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A recent systematic review of the literature has shown that in recent years numerous studies have been conducted on molecules that block inflammatory cytokines involved in intestinal inflammation or in the aberrant immune response present in patients with Inflammatory bowel disease. This review was published in Current Opinion in Gastroenterology.
A recent systematic review of the literature has shown that in recent years numerous studies have been conducted on molecules that block inflammatory cytokines involved in intestinal inflammation or in the aberrant immune response present in patients with Inflammatory bowel disease. This review was published in Current Opinion in Gastroenterology
In the development of IBD, various factors are involved such as genetic and immunological susceptibility and environmental factors with consequent dysregulation of the immune system in the intestinal tract.
The aberrant immune response involves both the innate and adapted immune system and leads to the production of a large number of pro-inflammatory cytokines and to the imbalance of Th1, Th2 and Th17 cytokines.
This imbalance in cytokine profile is important in a chronic inflammatory process, as it can lead to a pathogen-deficient response and promote recurrence of the disease. Cytokines are small peptide proteins produced by lymphocytes (especially T cells of the Th1, Th2 and Th17 phenotype), monocytes, macrophages, granulocytes, epithelial cells, endothelial cells and fibroblasts.
Crohn's disease has been badociated with increased Th1 and Th17 responses, whereas in ulcerative colitis there is an atypical Th2 response.
Given the complex interactions between the various cytokines involved in Crohn's disease and ulcerative colitis, the targeting of several cytokines is considered a reasonable approach to treating IBD.
There are several cytokine-based cytokine blocking mechanisms that directly inhibit a specific cytokine, a cytokine receptor, an intracellular signaling pathway downstream of a cytokine receptor, or the administration of cytokine. anti-inflammatory cytokines.
Several clinical studies were conducted considering these strategies. Clinical studies with p40 or p19 subunit-blocking agents of IL-12 / IL-23 and IL-23, respectively, have been shown to be effective in the treatment of patients with Crohn's disease.
Promising results have been found with small oral molecules effective in inducing and maintaining remission in IBD patients, particularly tofacitinib in ulcerative colitis (phase 2 and 3 studies) and filgotinib and Upadacitinib in Crohn's disease (phase 2 studies).
Blocking of other specific cytokines such as IL-13, IL-17 and inducible-10 protein did not demonstrate efficacy in response clinical, induction and maintenance of remission in patients with Crohn's disease.
New therapeutic strategies focusing on the blockage of one or more cytokines are being discussed for potential future use in patients with IBD.
Anti-IL12 and anti-IL23
Recent studies on the inhibition of IL12 / IL-23 have recently been reported.
Ustekinumab is an interleukin inhibitor that blocks: the p40 subunit of T cells, natural killer (NK) cells and antigen presenting cells, inhibiting ; biological activity of & # 39; IL-12 and the & # 39; IL-23 [19659004L'ustekinumabestuneoptioncourantedansletraitementdespatientsatteintsdelamaladiedeCrohnenparticulierchezlespersonnesréfractairesouintolérantesauxmédicamentsconventionnelsetauxanti-TNFLesétudesquiontconfirmésonefficacitéétaientUNITI-1UNITI-2etIM-UNITI[19659004] the risankizumab is a humanized monoclonal antibody targeting the p19 subunit , specific to IL-23.
The clinical trial results in patients with moderate to severe Crohn's disease suggest greater efficacy than placebo in inducing clinical remission in patients with 39, an active disease at both 200 and 600 mg.
Briakinumab is an all-human anti-IL-12 / 23p40 antibody that has shown, in phase 2b studies, not always significant, the induction and maintenance of remission in patients with moderate activity to severe disease. The results we have today in Crohn 's disease support the potential efficacy of briakinumab in these patients.
Anti-IL6
Serum IL-6 levels are related to disease activity in both Crohn's disease and ulcerative colitis and, following a anti-inflammatory treatment, there is a decline was correlated with the decrease in the activity of the disease and correlated with histological activity in patients with ulcerative colitis. Thus, anti-IL-6 antibodies appear to be a reasonable strategy for biological therapy of IBD.
Tocilizumab is an anti-IL-6R monoclonal antibody that is used to treat patients with rheumatoid arthritis (RA). Studies in patients with CD show high efficacy in inducing a clinical response and remission even in refractory patients (80% compared to 30% placebo).
Multicentre phase II studies have shown that PF-04236921 induces clinical response and remission in refractory patients with moderate to severe Crohn's disease.
IL-13 anti-IL13
is produced by specialized cells such as NK Tcells cells. In ulcerative colitis, IL-13 can alter the function of the epithelial barrier by affecting apoptosis of the epithelium, tight junctions, and return velocity. High levels of IL-13 gene expression have been found in colon biopsy of patients with ulcerative colitis. This tests the role of overproduction of IL-13 in active ulcerative colitis, suggesting that IL-13 blocking might be an effective target in the treatment of patients with ulcerative colitis.
Anrukinzumab is a humanized antibody (Ig-G1) that binds to IL-13 and inhibits IL-13 attack of IL-13. 4Ra (IL4 receptor), disrupting the inflammatory signal induced by IL-13. However, studies conducted to date have not shown significant difference with placebo.
Anti-IL17
IL-17 induces the recruitment of immune cells into peripheral tissues, an effect that requires the activation of a nuclear factor (NF-κB ) after that it was stimulated by the IL receptor. 17.
IL-17 also leads to the induction of numerous pro-inflammatory factors including TNF-a, IL-6, IL-23, and IL-17. IL-1b from innate immune cells and the presentation of antigenic cells, particularly dendritic cells.
It was discovered that IL-17 and Th17 cells are elevated in the serum and intestinal tissues of patients with IBD as well as the expression of genes and proteins are increased in active ulcerative colitis compared to ulcerative colitis in remission and healthy controls.
Secukinumab is a completely selective anti-IL-17 agent evaluated in 59 patients with Crohn's disease. Secukinumab treatment did not reduce the mean CDAI by at least 50 points compared to placebo at week 6 and higher rates of adverse events were observed compared with placebo, suggesting that the inhibition of IL-17A may have adverse effects. a subset of patients with Crohn's disease with objective evidence of inflammation.
Vidofludimus is a new small molecule that inhibits the expression of pro-inflammatory cytokines such as IL-17A and IL-17F and IFN-g by interfering with the Janus kinase (JAK) / signal transducer and the Transcriptional Activator (STAT) and NF-kB
An open-label study provided preliminary evidence of the clinical efficacy of vidofludimus in patients with IBD, particularly in steroid-dependent patients.
Embroidalumab (AMG 827) is a human antibody against IL-17RA that blocks the biological activity of several cytokines of IL-17, including IL-17A, IL-17F and IL-17A / F heterodimer. The results of a randomized double-blind study showed that brodalumab does not appear to be effective for the treatment of Crohn's disease.
CXCL10
Inducible protein-10 (IP-10) is a chemokine that promotes the migration of activated T cells; it is secreted by neutrophils, monocytes / macrophages, endothelium, fibroblasts, keratinocytes, dendritic cells and epithelial cells, including intestinal epithelial cells. However, the results obtained with the endelumab show an inability to achieve clinical remission suggesting that the blockage of IP10 might not be a valid therapeutic option.
Inhibition of JAKs
JAKs are intracellular cytoplasmic tyrosine kinases that, in collaboration with members of the STAT family, are fundamental for interacting and initiating signaling downstream of a wide range of cytokine receptors, growth factors and hormones.
JAK signaling pathways are involved in several cytokines and have recently been considered a therapeutic target for the treatment of IBD patients.
Tofacitinib is a potent oral small molecule that inhibits JAK1 and JAK3. OCTAVE studies have shown its great effectiveness in inducing and maintaining remission and in mucosal healing in patients with ulcerative colitis. The results in patients with Crohn's disease were not as exhilarating.
Filgotinib, a JAK-1 inhibitor, showed CDAI-100 scores, endoscopic response and remission in MC patients, in phase II trials, and achieved deeper remission better than placebo.
Upadacitinib, also an inhibitor of JAK-1, also resulted in a clinical and endoscopic response and remission with reduced levels of C-reactive protein compared to placebo.
Baracitinib, inhibitor JAK1 / JAK2 has not yet been evaluated in IBD.
In conclusion, in recent years, many drugs have been developed for IBD to therapeutic targets such as cytokines. The first involved the inhibition of IL-12 / IL-23 axis, as ustekinumab already approved for the treatment of patients with Crohn's disease refractory to conventional treatment and factor tumor necrosis, as well as risankizumab and briakinumab which also showed positive results in Crohn's patients in phase 2 studies.
Selective inhibition of other cytokines such as IL-6 (tocilizumab, PF -04236921), IL-13 (anrukinzumab) and IL-17 (secukinumab, vidofludimus, brodalumab) were evaluated as an alternative in the treatment of patients with IBD with poor results.
Finally, drugs that inhibit cytokine-activated signal transduction pathways, such as the selective inhibitor of JAK1 and JAK3 (tofacitinib), have shown promising results in phase 2 and 3 clinical trials in patients with ulcerative colitis. This molecule will probably be approved for the treatment of patients with ulcerative colitis. Filgotinib and upadacitinib, selective JAK1 inhibitors, have also shown preliminary efficacy in patients with Crohn's disease.
Yamamoto-Furusho JK. Inflammatory bowel disease: blocking of cytokines and signaling pathways of cytokines. Curr Opin Gastroenterol. 2018 Jul; 34 (4): 187-193. doi: 10.1097 / MOG.0000000000000444.
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