scholarly journals Efficacy, Safety and Future Perspectives of JAK Inhibitors in the IBD Treatment

2021 ◽  
Vol 10 (23) ◽  
pp. 5660
Author(s):  
Patrycja Dudek ◽  
Adam Fabisiak ◽  
Hubert Zatorski ◽  
Ewa Malecka-Wojciesko ◽  
Renata Talar-Wojnarowska
Keyword(s):  
Small Molecules ◽  
Low Cost ◽  
Treatment Strategies ◽  
Current Data ◽  
Janus Kinase ◽  
Jak Inhibitors ◽  
Medical Need ◽  
Promising Target ◽  
Thrombotic Complications ◽  
Inflammatory Bowel

Although development of biologics has importantly improved the effectiveness in inducing and maintaining remission in inflammatory bowel disease (IBD), biologic therapies still have several limitations. Effective, low-cost drug therapy with good safety profile and compliance is therefore a substantial unmet medical need. A promising target for IBD treatment strategies are Janus kinase (JAK) inhibitors, which are small molecules that interact with cytokines implicated in pathogenesis of IBD. In contrast to monoclonal antibodies, which are able to block a single cytokine, JAK inhibitors have the potential to affect multiple cytokine-dependent immune pathways, which may improve the therapeutic response in some IBD patients. Tofacitinib, inhibiting signaling via different types of JAKs, has been already approved for ulcerative colitis, and several other small-molecule are still under investigation. However, one of the main concerns about using JAK inhibitors is the risk of thromboembolic events. Moreover, patients with COVID-19 appear to have an increased susceptibility for immunothrombosis. Therefore, thrombotic complications may become a serious limitation in the use of JAK inhibitors in the SARS-CoV-2 pandemic. As many questions about safety and efficacy of small molecules still remain unclear, in our review we present the current data regarding approved JAK inhibitors, as well as those in clinical development for the treatment of IBD.

Thrombosis in IBD in the Era of JAK Inhibition

2020 ◽  
Vol 22 (1) ◽  
pp. 126-136
Author(s):  
Virginia Solitano ◽  
Gionata Fiorino ◽  
Ferdinando D’Amico ◽  
Laurent Peyrin-Biroulet ◽  
Silvio Danese
Keyword(s):  
Small Molecules ◽  
Arterial Thrombosis ◽  
Protective Role ◽  
Jak Inhibitors ◽  
Thrombotic Risk ◽  
Increased Risk ◽  
Bowel Diseases ◽  
Thrombotic Complications ◽  
Inflammatory Bowel ◽  
Inflammatory Effect

: Patients with inflammatory bowel diseases (IBD) have an increased risk of thrombosis. The interaction between inflammation and coagulation has been extensively studied. It is well-known that some drugs can influence the haemostatic system, but several concerns on the association between therapies and increased risk of thrombosis remain open. While biologics seem to have a protective role against thrombosis via their anti-inflammatory effect, some concerns about an increased risk of thrombosis with JAK inhibitors have been raised. We conducted a literature review to assess the association between biologics/small molecules and venous/arterial thrombotic complications. An increased risk of venous and arterial thrombosis was found in patients treated with corticosteroids, whereas anti-TNF were considered protective agents. No thromboembolic adverse event was reported with vedolizumab and ustekinumab. In addition, thromboembolic events rarely occurred in patients with ulcerative colitis (UC) after therapy with tofacitinib. The overall risk of both venous and arterial thrombosis was not increased based on the available evidence. Finally, in the era of JAK inhibitors, treatment should be individualized by evaluating the pre-existing potential thrombotic risk balanced with the intrinsic risk of the medication used.

scholarly journals Clinical and Mechanistic Characteristics of Current JAK Inhibitors in IBD

2020 ◽  
Author(s):  
Elleni J Pippis ◽  
Bruce R Yacyshyn
Keyword(s):  
Small Molecules ◽  
Initial Therapy ◽  
Janus Kinase ◽  
Response To Treatment ◽  
Jak Inhibitors ◽  
Gi Tract ◽  
Inflammatory Conditions ◽  
Medical Need ◽  
Immune Mediated ◽  
Potential Benefits

Abstract Crohn’s disease (CD) and ulcerative colitis (UC) are chronic, immune-mediated diseases of the gastrointestinal (GI) tract. Their etiology is complex and involves immune (eg, cytokines) and nonimmune (eg, environment) mediated contributions, causing inflammatory damage to the GI tract. Though cytokines contribute a major role in the inflammatory process of both CD and UC, there are some key differences in which cytokines are involved in the pathobiology of CD and UC. Over the past several years, new biologic-directed therapies have focused on controlling specific aspects of inflammation associated with both conditions. Although these treatments have benefited patients overall, approximately 30% of patients still do not respond to induction (initial) therapy, and up to 50% of patients lose response to treatment over a year. Many of these therapies are administered parenterally and have been associated with adverse events such as serious infections or malignancy. Therefore, there is a significant unmet medical need for these patients to minimize symptoms and promote GI healing. There are several therapeutic agents in the pipeline, including oral, small molecules, which hold much promise. One group of small molecules known as Janus kinase (JAK) inhibitors offers an additional option for treatment of chronic inflammatory conditions, based on currently available data. The article will focus on the potential benefits of JAK inhibitors as oral, small molecules, such as the potential role of selectivity, and potential risks.

scholarly journals Targeting Cytokine Signaling and Lymphocyte Traffic via Small Molecules in Inflammatory Bowel Disease: JAK Inhibitors and S1PR Agonists

2019 ◽  
Vol 10 ◽  
Author(s):  
Tamara Pérez-Jeldres ◽  
Christopher J. Tyler ◽  
Joshua D. Boyer ◽  
Thangaraj Karuppuchamy ◽  
Andrés Yarur ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Small Molecules ◽  
Bowel Disease ◽  
Cytokine Signaling ◽  
Jak Inhibitors ◽  
Inflammatory Bowel

scholarly journals JAK inhibitors and infections risk: focus on herpes zoster

2020 ◽  
Vol 12 ◽  
pp. 1759720X2093605
Author(s):  
Flavia Sunzini ◽  
Iain McInnes ◽  
Stefan Siebert
Keyword(s):  
Herpes Zoster ◽  
Viral Infections ◽  
Inflammatory Diseases ◽  
Janus Kinase ◽  
Jak Inhibitors ◽  
Pathogenic Role ◽  
Immune Mediated ◽  
Post Marketing ◽  
Inflammatory Bowel

Currently, there is a growing interest in Janus kinase (JAK) intracellular signalling since targeted inhibitors against these pathways are proving effective in the treatment of a range of immune-mediated diseases, such as rheumatoid arthritis (RA), psoriasis, psoriatic arthritis (PsA), inflammatory bowel disease and atopic dermatitis. In particular, post marketing experience and the increasing development of new pharmacological inhibitors of broad and increasingly selective JAK pathways provide new insights into the JAK pathway role in viral infections as well as their pathogenic role in immune-mediated inflammatory diseases. Herein we provide an overview of the biological role of JAK signalling and its role in immunity against viruses, with particular regard to herpes zoster reactivation. Thereafter, we will discuss the evidence currently available on the principal JAK inhibitors and their association with viral infections.

scholarly journals Patient's reported outcomes – a new philosophy for analyzing the effectiveness of therapy in immunoinflammatory diseases

2021 ◽  
Vol 15 (5) ◽  
pp. 121-127
Author(s):  
Article Editorial
Keyword(s):  
Clinical Manifestations ◽  
Janus Kinase ◽  
Depression And Anxiety ◽  
Jak Inhibitors ◽  
Disease Modifying Antirheumatic Drugs ◽  
Inflammatory Bowel ◽  
Low Activity ◽  
Immunopathological Process ◽  
Pro Inflammatory Cytokines

A fundamentally important task of modern pharmacotherapy of immunoinflammatory diseases (IID) is a significant improvement in the quality of life (QOL) of patients, the fastest and most complete elimination of the most unpleasant manifestations of the disease, restoration of function and working capacity. Specialists in the therapy of various IID took part in panel dedicated to the discussion of this problem: Professor E.L. Nasonov, PhD., member of the Academy of Science; Professor A.M. Lila, PhD; V.N. Amirjanova, PhD; A.E. Karateev, PhD; T.V. Korotaeva, PhD; O.V. Knyazev, PhD; T.A. Lisitsyna, PhD; M.M Hobeish, PhD; E.S. Filatova. PhD.One of the central issues was the discussion of the need to use the patient's reported outcomes (PROs) indicator in analyzing the results of IID therapy (rheumatoid arthritis, psoriatic arthritis, psoriasis and inflammatory bowel disease). The need for its use is due to the fact that the principal goal of treatment with modern disease modifying antirheumatic drugs (DMARDs) is not only to achieve low activity or remission of IID, but also to maximize the general condition and QOL of patients. Therefore, such manifestations of IID as pain, fatigue, dysfunction, depression and anxiety, etc., must be analyzed in the course of treatment. The development of these symptoms is determined by the main immunopathological process and is associated, among others, with systemic overproduction of a number of pro-inflammatory cytokines. Modern DMARDs: Janus kinase (JAK) inhibitors, in particular tofacitinib, are capable of directly blocking the effect of cytokines on cells (suppressing the intracellular JAK / STAT signaling pathway), quickly and effectively eliminating pain, fatigue and dysfunction. The use of JAK inhibitors seems to be especially appropriate in patients with IID with high inflammatory activity and severe clinical manifestations.

scholarly journals New biologics and small molecules in inflammatory bowel disease: an update

2019 ◽  
Vol 12 ◽  
pp. 175628481985320 ◽  
Author(s):  
João Sabino ◽  
Bram Verstockt ◽  
Séverine Vermeire ◽  
Marc Ferrante
Keyword(s):  
Inflammatory Bowel Disease ◽  
Small Molecules ◽  
Bowel Disease ◽  
Mucosal Healing ◽  
Janus Kinase ◽  
New Drugs ◽  
Phase Iii ◽  
Sustained Remission ◽  
Inflammatory Disorders ◽  
Inflammatory Bowel

Inflammatory bowel disease (IBD) is a spectrum of immune-mediated inflammatory disorders with a complex multifactorial pathogenesis, where different pathways may predominate in different individuals. This complexity will most likely require a panoply of drugs targeting different pathways if one wants to treat to steroid-free sustained remission and mucosal healing. Presently, the mainstay of medical management of IBD is based on 5-aminosalicylates, corticosteroids, thiopurines, methotrexate, antitumor necrosis factor, anti-alpha4 beta7 (α4β7) integrin and anti-interleukin (IL)-12/IL-23 therapies. The discovery of new pathways involved in the pathogenesis of IBD resulted in new drugs targeting Janus kinase/signal transducers and activators of transcription, IL-6, spingosine-1-phosphate, and phosphodiesterase 4, among others. These new therapies might result in more advantageous safety profiles. Several of these new drugs have already been successfully tested in other inflammatory disorders, such as psoriasis or rheumatoid arthritis. In this review, evidence from phase II and phase III randomized controlled clinical trials in patients with IBD involving new biologicals and small molecules are summarized.

scholarly journals Novel and Emerging Therapies for Inflammatory Bowel Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Badr Al-Bawardy ◽  
Raina Shivashankar ◽  
Deborah D. Proctor
Keyword(s):  
Small Molecules ◽  
Intestinal Inflammation ◽  
Janus Kinase ◽  
Treatment Target ◽  
Receptor Modulator ◽  
Emerging Therapies ◽  
Bowel Diseases ◽  
Sphingosine 1 Phosphate ◽  
Inflammatory Bowel ◽  
Systemic Manifestations

Inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn’s disease are chronic, relapsing and remitting disorders of intestinal inflammation with potential systemic manifestations. Despite the availability of current biologics, such as anti-tumor necrosis factor (anti-TNF), anti-integrins, anti-interleukins and small molecules such as tofacitinib, the rates of primary and secondary treatment failure remain high in IBD. This highlights the importance of continued development of new therapeutic targets and modifications of existing ones to improve the treatment response rates and to also improve the safety profile and tolerability of these medications. In this review we will discuss novel treatment target agents including selective janus kinase (JAK) inhibitors, anti-interleukin (IL) (IL-12/IL-23), leukocyte trafficking/migrating inhibitors (such as sphingosine-1-phosphate receptor modulator) and other small molecules currently in development.

Hit the Road JAK! The Role of New Oral Treatment in Inflammatory Bowel Disease

2021 ◽  
Author(s):  
Isabel Garrido ◽  
Susana Lopes ◽  
Guilherme Macedo
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Opportunistic Infections ◽  
Wide Spectrum ◽  
Oral Treatment ◽  
Janus Kinase ◽  
Jak Inhibitors ◽  
The Road ◽  
Inflammatory Bowel

Abstract Crohn disease (CD) and ulcerative colitis (UC) are considered chronic disorders of the gastrointestinal tract, lifelong medication often being necessary. Furthermore, they have significant implications on the quality of life. In the past few years, major advances have been achieved concerning the treatment of inflammatory bowel disease. These advances are expanding the possibilities for managing these patients. Janus kinase (JAK) inhibitors represent the most auspicious treatment to date because they consist of drugs that are orally administered, with a short half-life and low antigenicity. In addition, they seem to concurrently lessen various proinflammatory routes. In fact, tofacitinib has already been approved in patients with UC, both naïve and with prior exposure to tumor necrosis factor inhibitors. In CD, the results with tofacitinib have been less impressive. Several other JAK inhibitors are currently being investigated. However, given the wide spectrum of immunosuppressive effects, special attention has been given to the safety profile of these drugs, namely with regard to the occurrence of thromboembolic events, opportunistic infections, and malignancy. In this article, we review key evidence on the efficacy and safety of JAK inhibitors concerning both UC and CD.

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