moderate or severe CD was assessed using data from the CHARM and EXTEND trials, which have been previously described.1,23 In both trials, patients with CD for at least 4 months prior to screening and a baseline CDAI of 220–450 were eligible. Concomitant treatment with stable doses of corticosteroids, 5-aminosalicylates, and immunosuppressants was permitted; corticosteroids could be tapered at the investigator's discretion during the trials. Previous exposure to anti-TNF agents was permitted, provided the anti-TNF therapy had been discontinued at least 8 weeks (EXTEND) or 12 weeks (CHARM) prior to screening. In both trials, primary non-responders to a prior anti-TNF agent were excluded.

In the maintenance trials, patients received 4-week, open-label induction therapy with subcutaneous adalimumab (CHARM: 80 mg at baseline and 40 mg at week 2; EXTEND: 160 mg at baseline and 80 mg at week 2.) At week 4, patients entered the blinded phase, in which all patients were stratified by response (defined as = 70 point decrease in CDAI [CR-70]) and randomized to blinded treatment with subcutaneous adalimumab (CHARM: 40 mg every other week [eow], 40 mg weekly, or placebo [1:1:1]; EXTEND: 40 mg eow or placebo [1:1]). At or after week 8 (EXTEND) or week 12 (CHARM), patients who experienced disease flare or non-response could move to open-label adalimumab 40 mg eow. Patients with continued flare or non-response could move to open-label adalimumab 40 mg weekly. Disease flare was defined as an increase in CDAI = 70 points compared with week 4 and a CDAI > 220; non-response was defined as a lack of a CR-70 response compared with baseline.

2.2 Outcomes

Throughout the analyses, moderate CD is defined as baseline CDAI = 300, and severe CD is defined as baseline CDAI > 300. Baseline CRP is defined as either high (= 10 mg/L) or low (< 10 mg/L).

2.2.1 Quality of life in moderate compared with severe Crohn's disease

To evaluate the impact of CD on quality of life in patients according to baseline disease activity, we calculated the baseline median IBDQ scores in patients with moderate or severe CD in CLASSIC I, CHARM, and EXTEND. An IBDQ score = 135 was considered to reflect severely impaired quality of life. This value was derived by a regression line calculation that evaluated the correlation between IBDQ and CDAI (IBDQ = 201–0.22*CDAI), using a CDAI value of 300.24

2.2.2 Disease progression and hospitalization risk in placebo-treated patients

In order to analyze the influence of baseline CRP on disease activity over time in patients not receiving anti-TNF therapy, we evaluated CDAI trends over the course of the trial (at each study visit) in the patients in the CHARM study who received placebo. The last observation carried forward (LOCF) method was used to handle missing data after week 4. The visit times in CHARM and EXTEND were different, so the larger patient set from CHARM was used for the analysis. Patients were grouped according to baseline severity of Crohn's disease (moderate or severe) and high or low baseline CRP. Time to CD-related hospitalization for the same groups of placebo-treated patients was assessed during the double-blind period.

2.2.3 Remission

To evaluate the effect of baseline disease severity on the likelihood of success with induction therapy, clinical remission (CDAI < 150) was assessed at week 4 for patients in CLASSIC I who received induction with adalimumab (160/80 mg or 80/40 mg) or placebo, according to disease severity subgroups (moderate or severe). An analysis by high or low baseline CRP in the moderate subgroup was also performed. Non-responder imputation (NRI) was used to handle missing data.

To evaluate the likelihood of achieving remission after one year of adalimumab therapy in patients with moderate or severe Crohn's disease, pooled data from all randomized patients in CHARM and EXTEND were assessed for the placebo and adalimumab 40 mg eow and 40 mg weekly arms. Clinical remission at one year (defined as week 56 of CHARM and week 52 of EXTEND) was assessed in the intent-to-treat (ITT) and modified intent-to-treat (mITT) populations according to disease severity at baseline (moderate or severe), and in the moderate cohort by baseline CRP (high or low), using NRI for missing data or data obtained after move to open-label therapy. The ITT population included all randomized patients (regardless of response to open-label induction therapy). The mITT population consisted of the patients who responded (defined as achievement of CR-70 at week 4) to open-label induction, and represents patients who are most likely to continue on adalimumab in clinical practice.

2.3 Safety

Treatment-emergent adverse events were summarized by disease severity subgroups throughout each study, until 70 days after the last dose of study medication. For the pooled CHARM and EXTEND populations, safety results for the ITT are reported as events per 100 patient years.

2.4 Statistical analysis

Statistical analyses were performed with SAS statistical software (version 9.1, SAS Institute Inc., Cary, NC). All analyses were conducted post hoc. Demographic and baseline characteristics were compared using the chi-square test (categorical variables) or the Kruskal–Wallis test (continuous variables). Fisher's exact test was used to compare results from placebo- and adalimumab-treated groups. P values < 0.05 were considered significant. The patients in the study were not randomized according to baseline CDAI = or > 300; therefore, baseline differences may be responsible for differences in outcomes. The statistical significance of treatment differences between disease severity groups was evaluated based on Z score approximations.

The time to CD-related hospitalization in the double-blind period, beginning at randomization (week 4), was assessed using Kaplan–Meier analysis. Data were censored for patients who did not experience a CD-related hospitalization before completing the trial (through 70 days after the last dose of study drug), after receiving the first dose of adalimumab in the extension trial, after moving to open-label adalimumab, or upon dropping out of the study. Survival curves were compared using the log-rank test.

3 Results

3.1 Baseline demographics and clinical characteristics

With the exception of baseline CDAI, patient demographics and baseline characteristics were generally similar for the disease severity subgroups in CLASSIC I (Table 1) and in the pooled CHARM and EXTEND ITT population (Table 2; baseline characteristics and demographics for the mITT population are included in the supplemental material). The placebo patients in the severe CD group in CHARM/EXTEND had a slightly longer disease duration and higher baseline CRP than the other groups. The patients with severe CD in CHARM/EXTEND were slightly more likely to have received prior anti-TNF therapy than those with moderate disease activity. Median IBDQ values were higher in the patients with moderate disease, compared with those in the severe disease activity category in each trial, but there was substantial overlap in IBDQ scores between the moderate and severe cohorts (Fig. 1). Baseline median IBDQ scores for patients with moderate CD in each trial were near 135 (dotted line; CLASSIC I, median = 140; CHARM, median = 131; EXTEND, median = 132), indicating severely impaired quality of life in a substantial proportion of patients with “moderate” CD.

Figure 1

Baseline IBDQ scores, with median, 25th and 75th percentiles indicated (middle, lower, and upper horizontal lines, respectively), for CLASSIC I, CHARM, and EXTEND. Dotted line at IBDQ = 135 indicates threshold for severely impaired quality of life.

View this table:
1

Patient demographics and baseline characteristics: CLASSIC I.

CDAI = 300CDAI > 300
Placebo N = 46Adalimumab 80/40 N = 45Adalimumab 160/80 N = 41Placebo N = 28Adalimumab 80/40 N = 30Adalimumab 160/80 N = 35
Female; n (%)21 (45.7)28 (62.2)23 (56.1)16 (57.1)22 (73.3)17 (48.6)
Age, years; mean (SD)36.7 (12.05)37.1 (11.78)37.8 (10.66)37.8 (15.31)40.2 (11.31)39.4 (11.78)
White race; n (%)43 (93.5)42 (93.3)35 (85.4)25 (89.3)22 (73.3)32 (91.4)
Weight, kg; mean (SD)76.1 (21.3)75.8 (22.2)75.2 (16.8)71.5 (15.7)72.0 (15.2)80.2 (18.7)
Disease duration, years
Median (range)5.96 (0.4–31.3)5.71 (0.1–32.7)7.07 (0.4–36.7)5.48 (0.2–23.5)7.99 (0.5–33.9)5.67 (0.5–35.2)
CDAI; mean (SD)255.3 (22.96)259.4 (27.49)255.0 (23.64)362.0 (38.37)363.6 (37.93)342.2 (32.64)
CRP, mg/L; median (range)6.8 (0.3–84)12.5 (0.4–125)6.7 (0.2–50)10.0 (0.6–173)7.5 (0.8–149)8.2 (0.9–93)
Concomitant medications, n (%)
Corticosteroids17 (37.0)18 (40.0)14 (34.1)8 (28.6)13 (43.3)8 (22.9)
Immunosuppressants15 (32.6)14 (31.1)10 (24.4)7 (25.0)7 (23.3)12 (34.3)
Aminosalicylates22 (47.8)28 (62.2)25 (61.0)14 (50.0)13 (43.3)15 (42.9)
  • CDAI: Crohn's disease activity index; CRP: C–reactive protein.

    * Statistically significant at 0.05 level.

View this table:
Table 2

Patient Demographics and Baseline Characteristics: CHARM and EXTEND ITT, pooled data, including CHARM weekly dose group.

CDAI = 300CDAI > 300
Placebo N = 139Adalimumab 40 mg eow N = 155Adalimumab 40 mg weekly N = 131Placebo N = 187Adalimumab 40 mg eow N = 169Adalimumab 40 mg weekly N = 126
Female; n (%)84 (60.4)94 (60.6)73 (55.7)119 (63.6)109 (64.5)84 (66.7)
Age, years; mean (SD)37.8 (12.65)37.1 (11.69)37.9 (12.46)36.4 (10.85)36.6 (11.13)37.7 (11.75)
White race; n (%)134 (96.4)144 (92.9)119 (90.8)172 (92.0)160 (94.7)112 (88.9)
Weight, kg; mean (SD)73.4 (18.4)71.0 (16.1)72.9 (19.3)69.5 (17.6)70.1 (17.3)69.0 (17.4)
Disease duration, years
Median (range)6.57 (0.1–40.3)8.30 (0.4–37.0)7.00 (0.0–32.7)9.60 (0.4–32.6)7.90 (0.4–44.1)9.25 (0.2–38.7)
CDAI; mean (SD)256.6 (26.63)257.5 (24.64)264.1 (21.38)361.6 (50.78)360.8 (42.06)354.1 (40.26)
CRP, mg/L; median (range)7.3 (0.2–118)8.7 (0.3–182)8.1 (0.2–95)14.7 (0.1–287)9.7 (0.2–182)9.1 (0.3–350)
Prior anti-TNF use; n (%)68 (48.9)72 (46.5)64 (48.9)99 (52.9)91 (53.8)63 (50.0)
Concomitant medications, n (%)
Corticosteroids58 (41.7)64 (41.3)54 (41.2)85 (45.5)57 (33.7)62 (49.2)
Immunosuppressants70 (50.4)64 (41.3)59 (45.0)88 (47.1)76 (45.0)62 (49.2)
Aminosalicylates53 (38.1)45 (29.0)51 (38.9)82 (43.9)60 (35.5)43 (34.1)
  • CDAI: Crohn's disease activity index; CRP: C-reactive protein; eow: every other week; TNF: tumor necrosis factor.

    Statistically significant at 0.05 level.

3.2 Effect of CRP on disease progression and hospitalization risk

In the cohort of patients treated with placebo in the maintenance period of CHARM, the mean CDAI dropped from week 0 to week 4 in all subgroups as a result of induction therapy (Fig. 2). By week 12 and through week 56, mean CDAI increased from week 4 in all placebo subgroups. Patients with moderate Crohn's disease and high baseline CRP experienced a rapid recurrence of disease activity based on a mean CDAI similar to their baseline activity, and approaching that of patients with severe Crohn's disease and low CRP, despite differences in baseline CDAI of more than 90 points.

Figure 2

Mean (SD) CDAI over time in placebo subgroups of CHARM (LOCF after week 4).

In placebo-treated patients with moderate Crohn's disease and baseline CRP < 10 mg/L, 94.7% had not experienced a CD-related hospitalization by week 56 (Fig. 3). By contrast, in patients with moderate CD and CRP = 10 mg/L, 78.8% were free of CD-related hospitalization at week 56, similar to results for the patients with severe CD (81.8% for severe CD and low CRP; 79.0% for severe CD and high CRP). The hospitalization-free rates by week 56 were not statistically different among the 4 groups (log-rank test, P = 0.235).

Figure 3

Kaplan–Meier plot for time to CD-related hospitalization in the double-blind period, placebo group only, by baseline CDAI and baseline CRP.

3.3 Induction (week 4)

Adalimumab 160/80 was effective at inducing remission in patients with moderate or severe Crohn's disease (Fig. 4A). The remission rates achieved with the 80/40 dose were not statistically different compared with placebo for either cohort. Numerically higher rates of clinical remission and the greatest separation from placebo were seen in the moderate Crohn's disease cohort (29.0%) compared with the severe Crohn's disease cohort (19.3%) for the 160/80 dose group, with nearly one-half of moderate patients achieving remission at week 4; the P-value for comparison of these effect sizes was 0.437. Patients with moderate Crohn's disease and high CRP had the best chance of achieving remission, compared with patients with low CRP (Fig. 4B). The greatest efficacy and effect size compared with placebo for this high-risk group was observed with adalimumab 160/80 treatment (50.5%); the comparable value for the effect size in the low CRP group was 20.7%; P = 0.117 for the comparisons of the effect sizes.

Figure 4

Clinical remission at week 4 in CLASSIC I: A) by baseline Crohn's disease activity, and B) by baseline CRP in patients with moderate Crohn's disease.

3.4 Maintenance (week 52/56)

Maintenance treatment with adalimumab 40 mg eow or weekly was superior to placebo for achieving clinical remission in patients at one year, regardless of disease activity at baseline, with the moderate cohort achieving the highest rates (Fig. 5A). The results for weekly adalimumab were similar to those for adalimumab eow treatment. Adalimumab was superior to placebo in the moderate groups analyzed by baseline CRP for both doses. Patients with moderate Crohn's disease and elevated CRP treated with weekly dosing had the highest remission rates, and the greatest effect size compared with placebo treatment (Fig. 5B). The P-value for the comparison of effect sizes between adalimumab and placebo treatment in each CRP cohort was 0.620 for eow dosing (17.0% versus 21.7%) and 0.196 (28.4% versus 15.2%) for weekly dosing. Corresponding data for the mITT population are shown in Supplemental Fig. 1A and 1B.

Figure 5

Clinical remission at week 56 (CHARM) or week 52 (EXTEND): A) by baseline Crohn's disease activity, and B) by baseline CRP in patients with moderate Crohn's disease. Placebo and ADA eow groups include CHARM and EXTEND pooled data; ADA weekly group is from CHARM only.

Maintenance treatment with adalimumab 40 mg eow or weekly was superior to placebo for achieving clinical remission in patients at one year, regardless of disease activity at baseline, with the moderate cohort achieving the highest rates (Fig. 5A). The results for weekly adalimumab were similar to those for adalimumab eow treatment. Adalimumab was superior to placebo in the moderate groups analyzed by baseline CRP for both doses. Patients with moderate Crohn's disease and elevated CRP treated with weekly dosing had the highest remission rates, and the greatest effect size compared with placebo treatment (Fig. 5B). The P-value for the comparison of effect sizes between adalimumab and placebo treatment in each CRP cohort was 0.620 for eow dosing (17.0% versus 21.7%) and 0.196 (28.4% versus 15.2%) for weekly dosing. Corresponding data for the mITT population are shown in Supplemental Fig. 1A and 1B.

3.5 Safety

Treatment-emergent adverse events for the induction trial (Table 3) and events per 100 patient years for the pooled maintenance trials (ITT, Table 4) were summarized by disease severity subgroups. Event rates are reported for the maintenance double-blind period due to different durations of follow up in the placebo compared to adalimumab groups. The safety profiles were consistent with the known safety of adalimumab in patients with Crohn's disease and other conditions. In CLASSIC I, overall AEs, serious AEs, and serious infections were more likely to occur in the severe cohort. In the pooled maintenance studies, the overall rate of events was lower in the moderate cohort, as were the rates of serious infections. The rate of adverse events leading to discontinuation of the study drug was higher in the moderate than the severe cohort for patients receiving adalimumab. There were no cases of tuberculosis, demyelinating disease, or congestive heart failure, and no deaths in CLASSIC I, CHARM, or EXTEND. Events per 100 patient years for the mITT population in the pooled maintenance trials are included in the supplemental material.

View this table:
3

Adverse events in CLASSIC I, according to baseline disease activity.

CDAI = 300CDAI > 300
Placebo N = 46 n (%)ADA 80/40 N = 45 n (%)ADA 160/80 N = 41 n (%)Placebo N = 28 n (%)ADA 80/40 N = 30 n (%)ADA 160/80 N = 35 n (%)
Any adverse event (AE)33 (71.7)29 (64.4)28 (68.3)22 (78.6)22 (73.3)29 (82.9)
Serious AE1 (2.2)1 (2.2)02 (7.1)03 (8.6)
Severe AE1 (2.2)4 (8.9)6 (14.6)*6 (21.4)0**6 (17.1)
AE leading to discontinuation1 (2.2)1 (2.2)01 (3.6)00
AE at least possibly drug-related16 (34.8)18 (40.0)20 (48.8)11 (39.3)13 (43.3)17 (48.6)
Infection8 (17.4)7 (15.6)3 (7.3)4 (14.3)5 (16.7)9 (25.7)
Serious infection000002 (5.7)
Opportunistic infection000000
Allergic reaction1 (2.2)1 (2.2)1 (2.4)2 (7.1)00
Injection site pain3 (6.5)4 (8.9)2 (4.9)2 (7.1)03 (8.6)
Malignancy000000
Congestive heart failure000000
Demyelinating disease000000
Death000000
  • ADA: Adalimumab; AE: Adverse event; CDAI: Crohn's disease activity index.

    * and ** Statistically significant vs. placebo at 0.05 and 0.01 levels, respectively.

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4

Adverse events per 100 patient years during double-blind period, according to baseline disease activity; pooled data from CHARM and EXTEND, including CHARM weekly dose group.

CDAI = 300CDAI > 300
Placebo N = 139 PYs = 54.1 E (E/100PY)Any ADA N = 286 PYs = 162.4 E (E/100PY)Placebo N = 187 PYs = 59.7 E (E/100PY)Any ADA N = 295 PYs = 160.1 E (E/100PY)
Any adverse event (AE)535 (988.9)1307 (804.8)660 (1105.5)1334 (833.2)
Serious AE19 (35.1)34 (20.9)34 (57.0)31 (19.4)
Severe AE42 (77.6)67 (41.3)69 (115.6)66 (41.2)
AE leading to discontinuation16 (29.6)36 (22.2)25 (41.9)15 (9.4)
AE at least possibly drug-related142 (262.5)319 (196.4)121 (202.7)268 (167.4)
Infection104 (192.2)255 (157.0)104 (174.2)255 (159.3)
Serious infection3 (5.5)5 (3.1)6 (10.1)9 (5.6)
Opportunistic infection3 (5.5)4 (2.5)03 (1.9)
Allergic reaction6 (11.1)6 (3.7)08 (5.0)
Injection site pain1 (1.8)5 (3.1)2 (3.4)4 (2.5)
Malignancy1 (1.8)000
Congestive heart failure0000
Demyelinating disease0000
Death0000
  • ADA: adalimumab; AE: adverse event; CDAI: Crohn's disease activity index; E/100PY: events per 100 patient years.

4 Discussion

Subanalyses of data from the CLASSIC I, CHARM, and EXTEND clinical trials support the safety and efficacy of adalimumab for induction and maintenance of clinical remission in patients with moderate or severe Crohn's disease, as defined using baseline CDAI. Induction of clinical remission was numerically greater in patients with moderate versus severe Crohn's disease, with nearly one-half (46%) of patients in the moderate cohort who received the 160/80 induction dose achieving remission at week 4 (compared with 17% of patients receiving placebo); the corresponding values for severe CD were 23% and 4%. The one-year remission rates in patients who responded to induction therapy were numerically greater in the moderate cohort, with a similar effect size (adalimumab minus placebo) for maintenance of remission between patients with moderate versus severe CD.

Sole reliance on clinical symptoms to quantify or monitor CD activity is problematic due to the lack of a strong correlation between symptoms and inflammation. Recent analyses found that fecal and serum biomarkers (including CRP) were significantly associated with endoscopic Crohn's disease activity but not clinical symptoms as measured by CDAI.17,25 Additionally, most patients will progress to fibrostenotic or penetrating complications which may be irreversible and contribute to the need for costly surgery and hospitalization.26,27 Earlier treatment with anti-TNF agents may potentially prevent or reduce complications and intestinal resections, which reduce the effectiveness of subsequent therapy and adversely affect patient quality of life and productivity.28 Treatment with adalimumab or certolizumab pegol early in duration of Crohn's disease (regardless of disease severity at baseline) was reported to lead to better outcomes.29,30

Prescribers may be unwilling to introduce anti-TNF therapy in patients who are not severely symptomatic, because of concerns about safety and/or cost, and a belief that such patients do not require anti-TNF treatment. Nevertheless, published data have shown that even patients with less severe Crohn's-related symptoms experience poor quality of life compared with the general population or patients with other chronic conditions.31,32 These findings are supported by the results of this study's analysis of patient quality of life as quantified by IBDQ. Although baseline median IBDQ scores were higher in patients with moderate Crohn's disease versus severe CD (indicating less impairment in quality of life), there was substantial impact on quality of life in patients with moderate CD, as evidenced by the significant overlap in baseline scores between patients in the moderate and severe CD cohorts.

It is challenging, though desirable, to identify individuals with a poor long-term disease prognosis in order to select those with the best benefit/risk balance for treatment. Demographic factors have been suggested to identify patients more likely to suffer a complicated disease course, including young age at diagnosis, perianal disease at diagnosis, and early need for steroid therapy.33 The presence of high inflammatory burden, as indicated by serum CRP, may also help identify patients more likely to progress and eventually need more intensive therapy. CRP, an acute phase reactant produced mainly by hepatocytes via cytokine IL-6 stimulation,34 is a well-accepted and easily measured biomarker for inflammation, and elevated CRP values correlate with Crohn's disease activity and predict disease relapses.25,35 Kiss et al.36 reported that CRP at diagnosis aided in identification of patients with a more complicated disease phenotype. The current analysis supports the association of elevated CRP and negative outcomes in patients with moderate CD, as patients with moderate CD and elevated baseline CRP who were randomized to placebo experienced rapid recurrence of disease activity. This result was not surprising, based on pharmacokinetics and the progressive nature of CD. As the drug is eliminated, recrudescence would be expected. The symptomatic activity in the moderate CD and high CRP group approached that of patients with severe CD and low CRP by week 12, after an initial decline in activity following receipt of two induction doses of adalimumab. Additionally, among placebo-treated patients, those with moderate CD and high CRP had a similar risk of CD-related hospitalization as patients with severe CD.

The value of using CRP to identify patients most likely to benefit from anti-TNF treatment is also supported by the fact that factors such as irritable bowel syndrome (IBS) and bile acid malabsorption may mimic symptoms of CD without elevation of CRP,37,38 and up to 57% of CD patients who are in remission may experience IBS-like symptoms.39,40 In CLASSIC I, patients with elevated baseline CRP achieved higher rates of remission at week 4 than those with lower CRP.3 In the ITT population in CHARM, higher baseline CRP concentration (as well as lower baseline CDAI) was a significant factor in predicting maintenance of remission at week 26 and week 56.30 This is consistent with our results, in which patients with moderate CD and elevated baseline CRP had numerically higher rates of remission after induction than patients with low CRP. Among the moderate cohort, one-year efficacy with adalimumab maintenance therapy was superior to placebo regardless of baseline CRP, and broadly similar across dosing groups. The slightly higher remission rate in the weekly dosing group in the high CRP cohort is consistent with the finding of slightly higher efficacy for remission maintenance in patients with elevated baseline CRP in the primary CHARM results.1

The safety profiles of adalimumab in patients with moderate or severe CD were consistent with the known safety of adalimumab in patients with Crohn's disease and other conditions. The results of the safety analysis in the moderate and severe cohorts did not raise new concerns about the use of adalimumab in these subgroups of patients with CD.

This was a post hoc analysis, and patients were not randomized according to baseline disease activity, so differences in other baseline variables between groups may have influenced the outcomes. In addition, it is possible that achievement of remission, a dichotomous endpoint, is easier for patients with moderate disease, since a lesser change in CDAI is needed to reach < 150. Furthermore, all patients who were randomized to placebo received open-label induction with adalimumab, an approach that is not consistent with clinical practice. Due to the relatively long half-life of adalimumab, it is likely that the hospitalization and CDAI analyses in the placebo arm may have been influenced by a lingering therapeutic effect of adalimumab for several weeks after induction dosing. Finally, the clinical trials and the post hoc analyses were not powered to determine statistically significant differences between the effect sizes observed in the different subgroups. Though the effect sizes between the high and low CRP subgroups or the moderate and severe subgroups may have clinical relevance, a randomized controlled trial would be required to establish statistical significance.

In summary, the evidence suggests that patients with moderate Crohn's disease can be treated safely and effectively with adalimumab. Use of CRP to identify patients with moderate CD symptoms who are at greatest risk of disease progression may aid in selection of patients for earlier intervention with anti-TNF therapy, before severe symptoms and complications occur.

Supplementary Tables

Supplementary Fig. 1:Clinical remission in the mITT population at week 56 (CHARM) or week 52 (EXTEND): A) by baseline Crohn's disease activity, and B) by baseline CRP in patients with moderate Crohn's disease. Placebo and ADA eow groups include CHARM and EXTEND pooled data; ADA weekly group is from CHARM only.

Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.crohns.2013.02.016.

Specific author contributions

WJS, J-FC, JP: Conception and design, collection of data, interpretation of results, development of manuscript, and approval of final manuscript version. MC, AMR, RT: Conception and design, interpretation of results, development of manuscript, and approval of final manuscript version.

QZ, MY: Conception and design, performance of statistical analyses, interpretation of results, development of manuscript, and approval of final manuscript version.

Role of the sponsor

AbbVie reviewed and approved the manuscript; the authors maintained control over the final content. AbbVie funded the research and provided writing support. The authors thank Laurinda Cooker, PhD, of AbbVie, for writing the first draft and for editorial assistance.

Conflict of interest

WJS: Consultant: AbbVie (formerly Abbott), ActoGeniX NV, AGI Therapeutics, Inc., Alba Therapeutics Corporation, Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Astellas Pharma, Athersys, Inc., Atlantic Healthcare Limited, Axcan Pharma (now Aptalis), BioBalance Corporation, Boehringer-Ingelheim Inc., Bristol Meyers Squibb, Celgene, Celek Pharmaceuticals, Cellerix SL, Cerimon Pharmaceuticals, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine Pharmasciences, Eagle Pharmaceuticals, Eisai Medical Research Inc., Elan Pharmaceuticals, EnGene, Inc., Eli Lilly, Enteromedics, Exagen Diagnostics, Inc., Ferring Pharmaceuticals, Flexion Therapeutics, Inc., Funxional Therapeutics Limited, Genzyme Corporation, Genentech (now Roche), Gilead Sciences, Given Imaging, Glaxo Smith Kline, Human Genome Sciences, Ironwood Pharmaceuticals (previously Microbia Inc.), Janssen (previously Centocor), KaloBios Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Lycera Corporation, Meda Pharmaceuticals (previously Alaven Pharmaceuticals), Merck Research Laboratories, MerckSerono, Millennium Pharmaceuticals (subsequently merged with Takeda), Nisshin Kyorin Pharmaceuticals Co., Ltd., Novo Nordisk A/S, NPS Pharmaceuticals, Optimer Pharmaceuticals, Orexigen Therapeutics, Inc., PDL Biopharma, Pfizer, Procter and Gamble, Prometheus Laboratories, ProtAb Limited, Purgenesis Technologies, Inc., Receptos, Relypsa, Inc., Salient Pharmaceuticals, Salix Pharmaceuticals, Inc., Santarus, Schering Plough Corporation (acquired by Merck), Shire Pharmaceuticals, Sigmoid Pharma Limited, Sirtris Pharmaceuticals, Inc. (a GSK company), S.L.A. Pharma (UK) Limited, Targacept, Teva Pharmaceuticals, Therakos, Tillotts Pharma AG (acquired by Zeria Pharmaceutical Co., Ltd.), TxCell SA, UCB Pharma, Viamet Pharmaceuticals, Vascular Biogenics Limited (VBL), Warner Chilcott UK Limited, Wyeth (now Pfizer). Speakers fees: AbbVie (formerly Abbott), Bristol Meyers Squibb, and Janssen (previously Centocor). Grants/Research support: AbbVie (formerly Abbott), Bristol Meyers Squibb, Genentech, Glaxo Smith Kline, Janssen (previously Centocor), Millennium Pharmaceuticals (now Takeda), Novartis, Pfizer, Procter and Gamble Pharmaceuticals, Shire Pharmaceuticals, and UCB Pharma.

J-FC: Consultant: AbbVie (formerly Abbott), Amgen, Biogen Idec Inc., Boehringer-Ingelheim, Inc., Bristol Meyers Squibb, Cellerix SL, Chemocentryx, Inc., Centocor, Cosmo Technologies, Ltd., Elan Pharmaceuticals, Inc., Genentech, Giuliani SPA, Given Imaging, Glaxo Smith Kline, Immune Pharmaceuticals Ltd., Merck & Co., Inc., Millenium Pharmaceuticals Inc., Neovacs SA, Ocerra Therapeutics, Inc. (previously named Renovia, Inc.), Pfizer Inc. Prometheus, Sanofi, Schering Plough Corporation, Shire Pharmaceuticals, Synta Pharmaceutical Corporation, Takeda, Teva Pharmaceuticals, Therakos, TXcell, UCB Pharma (previously named Celltech Therapeutics, Ltd.), Wyeth Pharmaceuticals; Speakers fees: AbbVie (formerly Abbott), Centocor, Falk Pharma, Ferring, Given Imaging, Merck & Co., Inc., Schering Plough Corporation, Shire Pharmaceuticals, UCB Pharma; Grants/Research support: AbbVie (formerly Abbott), Ferring, Schering Plough Corporation, UCB Pharma, Giuliani SPA,; Stock ownership: Intestinal Biotech Development.

JP: Consultant: AbbVie (formerly Abbott), Bristol-Myers Squibb, Genentech Inc., MSD Laboratories, Pfizer Inc., Takeda Pharmaceutical Co, Ltd., UCB, Inc. Speakers fees: AbbVie (formerly Abbott), Ferring, Schering-Plough, Shire and UCB. Grant/Research support from AbbVie (formerly Abbott) and MSD Laboratories.

MC, AMR, QZ, MY, RT: Employed by AbbVie (formerly Abbott); shareholders of Abbott stock.

References

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