Naijun Chen

Adalimumab Induces Deep Remission in Patients With Crohn's Disease

BACKGROUND & AIMSnPatients with moderate to severe ileocolonic Crohns 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.nnnMETHODSnRates 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.nnnRESULTSnRates 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

Adalimumab Therapy Is Associated With Reduced Risk of Hospitalization in Patients With Ulcerative Colitis

10,360 (from weeks 12 through 52) compared with lack of deep remission.nnnCONCLUSIONSnIn 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.

Adalimumab improves patient-reported outcomes and reduces indirect costs in patients with moderate to severe Crohn's disease: Results from the CARE trial.

BACKGROUND & AIMSnAdalimumab is effective for induction and maintenance of remission in patients with moderate to severe ulcerative colitis (UC). We assessed whether adalimumab, in addition to standard UC therapy, reduced the risk for hospitalization (from all causes, from complications of UC, or from complications of UC or the drugs used to treat it) and colectomy in patients with moderate to severe UC compared with placebo.nnnMETHODSnData were combined from patients that received induction therapy (a 160-mg dose followed by an 80-mg dose of adalimumab) or placebo in 2 trials (ULTRA 1 and ULTRA 2; n = 963). The risks of hospitalization and colectomy were compared between groups using unadjusted rates during the 8-week induction period, and patient-year-adjusted rates during 52 weeks. Statistical differences between groups were determined using the χ(2) method and Z score normal approximations. Numbers of hospitalizations were compared using Poisson regression with time offset.nnnRESULTSnSignificant reductions in risk of all-cause, UC-related, and UC- or drug-related hospitalizations (by 40%, 50%, and 47%, respectively; P < .05 for all comparisons) were observed within the first 8 weeks of adalimumab therapy compared with placebo. Significantly lower incidence rates for all-cause (0.18 vs 0.26; P = .03), UC-related (0.12 vs 0.22; P = .002), and UC- or drug-related (0.14 vs 0.24; P = .005) hospitalizations were observed during 52 weeks of adalimumab therapy compared with placebo. Rates of colectomy did not differ significantly between patients given adalimumab vs placebo.nnnCONCLUSIONSnIn patients with moderate to severe UC, the addition of adalimumab to standard of care treatment reduced the number of hospitalizations for any cause, as well as for UC-related and UC- or drug-related complications, compared with placebo. ClinicalTrials.gov numbers, NCT00385736 and NCT00408629.

Anti–Tumor Necrosis Factor Therapy and Incidence of Parkinson Disease Among Patients With Inflammatory Bowel Disease

BACKGROUND AND AIMSnCrohns disease negatively affects patients quality of life and ability to work. We investigated the impact of adalimumab on work productivity, daily activities, and quality of life in an open-label trial (N=945). The population comprised both infliximab-naïve and -exposed patients, including infliximab primary non-responders.nnnMETHODSnPatients received adalimumab induction therapy (160 mg/80 mg at Weeks 0/2), followed by adalimumab 40 mg every other week for up to 20 weeks (patients with flares/non-response could receive 40 mg weekly at/after Week 12). The Work Productivity and Activity Impairment Questionnaire and Short Inflammatory Bowel Disease Questionnaire were assessed. Indirect cost savings were estimated based on the average work productivity improvements at Week 20.nnnRESULTSnMean baseline scores indicated severe productivity impairment and poor quality of life. At Week 20, 60% of infliximab-naïve and 47% of infliximab primary non-responders achieved clinically important improvements (≥9 points) on the Short Inflammatory Bowel Disease Questionnaire, and 51% and 43%, respectively, achieved the minimum clinically important difference (improvement ≥7 percentage points) for total work productivity impairment (non-responder imputation). At Week 20, 64% of infliximab-naïve and 55% of infliximab primary non-responders achieved clinically important improvements in total activity impairment. Estimated 20-week total indirect productivity-related cost savings were €3070 per infliximab-naïve patient and €2059 per infliximab-exposed patient.nnnCONCLUSIONSnAdalimumab therapy significantly improved work productivity and disease-specific quality of life for patients with moderate to severe Crohns disease. Patients who failed prior infliximab therapy and patients naïve to infliximab benefited from adalimumab, with potentially greater benefits for infliximab-naïve patients (NCT00409617).

P033 - Risk of Crohn's disease-related hospitalization in patients receiving long-term adalimumab therapy: 3-year data from CHARM and ADHERE

Importance Despite established genetic and pathophysiologic links between inflammatory bowel disease (IBD) and Parkinson disease (PD), clinical data supporting this association remain scarce. Although systemic inflammation is considered a potential biological mechanism shared between the 2 diseases, the role of reduced systemic inflammation through IBD-directed anti–tumor necrosis factor (anti-TNF) therapy in PD risk is largely unknown. Objective To compare the incidence of PD among individuals with or without IBD and to assess whether PD risk among patients with IBD is altered by anti-TNF therapy. Design, Setting, and Participants This is a retrospective cohort study analyzing information in the Truven Health MarketScan administrative claims database and the Medicare Supplemental Database between January 1, 2000, and March 31, 2016. Individuals were selected who had at least 2 claims for IBD diagnoses, at least 6 months of follow-up, and no prior diagnosis of PD on or before the IBD index date. Exposure to Anti-TNF therapy was measured from the anti-TNF index date to the last date of anti-TNF coverage or the end of enrollment or PD index date, whichever was earliest. Incidence rates per 1000 person-years were calculated, and crude and adjusted incidence rate ratios were estimated by Poisson regression models and presented with 95% CIs. Main Outcomes and Measures Incidence of PD among patients with IBD with or without exposure to anti-TNF therapy. Results In total, 144 018 individuals with IBD were matched on age, sex, and year of index date with 720 090 unaffected controls. Of them, 1796 individuals had at least 2 PD diagnoses and at least 1 filled PD-related prescription. The mean (SD) age of individuals with IBD was 51 (17) years, and 44% were men. The incidence of PD among patients with IBD was 28% higher than that among unaffected matched controls (adjusted incidence rate ratio, 1.28; 95% CI, 1.14-1.44; Pu2009<u2009.001). A 78% reduction in the incidence rate of PD was detected among patients with IBD who were exposed to anti-TNF therapy compared with those who were not exposed (adjusted incidence rate ratio, 0.22; 95% CI, 0.05-0.88; Pu2009=u2009.03). Conclusions and Relevance A higher incidence of PD was observed among patients with IBD than among individuals without IBD. Early exposure to antiinflammatory anti-TNF therapy was associated with substantially reduced PD incidence. These findings support a role of systemic inflammation in the pathogenesis of both diseases. Further studies are required to determine whether anti-TNF treatment administered to high-risk individuals may mitigate PD risk.

P008 - Adalimumab sustains quality-of-life improvements in patients with Crohn's disease: 3-year data from CHARM

P033 Risk of Crohn’s disease-related hospitalization in patients receiving long-term adalimumab therapy: 3-year data from CHARM and ADHERE E.V. Loftus Jr.1 *, B. Feagan2, N. Chen3, P. Mulani3, J. Chao3. 1Miles & Shirley Fiterman Center for Digestive Diseases, Mayo Clinic, Rochester, MN, USA, 2Robarts Research Institute, University of Western Ontario, London, ON, Canada, 3Abbott Laboratories, Abbott Park, IL, USA

P038 - Adalimumab sustains remission and quality-of-life improvements in anti-TNF-naive patients with Crohn's disease: 3-year data from CHARM

A C). Four of them (57%) had fistula associated CRC. They suffered from CD for a median of 13 years (range 12 33). Seven patients with CRC were matched 1:3 to randomly selected Crohn’s patients based on age (9 male, 12 female). The medical records of these patients were evaluated with respect to duration and pattern of intestinal involvement of CD, fistula history, intestinal surgery, perianal surgery, prior immunosuppressive and 5-ASA derivative intake. Three patients of the matched group had involvement of the terminal ileum, 13 of ileocolon, 1 of upper GI and 4 of ileocolon and upper GI tract, with a disease duration of a median of 26 years (range 5 62). From these 21 patients 11 suffered from perianal fistula (52%). Results: Colorectal cancer was significantly (p = 0.048) associated with longstanding anorectal fistula (median = 11 years, range 0 28) in the CRC group compared to the matched Crohn’s patients [median = 1 year (range 0 6)]. The formation of cancer in a fistula showed a significant (p = 0.08) correlation with duration of the perianal disease. Earlier colonic surgery seemed to protect from later malignancy (p = 0.036; 16 matched controls had colonic surgery versus 2 patients in the CRCgroup). No significant symptoms preceded rectal carcinoma, except for new blood drainage from fistula in 2 patients. Two patients underwent ileocolonoscopy within 1 year before the diagnosis of malignancy without hint of dysplasia or carcinoma and 2 patients underwent MRI of the pelvic region within 4 months before surgery without recognizing malignant changes. There were no significant differences in 5-ASA, azathioprine intake or infliximab therapy, perianal surgery, extension and duration of the Crohn’s disease in both groups. The one year survival rate was 84% in patients with CRC. Conclusion: Colorectal carcinoma is generally rare in patients with Crohn’s disease, but is frequently associated with the presence of longstanding (>10 years of duration) anorectal fistula. It occurred with minimal change of symptoms and was not visible in previous MRI.

P006 - Sustainability of adalimumab in improving the quality of life of patients with fistulizing Crohn's disease: 3-year data from CHARM

have pseudopolyposis in 20/146 pts (13%) (c2 test=1.02; p value NS). In the group of UC pts there are 31with left-sided disease and 61 with pancolitis. In the left sided group indidence of pseudopolyposis is 29% (9/29), and in pancolitis 11% (10/61) (c2 test 0.75, p value NS). Conclusion: There is no difference in prevalence of pseudopolyposis in patients with ulcerative colitis and Crohn colitis in our cohort, also no difference in incidence regarding the initial extension of the disease in UC. We can conclude that phenotype (UC:CC) isn’t relevant for the development of colonic pseudopolyposis.

P069 - The CARE trial: adalimumab improves work productivity and quality of life in patients with Crohn's disease

s of the 4th Congress of ECCO the European Crohn’s and Colitis Organisation S13 Of selected patients clinical data including age, gender, type of IBD, date of diagnosis of IBD and CRC, follow-up of IBD and CRC and extend of disease were collected from patient charts. Statistical analysis was performed using descriptive statistics, Kaplan Meier & log-rank tests and Cox-regression analysis. Results: In total, 78 of all 93 Dutch non-academic centers participated. We assessed 430 patient-charts and pathology reports. In 197 patients 65 years old, diagnosis of IBDrelated CRC was confirmed: 125 had ulcerative colitis (UC), 69 Crohn’s disease (CD) and 3 Indeterminate Colitis. Sixtyfour percent were males (126/197), 20 patients had PSC (10%), mean age at diagnosis of IBD was 35 years (±15) and of CRC 50 years (±10.6). Eighty-four patients (44%) had T3 tumors and 31 (16%) already had metastases at time of diagnosis. Mean time from diagnosis of IBD to diagnosis of CRC was 15.3 years (±11.7). Type of IBD, gender, concomitant PSC and/or pseudopolyps, and gravityand extension of inflammation were not significantly associated with time to diagnosis of CRC. Although the latter was not significant (p = 0.063), contrary to surveillance guidelines, there was a trend for patients with extensive UC to develop CRC at later stage (mean 16.7 years) than patients with left-sided colitis (mean 11 years). Diagnosis of IBD at older age was associated with earlier development of CRC (OR 1.09; 95%CI 1.07 1.10). Forty-eight percent of tumors were located in rectum or sigmoid and 73% occurred in previous inflamed areas. Location of inflammation was not predictive for tumor-location, but UC patients developed more left-sided tumors than CD patients (p = 0.022). In 58 hospitals the size of the IBD population could be assessed: 26,855 patients in total, of whom only 163 developed a CRC during 15 years follow-up. Conclusion: The risk of IBD-associated CRC is limited in a regular, secondary IBD population. Current surveillance strategies need to be adjusted, including equalisation of strategies for left-sided and pancolitis. A nested case-control is being performed, of which the results are expected early in 2009. P006 Sustainability of adalimumab in improving the quality of life of patients with fistulizing Crohn’s disease: 3-year data from CHARM D.A. Schwartz1 *, J.F. Colombel2, R. Panaccione3, B. Feagan4, M.A. Kamm5, N. Chen6, J. Chao6, P. Mulani6. 1Vanderbilt University Medical Center, Nashville, TN, USA, 2Hopital Claude Huriez, Centre Hospitalier Universitaire de Lille, Lille, France, 3University of Calgary, Calgary, AB, Canada, 4Robarts Research Institute, London, ON, Canada, 5University of Melbourne, Melbourne, Australia, 6Abbott, Abbott Park, IL, USA Introduction: Fistulas occur in 17% to 43% of patients with Crohn’s disease (CD) [1]. A previous analysis demonstrated that adalimumab improved qualify of life (QOL) for patients with fistulizing CD [2]. The objective of this analysis was to assess the long-term efficacy of adalimumab on QOL in patients with fistulizing disease through 3 years after enrollment in the CHARM trial. Methods: Patients in CHARM were randomized to placebo, adalimumab 40mg every other week (eow), or adalimumab 40mg weekly. At or after Week 12, patients with flare (increase in CD Activity Index [CDAI] 70 points compared with Week 4 and CDAI > 220) or nonresponse (did not attain 70-point decrease in CDAI compared with baseline) were switched to open-label adalimumab 40mg eow. At the end of CHARM (56 weeks), patients could enroll in an open-label extension (ADHERE), in which patients who completed CHARM on blinded therapy received open-label adalimumab eow and those already receiving open-label treatment maintained their therapy. In ADHERE, patients could change from eow to weekly treatment for flares or nonresponse. This analysis included patients who had fistulas at CHARM baseline, were randomized to adalimumab (eow or weekly) in CHARM, and enrolled in the open-label extension. The two adalimumab arms were combined for analysis. QOL measures evaluated included the Inflammatory Bowel Disease Questionnaire (IBDQ) and Short Form 36 (SF-36) Physical Component Summary (PCS) and Mental Component Summary (MCS) scores over time. Data were compared with baseline using the paired Student t-test. The percentages of patients with IBDQ 170 (which correlates with clinical remission) and who achieved an IBDQ change 16 (IBDQ minimum clinically important difference [MCID]) from baseline were also calculated. Last-observation-carried-forward (LOCF) analyses were used. Results: The table presents mean QOL measures for all fistulizing patients (n = 48) for the combined adalimumab groups. Statistically significant improvements from baseline were observed at Weeks 60 and 108 in the open-labelextension, representing approximately 2 and 3 years, respectively, from CHARM baseline. IBDQ remission was achieved in 60% of patients at 2 years from CHARM baseline and in 52% at 3 years from CHARM baseline. MCID for IBDQ was achieved in 81% of patients at 2 years from CHARM baseline and 79% of patients at 3 years from CHARM baseline. Long-term efficacy of adalimumab (EOW and weekly combined) on remission and QOL measures in patients with fistulas: LOCF analysis

S1056 Quality-of-Life Improvements in Patients with Crohn's Disease Treated for 3 Years with Adalimumab in An Open-Label Extension of CHARM

Introduction:Work Productivity and Activity Impairment (WPAI) questionnaire is a validated, self-administered tool that assesses the impact of disease on productivity. The Short Inflammatory Bowel Disease Questionnaire (SIBDQ) is a simple, validated, 10-item instrument that assesses health-related quality of life (HRQOL) in patients with inflammatory bowel disease. In the Crohn’s Patients Treated With Adalimumab: Results of a Safety and Efficacy Study (CARE), the efficacy and safety of adalimumab in a large population of patients whose treatment approximated usual clinical practice were evaluated. In this analysis, we investigated the impact of adalimumab treatment on work productivity and HRQOL in CARE. Methods: A total of 945 patients with Harvey Bradshaw Index score >7 enrolled in this multicenter, open-label, European, Phase IIIb trial. The study population included patients naive to biotherapy and patients who had failed infliximab therapy (primary nonresponders [PNR] to infliximab, lost response to infliximab, intolerant of infliximab, and other infliximab failures). Patients received induction therapy of 160-mg/80-mg adalimumab at Weeks 0/2, followed by adalimumab 40mg every-other-week maintenance therapy through at least Week 20 (patients with flares/nonresponse could receive 40mg weekly at/after Week 12). In this analysis, patients’ work productivity, as measured by WPAI, and HRQOL, as measured by SIBDQ, were analyzed. The WPAI tool, as adapted for CD, measures the percentage of overall impairment in work productivity (including absenteeism and presenteeism) and daily activity due to CD (0%=no impairment, 100%=total loss of work productivity/activity). An absolute change of 7% in WPAI score is the minimum clinically important difference (MCID). SIBDQ total scores range from 10 70, with greater scores indicating better HRQOL. A 9-point change in SIBDQ is correlated with a 100-point change in CDAI score. Both measures were assessed at baseline and Weeks 4, 8, 12, and 20, and changes from baseline were analyzed using paired Student t-tests. Results: Mean age of patients was 35.3 years, and 60% were female. Mean baseline total daily activity impairment (TAI) was 57% (n = 907). For employed patients, total work productivity impairment score (TWPI) was 51% (n = 442) at baseline, indicating severe impairment. Baseline quality of life of patients was substantially impaired (SIBDQ mean = 37±10). Mean changes in WPAI components and SIBDQ are summarized by reason for infliximab failure (table). Overall, at Week 20, 57% (518/910), 62% (559/907), and 47% (208/442) of patients achieved improvement of SIBDQ of 9 points (correlated with 100-point change in CDAI), TAI of at least 7 points (MCID), and TWPI of 7 points (MCID) (NRI). Conclusions: Adalimumab therapy significantly improved work productivity and quality of life for patients with moderately to severely active CD, including those naive to anti-TNF therapy and those who had failed infliximab therapy. These improvements were observed as early as Week 4 and maintained throughout the study. Mean absolute change in SIBDQ and two WPAI subscores with adalimumab therapy at Weeks 4 and 20 in CARE by prior use of infliximab (observed)