Next Article in Journal
Radiation Proctitis: The Potential Role of Hyaluronic Acid in the Prevention and Restoration of Any Damage to the Rectal Mucosa among Prostate Cancer Patients Submitted to Curative External Beam Radiotherapy
Previous Article in Journal
The Role of EUS-Guided Drainage in the Management of Postoperative Fluid Collections after Pancreatobiliary Surgery
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Editorial

Cytokines and Biologic Therapy in Patients with Inflammatory Bowel Diseases

1
Department of Medical Sciences, University of Turin, 10124 Turin, Italy
2
Unit of Gastroenterology, Molinette Hospital, 10126 Turin, Italy
*
Author to whom correspondence should be addressed.
Gastroenterol. Insights 2021, 12(4), 443-445; https://0-doi-org.brum.beds.ac.uk/10.3390/gastroent12040042
Submission received: 28 November 2021 / Accepted: 30 November 2021 / Published: 1 December 2021
(This article belongs to the Section Gastrointestinal Disease)
Inflammatory bowel diseases (IBD) are chronic inflammatory disorders, including Crohns’ disease (CD) and ulcerative colitis (UC), both characterized by a clinical relapsing course and an immune-mediated pathogenesis [1,2,3]. Together with genetics, environmental factors, and intestinal barrier integrity [4], cytokines have been identified as key players in the pathological process responsible for the onset and progression of IBD [5,6].
Cytokines are a wide group of small, secreted proteins ranging from 5 to 20 kDa that are actively released by different cell types and able to induce specific effects on target cells. Cytokines can be characterized by pleiotropic activity (i.e., the ability of a cytokine to exert different cell responses) and redundancy (i.e., the ability of more cytokines to induce similar effects), which can synergize or antagonize each other [7]. Moreover, these proteins can induce cascade effects, stimulating the production of other cytokines [7]. Based on their binding to different receptors, cytokines can be broadly grouped into 6 families: interleukin (IL)-1 family (such as IL-1α, IL-1β, IL-18, and IL-33), class 1 cytokines, also known as hematopoietins (such as IL-2, IL-4, IL-6, IL-12, and IL-23), class 2 cytokines, also known as interferons (IFN) (such as IFN-α, IFN-β, IFN-γ, IL-10, and IL-22), tumor necrosis factor (TNF) family (such as TNF-α, TNF-β, and Fas), IL-17 family (such as IL-17A, IL-17B, IL-17C, IL-17D, and IL-17F), and chemokines (such as IL-8 and chemokines C–C motif ligand) [8].
Disruption of the cytokine network responsible for the maintenance of the homeostasis between epithelial cells of the intestinal barrier and cells of the innate and adaptative immune system, represents the early event that leads to the initiation and establishment of chronic inflammation in IBD [9]. Among pro-inflammatory cytokines, TNF-α is a pleiotropic cytokine produced by different immune and stromal cells that plays a key role in the pathogenesis of IBD; this cytokine induces angiogenesis and hypervascularization, elicits a cascade effect on macrophages leading to the synthesis of additional pro-inflammatory cytokines (i.e., IL-1, IL-6, and TNF), and promotes tissue damage and loss of intestinal barrier integrity [10]. The IL-12/23 pathway is involved in IBD pathogenesis through promoting a pathological Th1 and Th17 response [11], leading to the synthesis of additional pro-inflammatory cytokines that contribute both to the pro-inflammatory milieu and to neutrophil recruitment [11]. IL-6 is another pleiotropic pro-inflammatory cytokine, mainly produced by macrophages and dendritic cells that is indispensable for Th17 differentiation from naïve CD4+ T cells [5,12]; the synergic action with IL-1β induces T-cells resistant to apoptosis and promotes neutrophil recruitment [5]. Among anti-inflammatory cytokines, IL-10 is produced by almost all leukocytes and plays a crucial role in the maintenance of intestinal homeostasis, mainly counteracting IL-6 and TNF [13].
Given the relevance of cytokines in the pathogenesis of IBD, several therapeutic approaches have been developed in order to modulate cytokine signaling, including direct inhibition of cytokines or their receptors. In this regard, from 1990 to the present, various formulations of monoclonal antibodies directed towards pro-inflammatory cytokines have been progressively developed, with infliximab (IFX) (anti-TNF-α) being the first chimeric monoclonal antibody approved for IBD therapy (1998 in USA and 1999 in Europe) [1]. Subsequently, several novel and less immunogenic biologic drugs based on fully humanized monoclonal antibodies were developed and introduced in the therapy of IBD, including adalimumab (ADA) (anti-TNF-α), golimumab (anti-TNF-α), certolizumab pegol (anti-TNF-α), and ustekinumab (anti-IL12/23). Though anti-TNF drugs showed high efficacy for the treatment of IBD patients, more than 40% of moderate-to-severe IBD patients do not respond to anti-TNF-α, while 20% lose the initial response within a year [14]. Likely, the blockade of a single cytokine may lead to the establishment of compensatory pathways, ultimately leading to loss of response to targeted therapy.
In recent decades, serum cytokines have been investigated in patients with IBD as potential markers for the prediction of responses to biologic drugs. In patients with CD under maintenance therapy with IFX, baseline IL-6, IL-12, IL-23, and IL-17A circulating levels were significantly different between sustained and non-sustained responders [15]. In patients with UC, a panel of 17 serum cytokines was investigated for the prediction of the therapeutic efficacy of IFX. Remarkably, IL-6 values at 8 weeks of IFX therapy were significantly different between responders and non-responders to 26 weeks of treatment; IL-6, as a possible biomarker of response, showed good diagnostic accuracy with an area under the curve (AUC) value of 0.802 (cut-off = 0.71 pg/mL, sensitivity (Se) = 0.92 and specificity (Sp) = 0.71) [16]. More recently, Bertani and colleagues investigated a panel of cytokines including IFN-γ, IL-1β, IL-6, IL-8, IL-10, IL-12, IL-17A, IL-23, and TNF-α for the prediction of clinical and endoscopic response in patients with UC treated with vedolizumab (VDZ) [17]. Overall, 12 patients (41.4%) achieved mucosal healing at the end of treatment; the outcome was associated with higher IL-6 and IL-8 values at baseline and with a significant decrease in IL-6 and IL-8 levels over the first 6 weeks [17]. The authors developed a nomogram based on baseline IL-6 and IL-8 values and their decline over the first 6 weeks of VDZ showed excellent diagnostic accuracy (AUC = 0.950, Se = 0.82 and Sp = 0.90) [17]. Similarly, they investigated the role of a panel of serum cytokines (IL-1β, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, IL-23, IL-33, IFN-γ, and TNF-α) at baseline and at 10 weeks of treatment as a possible predictor of clinical response to biologic therapy in patients with IBD (43 CD and 17 UC). In a multivariate analysis corrected for disease (CD or UC), type of biologic therapy, and disease activity, the reduction in serum IL-6 values from baseline to week 10 of treatment was the only predictor of clinical response at 12 months of therapy (odds ratio = 4.75, p = 0.022) [18].
Given the central role of cytokines in the pathogenesis of IBD (both those with intestinal and extra-intestinal localization [19]) and their increasing relevance as therapeutic targets, the number of studies evaluating the potential clinical role of circulating cytokines is steadily growing [20]. To date, promising results have been achieved, especially for circulating IL-6 during anti-TNF-α therapy. However, further multicenter prospective studies on large cohorts of patients are warranted to prove the clinical value of serum cytokines as reliable biomarkers for the management of patients with IBD undergoing biologic therapy.

Author Contributions

Conceptualization, G.P.C. and R.P.; investigation, G.P.C., A.N. and R.P.; resources, G.P.C., D.G.R. and R.P.; data curation, G.P.C. and A.N.; writing—original draft preparation, G.P.C. and A.N.; writing—review and editing, R.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Actis, G.C.; Pellicano, R.; Fagoonee, S.; Ribaldone, D.G. History of Inflammatory Bowel Diseases. J. Clin. Med. 2019, 8, 1970. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Banerjee, R.; Pal, P. Endoscopic Evaluation and Therapeutic Considerations of Small Bowel Crohn’s Disease. Gastroenterol. Insights 2021, 12, 238–258. [Google Scholar] [CrossRef]
  3. Pagnini, C.; Di Paolo, M.C.; Mariani, B.M.; Urgesi, R.; Pallotta, L.; Vitale, M.A.; Villotti, G.; d’Alba, L.; De Cesare, M.A.; Di Giulio, E.; et al. Mayo Endoscopic Score and Ulcerative Colitis Endoscopic Index Are Equally Effective for Endoscopic Activity Evaluation in Ulcerative Colitis Patients in a Real Life Setting. Gastroenterol. Insights 2021, 12, 217–224. [Google Scholar] [CrossRef]
  4. Caviglia, G.P.; Dughera, F.; Ribaldone, D.G.; Rosso, C.; Abate, M.L.; Pellicano, R.; Bresso, F.; Smedile, A.; Saracco, G.M.; Astegiano, M. Serum zonulin in patients with inflammatory bowel disease: A pilot study. Minerva Med. 2019, 110, 95–100. [Google Scholar] [CrossRef] [PubMed]
  5. Bertani, L.; Antonioli, L.; Fornai, M.; Tapete, G.; Baiano Svizzero, G.; Marchi, S.; Blandizzi, C.; Costa, F. Evaluation of cytokine levels as putative biomarkers to predict the pharmacological response to biologic therapy in inflammatory bowel diseases. Minerva Gastroenterol. Dietol. 2019, 65, 298–308. [Google Scholar] [CrossRef] [PubMed]
  6. Bertani, L.; Caviglia, G.P.; Antonioli, L.; Pellicano, R.; Fagoonee, S.; Astegiano, M.; Saracco, G.M.; Bugianesi, E.; Blandizzi, C.; Costa, F.; et al. Serum Interleukin-6 and -8 as Predictors of Response to Vedolizumab in Inflammatory Bowel Diseases. J. Clin. Med. 2020, 9, 1323. [Google Scholar] [CrossRef] [PubMed]
  7. Ozaki, K.; Leonard, W.J. Cytokine and cytokine receptor pleiotropy and redundancy. J. Biol. Chem. 2002, 277, 29355–29358. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  8. Liongue, C.; Sertori, R.; Ward, A.C. Evolution of Cytokine Receptor Signaling. J. Immunol. 2016, 197, 11–18. [Google Scholar] [CrossRef] [PubMed]
  9. Friedrich, M.; Pohin, M.; Powrie, F. Cytokine Networks in the Pathophysiology of Inflammatory Bowel Disease. Immunity 2019, 50, 992–1006. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  10. Neurath, M.F. New targets for mucosal healing and therapy in inflammatory bowel diseases. Mucosal Immunol. 2014, 7, 6–19. [Google Scholar] [CrossRef] [PubMed]
  11. Almradi, A.; Hanzel, J.; Sedano, R.; Parker, C.E.; Feagan, B.G.; Ma, C.; Jairath, V. Clinical Trials of IL-12/IL-23 Inhibitors in Inflammatory Bowel Disease. BioDrugs 2020, 34, 713–721. [Google Scholar] [CrossRef] [PubMed]
  12. Ahluwalia, B.; Moraes, L.; Magnusson, M.K.; Öhman, L. Immunopathogenesis of inflammatory bowel disease and mechanisms of biological therapies. Scand. J. Gastroenterol. 2018, 53, 379–389. [Google Scholar] [CrossRef] [PubMed]
  13. Keubler, L.M.; Buettner, M.; Häger, C.; Bleich, A. A Multihit Model: Colitis Lessons from the Interleukin-10-deficient Mouse. Inflamm. Bowel Dis. 2015, 21, 1967–1975. [Google Scholar] [CrossRef] [PubMed]
  14. Pugliese, D.; Privitera, G.; Pizzolante, F.; Gasbarrini, A.; Guidi, L.; Armuzzi, A. Therapeutic drug monitoring with vedolizumab in inflammatory bowel disease. Minerva Gastroenterol. Dietol. 2019, 65, 280–290. [Google Scholar] [CrossRef] [PubMed]
  15. Ogawa, K.; Matsumoto, T.; Esaki, M.; Torisu, T.; Iida, M. Profiles of circulating cytokines in patients with Crohn’s disease under maintenance therapy with infliximab. J. Crohns Colitis 2012, 6, 529–535. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Sato, S.; Chiba, T.; Nakamura, S.; Matsumoto, T. Changes in cytokine profile may predict therapeutic efficacy of infliximab in patients with ulcerative colitis. J. Gastroenterol. Hepatol. 2015, 30, 1467–1472. [Google Scholar] [CrossRef] [PubMed]
  17. Bertani, L.; Baglietto, L.; Antonioli, L.; Fornai, M.; Tapete, G.; Albano, E.; Ceccarelli, L.; Mumolo, M.G.; Pellegrini, C.; Lucenteforte, E.; et al. Assessment of serum cytokines predicts clinical and endoscopic outcomes to vedolizumab in ulcerative colitis patients. Br. J. Clin. Pharmacol. 2020, 86, 1296–1305. [Google Scholar] [CrossRef] [PubMed]
  18. Caviglia, G.P.; Rosso, C.; Stalla, F.; Rizzo, M.; Massano, A.; Abate, M.L.; Olivero, A.; Armandi, A.; Vanni, E.; Younes, R.; et al. On-Treatment Decrease of Serum Interleukin-6 as a Predictor of Clinical Response to Biologic Therapy in Patients with Inflammatory Bowel Diseases. J. Clin. Med. 2020, 9, 800. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  19. Finucci, A.; Ditto, M.C.; Parisi, S.; Borrelli, R.; Priora, M.; Realmuto, C.; Fusaro, E. Rheumatic manifestations in inflammatory bowel disease. Minerva Gastroenterol. 2021, 67, 79–90. [Google Scholar] [CrossRef] [PubMed]
  20. Gisbert, J.P.; Chaparro, M. Predictors of Primary Response to Biologic Treatment [Anti-TNF, Vedolizumab, and Ustekinumab] in Patients With Inflammatory Bowel Disease: From Basic Science to Clinical Practice. J. Crohns Colitis 2020, 14, 694–709. [Google Scholar] [CrossRef] [PubMed]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Caviglia, G.P.; Ribaldone, D.G.; Nicolosi, A.; Pellicano, R. Cytokines and Biologic Therapy in Patients with Inflammatory Bowel Diseases. Gastroenterol. Insights 2021, 12, 443-445. https://0-doi-org.brum.beds.ac.uk/10.3390/gastroent12040042

AMA Style

Caviglia GP, Ribaldone DG, Nicolosi A, Pellicano R. Cytokines and Biologic Therapy in Patients with Inflammatory Bowel Diseases. Gastroenterology Insights. 2021; 12(4):443-445. https://0-doi-org.brum.beds.ac.uk/10.3390/gastroent12040042

Chicago/Turabian Style

Caviglia, Gian Paolo, Davide Giuseppe Ribaldone, Aurora Nicolosi, and Rinaldo Pellicano. 2021. "Cytokines and Biologic Therapy in Patients with Inflammatory Bowel Diseases" Gastroenterology Insights 12, no. 4: 443-445. https://0-doi-org.brum.beds.ac.uk/10.3390/gastroent12040042

Article Metrics

Back to TopTop