Upadacitinib Achieves Clinical and Endoscopic Outcomes in Crohn's Disease Regardless of Prior Biologic Exposure.

BACKGROUND & AIMS: Upadacitinib, an oral Janus kinase inhibitor, achieved significantly higher rates of clinical remission and endoscopic response vs placebo during induction (U-EXCEL [NCT03345849], U-EXCEED [NCT03345836]) and maintenance (U-ENDURE [NCT03345823]) treatment in patients with moderate-to-severe Crohn's disease. Prior biologic failure is often associated with reduced responses to subsequent therapies. This post hoc analysis assessed upadacitinib efficacy by prior biologic failure status. METHODS: Patients were randomized to placebo or upadacitinib 45 mg (UPA45) for 12 weeks (induction). UPA45 clinical responders were enrolled in U-ENDURE and rerandomized to placebo, upadacitinib 15 mg, or upadacitinib 30 mg (UPA30) for 52 weeks. Assessments were by prior biologic failure. RESULTS: Of 1021 patients, 733 (71.8%) had prior biologic failure. Across outcomes and subgroups, upadacitinib-treated patients achieved higher rates vs placebo. During induction, upadacitinib had higher rates vs placebo for clinical remission based on stool frequency/abdominal pain score (without failure: 54.0% vs 28.3%; with failure: 42.2% vs 14.1%) and endoscopic response (without failure: 52.0% vs 16.2%; with failure: 35.7% vs 5.3%). In maintenance, the greatest treatment effect (upadacitinib vs placebo) was among patients with prior biologic failure treated with UPA30 (clinical remission without failure: 58.5% vs 32.7%; with failure: 42.5% vs 8.7%; endoscopic response without failure: 43.9% vs 17.9%; with failure: 38.9% vs 4.0%). Patients without vs with prior biologic failure had fewer adverse events. CONCLUSIONS: Upadacitinib led to higher absolutes rates of clinical and endoscopic outcomes in patients without vs with prior biologic failure. Patients treated with upadacitinib achieved greater rates of clinical and endoscopic improvements vs placebo, regardless of prior biologic exposure. CLINICALTRIALS: gov: NCT03345849, NCT03345836, NCT03345823.

Effect of Suboptimal Disease Control on Patient Quality of Life: Real-World Data from the Observational IBD-PODCAST Canada Trial.

BACKGROUND: The real-world application of STRIDE-II treatment targets to identify whether disease control is optimal in Crohn's disease (CD) and ulcerative colitis (UC) is not well known. AIMS: This study aimed to estimate proportions of patients with suboptimally controlled CD and UC in real-world Canadian healthcare settings and the impact on quality of life (QoL). METHODS: The noninterventional, multicenter, observational IBD-PODCAST Canada study comprised a single study visit involving routine assessments, patient- and clinician-completed questionnaires, and a retrospective chart review. Primary outcomes were proportions of patients with STRIDE-II-based red flags indicative of suboptimal disease control and mean ± standard deviation Short Inflammatory Bowel Disease Questionnaire (SIBDQ) scores. Secondary outcomes included proportions of patients and clinicians subjectively reporting suboptimal control. RESULTS: Among 163 enrolled patients from 10 sites, 45/87 patients with CD (51.7%; 95% CI: 40.8%, 62.6%) and 33/76 patients with UC (43.3%; 95% CI: 32.1%, 55.3%) had suboptimal disease control based on STRIDE-II criteria. Suboptimal control was subjectively reported at lower proportions (patients: CD, 15.0%; UC, 18.6%; clinicians: CD, 19.5%; UC, 25.0%). Numerically lower SIBDQ scores were observed with suboptimal control (CD, 43.0 ± 10.8; UC, 42.5 ± 12.0) than with optimal control (CD, 58.2 ± 7.2; UC, 57.8 ± 6.6). CONCLUSIONS: Approximately 50% (CD) and 40% (UC) of patients from real-world Canadian practices had suboptimal disease control based on STRIDE-II criteria. Suboptimal control was underestimated by patients and clinicians and accompanied by reduced QoL, suggesting further efforts to implement STRIDE-II treat-to-target strategies are needed.

A randomized controlled trial of a multicomponent online stress reduction intervention in inflammatory bowel disease.

Background: Psychological stress negatively impacts inflammatory bowel disease (IBD) outcomes. Patients have prioritized access to online interventions; yet, the data on these have been limited by mixed in-person/online interventions, low adherence, and non-randomized controlled trial (RCT) design. Objectives: We assessed the efficacy of and adherence to a 12-week online multicomponent stress reduction intervention in IBD. Design: This is a RCT. Methods: Adult participants on stable IBD medical therapy with elevated stress levels from four centers were randomized to intervention or control groups. Intervention participants received a 12-week online program including a weekly yoga, breathwork and meditation video (target 2-3 times/week), a weekly cognitive behavioral therapy/positive psychology informed video activity, and weekly 10-min check-ins by a study team member. Control participants received weekly motivational messages by email. All patients received standard of care IBD therapy. The primary outcome was Cohen's Perceived Stress Scale (PSS). Secondary outcomes evaluated mental health, resilience, health-related quality of life (HRQoL), symptom indices, acceptability, adherence, and inflammatory biomarkers. Analysis of covariance was used to determine between-group differences. Results: Of 150 screened patients, 101 were randomized to the intervention (n = 49) and control (n = 52) groups (mean age: 42.5 ± 14.1 years; M:F 1:3, 48% with ulcerative colitis and 52% with Crohn's disease). The between-group PSS improved by 22.4% (95% confidence interval, 10.5-34.3, p < 0.001). Significant improvements were seen in mental health, resilience, and HRQoL measures, with a median satisfaction score of 89/100 at the end of the 12 weeks. In the 44/49 patients who completed the intervention, 91% achieved program adherence targets. Conclusion: This 12-week online intervention improved perceived stress, mental health, and HRQoL, but did not impact IBD symptom indices or inflammatory biomarkers. The program was readily adopted and adhered to by participants with high retention rates. After iterative refinement based on participant feedback, future studies will evaluate the impact of a longer/more intense intervention on disease course. Registration: ClinicalTrials.gov Identifier NCT03831750. Plain Language Summary: An online stress reduction intervention in inflammatory bowel disease patients improves stress, mental health, and quality of life People with inflammatory bowel disease (IBD) have high levels of stress, anxiety, and depression. Although IBD patients have expressed the need for online mental wellness interventions, the existing data to support these interventions in IBD are limited. In this trial, 101 IBD patients had the chance to participate in a 12-week online stress reduction intervention. In those patients randomly selected to participate in the online intervention, each week they received the following: a 20- to 30-min yoga, breathwork, and meditation video that they were asked to do 2-3 times a week, a 10- to 20-min mental wellness activity they were asked to do once during the week, and a 10-min telephone check-in with a study team member. Participants who were not selected to use the online intervention received a weekly motivational message by email. In all, 90 of the 101 participants (89%) completed the study with the mean age of participants being 43 years and the majority being females (75%). Ninety-one percent of participants who completed the intervention met the program target of doing the yoga, breathwork, and meditation video at least 2 times per week. Significant improvements were seen in perceived stress (by 22.4%), depression (by 29.5%), anxiety (by 23.7%), resilience (by 10.6%), and quality of life (by 8.9%). No changes were seen in IBD severity or in blood markers of inflammation. In conclusion, this study demonstrates evidence that a 12-week online stress reduction intervention had low dropout rates, high adherence and beneficial effects on stress, mental health, and quality of life measures. Continued feedback will be sought from study participants and our IBD patient partners to refine the intervention and assess the impact in future studies of patients with active IBD, as well as the impact of a longer/more intense intervention.

Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials.

BACKGROUND: There is a great unmet need for advanced therapies that provide rapid, robust, and sustained disease control for patients with ulcerative colitis. We assessed the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. METHODS: This phase 3, multicentre, randomised, double-blind, placebo-controlled clinical programme consisted of two replicate induction studies (U-ACHIEVE induction [UC1] and U-ACCOMPLISH [UC2]) and a single maintenance study (U-ACHIEVE maintenance [UC3]). The studies were conducted across Europe, North and South America, Australasia, Africa, and the Asia-Pacific region at 199 clinical centres in 39 countries (UC1), 204 clinical centres in 40 countries (UC2), and 195 clinical centres in 35 countries (UC3). Patients aged 16-75 years with moderately to severely active ulcerative colitis (Adapted Mayo score 5-9; endoscopic subscore 2 or 3) for at least 90 days were randomly assigned (2:1) to oral upadacitinib 45 mg once daily or placebo for 8 weeks (induction studies). Patients who achieved clinical response following 8-week upadacitinib induction were re-randomly assigned (1:1:1) to upadacitinib 15 mg, upadacitinib 30 mg, or placebo for 52 weeks (maintenance study). All patients were randomly assigned using web-based interactive response technology. The primary endpoints were clinical remission per Adapted Mayo score at week 8 (induction) and week 52 (maintenance). The efficacy analyses in the two induction studies were based on the intent-to-treat population, which included all randomised patients who received at least one dose of treatment. In the maintenance study, the primary efficacy analyses reported in this manuscript were based on the first 450 (planned) clinical responders to 8-week induction therapy with upadacitinib 45 mg once daily. The safety analysis population in the induction studies consisted of all randomised patients who received at least one dose of treatment; in the maintenance study, this population included all patients who received at least one dose of treatment as part of the primary analysis population. These studies are registered at ClinicalTrials.gov, NCT02819635 (U-ACHIEVE) and NCT03653026 (U-ACCOMPLISH). FINDINGS: Between Oct 23, 2018, and Sept 7, 2020, 474 patients were randomly assigned to upadacitinib 45 mg once daily (n=319) or placebo (n=155) in UC1. Between Dec 6, 2018, and Jan 14, 2021, 522 patients were randomly assigned to upadacitinib 45 mg once daily (n=345) or placebo (n=177) in UC2. In UC3, a total of 451 patients (21 from the phase 2b study, 278 from UC1, and 152 from UC2) who achieved a clinical response after 8 weeks of upadacitinib induction treatment were randomly assigned again to upadacitinib 15 mg (n=148), upadacitinib 30 mg (n=154), and placebo (n=149) in the primary analysis population. Statistically significantly more patients achieved clinical remission with upadacitinib 45 mg (83 [26%] of 319 patients in UC1 and 114 [34%] of 341 patients in UC2) than in the placebo group (seven [5%] of 154 patients in UC1 and seven [4%] of 174 patients; p<0·0001; adjusted treatment difference 21·6% [95% CI 15·8-27·4] for UC1 and 29·0% [23·2-34·7] for UC2). In the maintenance study, clinical remission was achieved by statistically significantly more patients receiving upadacitinib (15 mg 63 [42%] of 148; 30 mg 80 [52%] of 154) than those receiving placebo (18 [12%] of 149; p<0·0001; adjusted treatment difference 30·7% [21·7-39·8] for upadacitinib 15 mg vs placebo and 39·0% [29·7-48·2] for upadacitinib 30 mg vs placebo). The most commonly reported adverse events in UC1 were nasopharyngitis (15 [5%] of 319 in the upadacitinib 45 mg group vs six [4%] of 155 in the placebo group), creatine phosphokinase elevation (15 [4%] vs three [2%]), and acne (15 [5%] vs one [1%]). In UC2, the most frequently reported adverse event was acne (24 [7%] of 344 in the upadacitinib 45 mg group vs three [2%] of 177 in the placebo group). In both induction studies, serious adverse events and adverse events leading to discontinuation of treatment were less frequent in the upadacitinib 45 mg group than in the placebo group (serious adverse events eight [3%] vs nine (6%) in UC1 and 11 [3%] vs eight [5%] in UC2; adverse events leading to discontinuation six [2%] vs 14 [9%] in UC1 and six [2%] vs nine [5%] in UC2). In UC3, the most frequently reported adverse events (≥5%) were worsening of ulcerative colitis (19 [13%] of 148 in the upadacitinib 15 mg group vs 11 [7%] of 154 in the upadacitinib 30 mg group vs 45 [30%] of 149 in the placebo group), nasopharyngitis (18 [12%] vs 22 [14%] vs 15 [10%]), creatine phosphokinase elevation (nine [6%] vs 13 [8%] vs three [2%]), arthralgia (nine [6%] vs five [3%] vs 15 [10%]), and upper respiratory tract infection (seven [5%] vs nine [6%] vs six [4%]). The proportion of serious adverse events (ten [7%] vs nine [6%] vs 19 [13%]) and adverse events leading to discontinuation (six [4%] vs ten [6%] vs 17 [11%]) was lower in both upadacitinib groups than in the placebo group. Events of cancer, adjudicated major adverse cardiac events, or venous thromboembolism were reported infrequently. There were no treatment-related deaths. INTERPRETATION: Upadacitinib demonstrated a positive efficacy and safety profile and could be an effective treatment option for patients with moderately to severely active ulcerative colitis. FUNDING: AbbVie.

Exploring Patient Perspectives on a 12-Week Online, Stress Reduction Intervention in Inflammatory Bowel Disease.

Background: Online stress reduction interventions may be useful adjuncts to standard medical therapies for inflammatory bowel disease (IBD). As part of the evaluation of a 12-week randomized control trial (RCT) of an online multicomponent stress reduction program, our aim for the current study was to use qualitative methods to more deeply explore the patient experience with the online programming. Methods: Upon completion of the 12-week RCT, all intervention participants were invited to participate in semistructured interviews. A qualitative descriptive approach was used. Interviews were analyzed through a theoretical thematic analysis process, whereby transcripts were coded, and codes then grouped into larger categories and themes. Results: A total of 56 interviews were analyzed with the emergence of 3 main themes: (1) IBD as a source of stress and uncertainty, (2) understanding the positive impacts of the stress reduction program, and (3) suggested strategies to enhance program desirability. IBD was described as causing uncertainty, significant disruptions to daily activities, and stress, which in turn worsened symptoms. The online program was associated with a perceived reduction in IBD symptom burden, an increased ability to manage daily and disease-associated stressors, and a more positive mindset. Variation in program content and fostering connections with others in the IBD community were identified as potential strategies to enhance future programming. Conclusions: This qualitative companion study highlights the power of the patient voice to deepen our understanding of the impact of IBD, and the potential benefit of an online stress reduction program including suggestions for iterative refinement.

Vedolizumab and Anti-Tumour Necrosis Factor α Real-World Outcomes in Biologic-Naïve Inflammatory Bowel Disease Patients: Results from the EVOLVE Study.

BACKGROUND AND AIMS: This study aimed to compare real-world clinical effectiveness and safety of vedolizumab, an α4ß7-integrin inhibitor, and anti-tumour necrosis factor-α [anti-TNFα] agents in biologic-naïve ulcerative colitis [UC] and Crohn's disease [CD] patients. METHODS: This was a 24-month retrospective medical chart study in adult UC and CD patients treated with vedolizumab or anti-TNFα in Canada, Greece and the USA. Inverse probability weighting was used to account for differences between groups. Primary outcomes were cumulative rates of clinical effectiveness [clinical response, clinical remission, mucosal healing] and incidence rates of serious adverse events [SAEs] and serious infections [SIs]. Secondary outcomes included cumulative rates of treatment persistence [patients who did not discontinue index treatment during follow-up] and dose escalation and incidence rates of disease exacerbations and disease-related surgeries. Adjusted analyses were performed using inverse probability weighting. RESULTS: A total of 1095 patients [604 UC, 491 CD] were included. By 24 months, rates of clinical effectiveness were similar between groups, but incidence rates of SAEs (hazard ratio [HR] = 0.42 [0.28-0.62]) and SIs (HR = 0.40 [0.19-0.85]) were significantly lower in vedolizumab vs anti-TNFα patients. Rates of treatment persistence [p < 0.01] by 24 months were higher in vedolizumab patients with UC. Incidence rates of disease exacerbations were lower in vedolizumab patients with UC (HR = 0.58 [0.45-0.76]). Other outcomes did not significantly differ between groups. CONCLUSION: In this real-world setting, first-line biologic therapy in biologic-naïve patients with UC and CD demonstrated that vedolizumab and anti-TNFα treatments were equally effective at controlling disease symptoms, but vedolizumab has a more favourable safety profile.

Efficacy of Upadacitinib in a Randomized Trial of Patients With Active Ulcerative Colitis.

BACKGROUND & AIMS: We evaluated the efficacy and safety of upadacitinib, an oral selective inhibitor of Janus kinase 1, as induction therapy for ulcerative colitis (UC). METHODS: We performed a multicenter, double-blind, phase 2b study of 250 adults with moderately to severely active UC and an inadequate response, loss of response, or intolerance to corticosteroids, immunosuppressive agents, and/or biologic therapies. Patients were randomly assigned to groups that received placebo or induction therapy with upadacitinib (7.5 mg, 15 mg, 30 mg, or 45 mg, extended release), once daily for 8 weeks. The primary endpoint was the proportion of participants who achieve clinical remission according to the adapted Mayo score at week 8. No multiplicity adjustments were applied. RESULTS: At week 8, 8.5%, 14.3%, 13.5%, and 19.6% of patients receiving 7.5 mg, 15 mg, 30 mg, or 45 mg upadacitinib, respectively, achieved clinical remission compared with none of the patients receiving placebo (P = .052, P = .013, P = .011, and P = .002 compared with placebo, respectively). Endoscopic improvement at week 8, defined as endoscopic subscore of ≤ 1, was achieved in 14.9%, 30.6%, 26.9%, and 35.7% of patients receiving upadacitinib 7.5 mg, 15 mg, 30 mg, or 45 mg, respectively, compared with 2.2% receiving placebo (P = .033, P < .001, P < .001, and P < .001 compared with placebo, respectively). One event of herpes zoster and 1 participant with pulmonary embolism and deep venous thrombosis (diagnosed 26 days after treatment discontinuation) were reported in the group that received upadacitinib 45 mg once daily. Increases in serum lipid levels and creatine phosphokinase with upadacitinib were observed. CONCLUSION: In a phase 2b trial, 8 weeks of treatment with upadacitinib was more effective than placebo for inducing remission in patients with moderately to severely active UC. (ClinicalTrials.gov, Number: NCT02819635).

BioAdvance Patient Support Program Survey: Positive Perception of Intravenous Infusions of Infliximab.

PURPOSE: To understand the perception of intravenous infusions in patients receiving infliximab (Remicade) within the BioAdvance patient support program (PSP). DESIGN: Intravenous infusion of infliximab occurs at approximately 200 clinics across Canada and is managed via the BioAdvance PSP. Patients were invited to complete a 28-question survey on demographics, disease/treatment characteristics, health rating, lifestyle, employment, and perception of intravenous infusions and the BioAdvance program. METHODOLOGY: Analyses were exploratory and descriptive; collected data were self-reported ordinal (Likert scale, unfavorable-to-favorable, 1-10). The Wilcoxon signed-rank test was used to assess statistical significance, and multinomial logistic regression identified predictors of a positive perception of intravenous infusions. RESULTS: 1,712 patients completed the survey. Most respondents had been treated with infliximab for >2 years (58%), had not been previously treated with a biologic (74%), and were receiving treatment for inflammatory bowel disease (76%). Sixty-two percent of patients were employed and most traveled for personal/work reasons (57%) and had a busy/active lifestyle (76%) while attending the BioAdvance clinics. Before treatment, participants rated their perceived favorability of intravenous infusions at 5/10 (median; interquartile range, 5-7); after multiple infusions, their rating increased significantly to 8 (7-9) (P<.001). Regression analysis identified four predictors of a positive infusion experience: French language, favorable ratings of health, accuracy of physician's description, and satisfaction with their BioAdvance coordinator. The vast majority of participants were likely to recommend the BioAdvance PSP. CONCLUSION: The survey results indicate that the majority of patients receiving infliximab have a positive infusion experience within the BioAdvance PSP.

Are IBD patients more likely to have a prior diagnosis of irritable bowel syndrome? Report of a case-control study in the General Practice Research Database.

BACKGROUND: Inflammatory bowel disease (IBD) patients are sometimes first diagnosed with irritable bowel syndrome (IBS), which may be construed as a misdiagnosis. OBJECTIVE: The objective of this article is to determine if this occurs more than expected by chance. METHODS: We conducted a case-control study nested in the General Practice Research Database. We selected incident cases of IBD and up to 10 matched controls for each. We assessed the proportions with IBS recorded prior to the IBD diagnosis and variation by age, sex, and calendar time. We compared proportions affected in fixed time periods and conducted conditional logistic regression to derive odds ratios. RESULTS: The 20, 193 cases were three times as likely as controls to have a prior record of IBS. Fifteen per cent of IBD cases and 5% of controls had IBS coded before diagnosis with 11% having a code for IBS over one year before IBD (cf. 5% of controls) and 6% over five years earlier (cf. 3%). These figures roughly doubled if typical antispasmodic therapies were assumed to represent IBS diagnoses. CONCLUSION: If excess IBS diagnoses represent misdiagnoses of IBD, our results suggest that about 10% of IBD patients are misdiagnosed and in 3% of cases this may persist for five or more years.

An excess of prior irritable bowel syndrome diagnoses or treatments in Celiac disease: evidence of diagnostic delay.

OBJECTIVE: It is recognized that celiac disease can present with symptoms characteristic of irritable bowel syndrome (IBS) and that a substantial proportion of patients referred to gastroenterologists with these symptoms may have celiac disease. The authors set out to discover how commonly those suffering with celiac disease are misdiagnosed as suffering from IBS and whether such misdiagnosis delays the correct diagnosis. MATERIALS AND METHODS: A case control study using computerized records from the General Practice Research Database was conducted. The authors compared the proportion of patients with celiac disease who had a diagnosis of or had undergone treatment for IBS over a variety of time periods before the diagnosis of celiac disease with the proportion of a matched group without celiac disease who were similarly diagnosed or treated. RESULTS: It was found that 16% of celiac patients had such a prior diagnosis compared to 4.9% of controls (a threefold increased risk of prior IBS; OR = 3.8, 95% CI: 3.6-4.2), and that if one looked at typical treatment for IBS rather than diagnostic codes, 28% of celiac patients appeared to have been treated compared to 9% of controls. Many of the diagnoses of IBS occurred within the last year before diagnosis of celiac disease, but there was a clear excess of IBS even 10 years earlier. CONCLUSIONS: In contemporary UK practice, it is likely that at least some patients with celiac disease spend many years being treated as having IBS. Following guidelines to test serologically for celiac disease will minimize this problem.

Urinary NMR metabolomic profiles discriminate inflammatory bowel disease from healthy.

BACKGROUND AND AIMS: Inflammatory bowel disease, a chronic inflammation of the intestinal tract, presents in two variations, Ulcerative Colitis (UC) and Crohn's disease (CD). Given that treatment of CD differs from UC, a single test that provided strong diagnostic ability would offer great clinical value. Two previous studies have indicated that CD can be distinguished from UC, and that both can be distinguished from non-IBD-type gastrointestinal disease, based on urinary and faecal metabolite profiling. METHODS: Analysis of healthy as well as CD and UC patients attending an IBD clinic was performed. IBD patients were classified into two groups (CD or UC) based on chart review of clinical, endoscopic, and histological assessment. Urine samples were obtained and analyzed using nuclear magnetic resonance (NMR) spectroscopy combined with targeted profiling techniques, followed by univariate and multivariate statistical analysis. RESULTS: Based on urinary metabolomics, individuals with IBD could be differentiated from healthy. Major differences between IBD and healthy included TCA cycle intermediates, amino acids, and gut microflora metabolites. Comparison of CD and UC patients revealed discrimination, but removal of patients with the surgical intervention confounder revealed that CD could not be discriminated from UC. CONCLUSIONS: This study highlights the potential for metabolomics to distinguish IBD from the healthy state but shows that careful consideration must be given to establishing disease-representative cohorts that are free of confounding factors.

Risedronate improves bone mineral density in Crohn's disease: a two year randomized controlled clinical trial.

BACKGROUND: Patients with Crohn's disease have an increased frequency of osteopenia and osteoporosis. This randomized, controlled, double-blind study assessed the efficacy of risedronate versus placebo in treating low bone mineral density (BMD) in patients with Crohn's disease. METHODS: 88 Crohn's disease outpatients with BMD T-score<-1.0 by dual-energy X-ray absorptiometry were randomly assigned to one of two treatment groups for the two year study duration: one group received risedronate 35 mg weekly while another received placebo. Both groups received daily calcium (Ca; 500 mg) and vitamin D (D; 400 IU) supplementation. Percent change in BMD relative to baseline was compared between the two therapies at 12 and 24 months. RESULTS: Using intent-to-treat analysis, at 12 months, risedronate+Ca+D increased BMD, relative to baseline, more than placebo+Ca+D in the femoral trochanter (1.4±3.4% vs -0.1±3.1%; p=0.03) and total hip (1.1±2.7% vs -0.1±2.5%;p=0.04). This trend in greater BMD continued for the 24 month duration of the study. There was no difference between the two treatment groups for changes in spine BMD. Subgroup analysis revealed that risedronate+Ca+D resulted in significantly better improvement in femoral trochanter BMD in non-smokers (p=0.01), males (p=0.01), those with a history of corticosteroid use in the preceding year (p=0.01), and current users of immunosuppressants (p=0.04). CONCLUSIONS: Risedronate, in addition to daily calcium and vitamin D supplementation, is superior to calcium and vitamin D alone in improving femoral trochanter and total hip BMD in patients with Crohn's disease.

Physician perspectives on unresolved issues in the use of conventional therapy in Crohn's disease: results from an international survey and discussion programme.

BACKGROUND AND AIMS: Data on the optimal use of conventional therapies in Crohn's disease are lacking in guidelines. An educational programme was established to explore questions raised in clinical practice and to provide practical answers. METHODS: Telephone interviews with 96 gastroenterologists and a web survey of 1370 gastroenterologists identified 26 key questions. Ten questions were taken forward to the next stage based on the opinion of an International Steering Committee. Draft answers to the questions were prepared from available evidence following a literature search. The draft answers were debated in national meetings of participating countries (n=36) and voted on using a standard scoring system. Revised answers went forward to an international meeting and were debated and voted on using the same methodology. Final answers were developed, based on evidence and clinical experience of the participants. RESULTS: Evidence on corticosteroid and immunomodulator use such as dosage, timing and duration, choice of drug or regimen, and safety is scarce. Key points of the answers included the importance of: identifying patients with poor prognosis; early intervention with optimal doses of immunomodulators; avoiding prolonged or repetitive corticosteroid therapy; achieving corticosteroid-free remission; achieving a balance between clinical benefit and safety when intensifying or prolonging therapy or combining different agents; re-evaluating therapy at appropriate time points; and considering the role of biomarkers and mucosal healing. CONCLUSIONS: The answers to 10 key questions were based on available evidence and clinical experience of programme participants. It is hoped they will be of practical use in everyday gastroenterology practice.

Vertebral fractures and role of low bone mineral density in Crohn's disease.

BACKGROUND & AIMS: Vertebral fractures in Crohn's (CD) patients with low bone mineral density (BMD) have been documented as between 14%-22%. Vertebral fractures in CD patients with normal BMD have not been reported. The objectives were to identify the prevalence of vertebral fractures in CD patients and associated predictive factors. METHODS: Two hundred twenty-four CD patients underwent vertebral BMD analysis and radiographs. Fractures were identified by using quantitative height reduction morphometry, and severity was assessed by spinal fracture index. RESULTS: Mean age was 40.6 +/- 11.0 years. Sixty percent reported corticosteroid use during the preceding year. Forty-five of 224 (20.0%) patients had 88 vertebral fractures. Sixteen of 45 patients with vertebral fractures had normal BMD (19.0% of all patients with normal BMD). Analysis of patients with or without vertebral fractures did not demonstrate significant differences in BMD or in corticosteroid use. Linear regression analysis demonstrated that elevations in body mass index, C-reactive protein, and parathyroid hormone were significantly predictive of vertebral fractures (r = 0.415, P < .05), and height reduction was >20% (r = 0.417, P < .05). CONCLUSIONS: This study demonstrates that vertebral fractures in CD patients occur with an equal frequency in those with low and with normal BMD, regardless of corticosteroid use. The mean age of CD patients with vertebral fractures was much lower than that reported in the general population for these fractures. Elevations in body mass index and C-reactive protein and parathyroid hormone levels were predictive of vertebral fractures.

Randomized trial of etidronate plus calcium and vitamin D for treatment of low bone mineral density in Crohn's disease.

BACKGROUND & AIMS: Crohn's disease causes an increase in osteopenia and osteoporosis. This study assessed the efficacy of adding etidronate to calcium and vitamin D supplementation for treatment of low bone mineral density in Crohn's disease. METHODS: One hundred fifty-four patients with Crohn's disease with decreased bone mineral density, determined by using dual-energy x-ray absorptiometry, were randomly assigned to receive etidronate (400 mg orally) or not for 14 days; both groups were then given daily calcium (500 mg) and vitamin D (400 IU) supplementation for 76 days. This cycle was repeated 8 times during a period of 24 months. Biochemical characteristics and bone mineral densities were assessed at 6, 12, and 24 months. RESULTS: After 24 months bone mineral density significantly increased from baseline in both the etidronate- and the non-etidronate-treated groups (both groups receiving calcium and vitamin D supplementation) at the lumbar spine (P < .001), ultradistal radius (P < .001), and trochanter (P = .004) sites, but not at the total hip. The increase in bone mineral density was similar in each treatment group. No bone mineral density differences were found when groups were analyzed according to gender, corticosteroid use, bone mineral density at baseline, or age. CONCLUSIONS: Low bone mineral density is frequently associated with Crohn's disease. Supplementation with daily calcium and vitamin D is associated with increases in bone mineral density. The addition of oral etidronate does not further enhance bone mineral density.

Bones and Crohn's: risk factors associated with low bone mineral density in patients with Crohn's disease.

Previous studies have confirmed that the prevalence of decreased bone mineral density is elevated in patients with inflammatory bowel disease. The objective of the current study was to determine the prevalence of osteopenia and osteoporosis in a cross-sectional outpatient population of 242 adult patients with Crohn's disease and to determine which clinical characteristics and serum and urine biochemical factors might be predictive of bone loss. Thirty-seven percent had normal bone density, 50.0% were osteopenic, and 12.9% were osteoporotic. Among the sites used to diagnose low bone mineral density, the femoral neck demonstrated the highest prevalence of osteopenia and the ultra-distal radius the highest prevalence of osteoporosis. However, low bone mineral density at one site was always predictive of low bone mineral density at the other. Corticosteroid use during the year before assessment was found to be consistently predictive of low bone mineral density in males but not in females. In contrast, low body mass index and high platelet counts were consistently predictive of low bone mineral density in females but not in males. Disease location, smoking, and age were not predictive of changes in bone mineral density.

The frequency of vitamin D deficiency in adults with Crohn's disease.

BACKGROUND: Vitamin D deficiency is a putative, pathogenic cofactor in the increase in osteopenia and osteoporosis seen in patients with Crohn's disease. OBJECTIVE: To determine the frequency of low serum 25-hydroxy-vitamin D3 (25-OHD) levels and the associated alterations in bone mineral density in a cohort of adults with Crohn's disease. METHODS: 25-OHD levels were determined in 242 consecutive patients with Crohn's disease seen in two tertiary inflammatory bowel disease referral centres. Bone mineral density was assessed by dual energy x-ray absorptiometry. RESULTS: Nineteen (8%) patients exhibited vitamin D deficiency (25-OHD less than 25 nmol/L) and 52 (22%) patients exhibited vitamin D insufficiency (25-OHD less than 40 nmol/L). Mean T-scores at the lumbar spine, femoral neck, total hip and ultradistal radius in the group with low 25-OHD did not differ from those of the normal 25-OHD group. Serum alkaline phosphatase and parathyroid hormone levels were higher in the low 25-OHD group than in the normal group. Decreased red blood cell (RBC) folate predicted low 25-OHD in male patients, while smoking, RBC folate and serum iron predicted low 25-OHD in female patients. The rate of low 25-OHD deficiency in the winter was significantly higher than that in the summer (11.9% versus 2.8%, respectively). CONCLUSION: Vitamin D-deficient Crohn's disease patients exhibit biochemical evidence of metabolic bone disease, without detectable differences in bone mineral density. Sunlight exposure, nutrition and smoking status were predictors of vitamin D deficiency in this patient cohort.