Janus Kinase Inhibitors: Next-Generation Treatment for Uveitis

Abstract

A large proportion of patients with visual impairment secondary to non-infectious uveitis may require DMARDs. Although these are highly effective, some patients may require alternatives to the currently available immunomodulators due to an inadequate response or undesirable side effects. Janus Kinase Inhibitors (JAKi) are already approved for several autoimmune diseases in rheumatology, gastroenterology and dermatology. To date, JAKi have been studied in phase 3 trials in various types of uveitis. Mechanism of Action: JAKi work by inhibiting the phosphorylation of Janus kinases, which are transmembrane proteins. This blocks the activation of transcription factors, which in turn downregulates cytokine expression and inflammatory mediators. JAKi represent an extremely effective novel therapeutic approach in rheumatology, gastroenterology and dermatology. They have already been approved for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis and atopic eczema. In earlier comparative studies with conventional biologics, a better therapeutic response was reported in some cases. Several published case reports report reduced cortisone levels in patients with uveitis who had responded poorly to conventional and biological DMARDs. Approval studies are under way for JIA-associated and ANA-positive anterior uveitis. In summary, JAKi represent an innovative treatment option for patients with non-infectious uveitis in whom DMARDs are contraindicated or ineffective.

Key words

uveitis - DMARDs - JAK/Stat pathway - Jak inhibitors

Publikationsverlauf

Eingereicht: 26. Oktober 2021

Angenommen: 14. Januar 2022

Artikel online veröffentlicht:
14. April 2022

• References/Literatur

• 1 Migone TS, Lin JX, Cereseto A. et al. Constitutively activated Jak-STAT pathway in T cells transformed with HTLV-I. Science 1995; 269: 79-81
• 2 Macchi P, Villa A, Giliani S. et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 1995; 377: 65-68
• 3 Fleischmann R, Cutolo M, Genovese MC. 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: 617-629
• 4 Liu J, Hou Y, Sun L. et al. A pilot study of tofacitinib for refractory Behcetʼs syndrome. Ann Rheum Dis 2020; 79: 1517-1520
• 5 Nash P, Kerschbaumer A, Dörner T. et al. Points to consider for the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: a consensus statement. Ann Rheum Dis 2021; 80: 71-87
• 6 Nash P. Clinical use of Jak 1 inhibitors for rheumatoid arthritis. Rheumatology (Oxford) 2021; 60: ii31-ii38
• 7 Mease P, Charles-Schoeman C, Cohen S. et al. Incidence of venous and arterial thromboembolic events reported in the tofacitinib rheumatoid arthritis, psoriasis and psoriatic arthritis development programmes and from real-world data. Ann Rheum Dis 2020; 79: 1400-1413
• 8 Ruperto N, Brunner HI, Zuber Z. et al. Pharmacokinetic and safety profile of tofacitinib in children with polyarticular course juvenile idiopathic arthritis: results of a phase 1, open-label, multicenter study. Pediatr Rheumatol Online J 2017; 15: 86
• 9 Brunner HL. Tofacitinib for the Treatment of Polyarthricular Course Juvenile Idiopathic Arthtitis: Results of a Phase randomised double-blind, Placebo controlled Study. ACR/ARP Annual Meeting. Atlanta; 2019. Im Internet (Stand: 16.02.2022): https://acrabstracts.org/abstract/tofacitinib-for-the-treatment-of-polyarticular-course-juvenile-idiopathic-arthritis-results-of-a-phase-3-randomized-double-blind-placebo-controlled-withdrawal-study/
• 10 Bing SJ, Lyu C, Xu B. et al. Tofacitinib inhibits the development of experimental autoimmune uveitis and reduces the proportions of Th1 but not of Th17 cells. Mol Vis 2020; 26: 641-651
• 11 Paley MA, Karacal H, Rao PK. et al. Tofacitinib for refractory uveitis and scleritis. Am J Ophthalmol Case Rep 2019; 13: 53-55
• 12 Bauermann P, Heiligenhaus A, Heinz C. Effect of Janus Kinase Inhibitor Treatment on Anterior Uveitis and Associated Macular Edema in an Adult Patient with Juvenile Idiopathic Arthritis. Ocul Immunol Inflamm 2019; 27: 1232-1234
• 13 Miserocchi E, Giuffre C, Cornalba M. et al. JAK inhibitors in refractory juvenile idiopathic arthritis-associated uveitis. Clin Rheumatol 2020; 39: 847-851
• 14 [Anonymous] Efficacy Study Of Tofacitinib In Pediatric JIA Population. Im Internet (Stand: 05.12.2021): https://ClinicalTrials.gov/show/NCT02592434
• 15 [Anonymous] Long-Term Safety Study Of Tofacitinib In Patients With Juvenile Idiopathic Arthritis. Im Internet (Stand: 05.12.2021): https://ClinicalTrials.gov/show/NCT01500551
• 16 [Anonymous] Pharmacokinetics Of CP-690,550 In Pediatric Patients With Juvenile Idiopathic Arthritis (JIA). Im Internet (Stand: 05.12.2021): https://ClinicalTrials.gov/show/NCT01513902
• 17 Fleischmann R, Takeuchi T, Schiff M. et al. Efficacy and Safety of Long-Term Baricitinib With and Without Methotrexate for the Treatment of Rheumatoid Arthritis: Experience With Baricitinib Monotherapy Continuation or After Switching From Methotrexate Monotherapy or Baricitinib Plus Methotrexate. Arthritis Care Res (Hoboken) 2020; 72: 1112-1121
• 18 Alten R, Nitschmann S. [Janus kinase inhibitor baricitinib for rheumatoid arthritis: Randomized, double-blind, placebo- and active-controlled, phase 3 study evaluating the efficacy and safety of baricitinib in patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to methotrexate therapy (RA-BEAM)]. Internist (Berl) 2017; 58: 1341-1344
• 19 Wells AF, Greenwald M, Bradley JD. et al. Baricitinib in Patients with Rheumatoid Arthritis and an Inadequate Response to Conventional Disease-Modifying Antirheumatic Drugs in United States and Rest of World: A Subset Analysis. Rheumatol Ther 2018; 5: 43-55
• 20 Wells AF, Jia B, Xie L. et al. Efficacy of Long-Term Treatment with Once-Daily Baricitinib 2 mg in Patients with Active Rheumatoid Arthritis: Post Hoc Analysis of Two 24-Week, Phase III, Randomized, Controlled Studies and One Long-Term Extension Study. Rheumatol Ther 2021; 8: 987-1001
• 21 Sanchez GAM, Reinhardt A, Ramsey S. et al. JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J Clin Invest 2018; 128: 3041-3052
• 22 A Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Upadacitinib in Pediatric Subjects With Polyarticular Course Juvenile Idiopathic Arthritis. Im Internet (Stand: 05.12.2021): https://ClinicalTrials.gov/show/NCT03725007
• 23 Sarny S, Hucke M, El-Shabrawi Y. Treatment of Mucous Membrane Pemphigoid With Janus Kinase Inhibitor Baricitinib. JAMA Ophthalmol 2018; 136: 1420-1422
• 24 A Study of Baricitinib (LY3009104) in Participants From 2 Years to Less Than 18 Years Old With Active JIA-Associated Uveitis or Chronic Anterior Antinuclear Antibody-Positive Uveitis. Im Internet (Stand: 05.12.2021): https://ClinicalTrials.gov/show/NCT04088409
• 25 A Study to Evaluate the Safety and Efficacy of Upadacitinib in Participants With Giant Cell Arteritis. Im Internet (Stand: 05.12.2021): https://ClinicalTrials.gov/show/NCT03725202
• 26 Pavelka K, Szekanecz Z, Damjanov N. et al. Upadacitinib versus placebo or adalimumab with background methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate: a subgroup analysis of a phase III randomized controlled trial in Central and Eastern European patients. Drugs Context 2020; 9: 2020-7-5
• 27 Avci AB, Feist E, Burmester GR. Early phase studies of JAK1 selective inhibitors in rheumatoid arthritis. Rheumatology (Oxford) 2021; 60: ii11-ii16
• 28 Du L, Yip YWY, Ng HK. et al. Ruxolitinib Alleviates Uveitis Caused by Salmonella typhimurium Endotoxin. Microorganisms 2021; 9: 1481
• 29 Harrington R, Al Nokhatha SA, Conway R. JAK Inhibitors in Rheumatoid Arthritis: An Evidence-Based Review on the Emerging Clinical Data. J Inflamm Res 2020; 13: 519-531
• 30 Mori S, Ogata F, Tsunoda R. Risk of venous thromboembolism associated with Janus kinase inhibitors for rheumatoid arthritis: case presentation and literature review. Clin Rheumatol 2021; 40: 4457-4471
• 31 Xie W, Huang Y, Xiao S. et al. Impact of Janus kinase inhibitors on risk of cardiovascular events in patients with rheumatoid arthritis: systematic review and meta-analysis of randomised controlled trials. Ann Rheum Dis 2019; 78: 1048-1054
• 32 Genovese MC, Smolen JS, Takeuchi T. et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis over a median of 3 years of treatment: an updated integrated safety analysis. Lancet Rheumatol 2020; 2: e347-e357
• 33 A Study of Baricitinib in Participants With Rheumatoid Arthritis. Im Internet (Stand: 05.12.2021): https://ClinicalTrials.gov/show/NCT04086745
• 34 He C, Yu CR, Mattapallil MJ. et al. SOCS1 Mimetic Peptide Suppresses Chronic Intraocular Inflammatory Disease (Uveitis). Mediators Inflamm 2016; 2016: 2939370
• 35 Jessica Chang TY, Pope JE. How COVID-19 affects patients receiving anticytokine and JAK inhibitors in rheumatology and dermatology. Immunotherapy 2020; 12: 1115-1119
• 36 Haberman R, Axelrad J, Chen A. et al. Covid-19 in Immune-Mediated Inflammatory Diseases – Case Series from New York. N Engl J Med 2020; 383: 85-88
• 37 Iancovici L, Khateeb D, Harel O. et al. Rheumatoid arthritis patients treated with Janus kinase inhibitors show reduced humoral immune responses following BNT162b2 vaccination. Rheumatology (Oxford) 2021;