Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 
  • Users Online: 260
  • Home
  • Print this page
  • Email this page

   Table of Contents      
COMMENTARY
Year : 2020  |  Volume : 68  |  Issue : 9  |  Page : 1939-1940

Commentary: Janus kinase inhibitors and their use in autoimmune ocular inflammatory disorders


Department of Ophthalmology, Bombay Hospital Institute of Medical Sciences, Mumbai, Maharashtra, India

Date of Web Publication20-Aug-2020

Correspondence Address:
Mayur R Moreker
4th Floor, New Wing, Bombay Hospital. 12, New Marine Lines. Mumbai - 400 020, Maharashtra
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijo.IJO_1656_20

Rights and Permissions

How to cite this article:
Moreker MR. Commentary: Janus kinase inhibitors and their use in autoimmune ocular inflammatory disorders. Indian J Ophthalmol 2020;68:1939-40

How to cite this URL:
Moreker MR. Commentary: Janus kinase inhibitors and their use in autoimmune ocular inflammatory disorders. Indian J Ophthalmol [serial online] 2020 [cited 2020 Sep 22];68:1939-40. Available from: http://www.ijo.in/text.asp?2020/68/9/1939/292540



Each autoimmune inflammatory disease has a cytokine profile of its own which is important in pathogenesis of that disease. Management of autoimmune inflammatory diseases requires regulation of associated elevated cytokine signaling and further its uncontrolled cytokine effects. Previously, inhibition of cytokine functions by monoclonal antibodies against cytokines or their receptors has been successfully used to control inflammatory diseases.[1]

The Janus kinase (JAK) family of nonreceptor tyrosine kinases that transduce signals from cytokines are key intracellular components of cytokine signaling. Recently, there has been interest in the management of systemic autoimmune inflammatory diseases by moderating them.[1] In mammals, the JAK–signal transducers and activators of transcription (STAT) pathways are constituted of four JAK kinases (JAK1–3 and tyrosine kinase 2 [TYK2]) and seven STATs (STAT1–6, including homologs STAT5a and STAT5b).

The all-important “signaling cascade” is initiated by cytokine binding to its receptor (cytokine receptor).

  • This leads to association/rearrangement of the receptor subunits
  • This leads to JAK activation by transphosphorylation
  • Activated JAKs phosphorylate the receptors, allowing STATs to bind to the receptor
  • This leads to the STATs become phosphorylated
  • The phosphorylated STATs then form either homo- or heterodimers, which translocate into the nucleus where they bind their cognate promoter elements to regulate transcription of target genes.[1]


Each cytokine receptor is known to recruit a specific combination of JAK kinases. This becomes important and allows for potentially targeting of JAKs in the management of autoimmune inflammatory diseases.[1]

The interest in Janus kinase inhibitors (JAKinibs) started after the identification of JAK3 as a key regulator of lymphocytes and the development of tofacitinib. Herein, we specifically first take the example of a systemic autoimmune inflammatory disease like rheumatoid arthritis (RA) to understand tofacitinib. Cytokines including tumor necrosis factor (TNF) alpha, interleukin (IL)-1, IL-6, IL-7, IL-15, IL-17, IL-18, IL-21, IL-23, IL-32, IL-33, and granulocyte-macrophage colony-stimulating factor (GM-CSF) have vital roles in pathogenesis of RA.[2] Of these, TNF, IL-1, and IL-6 signaling pathways have previously been successfully targeted with biological drugs. IL-6 inhibitor tocilizumab, a monoclonal antibody, thus finds a role in the management of RA.[3] However, these biological agents are large proteins. They require either intravenous or subcutaneous injection and may cause immunogenicity. IL-6 signals through the above mentioned JAK kinases (JAK1, JAK2, and/or TYK2) which phosphorylate and activate STAT3. This has led to obvious interest in smaller molecule inhibitors of the cytokine signaling pathways. Herein, may lie the role of a Janus kinase inhibitor like tofacitinib. Tofacitinib, a Janus kinase (JAK3/JAK1) inhibitor, is the first JAK inhibitor approved by the US Food and Drug Administration in November 2012 and European Medicines Agency in March 2017 for the treatment of moderate-to-severe active RA in patients with an inadequate response to methotrexate. Tofacitinib (5 mg twice daily) alone and in combination with methotrexate is found to be efficacious and the clinical response is felt to be similar to TNF antagonists.[4],[5] Tofacitinib has a rapid onset of action of 2–4 weeks (in combination with methotrexate) compared with placebo [4] and is generally well-tolerated with adverse reactions like infections (that are also otherwise typical for biologics), reduction in CD4 + T cell count, elevation of cholesterol levels, headache, and slight reversible increases in serum creatinine levels.[1] The increased risk of herpes zoster distinguishes its safety profile from that of biological agents. But the relative short half-life of these JAKinibs makes it possible to expect a quick reversal of their immunosuppressive effect in case of an infection.[1]

As far as ocular inflammatory disorders are concerned, IL-2, IL-6, and IL-23 all activate JAK-STAT signaling and use of monoclonal antibodies like daclizumab, tocilizumab, and ustekinumab that block them have previously been reported to be efficacious in uveitis. Thus understandably, JAKinibs targeting JAK-STAT signaling may be felt to be effective in uveitis. Indeed, there are initial reports of a favorable clinical response of ocular inflammation to tofacitinib. In two patients from a single previous publication (refractory uveitis and scleritis), where tofacitinib was used in combination with methotrexate,[6] as well as, in one patient in a recent publication [7] (Vogt–Koyanagi–Harada Disease), where tofacitinib was used in combination with oral prednisolone, clinical effect of tofacitinib was noted approximately 4 weeks after the initiation of therapy and this is similar to the previous experience in RA.[4] An 8-week administration of topical tofacitinib has been reported to be well tolerated with reduction of markers of ocular surface inflammation in dry eye disease.[8] Thus, the role of JAKinibs like tofacitinib, for ocular inflammatory disorders, both in the presence and absence of systemic disease is indeed exciting and definitely warrants further interest.



 
  References Top

1.
Virtanen AT, Haikarainen T, Raivola J, Silvennoinen O. Selective JAKinibs: Prospects in inflammatory and autoimmune diseases. BioDrugs 2019;33:15-32.  Back to cited text no. 1
    
2.
McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med 2011;365:2205-19.  Back to cited text no. 2
    
3.
Isomäki P, Junttila I, Vidqvist KL, Korpela M, Silvennoinen O. The activity of JAK-STAT pathways in rheumatoid arthritis: Constitutive activation of STAT3 correlates with interleukin 6 levels. Rheumatology 2015;54:1103-13.  Back to cited text no. 3
    
4.
van Vollenhoven R, Fleischmann R, Cohen S, Lee E, García Meijide J, Wagner S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med 2012;367:508-19.  Back to cited text no. 4
    
5.
Fleischmann R, Cutolo M, Genovese M, Lee E, Kanik K, Sadis S, et al. Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum 2012;64:617-29.  Back to cited text no. 5
    
6.
Paley MA, Karacal H, Rao PK, Margolis TP, Miner JJ. Tofacitinib for refractory uveitis and scleritis. Am J Ophthalmol Case Rep 2018;13:53-5.  Back to cited text no. 6
    
7.
Dutta Majumder P, Shah A, Kaushik V. Tofacitinib in Vogt-Koyanagi-Harada disease. Indian J Ophthalmol 2020;68:1938-9.  Back to cited text no. 7
    
8.
Huang JF, Yafawi R, Zhang M, McDowell M, Rittenhouse KD, Sace F, et al. Immunomodulatory effect of the topical ophthalmic Janus kinase inhibitor tofacitinib (CP-690,550) in patients with dry eye disease. Ophthalmology 2012;119:e43-50.  Back to cited text no. 8
    




 

Top
 
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
References

 Article Access Statistics
    Viewed238    
    Printed2    
    Emailed0    
    PDF Downloaded58    
    Comments [Add]    

Recommend this journal