ORIGINAL ARTICLE

Clinical utility of peripheral blood

laboratory testing in the diagnostic
workup of prurigo nodularis:
A multicenter cohort study
Hannah L. Cornman, BS, Junwen Deng, BA, Anusha Kambala, BS, Varsha Parthasarathy, BS,
Sriya V. Reddy, BS, and Shawn G. Kwatra, MD

Background: Prurigo nodularis (PN) is a chronic inflammatory skin disease associated with several
systemic comorbidities. However, there is lack of evidence supporting specific laboratory testing in the
diagnostic workup of PN patients.

Objective: To characterize the frequency and severity of clinical laboratory abnormalities in PN patients
compared to controls.

Methods: Cross-sectional study of adult patients between October, 2015 and August, 2021 using TriNetX, a
global health records database encompassing over 74 million patients.

Results: A total of 12,157 PN patients were matched to 12,157 controls. Significantly, greater proportions of
PN patients had moderate-to-severely decreased hemoglobin, elevated transaminases, decreased albumin,
increased bilirubin, increased serum creatinine, decreased estimated glomerular filtration rate, higher
hemoglobin A1c levels, and alterations in thyroid stimulating hormone.

Limitations: Our data identifies associated laboratory abnormalities in PN patients but is unable to support
a causal relationship.

Conclusion: PN patients are more likely to have laboratory abnormalities on renal, hepatic, hematologic,
endocrine, and metabolic laboratory testing, demonstrating a role for systemic testing in the diagnostic
workup of PN patients. ( JAAD Int 2023;13:74-82.)

Key words: diagnostic; itch; prurigo nodularis; pruritus; systemic; workup.

INTRODUCTION extremities and trunk.1,2 PN results in a significant

Prurigo nodularis (PN) is an intensely pruritic, overall reduction in health-related quality of life
chronic inflammatory skin disease characterized by (QOL) among patients, and is associated with multi-
symmetrically distributed firm nodules on the ple systemic comorbidities including liver disease,

From the Department of Dermatology, Johns Hopkins University with the understanding that this information may be publicly
School of Medicine, Baltimore, Maryland. available.
Drs Cornman and Deng are co-first authors with contributed Accepted for publication July 31, 2023.
equally to this article. Correspondence to: Shawn G. Kwatra, MD, Associate Professor of
Funding sources: Shawn G. Kwatra is supported by the National Dermatology and Oncology, Director, Johns Hopkins Itch
Institute of Arthritis and Musculoskeletal and Skin Diseases of Center, Department of Dermatology, Johns Hopkins
the National Institutes of Health under Award Number University School of Medicine, Office: Room 206, Lab: Suite
K23AR077073-01A1. The content is solely the responsibility of 216, Koch CRBII, 1550 Orleans St, Baltimore, MD 21231. E-mail:
the authors and does not necessarily represent the official [email protected].
views of the National Institutes of Health. 2666-3287
IRB approval status: Waived. Ó 2023 by the American Academy of Dermatology, Inc. Published
Patient consent: Consent for the publication of recognizable by Elsevier Inc. This is an open access article under the CC BY
patient photographs or other identifiable material was ob- license (http://creativecommons.org/licenses/by/4.0/).
tained by the authors and included at the time of article https://doi.org/10.1016/j.jdin.2023.07.015
submission to the journal stating that all patients gave consent

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JAAD INT Cornman et al 75
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chronic renal failure, diabetes, cardiovascular dis- results were delineated based on the National Cancer
ease, infections, and malignancies.3-10 The diagnostic Institute Common Terminology Criteria for Adverse
workup and management of patients with PN are Events (CTCAE) v5.0 grading system, where grades
frequently challenging and systemic laboratory 1-4 represent mild, moderate, severe, or life-
testing is often recommended, particularly as the threatening consequences, respectively.17 The
treatment for PN often requires use of systemic CTCAE is a well-established grading system for
therapy.11,12 However, there is a lack of data support- adverse events and in this case allows for standard-
ing peripheral blood testing ized reporting of laboratory-
for the diagnostic workup of identified dysregulation.
PN. To gain a better under- CAPSULE SUMMARY Where the CTCAE did not
standing of PN-associated al- specifically define laboratory
terations in peripheral blood gradations (eg leukocytes,
d There is currently a lack of clinical
laboratory markers and their neutrophils, thyrotropin) or
evidence supporting a laboratory
implications in PN patients, where CTCAE grades were
workup of systemic conditions in prurigo
we performed a cross- defined relative to upper and
nodularis (PN) patients.
sectional study comparing lower limits of normal (eg
the frequency and severity d This study finds PN patients are more alanine aminotransferase, al-
of peripheral blood labora- likely to have abnormalities in renal, bumin, bilirubin), the corre-
tory alterations in PN patients hepatic, hematologic, endocrine, and sponding reference values
and control patients at the metabolic laboratory testing, suggesting published by the American
time of initial clinical a role for this testing in PN diagnostic Board of Internal Medicine
presentation. workup. (ABIM) were instead
applied.18
METHODS
Patient population Statistical analysis
This multicenter cross-sectional study was con- PN and control patients were 1:1 propensity score
ducted using TriNetX, a global research network matched by age, sex, race, and ethnicity using a
comprised of electronic medical records from over greedy nearest neighbor matching algorithm.
74 million patients in 50 health care organizations, Baseline demographics were compared using the
particularly in the United States, United Kingdom, Student’s t-test for continuous variables and a Chi-
Spain, Italy, India, Malaysia, and Australia. PN square test for categorical variables. The proportions
patients were $18 years old and had at least 2 of patients with altered laboratory values, stratified
diagnoses of PN using the International Classification by grade of dysregulation, were analyzed using Chi-
of Diseases, Tenth Revision (ICD-10) code L28.1, square tests for proportions. The results from
validated for the identification of prurigo nodularis,13 Chi-square testing were interrogated through the
from October 1, 2015 to August 31, 2021. Control posthoc pairwise analysis of adjusted Z-values from
patients were also $18 years old, had an encounter each comparison, and all P-values were adjusted for
for a medical exam without specific complaint (ICD- multiple hypothesis testing using the Bonferroni
10 codes Z00 or Z01), and had no diagnoses of correction at an a priori alpha of 0.05.19 Results
dermatitis (ICD-10 codes L20-L30). As the TriNetX with an adjusted P-value \ .05 were considered
database utilizes only de-identified data, our study significant. All statistical calculations were per-
was deemed exempt from the Johns Hopkins School formed using the TriNetX platform or IBM SPSS
of Medicine Institutional Review Board (IRB). Statistics 27.

Laboratory parameters assessment RESULTS

The index date for each patient was defined as the The demographic characteristics of PN and con-
date on which they were first diagnosed with the trol patient cohorts are shown in Table I. We
ICD-10 code L28.1 for PN patients or with the ICD-10 identified 12,157 PN patients, who were matched
code Z00 or Z01 for control patients. To capture via a propensity score algorithm to 12,157 controls.
laboratory values obtained close to the same time as Demographics of the matched cohort included a
the initial condition diagnosis, laboratory results in mean age of 57.9 (616) years, 59.9% female sex,
PN and control patients were restricted to within 65.5% white, and 19.9% black or African American
1 month after the index date. As described previ- race.
ously,14-16 in order to determine clinically meaning- The grading criteria for defining laboratory ab-
ful abnormalities in laboratory testing, laboratory normalities are shown in Supplementary Table S1,
76 Cornman et al JAAD INT
DECEMBER 2023

Table I. Demographic characteristics of prurigo

Abbreviations used:
nodularis (PN) patients and controls after
ABIM: American Board of Internal Medicine propensity score matching
ALP: alkaline phosphatase
ALT: alanine aminotransferase Prurigo nodularis Controls
AST: aspartate aminotransferase Characteristic (n = 12,157) (n = 12,157) P-value
BU: blood urea nitrogen
CTCAE: common terminology criteria for adverse Age at index, mean 58.8 (15.4) 58.8 (15.4) 1.0
events (SD), y
eGFR: estimated glomerular filtration rate Sex, no. (%)
ESR: erythrocyte sedimentation rate Males 4977 (40.9) 4977 (40.9) 1.0
HbA1c: hemoglobin A1c Females 7180 (59.1) 7180 (59.1) 1.0
ICD-10: international statistical classification of
diseases and related health problems, Race, no. (%)
tenth revision Caucasian 7800 (64.2) 7800 (64.2) 1.0
PN: prurigo nodularis African American 2613 (21.5) 2613 (21.5) 1.0
Th: T-helper Asian 326 (2.7) 326 (2.7) 1.0
TSH: thyroid stimulating hormone
Unknown 1366 (11.2) 1366 (11.2) 1.0
Ethnicity, no. (%)
Hispanic 775 (6.4) 775 (6.4) 1.0
Not Hispanic 9469 (77.9) 9469 (77.9) 1.0
available via Mendeley at https://data.mendeley.
com/datasets/hdhmvjr67z/1. Compared to controls, SD, Standard deviation; y, year.
a significantly higher proportion of PN patients had
abnormal laboratory values across several routine
diabetic-level hemoglobin A1c (HbA1c) (47.5% vs
laboratory parameters (Tables II-IV, Fig 1). PN
25.7%, P-adj \ .0001) and increases (15.6% vs 8.9%,
patients had higher proportions of grade 2 decreases
P-adj \ .0001) or decreases (9.5% vs 5.2%,
in hemoglobin (13.1% vs 9.2%, P-adj \ .0001), grade
P-adj = .0003) in thyroid stimulating hormone
2 increases in lymphocytes (3.9% vs 1.9%, P-
(TSH). Finally, higher proportions of PN patients
adj = .002), and overall ungraded elevations in
had elevated erythrocyte sedimentation rate (ESR)
neutrophils (32.4% vs 24.6%, P-adj \ .0001) and
(56.9% vs 44.8%, P-adj = .041).
eosinophils (43.4% vs 35.0%, P-adj \ .0001) (Table
II).
Greater proportions of PN patients also had DISCUSSION
heightened liver enzyme markers and alterations in This large multicenter study on PN patients
other hepatically produced markers such as albumin identifies laboratory abnormalities using real-world
and bilirubin (Table III). Specifically, PN patients had data, providing deeper insight into the diagnostic
grade 2 elevations in alanine aminotransferase (ALT) workup and management of PN. The results of our
(2.3% vs 1.2%, P-adj = .032), grade 2 (3.3% vs 1.0%, P- investigation demonstrate that compared to controls,
adj \ .0001) and grade 3 (1.4% vs 0.5%, P-adj = .013) PN patients have significantly higher frequencies of
elevations in aspartate aminotransferase (AST), and alterations in common laboratory tests such as com-
grade 2 (2.8% vs 0.6%, P-adj \ .0001) and grade 3 plete blood count, basal metabolic panel, hepatic
(0.8% vs 0.3%, P-adj = .037) elevations in alkaline and renal function testing, thyroid function testing,
phosphatase (ALP). PN patients were also more and diabetes testing. These results reinforce the
likely to have decreases in albumin (grade 2, 8.4% presence of systemic dysregulation in multiple
vs 5.3%, P-adj \ .0001), as well as increases in total axes, including endocrine, immune, hepatic, renal,
bilirubin (grade 2, 5.4% vs 2.9%, P-adj = .0001) and and hemostatic among PN patients.
direct bilirubin (grade 3, 11.6% vs 4.8%, P-adj = .005). Importantly, we found that laboratory testing
PN patients also had higher proportions of renal within 1 month of PN diagnosis identified a higher
and endocrine laboratory abnormalities (Table IV). prevalence of renal insufficiency, liver dysfunction,
PN patients had signs of worse renal function, as and diabetes compared to ICD-10 code diagnoses of
higher proportions of PN patients experienced acute and chronic kidney disease (ICD-10 N17-19),
higher blood urea nitrogen (34.9% vs 25.9%, P-adj liver disease (ICD-10 K70-77), and diabetes (ICD-10
\ .0001), any graded level of elevation in serum E08-E13), respectively (P \ .0001 for all). For
creatinine (P-adj \ .0001 in all grades), and de- example, 25.2% of PN patients had a prior comorbid
creases in grades 2-4 of the estimated glomerular diagnosis of acute or chronic kidney disease,
filtration rate (eGFR) (P-adj \.0001 in all grades). PN whereas 33.2% of PN patients had CTCAE grade 2-4
patients also had signs of endocrine dysfunction, as abnormalities in eGFR, which indicates renal
significantly higher proportions of patients had dysfunction significant enough to recommend
JAAD INT Cornman et al 77
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Table II. Hematologic laboratory abnormalities in prurigo nodularis (PN) and control patients by CTCAE grade
or reference range cutoff
Relative risk
Parameter Grade or cutoff parameter PN, n (%) Controls, n (%) (95% CI) P-value Adjusted P-value*
Hemoglobin (g/dL) Normal 939 (40.2) 2747 (54.4) 0.74 (0.69-0.78) \.0001 \.0001
Grade 1 (10.0 to \ LLN) 979 (41.9) 1644 (32.6) 1.29 (1.21-1.37) \.0001 \.0001
Grade 2 (8.0 to \10.0) 306 (13.1) 464 (9.2) 1.42 (1.24-1.63) \.0001 \.0001
Grade 3 (\8.0) 114 (4.9) 192 (3.8) 1.28 (1.02-1.61) .032 .126
Leukocytes (103/uL) Normal 1484 (84.1) 3118 (85.5) 0.98 (0.96-1.01) .185 .370
Elevated ([11) 280 (15.9) 529 (14.5) 1.09 (0.96-1.25)
Lymphocytes(103/uL) Normal 1024 (89.4) 1729 (86.2) 1.04 (1.01-1.06) .010 .041
Grade 1 (N/A) - - - - -
Grade 2 ([4-20) 45 (3.9) 38 (1.9) 2.07 (1.35-3.17) .001 .002
Grade 3 ([20) 77 (6.7) 239 (11.9) 0.56 (0.44-0.72) \.0001 \.0001
Neutrophils (%) Normal 641 (67.6) 1221 (75.4) 0.90 (0.85-0.95) \.0001 \.0001
Elevated ([70%) 307 (32.4) 399 (24.6) 1.31 (1.16-1.49)
Eosinophils (%) Normal 952 (56.6) 1944 (65.0) 0.87 (0.83-0.92) \.0001 \.0001
Elevated ([3%) 730 (43.4) 1049 (35.0) 1.24 (1.15-1.33)

CI, Confidence interval; LLN, lower limit of normal; PN, prurigo nodularis.
*P-values were adjusted using Bonferroni correction.

Table III. Hepatic laboratory abnormalities in prurigo nodularis (PN) and control patients by Common
Terminology Criteria for Adverse Events (CTCAE) grade or reference range cutoff
Parameter Grade or cutoff parameter PN, n (%) Controls, n (%) Relative risk (95% CI) P-value Adjusted P-value*
ALT (U/L) Normal 1259 (78.6) 2438 (85.8) 0.92 (0.89-0.94) \.0001 \.0001
Grade 1 ([ULN-33 ULN) 278 (17.4) 342 (12.0) 1.44 (1.25-1.67) \.0001 \.0001
Grade 2 ([3-53 ULN) 37 (2.3) 35 (1.2) 1.88 (1.19-2.96) .006 .032
Grade 3 ([5-203 ULN) 17 (1.1) 15 (0.5) 2.01 (1.01-4.01) .043 .217
Grade 4 ([203ULN) 10 (0.6) 10 (0.4) 1.77 (0.74-4.25) .194 .968
AST (U/L) Normal 1333 (78.4) 2717 (89.7) 0.87 (0.85-0.90) \.0001 \.0001
Grade 1 ([ULN-33 ULN) 279 (16.4) 257 (8.5) 1.93 (1.65-2.27) \.0001 \.0001
Grade 2 ([3-53 ULN) 56 (3.3) 29 (1.0) 3.44 (2.20-5.36) \.0001 \.0001
Grade 3 ([5-203 ULN) 23 (1.4) 16 (0.5) 2.56 (1.36-4.83) .003 .013
Grade 4 ([203 ULN) 10 (0.6) 10 (0.3) 1.78 (0.74-4.27) .190 .951
ALP (U/L) Normal 3194 (91.1) 1311 (76.8) 0.84 (0.82-0.87) \.0001 \.0001
Grade 1 ([ULN-2.53 ULN) 335 (19.6) 268 (7.6) 2.57 (2.21-2.9) \.0001 \.0001
Grade 2 ([2.5-53 ULN) 47 (2.8) 22 (0.6) 4.39 (2.65-7.25) \.0001 \.0001
Grade 3 ([5-203 ULN) 14 (0.8) 10 (0.3) 2.87 (1.28-6.46) .007 .037
Grade 4 ([203ULN) 0 (0.0) 10 (0.3) 0.00 .027 .136
Albumin (g/dL) Normal 1308 (71.7) 2892 (81.3) 0.88 (0.85-0.91) \.0001 \.0001
Grade 1 (3-LLN g/dL) 291 (16.0) 342 (9.6) 1.66 (1.44-1.92) \.0001 \.0001
Grade 2 (2-\3 g/dL) 153 (8.4) 189 (5.3) 1.58 (1.29-1.94) \.0001 \.0001
Grade 3 (\2 g/dL) 71 (3.9) 135 (3.8) 1.03 (0.77-1.36) .857 1
Bilirubin, total (mg/dL) Normal 1238 (81.9) 2759 (86.1) 0.95 (0.93-0.98) .0002 .001
Grade 1 ([ULN-1.5xULN) 151 (10.0) 306 (9.7) 1.03 (0.85-1.23) .631 1
Grade 2 ([1.5-33 ULN) 81 (5.4) 91 (2.9) 1.85 (1.38-2.48) \.0001 .0001
Grade 3 ([3-103 ULN) 31 (2.1) 37 (1.2) 1.74 (1.38-2.48) .016 .080
Grade 4 ([103 ULN) 10 (0.7) 10 (0.3) 2.08 (0.87-4.98) .085 .427
Bilirubin, direct (mg/dL) Normal 173 (52.7) 246 (68.9) 0.76 (0.68-0.87) \.0001 \.0001
Grade 1 ([ULN-1.53 ULN) 64 (19.5) 53 (14.8) 1.31 (0.94-1.83) .105 .526
Grade 2 ([1.5-33 ULN) 42 (12.8) 29 (8.1) 1.58 (1.01-2.47) .044 .222
Grade 3 ([3-103 ULN) 38 (11.6) 17 (4.8) 2.43 (1.40-4.22) .001 .005
Grade 4 ([103 ULN) 11 (3.4) 12 (3.4) 1.00 (0.45-2.23) .992 1

ALP, Alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; LLN, lower limit of normal;
PN, prurigo nodularis; ULN, upper limit of normal.
*P-values were adjusted using Bonferroni correction.
78 Cornman et al JAAD INT
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Table IV. Renal/Endocrine laboratory abnormalities in prurigo nodularis (PN) and control patients by Common
Terminology Criteria for Adverse Events (CTCAE) grade or reference range cutoff
Relative risk
Parameter Grade or cutoff parameter PN, n (%) Controls, n (%) (95% CI) P-value Adjusted P-value*
BUN (mg/dL) Normal 1335 (65.1) 3134 (74.1) 0.88 (0.85-0.91) \.0001 \.0001
Elevated ([20) 715 (34.9) 1095 (25.9) 1.35 (1.25-1.46)
Creatinine (mg/dL) Normal 1692 (67.3) 4269 (80.6) 0.83 (0.81-0.86) \.0001 \.0001
Grade 1 ([ULN-1.53 ULN) 436 (17.3) 717 (13.5) 1.28 (1.15-1.43) \.0001 \.0001
Grade 2 ([1.5-33 ULN) 190 (7.6) 181 (3.4) 2.21 (1.81-2.69) \.0001 \.0001
Grade 3 ([3-63 ULN) 107 (4.3) 84 (1.6) 2.68 (2.02-3.56) \.0001 \.0001
Grade 4 ([63 ULN) 89 (3.5) 43 (0.8) 4.36 (3.04-6.25) \.0001 \.0001
eGFR (mL/min/[1.73 m2]) Normal 697 (29.9) 1660 (35.8) 0.84 (0.78-0.90) \.0001 \.0001
Grade 1 (60 to \ LLN) 864 (37.0) 2147 (46.2) 0.80 (0.75-0.85) \.0001 \.0001
Grade 2 (30-59) 508 (21.8) 638 (13.7) 1.58 (1.43-1.76) \.0001 \.0001
Grade 3 (15-29) 126 (5.4) 104 (2.2) 2.41 (1.87-3.11) \.0001 \.0001
Grade 4 (\15) 139 (6.0) 94 (2.0) 2.94 (2.28-3.80) \.0001 \.0001
ESR (mm/h) Normal 85 (43.1) 95 (55.2) 0.78 (0.64-0.96) .020 .041
Elevated ([20) 112 (56.9) 77 (44.8) 1.27 (1.03-1.56)
HbA1c (%) Normal 175 (24.3) 724 (41.3) 0.59 (0.51-0.68) \.0001 \.0001
Prediabetes (5.7-\6.5%) 203 (28.2) 579 (33.0) 0.85 (0.75-0.98) .019 .058
Diabetes ([6.5%) 342 (47.5) 451 (25.7) 1.85 (1.65-2.06) \.0001 \.0001
TSH (m [IU]/L) Normal 499 (74.9) 1644 (85.9) 0.87 (0.83-0.91) \.0001 \.0001
Elevated ([4) 104 (15.6) 170 (8.9) 1.76 (1.40-2.21) \.0001 \.0001
Decreased (\0.5) 63 (9.5) 100 (5.2) 1.81 (1.34-2.45) .0001 .0003

BUN, Blood urea nitrogen; CI, confidence interval; eGFR, estimated glomerular filtration rate; ESR, erythrocyte sedimentation rate; HbA1c,
hemoglobin A1c; LLN, lower limit of normal; PN, prurigo nodularis; TSH, thyroid stimulating hormone; ULN, upper limit of normal.
*P-values were adjusted using Bonferroni correction.

intervention.17 Additionally, we found that 20.3% of indication for hospitalization or prolongation of

PN patients had a prior diagnosis of liver disease but hospitalization.17 Additionally, PN patients have
27.8% had CTCAE Grade 2-4 abnormalities in direct significantly increased odds of CTCAE grade 4
bilirubin. Finally, we found that 31.6% of PN patients laboratory abnormalities in creatinine and eGFR.
had a prior diagnosis of diabetes, but 47.5% of PN CTCAE Grade 4 laboratory abnormalities are
patients had a diabetic range HbA1c (greater than considered to have life-threatening consequences
6.5%). These findings suggest that laboratory testing and urgent intervention is indicated.17
has potential to identify more patients with comor- Regarding treatment selection, numerous medi-
bidities than medical record review alone, and is cations which are commonly used to treat PN require
therefore beneficial for patient management. dose adjustment or are contraindicated based on
This study not only adds to the existing body of liver or renal function impairment. For example,
literature demonstrating an increased prevalence of guidelines recommend dose reduction of gabapen-
comorbid systemic conditions in patients with PN, tin and pregabalin for patients with CTCAE grades
but it also quantitatively characterizes laboratory 2-4 abnormalities in eGFR,20,21 all of which we found
abnormalities present in PN patients, which to our were more likely to be present in PN patients.
knowledge, has not yet been reported on in the Additionally, guidelines recommend dose reduction
literature. The severity of laboratory abnormalities of methotrexate for patients with CTCAE grade 1
we revealed underscores the severity of comorbid abnormalities in eGFR, avoidance of methotrexate
disease in this population and has significant impli- use in most patients with CTCAE grades 2-4 abnor-
cations for treatment selection and management of malities in eGFR (eGFR \50), and dose reduction in
the overall health of PN patients. patients with CTCAE grades 2-4 abnormalities in
Specifically, we found that patients with PN have transaminases.22,23 All of these abnormalities, again,
significantly increased odds of CTCAE grade 3 were more likely to be present in PN patients.
AST/ALP elevation, direct bilirubin elevation, Obtaining this information on laboratory abnormal-
creatinine elevation, and eGFR reduction. CTCAE ities during the initial evaluation of a PN patient can
grade 3 laboratory abnormalities are considered to improve the management of PN patients’ overall
be severe or medically significant, disabling, and an well-being and guide therapeutic selection.
JAAD INT Cornman et al 79
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Fig 1. Relative risk of laboratory abnormalities in prurigo nodularis and control patients. A,
Relative risks (RRs) of graded laboratory abnormalities in prurigo nodularis (PN ) patients
compared with control patients, with values of RRs depicted within each cell. B, RR of
ungraded laboratory abnormalities in prurigo nodularis (PN ) patients compared with control
patients. *P \.05, **P \.0001. ALT, Alanine aminotransferase; AST, aspartate aminotransferase;
ALP, alkaline phosphatase; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration
rate; ESR, erythrocyte sedimentation rate; HbA1c, hemoglobin A1c; TSH, thyroid stimulating
hormone.

Focusing on specific laboratory abnormalities anemia of chronic disease.24 These anemias have
revealed in our study, we found that significantly also been shown to be associated with other inflam-
higher proportions of PN patients had lower hemo- matory dermatoses such as atopic dermatitis.25
globin than controls. These results corroborate pre- Abnormalities in hemoglobin and red blood cell
vious findings describing multiple causes of anemia count are therefore important parameters for physi-
in PN patients, including iron deficiency anemia and cians to monitor and address.
80 Cornman et al JAAD INT
DECEMBER 2023

We also found inflammatory patterns in the Americans are disproportionately affected by PN,
laboratory results of PN patients. Significantly, and African American patients with PN tend to have
greater proportions of PN patients exhibited higher faster progression of chronic renal disease and
lymphocytes, neutrophils, and eosinophils on labo- higher comorbidity burden compared to their
ratory testing compared to controls. Immune cells in Caucasian counterparts, screening for renal disease
the skin release mediators such as interleukin (IL)-31, may be particularly useful in this patient
histamine, tryptase, eosinophils, prostaglandins, and population.6,34,35
neuropeptides, which can cause intense itch and Our results additionally corroborated prior
inflammation.2 T cell populations have been impli- studies that reported the association of PN with
cated as key players in the pathogenesis of PN, metabolic syndrome and endocrine conditions. We
including T-helper (Th-)2, Th17, and Th22 cells and found that more PN patients had diabetic-grade
their cytokines.8,26 Lesional PN skin has also been hemoglobin A1c levels compared to controls, affirm-
shown to display increased neutrophil and eosino- ing PN’s association with diabetes.4,10,36 HbA1c
phil infiltrates.27 Eosinophils have been shown to testing can be beneficial to dermatologists during
play a role in the cutaneous inflammation process via their initial assessment of PN patients for several
degranulation into the skin of PN patients, where reasons. First, diabetes is widely recognized to be
they promote inflammation and can induce pruritus associated with pruritus and neuropathy, both of
through nerve fiber modulation.28,29 Furthermore, which have the potential to exacerbate PN patho-
ESR was also found to be significantly elevated in PN genesis. Consequently, incorporating A1c testing
patients. ESR is a marker that is associated with a during the initial evaluation of PN patients can
variety of systemic comorbidities, including diabetes facilitate a more comprehensive understanding of
mellitus, renal disease, heart diseases, infections, and the underlying contributors to PN development.
malignancy.30 These results reinforce the systemic Moreover, this knowledge can foster collaboration
nature of inflammation in PN, and are consistent with with endocrine specialists or primary care providers,
prior studies which have found elevated levels of enabling efforts to improve glucose control. By
various inflammatory markers in the peripheral addressing glucose control issues, dermatologists
blood of PN patients.26,31,32 Systemic inflammation can potentially ameliorate the impact of diabetes-
has potential to mediate greater morbidity burden in related pruritus, ultimately benefiting both the pa-
PN, highlighting the importance of complete blood tient’s PN condition and their overall well-being.
count with differential testing in the workup of PN Finally, higher proportions of PN patients also had
patients. abnormalities on thyroid function, with PN patients
Our results also revealed severe (CTCAE grade 3 demonstrating significantly increased odds of having
and grade 4) hepatic and renal dysregulation in PN. both elevated or decreased TSH. The association of
These significant levels of hepatic and renal dysfunc- prurigo nodularis with hypothyroidism has previ-
tion should be addressed in collaboration with the ously only been reported in a case report, and there
appropriate specialists or primary care providers, is no published association of PN with hyperthy-
both to improve the overall well-being of PN roidism.37 Thus, our results suggest that thyroid
patients, and because they are known to cause disease may be more prevalent in PN patients than
pruritus and could therefore be contributing factors previously known, and provide a basis for further
to the development of PN. Compared to controls, investigation of comorbid thyroid disease in the PN
higher proportions of PN patients had elevations in population.
AST, ALT, ALP, and total and direct bilirubin. PN Limitations of this study include potential misclas-
patients should be evaluated as clinically indicated sification of PN in the electronic medical records. To
for underlying etiologies, including cholestatic hep- counteract this issue, we required patients to have
atitis and viral hepatitis, which have been previously been diagnosed with PN at least twice in their health
reported in association with PN.4,33 PN patients also record. Because the electronic diagnosis of prurigo
tended to have significantly decreased levels of nodularis was only introduced along with the instate-
albumin, which can be caused by hepatic underpro- ment of the ICD-10 system in October 2015, mea-
duction or increased renal losses. Additionally, surement of patient outcomes was limited to only
higher proportions of PN patients had elevated 5 years. Furthermore, the exact causes of the
blood urea nitrogen (BUN) and creatinine levels patients’ laboratory dysregulation could not be
and lower eGFR than controls. Renal disease has elicited from the database.
been documented in association with PN, and end In conclusion, PN is significantly associated with
stage renal disease is one of the top reasons for alterations in laboratory parameters on peripheral
hospital admission in PN patients.6 Since African blood testing which can be detected at the patient’s
JAAD INT Cornman et al 81
VOLUME 13

initial clinical presentation. Of clinical significance, 10. Huang AH, Roh YS, Sutaria N, et al. Real-world disease burden
PN patients more frequently have severe laboratory and comorbidities of pediatric prurigo nodularis. J Am Acad
Dermatol. 2022;86(3):655-657. https://doi.org/10.1016/j.jaad.
abnormalities for which intervention is indicated, 2021.02.030
and which may impact therapeutic selection. 11. Elmariah S, Kim B, Berger T, et al. Practical approaches
Therefore, the care of PN patients should include for diagnosis and management of prurigo nodularis: United
consideration for other systemic comorbidities, and States expert panel consensus. J Am Acad Dermatol. 2021;
clinicians should maintain a high index of suspicion 84(3):747-760. https://doi.org/10.1016/j.jaad.2020.07.025
12. Kwon CD, Khanna R, Williams KA, Kwatra MM, Kwatra SG.
for differential diagnoses that include renal, hepatic, Diagnostic workup and evaluation of patients with prurigo
hematologic, endocrine, and metabolic diseases. nodularis. Medicines. 2019;6(4):97. https://doi.org/10.3390/
Based on the findings of this study, the recommen- medicines6040097
ded initial workup for patients with PN includes a 13. Roh YS, Marani M, Choi U, et al. Validation of international
complete blood count, renal function test, liver classification of diseases tenth revision code for prurigo
nodularis. J Am Acad Dermatol. 2022;87(2):482-484. https://
function test, thyroid function tests, and hemoglobin doi.org/10.1016/j.jaad.2021.10.026
A1c. 14. Barbieri JS, Shin DB, Wang S, Margolis DJ, Takeshita J. The
clinical utility of laboratory monitoring during isotretinoin
Conflicts of interest therapy for acne and changes to monitoring practices over
Dr Kwatra is an advisory board member/consultant for time. J Am Acad Dermatol. 2020;82(1):72-79. https://doi.org/10.
Abbvie, Aslan Pharmaceuticals, Arcutis Biotherapeutics, 1016/j.jaad.2019.06.025
Castle Biosciences, Celldex Therapeutics, Galderma, 15. Hansen TJ, Lucking S, Miller JJ, Kirby JS, Thiboutot DM,
Zaenglein AL. Standardized laboratory monitoring with use
Genzada Pharmaceuticals, Incyte Corporation, Johnson &
of isotretinoin in acne. J Am Acad Dermatol. 2016;75(2):323-
Johnson, Leo Pharma, Novartis Pharmaceuticals
328. https://doi.org/10.1016/j.jaad.2016.03.019
Corporation, Pfizer, Regeneron Pharmaceuticals, and 16. Zane LT, Leyden WA, Marqueling AL, Manos MM. A
Sanofi and has served as an investigator for Galderma, population-based analysis of laboratory abnormalities
Incyte, Pfizer, and Sanofi. All other authors report no during isotretinoin therapy for acne vulgaris. Arch Dermatol.
conflicts of interest. 2006;142(8):1016-1022. https://doi.org/10.1001/archderm.142.
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