Summary
Background
Increase in lipid levels associated with the treatment of inflammatory bowel disease (IBD) has previously been reported. However, it is unknown if this effect is similar for all ...IBD drug classes.
Aim
To precisely assess the effect of different IBD drug classes on lipid profiles
Methods
We performed a systematic literature search of randomised controlled trials and observational cohort studies that assessed lipid levels before and after induction (≤10 weeks) and maintenance (>10 weeks) of IBD treatment. Data of 11 studies (1663 patients) were pooled using random effects models. The influence of patient and disease characteristics on treatment effects on total cholesterol levels was analysed in 6 studies (1211 patients) for which individual data were available, using linear mixed models.
Results
A statistically significant increase in total cholesterol was observed after induction treatment with corticosteroids (+1.19 mmol/L, 95% confidence interval CI95 +0.52 to +2.59), and tofacitinib (+0.66 mmol/L, CI95 +0.42 to +0.79), but not after anti−TNFα treatment (−0.11 mmol/L, CI95 −0.26 to +0.36 mmol/L). Similar differences were observed after maintenance treatment. Treatment effects were significantly related to age, but not with other factors. Lipid changes were inversely correlated with but not modified by CRP changes.
Conclusions
Increase in total cholesterol levels was strongest for corticosteroids followed by tofacitinib but was not observed for anti‐TNFα agents. Whether total cholesterol change associated with IBD treatment has an effect on cardiovascular risk requires further study.
Systematic review and meta‐analysis: effect of inflammatory bowel disease therapy on lipid levels
Around 30% of patients with inflammatory bowel disease (IBD) are refractory to current IBD drugs or relapse over time. Novel treatments are called for, and low dose Naltrexone (LDN) may provide a ...safe, easily accessible alternative treatment option for these patients. We investigated the potential of LDN to induce clinical response in therapy refractory IBD patients, and investigated its direct effects on epithelial barrier function.
Patients not in remission and not responding to conventional therapy were offered to initiate LDN as a concomitant treatment. In total 47 IBD patients prescribed LDN were followed prospectively for 12 weeks. Where available, endoscopic remission data, serum and biopsies were collected. Further the effect of Naltrexone on wound healing (scratch assay), cytokine production and endoplasmic reticulum (ER) stress (GRP78 and CHOP western blot analysis, immunohistochemistry) were investigated in HCT116 and CACO2 intestinal epithelial cells, human IBD intestinal organoids and patient samples.
Low dose Naltrexone induced clinical improvement in 74.5%, and remission in 25.5% of patients. Naltrexone improved wound healing and reduced ER stress induced by Tunicamycin, lipopolysaccharide or bacteria in epithelial barriers. Inflamed mucosa from IBD patients showed high ER stress levels, which was reduced in patients treated with LDN. Cytokine levels in neither epithelial cells nor serum from IBD patients were affected.
Naltrexone directly improves epithelial barrier function by improving wound healing and reducing mucosal ER stress levels. Low dose Naltrexone treatment is effective and safe, and could be considered for the treatment of therapy refractory IBD patients.
Background & Aims Patients with perianal fistulizing Crohn’s disease have a poor prognosis because these lesions do not heal well. We evaluated the effects of local administration of bone ...marrow−derived mesenchymal stromal cells (MSCs) to these patients from healthy donors in a double-blind, placebo-controlled study. Methods Twenty-one patients with refractory perianal fistulizing Crohn’s disease were randomly assigned to groups given injections of 1 × 107 (n = 5, group 1), 3 × 107 (n = 5, group 2), or 9 × 107 (n = 5, group 3) MSCs, or placebo (solution with no cells, n = 6), into the wall of curettaged fistula, around the trimmed and closed internal opening. The primary outcome, fistula healing, was determined by physical examination 6, 12, and 24 weeks later; healing was defined as absence of discharge and <2 cm of fluid collection—the latter determined by magnetic resonance imaging at week 12. All procedures were performed at Leiden University Medical Center, The Netherlands, from June 2012 through July 2014. Results No adverse events were associated with local injection of any dose of MSCs. Healing at week 6 was observed in 3 patients in group 1 (60.0%), 4 patients in group 2 (80.0%), and 1 patient in group 3 (20.0%), vs 1 patient in the placebo group (16.7%) ( P = .08 for group 2 vs placebo). At week 12, healing was observed in 2 patients in group 1 (40.0%), 4 patients in group 2 (80.0%), and 1 patient in group 3 (20.0%), vs 2 patients in the placebo group (33.3%); these effects were maintained until week 24 and even increased to 4 (80.0%) in group 1. At week six, 4 of 9 individual fistulas had healed in group 1 (44.4%), 6 of 7 had healed in group 2 (85.7%), and 2 of 7 had healed in group 3 (28.6%) vs 2 of 9 (22.2%) in the placebo group ( P = .04 for group 2 vs placebo). At week twelve, 3 of 9 individual fistulas had healed in group 1 (33.3%), 6 of 7 had healed in group 2 (85.7%), 2 of 7 had healed in group 3 (28.6%), and 3 of 9 had healed in the placebo group (33.3%). These effects were stable through week 24 and even increased to 6 of 9 (66.7%) in group 1 ( P = .06 group 2 vs placebo, weeks 12 and 24). Conclusions Local administration of allogeneic MSCs was not associated with severe adverse events in patients with perianal fistulizing Crohn’s disease. Injection of 3 × 107 MSCs appeared to promote healing of perianal fistulas. ClinicalTrials.gov ID NCT01144962.
Despite potent drugs and surgical techniques, the treatment of perianal fistulizing Crohn's disease (CD) remains challenging. We assessed treatment strategies for perianal fistulizing CD and their ...effect on remission, response, and relapse.
Patients with perianal fistulizing CD visiting the Erasmus MC between January 1, 1980 and January 1, 2000 were identified. Demographics, fistula characteristics, and received treatments aimed at the outcome of these strategies were noted.
In total, 232 patients were identified (98 male; 42.2%). Median follow-up was 10.0 years (range, 0.5-37.5 yr). Complex fistulas were present in 78.0%. Medical treatment (antibiotics, steroids, immunosuppressants, and anti-tumor necrosis factor) commenced in 79.7% of the patients and in 53.2%, surgery (colectomy, fistulectomy, stoma, and rectum amputation) was performed. Simple fistulas healed more often than complex fistulas (88.2% versus 64.6%; P < 0.001). Rectum involvement was not associated with a lower remission rate, and anti-tumor necrosis factor therapy did not increase complete fistula healing rates in simple and complex fistula. Initially, healed fistulas recurred in 26.7% in case of simple fistulas and in 41.9% in case of complex fistulas (P = 0.051). Only 37.0% of the complex fistulas were in remission at the end of follow-up compared with 66.7% of the simple fistulas (P < 0.001).
Only the minority of CD complex perianal fistulas were in remission after conventional treatment strategies after a median follow-up of 10 years. Simple fistulas were more likely to heal than complex fistulas, and less of these healed fistulas relapsed. However, more than 3 quarters of the patients had complex perianal fistulas.
We evaluated the ability of vedolizumab to induce endoscopic and histologic remission in patients with Crohn's disease (CD).
We performed a prospective study of 110 patients with active CD, based on ...CD activity index (CDAI) scores >220 and mucosal ulcerations, who received open-label vedolizumab (300 mg) infusions at weeks 0, 2, and 6, and every 8 weeks thereafter through week 52 at tertiary centers in Europe. Patients received an additional infusion at week 10 if their CDAI score had not decreased by 70 points. Patients underwent ileocolonoscopy with collection of biopsies at baseline and weeks 26 and 52; a local and central reader determined simple endoscopic index for CD (SES-CD) scores. Histologic features were assessed by a blinded pathologist at week 26. Serum concentrations of vedolizumab were measured at serial time points. The primary outcome was endoscopic and histologic remission in patients with active CD treated with vedolizumab for 52 weeks.
At weeks 26 and 52, 36 patients (29%) and 34 patients (31%), respectively, were in corticosteroid-free clinical remission (CDAI score <150), respectively. Based on intent-to-treat analysis, endoscopic remission (SES-CD score <4) was achieved by 36 patients (33%) and 40 patients (36%) at weeks 26 and 52. Endoscopic responses (decrease in SES-CD score ≥50%) occurred in 44 patients (40%) at week 26 and 5 patients (45%) at week 52. Serum concentrations of vedolizumab were higher at weeks 2, 10, and 22 in patients with lower SES-CD scores. Histologic remission at week 26 was observed in 43 (64%) of 67 patients based on Geboes Score and 37 (66%) of 56 patients based on Robarts Histopathology Index scores in analyses of paired biopsies with inflammation at baseline. Serum concentrations of vedolizumab above 10 mg/L at week 22 were associated with endoscopic remission at week 26.
In a prospective trial, we found that approximately one-third of patients with CD achieve endoscopic remission after 52 weeks of treatment with vedolizumab and two-thirds achieve histologic remission at week 26. Higher serum concentrations of vedolizumab were associated with better outcomes. EUDRACT no: 2014–005376–29.
Abstract
Background and Aims
The long-term safety and efficacy of allogeneic bone marrow-derived mesenchymal stromal cell bmMSC therapy in perianal Crohn’s disease CD fistulas is unknown. We aimed to ...provide a 4-year clinical evaluation of allogeneic bmMSC treatment of perianal CD fistulas.
Methods
A double-blind dose-finding study for local bmMSC therapy in 21 patients with refractory perianal fistulising Crohn’s disease was performed at the Leiden University Medical Center in 2012–2014. All patients treated with bmMSCs 1 x 107 bmMSCs cohort 1, n = 5; 3 × 107 bmMSCs cohort 2, n = 5; 9 × 107 bmMSCs cohort 3, n = 5 were invited for a 4-year evaluation. Clinical events were registered, fistula closure was evaluated, and anti-human leukocyte antigen HLA antibodies were assessed. Patients were also asked to undergo a pelvic magnetic resonance imaging MRI and rectoscopy.
Results
Thirteen out of 15 patients 87% treated with bmMSCs were available for long-term follow-up. Two non-MSC related malignancies were observed. No serious adverse events thought to be related to bmMSC therapy were found. In cohort 2 n = 4, all fistulas were closed 4 years after bmMSC therapy. In cohort 1 n = 4 63%, and in cohort 3 n = 5 43%, of the fistulas were closed, respectively. In none of the patients anti-HLA antibodies could be detected 24 weeks and 4 years after therapy. Pelvic MRI showed significantly smaller fistula tracts after 4 years.
Conclusions
Allogeneic bmMSC therapy for CD-associated perianal fistulas is also in the long-term a safe therapy. In bmMSC-treated patients, fistulas with closure at Week 24 were still closed after 4 years.
Mouse models have shown that interleukin (IL)6 stimulates survival, proliferation and progression to cancer of intestinal epithelial cells via activation of signal transducers and activators of ...transcription 3 (STAT3).
To investigate the expression of IL6/phosphorylated STAT3 (p-STAT3)/suppressor of cytokine signalling 3 (SOCS3) in biopsy specimens from patients with ulcerative colitis (UC) and UC-related colorectal cancer (CRC) progression.
Biopsy specimens from patients with inactive UC (n=18), active UC (n=28), UC with low-grade dysplasia (LGD) (n=9), UC with high-grade dysplasia (HGD) (n=7), UC-CRC (n=11) and sporadic CRC (n=14) were included. Biopsy specimens (n=9) from patients without colonic abnormalities served as control. The protein expression of IL6, p-STAT3 and SOCS3 was determined immunohistochemically.
Patients with active UC had significantly more IL6 and p-STAT3-positive epithelial cells than both patients with inactive UC and controls (strong positive IL6: 53.6%, 11.1% and 0%, respectively; p-STAT3: 64.3%, 22.2% and 11.1%, respectively; all p<or=0.012). SOCS3-positive cells were significantly increased in colonic epithelium of both inactive and active UC compared with controls (strong positive: 94.4%, 96.4% and 11.1%, respectively; both p<0.001). In dysplasia and cancer, significantly more epithelial cells expressed IL6 and p-STAT3 compared with controls (strong positive IL6: 72.7% and 0% respectively; p-STAT3: 54.5% and 11.1%, respectively; both p<0.05), whereas the proportion of SOCS3-positive cells in this progression reduced (LGD 33.3%; HGD 14.3%; UC-CRC 9.1%). In addition, methylation of the SOCS3 gene was detected in epithelial cells from UC-CRC biopsy specimens.
The importance of IL6/p-STAT3 in patients with inflammation-induced CRC was demonstrated. Moreover, SOCS3 may be involved in UC pathogenesis and the absence of SOCS3 seems critical for CRC progression.
To assess time trends in intestinal resection and re-resection in Crohn's disease (CD) patients.
CD treatment has changed considerably over the past decades. The effect of these advances on the ...necessity of intestinal resections and the risk of re-resection is unclear.
In this nationwide cohort study, adult CD patients with ileocolonic, small bowel, colon, or rectum resections between 1991 and 2015 were included. Data were retrieved from the Dutch nationwide network and registry of histopathology and cytopathology (PALGA). Time trends were analyzed with a broken stick model and Cox proportional hazard model with smoothing splines.
The identified cohort comprised 8172 CD patients (3293/4879 male/female) in whom 10,315 intestinal resections were performed. The annual intestinal resection rate decreased nonlinearly from
1.9/100,000 (1991) to 0.2/100,000 (2015). A significantly steeper-decrease was observed before 1999 (slope –0.13) as compared to subsequent years (slope –0.03) (p<0.001). Analogous trends were observed for ileocolonic, small bowel, and colon resections. Overall cumulative risk of re-resection was 10.9% at 5 years, 18.6% at 10 years, and 28.3% at 20 years after intestinal resection. The hazard for intestinal re-resection showed a nonlinear decreasing trend, with hazard ratio 0.39 (95% confidence interval 0.36-0.44) in 2000 and hazard ratio 0.25 (95% confidence interval 0.18-0.34) in 2015 as compared to 1991.
Over the past 25 years, intestinal resection rate has decreased significantly for ileocolonic, small bowel, and colonic CD. In addition, current postoperative CD patients are at 75% lower risk of intestinal re-resection.
To assess whether a combination of adalimumab and ciprofloxacin is superior to adalimumab alone in the treatment of perianal fistulising Crohn's disease (CD).
Randomised, double-blind, placebo ...controlled trial in eight Dutch hospitals. In total, 76 CD patients with active perianal fistulising disease were enrolled. After adalimumab induction therapy (160/80 mg week 0, 2), patients received 40 mg every other week together with ciprofloxacin 500 mg or placebo twice daily for 12 weeks. After 12 weeks, adalimumab was continued. Follow-up was 24 weeks. Primary endpoint (clinical response) was defined as 50% reduction of fistulas from baseline to week 12. Secondary endpoints included remission (closure of all fistulas), Perianal Crohn's Disease Activity Index, Crohn's Disease Activity Index (CDAI) and Inflammatory Bowel Disease Questionnaire (IBDQ).
Clinical response was observed in 71% of patients treated with adalimumab plus ciprofloxacin and in 47% treated with adalimumab plus placebo (p=0.047). Likewise, remission rate at week 12 was significantly higher (p=0.009) in the combination group (65%) compared with adalimumab plus placebo (33%). Combination treatment was associated with a higher mean CDAI change and mean IBDQ change at week 12 (p=0.005 and p=0.009, respectively). At week 24, no difference in clinical response between the two treatment groups was observed (p=0.22). No difference in safety issues was observed.
Combination therapy of adalimumab and ciprofloxacin is more effective than adalimumab monotherapy to achieve fistula closure in CD. However, after discontinuation of antibiotic therapy, the beneficial effect of initial coadministration is not maintained.
ClinicalTrials.gov Identifier: NCT00736983.
Summary
Background
To timely detect myelotoxicity and hepatotoxicity, laboratory monitoring at 3‐month intervals is advised throughout thiopurine maintenance treatment for IBD. However, reported ...incidence rates of myelotoxicity and hepatotoxicity in maintenance treatment are low.
Aim
To assess incidence rates and clinical consequences of myelotoxicity and hepatotoxicity in thiopurine maintenance therapy after at least 1 year of thiopurine treatment.
Methods
Retrospective analysis of therapy adjustment for laboratory toxicity in adult IBD patients after 12 consecutive months of azathioprine (AZA) or mercaptopurine monotherapy (ie baseline) between 2000 and 2016. Incidence rates of laboratory toxicity (ie myelotoxicity leucocyte count <4.0 × 10e9/L, and/or platelet count <150 × 10e9/L and/or hepatotoxicity (gamma‐glutamyltransferase GGT, alkaline phosphatase AP, ALT and/or AST above ULN, excluding isolated increased AST/AP) and associated diagnostic procedures and complications were assessed.
Results
In total, 12,391 laboratory assessments were performed on 1132 patients (56% female, AZA 74%) during 3.3 years of median follow‐up. Median monitoring frequency was 3.1 assessments/treatment year. Only 83/12,391 (0.7%) assessments resulted in therapy adjustment, dose reduction in 46 patients, cessation in 28 and allopurinol initiation in nine; risk of therapy adjustment was 1.9% per treatment year. Incidence rates of myelotoxicity were 7.1% (5.1% mild/1.8% moderate/0.1% severe) and hepatotoxicity 5.1% (3.8% mild/1.1% moderate/0.2% severe) per treatment year. Treatment‐related complications with concurrent laboratory toxicity occurred in 12 patients (1.1%) and would not have been prevented by monitoring.
Conclusion
Severe laboratory toxicity is uncommon after 1 year of thiopurine monotherapy at 4‐month monitoring intervals. Therapy adjustments are rare after detection of laboratory toxicity. After 1 year of thiopurine monotherapy, laboratory monitoring may be lowered to less than a 4‐month interval.
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