Crohn's disease (CD), first characterized in 1932 by Dr. Burrill B. Crohn and his colleagues, Dr. Leon Ginzburg and Dr. Gordon D. Oppenheimer, is a chronic inflammatory condition affecting the gastrointestinal (GI) tract. Classified as an inflammatory bowel disease (IBD) along with ulcerative colitis (UC), Crohn’s disease can impact any part of the digestive system from the mouth to the anus, affecting the entire thickness of the gastrointestinal wall. This distinguishes it from UC, which is confined to the innermost lining of the large intestine as seen in Figure 1. The precise etiology of Crohn's disease remains unclear, but genetic predisposition and environmental factors influence its occurrence in individuals.
(InflammatoryBowel Disease (IBD),2022) https://www.hopkinsmedicine.org/health/conditions-and-diseases/inflammatory-bowel-disease
Figure 1: Areas of digestive tract affects by Ulcerative Colitis and Crohn’s Disease
Epidemiology and Demographics
Crohn's disease affects approximately 1.3% of Americans, according to the Centers for Disease Control and Prevention (CDC), and Canada reports one of the highest prevalence and incidence rates globally, with about 161,000 diagnosed individuals. The disease affects men and women equally and can manifest at any age, though diagnoses are more common in young children and individuals aged 40-50. Family history is a significant risk factor, with studies indicating a connection between developing Crohn’s disease and having a family history of IBD, with risks ranging from 1.5% to 28%. Although historically more prevalent among Caucasians, recent trends show increasing occurrences among Hispanics and Asians.
Pathophysiology and Clinical Manifestations
Genetic, environmental, and individual health factors influence the manifestation of Crohn's disease. Symptoms vary widely from abdominal pain, diarrhea, and weight loss, to fatigue. Inflammation caused by Crohn’s can lead to complications such as strictures, fistulas, and malnutrition. The variability in symptoms and disease progression makes Crohn’s challenging to diagnose and manage.
Ritlecitinib (Litfulo): A Promising Therapeutic Agent
Litfulo is the brand name, scientifically known as Ritlecitinib tosylate manufactured by Pfizer, and is emerging as a promising therapeutic agent for Crohn’s disease. Ritlecitinib is a highly selective inhibitor of Janus kinase 3 (JAK3) and the tyrosine kinase expressed in the hepatocellular carcinoma (TEC) kinase family. The high selectivity of Ritlecitinib for JAK3 is due to its ability to form an irreversible covalent bond with a cysteine residue at position 909 (Cys-909) in JAK3, a feature not present in other JAK isoforms where this cysteine is replaced by serine.
Mechanism of Action
Ritlecitinib functions as a dual inhibitor, primarily targeting JAK3 by irreversibly obstructing the adenosine triphosphate (ATP)-binding site while sparing the other JAK isoforms (JAK1, JAK2, and Tyrosine Kinase 2, TYK2). Additionally, it selectively inhibits the TEC kinase family, including Bruton's tyrosine kinase and others. This targeted inhibition modulates gamma chain cytokine pathways, crucial in the pathophysiology of IBD, such as IL-7, IL-9, IL-15, and IL-21, without impacting immunoregulatory cytokines like IL-10, IL-27, and IL-21, which are vital for maintaining immune homeostasis in the gut.
Clinical Applications and Trials
Litfulo has been approved by the Food and Drug Association (FDA) for treating severe forms of alopecia areata in adults and adolescents aged 12 and older and by the European Medicine Agency (EMA) in 2023. It is also being investigated for other conditions, including vitiligo, moderate to severe ulcerative colitis, and various subtypes of cutaneous T-cell lymphoma.
Conclusion
Crohn's disease remains a complex and challenging condition to manage due to its diverse presentation and the intricacies of its underlying mechanisms. Litfulo (Ritlecitinib tosylate) represents a promising therapeutic option, offering targeted inhibition of pathways critical in the disease's pathophysiology while sparing essential immunoregulatory functions. As clinical trials progress, Ritlecitinib may soon become a key player in the therapeutic landscape of Crohn's disease, providing hope for more effective and personalized treatment strategies.
References
Accessed March 6, 2024. https://labeling.pfizer.com/ShowLabeling.aspx?id=19638
Casalegno Garduño R, Däbritz J. New Insights on CD8+ T Cells in Inflammatory Bowel Disease and Therapeutic Approaches. Front Immunol. 2021;12:738762. doi:10.3389/fimmu.2021.738762
Clinical and Demographic Profile of Inflammatory Bowel Disease Patient | CEG. Accessed March 6, 2024. https://www.dovepress.com/clinical-and-demographic-profile-of-inflammatory-bowel-disease-patient-peer-reviewed-fulltext-article-CEG
Definition & Facts for Crohn’s Disease - NIDDK. National Institute of Diabetes and Digestive and Kidney Diseases. Accessed March 6, 2024. https://www.niddk.nih.gov/health-information/digestive-diseases/crohns-disease/definition-facts
European Commission Approves Pfizer’s LITFULOTM for Adolescents and Adults With Severe Alopecia Areata | Pfizer. Accessed March 6, 2024. https://www.pfizer.com/news/press-release/press-release-detail/european-commission-approves-pfizers-litfulotm-adolescents
Inflammatory Bowel Disease (IBD). (2022, May 16). Johns Hopkins Medicine. https://www.hopkinsmedicine.org/health/conditions-and-diseases/inflammatory-bowel-disease
FDA Approves Pfizer’s LITFULOTM (Ritlecitinib) for Adults and Adolescents With Severe Alopecia Areata | Pfizer. Accessed March 6, 2024. https://www.pfizer.com/news/press-release/press-release-detail/fda-approves-pfizers-litfulotm-ritlecitinib-adults-and
GIS. Crohn’s Disease. Gastrointestinal Society. Accessed March 6, 2024. https://badgut.org/information-centre/a-z-digestive-topics/crohns-disease/
Kappelman MD, Moore KR, Allen JK, Cook SF. Recent trends in the prevalence of Crohn’s disease and ulcerative colitis in a commercially insured US population. Dig Dis Sci. 2013;58(2):519-525. doi:10.1007/s10620-012-2371-5
Overview of Crohn’s Disease | Crohn’s & Colitis Foundation. Accessed March 6, 2024. https://www.crohnscolitisfoundation.org/patientsandcaregivers/what-is-crohns-disease/overview
Ritlecitinib tosylate | DrugBank Online. Accessed March 6, 2024. https://go.drugbank.com/salts/DBSALT003482
Telliez JB, Dowty ME, Wang L, et al. Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition. ACS Chem Biol. 2016;11(12):3442-3451. doi:10.1021/acschembio.6b00677
Xu H, Jesson MI, Seneviratne UI, et al. PF-06651600, a Dual JAK3/TEC Family Kinase Inhibitor. ACS Chem Biol. 2019;14(6):1235-1242. doi:10.1021/acschembio.9b00188 Assessed and Endorsed by the MedReport Medical Review Board