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Autologous Mesenchymal Stem Cells, Applied in a Bioabsorbable Matrix, for Treatment of Perianal Fistulas in Patients With Crohn's Disease.
Dietz, AB, Dozois, EJ, Fletcher, JG, Butler, GW, Radel, D, Lightner, AL, Dave, M, Friton, J, Nair, A, Camilleri, ET, et al
Gastroenterology. 2017;(1):59-62.e2
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Abstract
In patients with Crohn's disease, perianal fistulas recur frequently, causing substantial morbidity. We performed a 12-patient, 6-month, phase 1 trial to determine whether autologous mesenchymal stem cells, applied in a bioabsorbable matrix, can heal the fistula. Fistula repair was not associated with any serious adverse events related to mesenchymal stem cells or plug placement. At 6 months, 10 of 12 patients (83%) had complete clinical healing and radiographic markers of response. We found placement of mesenchymal stem cell-coated matrix fistula plugs in 12 patients with chronic perianal fistulas to be safe and lead to clinical healing and radiographic response in 10 patients. ClinicalTrials.gov Identifier: NCT01915927.
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Efficacy, Safety, and Long-term Outcome of Serial Endoscopic Balloon Dilation for Upper Gastrointestinal Crohn's Disease-associated Strictures-A Cohort Study.
Singh, A, Agrawal, N, Kurada, S, Lopez, R, Kessler, H, Philpott, J, Shen, B, Lashner, B, Rieder, F
Journal of Crohn's & colitis. 2017;(9):1044-1051
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BACKGROUND Gastric and duodenal Crohn's disease [CD]-associated strictures are rare. Evidence on endoscopic balloon dilation [EBD] of upper gastrointestinal [GI] CD strictures is limited, in particular in respect to serial dilations. METHODS Prospective short- and long-term outcome data as well as complication rates on a cohort of upper GI CD-associated stricture dilations [stomach and duodenum] were collected from 1999 to 2015. Factors linked with clinical and technical success, long-term efficacy and complication rates were investigated. RESULTS A total of 35 CD patients with symptomatic CD-associated upper GI strictures [20% gastric, 67% duodenal, 11% both; mean age at diagnosis 25 years; mean CD duration to stricture 79.9 months; median post-dilation follow-up 22.1 months] underwent a total of 96 pneumatic dilations [33 gastric and 63 duodenal]. The median maximal dilation diameter was 15 mm. Technical success was achieved in 93% and clinical success in 87%, with a complication rate of 4% per procedure. The mean time to re-dilation was 2.2 months and mean time to stricture-related surgery after first dilation was 2.8 months. There was no difference in short-term efficacy, safety, or long-term outcome between the first and any later dilation procedure in the same patient. CONCLUSIONS Pneumatic dilation of upper GI CD-associated strictures has a high rate of short-term technical and clinical success, with moderate long-term efficacy and acceptable complication rates. Serial dilations do not change the efficacy and could be a feasible option to delay or prevent surgical intervention.
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Safety of Long-term Treatment With Certolizumab Pegol in Patients With Crohn's Disease, Based on a Pooled Analysis of Data From Clinical Trials.
Loftus, EV, Colombel, JF, Schreiber, S, Randall, CW, Regueiro, M, Ali, T, Arendt, C, Coarse, J, Spearman, M, Kosutic, G
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2016;(12):1753-1762
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BACKGROUND & AIMS Treatments for Crohn's disease (CD) have been linked to serious infections, malignancies, and dermatologic complications. We pooled and analyzed clinical trials of certolizumab pegol, a pegylated humanized Fab' fragment against tumor necrosis factor, to quantify safety events in patients with CD. METHODS We collected data from 5 placebo-controlled trials, 9 open-label studies, and 1 dose-regimen study, conducted globally through April 2014. A total of 2570 patients with moderate to severe CD were treated with certolizumab pegol, with 4378.1 patient-years of exposure. Data were analyzed in 2 groups: patients from placebo-controlled (PC) trials treated with placebo (n = 875) or certolizumab pegol (n = 919) for 6 to 38 weeks (the PC group) or all patients exposed to certolizumab pegol (n = 2570), for durations of 6 to 362 weeks (the all-studies group). Incidence rates (IRs; incidence/100 patient-years) of adverse events (AEs) were calculated from first dose through 70 days (approximately 5 half-lives) after the last dose. RESULTS In the PC group, IRs for serious AEs were similar among patients given certolizumab pegol (31.35/100 patient-years) vs placebo (24.33/100 patient-years). IRs of serious infections or malignancies were low among patients receiving short-term treatment with certolizumab pegol (8.49/100 patient-years and 1.01/100 patient-years, respectively, in the PC group) and did not increase with long-term treatment (6.47/100 patient-years and 0.80/100 patient-years, respectively, in the all-studies group). IRs of psoriasis or psoriasiform dermatitis were low in the PC group (1.01/100 patient-years and 0/100 patient-years, respectively); in the placebo group, these IRs were 0.38 per 100 patient-years and 0 per 100 patient-years, respectively. IRs of psoriasis or psoriasiform dermatitis did not increase with long-term treatment (0.93/100 patient-years and 0.09/100 patient-years, respectively, in the all-studies group). CONCLUSIONS Based on an analysis of data pooled from 15 trials of patients with CD, the safety profile for long-term therapy with certolizumab pegol therapy is similar to that reported from short-term studies. Overall rates of AEs, serious infections, malignancies, and psoriasis did not increase with long-term treatment, suggesting a favorable risk-benefit ratio with long-term certolizumab pegol therapy in CD. Clinicaltrials.gov identifiers: NCT00291668, NCT00152490, NCT00152425, NCT00308581, NCT00349752, NCT00552058, NCT00329550, NCT00329420, NCT00160524, NCT00160706, NCT00297648, NCT00333788, NCT00307931, NCT00356408, and NCT00552344 (https://www.clinicaltrials.gov/ct2/search).
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Efficacy and Safety of Escalation of Adalimumab Therapy to Weekly Dosing in Pediatric Patients with Crohn's Disease.
Dubinsky, MC, Rosh, J, Faubion, WA, Kierkus, J, Ruemmele, F, Hyams, JS, Eichner, S, Li, Y, Huang, B, Mostafa, NM, et al
Inflammatory bowel diseases. 2016;(4):886-93
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BACKGROUND The efficacy of adalimumab in inducing and maintaining remission in children with moderately to severely active Crohn's disease was shown in the IMAgINE 1 trial (NCT00409682). As per protocol, nonresponders or patients experiencing flare(s) on every other week (EOW) maintenance dosing could escalate to weekly dosing; we aimed to determine the therapeutic benefits of weekly dose escalation in this subpopulation. METHODS Week 52 remission and response rates were assessed in patients who escalated to weekly dosing from their previous EOW schedule, which was according to randomized treatment dose (higher dose [HD] adalimumab [≥40 kg, 40 mg EOW; <40 kg, 20 mg EOW] or lower dose [LD; ≥40 kg, 20 mg EOW; <40 kg, 10 mg EOW]). Adverse events were reported for patients remaining on EOW dosing and patients receiving weekly dosing. RESULTS Escalation to weekly dosing occurred in 48/95 (50.5%) patients randomized to LD and 35/93 (37.6%) patients randomized to HD adalimumab (P = 0.076). Week 52 remission and response rates were 18.8% and 47.9% for patients receiving LD adalimumab weekly and 31.4% and 57.1% for patients receiving HD adalimumab weekly, respectively (LD versus HD, P = 0.19 for remission; P = 0.41 for response). Adverse event rates were similar for patients receiving EOW and weekly adalimumab. CONCLUSIONS Weekly adalimumab dosing was clinically beneficial for children with Crohn's disease who experienced nonresponse or flare on EOW dosing. No increased safety risks were observed with weekly dosing.
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Effect of short-term partial enteral nutrition on the treatment of younger patients with severe Crohn's disease.
Kang, Y, Kim, S, Kim, SY, Koh, H
Gut and liver. 2015;(1):87-93
Abstract
BACKGROUND/AIMS: To analyze the effect of short-term supportive temporary partial enteral nutrition therapy for treating severe pediatric Crohn's disease (CD). METHODS We conducted a prospective, open-label study in pediatric patients with CD (n=78) from January 2007 to December 2011. The CD patients were divided into three groups according to disease severity (mild, moderate, and severe). Seventeen patients with severe CD received short-term partial enteral nutrition (SPEN) in addition to their general diet for 4 weeks after the induction of remission with medical treatment. This SPEN group was further divided into two groups by age (<13 years, ≥13 years). Nutritional parameters and Pediatric Crohn's Disease Activity Index scores were analyzed at the initial enrollment and following 1 year of treatment for all groups. RESULTS Nutritional status improved substantially after 1 year of treatment in the severe CD group. Nutritional status in the SPEN group improved considerably more than that in the non-SPEN group. Additionally, the <13-year-old group demonstrated better nutritional status improvement than the ≥13-year-old group. CONCLUSIONS SPEN may be effective in pediatric patients with severe CD for improving nutritional status and moderating disease severity.
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Briakinumab for treatment of Crohn's disease: results of a randomized trial.
Panaccione, R, Sandborn, WJ, Gordon, GL, Lee, SD, Safdi, A, Sedghi, S, Feagan, BG, Hanauer, S, Reinisch, W, Valentine, JF, et al
Inflammatory bowel diseases. 2015;(6):1329-40
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BACKGROUND This study assessed the efficacy and safety of briakinumab, a human anti-IL-12/23p40 monoclonal antibody, compared with placebo for the induction and maintenance of remission in patients with moderately to severely active Crohn's disease. METHODS In this phase 2b, multicenter, double-blind, parallel group study, 246 patients stratified by prior tumor necrosis factor-antagonist use and response, were randomized (1:1:1:3) to 4 intravenous induction regimens: placebo, 200, 400, or 700 mg briakinumab, at weeks 0/4/8. At week 12, responders in the placebo or 400-mg induction groups entered the maintenance phase with the same regimen, whereas responders in the 700-mg induction group were rerandomized (1:1:1) to receive placebo, 200, or 700 mg briakinumab at weeks 12/16/20. At week 24, patients in remission stopped receiving study drug (withdrawal phase) until relapse. Patients experiencing relapse, nonresponders, and nonremitters could enter the open-label phase. RESULTS The primary end point of clinical remission at week 6 was not met. There were numerically greater rates of remission and response at 6, 12, or 24 weeks in patients treated with briakinumab. The safety and tolerability profile of briakinumab was similar in the induction and maintenance phases of the trial. CONCLUSIONS Briakinumab showed a similar safety and tolerability profile to placebo in the induction and maintenance phases, and comparable rates of serious adverse events, adverse events leading to discontinuation, and malignancy. These data provide support for the potential efficacy of briakinumab and other IL-12/23 inhibitors in the treatment of moderate-to-severe Crohn's disease.
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Alendronate improves low bone mineral density induced by steroid therapy in Crohn's disease.
Tsujikawa, T, Andoh, A, Inatomi, O, Bamba, S, Nakahara, T, Sasaki, M, Saito, H, Fujiyama, Y
Internal medicine (Tokyo, Japan). 2009;(12):933-7
Abstract
AIM: We investigated whether steroid therapy for Crohn's disease (CD) patients influences bone mineral density (BMD), and whether alendronate is effective for improving this loss of BMD. METHODS We recruited 16 outpatients with CD. The BMD of the whole body, the lumbar spine, and the proximal femoral neck was measured by dual-energy X-ray absorptimetry. The BMD was expressed as a T score. Some CD patients with low BMD values had been given vitamin K2 or alendronate for one year. RESULTS In the steroid-dependent group, the mean dose of prednisolone was 968 mg per year and 2.7 mg per day. Although the duration of the disease was not related to the T score, the amount of total steroids was negatively correlated with the T score among patients taking no preventative drugs. The T score in the vitamin K2 group after one year did was not altered in the 3 areas examined. On the other hand, the T score in the alendronate group increased by 2.8% for the whole body, 4.5% in the lumbar spine, and 3.4% in the proximal femoral neck. CONCLUSION The BMD of Japanese CD patients was decreased depending on the total amount of steroid administered, and oral alendronate improved the loss of BMD.
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Rapid hip bone loss in active Crohn's disease patients receiving short-term corticosteroid therapy.
Tobias, JH, Sasi, MR, Greenwood, R, Probert, CS
Alimentary pharmacology & therapeutics. 2004;(9):951-7
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BACKGROUND Uncertainty over whether corticosteroids cause bone loss in patients with Crohn's disease may reflect their short, intermittent use. AIM: We investigated whether a 2-month course of prednisolone is associated with detectable bone loss. METHODS Fifteen patients with active Crohn's disease and 19 controls with inactive Crohn's disease were recruited. Bone mineral density of the lumbar spine and hip was measured at baseline and 2 and 8 months. RESULTS At 2 months, significant bone loss was found in patients with active disease (femoral neck -2.7%, P < 0.002; Ward's triangle -3.9%, P < 0.01). Although bone mineral density was still lower at 8 months, these differences were no longer significant (-1.3% and -3.4%, femoral neck and Ward's triangle, respectively). No significant change in hip bone mineral density was observed in controls. Previous corticosteroid use was not significantly associated with baseline bone mineral density, although significant independent associations were observed between weight, site of disease and lumbar spine bone mineral density, and between dietary calcium deficiency and femoral neck and Ward's triangle bone mineral density. CONCLUSION Significant bone loss at the hip can be detected in patients receiving corticosteroid treatment for 2 months for active Crohn's disease ; however, it remains unclear whether this is because of disease activity or its treatment. This rapid bone loss may represent a risk factor for fracture and justify bone protective therapy.
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Therapy of osteoporosis in patients with Crohn's disease: a randomized study comparing sodium fluoride and ibandronate.
von Tirpitz, C, Klaus, J, Steinkamp, M, Hofbauer, LC, Kratzer, W, Mason, R, Boehm, BO, Adler, G, Reinshagen, M
Alimentary pharmacology & therapeutics. 2003;(6):807-16
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BACKGROUND Osteoporosis is a frequent complication in Crohn's disease. Although the efficacy of both sodium fluoride and aminobisphosphonates in postmenopausal osteoporosis has been investigated in long-term therapy studies, no long-term results are available regarding the effect of these agents in the management of osteoporosis in patients with Crohn's disease. METHODS Eighty-four patients with Crohn's disease and pathological bone mineral density findings were randomized to receive either vitamin D3 (1000 IU) and calcium citrate (800 mg) daily (group A) or sodium fluoride (25 mg b.d., group B) or intravenous ibandronate (1 mg every 3 months, group C) in addition to daily calcium/vitamin D substitution. On admission to the study and after 12 and 27 months, patients underwent dual-energy X-ray absorptiometry and radiological examination of the spine. RESULTS Sixty-eight patients completed the 1-year observation period and were available for the intention-to-treat analysis. No new vertebral fractures were diagnosed. In group A, lumbar bone density increased by 2.6% (P = 0.066, N.S.), in group B by 5.7% (P = 0.003) and in group C by 5.4% (P = 0.003). Therapy with sodium fluoride was associated with an increase in osteocalcin (N.S.), whereas administration of ibandronate was associated with a decrease in the resorption parameter, carboxy-terminal cross-linked type-I collagen telopeptide (P < 0.05). Both sodium fluoride and ibandronate resulted in significant decreases in the serum concentration of osteoprotegerin after 9 months (P < 0.001). CONCLUSIONS The findings of the present study show that both sodium fluoride and ibandronate are effective in combination with calcium and vitamin D substitution in the management of osteopenia and osteoporosis in patients with Crohn's disease. Both agents are safe and well tolerated, and induce continuous increases in lumbar bone density.
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[Efficacy of hydrostatic balloon dilatation of anastomotic Crohn's disease strictures].
Blanchet, E, Beau, P
Gastroenterologie clinique et biologique. 2003;(12):1105-9
Abstract
OBJECTIVES To estimate the efficacy of hydrostatic balloon dilatation (HD) of anastomotic strictures of Crohn's disease and the impact of medical treatment on the duration of HD effects. METHODS Sixteen patients with anastomotic stricture (average length: 4.7 cm) were treated by HD and followed-up for a median duration of 24 months. Immunosuppressive treatment was given when a second HD was necessary. RESULTS HD failed in 3 patients (19%). Thirty-two HD are performed in the other 13 (1 HD: 6; 2 HD: 2; > 2 HD: 5). No severe complication was observed. Eight patients received immunosuppressive treatment started before the first HD in 4 cases or following the second HD in 4 cases. Based on actuarial analysis, clinical and surgical recurrence rates were 39% and 0% at 1 year and 73% and 12% at 2 years, respectively. Time between the first and the second HD were not statistically different (P=0.24) for HD performed with (11.5 +/- 8.8 months; range: 5-30) or without (8.0 +/- 6.9 months; range: 2-17) immunosuppressive treatment. CONCLUSION HD delays the surgical timing for anastomotic Crohn's disease strictures. Medical treatment associated with HD does not seem to modify the duration of the clinical remission.