[Skip to Navigation]
Figure 1.  PRISMA Flow Diagrams for the Selection of Cohort Studies and Randomized Clinical Trials
PRISMA Flow Diagrams for the Selection of Cohort Studies and Randomized Clinical Trials

AD indicates atopic dermatitis; VTE, venous thromboembolism.

Figure 2.  Association of Atopic Dermatitis (AD) With Incident Venous Thromboembolism (VTE)
Association of Atopic Dermatitis (AD) With Incident Venous Thromboembolism (VTE)

The meta-analysis found no significant association of AD with incident VTE (hazard ratio [HR], 0.95; 95% CI, 0.62-1.45). IV indicates inverse variance.

Table 1.  Characteristics of Included Studies
Characteristics of Included Studies
Table 2.  Summary of Risk of Bias Assessment
Summary of Risk of Bias Assessment
1.
Langan  SM, Irvine  AD, Weidinger  S.  Atopic dermatitis.   Lancet. 2020;396(10247):345-360. doi:10.1016/S0140-6736(20)31286-1 PubMedGoogle ScholarCrossref
2.
Wang  CH, Fu  Y, Chi  CC.  Association of atopic dermatitis with inflammatory bowel disease: a systematic review and meta-analysis.   Dermatol Sin. 2020;38(3):159-165. doi:10.4103/ds.ds_20_20 Google ScholarCrossref
3.
Sidbury  R, Davis  DM, Cohen  DE,  et al; American Academy of Dermatology.  Guidelines of care for the management of atopic dermatitis: section 3: management and treatment with phototherapy and systemic agents.   J Am Acad Dermatol. 2014;71(2):327-349. doi:10.1016/j.jaad.2014.03.030 PubMedGoogle ScholarCrossref
4.
Ee  S, Tay  YK, Chu  CY, Hon  KL, Leong  KF, Wananukul  S.  A study on the knowledge, attitudes, and practices of Asian dermatologists in the management of atopic dermatitis.   Dermatol Sin. 2020;38(2):67-80. doi:10.4103/ds.ds_31_19 Google ScholarCrossref
5.
Chovatiya  R, Paller  AS.  JAK inhibitors in the treatment of atopic dermatitis.   J Allergy Clin Immunol. 2021;148(4):927-940. doi:10.1016/j.jaci.2021.08.009 PubMedGoogle ScholarCrossref
6.
Arshad  N, Bjøri  E, Hindberg  K, Isaksen  T, Hansen  JB, Braekkan  SK.  Recurrence and mortality after first venous thromboembolism in a large population-based cohort.   J Thromb Haemost. 2017;15(2):295-303. doi:10.1111/jth.13587 PubMedGoogle ScholarCrossref
7.
Søgaard  KK, Schmidt  M, Pedersen  L, Horváth-Puhó  E, Sørensen  HT.  30-year mortality after venous thromboembolism: a population-based cohort study.   Circulation. 2014;130(10):829-836. doi:10.1161/CIRCULATIONAHA.114.009107 PubMedGoogle ScholarCrossref
8.
Setyawan  J, Mu  F, Yarur  A,  et al.  Risk of thromboembolic events and associated risk factors, including treatments, in patients with immune-mediated diseases.   Clin Ther. 2021;43(8):1392-1407.e1. doi:10.1016/j.clinthera.2021.06.008 PubMedGoogle ScholarCrossref
9.
Shaheen  MS, Silverberg  JI.  Association of inflammatory skin diseases with venous thromboembolism in US adults.   Arch Dermatol Res. 2021;313(4):281-289. doi:10.1007/s00403-020-02099-6 PubMedGoogle ScholarCrossref
10.
US Food and Drug Administration. FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. Accessed January 9, 2022. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death
11.
Yates  M, Mootoo  A, Adas  M,  et al.  Venous thromboembolism risk with JAK inhibitors: a meta-analysis.   Arthritis Rheumatol. 2021;73(5):779-788. doi:10.1002/art.41580 PubMedGoogle ScholarCrossref
12.
Bilal  J, Riaz  IB, Naqvi  SAA,  et al.  Janus kinase inhibitors and risk of venous thromboembolism: a systematic review and meta-analysis.   Mayo Clin Proc. 2021;96(7):1861-1873. doi:10.1016/j.mayocp.2020.12.035 PubMedGoogle ScholarCrossref
13.
Ytterberg  SR, Bhatt  DL, Mikuls  TR,  et al; ORAL Surveillance Investigators.  Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis.   N Engl J Med. 2022;386(4):316-326. doi:10.1056/NEJMoa2109927 PubMedGoogle ScholarCrossref
14.
Stroup  DF, Berlin  JA, Morton  SC,  et al.  Meta-analysis of observational studies in epidemiology: a proposal for reporting.   JAMA. 2000;283(15):2008-2012. doi:10.1001/jama.283.15.2008 PubMedGoogle ScholarCrossref
15.
Page  MJ, McKenzie  JE, Bossuyt  PM,  et al.  The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.   BMJ. 2021;372(71):n71. doi:10.1136/bmj.n71 PubMedGoogle ScholarCrossref
16.
Wells  GA, Shea  B, O’Connell  D,  et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analysis. Accessed November 23, 2006. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.
17.
Sterne  JAC, Savović  J, Page  MJ,  et al.  RoB 2: a revised tool for assessing risk of bias in randomised trials.   BMJ. 2019;366:l4898. doi:10.1136/bmj.l4898 PubMedGoogle ScholarCrossref
18.
Higgins  JPT, Thomas  J, Chandler  J,  et al.  Cochrane Handbook for Systematic Reviews of Interventions Version 6.2). Cochrane; 2021.
19.
Ryan  C, Leonardi  CL, Krueger  JG,  et al.  Association between biologic therapies for chronic plaque psoriasis and cardiovascular events: a meta-analysis of randomized controlled trials.   JAMA. 2011;306(8):864-871. doi:10.1001/jama.2011.1211 PubMedGoogle ScholarCrossref
20.
Higgins  JP, Thompson  SG, Deeks  JJ, Altman  DG.  Measuring inconsistency in meta-analyses.   BMJ. 2003;327(7414):557-560. doi:10.1136/bmj.327.7414.557 PubMedGoogle ScholarCrossref
21.
Meyers  KJ, Silverberg  JI, Rueda  MJ,  et al.  Risk of venous thromboembolism among patients with atopic dermatitis: a cohort study in a US administrative claims database.   Dermatol Ther (Heidelb). 2021;11(3):1041-1052. doi:10.1007/s13555-021-00538-4 PubMedGoogle ScholarCrossref
22.
Schneeweiss  MC, Kim  SC, Wyss  R,  et al.  Incidence of venous thromboembolism in patients with dermatologist-diagnosed chronic inflammatory skin diseases.   JAMA Dermatol. 2021;157(7):805-816. doi:10.1001/jamadermatol.2021.1570 PubMedGoogle ScholarCrossref
23.
Bieber  T, Simpson  EL, Silverberg  JI,  et al; JADE COMPARE Investigators.  Abrocitinib versus placebo or dupilumab for atopic dermatitis.   N Engl J Med. 2021;384(12):1101-1112. doi:10.1056/NEJMoa2019380 PubMedGoogle ScholarCrossref
24.
Blauvelt  A, Teixeira  HD, Simpson  EL,  et al.  Efficacy and safety of upadacitinib vs dupilumab in adults with moderate-to-severe atopic dermatitis: a randomized clinical trial.   JAMA Dermatol. 2021;157(9):1047-1055. doi:10.1001/jamadermatol.2021.3023 PubMedGoogle ScholarCrossref
25.
Blauvelt  A, Silverberg  JI, Lynde  CW,  et al.  Abrocitinib induction, randomized withdrawal, and retreatment in patients with moderate-to-severe atopic dermatitis: results from the JAK1 Atopic Dermatitis Efficacy and Safety (JADE) REGIMEN phase 3 trial.   J Am Acad Dermatol. 2022;86(1):104-112. doi:10.1016/j.jaad.2021.05.075 PubMedGoogle ScholarCrossref
26.
Eichenfield  LF, Flohr  C, Sidbury  R,  et al.  Efficacy and safety of abrocitinib in combination with topical therapy in adolescents with moderate-to-severe atopic dermatitis: the JADE TEEN randomized clinical trial.   JAMA Dermatol. 2021;157(10):1165-1173. doi:10.1001/jamadermatol.2021.2830 PubMedGoogle ScholarCrossref
27.
Gooderham  MJ, Forman  SB, Bissonnette  R,  et al.  Efficacy and safety of oral Janus kinase 1 inhibitor abrocitinib for patients with atopic dermatitis: a phase 2 randomized clinical trial.   JAMA Dermatol. 2019;155(12):1371-1379. doi:10.1001/jamadermatol.2019.2855 PubMedGoogle ScholarCrossref
28.
Guttman-Yassky  E, Thaçi  D, Pangan  AL,  et al.  Upadacitinib in adults with moderate to severe atopic dermatitis: 16-week results from a randomized, placebo-controlled trial.   J Allergy Clin Immunol. 2020;145(3):877-884. doi:10.1016/j.jaci.2019.11.025 PubMedGoogle ScholarCrossref
29.
Guttman-Yassky  E, Teixeira  HD, Simpson  EL,  et al.  Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials.   Lancet. 2021;397(10290):2151-2168. doi:10.1016/S0140-6736(21)00588-2 PubMedGoogle ScholarCrossref
30.
Katoh  N, Ohya  Y, Murota  H,  et al.  A phase 3 randomized, multicenter, double-blind study to evaluate the safety of upadacitinib in combination with topical corticosteroids in adolescent and adult patients with moderate-to-severe atopic dermatitis in Japan (Rising Up): An interim 24-week analysis.   JAAD Int. 2021;6:27-36. doi:10.1016/j.jdin.2021.11.001 PubMedGoogle ScholarCrossref
31.
Reich  K, Kabashima  K, Peris  K,  et al.  Efficacy and safety of baricitinib combined with topical corticosteroids for treatment of moderate to severe atopic dermatitis: a randomized clinical trial.   JAMA Dermatol. 2020;156(12):1333-1343. doi:10.1001/jamadermatol.2020.3260 PubMedGoogle ScholarCrossref
32.
Reich  K, Teixeira  HD, de Bruin-Weller  M,  et al.  Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial.   Lancet. 2021;397(10290):2169-2181. doi:10.1016/S0140-6736(21)00589-4 PubMedGoogle ScholarCrossref
33.
Silverberg  JI, Simpson  EL, Thyssen  JP,  et al.  Efficacy and safety of abrocitinib in patients with moderate-to-severe atopic dermatitis: a randomized clinical trial.   JAMA Dermatol. 2020;156(8):863-873. doi:10.1001/jamadermatol.2020.1406 PubMedGoogle ScholarCrossref
34.
Simpson  EL, Sinclair  R, Forman  S,  et al.  Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial.   Lancet. 2020;396(10246):255-266. doi:10.1016/S0140-6736(20)30732-7 PubMedGoogle ScholarCrossref
35.
Simpson  EL, Lacour  JP, Spelman  L,  et al.  Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials.   Br J Dermatol. 2020;183(2):242-255. doi:10.1111/bjd.18898 PubMedGoogle ScholarCrossref
36.
Simpson  EL, Forman  S, Silverberg  JI,  et al.  Baricitinib in patients with moderate-to-severe atopic dermatitis: results from a randomized monotherapy phase 3 trial in the United States and Canada (BREEZE-AD5).   J Am Acad Dermatol. 2021;85(1):62-70. doi:10.1016/j.jaad.2021.02.028 PubMedGoogle ScholarCrossref
37.
Zhao  Y, Zhang  L, Ding  Y,  et al.  Efficacy and safety of SHR0302, a highly selective Janus kinase 1 inhibitor, in patients with moderate to severe atopic dermatitis: a phase II randomized clinical trial.   Am J Clin Dermatol. 2021;22(6):877-889. doi:10.1007/s40257-021-00627-2 PubMedGoogle ScholarCrossref
38.
Hsu  DY, Dalal  P, Sable  KA,  et al.  Validation of International Classification of Disease Ninth Revision codes for atopic dermatitis.   Allergy. 2017;72(7):1091-1095. doi:10.1111/all.13113 PubMedGoogle ScholarCrossref
39.
Hanifin  JM, Rajka  G.  Diagnostic features of atopic dermatitis.   Acta Derm Venereol Suppl (Stockh). 1980;92:44-47. https://www.medicaljournals.se/acta/content_files/files/pdf/60/92/924447.pdfGoogle Scholar
40.
Eichenfield  LF, Tom  WL, Chamlin  SL,  et al.  Guidelines of care for the management of atopic dermatitis: section 1: diagnosis and assessment of atopic dermatitis.   J Am Acad Dermatol. 2014;70(2):338-351. doi:10.1016/j.jaad.2013.10.010 PubMedGoogle ScholarCrossref
41.
Liu  P, Zhao  Y, Mu  ZL,  et al.  Clinical features of adult/adolescent atopic dermatitis and Chinese criteria for atopic dermatitis.   Chin Med J (Engl). 2016;129(7):757-762. doi:10.4103/0366-6999.178960 PubMedGoogle ScholarCrossref
42.
Davis  DMR, Drucker  AM, Alikhan  A,  et al.  American Academy of Dermatology guidelines: awareness of comorbidities associated with atopic dermatitis in adults.   J Am Acad Dermatol. 2022;86(6):1335-1336.e18. doi:10.1016/j.jaad.2022.01.009 PubMedGoogle ScholarCrossref
43.
Ascott  A, Mulick  A, Yu  AM,  et al.  Atopic eczema and major cardiovascular outcomes: a systematic review and meta-analysis of population-based studies.   J Allergy Clin Immunol. 2019;143(5):1821-1829. doi:10.1016/j.jaci.2018.11.030 PubMedGoogle ScholarCrossref
44.
Armstrong  EJ, Harskamp  CT, Armstrong  AW.  Psoriasis and major adverse cardiovascular events: a systematic review and meta-analysis of observational studies.   J Am Heart Assoc. 2013;2(2):e000062. doi:10.1161/JAHA.113.000062 PubMedGoogle ScholarCrossref
45.
Chen  TL, Lee  LL, Huang  HK,  et al.  Association of psoriasis with incident venous thromboembolism and peripheral vascular disease: a systematic review and meta-analysis.   JAMA Dermatol. 2022;158(1):59-67. doi:10.1001/jamadermatol.2021.4918 PubMedGoogle ScholarCrossref
46.
Undas  A, Cieśla-Dul  M, Drążkiewicz  T, Potaczek  DP, Sadowski  J.  Association between atopic diseases and venous thromboembolism: a case-control study in patients aged 45 years or less.   J Thromb Haemost. 2011;9(4):870-873. doi:10.1111/j.1538-7836.2011.04198.x PubMedGoogle ScholarCrossref
47.
Vinogradova  Y, Coupland  C, Hippisley-Cox  J.  Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases.   BMJ. 2019;364:k4810. doi:10.1136/bmj.k4810 PubMedGoogle ScholarCrossref
48.
Mahmoodi  BK, Cushman  M, Anne Næss  I,  et al.  Association of traditional cardiovascular risk factors with venous thromboembolism: an individual participant data meta-analysis of prospective studies.   Circulation. 2017;135(1):7-16. doi:10.1161/CIRCULATIONAHA.116.024507 PubMedGoogle ScholarCrossref
49.
Pandher  K, Ghamrawi  RI, Heron  CE, Feldman  SR.  Controversial cardiovascular and hematologic comorbidities in atopic dermatitis.   Arch Dermatol Res. 2022;314(4):317-324. doi:10.1007/s00403-021-02240-zPubMedGoogle ScholarCrossref
50.
Potaczek  DP.  Links between allergy and cardiovascular or hemostatic system.   Int J Cardiol. 2014;170(3):278-285. doi:10.1016/j.ijcard.2013.11.029 PubMedGoogle ScholarCrossref
51.
Tamagawa-Mineoka  R, Katoh  N, Ueda  E, Masuda  K, Kishimoto  S.  Elevated platelet activation in patients with atopic dermatitis and psoriasis: increased plasma levels of beta-thromboglobulin and platelet factor 4.   Allergol Int. 2008;57(4):391-396. doi:10.2332/allergolint.O-08-537 PubMedGoogle ScholarCrossref
52.
Koczy-Baron  E, Jochem  J, Kasperska-Zajac  A.  Increased plasma concentration of vascular endothelial growth factor in patients with atopic dermatitis and its relation to disease severity and platelet activation.   Inflamm Res. 2012;61(12):1405-1409. doi:10.1007/s00011-012-0543-6 PubMedGoogle ScholarCrossref
53.
Nastałek  M, Potaczek  DP, Wojas-Pelc  A, Undas  A.  Plasma platelet activation markers in patients with atopic dermatitis and concomitant allergic diseases.   J Dermatol Sci. 2011;64(1):79-82. doi:10.1016/j.jdermsci.2011.07.001 PubMedGoogle ScholarCrossref
54.
Alshehri  FSM, Whyte  CS, Tuncay  A, Williams  ML, Wilson  HM, Mutch  NJ.  Monocytes expose factor XIII-A and stabilize thrombi against fibrinolytic degradation.   Int J Mol Sci. 2021;22(12):6591. doi:10.3390/ijms22126591 PubMedGoogle ScholarCrossref
55.
Smiley  ST, Boyer  SN, Heeb  MJ, Griffin  JH, Grusby  MJ.  Protein S is inducible by interleukin 4 in T cells and inhibits lymphoid cell procoagulant activity.   Proc Natl Acad Sci U S A. 1997;94(21):11484-11489. doi:10.1073/pnas.94.21.11484 PubMedGoogle ScholarCrossref
56.
Caughey  GH.  Tryptase genetics and anaphylaxis.   J Allergy Clin Immunol. 2006;117(6):1411-1414. doi:10.1016/j.jaci.2006.02.026 PubMedGoogle ScholarCrossref
57.
Simpson  EL, Silverberg  JI, Nosbaum  A,  et al.  Integrated safety analysis of abrocitinib for the treatment of moderate-to-severe atopic dermatitis from the phase II and phase III clinical trial program.   Am J Clin Dermatol. 2021;22(5):693-707. doi:10.1007/s40257-021-00618-3 PubMedGoogle ScholarCrossref
58.
King  B, Maari  C, Lain  E,  et al.  Extended safety analysis of baricitinib 2 mg in adult patients with atopic dermatitis: an integrated analysis from eight randomized clinical trials.   Am J Clin Dermatol. 2021;22(3):395-405. doi:10.1007/s40257-021-00602-x PubMedGoogle ScholarCrossref
59.
Silverberg  JI, de Bruin-Weller  M, Bieber  T,  et al.  Upadacitinib plus topical corticosteroids in atopic dermatitis: Week 52 AD Up study results.   J Allergy Clin Immunol. 2022;149(3):977-987.e14. doi:10.1016/j.jaci.2021.07.036 PubMedGoogle ScholarCrossref
60.
Soto  E, Banfield  C, Gupta  P, Peterson  MC.  Kinetic-pharmacodynamic model of platelet time course in patients with moderate-to-severe atopic dermatitis treated with oral Janus kinase 1 inhibitor abrocitinib.   CPT Pharmacometrics Syst Pharmacol. 2020;9(10):553-560. doi:10.1002/psp4.12548 PubMedGoogle ScholarCrossref
61.
Anderson  FA  Jr, Spencer  FA.  Risk factors for venous thromboembolism.   Circulation. 2003;107(23)(suppl 1):I9-I16. PubMedGoogle Scholar
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    Views 4,436
    Citations 0
    Original Investigation
    August 24, 2022

    Association of Risk of Incident Venous Thromboembolism With Atopic Dermatitis and Treatment With Janus Kinase Inhibitors: A Systematic Review and Meta-analysis

    Author Affiliations
    • 1Department of Dermatology, Taipei Veterans General Hospital, Taipei, Taiwan
    • 2Center for Aging and Health, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
    • 3Department of Nursing, Tzu Chi University of Science and Technology, Hualien, Taiwan
    • 4Department of Family Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
    • 5Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
    • 6Library, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
    • 7School of Medicine, Tzu Chi University, Hualien, Taiwan
    • 8Department of Dermatology, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
    • 9School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
    JAMA Dermatol. 2022;158(11):1254-1261. doi:10.1001/jamadermatol.2022.3516
    Key Points

    Question  Do patients with atopic dermatitis (AD), particularly those receiving treatment with Janus kinase (JAK) inhibitors, have an increased risk for venous thromboembolism (VTE)?

    Findings  This systematic review and meta-analysis included 2 cohort studies and 15 randomized clinical trials with 466 993 participants. The analysis found no significant association of AD with incident VTE nor an increased risk of incident VTE among participants with AD who were receiving JAK inhibitors.

    Meaning  The study results indicate that the evidence to date is insufficient to determine a significant association of AD with VTE and support the current warning of VTE being associated with JAK inhibitors in treating AD; future real-world long-term data are warranted.

    Abstract

    Importance  The risk of venous thromboembolism (VTE) among patients with atopic dermatitis (AD), especially when receiving treatment with Janus kinase (JAK) inhibitors, is unclear.

    Objective  To determine the association of AD with incident VTE and evaluate the risk of incident VTE among patients with AD who were receiving treatment with JAK inhibitors.

    Data Sources  The MEDLINE, Embase, Cochrane Library, and Web of Science databases were searched with no restrictions on language nor geographic locations from their respective inception to February 5, 2022.

    Study Selection  Cohort studies examining the association of AD with incident VTE and randomized clinical trials (RCTs) reporting VTE events in participants with AD receiving JAK inhibitors were included. Around 0.7% of initially identified articles met the selection criteria.

    Data Extraction and Synthesis  The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed. The risk of bias of included cohort studies and RCTs was assessed by the Newcastle-Ottawa Scale and the Cochrane Risk of Bias Tool 2, respectively. A random-effects model meta-analysis was conducted to calculate the pooled hazard ratio (HR) and risk difference for incident VTE.

    Main Outcomes and Measures  The HRs for incident VTE associated with AD and risk difference for incident VTE between participants with AD who were receiving treatment with JAK inhibitors and controls receiving placebo or dupilumab.

    Results  Two cohort studies and 15 RCTs with a total of 466 993 participants were included. The meta-analysis found no significant association of AD with incident VTE (HR, 0.95; 95% CI 0.62-1.45; incidence rate of VTE, 0.23 events/100 patient-years). Overall, 3 of 5722 patients with AD (0.05%) who were receiving treatment with JAK inhibitors experienced VTE compared with 1 of 3065 patients with AD (0.03%) receiving placebo or dupilumab (Mantel-Haenszel risk difference, 0; 95% CI, 0-0). The incidence rate of VTE was 0.15 and 0.12 events per 100 patient-years in participants with AD receiving JAK inhibitors and placebo, respectively. The findings were similar in 4 unique JAK inhibitors (abrocitinib, baricitinib, upadacitinib, and SHR0302).

    Conclusions and Relevance  The results of this systematic review and meta-analysis suggest that the currently available evidence does not detect an increased risk of VTE associated with AD or treatment with JAK inhibitors. These findings may provide a reference for clinicians in prescribing JAK inhibitors for patients with AD.

    Introduction

    Atopic dermatitis (AD) is a prevalent inflammatory dermatosis with increasing worldwide prevalence.1,2 Symptoms, such as relapsing pruritus and visible lesions, may last for a few years and even persist throughout life, necessitating effective treatments.3,4 Janus kinase (JAK) inhibitors have become a promising treatment option for patients with AD because they have been associated with favorable clinical outcomes in clinical trials.5

    Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a potentially life-threatening illness associated with high recurrence rates and mortality.6,7 While several studies have investigated the potential associations of AD with VTE, the results were inconsistent.8,9 Because the US Food and Drug Administration issued a black box warning about an increased risk of blood clots for tofacitinib, baricitinib, and upadacitinib in treating arthritis and other chronic inflammatory conditions, concerns have been raised regarding the risk of VTE being associated with JAK inhibitor therapy.10 Previous meta-analyses regarding several immune-mediated inflammatory diseases, such as psoriasis, rheumatoid arthritis, and inflammatory bowel disease, have found no significant increased risk of VTE in patients receiving treatment with JAK inhibitors.11,12 However, a recent randomized clinical trial reported a 3.52-fold increased risk of VTE associated with treatment with tofacitinib, 10 mg, twice daily, for rheumatoid arthritis among patients 50 years or older who had at least 1 additional cardiovascular risk factor.13 Although JAK inhibitors have been approved in treating AD over recent years, to our knowledge, there has been no systematic evaluation of the risk of VTE among patients with AD and the corresponding safety profile of JAK inhibitors in treating AD. To address this knowledge gap, this systematic review and meta-analysis aimed to evaluate the current evidence on the association of AD with incident VTE and the risk of incident VTE in patients with AD who were receiving treatment with JAK inhibitors.

    Methods

    This systematic review and meta-analysis followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE)14 and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.15 The prespecified study protocol was registered with PROSPERO (CRD42022307784). The study was granted an exemption from institutional review board approval from the Chang Gung Medical Foundation.

    Data Sources and Evidence Search

    A comprehensive literature search was performed on electronic databases (including MEDLINE, Embase, Cochrane Library, and Web of Science) from their respective inception to February 5, 2022. The search strategy was designed with the assistance of an experienced librarian (L.C.) (eTable in the Supplement). There were neither language nor geographic limitations. The references of eligible studies and relevant reviews were also manually scrutinized for additional studies.

    Eligibility Criteria

    To investigate the association of AD with incident VTE, we first included studies that met the following criteria: (1) cohort studies examining the association of AD with incident VTE; (2) an exposure group comprising individuals with AD and a nonexposure control group comprising people without AD; (3) reporting the risk estimates of incident VTE. We only included cohort studies to reduce recall bias and examine the temporal association between AD and incident VTE.

    To further evaluate the risk of VTE in patients with AD who were treated with JAK inhibitors, we included studies that fulfilled the following criteria: (1) phase 2 and phase 3 randomized clinical trials (RCTs) investigating the safety of JAK inhibitors for patients with AD; (2) an intervention group comprising participants with AD receiving treatment with JAK inhibitors and a control group comprising participants with AD receiving either placebo or dupilumab; (3) reporting the number of VTE events. Open-label or long-term extension studies without a control arm were excluded. Studies with patients using topical JAK inhibitors (eg, delgocitinib, ruxolitinib, and tofacitinib) were also excluded.

    When multiple studies presented results from the same database or RCT, we only included the one with the most comprehensive data. We only included studies with confirmed diagnoses of AD and VTE by validated diagnostic codes or clinical criteria. Review articles, editorials, case reports, cross-sectional studies, case-control studies, and studies with nonhuman participants were excluded. Two independent authors (T.C. and L.L.) selected studies by screening the titles and abstracts of the initial literature search. The full text of potentially relevant publications was retrieved for confirming eligibility. Disagreements were resolved through discussion with 2 senior authors (H.H. and C.C.) until reaching consensus.

    Data Extraction and Risk of Bias Assessment

    Two authors (T.C. and L.L.) independently collated the following data using a standardized data sheet: first author, year of publication, country, database or clinical trial identifier, study period, patient characteristics (sample size, age, and sex), definition of AD, and outcomes of interest (risk estimates or the number of VTE events). For the included cohort studies, we extracted the adjusted hazard ratio (HR) with 95% CIs. The risk estimates with the most appropriate adjustment for confounders, such as age, sex, and comorbidities, were used for data synthesis. For the included RCTs, we extracted the number of VTE events. Both DVT and PE were considered VTE events. For studies that did not report sufficient information for meta-analysis, we contacted the corresponding authors for additional data.

    The risk of bias of included cohort studies was assessed using the Newcastle-Ottawa Scale,16 whereas that of RCTs was appraised using the Cochrane risk of bias tool (RoB 2).17 Two authors (T.C. and L.L.) independently performed the risk of bias assessment. Any discrepancy in the extracted data and risk of bias assessment was resolved by discussion with senior authors (H.H. and C.C.).

    Statistical Analysis

    We used Review Manager, version 5.4.1 (The Cochrane Collaboration, 2020) to conduct meta-analyses.18 Two meta-analyses were separately performed for cohort studies (the association of AD with incident VTE) and RCTs (the risk of incident VTE among patients with AD who were receiving treatment with JAK inhibitors). A P value of <.05 was deemed significant. The pooled HRs and corresponding CIs were synthesized to determine the association of AD with incident VTE. Absolute risk differences were used to measure the risk of incident VTE in patients receiving treatment with various JAK inhibitors when compared with those using placebo or dupilumab.19 The random-effects model was applied for meta-analyses based on the assumption of considerable clinical heterogeneity.20 For RCTs with 0 events of VTE reported in both arms, a fixed value of 0.5 was added to correct for computational errors.18 Heterogeneity between individual studies was quantified using the I2 statistics, with an I2 of greater than 50% indicating at least moderate heterogeneity. Publication bias was evaluated by inspecting funnel plots if there were 10 or more studies for an outcome.

    Results
    Selection of Studies

    The PRISMA study flow diagrams for the cohort study and RCT selection are illustrated in Figure 1. A total of 2370 citations were obtained from the initial database search. After removal of duplicates and screening of titles and abstracts, the full text of 135 records was assessed for eligibility (25 studies [18.5%] and 110 studies [81.5%] in the selection of cohort studies and RCTs, respectively). Eventually, we included 2 cohort studies21,22 and 15 RCTs23-37 with a total of 466 993 participants. Only 0.7% of initially identified studies fulfilled the selection criteria.

    Characteristics of Included Studies

    Table 121-37 outlines the characteristics of the included studies. The two cohort studies were conducted in the US, whereas most RCTs were conducted across multiple countries. The definition of AD in cohort studies was based on validated International Classification of Diseases, Ninth Revision (ICD-9) and ICD-10 codes.38 The diagnosis of AD in RCTs was based on the Hanifin and Rajka criteria,39 diagnostic criteria proposed by the American Academy of Dermatology,40 and Chinese criteria.41 The participants in the included RCTs were primarily young and middle-aged adults; however, the study by Eichenfield et al26 included mainly adolescents. Four JAK inhibitors (abrocitinib, baricitinib, upadacitinib, and SHR0302) were investigated.

    Risk of Bias Assessment

    The risk of bias assessment is summarized in Table 2.21-37 The 2 cohort studies were considered of high quality on the Newcastle-Ottawa Scale.21,22 As to bias in outcome measurement, 5 RCTs were rated as some concerns because there was no information about whether the outcome assessors were masked to the treatments when adjudicating VTE events.

    Association of AD With Incident VTE

    Two studies with 458 206 participants (397 370 and 60 836 participants in Meyers et al21 and Schneeweiss et al,22 respectively) examined the association of AD with incident VTE. The crude incidence rate of VTE among patients with AD was 0.24 and 0.18 events per 100 patient-years in Meyers et al21 and Schneeweiss et al,22 respectively. As illustrated in Figure 2, the risk for incident VTE did not significantly increase among patients with AD compared with non-AD controls (pooled HR, 0.95; 95% CI, 0.62-1.45; I2 = 92%). The overall incidence rate of VTE for patients with AD was 0.23 events per 100 patient-years.

    Risk of Incident VTE in Participants With AD Receiving Treatment With Janus Kinase Inhibitors

    Fifteen studies with 8787 participants provided data on VTE events in patients with AD who were receiving treatment with JAK inhibitors.23-37 Overall, 3 of 5722 participants (0.05%) with AD receiving JAK inhibitors experienced VTE events compared with 1 of 3065 participants (0.03%) with AD receiving placebo or dupilumab. As demonstrated in eFigure 1 in the Supplement, the meta-analysis found no significant difference in the risk of incident VTE between participants with AD receiving JAK inhibitors and controls with AD receiving placebo or dupilumab (Mantel-Haenszel risk difference, 0; 95% CI, 0-0; I2 = 0%). The findings were similar across all 4 JAK inhibitors. During the placebo-controlled phase across all RCTs, the overall incidence rate of VTE was 0.15 events per 100 patient-years among participants with AD who were receiving JAK inhibitors, while the incidence rate of VTE in participants with AD receiving placebo was 0.12 events per 100 patient-years. No VTE events were recorded in the trials comparing JAK inhibitors with dupilumab. No publication bias was identified by inspecting the funnel plot (eFigure 2 in the Supplement).

    Discussion

    To our knowledge, this study is the first meta-analysis to investigate the risk of incident VTE in patients with AD. The evidence from cohort studies revealed no statistically significant association between AD and incident VTE. The overall incidence rate of VTE was 0.23 events per 100 patient-years among patients with AD. Meanwhile, the current evidence from RCTs demonstrated no significant differences in the risk of incident VTE between patients with AD who were receiving treatment with JAK inhibitors and patients with AD receiving placebo or dupilumab. The incidence rate of VTE was 0.15 events per 100 patient-years in patients with AD receiving JAK inhibitors.

    According to a recently published guideline,42 AD has been associated with few cardiovascular comorbidities.43 The associations are not as strong as those observed with psoriasis,44,45 which do not prompt cardiovascular screening or treatment for individuals with AD. In the case of VTE, the results of the present meta-analysis suggested that AD is not a risk factor for incident VTE. By contrast, a cross-sectional survey conducted by Shaheen et al9 reported a positive association between AD and prevalent VTE (adjusted odds ratio, 1.22; 95% CI, 1.17-1.27). In a case-control study carried out by Undas et al,46 atopic diseases were more prevalent in patients with VTE (38%) than non-VTE controls (23%). Nevertheless, these studies could not assess causality and did not adjust important confounders, such as hormone therapies and smoking status.47,48 Another study using an administrative claims database from the US presented subgroup data of VTE and showed a trend of lower risks of DVT and PE in patients with AD.8

    The changes in the coagulation and fibrinolysis system among patients with AD are still unclear.49,50 Elevated plasma levels of platelet activation factors have been observed in patients with AD.51 However, these coagulation markers were not associated with AD severity.52,53 Inflammatory cytokines in AD, such as interleukin (IL)–4 and IL-13, may interact with coagulation cascades in animal models.54,55 Studies have also found that proinflammatory mast cells and tryptases in AD could modulate fibrinolysis, in which is associated with a decreased risk of thrombi formation.56 More research is needed to understand whether the laboratory findings in patients with AD are clinically relevant.

    Among the included RCTs, 3 VTE events occurred in participants who were receiving treatment with JAK inhibitors during the randomized placebo-controlled periods. In the JADE REGIMEN trial, a patient receiving abrocitinib, 100 mg, once daily, experienced sudden vision loss and received a diagnosis of retinal vein thrombosis.25,30 Another participant receiving abrocitinib, 200 mg, once daily, was also documented as having PE, which was not considered treatment-related by Gooderham et al.27 The other event of PE was reported with a patient receiving treatment with baricitinib, 4 mg, once daily, in the BREEZE-AD7 trial.31 However, recent studies have provided additional data on VTE in patients with AD who were receiving treatment with JAK inhibitors during the open-label extension periods. A safety analysis of abrocitinib that combined the results of 5 RCTs and a long-term extension study (JADE EXTEND) reported 5 adjudicated VTE events, all in the 200-mg group.57 In a post hoc analysis focusing on 2-mg baricitinib exclusively, no VTE events were recorded.58 During the 52-week follow-up of AD Up trials, 1 patient using upadacitinib received an incidental diagnosis of PE.59 In the present meta-analysis of JAK inhibitors, comparable risks of VTE were indicated in patients receiving JAK inhibitors and those receiving placebo or dupilumab. These results were consistent with previous meta-analyses of JAK inhibitors regarding multiple indications.11,12 Controlling inflammation via inhibition of the JAK pathways may reduce platelet activity and lower VTE events. Dose-response decreases in platelet counts have been observed in several RCTs among patients with AD treated with JAK inhibitors.25,26,60However, some of the included trials did not outline VTE risk factors of the enrollees at baseline (eg, prior VTE or recent surgical history),61 which might have introduced selection bias in reporting VTE events. With the increasing applications of JAK inhibitors in AD, more clinical data are needed to identify patients at high risk for VTE.

    Strengths and Limitations

    The major strength of this systematic review and meta-analysis is the inclusion of population-based cohort studies and high-quality RCTs to provide up-to-date evidence. The existing evidence from cohort studies suggests that AD is not associated with incident VTE. The evidence from RCTs indicates retention of a null hypothesis of no difference in the risk of VTE between patients with AD who were receiving treatment with JAK inhibitors and controls receiving placebo or dupilumab. Nevertheless, the results of this study need to be considered with some limitations. First, the generalizability may be limited because the included studies were mainly conducted in Western countries. Second, statistical heterogeneity was present in the meta-analysis on the association between AD and VTE. A subgroup analysis or meta-regression to identify potential effect modifiers was infeasible because of the limited number of studies (n = 2). While the crude incidence rate was similar between the 2 included cohort studies, the adjusted HRs were different. Imbalances in health care utilization and differences in confounding adjustments might explain the different risk estimates. Third, the included studies did not report the VTE risk among different patterns of AD (ie, persistent, relapsing, or adulthood-onset forms). Because age is an important risk factor for VTE,61 a subanalysis according to the onset of AD is encouraged. Fourth, the included RCTs may be underpowered or of too short duration to detect rare or long-term adverse events, such as VTE. Given the 5722 patients with AD in the JAK inhibitor group and 3065 patients in the control group, the number of participants in both arms may still be too low for inferences about safety. Hence, the results from the trial-based meta-analysis must be interpreted with caution.

    Conclusions

    The results of this systematic review and meta-analysis suggest that evidence from cohort studies does not detect an increased risk of incident VTE among patients with AD, nor does the evidence from RCTs detect significant differences in the risk of incident VTE between patients with AD who were receiving treatment with JAK inhibitors and controls receiving placebo or dupilumab. These findings may provide a reference for clinicians in prescribing JAK inhibitors for patients with AD. Further evidence from real-world data on longer-term safety are warranted.

    Back to top
    Article Information

    Accepted for Publication: July 1, 2022.

    Published Online: August 24, 2022. doi:10.1001/jamadermatol.2022.3516

    Corresponding Author: Ching-Chi Chi, MD, MMS, DPhil, Department of Dermatology, Chang Gung Memorial Hospital, Linkou, 5, Fuxing St, Guishan Dist, Taoyuan 33305, Taiwan (chingchi@cgmh.org.tw).

    Author Contributions: Dr Chen and Prof Chi had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: T. Chen, Chi.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: T. Chen, Huang.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: T. Chen, Lee.

    Administrative, technical, or material support: Loh, Chi.

    Supervision: Chi.

    Conflict of Interest Disclosures: None reported.

    Additional Contributions: We thank the Department of Medical Research of Hualien Tzu Chi Hospital and the Buddhist Tzu Chi Medical Foundation for their assistance.

    References
    1.
    Langan  SM, Irvine  AD, Weidinger  S.  Atopic dermatitis.   Lancet. 2020;396(10247):345-360. doi:10.1016/S0140-6736(20)31286-1 PubMedGoogle ScholarCrossref
    2.
    Wang  CH, Fu  Y, Chi  CC.  Association of atopic dermatitis with inflammatory bowel disease: a systematic review and meta-analysis.   Dermatol Sin. 2020;38(3):159-165. doi:10.4103/ds.ds_20_20 Google ScholarCrossref
    3.
    Sidbury  R, Davis  DM, Cohen  DE,  et al; American Academy of Dermatology.  Guidelines of care for the management of atopic dermatitis: section 3: management and treatment with phototherapy and systemic agents.   J Am Acad Dermatol. 2014;71(2):327-349. doi:10.1016/j.jaad.2014.03.030 PubMedGoogle ScholarCrossref
    4.
    Ee  S, Tay  YK, Chu  CY, Hon  KL, Leong  KF, Wananukul  S.  A study on the knowledge, attitudes, and practices of Asian dermatologists in the management of atopic dermatitis.   Dermatol Sin. 2020;38(2):67-80. doi:10.4103/ds.ds_31_19 Google ScholarCrossref
    5.
    Chovatiya  R, Paller  AS.  JAK inhibitors in the treatment of atopic dermatitis.   J Allergy Clin Immunol. 2021;148(4):927-940. doi:10.1016/j.jaci.2021.08.009 PubMedGoogle ScholarCrossref
    6.
    Arshad  N, Bjøri  E, Hindberg  K, Isaksen  T, Hansen  JB, Braekkan  SK.  Recurrence and mortality after first venous thromboembolism in a large population-based cohort.   J Thromb Haemost. 2017;15(2):295-303. doi:10.1111/jth.13587 PubMedGoogle ScholarCrossref
    7.
    Søgaard  KK, Schmidt  M, Pedersen  L, Horváth-Puhó  E, Sørensen  HT.  30-year mortality after venous thromboembolism: a population-based cohort study.   Circulation. 2014;130(10):829-836. doi:10.1161/CIRCULATIONAHA.114.009107 PubMedGoogle ScholarCrossref
    8.
    Setyawan  J, Mu  F, Yarur  A,  et al.  Risk of thromboembolic events and associated risk factors, including treatments, in patients with immune-mediated diseases.   Clin Ther. 2021;43(8):1392-1407.e1. doi:10.1016/j.clinthera.2021.06.008 PubMedGoogle ScholarCrossref
    9.
    Shaheen  MS, Silverberg  JI.  Association of inflammatory skin diseases with venous thromboembolism in US adults.   Arch Dermatol Res. 2021;313(4):281-289. doi:10.1007/s00403-020-02099-6 PubMedGoogle ScholarCrossref
    10.
    US Food and Drug Administration. FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. Accessed January 9, 2022. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death
    11.
    Yates  M, Mootoo  A, Adas  M,  et al.  Venous thromboembolism risk with JAK inhibitors: a meta-analysis.   Arthritis Rheumatol. 2021;73(5):779-788. doi:10.1002/art.41580 PubMedGoogle ScholarCrossref
    12.
    Bilal  J, Riaz  IB, Naqvi  SAA,  et al.  Janus kinase inhibitors and risk of venous thromboembolism: a systematic review and meta-analysis.   Mayo Clin Proc. 2021;96(7):1861-1873. doi:10.1016/j.mayocp.2020.12.035 PubMedGoogle ScholarCrossref
    13.
    Ytterberg  SR, Bhatt  DL, Mikuls  TR,  et al; ORAL Surveillance Investigators.  Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis.   N Engl J Med. 2022;386(4):316-326. doi:10.1056/NEJMoa2109927 PubMedGoogle ScholarCrossref
    14.
    Stroup  DF, Berlin  JA, Morton  SC,  et al.  Meta-analysis of observational studies in epidemiology: a proposal for reporting.   JAMA. 2000;283(15):2008-2012. doi:10.1001/jama.283.15.2008 PubMedGoogle ScholarCrossref
    15.
    Page  MJ, McKenzie  JE, Bossuyt  PM,  et al.  The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.   BMJ. 2021;372(71):n71. doi:10.1136/bmj.n71 PubMedGoogle ScholarCrossref
    16.
    Wells  GA, Shea  B, O’Connell  D,  et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analysis. Accessed November 23, 2006. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.
    17.
    Sterne  JAC, Savović  J, Page  MJ,  et al.  RoB 2: a revised tool for assessing risk of bias in randomised trials.   BMJ. 2019;366:l4898. doi:10.1136/bmj.l4898 PubMedGoogle ScholarCrossref
    18.
    Higgins  JPT, Thomas  J, Chandler  J,  et al.  Cochrane Handbook for Systematic Reviews of Interventions Version 6.2). Cochrane; 2021.
    19.
    Ryan  C, Leonardi  CL, Krueger  JG,  et al.  Association between biologic therapies for chronic plaque psoriasis and cardiovascular events: a meta-analysis of randomized controlled trials.   JAMA. 2011;306(8):864-871. doi:10.1001/jama.2011.1211 PubMedGoogle ScholarCrossref
    20.
    Higgins  JP, Thompson  SG, Deeks  JJ, Altman  DG.  Measuring inconsistency in meta-analyses.   BMJ. 2003;327(7414):557-560. doi:10.1136/bmj.327.7414.557 PubMedGoogle ScholarCrossref
    21.
    Meyers  KJ, Silverberg  JI, Rueda  MJ,  et al.  Risk of venous thromboembolism among patients with atopic dermatitis: a cohort study in a US administrative claims database.   Dermatol Ther (Heidelb). 2021;11(3):1041-1052. doi:10.1007/s13555-021-00538-4 PubMedGoogle ScholarCrossref
    22.
    Schneeweiss  MC, Kim  SC, Wyss  R,  et al.  Incidence of venous thromboembolism in patients with dermatologist-diagnosed chronic inflammatory skin diseases.   JAMA Dermatol. 2021;157(7):805-816. doi:10.1001/jamadermatol.2021.1570 PubMedGoogle ScholarCrossref
    23.
    Bieber  T, Simpson  EL, Silverberg  JI,  et al; JADE COMPARE Investigators.  Abrocitinib versus placebo or dupilumab for atopic dermatitis.   N Engl J Med. 2021;384(12):1101-1112. doi:10.1056/NEJMoa2019380 PubMedGoogle ScholarCrossref
    24.
    Blauvelt  A, Teixeira  HD, Simpson  EL,  et al.  Efficacy and safety of upadacitinib vs dupilumab in adults with moderate-to-severe atopic dermatitis: a randomized clinical trial.   JAMA Dermatol. 2021;157(9):1047-1055. doi:10.1001/jamadermatol.2021.3023 PubMedGoogle ScholarCrossref
    25.
    Blauvelt  A, Silverberg  JI, Lynde  CW,  et al.  Abrocitinib induction, randomized withdrawal, and retreatment in patients with moderate-to-severe atopic dermatitis: results from the JAK1 Atopic Dermatitis Efficacy and Safety (JADE) REGIMEN phase 3 trial.   J Am Acad Dermatol. 2022;86(1):104-112. doi:10.1016/j.jaad.2021.05.075 PubMedGoogle ScholarCrossref
    26.
    Eichenfield  LF, Flohr  C, Sidbury  R,  et al.  Efficacy and safety of abrocitinib in combination with topical therapy in adolescents with moderate-to-severe atopic dermatitis: the JADE TEEN randomized clinical trial.   JAMA Dermatol. 2021;157(10):1165-1173. doi:10.1001/jamadermatol.2021.2830 PubMedGoogle ScholarCrossref
    27.
    Gooderham  MJ, Forman  SB, Bissonnette  R,  et al.  Efficacy and safety of oral Janus kinase 1 inhibitor abrocitinib for patients with atopic dermatitis: a phase 2 randomized clinical trial.   JAMA Dermatol. 2019;155(12):1371-1379. doi:10.1001/jamadermatol.2019.2855 PubMedGoogle ScholarCrossref
    28.
    Guttman-Yassky  E, Thaçi  D, Pangan  AL,  et al.  Upadacitinib in adults with moderate to severe atopic dermatitis: 16-week results from a randomized, placebo-controlled trial.   J Allergy Clin Immunol. 2020;145(3):877-884. doi:10.1016/j.jaci.2019.11.025 PubMedGoogle ScholarCrossref
    29.
    Guttman-Yassky  E, Teixeira  HD, Simpson  EL,  et al.  Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials.   Lancet. 2021;397(10290):2151-2168. doi:10.1016/S0140-6736(21)00588-2 PubMedGoogle ScholarCrossref
    30.
    Katoh  N, Ohya  Y, Murota  H,  et al.  A phase 3 randomized, multicenter, double-blind study to evaluate the safety of upadacitinib in combination with topical corticosteroids in adolescent and adult patients with moderate-to-severe atopic dermatitis in Japan (Rising Up): An interim 24-week analysis.   JAAD Int. 2021;6:27-36. doi:10.1016/j.jdin.2021.11.001 PubMedGoogle ScholarCrossref
    31.
    Reich  K, Kabashima  K, Peris  K,  et al.  Efficacy and safety of baricitinib combined with topical corticosteroids for treatment of moderate to severe atopic dermatitis: a randomized clinical trial.   JAMA Dermatol. 2020;156(12):1333-1343. doi:10.1001/jamadermatol.2020.3260 PubMedGoogle ScholarCrossref
    32.
    Reich  K, Teixeira  HD, de Bruin-Weller  M,  et al.  Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial.   Lancet. 2021;397(10290):2169-2181. doi:10.1016/S0140-6736(21)00589-4 PubMedGoogle ScholarCrossref
    33.
    Silverberg  JI, Simpson  EL, Thyssen  JP,  et al.  Efficacy and safety of abrocitinib in patients with moderate-to-severe atopic dermatitis: a randomized clinical trial.   JAMA Dermatol. 2020;156(8):863-873. doi:10.1001/jamadermatol.2020.1406 PubMedGoogle ScholarCrossref
    34.
    Simpson  EL, Sinclair  R, Forman  S,  et al.  Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial.   Lancet. 2020;396(10246):255-266. doi:10.1016/S0140-6736(20)30732-7 PubMedGoogle ScholarCrossref
    35.
    Simpson  EL, Lacour  JP, Spelman  L,  et al.  Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials.   Br J Dermatol. 2020;183(2):242-255. doi:10.1111/bjd.18898 PubMedGoogle ScholarCrossref
    36.
    Simpson  EL, Forman  S, Silverberg  JI,  et al.  Baricitinib in patients with moderate-to-severe atopic dermatitis: results from a randomized monotherapy phase 3 trial in the United States and Canada (BREEZE-AD5).   J Am Acad Dermatol. 2021;85(1):62-70. doi:10.1016/j.jaad.2021.02.028 PubMedGoogle ScholarCrossref
    37.
    Zhao  Y, Zhang  L, Ding  Y,  et al.  Efficacy and safety of SHR0302, a highly selective Janus kinase 1 inhibitor, in patients with moderate to severe atopic dermatitis: a phase II randomized clinical trial.   Am J Clin Dermatol. 2021;22(6):877-889. doi:10.1007/s40257-021-00627-2 PubMedGoogle ScholarCrossref
    38.
    Hsu  DY, Dalal  P, Sable  KA,  et al.  Validation of International Classification of Disease Ninth Revision codes for atopic dermatitis.   Allergy. 2017;72(7):1091-1095. doi:10.1111/all.13113 PubMedGoogle ScholarCrossref
    39.
    Hanifin  JM, Rajka  G.  Diagnostic features of atopic dermatitis.   Acta Derm Venereol Suppl (Stockh). 1980;92:44-47. https://www.medicaljournals.se/acta/content_files/files/pdf/60/92/924447.pdfGoogle Scholar
    40.
    Eichenfield  LF, Tom  WL, Chamlin  SL,  et al.  Guidelines of care for the management of atopic dermatitis: section 1: diagnosis and assessment of atopic dermatitis.   J Am Acad Dermatol. 2014;70(2):338-351. doi:10.1016/j.jaad.2013.10.010 PubMedGoogle ScholarCrossref
    41.
    Liu  P, Zhao  Y, Mu  ZL,  et al.  Clinical features of adult/adolescent atopic dermatitis and Chinese criteria for atopic dermatitis.   Chin Med J (Engl). 2016;129(7):757-762. doi:10.4103/0366-6999.178960 PubMedGoogle ScholarCrossref
    42.
    Davis  DMR, Drucker  AM, Alikhan  A,  et al.  American Academy of Dermatology guidelines: awareness of comorbidities associated with atopic dermatitis in adults.   J Am Acad Dermatol. 2022;86(6):1335-1336.e18. doi:10.1016/j.jaad.2022.01.009 PubMedGoogle ScholarCrossref
    43.
    Ascott  A, Mulick  A, Yu  AM,  et al.  Atopic eczema and major cardiovascular outcomes: a systematic review and meta-analysis of population-based studies.   J Allergy Clin Immunol. 2019;143(5):1821-1829. doi:10.1016/j.jaci.2018.11.030 PubMedGoogle ScholarCrossref
    44.
    Armstrong  EJ, Harskamp  CT, Armstrong  AW.  Psoriasis and major adverse cardiovascular events: a systematic review and meta-analysis of observational studies.   J Am Heart Assoc. 2013;2(2):e000062. doi:10.1161/JAHA.113.000062 PubMedGoogle ScholarCrossref
    45.
    Chen  TL, Lee  LL, Huang  HK,  et al.  Association of psoriasis with incident venous thromboembolism and peripheral vascular disease: a systematic review and meta-analysis.   JAMA Dermatol. 2022;158(1):59-67. doi:10.1001/jamadermatol.2021.4918 PubMedGoogle ScholarCrossref
    46.
    Undas  A, Cieśla-Dul  M, Drążkiewicz  T, Potaczek  DP, Sadowski  J.  Association between atopic diseases and venous thromboembolism: a case-control study in patients aged 45 years or less.   J Thromb Haemost. 2011;9(4):870-873. doi:10.1111/j.1538-7836.2011.04198.x PubMedGoogle ScholarCrossref
    47.
    Vinogradova  Y, Coupland  C, Hippisley-Cox  J.  Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases.   BMJ. 2019;364:k4810. doi:10.1136/bmj.k4810 PubMedGoogle ScholarCrossref
    48.
    Mahmoodi  BK, Cushman  M, Anne Næss  I,  et al.  Association of traditional cardiovascular risk factors with venous thromboembolism: an individual participant data meta-analysis of prospective studies.   Circulation. 2017;135(1):7-16. doi:10.1161/CIRCULATIONAHA.116.024507 PubMedGoogle ScholarCrossref
    49.
    Pandher  K, Ghamrawi  RI, Heron  CE, Feldman  SR.  Controversial cardiovascular and hematologic comorbidities in atopic dermatitis.   Arch Dermatol Res. 2022;314(4):317-324. doi:10.1007/s00403-021-02240-zPubMedGoogle ScholarCrossref
    50.
    Potaczek  DP.  Links between allergy and cardiovascular or hemostatic system.   Int J Cardiol. 2014;170(3):278-285. doi:10.1016/j.ijcard.2013.11.029 PubMedGoogle ScholarCrossref
    51.
    Tamagawa-Mineoka  R, Katoh  N, Ueda  E, Masuda  K, Kishimoto  S.  Elevated platelet activation in patients with atopic dermatitis and psoriasis: increased plasma levels of beta-thromboglobulin and platelet factor 4.   Allergol Int. 2008;57(4):391-396. doi:10.2332/allergolint.O-08-537 PubMedGoogle ScholarCrossref
    52.
    Koczy-Baron  E, Jochem  J, Kasperska-Zajac  A.  Increased plasma concentration of vascular endothelial growth factor in patients with atopic dermatitis and its relation to disease severity and platelet activation.   Inflamm Res. 2012;61(12):1405-1409. doi:10.1007/s00011-012-0543-6 PubMedGoogle ScholarCrossref
    53.
    Nastałek  M, Potaczek  DP, Wojas-Pelc  A, Undas  A.  Plasma platelet activation markers in patients with atopic dermatitis and concomitant allergic diseases.   J Dermatol Sci. 2011;64(1):79-82. doi:10.1016/j.jdermsci.2011.07.001 PubMedGoogle ScholarCrossref
    54.
    Alshehri  FSM, Whyte  CS, Tuncay  A, Williams  ML, Wilson  HM, Mutch  NJ.  Monocytes expose factor XIII-A and stabilize thrombi against fibrinolytic degradation.   Int J Mol Sci. 2021;22(12):6591. doi:10.3390/ijms22126591 PubMedGoogle ScholarCrossref
    55.
    Smiley  ST, Boyer  SN, Heeb  MJ, Griffin  JH, Grusby  MJ.  Protein S is inducible by interleukin 4 in T cells and inhibits lymphoid cell procoagulant activity.   Proc Natl Acad Sci U S A. 1997;94(21):11484-11489. doi:10.1073/pnas.94.21.11484 PubMedGoogle ScholarCrossref
    56.
    Caughey  GH.  Tryptase genetics and anaphylaxis.   J Allergy Clin Immunol. 2006;117(6):1411-1414. doi:10.1016/j.jaci.2006.02.026 PubMedGoogle ScholarCrossref
    57.
    Simpson  EL, Silverberg  JI, Nosbaum  A,  et al.  Integrated safety analysis of abrocitinib for the treatment of moderate-to-severe atopic dermatitis from the phase II and phase III clinical trial program.   Am J Clin Dermatol. 2021;22(5):693-707. doi:10.1007/s40257-021-00618-3 PubMedGoogle ScholarCrossref
    58.
    King  B, Maari  C, Lain  E,  et al.  Extended safety analysis of baricitinib 2 mg in adult patients with atopic dermatitis: an integrated analysis from eight randomized clinical trials.   Am J Clin Dermatol. 2021;22(3):395-405. doi:10.1007/s40257-021-00602-x PubMedGoogle ScholarCrossref
    59.
    Silverberg  JI, de Bruin-Weller  M, Bieber  T,  et al.  Upadacitinib plus topical corticosteroids in atopic dermatitis: Week 52 AD Up study results.   J Allergy Clin Immunol. 2022;149(3):977-987.e14. doi:10.1016/j.jaci.2021.07.036 PubMedGoogle ScholarCrossref
    60.
    Soto  E, Banfield  C, Gupta  P, Peterson  MC.  Kinetic-pharmacodynamic model of platelet time course in patients with moderate-to-severe atopic dermatitis treated with oral Janus kinase 1 inhibitor abrocitinib.   CPT Pharmacometrics Syst Pharmacol. 2020;9(10):553-560. doi:10.1002/psp4.12548 PubMedGoogle ScholarCrossref
    61.
    Anderson  FA  Jr, Spencer  FA.  Risk factors for venous thromboembolism.   Circulation. 2003;107(23)(suppl 1):I9-I16. PubMedGoogle Scholar
    ×