1. RESEARCH POSTER PRESENTATION DESIGN © 2012
www.PosterPresentations.com
Crohn’s disease (CD) is an inflammatory bowel disease that is
characterized by intestinal inflammation, specifically the colon and ileum.
Additional symptoms of this disease include abdominal pain, bloody diarrhea,
fever and weight loss.1
The cause behind CD is currently unknown but, studies have attributed
genetic and environmental factors, as well as inappropriate immune responses.3
In CD, the intestinal epithelial breaks down, resulting in failure to clear
the infections and have bowel luminal contents that gain access to underlying
tissues. Macrophages are triggered to secrete cytokines to activate; this can
induce lymphocyte activation and chronic inflammation seen in CD lesions.4
Toll-like receptors (TLR) on the cell membrane bind to pathogenic
components. The ligation of these TLRs activates signaling pathways that
activate NF-κB and mitogen-activated protein kinases.
This stimulates the expression of pro-inflammatory and anti-
inflammatory genes. In CD, the TH1 pathway is converted to a TH17 pathway
induced by IL-17 ligation. The expression of these T-cells increase neutrophil
production, creating an inflammatory response and inducing an autoimmune
reaction that is CD.5
Figure 3. Depicts regions where incidence of Crohn’s Disease is the highest.6
Figure 4. Displays the ages of prevalence per 100 000 persons.7
High–incidence areas for CD include Northern Europe and North America
with 1 in 12 000 cases arising per year. Rates of CD in low-incidence areas are
continuously rising.8 Both genders are affected equally with Caucasian and
Ashkenazi Jewish descent having a higher risk of development. The mean age of
diagnosis is 33 to 45 years old. Exacerbating factors for CD include cigarette
smoking, appendectomy, oral contraceptives, diet-related factors, mycobacterial
infection, measles infection or vaccination and perinatal and childhood factors.8
Introduction
Prednisone is a synthetic glucocorticoid (GC) for the remission in CD and is
an oral tablet. It undergoes hepatic metabolism though 11-β-
hydroxydehydrogenase to be converted into the active form of Prednisolone.9
It diffuses the cell membrane and binds to the GC receptor (GCR) in the
cytoplasm to dimerize and form a GC/GCR complex. This translocates to the
nucleus where it binds to GC response elements (GREs) on GC-responsive
genes. This causes an increased expression of anti-inflammatory proteins.10 An
inhibitory response between GC/GCR complex and the tumour necrosis factor
alpha (TNF-α) signalling occurs; preventing activation of NF-κB. Through this,
prednisone leads to a decreased activation of the immune system and a
decrease in the symptoms in CD.10
Initially, CD patients receive 40 mg daily over 8-12 months. After achieving
a clinical response, the dosage decreases to 5-10mg weekly to 2.5-5 mg weekly.
Prednisone achieves peak plasma concentrations after 1-3 hours and has a
plasma half-life 3.4-8.4 hours.11
The effectiveness of prednisone was evaluated in the 1970s, through a
randomized control trial conducted by the National Cooperative Crohn’s
Disease Study (NCCDS).12
The side-effects observed with prednisone are: weight gain, blurred vision,
osteoporosis, reduced intestinal flora, black stool, fatigue, joint pain, facial
swelling, osteonecrosis, insomnia, and hepatic steatosis.14
When prescribing drugs to alleviate detrimental symptoms of CD, it is
important to monitor for giant cell arteritis (GCA), a complication related to GC
therapy.19 It requires balancing inflammatory disease with the medication’s side
effects. Most immunosuppressive drugs used for CD disease have significant side
effects, such as infection or lymphoma.20 Physicians prescribe medications alone
or in combination to eliminate the inflammation that causes both the symptoms
and complications related to disease.
The rationale for choosing infliximab as adjunctive therapy for CD was
based on the results of a recent open-label pilot study showing that infliximab
reduced GC requirements in 4 patients with CD who were GC resistant and who
had side effects to these drugs.22
Figure 13. The graph depicts an estimate of the proportion of patients who remained
relapse-free through the end of the study.21
The cumulative probability of not having relapse or recurrence over time
did not statistically differ between the groups (P = 0.53, Cox regression stratified
by study center). IFX = infliximab.21
The two groups did not differ in the proportion of patients no longer
taking prednisone, the numbers of relapses and recurrences, the duration of
prednisone treatment, and the cumulative prednisone dose.20 Therefore, due to
the lack of evidence that the IFX did not significantly reduce the amount of
prednisone required for patients to decrease levels of TNF-α or reduce chances
of giant cell arteritis (GCA), the recommended treatment is prednisone alone.
Deion D’Souza, Monica Naddafi, Christelle Ah Sen
Crohn’s Disease: An Overview of
Pharmacological Therapeutics
Initial Therapeutic: Prednisone
Figure 11. The study flow of the trials conducted between
prednisone and placebo vs. prednisone and infliximab.21
Initial vs Current Therapeutic
Infliximab is a IgG1 antibody and binds to TNF-α. Infliximab causes remission
and prevents relapse in CD patients.15 It acts as an anti-TNF therapeutic to
neutralize cytokines and increases intestinal mucosal T-cell susceptibility of
apoptosis.16
Infliximab has an anti-inflammatory mechanism that uses anti-TNF-α
antibodies to neutralize TNF. Infliximab in-vitro and in-vivo affects TNF-α survival
and inhibits granulocyte-macrophage colony stimulating factor (GM-CSF); a
cytokine of the pro-inflammatory processes.16
The downregulation of TNF- α induces GM-CSF expression, increasing the
apoptosis in T cells. Th1 cells, when activated, are a central component of the
immuno-inflammatory process in CD, producing interferon-gamma (IFN-γ), IL-2, IL-
12 and TNF-α. Infliximab reduces Th1 cytokines and there is a decrease of in-vitro
production of TNF- α and IFN-γ by intestinal and peripheral blood T cells. Infliximab
therapy causes an increase in apoptotic lamina propria T cells and inhibits
production of GM-CSF by mucosal T cells.16
Granulomas, a characteristic pathological finding in CD, contain Th1 cells.
Therefore, TNF- α is present at high concentrations and is why TNF- α neutralizing
agents are used to reduce chronic inflammatory disordered cells.16
A single-dose of infliximab is safe and effective for the management of acute
CD. The ACCENT 1 clinical trial assessed the efficacy and safety of repeated
infusions of infliximab in patients who improved after an initial infusion.
The hypothesis was that the maintenance of infliximab treatment is a more
effective than a single infusion. Results showed that maintenance treatment with
infliximab every 8 weeks has better results than subsequent placebo treatment in
patients who responded to a single infliximab infusion. Patients with infliximab
infusions were more likely to maintain clinical remissions and to discontinue
corticosteroids complications.
These outcomes imply that infliximab can have both a rapid onset, as well as
a lasting benefit over 1 year. In addition, a third of the patients who were on
steroids were able to reduce steroid use and were spared of its symptoms.1
The side effects observed with the use of infliximab are: headache,
dizziness, nausea, injection-site irritation, flushing and chest pain. The risk-benefit
ratio for patients at a high risk of infection should be considered prior to the
infliximab therapy.18
(1)
Figure 6. Mechanism of Action. Prednisone is metabolized. It binds to the GR and forms the GC/GR
complex. Pathway 1 binds to GREs and upregulates production of anti-inflammatory proteins. TNFα
binds to a membrane-bound receptor and activates a signalling cascade that activates NF-κB. Pathway 2,
the GC/GCR complex stops TNFα signalling. by binding to the NF-κB element gene.
Figure 5. Metabolism of Prednisone.
Figure 7. The results of prednisone
therapy is displayed for 1 month
and 12 months. 48% of CD patients
at 1 month displayed remission,
32% showed improvements. Of
those 48% that had remission, and
54% continued with remission at
the end of 12 months. Of the 32%
that improved, 52% continued to
show improvements. Overall, 44%
were observed to have a prolonged
response to the prednisone.
Figure 2.
Binding of
microbial
adjuvants to
extracellular
and intracellular
pattern-
recognition
receptors.5
Figure 1.
Image A: normal small intestine
Image B: The CD small intestine
with cobblestoning, thickened
wall, fat-wrapping
Image C: histology of a normal
small intestine
Image D: Histology of a CD small
intestine
Image E: colonoscopic image of
the normal small intestine
Image F: cobblestoning of the
small intestine in CD. 2
Conclusion
The differences in effectives and
side effects of CD’s earliest
treatment, prednisone, and a recent
treatment, infliximab, were
compared.21 A 52-week double-
blind, randomized, placebo-
controlled study comparing the
efficacy and tolerability of oral
prednisone plus infliximab vs. oral
prednisone plus placebo as first-line
treatment was conducted. Patients
were assigned to receive placebo or
infliximab, 3 mg/kg of body weight,
at weeks 0, 2, 6, 14, and 22.21
Current Therapeutic: Infliximab
Figure 8. Infliximab structure. It bind with high affinity to TNF-α, neutralizing and causing an increased rate of
intestinal mucosal T-cell apoptosis.17
Figure 9. Infliximab binding to the transmembrane TNF-α receptors and starting a cellular cascade resulting in
downregulated GM-CSF expression and an increased rate of T-cell apoptosis.17
Figure 12. Results seen in the box plots showing the A) inflammatory IL-6 level B) C-reactive protein
(CRP) level, and C) erythrocyte sedimentation rate (ESR) at the time of first relapse. Solid horizontal
lines: medians, boxes: interquartile ranges, dashed horizontal lines: means, and error bars: standard
deviation. Values were available for 13 placebo recipients and 21 infliximab recipients.21
Figure 10. Clinical response vs.
clinical remission.
Group 1: placebo group. Group 2:
received 5mg/kg infliximab at
weeks 2 and 6 and every 8 weeks
thereafter until week 46. Group 3:
received 5 mg/kg infliximab at
weeks 2 and 6 followed by 10
mg/kg thereafter. Groups 2 and 3
were more likely to be in clinical
remission at 30 weeks. Similar
results were observed at 54
weeks.18
[1] Stappenbeck, T.S., et al. (2011). Crohn disease: a current perspective on genetics, autophagy and immunity. Autophagy, 7(4), 355–74.
[2] JHIMICall. (2015). Crohn’s Disease: Introduction. When seconds count.
[3] MacDonald, T. T. (1993). Aetiology of Crohn’s disease. Archives of Disease in Childhood, 68(5), 623–5.
[4] Fuhler et al. (2015). Linkage between genotype and immunological phenotype in Crohn’s disease. Annals of Translational Medicine. 3, 16.
[5] Sartor, B. (2006). Mechanisms of Disease: pathogenesis of Crohn's disease and ulcerative colitis. Nature Clinical Practice Gastroenterology & Hepatology. 3, 390-407.
[6] Kaplan, G. (2015). The global burden of IBD: from 2015 to 2025. Nature Reviews Gastroenterology & Hepatology. 150
[7] Sjöberg, et al. (2014). Incidence and clinical course of Crohn's disease during the first
year — Results from the IBD Cohort of the Uppsala Region (ICURE) of Sweden 2005–2009. Journal of Crohn’s and Colitis. 215-222
[8] Loftus et al. (2014). Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology. 126, 1504 - 1517.
[9] Frey, B. M., Seeberger, M., & Frey, F. J. (1985). Pharmacokinetics of 3 prednisolone prodrugs. Evidence of therapeutic inequivalence in renal transplant patients with rejection. Transplantation, 39(3), 270–4.
[10] Barnes, P. J. (1998). Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clinical Science (London, England : 1979), 94(6), 557–72.
[11] Pickup, M. E. Clinical pharmacokinetics of prednisone and prednisolone. Clinical Pharmacokinetics, 4(2), 111–28.
[12] Summers, R. W., Switz, D. M., Sessions, J. T., Becktel, J. M., Best, W. R., Kern, F., & Singleton, J. W. (1979). National Cooperative Crohn’s Disease Study: results of drug treatment. Gastroenterology, 77(4-2), 847–69.
[13] Munkholm, et al. (1994). Gut. 35, 360-362.
[14] Stanbury, R. M., & Graham, E. M. (1998). Systemic corticosteroid therapy---side effects and their management. British Journal of Ophthalmology, 82(6), 704–708.
[15] Maser, E. A., Villela, R., Silverberg, M. S., & Greenberg, G. R. (2006). Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn’s disease. Clinical Gastroenterology and Hepatology : The
Official Clinical Practice Journal of the American Gastroenterological Association, 4(10), 1248–54.
[16] Kirman, I., Whelan, R. L., & Nielsen, O. H. (2004). Infliximab. European Journal of Gastroenterology & Hepatology, 16(7), 639–641.
[17] Arsiwala, S. (2013). Infliximab: Efficacy in psoriasis. Indian Jounal of Dermatology, Venereology and Leprology, 79(7), 25-34.
[18] Hanauer, S. B., Feagan, B. G., Lichtenstein, G. R., Mayer, L. F., Schreiber, S., Colombel, J. F., Rutgeerts, P. (2002). Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet (London, England), 359(9317), 1541–9
[19] Hoffman et al. (2007). Infliximab for Maintenance of Glucocorticosteroid-Induced Remission of Giant Cell Arteritis: A Randomized Trial. Ann Intern Med. 46(9), 621-630.
[20] Rutgeerts et al. (2004). Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease. Gastroenterology. 126; 2, 402 – 413.
[21] Lecluse et al. (2008). Review and Expert Opinion on Prevention and Treatment of Infliximab-related Infusion Reactions. The British Journal of Dermatology. 159(3), 527-536.
[22] Agency for Healthcare Research and Quality. (2010). Comparative Effectiveness of Pharmacologic Therapies for the Management of Crohn’s Disease. Effective Health Care Program. 1, 685.