51 research outputs found
Ferric maltol therapy for iron deficiency anaemia in patients with inflammatory bowel disease: long-term extension data from a Phase 3 study
Background Ferric maltol was effective and well-tolerated in iron deficiency anaemia patients with inflammatory bowel disease during a 12-week placebo-controlled trial. Aim To perform a Phase 3 extension study evaluating long-term efficacy and safety with ferric maltol in inflammatory bowel disease patients in whom oral ferrous therapies had failed to correct iron deficiency anaemia. Methods After 12 weeks of randomised, double-blind treatment, patients with iron deficiency anaemia and mild-to-moderate ulcerative colitis or Crohn's disease received open-label ferric maltol 30 mg b.d. for 52 weeks. Results 111 patients completed randomised treatment and 97 entered the open-label ferric maltol extension. In patients randomised to ferric maltol ('continued'; n = 50), mean +/- s.d. haemoglobin increased by 3.07 +/- 1.46 g/dL between baseline and Week 64. In patients randomised to placebo ('switch'; n = 47), haemoglobin increased by 2.19 +/- 1.61 g/dL. Normal haemoglobin was achieved in high proportions of both continued and switch patients (89% and 83% at Week 64, respectively). Serum ferritin increased from 8.9 lg/L (baseline) to 26.0 lg/L (Week 12) in ferric maltol-treated patients, and to 57.4 lg/L amongst all patients at Week 64. In total, 80% of patients reported = 1 adverse event by Week 64. Adverse events considered related to ferric maltol were recorded in 27/111 (24%) patients: 8/18 discontinuations due to adverse events were treatment-related. One patient was withdrawn due to increased ulcerative colitis activity. Conclusions Normal haemoglobin was observed in = 80% of patients from weeks 20-64 of long-term ferric maltol treatment, with concomitant increases in iron storage parameters. Ferric maltol was well-tolerated throughout this 64-week study
Ferric maltol is effective in correcting iron deficiency anemia in patients with inflammatory bowel disease: results from a phase-3 clinical trial program
BACKGROUND: Iron deficiency anemia (IDA) is frequently seen in inflammatory bowel disease. Traditionally, oral iron supplementation is linked to extensive gastrointestinal side effects and possible disease exacerbation. This multicenter phase-3 study tested the efficacy and safety of ferric maltol, a complex of ferric (Fe) iron with maltol (3-hydroxy-2-methyl-4-pyrone), as a novel oral iron therapy for IDA. METHODS: Adult patients with quiescent or mild-to-moderate ulcerative colitis or Crohn's disease, mild-to-moderate IDA (9.5-12.0 g/dL and 9.5-13.0 g/dL in females and males, respectively), and documented failure on previous oral ferrous products received oral ferric maltol capsules (30 mg twice a day) or identical placebo for 12 weeks according to a randomized, double-blind, placebo-controlled study design. The primary efficacy endpoint was change in hemoglobin (Hb) from baseline to week 12. Safety and tolerability were assessed. RESULTS: Of 329 patients screened, 128 received randomized therapy (64 ferric maltol-treated and 64 placebo-treated patients) and comprised the intent-to-treat efficacy analysis: 55 ferric maltol patients (86%) and 53 placebo patients (83%) completed the trial. Significant improvements in Hb were observed with ferric maltol versus placebo at weeks 4, 8, and 12: mean (SE) 1.04 (0.11) g/dL, 1.76 (0.15) g/dL, and 2.25 (0.19) g/dL, respectively (P < 0.0001 at all time-points; analysis of covariance). Hb was normalized in two-thirds of patients by week 12. The safety profile of ferric maltol was comparable with placebo, with no impact on inflammatory bowel disease severity. CONCLUSIONS: Ferric maltol provided rapid clinically meaningful improvements in Hb and showed a favorable safety profile, suggesting its possible use as an alternative to intravenous iron in IDA inflammatory bowel disease
Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells
Common variable immunodeficiency disorder (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by B-cell abnormalities and inadequate antibody response. CVID patients have considerable autoimmune comorbidity and we therefore hypothesized that genetic susceptibility to CVID may overlap with autoimmune disorders. Here, in the largest genetic study performed in CVID to date, we compare 778 CVID cases with 10, 999 controls across 123, 127 single-nucleotide polymorphisms (SNPs) on the Immunochip. We identify the first non-HLA genome-wide significant risk locus at CLEC16A (rs17806056, P = 2.0 x 10(-9)) and confirm the previously reported human leukocyte antigen (HLA) associations on chromosome 6p21 (rs1049225, P = 4.8 x 10(-16)). Clec16a knockdown (KD) mice showed reduced number of B cells and elevated IgM levels compared with controls, suggesting that CLEC16A may be involved in immune regulatory pathways of relevance to CVID. In conclusion, the CLEC16A associations in CVID represent the first robust evidence of non-HLA associations in this immunodeficiency condition
Influence of genetic variants on development and course of inflammatory bowel diseases
Kein wissenschaftliches Forschungsgebiet hat in den letzten Jahren einen
solchen Zugewinn an Informationen zu der Entstehung diverser Krankheiten
beigetragen wie die Molekulargenetik. Glücklicherweise trifft dies
insbesondere auf die chronisch entzündlichen Darmerkrankungen zu, wo im
Vergleich zu anderen Erkrankungen wie arterielle Hypertonie, Diabetes mellitus
Typ II sowie die rheumatoide Arthritis deutlich mehr Suszeptibilitätsgene
vermutet werden (241). Die Identifikation relevanter pathophysiologischer
Konzepte – Bakterienerkennung über das angeborene Immunsystem, Autophagie
sowie die Subpopulation der TH17-Lymphozyten – stellen einen wichtigen Beitrag
dar, hierauf aufbauende neue therapeutische Ansätze werden jedoch weiterhin
erwartet. Die individuelle Genotypisierung eines Patienten könnte jedoch zu
folgenden Zwecken verwendet werden: einerseits eine bessere Vorhersagbarkeit
des Krankheitsverlaufs mit hieran adaptierter Therapie sowie zudem Ansprechen
und Nebenwirkungen des ausgewählten Medikaments. Die gegenwärtige Diskussion
einer frühen und aggressiven Therapie beim M. Crohn ist auch dadurch
limitiert, dass wir keine relevanten Marker haben, die solche Patienten
eindeutig als aggressive Verlaufsform identifizieren. Bei der Vielzahl der
bislang bekannten genetischen Varianten der chronisch entzündlichen
Darmerkrankungen steht weiterhin die NOD2-Mutation im Vordergrund. Patienten
mit Mutationen im NOD2-Gen zeigen einen aggressiven Krankheitsverlauf. Es
kommt unabhängig vom Befall des terminalen Ileums im Verlauf häufig zu einer
Operation im Ileozökalbereich. Zudem weisen Merkmalsträger ein hohes
postoperatives Rezidivrisiko auf. Klinische Studien sollten somit eine
Genotypisierung für NOD2-Mutationen zur Subklassifizierung durchführen, um zu
klären, ob eine aggressivere Therapie – welcher Form auch immer –
gerechtfertigt ist. Einen solchen Zusammenhang zu einem bestimmten Phänotyp
ist bislang für keine andere Variante beschreiben worden. Dies gilt
insbesondere für die p.Arg381Gln-Variante im IL23R-Gen sowie p.Thr300Ala-
Variante innerhalb des ATG16L1-Gens. Möglicherweise müssen hier erst weitere
Varianten in TH17-Genen (JAK2, STAT3) sowie in Autophagie-Genen (IRGM)
untersucht werden, bevor ein definitiver Phänotyp identifiziert werden kann.
Zudem sind erste Varianten identifiziert worden, die einen Einfluss auf die
intestinale Barrierestörung beim M. Crohn haben könnten: erneut das NOD2-Gen
sowie das Myosin-IXb-Gen. Hier zeigen sich Assoziationen zu einer erhöhten
intestinalen Permeabilität in vivo. Ausgehend von der Hypothese, dass die
intestinale Barrierestörung entweder ein früher Entwicklungsprozess ist oder
nach Ausbrechen der Erkrankung das Rezidivrisiko erhöht, könnte die
Beeinflussung dieser beiden Signalwege ein therapeutischer Ansatz zur
Rezidivprophylaxe sein. Weitere CED-Gene – IL23R, ATG16L1, DLG5, CD14, TLR4,
CARD8 – scheinen jedoch keinen Einfluss auf die Barrierestörung haben. Von
besonderem Interesse sind die genauen Mechanismen, mit denen NOD2 und MYO9B
die intestinale Permeabilität erhöhen, diese sind jedoch weiterhin unbekannt.
Trotz dieser Fortschritte führt die unerwartet hohe Anzahl an genetischen
Varianten für chronisch entzündliche Darmerkrankungen an einen Scheideweg, der
über Sinn und Zweck der Genotypisierung entscheiden wird. Der gegenwärtige
Kenntnisstand reicht nicht aus, um eine Genotypisierung in Diagnostik oder
Therapie der chronisch entzündlichen Darmerkrankungen einzubeziehen. Dies wird
bislang nur zu wissenschaftlichen Zwecken durchgeführt. Hier sind zwingend
prospektive Studien notwendig, sonst wird der klinische Nutzen für Patienten
gering sein.Recent moleculargenetic studies have increased the number of putative genetic
variants to be involved in the pathophysiology of inflammatory bowel diseases
(IBD). This has highlighted new and unexpected pathways, such aus autophagy
and IL23-signalling for IBD development. One unsolved phenomenen in IBD is a
disturbed epithelial barrier function that is suggested to increase e.g.
bacterial antigen uptake and thus support chronic inflammation. From a
clinicians point of view, genotyping for specific variants should help to
improve diagnosis, predict disease behaviour and foresee response to medical
treatment. This would help to identify patients with severe disease behaviour
and improve therapy. Although numerous variants have been found so far, we
could show in different populations that mutations in the NOD2 gene are
assocaietd with an aggressive disease behaviour: early onset, ileocecal
resections early within the disease, and frequent surgical recurrence. Future
studies should therefore estimate whether aggressive treatment in patients
positive for NOD2 mutations would benefit from a more aggressive therapy. Such
a significant genotype phenotype correlation was not observed for any other of
the variants analysed in our studies, such as p.Arg381Gln within IL23R and
p.Thr300Ala within ATG16L1. In addition, we have showen that a frameshift
mutation within NOD2, p.Leu1007fs, is associated with an increased intestinal
permeability in Crohn’s disease. Furthermore, variants in the Myosin IXb gene
also increase the risk for an increased intestinal permeability. With respect
to many other variants in genes like IL23R, ATG16L1, DLG5, CD14, TLR4, CARD8,
no such association was observed. Despite these new and important findings, a
lot of work needs to be done to clearly define the phenotype relationship of
IBD genetics. Furthermore the molecular mechanism of how NOD2 and Myosin IXb
variants contribute to barrier dysfunction need to be identified
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