Efficacy and Safety of Adalimumab in Canadian Patients with Moderate to Severe Crohn’s Disease: Results of the Adalimumab in Canadian SubjeCts with ModErate to Severe Crohn’s DiseaSe (ACCESS) Trial

Oxidative stress is thought to play a key role in the development of intestinal damage in inflammatory bowel disease (IBD), because of its primary involvement in intestinal cells' aberrant immune and inflammatory responses to dietary antigens and to the commensal bacteria. During the active disease phase, activated leukocytes generate not only a wide spectrum of pro-inflammatory cytokines, but also excess oxidative reactions, which markedly alter the redox equilibrium within the gut mucosa, and maintain inflammation by inducing redoxsensitive signaling pathways and transcription factors. Moreover, several inflammatory molecules generate further oxidation products, leading to a self-sustaining and auto-amplifying vicious circle, which eventually impairs the gut barrier. The current treatment of IBD consists of long-term conventional anti-inflammatory therapy and often leads to drug refractoriness or intolerance, limiting patients' quality of life. Immune modulators or anti-tumor necrosis factor a antibodies have recently been used, but all carry the risk of significant side effects and a poor treatment response. Recent developments in molecular medicine point to the possibility of treating the oxidative stress associated with IBD, by designing a proper supplementation of specific lipids to induce local production of anti-inflammatory derivatives, as well as by developing biological therapies that target selective molecules (i.e., nuclear factor-jB, NADPH oxidase, prohibitins, or inflammasomes) involved in redox signaling. The clinical significance of oxidative stress in IBD is now becoming clear, and may soon lead to important new therapeutic options to lessen intestinal damage in this disease.

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“…Adalimumab therapy showed a sustained steroid-free remission and fistula healing in Canadian patients with moderate-to-severe CD (199).…”

Section: Oxidative Stress and Inflammation In The Gutmentioning

confidence: 92%

Inflammatory Bowel Disease: Mechanisms, Redox Considerations, and Therapeutic Targets

Biasi

Leonarduzzi

Oteiza

et al. 2013

Antioxidants & Redox Signaling

230

145

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“…Patients with CD who had received at least 1 dose of adalimumab during randomized placebo-controlled or open-label trials of adalimumab for the induction or maintenance of remission or mucosal healing (CLASSIC I and II, GAIN, CHARM, EXTEND, CARE, ACCESS, and a Japanese study) (11)(12)(13)(14)(15)(16)(17)(18)(19) or during the corresponding open-label long-term extension study (ADHERE) ( 20,21 ) were included. Patients who initiated therapy with placebo in any of the above studies were excluded, as our aim was to examine the added infection risk with combination therapy given that the current standard of care for the treatment of moderate-tosevere CD is a combination therapy or anti-TNF monotherapy ( 1 ), and due to relatively low duration of exposure to placebo in the data set, the number of infections that occurred in patients receiving placebo was too low for any meaningful assessment.…”

Section: Analysis Populationmentioning

confidence: 99%

“…CARE was a 20-week single-arm open-label study in Europe ( 16 ). ACCESS was a 24-week single-arm open-label study in Canada ( 17 ). Th e Japanese study had a blinded induction phase lasting up to 8 weeks, followed by a blinded 52-week maintenance phase, followed by an open-label extension phase lasting up to additional 184 weeks ( 18,19 ).…”

Section: Analysis Populationmentioning

confidence: 99%

Crohn’s Disease Activity and Concomitant Immunosuppressants Affect the Risk of Serious and Opportunistic Infections in Patients Treated With Adalimumab

Osterman

Sandborn

Colombel

et al. 2016

American Journal of Gastroenterology

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“…Adalimumab, a fully human IgG1 monoclonal antibody to TNF-, was found to be effective in patients with CD refractory to conventional therapy and in patients with an attenuated response to infliximab [211,227,228]. Recent study showed that adalimumab could induce and maintain clinical remission in patients with moderate-to-severe UC as well, who did not have a satisfactory response to steroids or immunosuppressive agents [229].…”

Section: Inhibition Of Pro-inflammatory Cytokines 3211 Inhibitorsmentioning

confidence: 99%

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

Gyires¹,

Tóth²,

Zádori

2014

CPD

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Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory condition of the gastrointestinal tract. The two main forms of IBD are Crohn's disease and ulcerative colitis. According to the recent concept the disease is caused by a combination of factors, including genetics, immune dysregulation, barrier dysfunction and the change in microbial flora. Environmental factors, such as changes in diet, antibiotic use, smoking or improved domestic hygiene (e.g. eradication of intestinal helminths) probably contribute to the development and increased prevalence of IBD. Dysregulation of mucosal immunity in IBD causes an overproduction of inflammatory cytokines which resulted in uncontrolled intestinal inflammation. Based on extensive research over the last decade, besides the conventional therapy, there are several novel pathways and specific targets, on which focus new therapeutics. New therapeutics aim 1./ to correct genetic susceptibility by stimulating NOD2 expression, TLR3 signaling or inhibition of TLR4 pathway, 2./ to restore the immune dysregulation by inhibition of pro-inflammatory cytokines (TNF-, IL-6, IL-13, IL-17, IL-18, IL-21), Th1 polarisation (IL-2, IL-12, IL-23, IFN-), T-cell activation, leukocyte adhesion, as well as by immunostimulation (GM-CSF, G-CSF) and anti-inflammatory cytokines (IL-10, IL-11, IFN--1a), 3./ to restore mucosal barrier function and stimulate mucosal healing by different growth factors, such as GH, EGF, KGF, TGF-, VEGF, 4./ to restore the normal bacterial flora by antibiotics, probiotics. However, in spite of these numerous potential targets, the true value and clinical significance of most of the new biologics and molecules are not clear yet.

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Efficacy and Safety of Adalimumab in Canadian Patients with Moderate to Severe Crohn’s Disease: Results of the Adalimumab in Canadian SubjeCts with ModErate to Severe Crohn’s DiseaSe (ACCESS) Trial

Cited by 73 publications

References 30 publications

Inflammatory Bowel Disease: Mechanisms, Redox Considerations, and Therapeutic Targets

Inflammatory Bowel Disease: Mechanisms, Redox Considerations, and Therapeutic Targets

Crohn’s Disease Activity and Concomitant Immunosuppressants Affect the Risk of Serious and Opportunistic Infections in Patients Treated With Adalimumab

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

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