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JAK inhibitors are the first new approved oral therapy for rheumatoid arthritis in years . They constitute a new class of drugs that already play a relevant role in the treatment algorithm
Most of the safety information for this class of drugs comes from the tofacitinib development programme and post-marketing experience . Some of the changes in laboratory parameters resemble those seen with the bDMARD , tocilizumab , reflecting the inhibition of IL-6 . Changes seen with tofacitinib include a decrease in lymphocytes , neutrophils , natural killer cells and platelets , increased levels of transaminases and lipids , and a small increase in serum creatinine . During the development process , only a small percentage of patients developed serious adverse events related to these ; further work in necessary to completely understand the consequences of these changes . 25 Baricitinib showed similar laboratory changes but differences were detected in relation to lymphocyte and platelet counts , which mostly remained unchanged , and levels of haemoglobin , which were reduced . Special concern regarding thrombotic risk is raised . Further information is needed to clarify this issue . Data for other JAK inhibitors are preliminary but it seems that differences in laboratory parameters observed between JAK inhibitors are difficult to explain looking at only their different effect on JAKs . It has to be considered that information of these newer molecules comes from phase II studies where different doses are used , losing JAK inhibitors ’ specificity at higher doses .
There are limited data on the malignancy risk associated with the use of JAK inhibitors . Information comes from tofacitinib and baricitinib long-term extension studies and the risk of cancer seems to be similar to that observed with bDMARDs . 13 , 26 There are no long-term data for other JAK inhibitors . Even though preliminary data are encouraging , many more years of exposure are needed to profile the malignancy risk of this class of drugs .
Serious infection rates with tofacitinib and baricitinib are similar to those observed with bDMARDs . 11 , 26 Particular reference to varicella zoster virus has to be made . There is an increase in the risk of herpes zoster in patients receiving JAK inhibitors that seems to be a class effect because it is described with most of them . 25 Treatment with tofacitinib showed an increase of the risk in clinical trials 27 that was confirmed with real-world data . 28 Most of the cases were localised infections , no visceral disease or deaths were reported and the concomitant use of steroids or methotrexate considerably influenced the risk . 29 Patients receiving tofacitinib as monotherapy had a significant reduced risk of herpes zoster . Studies with baricitinib and other JAK inhibitors , even though less consistent because of reduced years of exposure , show similar results . There is a live vaccine to prevent herpes zoster but attenuated live vaccines are contraindicated in patients receiving JAK inhibitors . The exact interval that is required between vaccination and the start of JAK inhibitor treatment needs to be determined .
To date , the safety profile of JAK inhibitors seems to be similar to that of bDMARDs , with the exception of herpes zoster . 25 Apart from tofacitinib and , to a lesser extent , baricitinib , safety data on JAK inhibitors are limited and further studies are needed but it seems that the safety profiles of JAK inhibitors will be difficult to predict on the basis of their selectivity .
References 1Feldmann M , Maini SR . Role of cytokines in rheumatoid arthritis : an education in pathophysiology and therapeutics . Immunol Rev 2008 ; 223:7 – 19 . 2 Smolen JS et al . Proposal for a new nomenclature of diseasemodifying antirrheumatic drugs . Ann Rheum Dis 2014 ; 73:3 – 5 . 3 O ’ Shea JJ et al . Janus kinase inhibitors in autoimmune diseases . Ann Rheum Dis 2013 ; 72:111 – 15 . 4 Smolen JS et al . EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirrheumatic drugs : 2016 update . Ann Rheum Dis 2017 ; 76:960 – 77 . 5 Rubbert-Roth A , Finckh A . Treatment options in patients with rheumatoid arthritis failing initial TNF inhibitor therapy : a critical review . Arthritis Res Ther 2009 ; 11 : S1 . 6 Fleischmann R et al . Placebocontrolled trial of tofacitinib monotherapy in rheumatoid arthritis . N Engl J Med 2012 ; 367:495 – 507 . 7 Fleischmann R et al . Baricitinib , methotrexate , or combination in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment . Arthritis Rheumatol 2017 ; 69:506 – 17 . 8 Van Vollenhoven RF et al . Tofacitinib or adalimumab versus placebo in rheumatoid arthritis . N Engl J Med 2012 ; 367:508 – 19 . 9 Fleischmann R et al . Efficacy and safety of tofacitinib monotherapy , tofacitinib with methotrexate , and adalimumab with methotrexate in patients with rheumatoid arthritis ( ORAL Strategy ): a phase 3b / 4 , doubleblind , head-to-head , randomised controlled trial . Lancet 2017 ; S0140-6736 ( 17 ) 31618-5 . 10 Burmester GR et al . Tofacitinib ( CP-690-550 ) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors : a randomized phase 3 trial . Lancet 2013 ; 381:451 – 60 . 11 Cohen S et al . Analysis of infections and all-cause mortality in phase II , phase III , and long-term extension studies of tofacitinib in patients with rheumatoid arthritis . Arthritis Rheumatol 2014 ; 66:2924 – 37 . 12 Lee EB et al . Tofacitinib versus methotrexate in rheumatoid arthritis . N Engl J Med 2014 ; 370:2377 – 86 . 13 Curtis JR et al . Tofacitinib , an oral Janus kinase inhibitor : analysis of malignancies across the rheumatoid arthritis clinical development programme . Ann Rheum Dis 2016 ; 75:831 – 41 . 14 Taylor PC et al . Baricitinib versus placebo or adalimumab in rheumatoid arthritis . N Engl J Med 2017 ; 376:652 – 62 . 15 Dougados M . Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDS : results from the RA-BUILD study . Ann Rheum Dis 2017 ; 76:88 – 95 . 16 Genovese MC et al . Baricitinib in patients with refractory rheumatoid arthritis . N Engl J Med 2016 ; 374:1243 – 52 . 17 Vanhoutte F et al . Efficacy , safety , pharmacokinetics , and pharmacodynamics of filgotinib , a selective Janus kinase 1 inhibitor , after short-term treatment of
rheumatoid arthritis : Results of two randomized Phase IIA trials . Arthritis Rheumatol 2017 ; 69 ( 10 ): 1949 – 59 . 1818 Westhovens 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 , dosefinding study ( DARWIN 1 ). Ann Rheum Dis 2017 ; 76:998 – 1008 . 19 Kavanaugh A 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 , dosefinding study ( DARWIN 2 ). Ann Rheum Dis 2017 ; 76:1009 – 19 . 20 Genovese MC et al . Efficacy and safety of ABT-494 , a selective JAK-1 inhibitor , in a Phase IIb study in patients with rheumatoid arthritis and an inadequate response to methotrexate . Arthritis Rheumatol 2016 ; 68:2857 – 66 . 21 Kremer JM et al . A Phase IIb study of ABT-494 , a selective JAK-1 inhibitor , in patients with rheumatoid arthritis and an inadequate response to anti-tumor necrosis factor therapy . Arthritis Rheumatol 2016 ; 2867 – 77 . 22 Genovese MC et al . VX-509 ( decernotinib ), an oral selective JAK-3 inhibitor , in combination with methotrexate in patients with rheumatoid arthritis . Arthritis Rheumatol 2016 ; 68:46 – 55 . 23 Kivitz AJ 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 ; 69:709 – 19 . 24 Genovese MC et al . Peficitinib , a JAK inhibitor , in combination with limited conventional synthetic disease . modifying antirrheumatic drugs in the treatment of moderate-to-severe rheumatoid arthritis . Arthritis Rheumatol 2017 ; 69:932 – 42 . 25 Winthrop KL . The emerging safety profile of JAK inhibitors in rheumatic disease . Nature Rev 2017 ; 13 ( 4 ): 234 – 43 . 26 Smolen J et al . Safety profile of baricitinib in patients with active RA : an integrated analysis . Ann Rheum Dis 2016 ; 75:243 – 4 . 27 Winthrop KL et al . Herpes zoster and tofacitinib therapy in patients with rheumatoid arthritis . Arthritis Rheumatol 2014 ; 66:2675 – 84 . 28 Curtis JR et al . Real-world comparative risks of herpes virus infections in tofacitinib and biologic-treated patients with rheumatoid arthritis . Ann Rheum Dis 2016 ; 75:1843 – 7 . 29 Winthrop KL et al . Herpes zoster and tofacitinib : the risk of concomitant nonbiologic therapy . Ann Rheum Dis 2015 ; 74:741 .
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