Rheumatoid Arthritis and JAK-STAT Inhibitors: Prospects of Topical
Delivery

Suchitra      Nishal; Vikas      Jhawat; Parmita      Phaugat; Rohit      Dutt
doi:10.2174/1574885517666220329185842
Abstract

Rheumatoid arthritis (RA) is the most common musculoskeletal disease in the world. The clinical prospects have increased tremendously since the advent of biological agents as therapy options. NSAIDs such as indomethacin, celecoxib, and etoricoxib are used often in the treatment of RA but off-target effects decrease their use. DMARDs such as methotrexate and etanercept were also effective in the treatment of RA, but tolerance to methotrexate developed in many cases. Janus kinase inhibitors (JAKi) have also gained popularity as a treatment option for rheumatoid arthritis. Tofacitinib is the foremost JAK inhibitor used to treat RA as an individual agent or in combination with other DMARDs. The most frequently used route of administration for JAKi is oral. Since oral formulations of JAK inhibitors have a number of health hazards, such as systemic toxicity and patient noncompliance, topical formulations of JAK inhibitors have emerged as a preferable alternative for administering JAK inhibitors. Tofacitinib delivered topically seems to have the potential to eliminate or reduce the occurrences of negative effects when compared to tofacitinib taken orally. Given the scarcity of knowledge on the techniques for topical distribution of JAKi, more effort will be required to develop a stable topical formulation of JAKi to address the limitations of the oral route. The current review looks at JAK inhibitors and how they have been used to generate topical formulations of them.
Keywords: Rheumatoid arthritis, NSAIDs, DMARDs, JAK-STAT inhibitors, tofacitinib, topical formulations.
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[1] 
Perricone C, Shoenfeld Y. Mosaic of autoimmunity: The novel factors of autoimmune diseases.  Academic Press 2019; pp. 7-11.
[http://dx.doi.org/10.1016/B978-0-12-814307-0.00002-5] 
[2] 
Kahlenberg JM, Fox DA. Advances in the medical treatment of rheumatoid arthritis. Hand Clin  2011; 27(1): 11-20.
[http://dx.doi.org/10.1016/j.hcl.2010.09.002] [PMID:  21176795] 
[3] 
Cherascu B. Diagnosing rheumatoid arthritis. Virtual Mentor  2011; 13(5): 295-8.
[PMID:  23131360] 
[4] 
Malemud CJ. The role of the JAK/STAT signal pathway in rheumatoid arthritis. Ther Adv Musculoskelet Dis  2018; 10(5-6): 117-27.
[http://dx.doi.org/10.1177/1759720X18776224] [PMID:  29942363] 
[5] 
Yen JH, Moore BE, Nakajima T, et al. Major histocompatibility complex class I-recognizing receptors are disease risk genes in rheumatoid arthritis. J Exp Med  2001; 193(10): 1159-67.
[http://dx.doi.org/10.1084/jem.193.10.1159] [PMID:  11369787] 
[6] 
McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med  2011; 365(23): 2205-19.
[http://dx.doi.org/10.1056/NEJMra1004965] [PMID:  22150039] 
[7] 
Littlejohn EA, Monrad SU. Early diagnosis and treatment of rheumatoid arthritis. Prim Care  2018; 45(2): 237-55.
[http://dx.doi.org/10.1016/j.pop.2018.02.010] [PMID:  29759122] 
[8] 
Combe B. Progression in early rheumatoid arthritis. Best Pract Res Clin Rheumatol  2009; 23(1): 59-69.
[http://dx.doi.org/10.1016/j.berh.2008.11.006] [PMID:  19233046] 
[9] 
Neumann E, Lefèvre S, Zimmermann B, Gay S, Müller-Ladner U. Rheumatoid arthritis progression mediated by activated synovial fibroblasts. Trends Mol Med  2010; 16(10): 458-68.
[http://dx.doi.org/10.1016/j.molmed.2010.07.004] [PMID:  20739221] 
[10] 
Tak PP, Bresnihan B. The pathogenesis and prevention of joint damage in rheumatoid arthritis: Advances from synovial biopsy and tissue analysis. Arthritis Rheum  2000; 43(12): 2619-33.
[http://dx.doi.org/10.1002/1529-0131(200012)43:12<2619:AID-ANR1>3.0.CO;2-V] [PMID:  11145019] 
[11] 
Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet  2001; 358(9285): 903-11.
[http://dx.doi.org/10.1016/S0140-6736(01)06075-5] [PMID:  11567728] 
[12] 
Oliver JE, Silman AJ. Risk factors for the development of rheumatoid arthritis. Scand J Rheumatol  2006; 35(3): 169-74.
[http://dx.doi.org/10.1080/03009740600718080] [PMID:  16766362] 
[13] 
Byram K, Chinratanalab S, Sergent J. Essentials of physical medicine and rehabilitation. In: E-Book: Musculoskeletal disorders, pain, and rehabilitation.  Elsevier 2020; pp. 876-1.
[http://dx.doi.org/10.1016/B978-0-323-54947-9.00152-8] 
[14] 
Klareskog L, Padyukov L, Rönnelid J, Alfredsson L. Genes, environment and immunity in the development of rheumatoid arthritis. Curr Opin Immunol  2006; 18(6): 650-5.
[http://dx.doi.org/10.1016/j.coi.2006.06.004] [PMID:  17010589] 
[15] 
Livshits G, Kalinkovich A. Hierarchical, imbalanced pro-inflammatory cytokine networks govern the pathogenesis of chronic arthropathies. Osteoarthritis Cartilage  2018; 26(1): 7-17.
[http://dx.doi.org/10.1016/j.joca.2017.10.013] [PMID:  29074297] 
[16] 
Guo Q, Wang Y, Xu D, Nossent J, Pavlos NJ, Xu J. Rheumatoid arthritis: Pathological mechanisms and modern pharmacologic therapies. Bone Res  2018; 6(1): 15.
[http://dx.doi.org/10.1038/s41413-018-0016-9] [PMID:  29736302] 
[17] 
O’Shea JJ, Kontzias A, Yamaoka K, Tanaka Y, Laurence A. Janus kinase inhibitors in autoimmune diseases. Ann Rheum Dis  2013; 72(Suppl. 2): ii111-5.
[http://dx.doi.org/10.1136/annrheumdis-2012-202576] [PMID:  23532440] 
[18] 
Jung SM, Kim KW, Yang CW, Park SH, Ju JH. Cytokine-mediated bone destruction in rheumatoid arthritis. J Immunol Res  2014; 2014: 263625.
[http://dx.doi.org/10.1155/2014/263625] [PMID:  25295284] 
[19] 
Fearon U, Hanlon MM, Wade SM, Fletcher JM. Altered metabolic pathways regulate synovial inflammation in rheumatoid arthritis. Clin Exp Immunol  2019; 197(2): 170-80.
[http://dx.doi.org/10.1111/cei.13228] [PMID:  30357805] 
[20] 
Taylor PC. Aetiopathology of rheumatoid arthritis. Medicine (Baltimore)  2014; 42(5): 227-30.
[http://dx.doi.org/10.1016/j.mpmed.2014.02.010] 
[21] 
Kawai VK, Stein CM, Perrien DS, Griffin MR. Effects of anti-tumor necrosis factor α agents on bone. Curr Opin Rheumatol  2012; 24(5): 576-85.
[http://dx.doi.org/10.1097/BOR.0b013e328356d212] [PMID:  22810364] 
[22] 
Zou S. Five balances in the management of rheumatoid arthritis. J Biosci Med (Irvine)  2017; 5(9): 10-21.
[http://dx.doi.org/10.4236/jbm.2017.59002] 
[23] 
Sivalingam SP, Thumboo J, Vasoo S, Thio ST, Tse C, Fong KY. In vivo pro- and anti-inflammatory cytokines in normal and patients with rheumatoid arthritis. Ann Acad Med Singap  2007; 36(2): 96-9.
[PMID: 17364074] 
[24] 
Isomäki P, Punnonen J. Pro- and anti-inflammatory cytokines in rheumatoid arthritis. Ann Med  1997; 29(6): 499-507.
[http://dx.doi.org/10.3109/07853899709007474] [PMID:  9562516] 
[25] 
Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol  1996; 14(1): 397-440.
[http://dx.doi.org/10.1146/annurev.immunol.14.1.397] [PMID:  8717520] 
[26] 
Brennan FM, Maini RN, Feldmann M. Role of pro-inflammatory cytokines in rheumatoid arthritis. Springer Semin Immunopathol  1998; 20(1-2): 133-47.
[http://dx.doi.org/10.1007/BF00832003] 
[27] 
Clark AR, Dean JL. The p38 MAPK pathway in rheumatoid arthritis: A sideways look. Open Rheumatol J  2012; 6: 209-19.
[http://dx.doi.org/10.2174/1874312901206010209] [PMID:  23028406] 
[28] 
Guma M, Hammaker D, Topolewski K, et al. Antiinflammatory functions of p38 in mouse models of rheumatoid arthritis: Advantages of targeting upstream kinases MKK-3 or MKK-6. Arthritis Rheum  2012; 64(9): 2887-95.
[http://dx.doi.org/10.1002/art.34489] [PMID:  22488549] 
[29] 
Beardmore VA, Hinton HJ, Eftychi C, et al. Generation and characterization of p38β (MAPK11) gene-targeted mice. Mol Cell Biol  2005; 25(23): 10454-64.
[http://dx.doi.org/10.1128/MCB.25.23.10454-10464.2005] [PMID:  16287858] 
[30] 
Schieven GL. The biology of p38 kinase: A central role in inflammation. Curr Top Med Chem  2005; 5(10): 921-8.
[http://dx.doi.org/10.2174/1568026054985902] [PMID:  16178737] 
[31] 
Kumar S, Boehm J, Lee JC. p38 MAP kinases: Key signalling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discov  2003; 2(9): 717-26.
[http://dx.doi.org/10.1038/nrd1177] [PMID:  12951578] 
[32] 
Ridley SH, Sarsfield SJ, Lee JC, et al. Actions of IL-1 are selectively controlled by p38 mitogen-activated protein kinase: Regulation of prostaglandin H synthase-2, metalloproteinases, and IL-6 at different levels. J Immunol  1997; 158(7): 3165-73.
[PMID: 9120270] 
[33] 
Ahmad R, Sylvester J, Zafarullah M. MyD88, IRAK1 and TRAF6 knockdown in human chondrocytes inhibits interleukin-1-induced matrix metalloproteinase-13 gene expression and promoter activity by impairing MAP kinase activation. Cell Signal  2007; 19(12): 2549-57.
[http://dx.doi.org/10.1016/j.cellsig.2007.08.013] [PMID:  17905570] 
[34] 
Deng GM, Kyttaris VC, Tsokos GC. Targeting Syk in autoimmune rheumatic diseases. Front Immunol  2016; 7: 78-83.
[http://dx.doi.org/10.3389/fimmu.2016.00078] [PMID:  27014261] 
[35] 
Iwata S, Nakayamada S, Fukuyo S, et al. Activation of Syk in peripheral blood B cells in patients with rheumatoid arthritis: A potential target for abatacept therapy. Arthritis Rheumatol  2015; 67(1): 63-73.
[http://dx.doi.org/10.1002/art.38895] [PMID:  25303149] 
[36] 
Elliott ER, Van Ziffle JA, Scapini P, Sullivan BM, Locksley RM, Lowell CA. Deletion of Syk in neutrophils prevents immune complex arthritis. J Immunol  2011; 187(8): 4319-30.
[http://dx.doi.org/10.4049/jimmunol.1100341] [PMID:  21918195] 
[37] 
Barnard C. Rheumatoid arthritis. JAK inhibitors: The next generation
of drugs for treating rheumatoid arthritis? 2017. Available
from: https://rheumatology.medicinematters.com/rheumatoid-arth ritis-/jak-inhibitors/jak-inhibitors-the-next-generation-of-drugs-for-treating-rheumat/12336972 Accessed on 19 May 2020.
[38] 
Muller R. JAK inhibitors in 2019, synthetic review in 10 points. Eur J Intern Med  2019; 66: 9-17.
[http://dx.doi.org/10.1016/j.ejim.2019.05.022] [PMID:  31178258] 
[39] 
Kotenko SV, Pestka S. Jak-Stat signal transduction pathway through the eyes of cytokine class II receptor complexes. Oncogene  2000; 19(21): 2557-65.
[http://dx.doi.org/10.1038/sj.onc.1203524] [PMID:  10851054] 
[40] 
Miscia S, Marchisio M, Grilli A, et al. Tumor necrosis factor alpha (TNF-alpha) activates Jak1/Stat3-Stat5B signaling through TNFR-1 in human B cells. Cell Growth Different  2002; 13(1): 13-8.
[41] 
Norman P. Selective JAK inhibitors in development for rheumatoid arthritis. Expert Opin Investig Drugs  2014; 23(8): 1067-77.
[http://dx.doi.org/10.1517/13543784.2014.918604] [PMID:  24818516] 
[42] 
Broxmeyer HE. Erythropoietin: Multiple targets, actions, and modifying influences for biological and clinical consideration. J Exp Med  2013; 210(2): 205-8.
[http://dx.doi.org/10.1084/jem.20122760] [PMID:  23401569] 
[43] 
Kawamura M, McVicar DW, Johnston JA, et al. Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes. Proc Natl Acad Sci USA  1994; 91(14): 6374-8.
[http://dx.doi.org/10.1073/pnas.91.14.6374] [PMID:  8022790] 
[44] 
O’Shea JJ, Pesu M, Borie DC, Changelian PS. A new modality for immunosuppression: Targeting the JAK/STAT pathway. Nat Rev Drug Discov  2004; 3(7): 555-64.
[http://dx.doi.org/10.1038/nrd1441] [PMID:  15232577] 
[45] 
Gómez-Valadés AG, Llamas M, Blanch S, et al. Specific Jak3 downregulation in lymphocytes impairs γc cytokine signal transduction and alleviates antigen-driven inflammation in vivo. Mol Ther Nucleic Acids  2012; 1: e42-53.
[http://dx.doi.org/10.1038/mtna.2012.37] [PMID:  23344234] 
[46] 
Darnell JE Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science  1994; 264(5164): 1415-21.
[http://dx.doi.org/10.1126/science.8197455] [PMID:  8197455] 
[47] 
Stark GR, Darnell JE Jr. The JAK-STAT pathway at twenty. Immunity  2012; 36(4): 503-14.
[http://dx.doi.org/10.1016/j.immuni.2012.03.013] [PMID:  22520844] 
[48] 
Sohn SJ, Barrett K, Van Abbema A, et al. A restricted role for TYK2 catalytic activity in human cytokine responses revealed by novel TYK2-selective inhibitors. J Immunol  2013; 191(5): 2205-16.
[http://dx.doi.org/10.4049/jimmunol.1202859] [PMID:  23894201] 
[49] 
Ishizaki M, Muromoto R, Akimoto T, et al. Tyk2 is a therapeutic target for psoriasis-like skin inflammation. Int Immunol  2014; 26(5): 257-67.
[http://dx.doi.org/10.1093/intimm/dxt062] [PMID:  24345760] 
[50] 
Liang J, Tsui V, Van Abbema A, et al. Lead identification of novel and selective TYK2 inhibitors. Eur J Med Chem  2013; 67: 175-87.
[http://dx.doi.org/10.1016/j.ejmech.2013.03.070] [PMID:  23867602] 
[51] 
Padjen I, Crnogaj MR. Anić B. Conventional disease-modifying agents in rheumatoid arthritis - a review of their current use and role in treatment algorithms. Reumatologia  2020; 58(6): 390-400.
[http://dx.doi.org/10.5114/reum.2020.101400] [PMID:  33456082] 
[52] 
Curtis JR, Singh JA. Use of biologics in rheumatoid arthritis: Current and emerging paradigms of care. Clin Ther  2011; 33(6): 679-707.
[http://dx.doi.org/10.1016/j.clinthera.2011.05.044] [PMID:  21704234] 
[53] 
O’Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. The JAK-STAT pathway: Impact on human disease and therapeutic intervention. Annu Rev Med  2015; 66: 311-28.
[http://dx.doi.org/10.1146/annurev-med-051113-024537] [PMID:  25587654] 
[54] 
Matthew M. Seavey, Pawel Dobrzanski. The many faces of Janus kinase. Biochem Pharmacol  2012; 83: 1136-45.
[http://dx.doi.org/10.1016/j.bcp.2011.12.024] 
[55] 
Leonard WJ, O’Shea JJ. Jaks and STATs: Biological implications. Annu Rev Immunol  1998; 16(1): 293-322.
[http://dx.doi.org/10.1146/annurev.immunol.16.1.293] [PMID:  9597132] 
[56] 
Leonard WJ. Role of Jak kinases and STATs in cytokine signal transduction. Int J Hematol  2001; 73(3): 271-7.
[http://dx.doi.org/10.1007/BF02981951] [PMID:  11345192] 
[57] 
Imada K, Leonard WJ. The Jak-STAT pathway. Mol Immunol  2000; 37(1-2): 1-11.
[http://dx.doi.org/10.1016/S0161-5890(00)00018-3] [PMID:  10781830] 
[58] 
Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J Cell Sci  2004; 117(Pt 8): 1281-3.
[http://dx.doi.org/10.1242/jcs.00963] [PMID:  15020666] 
[59] 
Kotyla PJ. Are janus kinase inhibitors superior over classic biologic agents in ra patients? BioMed Res Int  2018; 2018: 7492904.
[http://dx.doi.org/10.1155/2018/7492904] [PMID:  29862290] 
[60] 
Waickman AT, Park JY, Park JH. The common γ-chain cytokine receptor: tricks-and-treats for T cells. Cell Mol Life Sci  2016; 73(2): 253-69.
[http://dx.doi.org/10.1007/s00018-015-2062-4] [PMID:  26468051] 
[61] 
Roskoski R Jr. Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases. Pharmacol Res  2016; 111: 784-803.
[http://dx.doi.org/10.1016/j.phrs.2016.07.038] [PMID:  27473820] 
[62] 
Broughton SE, Hercus TR, Lopez AF, Parker MW. Cytokine receptor activation at the cell surface. Curr Opin Struct Biol  2012; 22(3): 350-9.
[http://dx.doi.org/10.1016/j.sbi.2012.03.015] [PMID:  22521507] 
[63] 
West K. CP-690550, a JAK3 inhibitor as an immunosuppressant
for the treatment of rheumatoid arthritis, transplant rejection, psoriasis
and other immune-mediated disorders. Curr Opin Invest
Drugs (London, England: 2000)  2009; 10(5): 491-504.
[64] 
Fridman JS, Scherle PA, Collins R, et al. Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: Preclinical characterization of INCB028050. J Immunol  2010; 184(9): 5298-307.
[http://dx.doi.org/10.4049/jimmunol.0902819] [PMID:  20363976] 
[65] 
Stump KL, Lu LD, Dobrzanski P, et al. A highly selective, orally active inhibitor of Janus kinase 2, CEP-33779, ablates disease in two mouse models of rheumatoid arthritis. Arthritis Res Ther  2011; 13(2): R68.
[http://dx.doi.org/10.1186/ar3329] [PMID:  21510883] 
[66] 
Lopez-Matencio JM, Nietoa CM, Castaneda S. JAKinibs in inflammatory rheumatic diseases. Clinical perspective. J Arthritis  2018; 7: e119.
[http://dx.doi.org/10.4172/2167-7921.1000e119] 
[67] 
Yamaoka K. Janus kinase inhibitors for rheumatoid arthritis. Curr Opin Chem Biol  2016; 32: 29-33.
[http://dx.doi.org/10.1016/j.cbpa.2016.03.006] [PMID:  26994322] 
[68] 
Chaudhari K, Rizvi S, Syed BA. Rheumatoid arthritis: Current and future trends. Nat Rev Drug Discov  2016; 15(5): 305-6.
[http://dx.doi.org/10.1038/nrd.2016.21] [PMID:  27080040] 
[69] 
T Virtanen A, Haikarainen T, Raivola J, Silvennoinen O. Selective JAKinibs: Prospects in inflammatory and autoimmune diseases. BioDrugs  2019; 33(1): 15-32.
[http://dx.doi.org/10.1007/s40259-019-00333-w] [PMID:  30701418] 
[70] 
Winthrop KL. The emerging safety profile of JAK inhibitors in rheumatic disease. Nat Rev Rheumatol  2017; 13(4): 234-43.
[http://dx.doi.org/10.1038/nrrheum.2017.23] [PMID:  28250461] 
[71] 
Jegatheeswaran J, Turk M, Pope JE. Comparison of Janus kinase inhibitors in the treatment of rheumatoid arthritis: A systemic literature review. Immunotherapy  2019; 11(8): 737-54.
[http://dx.doi.org/10.2217/imt-2018-0178] [PMID:  30955397] 
[72] 
Thompson C, Davies R, Choy E. Anti cytokine therapy in chronic inflammatory arthritis. Cytokine  2016; 86: 92-9.
[http://dx.doi.org/10.1016/j.cyto.2016.07.015] [PMID:  27497159] 
[73] 
Ghoreschi K, Jesson MI, Li X, et al. Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). J Immunol  2011; 186(7): 4234-43.
[http://dx.doi.org/10.4049/jimmunol.1003668] [PMID:  21383241] 
[74] 
Vélez P, Jaller JJ, Escalante WJ, et al. Tofacitinib, an oral Janus kinase inhibitor, in patients from Colombia with rheumatoid arthritis: Pooled efficacy and safety analyses of data from phase III studies. Rev Colomb Reumatol  2018; 25(4): 233-44.
[http://dx.doi.org/10.1016/j.rcreu.2018.08.002] 
[75] 
Cutolo M, Meroni M. Clinical utility of the oral JAK inhibitor tofacitinib in the treatment of rheumatoid arthritis. J Inflamm Res  2013; 6: 129-37.
[http://dx.doi.org/10.2147/JIR.S35901] [PMID:  24453498] 
[76] 
Radominski SC, Cardiel MH, Citera G, et al. Tofacitinib, an oral Janus kinase inhibitor, for the treatment of Latin American patients with rheumatoid arthritis: Pooled efficacy and safety analyses of Phase 3 and long-term extension studies. Reumatol Clin  2017; 13(4): 201-9.
[http://dx.doi.org/10.1016/j.reuma.2016.04.010] 
[77] 
Al-Salama ZT, Scott LJ. Baricitinib: A review in rheumatoid arthritis. Drugs  2018; 78(7): 761-72.
[http://dx.doi.org/10.1007/s40265-018-0908-4] [PMID:  29687421] 
[78] 
Bae SC, Lee YH. Comparison of the efficacy and safety of tofacitinib and baricitinib in patients with active rheumatoid arthritis: A Bayesian network meta-analysis of randomized controlled trials. Z Rheumatol  2019; 78(6): 559-67.
[http://dx.doi.org/10.1007/s00393-018-0531-5] [PMID:  30191390] 
[79] 
Kawalec P. Śladowska K, Malinowska-Lipień I, Brzostek T,
Kózka M. New alternative in the treatment of rheumatoid arthritis:
Clinical utility of baricitinib. Ther Clin Risk Manag  2019; 15: 275-84.
[http://dx.doi.org/10.2147/TCRM.S192440] [PMID:  30858707] 
[80] 
Serhal L, Edwards CJ. Upadacitinib for the treatment of rheumatoid arthritis. Expert Rev Clin Immunol  2019; 15(1): 13-25.
[http://dx.doi.org/10.1080/1744666X.2019.1544892] [PMID:  30394138] 
[81] 
Burmester GR, Kremer JM, Van den Bosch F, et al. Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet  2018; 391(10139): 2503-12.
[http://dx.doi.org/10.1016/S0140-6736(18)31115-2] [PMID:  29908669] 
[82] 
Westhovens R, Taylor PC, Alten R, et al. Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: Results from a randomised, dose-finding study (DARWIN 1). Ann Rheum Dis  2017; 76(6): 998-1008.
[http://dx.doi.org/10.1136/annrheumdis-2016-210104] [PMID:  27993829] 
[83] 
Kavanaugh A, Kremer J, Ponce L, et al. Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: Results from a randomised, dose-finding study (DARWIN 2). Ann Rheum Dis  2017; 76(6): 1009-19.
[http://dx.doi.org/10.1136/annrheumdis-2016-210105] [PMID:  27993828] 
[84] 
Namour F, Desrivot J, Van der Aa A, Harrison P, Tasset C, van’t Klooster G. Clinical confirmation that the selective JAK1 inhibitor filgotinib (GLPG0634) has a low liability for drug-drug interactions. Drug Metab Lett  2016; 10(1): 38-48.
[http://dx.doi.org/10.2174/1872312810666151223103353] [PMID:  26693854] 
[85] 
Kivitz AJ, Gutierrez-Ureña SR, Poiley J, et al. Peficitinib, a JAK inhibitor, in the treatment of moderate-to-severe rheumatoid arthritis in patients with an inadequate response to methotrexate. Arthritis Rheumatol  2017; 69(4): 709-19.
[http://dx.doi.org/10.1002/art.39955] [PMID:  27748083] 
[86] 
Genovese MC, Greenwald M, Codding C, et al. Peficitinib, a JAK inhibitor, in combination with limited conventional synthetic disease-modifying antirheumatic drugs in the treatment of moderate-to-severe rheumatoid arthritis. Arthritis Rheumatol  2017; 69(5): 932-42.
[http://dx.doi.org/10.1002/art.40054] [PMID:  28118538] 
[87] 
Gadina M, Schwartz DM, O’Shea JJ. Decernotinib: A Next-Generation Jakinib. Arthritis Rheumatol  2016; 68(1): 31-4.
[http://dx.doi.org/10.1002/art.39463] [PMID:  26479275] 
[88] 
Zhang L, Li YG, Li YH, et al. Increased frequencies of Th22 cells as well as Th17 cells in the peripheral blood of patients with ankylosing spondylitis and rheumatoid arthritis. PLoS One  2012; 7(4): e31000.
[http://dx.doi.org/10.1371/journal.pone.0031000] [PMID:  22485125] 
[89] 
Ciccia F, Guggino G, Rizzo A, et al. Potential involvement of IL-9 and Th9 cells in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford)  2015; 54(12): 2264-72.
[http://dx.doi.org/10.1093/rheumatology/kev252] [PMID:  26178600] 
[90] 
Furqan M, Mukhi N, Lee B, Liu D. Dysregulation of JAK-STAT
pathway in hematological malignancies and JAK inhibitors for
clinical application. Biomarker research  2013; 1(1): 5.1-10.
[http://dx.doi.org/10.1186/2050-7771-1-5] 
[91] 
O’Shea JJ, Gadina M. Selective Janus kinase inhibitors come of age. Nat Rev Rheumatol  2019; 15(2): 74-5.
[http://dx.doi.org/10.1038/s41584-018-0155-9] [PMID:  30622297] 
[92] 
Solimani F, Meier K, Ghoreschi K. Emerging topical and systemic JAK inhibitors in dermatology. Front Immunol  2019; 2019: 02847.
[http://dx.doi.org/10.3389/fimmu.2019.02847] 
[93] 
Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O’Shea JJ. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov  2017; 16(12): 843-62.
[http://dx.doi.org/10.1038/nrd.2017.201] [PMID:  29104284] 
[94] 
Tanwar H, Sachdeva R. Transdermal drug delivery system: A review. Int J Pharm Sci Res  2016; 7(6): 2274-90.
[95] 
Chang RK, Raw A, Lionberger R, Yu L. Generic development of topical dermatologic products: Formulation development, process development, and testing of topical dermatologic products. AAPS J  2013; 15(1): 41-52.
[http://dx.doi.org/10.1208/s12248-012-9411-0] [PMID:  23054971] 
[96] 
Craiglow BG. Topical tofacitinib solution for the treatment of alopecia areata affecting eyelashes. JAAD Case Rep  2018; 4(10): 988-9.
[http://dx.doi.org/10.1016/j.jdcr.2018.07.018] [PMID:  30417059] 
[97] 
Beals CR, WoldeMussie E, Gukasyan HJ, Ma J. Pharmaceutical
compositions and methods of treating dry eye disorders. US Patent
US 8,541,426, 2013.
[98] 
Brendan J. Crystalline pyrrolo2,3-dipyrimidine compounds. US
Patent US 2012/0258976A1, 2012.
[99] 
Chen CM, Lu GW, Liaw LY, et al. Topical formulations comprising
tofacitinib. US Patent US16/254,076, 2019.https://patents.google.com/patent/US20190231782A1/en
[100] 
Alves de Medeiros AK, Speeckaert R, Desmet E, Van Gele M, De Schepper S, Lambert J. JAK3 as an emerging target for topical treatment of inflammatory skin diseases. PLoS One  2016; 11(10): e0164080.
[http://dx.doi.org/10.1371/journal.pone.0164080] [PMID:  27711196] 
[101] 
Ports WC, Khan S, Lan S, et al. A randomized phase 2a efficacy and safety trial of the topical Janus kinase inhibitor tofacitinib in the treatment of chronic plaque psoriasis. Br J Dermatol  2013; 169(1): 137-45.
[http://dx.doi.org/10.1111/bjd.12266] [PMID:  23387374] 
[102] 
Banerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. JAK–STAT signaling as a target for inflammatory and autoimmune diseases: Current and future prospects. Drugs  2017; 77(5): 521-46.
[http://dx.doi.org/10.1007/s40265-017-0701-9] [PMID:  28255960] 
[103] 
Samadi A, Ahmad Nasrollahi S, Hashemi A, Nassiri Kashani M, Firooz A. Janus kinase (JAK) inhibitors for the treatment of skin and hair disorders: A review of literature. J Dermatolog Treat  2017; 28(6): 476-83.
[http://dx.doi.org/10.1080/09546634.2016.1277179] [PMID:  28024126] 
[104] 
Sakimoto T, Ishimori A. Anti-inflammatory effect of topical administration of tofacitinib on corneal inflammation. Exp Eye Res  2016; 145: 110-7.
[http://dx.doi.org/10.1016/j.exer.2015.12.005] [PMID:  26689752] 
[105] 
Purohit VS, Ports WC, Wang C, Riley S. Systemic tofacitinib concentrations in adult patients with atopic dermatitis treated with 2% tofacitinib ointment and application to pediatric study planning. J Clin Pharmacol  2019; 59(6): 811-20.
[http://dx.doi.org/10.1002/jcph.1360] [PMID:  30556911] 
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DOI https://dx.doi.org/10.2174/1574885517666220329185842	Print ISSN 1574-8855
Publisher Name Bentham Science Publisher	Online ISSN 2212-3903
Current Drug Therapy

Rheumatoid Arthritis and JAK-STAT Inhibitors: Prospects of Topical Delivery

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