Abstract
Background
We evaluated whether integration of novel diets for donors and patients, in addition to faecal transplantation FT, could increase FT remission rate in refractory ulcerative ...colitis UC.
Methods
This was a blinded, randomised, controlled trial in adults with active UC, defined by a simple clinical colitis activity index SCCAI of ≥5 and ≤11 and endoscopic Mayo score 2–3, refractory to medication. Group 1 received free diet and single donor standard FT by colonoscopy on Day 1and rectal enemas on Days 2 and 14 without dietary conditioning of the donor. Group 2 received FT as above but with dietary pre-conditioning of the donor for 14 days and a UC Exclusion Diet UCED for the patients. Group 3 received the UCED alone. The primary endpoint was Week 8 clinical steroid-free remission, defined as SCCAI <3.
Results
Of 96 planned patients, 62 were enrolled. Remission Week 8 Group 1 was 2/17 11.8%, Group 2 was 4/19 21.1%, Group 3 was 6/15 40% non-significant. Endoscopic remission Group 1 was 2/17 12%, Group 2 was 3/19 16%, Group 3 was 4/15 27% Group 1 vs 3 p = 0.38. Mucosal healing Mayo 0 was achieved only in Group 3 3/15, 20% vs 0/36 FT patients p = 0.022. Exacerbation of disease occurred in 3/17 17.6% of Group 1, 4/19 21.1% of Group 2, and 1/15 6.7% of Group 3 Group 2 vs 3, p = 0.35.
Conclusions
UCED alone appeared to achieve higher clinical remission and mucosal healing than single donor FT with or without diet. The study was stopped for futility by a safety monitoring board.
Background:
Thiopurines are considered immunosuppressive agents and may be associated with an increased risk for infections. However, few inflammatory bowel disease (IBD) patients are appropriately ...vaccinated, and data on their ability to mount an immune response are vague. We evaluated the effects of the thiopurines, azathioprine (AZA) and 6‐mercaptopurine (6‐MP), on cellular and humoral immune responses in IBD patients.
Methods:
A prospective clinical investigation was conducted on IBD patients referred for thiopurine treatment. Immune competence was evaluated by assessing lymphocyte counts and phenotype, response to mitogen and antigen stimulation, immunoglobulin levels, and response to pneumococcal and tetanus vaccines (before treatment, week 0), and to Haemophilus influenza type b vaccine (at week 24).
Results:
Thirty‐one Crohn's disease and 12 ulcerative colitis patients who completed at least 24 weeks of therapy were included. The posttherapy average 6‐MP dose was 1.05 ± 0.30 mg/kg, and white blood cell counts had decreased significantly from baseline values (P < 0.002). The posttreatment response to mitogens and antigens and the immunoglobulin levels were unchanged. Responses to vaccines were normal both in thiopurine‐naïve and thiopurine‐treated patients, suggesting that these patients were immunologically intact while on thiopurine therapy and capable of generating normal immune responses in vivo.
Conclusions:
There is no evidence for any intrinsic systemic immunodeficiency in IBD patients. Thiopurines at the doses used for treating IBD showed no significant suppressive effect on the systemic cellular and humoral immune responses evaluated. Thiopurine‐treated IBD patients can be safely and efficiently vaccinated. (Inflamm Bowel Dis 2011;)
Several fecal microbial transplantation (FMT) approaches for ulcerative colitis (UC) have been investigated with conflicting results. We have recently published the clinical outcomes from the ...CRAFT-UC Trial using FMT with the UC Exclusion Diet (UCED), compared with FMT alone. Here we aimed to compare the two FMT strategies in terms of microbial profile and function.
Subjects recruited to the CRAFT-UC study with available pre- and post-intervention fecal samples were included. Donors received diet conditioning for 14 days based on the UCED principles. Group-1 received single FMT by colonoscopy (Day 1) and enemas (Days 2 and 14) without donors' dietary conditioning (N=11). Group-2 received FMT but with donors' dietary pre-conditioning and UCED for the patients (N=10). Fecal samples were assessed by DNA shotgun metagenomic sequencing.
Following diet conditioning, donors had depletion in metabolic pathways involved in sulfur-containing amino acids biosynthesis. Only Group-2 showed significant shifts towards the donors' microbial composition (ADONIS: R2=0.15, p=0.008) and significant increased Eubacterium_sp_AF228LB post-intervention (β-coefficient 2.66, 95%CI 2.1-3.3, q<0.05) which was inversely correlated with fecal calprotectin (rho=-0.52, p=0.035). Moreover, pathways involved in gut inflammation and barrier function including branched chain amino acids were enriched post intervention in Group-2 and were significantly inversely correlated with fecal calprotectin.
FMT from diet conditioned donors followed by the UCED led to microbial alterations associated with favorable microbial profile which correlated with decreased fecal calprotectin. Our findings support further exploration of additive benefit of dietary intervention for both donors and patients undergoing FMT as a potential treatment of UC.
Celiac Disease Diagnosed in the Elderly Lurie, Yoav; Landau, Dan-Avi; Pfeffer, Jorge ...
Journal of clinical gastroenterology,
2008-January, 2008, 2008-Jan, 2008-01-00, 20080101, Letnik:
42, Številka:
1
Journal Article
Recenzirano
BACKGROUND AND AIMSIn the past 20 years, a growing proportion of new cases of celiac disease (CD) are diagnosed in adults and in patients with extraintestinal manifestations. Our understanding of the ...extremely wide spectra of manifestations and the profound effects on elderly patients is improving. Nevertheless, CD is still underdiagnosed in elderly patients. In this study, we describe a case series of CD patients diagnosed after the age of 60.
METHODSA retrospective chart review was preformed in cases of CD diagnosed after the age of 60. Patients were included if they had positive serology and histologic findings compatible with CD. Eligible patients were reinterviewed, and demographic, clinical, and laboratory information were recorded.
RESULTSDuring the study period, 7 patients with CD diagnosed after the age of 60 were identified. The most common presenting findings were weight loss, iron deficiency anemia, and diarrhea. Two patients suffered from severe early osteoperosis and 2 additional patients had elevated liver function tests. Neurologic manifestation was suspected in 3 cases. Two female patients presented with cognitive decline that was attributed to Alzheimer dementia but ameliorated after the initiation of gluten-free diet. The third patient had peripheral neuropathy that completely resolved after the initiation of gluten-free diet. Median lag in diagnosis was 8 years. Diet treatment led to complete resolution of symptoms in most cases and a significant weight gain (median 7.75 kg, range 5 to 11). One patient developed a fatal intestinal T-cell lymphoma.
CONCLUSIONSIn this case series, we have described several cases of CD in patients over the age of 60 with a varied spectrum of manifestations. We have also found a significant lag in diagnosis and treatment. We believe that it is important to promote the identification of CD as a possible culprit in varied clinical conditions in the elderly population.
The development of secondary lymphoid organs, such as lymph nodes (LNs), in the embryo results from the reciprocal action between lymphoid tissue inducer (LTi) cells and stromal cells. However, the ...initial events inducing LN anlagen formation before the LTi stromal cells cross-talk interactions take place are not fully elucidated. In this study, we show that the inguinal LN anlagen in mouse embryos developed from mesenchymal cells surrounding the lymph sacs, spherical structures of endothelial cells that bud from veins. Using inguinal and mesenteric LNs (mLNs), we provide evidence supporting a two-step maturation model for stromal cells: first, ICAM-1(-)VCAM-1(-) mesenchymal precursor cells become ICAM-1(int)VCAM-1(int) cells, in a process independent of LTi cells and lymphotoxin beta receptor (LTbetaR) signaling. The second step involves the maturation of ICAM-1(int)VCAM-1(int) cells to ICAM-1(high)VCAM-1(high) mucosal addressin cell adhesion molecule-1(+) organizer cells and depends on both LTi cells and LTbetaR. Addition of alphaLTbetaR agonist to LN organ cultures was sufficient to induce ICAM-1(int)VCAM-1(int) cells to mature. In LtbetaR(-/-) embryos, both inguinal and mLN stromal cells showed a block at the ICAM-1(int)VCAM-1(int) stage, and, contrary to inguinal LNs, mLNs persist longer and contained LTi cells, which correlated with the sustained gene expression of Il-7, Cxcl13, and, to a lesser degree, Ccl21. Taken together, these results highlight the importance of the signals and cellular interactions that induce the maturation of stromal cells and ultimately lead to the formation of lymphoid tissues.
Exclusive enteral nutrition EEN and corticosteroids CS induce similar rates of remission in mild to moderate paediatric Crohn's disease CD, but differ with regard to mucosal healing. Our goal was to ...evaluate if EEN at diagnosis was superior to CS for improving long-term outcomes.
We prospectively followed newly diagnosed children aged < 17 years, with mild to moderate CD at baseline, for 2 years in the GROWTH CD study. Patients were evaluated at baseline and at 8, 12, 78, and 104 weeks. Remission, relapses, complications fibrostenotic disease, penetrating disease, and active perianal disease and growth were recorded throughout the study. A propensity score analysis was performed.
A total of 147 children mean age 12.9 ± 3.2 years, treated by EEN n = 60 or CS n = 87 were included. New complications developed in 13.7% of CS 12/87 versus 11.6% of EEN 7/60, p = 0.29. Remission was achieved in 41/87 47% in CS and 38/60 63% EEN, p = 0.036. Median time to relapse did not differ 14.4 ± 1 months with CS, 16.05 ± 1.1 EEN, p = 0.28. Mean height Z scores decreased from Week 0 to Week 78 with CS -0.34 ± 1.1 to -0.51 ± 1.2, p = 0.01, but not with EEN -0.32 ± 1.1 to -0.22 ± 0.9, p = 0.56. In a propensity score analysis, EEN was superior to CS for inducing remission p = 0.05 and trended to superiority for height Z score p = 0.055.
Use of EEN was associated with higher remission rates and a trend toward better growth but with similar relapse and complication rates in new-onset mild to moderate paediatric CD.
The thymic medulla represents a key site for the induction of T cell tolerance. In particular, autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) provide a spectrum of ...tissue-restricted Ags that, through both direct presentation and cross-presentation by dendritic cells, purge the developing T cell repertoire of autoimmune specificities. Despite this role, the mechanisms of Aire(+) mTEC development remain unclear, particularly those stages that occur post-Aire expression and represent mTEC terminal differentiation. In this study, in mouse thymus, we analyze late-stage mTEC development in relation to the timing and requirements for Aire and involucrin expression, the latter a marker of terminally differentiated epithelium including Hassall's corpuscles. We show that Aire expression and terminal differentiation within the mTEC lineage are temporally separable events that are controlled by distinct mechanisms. We find that whereas mature thymocytes are not essential for Aire(+) mTEC development, use of an inducible ZAP70 transgenic mouse line--in which positive selection can be temporally controlled--demonstrates that the emergence of involucrin(+) mTECs critically depends upon the presence of mature single positive thymocytes. Finally, although initial formation of Aire(+) mTECs depends upon RANK signaling, continued mTEC development to the involucrin(+) stage maps to activation of the LTα-LTβR axis by mature thymocytes. Collectively, our results reveal further complexity in the mechanisms regulating thymus medulla development and highlight the role of distinct TNFRs in initial and terminal differentiation stages in mTECs.
Robust evaluation of induction therapies using both clinical and inflammatory outcomes in pediatric Crohn's disease (CD) are sparse. We attempted to evaluate clinical, inflammatory, and composite ...outcomes of induction of remission therapies (normal C reactive protein CRP remission) in a large pediatric prospective multicenter study.
Patients enrolled at diagnosis into the growth relapse and outcomes with therapy in Crohn's disease study were evaluated for disease activity, CRP, and fecal calprotectin at 8, 12 and 52 weeks after starting treatment. The primary endpoint was week-12 steroid-free remission defined by pediatric Crohn's disease activity index and CRP <0.5 mg/dL. The protocol required tapering off corticosteroids by week 11.
We analyzed 222 patients (mean age, 12.9 ± 3.2 yr) main evaluated treatment options included: 5-ASA (n = 29), exclusive enteral nutrition (n = 43), and corticosteroids (n = 114). Clinical remission at week 12 was achieved in 155 (73%) patients; both exclusive enteral nutrition and steroids were associated with normal CRP remission at week 12, although in a post hoc subgroup analysis exclusive enteral nutrition was superior in mild-to-moderate disease for this outcome. Among those in steroid-free remission in week 12, normal CRP predicted 1-year sustained remission (86% for normal CRP versus 61% for elevated CRP; P = 0.02). Baseline severity and early immunomodulation were similar in both groups.
Normal CRP steroid-free remission at week 12 was impacted by type of induction therapy, but not by early immunomodulation. It was associated with more corticosteroids-free remission at week 52 and a trend for less relapses.