Efficacy and Safety of Janus Kinase Inhibitors in Lupus Nephritis Patients- Clinical Trials and Case Reports
Main Article Content
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect multiple organs and systems that has a variable clinical course and prognosis among different patients. Lupus nephritis (LN) is one of the most common and severe organ manifestations of SLE which is associated with significant morbidity and mortality with up to 20% of patients progressing to end stage renal disease. Despite the improvements in therapeutic options, there is a significant proportion of refractory patients and a considerable amount of damage accrual and treatment associated morbidity even among patients that respond to the current treatment modalities. Janus kinase (JAK) inhibitors are currently successfully used in rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis patients. JAK inhibitors simultaneously block the signalling of multiple cytokines and represent a promising class of therapeutic agents for SLE which has a high immunological heterogeneity. Some animal studies demonstrated the significance of JAK/STAT pathway in the pathogenesis of LN and the possible role of JAK inhibitors in alleviating the renal inflammation in animal models of LN. This review covers the clinical data on the use of JAK inhibitors in LN patients by focusing on the clinical trials and few case reports that assess the efficacy and safety of JAK inhibitors in LN patients.
Article Details
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
2. Richter P, Cardoneanu A, Burlui AM, Macovei LA, Bratoiu I, Buliga-Finis ON, Rezus E. Why Do We Need JAK Inhibitors in Systemic Lupus Erythematosus? Int J Mol Sci. 2022 Oct 4;23 (19):11788. doi: 10.3390/ijms231911788.
3. Alforaih N, Whittall-Garcia L, Touma Z. A Review of Lupus Nephritis. J Appl Lab Med. 2022 Oct 29;7(6):1450-1467. doi: 10.1093/jalm/jfac036.
4. Anders HJ, Saxena R, Zhao MH, Parodis I, Salmon JE, Mohan C. Lupus nephritis. Nat Rev Dis Primers. 2020 Jan 23;6(1):7. doi: 10.1038/s41572-019-0141-9.
5. Lazar S, Kahlenberg JM. Systemic Lupus Erythematosus: New Diagnostic and Therapeutic Approaches. Annu Rev Med. 2023 Jan 27;74:339-352. doi: 10.1146/annurev-med-043021-032611.
6. Nakayamada S, Tanaka Y. Novel JAK inhibitors under investigation for systemic lupus erythematosus: - where are we now? Expert Opin Investig Drugs. 2023 Jul-Dec;32(10):901-908. doi: 10.1080/13543784.2023.2264172.
7. Hu X, Li J, Fu M, Zhao X, Wang W. The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther. 2021 Nov 26;6(1): 402. doi: 10.1038/s41392-021-00791-1.
8. Yamaoka K, Oku K. JAK inhibitors in rheumatology. Immunol Med. 2023 Sep;46(3):143-152. doi: 10.1080/25785826.2023.2172808.
9. 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 Sep 14;13:519-531. doi: 10.2147/JIR.S219586.
10. Ytterberg SR, Bhatt DL, Mikuls TR, Koch GG, Fleischmann R, Rivas JL, Germino R, Menon S, Sun Y, Wang C, Shapiro AB, Kanik KS, Connell CA; ORAL Surveillance Investigators. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. N Engl J Med. 2022 Jan 27;386(4):316-326. doi: 10.1056/NEJMoa2109927.
11. Wang S, Yang N, Zhang L, Huang B, Tan H, Liang Y, Li Y, Yu X. Jak/STAT signaling is involved in the inflammatory infiltration of the kidneys in MRL/lpr mice. Lupus. 2010 Sep;19(10):1171-80. doi: 10.1177/0961203310367660.
12. Zhou M, Guo C, Li X, Huang Y, Li M, Zhang T, Zhao S, Wang S, Zhang H, Yang N. JAK/STAT signaling controls the fate of CD8+CD103+ tissue-resident memory T cell in lupus nephritis. J Autoimmun. 2020 May;109:102424.
doi: 10.1016/j.jaut.2020.102424.
13. Yan Q, Chen W, Song H, Long X, Zhang Z, Tang X, Chen H, Lin H, Sun L. Tofacitinib Ameliorates Lupus Through Suppression of T Cell Activation Mediated by TGF-Beta Type I Receptor. Front Immunol. 2021 Jul 29;12:675542. doi: 10.3389/fimmu.2021.675542.
14. Lee J, Park Y, Jang SG, Hong SM, Song YS, Kim MJ, Baek S, Park SH, Kwok SK. Baricitinib Attenuates Autoimmune Phenotype and Podocyte Injury in a Murine Model of Systemic Lupus Erythematosus. Front Immunol. 2021 Aug 23;12: 704526. doi: 10.3389/fimmu.2021.704526.
15. Lu LD, Stump KL, Wallace NH, Dobrzanski P, Serdikoff C, Gingrich DE, Dugan BJ, Angeles TS, Albom MS, Mason JL, Ator MA, Dorsey BD, Ruggeri BA, Seavey MM. Depletion of autoreactive plasma cells and treatment of lupus nephritis in mice using CEP-33779, a novel, orally active, selective inhibitor of JAK2. J Immunol. 2011 Oct 1;187(7):3840-53. doi: 10.4049/jimmunol.1101228.
16. Lei Y, Sehnert B, Voll RE, Jacobs-Cachá C, Soler MJ, Sanchez-Niño MD, Ortiz A, Bülow RD, Boor P, Anders HJ. A multicenter blinded preclinical randomized controlled trial on Jak1/2 inhibition in MRL/MpJ-Faslpr mice with proliferative lupus nephritis predicts low effect size. Kidney Int. 2021 Jun;99(6):1331-1341.
doi: 10.1016/j.kint.2021.01.024..
17. Baker M, Chaichian Y, Genovese M, Derebail V, Rao P, Chatham W, Bubb M, Lim S, Hajian H, Gurtovaya O, Patel U, Tumlin J. Phase II, randomised, double-blind, multicentre study evaluating the safety and efficacy of filgotinib and lanraplenib in patients with lupus membranous nephropathy. RMD Open. 2020 Dec;6(3):e001490. doi: 10.1136/ rmdopen-2020-001490.
18. Bristol-Myers Squibb. An Investigational Study to Evaluate the Safety and Effectiveness of BMS-986165 With Background Treatment in Participants With Lupus Nephritis. ClinicalTrials.gov identifier: NCT03943147. Updated 17 October, 2022. Accessed 15 October 2024. https://clinicaltrials.gov/study/NCT03943147
19. Hassanien M. Efficiency of Use of Baracetinib in Treatment of Lupus Nephritis. ClinicalTrials.gov identifier: NCT05432531. Updated 4 January 2023. Accessed 20 October 2024.
https://clinicaltrials.gov/study/NCT05432531
20. Garufi C, Mancuso S, Spinelli FR, Truglia S, Ceccarelli F, Alessandri C, Conti F. Janus kinases inhibitors for treating patients with rhupus. Joint Bone Spine. 2020 Dec;87(6):673-674. doi: 10.1016/j.jbspin.2020.05.010.
21. Peng J, Wang Y, Han X, Zhang C, Chen X, Jin Y, Yang Z, An Y, Zhang J, Liu Z, Chen Y, Gao E, Zhang Y, Xu F, Zheng C, Zhou Q, Liu Z. Clinical Implications of a New DDX58 Pathogenic Variant That Causes Lupus Nephritis due to RIG-I Hyperactivation. J Am Soc Nephrol. 2023 Feb 1;34 (2):258-272. doi: 10.1681/ASN.2022040477
22. Strand V. Clinical trial design in systemic lupus erythematosus: lessons learned and future directions. Lupus. 2004;13(5):406-11. doi: 10.1191/0961203303lu1034oa. PMID: 15230300.