Real-World Prevalence of Prurigo Nodularis and Burden of Associated Diseases

Prurigo nodularis (PN) is a chronic dermatosis characterized by intensely pruritic, symmetrically distributed hyperkeratotic nodules. Although the cause of the disease is unknown, PN often develops in the context of systemic, dermatologic, and neuropsychiatric conditions (Boozalis et al., 2018Boozalis E. Tang O. Patel S. Semenov Y.R. Pereira M.P. Ständer S. et al.Ethnic differences and comorbidities of 909 prurigo nodularis patients.J Am Acad Dermatol. 2018; 79: 714-719.e3Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, Iking et al., 2013Iking A. Grundmann S. Chatzigeorgakidis E. Phan N.Q. Klein D. Ständer S. Prurigo as a symptom of atopic and non-atopic diseases: aetiological survey in a consecutive cohort of 108 patients.J Eur Acad Dermatol Venereol. 2013; 27: 550-557Crossref PubMed Scopus (82) Google Scholar, Winhoven and Gawkrodger, 2007Winhoven S.M. Gawkrodger D.J. Nodular prurigo: metabolic diseases are a common association.Clin Exp Dermatol. 2007; 32: 224-225Crossref PubMed Scopus (14) Google Scholar). Despite this, limited data are available on the epidemiology of PN and burden of associated diseases (Boozalis et al., 2018Boozalis E. Tang O. Patel S. Semenov Y.R. Pereira M.P. Ständer S. et al.Ethnic differences and comorbidities of 909 prurigo nodularis patients.J Am Acad Dermatol. 2018; 79: 714-719.e3Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, Iking et al., 2013Iking A. Grundmann S. Chatzigeorgakidis E. Phan N.Q. Klein D. Ständer S. Prurigo as a symptom of atopic and non-atopic diseases: aetiological survey in a consecutive cohort of 108 patients.J Eur Acad Dermatol Venereol. 2013; 27: 550-557Crossref PubMed Scopus (82) Google Scholar). Here we estimate the prevalence of PN and the burden of associated conditions in a real-world, US population using a national claims database. Institutional review board approval was granted by the Johns Hopkins University School of Medicine. Data from the IBM MarketScan Commercial Claims and Encounters Database (IBM Watson Health) between October 2015 and December 2016 were analyzed, using standard codes based on the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM). Adults with PN were defined as patients aged 18 to 64 years with ≥2 medical claims for PN (ICD-10-CM: L28.1) and continuous enrollment for ≥3 months before and after the index diagnosis (Supplementary Material). Three cohorts without PN were respectively identified for comparison: age- and sex- matched controls from the general population, patients with atopic dermatitis (AD), and patients with psoriasis. Patient demographics were recorded on the index date, with comorbidities selected based on associations with PN in previous literature and clinical experience (Boozalis et al., 2018Boozalis E. Tang O. Patel S. Semenov Y.R. Pereira M.P. Ständer S. et al.Ethnic differences and comorbidities of 909 prurigo nodularis patients.J Am Acad Dermatol. 2018; 79: 714-719.e3Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, Iking et al., 2013Iking A. Grundmann S. Chatzigeorgakidis E. Phan N.Q. Klein D. Ständer S. Prurigo as a symptom of atopic and non-atopic diseases: aetiological survey in a consecutive cohort of 108 patients.J Eur Acad Dermatol Venereol. 2013; 27: 550-557Crossref PubMed Scopus (82) Google Scholar, Jørgensen et al., 2017Jørgensen K.M. Egeberg A. Gislason G.H. Skov L. Thyssen J.P. Anxiety, depression and suicide in patients with prurigo nodularis.J Eur Acad Dermatol Venereol. 2017; 31: e106-e107Crossref PubMed Scopus (23) Google Scholar, Kaushik et al., 2014Kaushik S.B. Cerci F.B. Miracle J. Pokharel A. Chen S.C. Chan Y.H. et al.Chronic pruritus in HIV-positive patients in the southeastern United States: its prevalence and effect on quality of life.J Am Acad Dermatol. 2014; 70: 659-664Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, Winhoven and Gawkrodger, 2007Winhoven S.M. Gawkrodger D.J. Nodular prurigo: metabolic diseases are a common association.Clin Exp Dermatol. 2007; 32: 224-225Crossref PubMed Scopus (14) Google Scholar, Wu et al., 2013Wu T.P. Miller K. Cohen D.E. Stein J.A. Keratoacanthomas arising in association with prurigo nodules in pruritic, actinically damaged skin.J Am Acad Dermatol. 2013; 69: 426-430Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar;). For comparison, known comorbidities of AD and psoriasis were also included (Brunner et al., 2017Brunner P.M. Silverberg J.I. Guttman-yassky E. Paller A.S. Kabashima K. Amagai M. et al.Increasing comorbidities suggest that atopic dermatitis is a systemic disorder.J Invest Dermatol. 2017; 137: 18-25Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, Shah et al., 2017Shah K. Mellars L. Changolkar A. Feldman S.R. Real-world burden of comorbidities in US patients with psoriasis.J Am Acad Dermatol. 2017; 77: 287-292.e4Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar) (Table 1).Table 1Associated Conditions in Prurigo Nodularis, Matched Controls, Atopic Dermatitis, and PsoriasisComorbiditiesPrurigo Nodularis (N = 7,095)Matched1Matched to the prurigo nodularis group on age and sex. controls (N = 16,595)AD (N = 23,882)Psoriasis (N = 39,283)Mental health, n (%) Anxiety1,513 (21.3)2,048 (12.3)4,183 (17.5)7.425 (18.9) Schizophrenia28 (0.4)29 (0.2)69 (0.29)133 (0.34) Mood disorder1,228 (17.3)1,415 (8.5)2,648 (11.1)5,447 (13.9) Eating disorder32 (0.45)16 (0.10)71 (0.30)123 (0.31) ADHD299 (4.2)248 (1.5)726 (3.0)1,251 (3.2) Substance use553 (7.8)823 (5.0)1,373 (5.8)3,402 (8.7) Self-harm13 (0.18)10 (0.10)23 (0.10)53 (0.13)Infectious, n (%) HIV39 (0.55)34 (0.2)86 (0.36)106 (0.27) Any hepatitis40 (0.56)67 (0.4)122 (0.51)266 (0.68) Hepatitis B15 (0.21)22 (0.1)68 (0.28)113 (0.29) Hepatitis C37 (0.52)56 (0.3)76 (0.32)232 (0.59) Helicobacter pylori26 (0.37)41 (0.2)81 (0.34)135 (0.34)Autoimmune, n (%) Celiac disease26 (0.37)23 (0.1)125 (0.52)151 (0.38) Thyroid disease74 (1.0)125 (0.8)265 (1.1)427 (1.1) Crohn's disease43 (0.61)42 (0.3)123 (0.52)430 (1.1) Ulcerative colitis58 (0.82)83 (0.5)146 (0.61)356 (0.91) DM1150 (2.1)159 (1.0)193 (0.81)546 (1.4)Dermatologic/allergic, n (%) Psoriasis224 (3.2)111 (0.7)550 (2.3)— Xerosis cutis381 (5.4)117 (0.7)1,320 (5.5)981 (2.5) Neurotic excoriation94 (1.3)3 (0.0)53 (0.22)18 (0.05) Actinic keratoses1,676 (23.6)859 (5.2)1,728 (7.2)2,804 (7.1) Seborrheic dermatitis231 (3.3)104 (0.6)1,019 (4.3)1,212 (3.1) Atopic dermatitis236 (3.3)60 (0.4)—420 (1.1) Asthma593 (8.4)859 (5.2)3,839 (16.1)2,894 (7.4) Urticaria181 (2.6)155 (0.9)1,674 (7.0)626 (1.6)Malignancies, n (%) Hodgkin's lymphoma5 (0.07)7 (0.0)16 (0.07)32 (0.08) NHL32 (0.45)33 (0.2)72 (0.30)160 (0.41) Multiple myeloma2 (0.03)8 (0.0)10 (0.04)38 (0.10)Endocrine, n (%) Metabolic syndrome76 (1.1)145 (0.9)202 (0.85)419 (1.1) DM21,131 (15.9)1,955 (11.8)1,944 (8.1)5,491 (14.0) Lipid disorders2,962 (41.8)5,388 (32.5)6,035 (25.3)14,077 (35.8) HTN2,947 (41.5)5,340 (32.2)5,870 (24.6)14,192 (36.1) Osteoporosis188 (2.7)297 (1.8)389 (1.6)792 (2.0) Obesity1,173 (16.5)1,818 (11.0)3,012 (12.6)7,068 (18.0)Other systemic illness, n (%) Anemia47 (0.66)80 (0.5)142 (0.59)286 (0.73) Chronic kidney disease258 (3.6)332 (2.0)334 (1.4)954 (2.4) Dialysis37 (0.52)18 (0.1)21 (0.09)40 (0.10) Congestive heart failure105 (1.5)114 (0.7)157 (0.66)507 (1.3) Cerebrovascular disease209 (3.0)250 (1.5)350 (1.5)785 (2.0) Coronary heart disease491 (6.9)673 (4.1)666 (2.8)1,910 (4.9) Myocardial infarction39 (0.55)99 (0.6)54 (0.23)209 (0.53) COPD247 (3.5)333 (2.0)505 (2.1)1,152 (2.9)Abbreviations: AD, atopic dermatitis; ADHD, attention-deficit/hyperactivity disorder; COPD, chronic obstructive pulmonary disease; DM1, type 1 diabetes; DM2, type 2 diabetes; HIV, human immunodeficiency virus infection; HTN, hypertension; NHL, non-Hodgkin lymphoma.1 Matched to the prurigo nodularis group on age and sex. Open table in a new tab Abbreviations: AD, atopic dermatitis; ADHD, attention-deficit/hyperactivity disorder; COPD, chronic obstructive pulmonary disease; DM1, type 1 diabetes; DM2, type 2 diabetes; HIV, human immunodeficiency virus infection; HTN, hypertension; NHL, non-Hodgkin lymphoma. Of the patients identified, 7,095 had PN, 16,595 were matched controls, 23,882 had AD without PN, and 38,283 had psoriasis without PN (Supplementary Table S1). Using the 2016 US population aged 18 to 64 years as reference, prevalence of PN in the United States was estimated as 87,634 (72 per 100,000) in this demographic. Mean age was highest at 50.9 years for patients with PN and their matched controls; females were the majority in all groups. Patients with PN had increased likelihood of eating disorders (odds ratio [OR] = 4.66, 95% confidence interval [CI] = 2.58, 8.39), self-harm (OR = 3.17, 95% CI = 1.36, 7.41), attention-deficit/hyperactivity disorder (OR = 2.89, 95% CI = 2.42, 3.46), schizophrenia (OR = 2.26, 95% CI = 1.33, 3.85), mood disorders (OR = 2.24, 95% CI = 2.05, 2.46), anxiety (OR = 1.93, 95% CI = 1.78, 2.09), and substance use disorders (OR = 1.62, 95% CI = 1.43, 1.83). PN also had increased likelihood of HIV infection (OR = 2.68, 95% CI = 1.66, 4.33) and non-Hodgkin lymphoma (OR = 2.28, 95% CI = 1.28, 4.05). For dermatologic conditions, increased neurotic excoriations (OR = 71.2, 95% CI = 23.3, 218), AD (OR = 9.48, 95% CI = 6.69, 13.4), and psoriasis (OR = 4.82, 95% CI = 3.66, 6.35) were seen in PN. PN was also associated with obesity (OR = 1.61, 95% CI = 1.47, 1.76), hypertension (OR = 1.50, 95% CI = 1.41, 1.60), and type 2 diabetes (OR = 1.42, 95% CI = 1.3, 1.55). Finally, PN had higher likelihood of receiving dialysis (OR = 4.88, 95% CI = 2.40, 9.92), chronic kidney disease (OR = 1.85, 95% CI = 1.52, 2.25), heart failure (OR = 2.18, 95% CI = 1.58, 3.02), cerebrovascular disease (OR = 1.98, 95% CI = 1.59, 2.47), coronary heart disease (OR = 1.76, 95% CI = 1.53, 2.03), and chronic obstructive pulmonary disease (OR = 1.76, 95% CI = 1.45, 2.14) (Figure 1). Similar trends were observed in adjusted comparisons with AD and psoriasis, respectively (Supplementary Figures S1 and S2). Our results emphasize the significantly increased burden of conditions associated with PN, both relative to matched controls and other inflammatory skin disorders (Figure 1). Mental health conditions have been associated with not only PN but also AD and psoriasis (Boozalis et al., 2018Boozalis E. Tang O. Patel S. Semenov Y.R. Pereira M.P. Ständer S. et al.Ethnic differences and comorbidities of 909 prurigo nodularis patients.J Am Acad Dermatol. 2018; 79: 714-719.e3Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, Brunner et al., 2017Brunner P.M. Silverberg J.I. Guttman-yassky E. Paller A.S. Kabashima K. Amagai M. et al.Increasing comorbidities suggest that atopic dermatitis is a systemic disorder.J Invest Dermatol. 2017; 137: 18-25Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, Jørgensen et al., 2017Jørgensen K.M. Egeberg A. Gislason G.H. Skov L. Thyssen J.P. Anxiety, depression and suicide in patients with prurigo nodularis.J Eur Acad Dermatol Venereol. 2017; 31: e106-e107Crossref PubMed Scopus (23) Google Scholar, Shah et al., 2017Shah K. Mellars L. Changolkar A. Feldman S.R. Real-world burden of comorbidities in US patients with psoriasis.J Am Acad Dermatol. 2017; 77: 287-292.e4Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar;). Increased mental health disorders in PN compared to all groups underscore the profound impact of PN on psychological well-being. PN was additionally associated with systemic illnesses, HIV infection, and non-Hodgkin lymphoma. In addition to confirming previous links between PN and kidney disease, our results suggest that PN may be more specifically linked to end-stage disease requiring dialysis (Boozalis et al., 2018Boozalis E. Tang O. Patel S. Semenov Y.R. Pereira M.P. Ständer S. et al.Ethnic differences and comorbidities of 909 prurigo nodularis patients.J Am Acad Dermatol. 2018; 79: 714-719.e3Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). Further evidence of the systemic nature of PN is given by its association with cardio- and cerebrovascular diseases, even in excess of the known risk in patients with AD or psoriasis (Brunner et al., 2017Brunner P.M. Silverberg J.I. Guttman-yassky E. Paller A.S. Kabashima K. Amagai M. et al.Increasing comorbidities suggest that atopic dermatitis is a systemic disorder.J Invest Dermatol. 2017; 137: 18-25Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, Shah et al., 2017Shah K. Mellars L. Changolkar A. Feldman S.R. Real-world burden of comorbidities in US patients with psoriasis.J Am Acad Dermatol. 2017; 77: 287-292.e4Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). Our data also strengthens previous findings of the association of PN with HIV infection and non-Hodgkin lymphoma, respectively, as well as with hypertension and diabetes mellitus (Magand et al., 2011Magand F. Nacher M. Cazorla C. Cambazard F. Marie D.S. Couppié P. Predictive values of prurigo nodularis and herpes zoster for HIV infection and immunosuppression requiring HAART in French Guiana.Trans R Soc Trop Med Hyg. 2011; 105: 401-404Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, Larson et al., 2019Larson V.A. Tang O. Ständer S. Miller L.S. Kang S. Kwatra S.G. Association between prurigo nodularis and malignancy in middle-aged adults.[e-pub ahead of print].J Am Acad Dermatol. 2019; (accessed 1 June 2019)https://doi.org/10.1016/j.jaad.2019.03.083Abstract Full Text Full Text PDF Scopus (12) Google Scholar, Winhoven and Gawkrodger, 2007Winhoven S.M. Gawkrodger D.J. Nodular prurigo: metabolic diseases are a common association.Clin Exp Dermatol. 2007; 32: 224-225Crossref PubMed Scopus (14) Google Scholar). Notably, most metabolic and endocrine diseases were increased in PN than in matched controls or AD, but similar between PN and psoriasis. This may be due to the well-established, dose-dependent association of more severe psoriasis with high risk of metabolic diseases (Gelfand and Yeung, 2012Gelfand J.M. Yeung H. Metabolic syndrome in patients with psoriatic disease.J Rheumatol Suppl. 2012; 89: 24-28Crossref PubMed Scopus (63) Google Scholar, Gisondi et al., 2018Gisondi P. Fostini A.C. Fossà I. Girolomoni G. Targher G. Psoriasis and the metabolic syndrome.Clin Dermatol. 2018; 36: 21-28Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). Finally, increased likelihood of allergic conditions in PN compared with matched controls might be attributed to the subset of patients with PN who are atopic. AD and allergic predisposition were shown to be increased in PN, especially in earlier-onset PN (Tanaka et al., 1995Tanaka M. Aiba S. Matsumura N. Aoyama H. Tagami H. Prurigo nodularis Consists of two Distinct Forms: early-Onset Atopic and Late-Onset Non-Atopic.Dermatology. 1995; 190: 269-276Crossref PubMed Scopus (68) Google Scholar, Iking et al., 2013Iking A. Grundmann S. Chatzigeorgakidis E. Phan N.Q. Klein D. Ständer S. Prurigo as a symptom of atopic and non-atopic diseases: aetiological survey in a consecutive cohort of 108 patients.J Eur Acad Dermatol Venereol. 2013; 27: 550-557Crossref PubMed Scopus (82) Google Scholar). Limitations include the study population of insured patients (18 to 64 years old), which may reduce generalizability as well as underestimate the true prevalence of PN and concomitant diseases. Furthermore, ICD-10-CM codes were not mandated for claims in the United States until October 2015. This limited the study period and cohort sample sizes, because ICD-10-CM is required for unique identification of PN. Validation studies using ICD-10-CM codes for PN identification are needed, as well as exploration of potential upcoding in claims data. Because conditions queried in our study were identified using previous literature, Bonferroni correction for multiple comparisons was not applied and results should be interpreted accordingly. Stratification for racial differences was not possible because race and/or ethnicity details are not available in claims data. In summary, PN is a severe, pruritic disease with increased systemic burden compared with other inflammatory skin disorders, and is significantly associated with mental health disorders, systemic illnesses, and HIV infection. Further research is needed to clarify whether the comorbidities identified in this study are true causes of PN compared with associated diseases. Awareness of related conditions can also help guide comprehensive workup and management of PN. In patients with PN of unknown origin, screening for HIV, renal impairment, and mental health conditions is reasonable. Furthermore, connecting all patients with PN to primary care for assessment and follow-up of chronic, systemic conditions might help reduce associated morbidity. Future work should examine the epidemiology of PN in children and older patients over the age 65 years as well as the role of treatment effects on the disease associations observed. The data that support the findings of this study are available from IBM. Restrictions apply to the availability of these data, which were used under license for this study. Amy H. Huang: https://orcid.org/0000-0003-2510-6269 Joseph K. Canner: https://orcid.org/0000-0001-5095-8709 Raveena Khanna: https://orcid.org/0000-0002-7542-1016 Sewon Kang: https://orcid.org/0000-0002-7841-9392 Shawn G. Kwatra: https://orcid.org/0000-0003-3736-1515 SGK is an advisory board member for Menlo and Trevi Therapeutics and has received grant funding from Kiniksa Pharmaceuticals. SK is a consultant for Menlo Therapeutics and an advisory board member for Unilever. The other authors state no conflict of interest. SGK received grant funding from the Skin of Color Society and is a recipient of the Dermatology Foundation Medical Dermatology Career Development Award. AHH, SGK, and JKC had full access to all of the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. Conceptualization: AHH, SGK; Data Curation: AHH, SGK, JKC, RK; Formal Analysis: JKC; Funding Acquisition: SGK; Investigation: AHH, JKC, SGK; Methodology: AHH, JKC, SGK; Project Administration: SGK; Resources: SGK, JKC; Software: JKC; Supervision: SGK; Writing – Original Draft Preparation: AHH, SGK; Writing – Review and Editing: SK, JKC, RK From October 2015 to December 2016, the IBM MarketScan database included complete longitudinal records of inpatient and outpatient services, long-term care, and prescription drug claims using standard codes for diagnosis based on International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM). Between October 2015 and December 2016, the database contained claims for services provided to 24,049,563 enrollees and included 23,042,569 person-years of coverage. All MarketScan database records meet criteria for a limited-use dataset with no direct identifiers. Using ICD-10-CM diagnosis codes, medical claims for mental health, infectious, autoimmune, dermatologic/allergic, malignant, endocrine, and other systemic comorbidities were identified during the study period. Specific codes for a diagnosis or group of diagnoses were determined using published literature. For comparison with the Prurigo nodularis (PN) cohort, three cohorts without PN were identified: age- and sex-matched controls from the general population, patients with atopic dermatitis, and patients with psoriasis. Controls from the general population were first identified by choosing a systemic sample of enrollment ID's for patients with at least 6 months of continuous enrollment without a diagnosis of interest. Using the coarsened-exact matching method, patients with PN were then matched on age and sex to controls without PN who had medical claims during the same time period (Blackwell et al., 2009Blackwell M. Iacus S. King G. Porro C.E.M., G. Coarsened exact matching in Stata..Stata J. 2009; 4: 524-546Crossref Google Scholar). The resulting coarsened-exact matching weighting factor was used in subsequent tabulations and regression models to compare patients with PN to matched controls. Patients with other inflammatory skin disorders were identified as those aged 18 to 64 years with two or more medical claims in the same time period for atopic dermatitis (ICD-10-CM: L20.9) or psoriasis (ICD-10-CM: L40.9), respectively, with at least 3 months of continuous enrollment before and after the index diagnosis. Demographic characteristics were recorded for patients with PN and the comparison populations, with the chi-square test used to compare proportions of categorical variables. With the US population as reference, a weighted national sample was used to estimate the prevalence of prurigo nodularis. Simple and multivariable logistic regression were performed to calculate the odds ratios of each comorbidity in patients with PN versus comparison populations, with adjusted models accounting for potential confounders of age and sex. The threshold for statistical significance was set a priori at 0.05. All analyses were conducted using Stata MP/14.2 (StataCorp, College Station, TX). Abbreviations: COBRA (Consolidated Omnibus Budget Reconciliation Act; SD, Standard deviation.