[Show abstract][Hide abstract] ABSTRACT: Intestinal helminth parasites are potent inducers of T helper type 2 (Th2) response and have a regulatory role, notably on intestinal inflammation. As infection with schistosomes is unlikely to provide a reliable treatment of inflammatory bowel diseases, we have investigated the beneficial effect of a schistosome enzymatic protein, the 28-kDa glutathione S-transferase (P28GST), on the modulation of disease activity and immune responses in experimental colitis. Our results showed that immunization with recombinant P28GST is at least as efficient as established schistosome infection to reduce colitis lesions and expression of pro-inflammatory cytokines. Considering underlying mechanisms, the decrease of inflammatory parameters was associated with the polarization of the immune system toward a Th2 profile, with local and systemic increases of interleukin (IL)-13 and IL-5. Dense eosinophil infiltration was observed in the colons of P28GST-immunized rats and mice. Depletion of eosinophils by treatment with an anti-Siglec-F monoclonal antibody and use of IL-5-deficient mice led to the loss of therapeutic effect, suggesting the crucial role for eosinophils in colitis prevention by P28GST. These findings reveal that immunization with P28GST, a unique recombinant schistosome enzyme, ameliorates intestinal inflammation through eosinophil-dependent modulation of harmful type 1 responses, representing a new immuno-regulatory strategy against inflammatory bowel diseases.Mucosal Immunology advance online publication, 15 July 2015; doi:10.1038/mi.2015.62.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: The protein Hwp1, expressed on the pathogenic phase of Candida albicans, presents sequence analogy with the gluten protein gliadin and is also a substrate for transglutaminase. This had led to the suggestion that C. albicans infection (CI) may be a triggering factor for Celiac disease (CeD) onset. We investigated cross-immune reactivity between CeD and CI. METHODS: Serum IgG levels against recombinant Hwp1 and serological markers of CeD were measured in 87 CeD patients, 41 CI patients, and 98 healthy controls (HC). IgA and IgG were also measured in 20 individuals from each of these groups using microchips sensitized with 38 peptides designed from the N-terminal of Hwp1. RESULTS: CI and CeD patients had higher levels of anti-Hwp1 (p=0.0005 and p=0.004) and anti-gliadin (p=0.002 and p=0.0009) antibodies than HC but there was no significant difference between CeD and CI patients. CeD and CI patients had higher levels of anti-transglutaminase IgA than HC (p=0.0001 and p=0.0039). During CI, the increase in anti-Hwp1 paralleled the increase in anti-gliadin antibodies. Microchip analysis showed that CeD patients were more reactive against some Hwp1 peptides than CI patients, and that some deamidated peptides were more reactive than their native analogs. Binding of IgG from CeD patients to Hwp1 peptides was inhibited by gammaIII gliadin peptides. CONCLUSIONS: Humoral cross-reactivity between Hwp1 and gliadin was observed during CeD and CI. Increased reactivity to Hwp1 deamidated peptide suggests that transglutaminase is involved in this interplay. These results support the hypothesis that CI may trigger CeD onset in genetically-susceptible individuals.
PLoS ONE 03/2015; 10(3-3):e0121776. DOI:10.1371/journal.pone.0121776 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective Laquinimod is an oral therapeutic agent under investigation for the treatment of Crohn's disease (CD), Huntington's disease, lupus nephritis and multiple sclerosis. This dose escalation study evaluated the safety and efficacy of laquinimod as induction therapy in patients with active moderate–severe CD.
Design Multicentre, double-blind, sequential-cohort, randomised controlled trial with laquinimod doses of 0.5, 1, 1.5 or 2 mg/day or placebo (n=45 per cohort randomised in a 2:1 ratio) for 8 weeks with 4-week follow-up. Stable concomittant therapies and prior use of anti-tumour necrosis factor agents were permitted. Comprehensive safety assessments were performed and efficacy analyses included the proportions of patients in clinical remission (CD Activity Index (CDAI) <150 and no treatment failure (TF)), and with a clinical response (70 or 100 point CDAI reduction from baseline or remission and no TF).
Results 117 patients received laquinimod and 63 patients received placebo. The overall incidence of adverse events (AEs) in the laquinimod group was similar to the pooled placebo group (86.2%–96.7% vs 82.5%) and most AEs were mild to moderate in severity. Treatment with laquinimod 0.5 mg showed consistent effects on remission (48.3% (CI 31% to 66%) vs 15.9% (CI 9% to 27%)), response 100 (55.2% (CI 37% to 71%) vs 31.7% (CI 22% to 44%)) and response 70 (62.1% (CI 44% to 77%) vs 34.9% (CI 24% to 47%)) versus placebo. Laquinimod 1.0 mg showed less benefit (26.7% remission (CI 14% to 44%) and 53.3% response 70 (CI 36% to 70%)), and no effect was noted on remission/response at higher doses.
Conclusions Laquinimod was safe and well tolerated, and the effects on remission and response of the 0.5 mg dose suggest a treatment benefit in patients with CD.
Trial registration number NCT00737932.
Gut 10/2014; 64(8). DOI:10.1136/gutjnl-2014-307118 · 13.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Patients with moderately to severely active ulcerative colitis occasionally do not respond to or lose initial response to maintenance dosing of anti-TNF therapy.AimTo report the efficacy of escalation from every other week (EOW) to weekly adalimumab dosing in patients from the clinical trial ULTRA 2 (NCT00408629), by week 8 response (i.e. response after adalimumab induction therapy).Methods
Week 52 remission, response, and mucosal healing rates were assessed in ULTRA 2 adalimumab-randomised patients who escalated to weekly dosing. Patients were stratified by week 8 response per partial Mayo score. Kaplan–Meier and logistic regression analyses estimated time to weekly dosing and defined predictors of escalation to weekly dosing, respectively. Adverse events were reported for patients receiving open-label adalimumab.ResultsThe rate of escalation to weekly dosing was 16.3% (20/123) for week 8 responders and 38.4% (48/125) for week 8 nonresponders. Week 52 remission, response and mucosal healing rates with weekly dosing were 20%, 45%, and 45% for week 8 responders and 2.1%, 25% and 29.2% for nonresponders, respectively (NRI). The median time to weekly dosing was 288 days for week 8 nonresponders and not estimable for responders. Prior anti-TNF use was a significant predictor of escalation to weekly dosing. Treatment-emergent adverse event rates were similar for patients receiving open-label EOW or weekly adalimumab.Conclusions
Escalation to weekly adalimumab dosing demonstrated clinical benefits for patients who lost response to therapy and may be beneficial for patients not initially responding to induction therapy. No new safety risks were identified with weekly dosing.
[Show abstract][Hide abstract] ABSTRACT: Background
The safety of anti-tumour necrosis factor (TNF) agents during pregnancy is a major concern for child-bearing women and physicians.AimTo assess the impact of anti-TNF therapy on adverse pregnancy and foetal outcomes in women with inflammatory bowel disease (IBD).Methods
Pregnancies occurring during anti-TNF treatment or less than 3 months after its cessation in IBD patients followed in GETAID centres were recorded from January 2009 to December 2010. Ninety-nine pregnancies in women without anti-TNF treatment were identified from the CESAME registry. We compared pregnancy and neonatal outcomes by a case–control study.ResultsIn the 124 IBD patients followed, 133 pregnancies were reported. At the conception time, 23% of patients had active disease. Eighty-eight per cent (n = 117) of the 133 pregnancies followed until delivery resulted in 118 liveborns (one twin pregnancy). Complications were observed in 47 (35%) women and 24 (20%) newborns. In multivariate analysis, factors associated with pregnancy complications were: current smoking (P = 0.004), a B2 (stenotic) phenotype in CD women (P = 0.004), occurrence of a flare during pregnancy (P = 0.006) and a past history of complicated pregnancy (P = 0.007). Current smoking was the only factor associated with severe (i.e. potentially lethal) pregnancy complications (P = 0.02). Having IBD for more than 10 years prior to conception was associated with newborn complications (P = 0.007). No difference was found with the control group for any of the pregnancy and neonatal outcomes.Conclusion
In our series, the safety profile of anti-TNF therapy during pregnancy and the neonatal period appears similar to control group of IBD women not treated with anti-TNF therapy.
[Show abstract][Hide abstract] ABSTRACT: After an earlier study defining immunolabeled lymphoid follicles, obstructed lymphatics, and granulomas of the diseased ilea of 24 Crohn's disease patients, we chose to trace the lymphatics of these cases and 10 additional by serial sectioning. Particular attention was given to establishing physical continuity between granuloma-obstructed lymphatics and lymphatics with ‘lymphocytic thrombi’. Formalin-fixed paraffin-embedded tissue blocks from resected diseased ilea and proximal colons from 34 patients were reviewed. Patients were 13 men and 21 women, aged 14–60 years. Duration of disease ranged from 1 month to 10 years. Immunohistochemistry employed D2-40 antibody to label lymphatics and anti-CD68 to label granulomas. Twenty-nine of the 34 (85%) resection tissues had lymphangectasia, in mucosa, submucosa, and subserosa. In 53% of the specimens, lymphatics of the various layers were obstructed by granulomas that filled the lumina. In 44%, 15/34, there were also distended lymphatics that were totally plugged with lymphocytes. In 10 of the 15, serial sections revealed continuity between the lymphocyte-plugged lymphatics and the endolymphatic granulomatous obstruction downstream. In 5 of the cases, D2-40 immunostaining revealed redundant lymphatic endothelium interwoven with the granuloma cells. Granulomas totally obstruct lymphatics in all layers of the intestine in Crohn's disease. Upstream of these obstructions, lymphatics are distended with lymphocytes. The degree and extent of this potentially irreversible ‘lymphangitis nodosa’ have undoubtedly confounded treatment regimens and clinical trials. There currently are no imaging methods to demonstrate the lymphangitis, nor treatments to resolve it.
[Show abstract][Hide abstract] ABSTRACT: Background & Aims
Subcutaneous golimumab, a fully human monoclonal antibody to tumor necrosis factor-α (TNFα), was evaluated as maintenance therapy in TNFα antagonist-naive adults with moderate-to-severe active ulcerative colitis, despite conventional therapy, who responded to golimumab induction therapy.
We performed a phase 3, double-blind trial of patients who completed golimumab induction trials (Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment, eg, PURSUIT). Patients who responded to induction therapy with golimumab (n = 464) were assigned randomly to groups given placebo or injections of 50 or 100 mg golimumab every 4 weeks through week 52. Patients who responded to placebo in the induction study continued to receive placebo. Nonresponders in the induction study received 100 mg golimumab. The primary end point was clinical response maintained through week 54; secondary end points included clinical remission and mucosal healing at both weeks 30 and 54.
Clinical response was maintained through week 54 in 47.0% of patients receiving 50 mg golimumab, 49.7% of patients receiving 100 mg golimumab, and 31.2% of patients receiving placebo (P = .010 and P < .001, respectively). At weeks 30 and 54, a higher percentage of patients who received 100 mg golimumab were in clinical remission and had mucosal healing (27.8% and 42.4%) than patients given placebo (15.6% and 26.6%; P = .004 and P = .002, respectively) or 50 mg golimumab (23.2% and 41.7%, respectively). Percentages of serious adverse events were 7.7%, 8.4%, and 14.3% among patients given placebo, 50 mg, or 100 mg golimumab, respectively; percentages of serious infections were 1.9%, 3.2%, and 3.2%, respectively. Among all patients given golimumab in the study, 3 died (from sepsis, tuberculosis, and cardiac failure, all in patients who received 100 mg golimumab) and 4 developed active tuberculosis.
Golimumab (50 mg or 100 mg) maintained clinical response through week 54 in patients who responded to induction therapy with golimumab and had moderate-to-severe active ulcerative colitis; patients who received 100 mg golimumab had clinical remission and mucosal healing at weeks 30 and 54. Safety was consistent with that reported for other TNFα antagonists and golimumab in other approved indications. ClinicalTrials.gov number: NCT00488631.