Prurigo nodularis has two disease endotypes, a cluster analysis shows

A cluster analysis of circulating plasma biomarkers in prurigo nodularis (PN) has identified two disease endotypes with inflammatory and noninflammatory biomarker profiles.

The findings confirm clinical observations of disease heterogeneity, and highlight that PN “involves a spectrum of neuroimmune dysfunction, where patients can be at either end of the spectrum [toward either immune or neural dysregulation],” said senior author Shawn G. Kwatra, MD, of the department of dermatology at Johns Hopkins University, Baltimore. “This is the beginning of personalized medicine in prurigo nodularis.”

He and others have long observed significant clinical heterogeneity both in the presentation of PN – with the nodules in African American patients, for instance, appearing larger, thicker, and more fibrotic – and in patients’ response to immunomodulating and neuromodulating therapies.

To avoid the introduction of bias, the researchers used an unsupervised machine-learning approach to analyze the levels of 12 inflammatory biomarkers in 20 patients with PN and in matched healthy controls. The biomarkers were chosen based on their demonstrated dysregulation in PN and other inflammatory dermatoses.

The researchers then conducted a population-level analysis using multicenter electronic medical record data to explore inflammatory markers and verify findings from the cluster analysis. The study was published online Oct. 27, 2021, in the Journal of Investigative Dermatology.

One cluster of the 20 patients had higher levels of nine inflammatory biomarkers representing multiple immune axes: Higher interleukin-1 alpha, IL-4, IL-5, IL-6, IL-10, IL-17A, IL-22, and IL-25. This cluster had a higher percentage of Black patients, a higher severity of itch, and lower quality of life scores, the authors report in the preprint.

The other cluster – without such an inflammatory profile – had fewer Black patients and a higher percentage of patients with myelopathy (e.g. spinal stenosis, spinal trauma, degenerative disc disease). The rates of inflammatory comorbidities and of immune- and neuromodulating treatments at the time of blood draw were relatively equivalent between the two clusters.

In the subsequent population-level analysis, using data from a global health research network of EMRs from almost 50 health care organizations, Black patients with PN were found to have higher erythrocyte sedimentation rate, C-reactive protein, ferritin, and eosinophils, and lower transferrin, than White patients with PN. (The analysis included only Black and White patients.)

There are no Food and Drug Administration–approved therapies for PN, and “clinicians need to be really creative in managing these patients,” Dr. Kwatra said.

“There may be suggestions at the bedside that patients have more immune dysregulation, or maybe I’ll see increased circulating blood eosinophils,” he said. “And there are those who don’t seem to have any immune dysregulation and have more features of neurosensitization ... who may have a history of neck pain or back injury.”

The existence of endotypes in PN suggests that patients may benefit from personalized therapies with either immunomodulating or neuromodulating treatments, he and his colleagues wrote. “Further neuroimmune phenotyping studies of PN may pave the way for a future precision medicine management approach.”

Studies of PN conducted in Europe have been almost exclusively in White patients, Dr. Kwatra noted, even though PN has been shown to disproportionately affect Black and other racial/ethnic-minority patients.

Black patients with PN were found to have the highest all-cause mortality over 20 years post diagnosis in a separate analysis of over 22,000 patients with PN. Using data from the same health research network, Dr. Kwatra and coinvestigators stratified patients by race/ethnicity and compared each subgroup with a corresponding subgroup of similar race/ethnicity to control for inherent differences in mortality.

Overall, patients with PN had higher all-cause mortality than controls (hazard ratio, 1.70), likely because of a high comorbidity burden, they wrote in their research letter. Black patients with PN had the highest mortality (HR, 2.07), followed by White (HR, 1.74) and Hispanic (HR, 1.62) patients.

PN may exacerbate existing racial disparities in the social determinants of health, and Black patients may suffer from greater systemic inflammation, Dr. Kwatra and coauthors wrote. Certainly, he said, these findings, as well as the finding of a distinct inflammatory signature in Black patients with PN, support “that the disease burden is much higher” in these patients.

Dr Kwatra disclosed that he is an advisory board member/consultant for Celldex Therapeutics, Galderma, Incyte, Pfizer, Regeneron, and Kiniksa Pharmaceuticals and has received grant funding from several companies. His research is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Grants from the Dermatology Foundation and the Skin of Color Society also helped fund the cluster analysis.

A cluster analysis of circulating plasma biomarkers in prurigo nodularis (PN) has identified two disease endotypes with inflammatory and noninflammatory biomarker profiles.

The findings confirm clinical observations of disease heterogeneity, and highlight that PN “involves a spectrum of neuroimmune dysfunction, where patients can be at either end of the spectrum [toward either immune or neural dysregulation],” said senior author Shawn G. Kwatra, MD, of the department of dermatology at Johns Hopkins University, Baltimore. “This is the beginning of personalized medicine in prurigo nodularis.”

He and others have long observed significant clinical heterogeneity both in the presentation of PN – with the nodules in African American patients, for instance, appearing larger, thicker, and more fibrotic – and in patients’ response to immunomodulating and neuromodulating therapies.

To avoid the introduction of bias, the researchers used an unsupervised machine-learning approach to analyze the levels of 12 inflammatory biomarkers in 20 patients with PN and in matched healthy controls. The biomarkers were chosen based on their demonstrated dysregulation in PN and other inflammatory dermatoses.

The researchers then conducted a population-level analysis using multicenter electronic medical record data to explore inflammatory markers and verify findings from the cluster analysis. The study was published online Oct. 27, 2021, in the Journal of Investigative Dermatology.

One cluster of the 20 patients had higher levels of nine inflammatory biomarkers representing multiple immune axes: Higher interleukin-1 alpha, IL-4, IL-5, IL-6, IL-10, IL-17A, IL-22, and IL-25. This cluster had a higher percentage of Black patients, a higher severity of itch, and lower quality of life scores, the authors report in the preprint.

The other cluster – without such an inflammatory profile – had fewer Black patients and a higher percentage of patients with myelopathy (e.g. spinal stenosis, spinal trauma, degenerative disc disease). The rates of inflammatory comorbidities and of immune- and neuromodulating treatments at the time of blood draw were relatively equivalent between the two clusters.

In the subsequent population-level analysis, using data from a global health research network of EMRs from almost 50 health care organizations, Black patients with PN were found to have higher erythrocyte sedimentation rate, C-reactive protein, ferritin, and eosinophils, and lower transferrin, than White patients with PN. (The analysis included only Black and White patients.)

There are no Food and Drug Administration–approved therapies for PN, and “clinicians need to be really creative in managing these patients,” Dr. Kwatra said.

“There may be suggestions at the bedside that patients have more immune dysregulation, or maybe I’ll see increased circulating blood eosinophils,” he said. “And there are those who don’t seem to have any immune dysregulation and have more features of neurosensitization ... who may have a history of neck pain or back injury.”

The existence of endotypes in PN suggests that patients may benefit from personalized therapies with either immunomodulating or neuromodulating treatments, he and his colleagues wrote. “Further neuroimmune phenotyping studies of PN may pave the way for a future precision medicine management approach.”

Studies of PN conducted in Europe have been almost exclusively in White patients, Dr. Kwatra noted, even though PN has been shown to disproportionately affect Black and other racial/ethnic-minority patients.

Black patients with PN were found to have the highest all-cause mortality over 20 years post diagnosis in a separate analysis of over 22,000 patients with PN. Using data from the same health research network, Dr. Kwatra and coinvestigators stratified patients by race/ethnicity and compared each subgroup with a corresponding subgroup of similar race/ethnicity to control for inherent differences in mortality.

Overall, patients with PN had higher all-cause mortality than controls (hazard ratio, 1.70), likely because of a high comorbidity burden, they wrote in their research letter. Black patients with PN had the highest mortality (HR, 2.07), followed by White (HR, 1.74) and Hispanic (HR, 1.62) patients.

PN may exacerbate existing racial disparities in the social determinants of health, and Black patients may suffer from greater systemic inflammation, Dr. Kwatra and coauthors wrote. Certainly, he said, these findings, as well as the finding of a distinct inflammatory signature in Black patients with PN, support “that the disease burden is much higher” in these patients.

Dr Kwatra disclosed that he is an advisory board member/consultant for Celldex Therapeutics, Galderma, Incyte, Pfizer, Regeneron, and Kiniksa Pharmaceuticals and has received grant funding from several companies. His research is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Grants from the Dermatology Foundation and the Skin of Color Society also helped fund the cluster analysis.

A cluster analysis of circulating plasma biomarkers in prurigo nodularis (PN) has identified two disease endotypes with inflammatory and noninflammatory biomarker profiles.

The findings confirm clinical observations of disease heterogeneity, and highlight that PN “involves a spectrum of neuroimmune dysfunction, where patients can be at either end of the spectrum [toward either immune or neural dysregulation],” said senior author Shawn G. Kwatra, MD, of the department of dermatology at Johns Hopkins University, Baltimore. “This is the beginning of personalized medicine in prurigo nodularis.”

He and others have long observed significant clinical heterogeneity both in the presentation of PN – with the nodules in African American patients, for instance, appearing larger, thicker, and more fibrotic – and in patients’ response to immunomodulating and neuromodulating therapies.

To avoid the introduction of bias, the researchers used an unsupervised machine-learning approach to analyze the levels of 12 inflammatory biomarkers in 20 patients with PN and in matched healthy controls. The biomarkers were chosen based on their demonstrated dysregulation in PN and other inflammatory dermatoses.

The researchers then conducted a population-level analysis using multicenter electronic medical record data to explore inflammatory markers and verify findings from the cluster analysis. The study was published online Oct. 27, 2021, in the Journal of Investigative Dermatology.

One cluster of the 20 patients had higher levels of nine inflammatory biomarkers representing multiple immune axes: Higher interleukin-1 alpha, IL-4, IL-5, IL-6, IL-10, IL-17A, IL-22, and IL-25. This cluster had a higher percentage of Black patients, a higher severity of itch, and lower quality of life scores, the authors report in the preprint.

The other cluster – without such an inflammatory profile – had fewer Black patients and a higher percentage of patients with myelopathy (e.g. spinal stenosis, spinal trauma, degenerative disc disease). The rates of inflammatory comorbidities and of immune- and neuromodulating treatments at the time of blood draw were relatively equivalent between the two clusters.

In the subsequent population-level analysis, using data from a global health research network of EMRs from almost 50 health care organizations, Black patients with PN were found to have higher erythrocyte sedimentation rate, C-reactive protein, ferritin, and eosinophils, and lower transferrin, than White patients with PN. (The analysis included only Black and White patients.)

There are no Food and Drug Administration–approved therapies for PN, and “clinicians need to be really creative in managing these patients,” Dr. Kwatra said.

“There may be suggestions at the bedside that patients have more immune dysregulation, or maybe I’ll see increased circulating blood eosinophils,” he said. “And there are those who don’t seem to have any immune dysregulation and have more features of neurosensitization ... who may have a history of neck pain or back injury.”

The existence of endotypes in PN suggests that patients may benefit from personalized therapies with either immunomodulating or neuromodulating treatments, he and his colleagues wrote. “Further neuroimmune phenotyping studies of PN may pave the way for a future precision medicine management approach.”

Studies of PN conducted in Europe have been almost exclusively in White patients, Dr. Kwatra noted, even though PN has been shown to disproportionately affect Black and other racial/ethnic-minority patients.

Black patients with PN were found to have the highest all-cause mortality over 20 years post diagnosis in a separate analysis of over 22,000 patients with PN. Using data from the same health research network, Dr. Kwatra and coinvestigators stratified patients by race/ethnicity and compared each subgroup with a corresponding subgroup of similar race/ethnicity to control for inherent differences in mortality.

Overall, patients with PN had higher all-cause mortality than controls (hazard ratio, 1.70), likely because of a high comorbidity burden, they wrote in their research letter. Black patients with PN had the highest mortality (HR, 2.07), followed by White (HR, 1.74) and Hispanic (HR, 1.62) patients.

PN may exacerbate existing racial disparities in the social determinants of health, and Black patients may suffer from greater systemic inflammation, Dr. Kwatra and coauthors wrote. Certainly, he said, these findings, as well as the finding of a distinct inflammatory signature in Black patients with PN, support “that the disease burden is much higher” in these patients.

Dr Kwatra disclosed that he is an advisory board member/consultant for Celldex Therapeutics, Galderma, Incyte, Pfizer, Regeneron, and Kiniksa Pharmaceuticals and has received grant funding from several companies. His research is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Grants from the Dermatology Foundation and the Skin of Color Society also helped fund the cluster analysis.