Anne Griffiths

SickKids, Toronto, Ontario, Canada

Are you Anne Griffiths?

Claim your profile

Publications (163)925.41 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: We aimed to explore the optimal dosing of intravenous-corticosteroids (IVCS) using a robust statistical method on the largest pediatric cohort of acute severe colitis (ASC) to date. Methods: 283 children treated with IVCS for ulcerative colitis were included and followed for 1 year (46% males, age 12.1 ± 3.9 years, disease duration 2 (IQR 0-14) months, baseline PUCAI 69 ± 13 points). Confounding by indication was addressed by matching high and low IVCS dose patients according to the propensity score (PS) method, using three cutoffs (1 mg/kg methylprednisolone to 40 mg/day, 1.25 mg/kg to 50 mg/day and 2 mg/kg to 80 mg/day). Results: The median IVCS dose in the entire cohort was 1.0 mg/kg (IQR 0.8-1.4) and 44 mg/day (32-60). 94/283 children were matched in the low-dose cutoff (1 mg/kg), 218/283 were matched in the middle cutoff (1.25 mg/kg), and 86/283 in the high dose cutoff (2 mg/kg). No differences were found in 25 pretreatment baseline variables in the three cutoffs, implying successful matching. There were no statistical differences in the outcomes of the two lower cutoffs (including need for salvage therapy during admission and by 1 years, admission duration, and day-5 PUCAI<35 points; all P > 0.05). In the high cutoff, the higher doses were somewhat better but this benefit reversed in a sensitivity analysis excluding one center. High doses were not associated with better outcome also in a PS-weighted regression model on the entire cohort. Conclusion: Our data support current guidelines that doses of IVCS higher than 1-1.5 mg/kg/d (maximum 40-60 mg/d) are not justified in ASC.
    No preview · Article · Jan 2016 · Journal of pediatric gastroenterology and nutrition
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: While family history provides important information on risk of developing Inflammatory Bowel Disease (IBD), genetic profiling of first degree relatives (FDR) of Crohn's Disease (CD) - affected individuals might provide additional information. We aimed to delineate the genetic contribution to the increased IBD susceptibility observed in FDR. Methods: N=976 Caucasian, healthy, non-related FDR; n=4997 independent CD and n=5000 healthy controls (HC); were studied. Genotyping for 158 IBD-associated single nucleotide polymorphisms (SNPs) was performed using the Illumina Immunochip. Risk allele frequency (RAF) differences between FDR and HC cohorts were correlated with those between CD and HC cohorts. CD and IBD genetic risk scores (GRS) were calculated and compared between HC, FDR and CD cohorts. Results: IBD-associated SNP RAF differences in FDR and HC cohorts were strongly correlated with those in CD and HC cohorts, correlation coefficient 0.63 [95%CI 0.53 - 0.72], p = 9.90 x 10(-19). There was a significant increase in CD-GRS (mean) comparing HC, FDR and CD cohorts: 0.0244, 0.0250 and 0.0257 respectively (p < 1 x 10(-7) for each comparison). There was no significant difference in the IBD-GRS between HC and FDR cohorts (p=0.81); however IBD-GRS was significantly higher in CD compared with FDR and HC cohorts (p < 10(-10) for each comparison). Conclusion: FDR of CD-affected individuals are enriched with IBD risk alleles compared with HC. Cumulative CD-specific genetic risk is increased in FDR compared with HC. Prospective studies are required to determine if genotyping would facilitate better risk stratification of FDR.
    No preview · Article · Oct 2015 · Journal of Crohn s and Colitis
  • Marialena Mouzaki · Anne Marie Griffiths

    No preview · Article · Apr 2015 · World review of nutrition and dietetics
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The Genetics, Environmental, Microbial Project is a multicenter study assessing etiological factors in Crohn's disease by studying healthy first-degree relatives (FDRs) of individuals affected by Crohn's disease. We aimed to evaluate the contribution of genetic, microbial, and environmental factors to the determination of intestinal permeability in healthy FDRs. IP was assessed using the lactulose-mannitol ratio (LacMan ratio). FDRs were genotyped for 167 inflammatory bowel disease-associated single nucleotide polymorphisms. Taxonomic profile of the fecal microbiota was determined by Illumina MiSeq pyrosequencing of 16S ribosomal RNA. The associations of LacMan ratio with demographic factors, inflammatory bowel disease-associated single nucleotide polymorphisms and the fecal microbiota were assessed. One hundred ninety-six white FDRs were included. Eleven percent of FDRs had an elevated LacMan ratio (≥0.03). A multivariate analysis demonstrated that younger subjects and nonsmokers had higher LacMan ratios, P = 3.62 × 10 and P = 0.03, respectively. The LacMan ratio was not significantly heritable, H2r, 0.13, P = 0.13. There was no association between any of the 167 inflammatory bowel disease-associated risk variants and LacMan ratio nor was there a correlation between fecal microbial composition and the LacMan ratio. We did not find LacMan ratio to be significantly heritable suggesting that the contribution of genetic factors to the determination of intestinal permeability in healthy FDRs is modest. Environmental factors, such as smoking, are likely more important determinants. The effect of age on intestinal barrier function has been underappreciated.
    Full-text · Article · Mar 2015 · Inflammatory Bowel Diseases
  • [Show abstract] [Hide abstract]
    ABSTRACT: Oral methotrexate (MTX) administration avoids weekly injections, reduces costs and may improve quality of life of patients with Crohn's disease (CD), especially children. Routes of administration have never been systematically compared in CD. We aimed to compare effectiveness and safety of orally (PO) versus subcutaneously (SC) administered MTX in paediatric CD. 226 children with CD treated with oral or subcutaneous MTX were included in a multicentre, retrospective 1-year cohort study (62% boys, mean age 13.8±2.8 years, 88% previous thiopurines). 38 (17%) were initially commenced on oral, 98 (43%) started subcutaneous and switched to oral and 90 (40%) were treated with subcutaneous only. Matching and 'doubly robust' weighted regression models were based on the propensity score method, controlling for confounding-by-indication bias. 11/23 pretreatment variables were different between the groups, but the propensity score modelling successfully balanced the treatment groups. 76 children (34%) had sustained steroid-free remission with a difference that did not reach significance between the PO and the SC groups (weighted OR=1.72 (95% CI 0.5 to 5.9); p=0.52). There were no differences in need for treatment escalation (p=0.24), elevated liver enzymes (p=0.59) or nausea (p=0.85). Height velocity was lower in the PO group (p=0.006) and time to remission was delayed in the PO group (p=0.036; Fleming (0, 1) test). In this largest paediatric CD cohort to date, SC administered MTX was superior to PO, but only in some of the outcomes and with a modest effect size. Therefore, it may be reasonable to consider switching children in complete remission treated with subcutaneous MTX to the oral route with close monitoring of inflammatory markers and growth. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    No preview · Article · Nov 2014 · Gut
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background In the treatment of Crohn's disease (CD), mucosal healing has become a major goal, with the hope of avoiding intestinal damage from chronic inflammation. Magnetic resonance enterography (MRE) has emerged as a non-invasive means of monitoring inflammation and damage.AimsAs part of the development of MRE-based multi-item measures of inflammation and damage for paediatric studies, we carried out a systematic review and meta-analysis to identify MRE variables used to describe these two distinct concepts.Methods2501 studies of MRI and CD were identified. Studies written in any language reporting individual MRE signs for patients diagnosed with CD were included. Two-hundred-and-forty-four studies were fully reviewed and 62 were included (inflammation, n = 51; damage, n = 24). Sensitivity, specificity and associated confidence intervals were calculated, and hierarchical summary ROC curves were constructed for each MRE sign.ResultsA total of 22 MRE signs were used to reflect inflammation, and 9 to reflect damage. Diagnostic accuracy of MRE signs of inflammation and damage was heterogeneous; however, wall enhancement, mucosal lesions and wall T2 hyperintensity were the most consistently useful for inflammation (most sensitivities >80% and specificities >90%), and detection of abscess and fistula were most consistently useful for damage (most sensitivities >90%, specificities >95%).Conclusions Identifying the best MRE variables to reflect inflammation and damage will maximise the utility of this rapidly emerging technique and is the first stage of constructing MRE-based indices for evaluating inflammation and intestinal damage.
    No preview · Article · Nov 2014 · Alimentary Pharmacology & Therapeutics
  • [Show abstract] [Hide abstract]
    ABSTRACT: Methotrexate (MTX) is an immunomodulator used in pediatric inflammatory bowel disease (IBD) maintenance regimens. However, MTX use is associated with liver toxicity. We aimed to systematically review and meta-analyze the incidence of hepatotoxicity with MTX use among children with IBD. We searched MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials databases from 1946 to April 2013 for cohort studies and collected information about the study design, IBD treatment results, and hepatotoxicity. Pooled proportions of toxicity with 95% confidence interval (CI) were estimated using a random-effects model. Twelve high-quality studies were included in this review. Fifty-seven of 457 patients treated with MTX developed varied degrees of abnormal liver biochemistry. The pooled proportion of patients with abnormal liver biochemistry was 10.2% (95% CI 5.4%-18.5%) across all studies included in the meta-analysis. Due to hepatotoxicity, dose reductions were required in 6.4% (95% CI 4.3%-9.5%), whereas 4.5% (95% CI 2.8%-7.2%) of patients required discontinuation. Hepatotoxicity after the use of MTX among IBD patients was a relatively common event. Monitoring for hepatotoxicity is strongly recommended, as discontinuation of MTX may be necessary in a significant proportion of children.
    No preview · Article · Nov 2013 · Inflammatory Bowel Diseases
  • [Show abstract] [Hide abstract]
    ABSTRACT: To assess infliximab pharmacokinetics in pediatric ulcerative colitis (UC). This phase 3, randomized, open-label multicenter study enrolled 60 children (6-17 yr) with moderate-to-severely active UC (Mayo score, 6-12; endoscopic subscore, ≥2), despite conventional therapy. Patients received infliximab 5-mg/kg induction infusions at weeks 0, 2, and 6. Week 8 clinical responders (n = 45) were randomized to infliximab 5 mg/kg given every (q) 8 weeks through week 46 or every 12 weeks (q12w) through week 42. Patients losing response during maintenance infliximab were eligible to increase the dose (5→10 mg/kg) and/or shorten the dosing interval (q12w→q8w). Blood samples were collected for infliximab concentration and pharmacokinetic determinations. Infliximab pharmacokinetics was not influenced by age (6-11 yr versus 12-17 yr), baseline immunomodulator use, or the extent of UC. At week 8, higher serum infliximab concentrations (≥41.1 μg/mL) were associated with greater proportions of patients achieving efficacy endpoints (clinical response, 92.9%; mucosal healing, 92.9%; and clinical remission, 64.3%) versus those with lower serum concentrations (<18.1 μg/mL; 53.9%, 53.9%, and 30.8%, respectively). At week 30, higher median trough serum infliximab concentrations were observed with infliximab 5 mg/kg q8w (1.9 μg/mL) versus q12w (0.8 μg/mL) and with infliximab 10 mg/kg (2.9 μg/mL) versus 5 mg/kg (1.1 μg/mL) among patients who are regimen adjusted. Infliximab pharmacokinetics/exposure-response relationship in patients with UC aged 6 to 17 years were generally comparable with those observed in reference adult UC populations, supporting using infliximab 5 mg/kg at weeks 0, 2, and 6 followed by maintenance dosing with 5 mg/kg q8w in these patients. A positive relationship was noted between serum infliximab level and clinical effect following induction therapy similar to adults.
    No preview · Article · Nov 2013 · Inflammatory Bowel Diseases
  • Anne M Griffiths
    [Show abstract] [Hide abstract]
    ABSTRACT: No single test is diagnostic of Crohn's disease (CD). In the presence of a compatible clinical presentation, diagnosis is by convention confirmed by a combination of imaging, serologic, endoscopic and histologic investigations. This diagnostic recommendation should be maintained, even though histology is often 'compatible with' rather than 'diagnostic of' suspected CD. The importance of histology varies depending on the specific sites of macroscopic disease. Histology is particularly important in distinguishing type of inflammatory bowel disease, when the colon predominantly is involved, and in confirming CD when macroscopic disease is atypically located. © 2013 S. Karger AG, Basel.
    No preview · Article · Sep 2013 · Digestive Diseases

  • No preview · Conference Paper · Jul 2013

  • No preview · Conference Paper · Jun 2013
  • [Show abstract] [Hide abstract]
    ABSTRACT: It has been suggested that IBD involves altered interactions between genetically determined immune responses to environmental challenges such as gut bacteria. In order to determine if composition of gut microbiotas are related to genes associated with risk for developing CD, we assessed the microbiome in a cohort of 578 FDR of CD patients enriched for the genetic variations associated with an increased risk of CD. The subjects were selected from the GEM Project cohort on the basis of their ethnicity. Bacterial DNA was extracted from stool samples using QIAamp DNA Stool Mini Kit and V1-V3 hypervariable regions of bacterial 16S rRNA genes were sequenced using 454 pyrosequencing. These sequences were treated using the QIIME pipeline and USEARCH. The operational taxonomic units (OTUs) obtained were assigned to taxonomic classification using the RDP 2.2 and Greengenes (Feb 2011) core sequences. We analyzed the relationship of OTU composition with 30 of the most common disease-associated polymorphisms (SNPs) genotyped using Sequenom Gold iPlex or TaqMan platforms. The data were rarefied 50 times at equal sampling depth and statistical tests were done using ANOVA with p-value False Discovery Rate corrected for multiple comparisons (36x104). A total of 3,377,987 reads were obtained with an average of 4,286 ± 72 reads per subject. Overall, the dominant genera in these samples were Bacteroidetes, Faecalibacterium and Roseburia (23.9%±0.9, 18.0% ± 0.6, 12.3% ± 0.4 of total OTUs, respectively). Differences in the microbiome makeup were associated with two interleukin 23 receptor (IL23R) SNPs, rs11209026 and rs11465804. Heterozygotes for rs11209026 (reduced risk for CD) were associated with higher proportions of Bacteroides, Odoribacter and lower proportions of Clostridium, Faecalibacterium, Lachnospira, and Subdoligranulum (with a range of p=10-8 to 0.02). Similar results were obtained with rs11465804. In addition, risk alleles of NOD2, rs2066844 and rs2066847, were associated with higher proportions of Gammaproteobacteria (p<0.04). The immunity-related GTPase family M (IRGM) rs13361189 risk allele was associated with a lower proportion of Bacteroidia and an increase of Erysipelotrichi (p<0.03). The toll-like receptor 4 (TLR4) risk allele rs4986790 was associated with a higher proportion of Streptococceace (p<0.05). These results indicate differences exist in the intestinal microbiota which are associated with SNPs in IL23R, IRGM, NOD2 and TLR4. These results from healthy FDR differ from prior studies of changes in microbiota in patients with CD, potentially indicating that genetic associations with microbiota may be difficult to evaluate in the context of established inflammation. Our results represent the largest study defining the association between differences in the microbiota and host CD risk alleles in asymptomatic individuals.
    No preview · Conference Paper · May 2013
  • Anne M Griffiths

    No preview · Article · May 2013 · Journal of pediatric gastroenterology and nutrition

  • No preview · Conference Paper · Mar 2013
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objectives: Despite a paucity of published supporting data, 5-aminosalicylate (5-ASA) use in pediatric ulcerative colitis (UC) is common. The present study describes the use and outcome of a large multicenter inception cohort of children with UC treated with 5-ASA. Methods: Data were obtained from the Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry, a prospective North American observational study of children newly diagnosed as having inflammatory bowel disease ages 16 years or younger. Patient data are recorded at diagnosis, 30 days, and then quarterly. Patients are managed by physician dictate, not protocol. Disease activity is classified by physician global assessment. The primary outcome examined was corticosteroid (CS) free, inactive UC at 1 year following initiation of 5-ASA within 30 days of diagnosis (with or without concomitant CS use) without the need for rescue therapy (immunomodulators, biologics, or colectomy). Results: Study subjects included 213 patients newly diagnosed as having UC who received oral 5-ASA compounds (115 of whom also received CS) during the first 30 days after diagnosis, and no other oral therapies for the treatment of UC. Of these 213 patients, 86 (40%) were CS free and physician global assessment inactive at 1 year without rescue. Outcome was not associated with disease severity at diagnosis, demographic or laboratory factors examined, or initial dose of 5-ASA used. Conclusions: Forty percent of children taking 5-ASA as primary maintenance therapy at diagnosis are in CS-free remission after 1 year of treatment. Further pediatric studies will be needed to address whether increased adherence and/or higher dosing schedules will improve outcomes.
    No preview · Article · Jul 2012 · Journal of pediatric gastroenterology and nutrition
  • [Show abstract] [Hide abstract]
    ABSTRACT: The IMAgINE 1 study (NCT00409682) evaluated the safety and efficacy of adalimumab double-blind maintenance dosing regimens following open-label induction for pediatric patients with moderate to severe Crohn's disease (CD). We studied 192 patients with Pediatric Crohn's Disease Activity Index (PCDAI) scores >30 for whom conventional treatment was unsuccessful. Patients received open-label induction therapy with subcutaneous adalimumab at weeks 0 and 2 (160 mg and 80 mg, or 80 mg and 40 mg, for body weight ≥40 kg or <40 kg). At week 4, 188 patients were assigned to groups based on achievement of clinical response (defined as decrease in PCDAI ≥15 points from baseline; 155/188 [82.4%]) and prior exposure to infliximab (82/188 [43.6%]). Groups were given double-blind maintenance therapy with adalimumab at high (40 mg or 20 mg for body weight ≥40 kg or <40 kg; n = 93) or low doses (20 mg or 10 mg for body weight ≥40 kg or <40 kg; n = 95) every other week for 48 weeks. Clinical remission (PCDAI ≤10) at week 26 (the primary end point) was compared between groups using the Cochran-Mantel-Haenszel test, adjusting for strata, with nonresponder imputation. Adverse events were monitored to evaluate safety. A total of 152 of 188 patients (80.9%) completed all 26 weeks of the study. At week 26, 63 patients (33.5%) were in clinical remission, with no significant difference between high- and low-dose groups (36/93 [38.7%] vs 27/95 [28.4%]; P = .075). No new safety signals were detected. Adalimumab induced and maintained clinical remission of children with CD, with a safety profile comparable to that of adult patients with CD. More children who received high compared with low dose were in remission at week 26, but the difference between dose groups was not statistically significant.
    No preview · Article · May 2012 · Gastroenterology
  • Mary E Sherlock · Anne M Griffiths
    [Show abstract] [Hide abstract]
    ABSTRACT: Pediatric inflammatory bowel disease encompasses a spectrum of disease phenotype, severity, and responsiveness to treatment. Intestinal healing rather than merely symptom control is an especially important therapeutic goal in young patients, given the potential for growth impairment as a direct effect of persistent chronic inflammation and the long life ahead, during which other disease complications may occur. Corticosteroids achieve rapid symptom control, but alternate steroid-sparing strategies with greater potential to heal the intestine must be rapidly adopted. Exclusive enteral nutrition is an alternate short-term treatment in pediatric Crohn's disease. The results of multi-center pediatric clinical trials of both infliximab and adalimumab in Crohn's disease and of infliximab in ulcerative colitis (all in children with unsatisfactory responses to other therapies) have now been reported and guide treatment regimens in clinical practice. Optimal patient selection and timing of anti-TNF therapy requires clinical judgment. Attention must be paid to sustaining responsiveness safely.
    No preview · Article · Apr 2012 · Current Gastroenterology Reports
  • [Show abstract] [Hide abstract]
    ABSTRACT: Budesonide (BUD) is being used in pediatric Crohn disease (CD) because it is believed to have the potential to reduce corticosteroid-related toxicity; however, few data are available describing its use. The aim of the present study was to describe BUD use in an inception cohort of pediatric patients with CD. Data were derived from the prospective Pediatric IBD Collaborative Research Group Registry established in 2002 in North America. Use of BUD in children with CD was examined. BUD was used in 119 of 932 (13%) of children with newly diagnosed CD, with 56 of 119 (47%) starting BUD ≤ 30 days of diagnosis (26/56 with ileum and/or ascending colon [IAC] disease). BUD was used as monotherapy (9%), in combination with 5-aminosalicylates (77%), or in combination with immunomodulators (43%). Forty-three percent (24/56) went on to receive conventional corticosteroid at some point following their first BUD course. For the 63 of 119 (53%) who started BUD beyond the diagnosis period, 51 of 63 (81%) also received prednisone, with BUD used as a means of weaning from prednisone in 17 of 63 (27%). Patients with IAC disease who received BUD ≤ 30 days of diagnosis were just as likely to have received conventional corticosteroids by 1 year as were those who did not receive BUD ≤ 30 days of diagnosis. Two-thirds (77/119) of patients received BUD for ≤ 6 months. BUD is being used among pediatric patients newly diagnosed as having CD, although the majority does not have disease limited to the IAC. BUD monotherapy was rare, and further data are required to better define the role of BUD in the treatment of pediatric CD.
    No preview · Article · Jan 2012 · Journal of pediatric gastroenterology and nutrition
  • Article: Reply.

    No preview · Article · Jan 2012 · The Journal of pediatrics
  • [Show abstract] [Hide abstract]
    ABSTRACT: We evaluated the efficacy and safety of infliximab for inducing and maintaining benefit in children with moderately to severely active ulcerative colitis (UC). Patients (6-17 years old) who had active UC (Mayo scores of 6-12; endoscopic subscores ≥ 2) and had not responded to or tolerated conventional treatment were given 5 mg/kg infliximab at weeks 0, 2, and 6. The primary end point was response at week 8 (decreases in Mayo scores ≥ 30% and ≥ 3 points and decreases in rectal bleeding subscores of ≥ 1 or an absolute subscore of ≤ 1). At week 8, only responders were randomly assigned to groups given infliximab every 8 or 12 weeks (q8w or q12w) and followed through week 54. Maintenance end points included pediatric UC activity index scores <10 points, defined as remission. At week 8, infliximab induced a response in 73.3% of patients (44 of 60) (95% confidence interval, 62.1%-84.5%; a positive result was defined by 95% confidence interval lower limit >40%). Among responders, twice as many were in remission at week 54 after q8w (8 of 21, 38.1%) than q12w (4 of 22, 18.2%; P = .146) therapy. Assuming the q8w remission rate for responders, the overall remission rate at week 54 would be 28.6%. Serious adverse events and infusion reactions occurred in similar proportions in the q8w and q12w groups. No deaths, malignancies, opportunistic infections, tuberculosis, or delayed hypersensitivity reactions were reported. Infliximab was safe and effective, inducing a response at week 8 in 73.3% of pediatric patients with moderate to severely active UC who did not respond to conventional therapy. The overall remission rate at week 54 for all enrolled patients was 28.6%, assuming the more effective q8w remission rate.
    No preview · Article · Dec 2011 · Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association

Publication Stats

9k Citations
925.41 Total Impact Points

Institutions

  • 1999-2015
    • SickKids
      • Division of Gastroenterology, Hepatology and Nutrition
      Toronto, Ontario, Canada
  • 1989-2014
    • University of Toronto
      • • Hospital for Sick Children
      • • Division of Gastroenterology
      • • Department of Paediatrics
      Toronto, Ontario, Canada
  • 2006-2009
    • The Children's Hospital of Philadelphia
      • Center for Applied Genomics
      Philadelphia, PA, United States
  • 2008
    • Royal Free London NHS Foundation Trust
      Londinium, England, United Kingdom
    • Mount Sinai Hospital, Toronto
      Toronto, Ontario, Canada