How XELJANZ Works

An alternative MoA targeting the JAK pathway1–3

XELJANZ inhibits the effects of pro-inflammatory cytokines through intracellular targeting of the JAK pathway3

  • XELJANZ works inside the cell to inhibit inflammation by blocking JAK-dependent signalling pathways4
  • This reduces the production of multiple pro-inflammatory cytokines4,5

XELJANZ in Action

JAK, Janus kinase; MOA, mode of action

References:
1. XELJANZ Summary of Product Characteristics.
2. Tanaka Y, Yamaoka K. Mod Rheumatol 2012; 23:415–424.
3. Fleischmann R. Curr Opin Rheumatol 2012; 24:335–341.
4. O’Shea JJ et al. Annu Rev Med 2015; 66:311–328.
5. McInnes IB, Liew FY. Nat Clin Pract Rheumatol 2005; 1:31–39

Summary of Product Characteristics       XELJANZ Prescribing Information

PP-XEL-GBR-2244. March 2020

Cytokines

The immune system is a complex but coordinated system of cells, tissues, and soluble molecules that constitute the body's defence against invasion by non-self entities, including infectious and inert agents and tumor cells.1

Immune homeostasis is the delicate balance of all immune responses used to fight disease.2 Immune homeostasis is affected by a number of different factors, both inherited and acquired:


Immune homeostasis naturally fluctuates over time, but in some cases the balance of pro-inflammatory and anti-inflammatory responses can shift to a new equilibrium, leading to diseases characterized by chronic immunosuppression or chronic inflammation.2

  • Chronic immunosuppression: too little inflammation may allow uncontrolled growth of pathogens or cancer cells
  • Chronic inflammation: too much inflammation may cause a variety of autoimmune conditions affecting one or several organ systems
References:
1. Murphy K, Weaver C. Janeway’s Immunobiology. 9th ed. New York, NY: Garland Science, Taylor & Francis Group, LLC; 2016.
2. Crimeen-Irwin B, et al. Failure of immune homeostasis -- the consequences of under and over reactivity. Curr Drug Targets Immune Endocr Metabol Disord 2005;5(4):413-422.

 

Cytokines regulate many biological processes

Cytokines (greek, cyto- ‘cell’ & kinos – ‘movement’) are small molecules that mediate communication between cells resulting in:1
• attraction of inflammatory and immune cells to a site within the body
• activation of cells to release products that lead to tissue destruction

Cytokines may be classified according to function;1 however, the definition of cytokine function is ever-changing, with many cytokines playing multiple roles and falling into more than one category:

  • Inflammatory Response: The traditional paradigm of ‘pro-inflammatory’ and ‘anti-inflammatory’ cytokines has been challenged in recent years, and it should be noted that individual cytokines can exert diverse and even opposing effects, depending on the environment in which they are acting.2 Cytokines that are commonly seen as ‘pro-inflammatory’ cytokines include the TNF/TNF superfamily and IL 1 superfamily,2 amongst others. Examples of ‘anti-inflammatory’ cytokines include IL4, IL-10, IL-13, IFN-α and TGF-β. Furthermore, specific cytokine receptors for IL-1, TNFα, and IL-18 also function as pro-inflammatory cytokine inhibitors.3
  • Chemotaxis: Chemotactic cytokines (‘chemokines’) stimulate the migration and activation of cells, especially phagocytic cells and lymphocytes. In the inflammatory response, they regulate the chemotaxis (movement in response to chemicals) of leukocytes, generally by attracting them to the site of inflammation.1 
  • Hematopoiesis: Hematopoietic cytokines are those known to be related to the formation of blood cells;4 e.g. erythropoietin, G-CSF and GM-CSF.5
  • Growth and differentiation: Some cytokines are growth factors (e.g. G-CSF and GM-CSF), which promote growth and development by directing cell maturation and differentiation and by mediating maintenance and repair of tissues.4
References:
1. Murphy K, Weaver C. Janeway’s Immunobiology. 9th ed. New York, NY: Garland Science, Taylor & Francis Group, LLC; 2016.
2. Muzes G et al. Changes of the cytokine profile in inflammatory bowel disease. World J Gastroenterol 2012:18(41):5848-5861
3. Opal SM & DePalo VA. Anti-inflammatory cytokines. Chest 2000;117(4):1162-1172.
4. Stedman TL. Stedman’s Medical Dictionary. 28th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006.
5. Metcalf D. Hematopoietic cytokines. Blood. 2008: 11(2):485-491.

 

Cytokines drive the inflammatory response in autoimmune diseases

In immune homeostasis, a complex network of cytokines balances pro-inflammatory and anti-inflammatory effects.1,2 Autoimmune diseases are, broadly speaking, the result of an imbalance between pro- and anti-inflammatory cytokines. In chronic autoimmune diseases, for example rheumatoid arthritis, joint destruction is driven by cytokine release.


* IL-1Rα , IL-18BP , IL-10 , TGFβ , IL-11 , IL-13.
** FTNF , LT , IL-1β , IL-6 , IL-7 , IL-8 , IL-12, IL-17, IL-18 , IL-23 , IFN

 

Cytokine loops: Continuing the inflammatory signal

The chronic inflammatory state in autoimmune diseases occurs as a result of a continuing pro-inflammatory ‘cytokine loops’ whereby cytokines attract and stimulate immune cells to release more cytokines, which further stimulate production of cytokines. This process can lead to perpetuation or amplification of the inflammatory state.2


References:
1. Chizzolini C, et al. Cytokines in chronic rheumatic diseases: is everything lack of homeostatic balance? Arthritis Res Ther 2009; 11(5): 246-256.
2. McInnes IB, Liew FY. Cytokine networks-towards new therapies for rheumatoid arthritis. Nat Clin Pract Rheumatol 2005; 1(1): 31-39.

 

Summary of Product Characteristics       XELJANZ Prescribing Information

PP-XEL-GBR-2243. March 2020

 

 

Intracellular signalling pathways

Cytokines operate in the extracellular environment, stimulating cells via cell surface receptors.1 For the cell to act on the cytokine signal, an intracellular signal must reach the nucleus and stimulate gene transcription.1 There are a number of intracellular pathways that are known to transmit signals from cytokine receptors at the cell surface to the cell nucleus (see diagram). Many integral membrane-bound cytokine receptors have intrinsic enzymatic activity and can trigger transmission of signals within the cell on their own. However, some receptors (type I and II cytokine receptors) lack this intrinsic enzymatic activity and must associate with cytoplasmic kinases, known as Janus kinases (JAKs), to initiate signal transmission within the cell.

JAK pathways: Janus kinases (JAKs) are involved in signalling by multiple different cytokines and are key mediators in the activation of the inflammatory response. JAKs associate with intracellular messenger proteins called STATs (signal transducers and activators of transcription) to transmit signals from cell surface receptors to the nucleus. The pathway is therefore also referred to as the JAK-STAT pathway. JAK-STAT signalling (primarily via JAK2) is also known to be important in hematopoiesis.2

MAPK pathways: Mitogen-activated protein kinases (MAPK) are a family of intracellular proteins, including ERK, p38 and JNK, which are involved in regulating a variety of cellular activities including proliferation, differentiation, survival, and death. MAPK pathways are implicated in the development of various types of cancer (via ERK) and neurodegenerative diseases (via p38 or JNK).3

SYK pathways: Spleen tyrosine kinase (SYK) and its homologue ZAP70 are known to relay adaptive immune receptor signalling but are also found in insects, suggesting a role in innate immunity as insects do not have an adaptive immune system. SYK and ZAP70 are also known to mediate diverse functions related to cellular adhesion, bone metabolism, vascular development and activation of platelets.4

NF-κB pathways: The nuclear factor-kappa B (NF-κB) family of transcription factors are crucial in signalling related to various biological processes, including immune response, inflammation, cell growth and survival, and development. Abnormal NF-κB signalling is implicated in the pathogenesis of a variety of autoimmune diseases and cancers.5

PI-3K pathways: Phosphoinositide 3-kinases (PI-3K) phosphorylate membrane-bound lipids to produce specific molecular messengers within the membrane, which stimulate complex signalling pathways to transfer a signal to the nucleus. PI-3K pathways are always activated in parallel with other intracellular signalling pathways, so the precise effects of their activation are difficult to define. However, certain Class I PI-3Ks are known to be involved in T- and B-cell development and differentiation and chemotaxis of immune cells to the site of inflammation.6

1. Murphy K, Weaver C. Janeway’s Immunobiology. 9th ed. New York, NY: Garland Science, Taylor & Francis Group, LLC; 2016.
2. Ghoreschi K, et al. Janus kinases in immune cell signalling. Immunol Rev 2009; 228(1): 273–287.
3. Kim EK, Choi EJ. Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta 2010;1802:396-405.
4. Mócsai A, et al. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat Rev Immunol 2010;10(6):387–402.
5. Park MH, Hong JT. Roles of NF-kB in cancer and inflammatory diseases and their therapeutic approaches. Cells. 2016;5(2):15.
6. Hawkins PT, Stephens LR. PI3K signalling in inflammation. Biochim Biophys Acta 2015;1851:882-897.

 

JAK pathways are key mediators in the activation of the inflammatory response

JAK is a family of non-receptor protein tyrosine kinases (PTKs) located in the cytoplasm of cells, rather than on the cell surface. When activated, JAKs stimulate a cascade involved in the production of pro-inflammatory cytokines. Overactivation of JAK can lead to inflammation and tissue destruction.1,2

The JAK family consists of 4 members: JAK1, JAK2, JAK3, and TYK2 (tyrosine kinase 2):1,3

  • JAK1, JAK2, and TYK2 are ubiquitously expressed
  • JAK3 (which pairs with JAK 1) is predominately expressed in hematopoietic cells

Each JAK protein has specificity for a different set of cytokine receptors.3

  • The function of the JAK protein is linked to the function of the cytokines that bind the receptors:

 

JAK dimers and STAT combinations

JAK subunits must form dimers in order to transmit the signal from the cell surface receptor. The Subunits can form either homodimers (e.g. JAK2/JAK2) or heterodimers (e.g. JAK1/JAK3).

Each JAK pairing has specificity for a different set of cytokines.4

Each JAK dimer transfers its signal to the nucleus through activation of one or more members of the STAT family of transcription factors. There are seven STAT family members: STAT 1, 2, 3, 4, 5a, 5b and 6. The precise combinations of JAKs and STATs involved in signalling differs between cytokine receptors.1,4,6,7

*Type II cytokine receptors such as those for IL-10, Il-19, IL-22 as well as gp130 subunit sharing receptors for IL-6 and IL-11 mainly signal through JAK 1, but also associate with JAK 2 AND TYK2.1

References:
1. Ghoreschi K, et al. Janus kinases in immune cell signalling. Immunol Rev 2009; 228(1): 273–287.
2. Smolen JS, Steiner G. Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov 2003; 2(6): 473–488.
3. Pesu M, et al. Therapeutic targeting of Janus kinases. Immunol Rev 2008; 223: 132–142.
4. Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol 2007; 178(5): 2623-2629.
5. Leonard WJ. Cytokines and immunodeficiency diseases. Nat Rev Immunol 2001; 1(3): 200-208.
6. O’Sullivan LA, et al. Cytokine receptor signaling through the Jak-Stat-Socs pathway in disease. Mol Immunol 2007;44:2497-2506.
7. Murphy K, Weaver C. Janeway’s Immunobiology. 9th ed. New York, NY: Garland Science, Taylor & Francis Group, LLC; 2016.

 

Summary of Product Characteristics       XELJANZ Prescribing Information

PP-XEL-GBR-2245. March 2020