[show abstract][hide abstract] ABSTRACT: Pyoderma gangrenosum (PG) and erythema nodosum (EN) are the most common cutaneous manifestations of inflammatory bowel disease (IBD) but little is known regarding their etiopathogenesis.
We performed a case-control study comparing characteristics between IBD patients with a documented episode of PG (PG+) and/or EN (EN+) with those without PG (PG-) and EN (EN-). Data on clinical features were obtained by chart review. IBD-related serology was determined using enzyme-linked immunosorbent assay and genome-wide data generated using Illumina technology. Standard statistical tests for association were used.
We identified a total of 92 cases of PG and 103 cases of EN with genetic and clinical characteristics, of which 64 PG and 55 EN cases were available for serological analyses. Fewer male subjects were identified in the PG(+) (odds ratio 0.6, P = 0.009) and EN(+) groups (odds ratio 0.31, P = 0 < 0.0001). Colonic disease, previous IBD-related surgery, and noncutaneous extra-intestinal manifestations were more common among both PG(+) and EN(+) patients compared with controls. PG(+) was associated with anti-nuclear cytoplasmic antibody seropositivity (P = 0.03) and higher anti-nuclear cytoplasmic antibody level (P = 0.02) in Crohn's disease. Genetic associations with PG included known IBD loci (IL8RA [P = 0.00003] and PRDM1 [0.03]) as well as with USP15 (4.8 × 10) and TIMP3 (5.6 ×10). Genetic associations with EN included known IBD susceptibility genes (PTGER4 [P = 8.8 × 10], ITGAL [0.03]) as well as SOCS5 (9.64 × 10), CD207 (3.14 × 10), ITGB3 (7.56 × 10), and rs6828740 (4q26) (P < 5.0 × 10). Multivariable models using clinical, serologic, and genetic parameters predicted PG (area under the curve = 0.8) and EN (area under the curve = 0.97).
Cutaneous manifestations in IBD are associated with distinctive genetic characteristics and with the similar clinical characteristics, including the development of other extra-intestinal manifestations suggesting shared and distinct etiologies.
[show abstract][hide abstract] ABSTRACT: Genetic susceptibility loci for Crohn's disease (CD) are numerous, complex, and likely interact with undefined components of the environment. It has been a challenge to link the effects of particular loci to phenotypes of cells associated with pathogenesis of CD, such as Paneth cells. We investigated whether specific phenotypes of Paneth cells associated with particular genetic susceptibility loci can be used to define specific subtypes of CD.
We performed a retrospective analysis of 119 resection specimens collected from patients with CD at 2 separate medical centers. Paneth cell phenotypes were classified as normal or abnormal (with disordered, diminished, diffuse, or excluded granule phenotypes) based on lysozyme-positive secretory granule morphology. To uncover the molecular basis of the Paneth cell phenotypes, we developed methods to determine transcriptional profiles from whole-thickness and laser-capture microdissected, formalin-fixed, paraffin-embedded tissue sections.
The proportion of abnormal Paneth cells was associated with the number of CD-associated NOD2 risk alleles. The cumulative number of NOD2 and ATG16L1 risk alleles had an additive effect on the proportion of abnormal Paneth cells. Unsupervised clustering analysis of demographic and Paneth cell data divided patients into 2 principal subgroups, defined by high and low proportions of abnormal Paneth cells. The disordered and diffuse abnormal Paneth cell phenotypes were associated with an altered transcriptional signature of immune system activation. We observed an inverse correlation between abnormal Paneth cells and the presence of granuloma. Moreover, high proportions of abnormal Paneth cells were associated with shorter time to disease recurrence after surgery.
Histologic analysis of Paneth cell phenotypes can be used to divide patients with CD into subgroups with distinct pathognomonic and clinical features.
[show abstract][hide abstract] ABSTRACT: BACKGROUND:: The ability to identify patients with Crohn's disease (CD) at highest risk of surgery would be invaluable in guiding therapy. Genome-wide association studies have identified multiple IBD loci with unknown phenotypic consequences. The aims of this study were to: (1) identify associations between known and novel CD loci with early resective CD surgery and (2) develop the best predictive model for time to surgery using a combination of phenotypic, serologic, and genetic variables. METHODS:: Genotyping was performed on 1,115 subjects using Illumina-based genome-wide technology. Univariate and multivariate analyses tested genetic associations with need for surgery within 5 years. Analyses were performed by testing known CD loci (n = 71) and by performing a genome-wide association study. Time to surgery was analyzed using Cox regression modeling. Clinical and serologic variables were included along with genotype to build predictive models for time to surgery. RESULTS:: Surgery occurred within 5 years in 239 subjects at a median time of 12 months. Three CD susceptibility loci were independently associated with surgery within 5 years (IL12B, IL23R, and C11orf30). Genome-wide association identified novel putative loci associated with early surgery: 7q21 (CACNA2D1) and 9q34 (RXRA, COL5A1). The most predictive models of time to surgery included genetic and clinical risk factors. More than a 20% difference in frequency of progression to surgery was seen between the lowest and highest risk groups. CONCLUSIONS:: Progression to surgery is faster in patients with CD with both genetic and clinical risk factors. IL12B is independently associated with need and time to early surgery in CD patients and justifies the investigation of novel and existing therapies that affect this pathway.
[show abstract][hide abstract] ABSTRACT: TL1A/TNFSF15 has been associated with IBD (inflammatory bowel disease) in GWAS (genome-wide association study) and plays a role mediating mucosal inflammation in IBD. Higher TL1A expression is associated with disease severity in both patients and mouse models. Although TL1A has been studied extensively for IBD-associated SNPs, the cis/trans-regulatory regions are poorly defined. Herein we identify response elements regulating TNFSF15 in primary human myeloid cells. Peripheral mononuclear cells transfected with TNFSF15 promoter constructs displayed 30-fold enhanced promoter activity in a minimal -74bp region. Transactivation was mediated partly by AP-1, since mutation of the AP-1 site resulting in loss of promoter activity. Monocytes transfected with c-Jun siRNA or treated with TAT-TI-JIP (JNK Inhibitor VII TAT-TI-JIP) demonstrated reduced TL1A mRNA and protein levels. Surprisingly, constructs larger than -74bp did not increase promoter expression (expression of -1275bp construct was 25% of -74bp activity), suggesting the presence of both activating and repressing TL1A promoter elements. In fact, mutation of the -210bp NFκB site enhanced promoter activity (60-fold) suggesting a repressive role for this site. DNA-protein binding to the TL1A AP-1 and NFκB elements was inhibited by excess consensus or TL1A oligonucleotides and binding and confirmed by chromatin immuno-precipitation analysis. Yet, despite the fact that the -210bp NFκB site acts as a suppressor element, overall mRNA and protein expression were inhibited in monocytes treated with MG132 (NFκB/proteasome inhibitor) or SN50 (NFκB-p50 blocking peptide), suggesting that NFκB acts as both an activator and silencer of TL1A expression. These data suggest that modulation of TL1A expression involves a complex interplay between positive and negative signals, binding to distinct regulatory regions.
[show abstract][hide abstract] ABSTRACT: Clostridium difficile infection (CDI) is a common and debilitating nosocomial infection with high morbidity and mortality. C. difficile mediates diarrhea and colitis by releasing two toxins, toxin A and toxin B. Since both toxins stimulate proinflammatory signaling pathways in human colonocytes and both are involved in the pathophysiology of CDI, neutralization of toxin A and B activities may represent an important therapeutic approach against CDI infection. Recent studies indicate that human monoclonal antibodies (mAbs) against toxin A and B reduced their cytotoxic and secretory activities, and prevented CDI in hamsters. Moreover, anti-toxin A and anti-toxin B mAbs together with antibiotics also effectively reduced recurrent CDI in humans. However, whether these mAbs neutralize toxin A- and toxin B-associated immune responses in human colonic mucosa or human peripheral blood monocytes (PBMCs) has never been examined. We used fresh human colonic biopsies and peripheral blood monocytes to evaluate the effects of these antibodies against toxin A- and B-associated cytokine release, proinflammatory signaling and histologic damage. Incubation of anti-toxin A (MK3415) or anti-toxin B (MK6072) mAbs with human PBMCs significantly inhibited toxin A- and toxin B-mediated TNFα and IL-1β expression. MK3415 and MK6072 also diminished toxin A- and toxin B- mediated NF-κB p65 phosphorylation in human monocytes, respectively and significantly reduced toxin A- and B- induced TNFα and IL-1β expression as well as histological damage in human colonic explants. Our results underline the effectiveness of MK3415 and MK6072 in blocking C. difficile toxin A- and toxin B-mediated inflammatory responses and histological damage.
Antimicrobial Agents and Chemotherapy 04/2013; · 4.57 Impact Factor
[show abstract][hide abstract] ABSTRACT: TL1A is a member of the TNF superfamily, and its expression is increased in the mucosa of inflammatory bowel disease patients. Moreover, patients with certain TNFSF15 variants over-express TL1A and have a higher risk of developing strictures in the small intestine. Consistently, mice with sustained Tl1a expression in either lymphoid or myeloid cells develop spontaneous ileitis and increased intestinal collagen deposition. Transgenic (Tg) mice with constitutive Tl1a expression in both lymphoid and myeloid cells were generated to assess their in vivo consequence. Constitutive expression of Tl1a in both lymphoid and myeloid cells showed increased spontaneous ileitis and collagen deposition than WT mice. T cells with constitutive expression of Tl1a in both lymphoid and myeloid cells were found to have a more activated phenotype, increased gut homing marker CCR9 expression, and enhanced Th1 and Th17 cytokine activity than WT mice. Although no differences in T cell activation marker, Th1 or Th17 cytokine activity, ileitis, or collagen deposition were found between constitutive Tl1a expression in lymphoid only, myeloid only, or combined lymphoid and myeloid cells. Double hemizygous Tl1a-Tg mice appeared to have worsened ileitis and intestinal fibrosis. Our findings confirm that TL1A-DR3 interaction is involved in T cell-dependent ileitis and fibrosis.
European journal of microbiology & immunology. 03/2013; 3(1):11-20.
[show abstract][hide abstract] ABSTRACT: Ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) share genetic and clinical features. IBD is associated with the presence of antibodies to a variety of commensal microorganisms including anti-Saccharomyces cerevesiae antibodies (ASCA), antineutrophil cytoplasmic antibodies (ANCA), anti-I2 (associated with anti-Pseudomonas activity), anti-Eschericia coli outer membrane porin C (anti-OmpC) and anti-flagellin antibodies (anti-CBir1). Subclinical intestinal inflammation may be present in up to 65% of patients with AS. This study evaluated the presence of antimicrobial antibodies in patients with AS alone, patients with AS and concomitant IBD (AS-IBD) and a control group of patients with mechanical back pain (MBP).
Sera were tested by ELISA for ASCA IgG and IgA, anti-OmpC, anti-CBir1 and ANCA in 76 patients with AS alone, 77 patients with AS-IBD and 48 patients with MBP. Antibody positivity rates, median quantitative antibody levels and the proportion of patients with antibody levels in the 4th quartile of a normal distribution were compared between the three groups of patients.
Patients with AS alone demonstrated higher anti-CBir1 antibody positivity rates and median antibody levels than MBP patients. Anti-CBir1 positivity in AS was associated with elevation of acute phase reactants. AS-IBD patients demonstrated elevated responses when compared to AS alone for ASCA, anti-OmpC and anti-CBir1. Quartile analysis confirmed the findings.
These data suggest that adaptive immune responses to microbial antigens occur in AS patients without clinical IBD and support the theory of mucosal dysregulation as a mechanism underlying the pathophysiology of AS.
Arthritis research & therapy 01/2013; 15(5):R166. · 4.27 Impact Factor
[show abstract][hide abstract] ABSTRACT: : Extracts of the plant Andrographis paniculata have been used to treat inflammatory diseases in Asian countries. A recent double-blind, placebo-controlled trial of HMPL-004 (A. paniculata extract) has demonstrated its safety and effectiveness for induction of clinical response, remission, and mucosal healing in patients with mild to moderate ulcerative colitis (UC). We aimed to determine if HMPL-004 could prevent the development of T-cell-dependent murine colitis and to define its in vivo mechanism(s) of action.
: CD4CD45RB T cells were transferred into Rag1 mice and gavaged daily with HMPL-004 or methyl cellulose (MC). Severity of colitis was evaluated by weight loss, histology, and cytokine expression.
: Mice treated with MC developed colitis within 4-7 weeks, as evaluated by weight loss, and severe intestinal inflammation. HMPL-004-treated mice did not lose weight and displayed only very mild intestinal inflammation. Tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, interferon-gamma (IFN-γ), and IL-22 expression were significantly decreased in HMPL-004-treated mice. We observed higher percentages of naïve CD4 T cells in the lamina propria of HMPL-004-treated mice. At early timepoints HMPL-004-treated mice have significantly reduced splenic cell counts, reduced CD4, and IL-17, and IFN-γ T cells. Furthermore, HMPL-004 inhibited the proliferation of CD4 T cells and differentiation into TH1/TH17 cells in vitro.
: HMPL-004 inhibits the development of chronic colitis by affecting early T-cell proliferation, differentiation, and TH1/TH17 responses in a T-cell-driven model of colitis, presenting a unique mechanism of action. Our data suggest that HMPL-004 could be an attractive herbal therapeutic for inflammatory bowel disease.
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Current instruments used to measure disease activity and health-related quality of life in patients with Crohn's disease (CD) and ulcerative colitis (UC) are often cumbersome, time-consuming, and expensive; although used in clinical trials, they are not convenient for clinical practice. A numeric rating scale (NRS) is a quick, inexpensive, and convenient patient-reported outcome that can capture the patient's overall perception of health. AIMS: The aim of this study was to assess the validity, reliability, and responsiveness of an NRS and evaluate its use in clinical practice in patients with CD and UC. METHODS: We prospectively evaluated patient-reported NRS scores and measured correlations between NRS and a range of severity measures, including physician-reported NRS, Crohn's disease activity index (CDAI), Harvey-Bradshaw index (HBI), inflammatory bowel disease questionnaire (IBDQ), and C-reactive protein (CRP) in patients with CD. Subsequently, we evaluated the correlation between the NRS and standard measures of health status (HBI or simple colitis clinical activity index [SCCAI]) and laboratory tests (sedimentation rate [ESR], CRP, and fecal calprotectin) in patients with CD and UC. RESULTS: The patient-reported NRS showed excellent correlation with CDAI (R (2) = 0.59, p < 0.0001), IBDQ (R (2) = 0.66, p < 0.0001), and HBI (R (2) = 0.32, p < 0.0001) in patients with CD. The NRS showed poor, but statistically significant correlation with SCCAI (R (2) = 0.25, p < 0.0001) in patients with UC. The NRS did not correlate with CRP, ESR, or calprotectin. The NRS was reliable and responsive to change. CONCLUSIONS: The NRS is a valid, reliable, and responsive measure that may be useful to evaluate patients with CD and possibly UC.
Digestive Diseases and Sciences 12/2012; · 2.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: INTRODUCTION: Inflammatory bowel disease (IBD) and ankylosing spondylitis (AS) are similar chronic inflammatory diseases whose definitive etiology is unknown. Following recent clinical and genetic evidence supporting an intertwined pathogenic relationship, we conducted a pilot study to measure fecal Calprotectin (fCAL) and IBD related serologies in AS patients. METHODS: Consecutive AS patients were recruited from a long term prospectively collected longitudinal AS cohort at Cedars-Sinai Medical Center (CSMC). Controls were recruited from CSMC employees or spouses of patients with AS. Sera were tested by enzyme-linked immunosorbent assay (ELISA) for IBD-associated serologies (antineutrophil cytoplasmic antibodies (ANCA), anti-Saccharomyces cerevisiae antibody (ASCA) IgG and IgA, Anti-I2, Anti-OmpC, and Anti-CBir1). The Bath ankylosing spondylitis disease activity index (BASDAI), Bath ankylosing spondylitis functional index (BASFI), and Bath ankylosing spondylitis radiology index (BASRI) were completed for AS patients. RESULTS: A total of 81 subjects (39 AS and 42 controls) were included for analysis. Average age of AS patients was 47 years and average disease duration was 22 years. AS patients were predominantly male; 76% were HLA-B27 positive. Median fCAL levels were 42micrograms/g and 17micrograms/g in the AS group and controls, respectively (p < 0.001). When using the manufacturer's recommended cut off for positivity of 50micrograms/g, stool samples of 41% of AS patients and 10% of controls were positive for fCAL (p = 0.0016). With the exception of ANCA, there were no significant differences in antibody levels between patients and controls. Median ANCA EU was 6.9 in AS patients and 4.3 in the controls. Among AS patients stratified by fCAL level, there were statistically significant differences between patients and controls for multiple IBD associated antibodies. CONCLUSIONS: Calprotectin levels were elevated in 41% of patients with AS with a cut off for positivity of 50micrograms/g. fCAL positive AS patients displayed higher medians of most IBD specific antibodies when compared to healthy controls or fCAL negative AS patients. Further studies are needed to determine if fCAL can be used to identify and characterize a subgroup of AS patients whose disease might be driven by subclinical bowel inflammation.
Arthritis research & therapy 11/2012; 14(6):R261. · 4.27 Impact Factor
[show abstract][hide abstract] ABSTRACT: The transcription factor B lymphocyte-induced maturation protein-1 (Blimp-1) plays important roles in embryonic development and immunity. Blimp-1 is required for the differentiation of plasma cells, and mice with T cell-specific deletion of Blimp-1 (Blimp-1CKO mice) develop a fatal inflammatory response in the colon. Previous work demonstrated that lack of Blimp-1 in CD4(+) and CD8(+) T cells leads to intrinsic functional defects, but little is known about the functional role of Blimp-1 in regulating differentiation of Th cells in vivo and their contribution to the chronic intestinal inflammation observed in the Blimp1CKO mice. In this study, we show that Blimp-1 is required to restrain the production of the inflammatory cytokine IL-17 by Th cells in vivo. Blimp-1CKO mice have greater numbers of IL-17-producing TCRβ(+)CD4(+)cells in lymphoid organs and in the intestinal mucosa. The increase in IL-17-producing cells was not restored to normal levels in wild-type and Blimp-1CKO-mixed bone marrow chimeric mice, suggesting an intrinsic role for Blimp-1 in constraining the production of IL-17 in vivo. The observation that Blimp-1-deficient CD4(+) T cells are more prone to differentiate into IL-17(+)/IFN-γ(+) cells and cause severe colitis when transferred to Rag1-deficient mice provides further evidence that Blimp-1 represses IL-17 production. Analysis of Blimp-1 expression at the single cell level during Th differentiation reveals that Blimp-1 expression is induced in Th1 and Th2 but repressed by TGF-β in Th17 cells. Collectively, the results described here establish a new role for Blimp-1 in regulating IL-17 production in vivo.
The Journal of Immunology 11/2012; · 5.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.
[show abstract][hide abstract] ABSTRACT: In patients with Crohn's disease, the efficacy of ustekinumab, a human monoclonal antibody against interleukin-12 and interleukin-23, is unknown.
We evaluated ustekinumab in adults with moderate-to-severe Crohn's disease that was resistant to anti-tumor necrosis factor (TNF) treatment. During induction, 526 patients were randomly assigned to receive intravenous ustekinumab (at a dose of 1, 3, or 6 mg per kilogram of body weight) or placebo at week 0. During the maintenance phase, 145 patients who had a response to ustekinumab at 6 weeks underwent a second randomization to receive subcutaneous injections of ustekinumab (90 mg) or placebo at weeks 8 and 16. The primary end point was a clinical response at 6 weeks.
The proportions of patients who reached the primary end point were 36.6%, 34.1%, and 39.7% for 1, 3, and 6 mg of ustekinumab per kilogram, respectively, as compared with 23.5% for placebo (P=0.005 for the comparison with the 6-mg group). The rate of clinical remission with the 6-mg dose did not differ significantly from the rate with placebo at 6 weeks. Maintenance therapy with ustekinumab, as compared with placebo, resulted in significantly increased rates of clinical remission (41.7% vs. 27.4%, P=0.03) and response (69.4% vs. 42.5%, P<0.001) at 22 weeks. Serious infections occurred in 7 patients (6 receiving ustekinumab) during induction and 11 patients (4 receiving ustekinumab) during maintenance. Basal-cell carcinoma developed in 1 patient receiving ustekinumab.
Patients with moderate-to-severe Crohn's disease that was resistant to TNF antagonists had an increased rate of response to induction with ustekinumab, as compared with placebo. Patients with an initial response to ustekinumab had significantly increased rates of response and remission with ustekinumab as maintenance therapy. (Funded by Janssen Research and Development; CERTIFI ClinicalTrials.gov number, NCT00771667.).
New England Journal of Medicine 10/2012; 367(16):1519-28. · 51.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: OBJECTIVES:Andrographis paniculata has in vitro inhibitory activity against TNF-α, IL-1β and NF-κB. A pilot study of A. paniculata extract (HMPL-004) suggested similar efficacy to mesalamine for ulcerative colitis.METHODS:A randomized, double-blind, placebo-controlled trial evaluated the efficacy of A. paniculata extract (HMPL-004) in 224 adults with mild-to-moderate ulcerative colitis. Patients were randomized to A. paniculata extract (HMPL-004) 1,200 mg or 1,800 mg daily or placebo for 8 weeks.RESULTS:In total, 45 and 60% of patients receiving A. paniculata 1,200 mg and 1,800 mg daily, respectively, were in clinical response at week 8, compared with 40% of those who received placebo (P=0.5924 for 1,200 mg vs. placebo and P=0.0183 for 1,800 mg vs. placebo). In all, 34 and 38% of patients receiving A. paniculata 1,200 mg and 1,800 mg daily, respectively, were in clinical remission at week 8, compared with 25% of those who received placebo (P=0.2582 for 1,200 mg vs. placebo and P=0.1011 for 1,800 mg vs. placebo). Adverse events developed in 60 and 53% of patients in the A. paniculata 1,200 mg and 1,800 mg daily groups, respectively, and 60% in the placebo group.CONCLUSIONS:Patients with mildly to moderately active ulcerative colitis treated with A. paniculata extract (HMPL-004) at a dose of 1,800 mg daily were more likely to achieve clinical response than those receiving placebo.Am J Gastroenterol advance online publication, 9 October 2012; doi:10.1038/ajg.2012.340.
The American Journal of Gastroenterology 10/2012; · 7.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: Mercaptopurine and azathioprine (AZA) are efficacious in treating IBD. 6-tioguanine (6-TGN) levels correlate with therapeutic efficacy, whereas high 6-methylmercaptopurine (6-MMP) levels are associated with hepatotoxicity and myelotoxicity. Some IBD patients exhibit dose-limiting preferential 6-MMP production, which may lead to undesired side effects and impact efficacy.
To review the outcomes of thiopurine split-dosing in patients with preferential 6-MMP metabolism.
A retrospective chart review of 179 IBD patients treated at the Cedars-Sinai IBD Center with AZA or mercaptopurine was performed. Preferential 6-MMP metabolisers with 6-MMP levels greater than 7000 pmol/8 × 10(8) erythrocytes who underwent split-dosing were identified and assessed for biochemical and clinical responses to these dose modifications.
A total of 20 of 179 patients met the criteria for preferential 6-MMP metabolism and underwent thiopurine split-dosing. Dividing the total daily thiopurine dose led to a reduction in 6-MMP levels (11785 vs. 5324 pmol/8 × 10(8) erythrocytes; P < 0.0001) without negatively affecting clinical disease activity or 6-TGN levels (239 vs. 216 pmol/8 × 10(8) erythrocytes; P = N.S.) and led to resolution of 6-MMP associated side effects (elevated transaminases, leucopenia and flu-like symptoms) in all but two patients. After mean follow-up of 36 months, 12 patients remained in clinical remission on split-dose mercaptopurine. Five of the remaining eight patients escalated to anti-TNF therapy, two progressed to surgery, and one switched to tioguanine therapy.
Split-dose administration of mercaptopurine/AZA represents an alternative option in IBD patients with preferential 6-MMP metabolism who might otherwise require steroid exposure or escalation of therapy.
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Clostridium difficile mediates intestinal inflammation by releasing toxin A (TxA), a potent enterotoxin. Cathelicidins (Camp as gene name, LL-37 peptide in humans and mCRAMP peptide in mice) are antibacterial peptides that also posses anti-inflammatory properties. OBJECTIVES: To determine the role of cathelicidins in models of Clostridium difficile infection and TxA-mediated ileal inflammation and cultured human primary monocytes. DESIGN: Wild-type (WT) and mCRAMP-deficient (Camp(-/-)) mice were treated with an antibiotic mixture and infected orally with C difficile. Some mice were intracolonically given mCRAMP daily for 3 days. Ileal loops were also prepared in WT mice and treated with either saline or TxA and incubated for 4 h, while some TxA-treated loops were injected with mCRAMP. RESULTS: Intracolonic mCRAMP administration to C difficile-infected WT mice showed significantly reduced colonic histology damage, apoptosis, tissue myeloperoxidase (MPO) and tumour necrosis factor (TNF)α levels. Ileal mCRAMP treatment also significantly reduced histology damage, tissue apoptosis, MPO and TNFα levels in TxA-exposed ileal loops. WT and Camp(-/-) mice exhibited similar intestinal responses in both models, implying that C difficile/TxA-induced endogenous cathelicidin may be insufficient to modulate C difficile/TxA-mediated intestinal inflammation. Both LL-37 and mCRAMP also significantly reduced TxA-induced TNFα secretion via inhibition of NF-κB phosphorylation. Endogenous cathelicidin failed to control C difficile and/or toxin A-mediated inflammation and even intestinal cathelicidin expression was increased in humans and mice. CONCLUSION: Exogenous cathelicidin modulates C difficile colitis by inhibiting TxA-associated intestinal inflammation. Cathelicidin administration may be a new anti-inflammatory treatment for C difficile toxin-associated disease.
[show abstract][hide abstract] ABSTRACT: Steroids, immunomodulators, and biologics, often in combination with one another, are frequently used in the treatment of Crohn's disease. Retrospective studies have yielded conflicting results regarding the influence of preoperative immunosuppressive therapy on postoperative complications after surgery in Crohn's disease. Unplanned hospital readmission is considered to be an index of quality surgical care.
The aim of this study was to examine the association, if any, between the number of preoperative immunosuppressive therapies and unplanned hospital readmission after surgery in patients with Crohn's disease.
Consecutive patients with Crohn's disease requiring abdominal surgery were identified from a prospectively maintained database. Preoperative immunosuppressive therapy within 3 months before surgery was categorized into 3 classes: steroids, immunomodulators, and biologics.
Unplanned readmission occurring within 30 days of hospital discharge was assessed. Trend analysis was performed with the use of the Cochrane-Armitage test.
The study group included 338 patients. Preoperative medical therapy included steroids (n = 199; 59%), immunomodulators (n = 162; 48%), and biologics (n = 59; 18%). Sixty-three patients (19%) were not treated with any immunosuppressive medications preoperatively, whereas 148 patients (44%), 108 patients (32%), and 19 patients (6%) were treated with 1, 2, or 3 classes of immunosuppressive medications. Twenty-eight patients (8.3%) had an unplanned readmission. The incidence of unplanned readmission was similar among patients treated with steroids (11%), immunomodulators (9%), and biologics (12%). The incidence of unplanned readmission was 3%, 7%, 11%, and 16% in patients treated with 0, 1, 2, or 3 preoperative medication classes (trend analysis p = 0.02). No significant differences were observed between patient groups treated with 0, 1, 2, or 3 preoperative immunosuppressive therapies with respect to patient, disease, or surgical factors.
Unplanned hospital readmission occurs frequently (8.3%) after surgery for Crohn's disease. Combination immunosuppressive therapy before surgery in patients with Crohn's disease appears to be associated with an increased incidence of postoperative unplanned hospital readmission.
Diseases of the Colon & Rectum 05/2012; 55(5):563-8. · 3.34 Impact Factor
[show abstract][hide abstract] ABSTRACT: The efficacy of abatacept, a selective costimulation modulator, in Crohn's disease (CD) and ulcerative colitis (UC) is unknown.
Four placebo-controlled trials evaluated the efficacy and safety of abatacept as induction (IP) and maintenance (MP) therapy in adults with active, moderate-to-severe CD (CD-IP; CD-MP) and UC (UC-IP1; UC-MP). In CD-IP and UC-IP1, 451 patients with CD and 490 patients with UC were randomized to abatacept 30, 10, or 3 mg/kg (according to body weight) or placebo, and dosed at weeks 0, 2, 4, and 8. In MP, 90 patients with CD and 131 patients with UC who responded to abatacept at week 12 in the induction trials were randomized to abatacept 10 mg/kg or placebo every 4 weeks through week 52.
In CD-IP, 17.2%, 10.2%, and 15.5% of patients receiving abatacept 30, 10, and 3 mg/kg achieved a clinical response at weeks 8 and 12, vs 14.4% receiving placebo (P = .611, P = .311, and P = .812, respectively). In UC-IP1, 21.4%, 19.0%, and 20.3% of patients receiving abatacept 30, 10, and 3 mg/kg achieved a clinical response at week 12, vs 29.5% receiving placebo (P = .124, P = .043, and P = .158, respectively). In CD-MP, 23.8% vs 11.1% of abatacept vs placebo patients were in remission at week 52. In UC-MP, 12.5% vs 14.1% of patients receiving abatacept vs placebo were in remission at week 52. Safety generally was comparable between groups.
The studies showed that abatacept is not efficacious for the treatment of moderate-to-severe CD or UC.