Journal of Investigative Dermatology Home

Cluster analysis of circulating plasma biomarkers in prurigo nodularis reveals a distinct systemic inflammatory signature in African Americans

Published:October 27, 2021DOI:


      Patients with prurigo nodularis (PN) suffer from intractable itch and dramatic reduction in quality of life. While there is significant clinical heterogeneity in the presentation of PN, disease endotypes remain unknown. We assayed circulating plasma cytokine concentrations in PN patients (n=20) along with matched healthy controls and utilized an unsupervised machine learning algorithm to identify disease endotypes. We found two distinct clusters of PN patients with non-inflammatory (Cluster 1) and inflammatory (Cluster 2) plasma profiles. Cluster 2 had more African-Americans (82%, n=9 vs. 33%, n=3; P=0.028), higher worst-itch numeric rating scale scores (9.5±0.9 vs. 8.3±1.2; P=0.036), and lower quality of life as reflected by higher Dermatology Life Quality Index scores (21.9±6.4 vs. 13.0±4.1; P=0.015). In addition, Cluster 1 had a higher rate of myelopathy (67%, n=6 vs. 18%, n=2; P=0.028). Compared to Cluster 1, Cluster 2 had higher levels of IL-1α, IL-4, IL-5, IL-6, IL-10, IL-17A, IL-22, IL-25, and IFN-α. With population-level analysis, African-American PN patients had higher erythrocyte sedimentation rate, C-reactive protein, ferritin, eosinophils, and lower transferrin than Caucasian PN patients. These findings indicate discrete clusters of PN patients with plasma biomarker profiles corresponding to distinct demographic and clinical characteristics, potentially allowing for precision medicine approaches to treat PN.


      PN ((prurigo nodularis)), AA ((African American)), ESR ((erythrocyte sedimentation rate)), CRP ((C-reactive protein)), IGA ((Investigator’s Global Assessment)), AD ((atopic dermatitis))
      To read this article in full you will need to make a payment
      Purchase one-time access
      Society Members (SID/ESDR), remember to log in for access.
      Subscribe to Journal of Investigative Dermatology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Aggarwal P.
        • Choi J.
        • Sutaria N.
        • Roh Y.S.
        • Wongvibulsin S.
        • Williams K.A.
        • Huang A.H.
        • Boozalis E.
        • Le T.
        • Chavda R.
        • Gabriel S.
        • Kwatra S.G.
        Clinical characteristics and disease burden in prurigo nodularis.
        Clin Exp Dermatol. 2021 May 10;
        • Aleem S.
        • Masood Q.
        • Hassan I.
        Correlation of C-reactive protein levels with severity of chronic urticaria.
        Indian J Dermatol. 2014; 59: 636
      1. Belzberg M, Alphonse MP, Brown I, Williams KA, Khanna R, Ho B, et al. Prurigo Nodularis Is Characterized by Systemic and Cutaneous T Helper 22 Immune Polarization. J Invest Dermatol. 202; 23:S0022-202X(21)01016-2.

        • Boozalis E.
        • Tang O.
        • Patel S.
        • Semenov Y.R.
        • Pereira M.P.
        • Stander S.
        • Kang S.
        • Kwatra S.G.
        Ethnic differences and comorbidities of 909 prurigo nodularis patients.
        J Am Acad Dermatol. 2018 Oct; 79: 714-719.e3
      2. Donnelly K. SNOMED-CT: The advanced terminology and coding system for eHealth. Stud Health Technol Inform. 2006;121:279-290.

        • Fukushi S.
        • Yamasaki K.
        • Aiba S.
        Nuclear localization of activated STAT6 and STAT3 in epidermis of prurigo nodularis.
        Br J Dermatol. 2011 Nov; 165: 990-996
        • Gono T.
        • Kawaguchi Y.
        • Hara M.
        • Masuda I.
        • Katsumata Y.
        • Shinozaki M.
        • et al.
        Increased ferritin predicts development and severity of acute interstitial lung disease as a complication of dermatomyositis.
        Rheumatology (Oxford). 2010; 49: 1354-1360
        • Gower J.
        A general coefficient of similarity and some of its properties.
        Biometrics. 1971; 27: 857-871
        • Hänel K.H.
        • Pfaff C.M.
        • Cornelissen C.
        • Amann P.M.
        • Marquardt Y.
        • Czaja K.
        • et al.
        Control of the Physical and Antimicrobial Skin Barrier by an IL-31-IL-1 Signaling Network.
        J Immunol. 2016; 196: 3233-3244
      3. Hennig C. Cluster-wise assessment of cluster stability. Computational Statistics & Data Analysis. 2007;15;52(1):258-271.

        • Huang A.H.
        • Williams K.A.
        • Kwatra S.G.
        Prurigo nodularis: Epidemiology and clinical features.
        J Am Acad Dermatol. 2020; 83: 1559-1565
        • Jensen L.E.
        Targeting the IL-1 family members in skin inflammation.
        Curr Opin Investig Drugs. 2010; 11: 1211-1220
        • Johansson O.
        • Liang Y.
        • Emtestam L.
        Increased nerve growth factor-and tyrosine kinase A-like immunoreactivities in prurigo nodularis skin–an exploration of the cause of neurohyperplasia.
        Arch Dermatol Res. 2002; 293: 614-619
        • Kaufman L.
        • Rousseeuw P.J.
        Partitioning around medoids (program pam).
        Finding groups in data: an introduction to cluster analysis. 1990; 344: 68-125
        • Kim H.J.
        • Zeidi M.
        • Bonciani D.
        • Pena S.M.
        • Tiao J.
        • Sahu S.
        • et al.
        Itch in dermatomyositis: the role of increased skin interleukin-31.
        Br J Dermatol. 2018; 179: 669-678
        • Klonowska J.
        • Gleń J.
        • Nowicki R.J.
        • Trzeciak M.
        New Cytokines in the Pathogenesis of Atopic Dermatitis-New Therapeutic Targets.
        Int J Mol Sci. 2018; 19: 3086
        • Konda D.
        • Chandrashekar L.
        • Rajappa M.
        • Kattimani S.
        • Thappa D.M.
        • Ananthanarayanan P.H.
        Serotonin and interleukin-6: Association with pruritus severity, sleep quality and depression severity in Prurigo Nodularis.
        Asian J Psychiatr. 2015; 17: 24-28
        • Kwatra S.G.
        Breaking the Itch–Scratch Cycle in Prurigo Nodularis.
        N Engl J Med. 2020; 382: 757-758
        • Larson V.A.
        • Tang O.
        • Stander S.
        • Miller L.S.
        • Kang S.
        • Kwatra S.G.
        Association between prurigo nodularis and malignancy in middle-aged adults.
        J Am Acad Dermatol. 2019 Nov; 81: 1198-1201
        • McColl M.
        • Boozalis E.
        • Aguh C.
        • Eseonu A.C.
        • Okoye G.A.
        • Kwatra S.G.
        Pruritus in Black Skin: Unique Molecular Characteristics and Clinical Features.
        J Natl Med Assoc. 2021; 113: 30-38
        • Murakami Y.
        • Furukawa S.
        • Nitta A.
        • Furukawa Y.
        Accumulation of nerve growth factor protein at both rostral and caudal stumps in the transected rat spinal cord.
        J Neurol Sci. 2002; 198: 63-69
        • Punzi L.
        • Pianon M.
        • Rossini P.
        • Schiavon F.
        • Gambari P.F.
        Clinical and laboratory manifestations of elderly onset psoriatic arthritis: a comparison with younger onset disease.
        Ann Rheum Dis. 1999; 58: 226-229
        • Rosenblatt M.
        A central limit theorem and a strong mixing condition.
        Proceedings of the National Academy of Sciences of the United States of America. 1956 Jan; 42: 43
        • Rousseeuw P.J.
        Silhouettes: A graphical aid to the interpretation and validation of cluster analysis.
        Computational and Applied Mathematics. 1987; 20: 53-65
        • Thijs J.L.
        • Strickland I.
        • Bruijnzeel-Koomen C.A.F.M.
        • Nierkens S.
        • Giovannone B.
        • Csomor E.
        • et al.
        Moving toward endotypes in atopic dermatitis: Identification of patient clusters based on serum biomarker analysis.
        J Allergy Clin Immunol. 2017; 140: 730-737
        • Tomassen P.
        • Vandeplas G.
        • Van Zele T.
        • Cardell L.O.
        • Arebro J.
        • Olze H.
        • et al.
        Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers.
        J Allergy Clin Immunol. 2016; 137 (e4): 1449-1456
        • Saravia J.
        • Chapman N.M.
        • Chi H.
        Helper T cell differentiation.
        Cell Mol Immunol. 2019; 16: 634-643
        • Ständer S.
        • Yosipovitch G.
        • Legat F.J.
        • Lacour J.P.
        • Paul C.
        • Narbutt J.
        • et al.
        Trial of Nemolizumab in Moderate-to-Severe Prurigo Nodularis.
        N Engl J Med. 2020; 382: 706-716
        • Sutaria N.
        • Choi J.
        • Roh Y.S.
        • Alphonse M.P.
        • Adawi W.
        • Lai J.
        • Pollock J.R.
        • Fontecilla Biles N.
        • Gabriel S.
        • Chavda R.
        • Kwatra S.G.
        Association of prurigo nodularis and infectious disease hospitalizations: a national cross-sectional study.
        Clin Exp Dermatol. 2021 Mar 24;
        • Takahashi H.
        • Tsuji H.
        • Hashimoto Y.
        • Ishida-Yamamoto A.
        • Iizuka H.
        Serum cytokines and growth factor levels in Japanese patients with psoriasis.
        Clin Exp Dermatol. 2010; 35: 645-649
        • Vakirlis E.
        • Lazaridou E.
        • Tzellos T.G.
        • Gerou S.
        • Chatzidimitriou D.
        • Ioannides D.
        Investigation of cytokine levels and their association with SCORAD index in adults with acute atopic dermatitis.
        J Eur Acad Dermatol Venereol. 2011; 25: 409-416
        • Vekaria A.S.
        • Brunner P.M.
        • Aleisa A.I.
        • Bonomo L.
        • Lebwohl M.G.
        • Israel A.
        • et al.
        Moderate-to-severe atopic dermatitis patients show increases in serum C-reactive protein levels, correlating with skin disease activity.
        F1000Res. 2017; 6: 1712
        • Whang K.A.
        • Kang S.
        • Kwatra S.G.
        Inpatient Burden of Prurigo Nodularis in the United States.
        Medicines (Basel). 2019 Aug 11; 6: 88
      4. Whang KA, Le TK, Khanna R, Williams KA, Roh YS, Sutaria N, Choi J, Gabriel S, Chavda R, Semenov Y, Kwatra SG. Health-related quality of life and economic burden of prurigo nodularis. J Am Acad Dermatol. 2021 May 28:S0190-9622(21)01028-8.

        • Williams K.A.
        • Huang A.H.
        • Belzberg M.
        • Kwatra S.G.
        Prurigo nodularis: Pathogenesis and management.
        J Am Acad Dermatol. 2020; 83: 1567-1575
        • Williams K.A.
        • Roh Y.S.
        • Brown I.
        • Sutaria N.
        • Bakhshi P.
        • Choi J.
        • et al.
        Pathophysiology, diagnosis, and pharmacological treatment of prurigo nodularis.
        Expert Rev Clin Pharmacol. 2020; 14: 67-77
        • Wongvibulsin S.
        • Sutaria N.
        • Kannan S.
        • et al.
        Transcriptomic analysis of atopic dermatitis in African Americans is characterized by Th2/Th17-centered cutaneous immune activation.
        Sci Rep. 2021; 11: 11175
      5. Wongvibulsin S, Sutaria N, Williams KA, Huang AH, Choi J, Roh YS, et al. A Nationwide Study of Prurigo Nodularis: Disease Burden and Healthcare Utilization in the United States. J Invest Dermatol. 2021;S0022-202X(21)01130-01131.

        • Zeidler C.
        • Pereira M.P.
        • Augustin M.
        • Spellman M.
        • Ständer S.
        Investigator's Global Assessment of Chronic Prurigo: A New Instrument for Use in Clinical Trials.
        Acta Derm Venereol. 2021; 101adv00401