A Polygenic Risk Score for Predicting Racial and Genetic Susceptibility to Prurigo Nodularis.

Prurigo nodularis (PN) is an understudied inflammatory skin disease characterized by pruritic, hyperkeratotic nodules. Identifying the genetic factors underlying PN could help to better understand its etiology and guide the development of therapies. In this study, we developed a polygenic risk score that predicts a diagnosis of PN (OR = 1.41, P = 1.6 × 10-5) in two independent and continentally distinct populations. We also performed GWASs, which uncovered genetic variants associated with PN, including one near PLCB4 (rs6039266: OR = 3.15, P = 4.8 × 10-8) and others near TXNRD1 (rs34217906: OR = 1.71, P = 6.4 × 10-7; rs7134193: OR = 1.57, P = 1.1 × 10-6). Finally, we discovered that Black patients have over a two-times greater genetic risk of developing PN (OR = 2.63, P = 7.8 × 10-4). Combining the polygenic risk score and self-reported race together was significantly predictive of PN (OR = 1.32, P = 4.7 × 10-3). Strikingly, this association was more significant with race than after adjusting for genetic ancestry. Because race is a sociocultural construct and not a genetically bound category, our findings suggest that genetics, environmental influence, and social determinants of health likely affect the development of PN and may contribute to clinically observed racial disparities.

Association of prurigo nodularis and infectious disease hospitalizations: a national cross-sectional study.

BACKGROUND: Prurigo nodularis (PN) is associated with a variety of systemic comorbidities, including infectious diseases such as HIV and viral hepatitis. There are limited data on other infectious disease comorbidities in patients with PN. AIM: To characterize infectious disease hospitalizations among patients with PN and the associated cost burden. METHODS: We searched the 2016-2017 National Inpatient Sample, a cross-sectional sample of 20% of all US hospitalizations, for infectious disease hospitalizations among patients with PN. Associations of PN with infections and related costs were determined using multivariable logistic and linear regression, adjusting for age, race, sex and insurance type. RESULTS: PN was associated with any infection overall (OR = 2.98, 95% CI 2.49-3.56), and with HIV, cutaneous, hepatobiliary, central nervous system, bacterial, viral and fungal/parasitic infections and for sepsis. Patients with PN had a higher mean cost of care (US$11 667 vs. US$8893, P < 0.001) and length of stay (5.5 vs. 4.2 days, P < 0.001) for any infection overall and for 7 of 13 other infections. Adjusting for age, race, sex and insurance coverage, PN was associated with higher cost (+30%, 95% CI +17 to +44%) and higher length of stay (+30%, 95% CI +18 to +44%) for any infection overall, and for several specific infections. These associations remained with alternate regression models adjusting for severity of illness. CONCLUSION: There is a high infectious disease burden among patients with PN, corresponding to higher healthcare utilization and spending. Clinicians must be aware of these associations when treating these patients with immunomodulatory drugs.

Ethnic differences and comorbidities of 909 prurigo nodularis patients.

BACKGROUND: Prurigo nodularis (PN) is a poorly understood, understudied pruritic dermatosis that reduces quality of life. OBJECTIVE: To characterize the demographics and comorbidities associated with PN. METHODS: Cross-sectional study of patients 18 years and older who were seen at the Johns Hopkins Health System between December 6, 2012, and December 6, 2017. RESULTS: Over the past 5 years, 909 patients with PN were seen at Johns Hopkins Health System. African American patients were 3.4 times more likely to have PN than white patients were (odds ratio [OR], 3.4; 95% confidence interval [CI], 2.9-3.9; P < .001). A comparison of the study patients and race-matched controls revealed that PN was significantly associated with a variety of systemic, cardiovascular, and psychiatric comorbidities, including chronic kidney disease, chronic hepatitis C, chronic obstructive pulmonary disease, congestive heart failure, depression, and atopic dermatitis. Black patients with PN were 10.5 times more likely (OR, 10.5; 95% CI, 7.9-13.9; P < .001) to have HIV than were race-matched controls with atopic dermatitis, and 8 times more likely (OR, 8.0; 95% CI, 5.7-11.1; P < .001) to have HIV than were African American patients with psoriasis. LIMITATIONS: Our data describe patients seen by 1 hospital system. Our data identify associated conditions and comorbidities but are unable to support a causal relationship. CONCLUSION: PN disproportionately affects African Americans and is associated with several systemic conditions, including HIV, chronic kidney disease, and diabetes.

Prurigo pigmentosa: a clinical and histopathological study of nine Chinese cases.

BACKGROUND: Prurigo pigmentosa (PP) is a chronic and recurrent inflammatory skin disease with the distinctive and prominent feature of reticulate hyperpigmentation. Most known cases have been reported in Japan; here we report nine Chinese cases. OBJECTIVE: To determine the clinical manifestation of prurigo pigmentosa and its effects in Chinese individuals compared to patients of other ethnicities. METHODS: We retrospectively analysed nine cases of PP. For all cases, clinical information was collected and reviewed, and skin biopsies were performed. Furthermore, we followed all nine patients to determine the recurrence rate. RESULTS: All nine patients fulfilled the diagnostic criteria of prurigo pigmentosa. The mean age of the patients at diagnosis was 27.4 years, and the patients were predominantly female. Skin lesions at different stages commonly co-occurred in the same patient. The most commonly affected part of the body was the back, but the armpit was also often involved. Patients responded well to minocycline treatment for the short duration of 8.62 days, and a lower recurrence rate (28.3%) was recorded after treatment. Biopsy revealed classic neutrophil and/or lymphocyte infiltration, spongiosis and necrotic keratocytes. Abscesses occasionally occurred in the follicular orifice. The abnormal presentation of hair follicles was also discovered. All characteristics were found to co-exist in different stages. CONCLUSION: We conclude that PP is easy to misdiagnose. Histopathological characteristics can co-exist at different stages, consistent with the clinical finding that different stages of skin lesions presented concurrently, contributing to misdiagnosis. Oral administration of minocycline not only yields an excellent response, but also effectively reduces the recurrence rate.

Chronic actinic prurigo presenting in an adopted child.

In diagnosing actinic prurigo (AP), the patients' ethnic background is very helpful as this condition is associated with very specific ethnic groups. We discuss a patient with an unknown family history who presented with a rash that initially seemed like lupus, but was subsequently diagnosed as AP upon further evaluations.

Treatment of idiopathic prurigo nodularis in Taiwanese patients with low-dose thalidomide.

Prurigo nodularis is an intensely pruritic dermatosis characterized by lichenified and excoriated papules and nodules. The course of prurigo nodularis is often chronic, and some patients respond very poorly to the standard therapeutic modalities. Because the pathogenesis of this disease remains obscure, the treatment of prurigo nodularis can be disappointing and frustrating for both the patients and physicians. Thalidomide, a tumor necrosis factor-alpha antagonist, has been suggested as an alternative treatment option for recalcitrant prurigo nodularis. In the past, the regimen for treatment of prurigo nodularis often required thalidomide at 200 mg/day. We recruited patients with intractable prurigo nodularis and treated them with low-dose thalidomide. Six patients with idiopathic prurigo nodularis were successfully treated with low-dose thalidomide (50-100 mg/day) without clinical development of peripheral neuropathy. In summary, our preliminary results suggest that low-dose thalidomide may be a safe and effective treatment option for patients with recalcitrant idiopathic prurigo nodularis.

Evidence that thalidomide modifies the immune response of patients suffering from actinic prurigo.

BACKGROUND: Actinic prurigo (AP) is a photodermatosis with a restricted ethnic distribution, mainly affecting Mestizo women (mixed Indian and European). The lesions are polymorphic and include macules, papules, crusts, hyperpigmentation and lichenification. Thalidomide, an effective immunomodulatory drug, was first used successfully to treat AP in 1973. In this work we describe the effect that thalidomide had on TNF-alpha sera levels and on IL-4- and IFN gamma (IFNgamma)-producing lymphocytes of actinic prurigo (AP) patients. METHODS: Actinic prurigo patients were analyzed before and after thalidomide treatment. The percentage of IL-4+ or IFNgamma+ CD3+ lymphocytes was analyzed in eight of them by flow cytometry. TNFalpha in sera was measured by ELISA in 11 patients. RESULTS: A direct correlation was observed between resolution of AP lesions and an increase in IFNgamma+ CD3+ peripheral blood mononuclear cells (P < or = 0.001) and a decrease in TNFalpha serum levels (no statistical difference). No IL-4+ CD3+ cells were detected. CONCLUSIONS: Our findings confirm that AP is a disease that has an immunological component and that thalidomide clinical efficacy is exerted not only through inhibition of TNFalpha synthesis, but also through modulation of INFgamma-producing CD3+ cells. These cells could be used as clinical markers for recovery.

Actinic prurigo: clinical features and HLA associations in a Canadian Inuit population.

BACKGROUND: Actinic prurigo (AP) is an idiopathic familial photodermatitis. AP of the Inuit is rarely reported and poorly characterized. OBJECTIVE: Our purpose was to examine the clinical features and HLA associations of AP in an Inuit population. METHODS: Thirty-seven Inuit subjects with AP were administered a questionnaire and underwent a cutaneous examination. Other causes of photosensitivity were excluded. HLA class I typing was performed by polymerase chain reaction and sequence-specific primers and class II typing by polymerase chain reaction and sequence-specific oligonucleotide probes. RESULTS: Subjects were 81.1% female, 67.6% had a family history of photosensitivity, and all experienced seasonal variation. The average age at onset of photosensitivity was 29 years, and only 27% had a trend toward improvement in photosensitivity. Involvement of eyes and nonexposed skin was reported in 62.2% and 18.9% of subjects, respectively. Physical examination revealed involvement of the face (64.9%), lip (32.4%), ear (13.5%), and dorsal aspect of the hand (24.3%). HLA-DRB1*14 was present in 51.2% of subjects and 26.2% of controls (P =.022, odds ratio = 2.975). This is a previously unreported HLA association. CONCLUSION: AP in the Inuit is a seasonal, pruritic photodermatitis, often commencing in adulthood and worsening over time. A novel association with HLA-DRB1*14 has been discovered. Overall, this novel HLA association, the absence of HLA associations previously reported in non-Inuit populations, and clinical distinguishing features support the concept that AP in the Inuit may have a distinct immunopathogenic basis that translates into a different phenotype. It also raises the question of whether AP in the Inuit is a distinct photosensitivity disorder specific to this group that has been genetically isolated because of geographic and cultural seclusion.

Major gene segregation of actinic prurigo among North American Indians in Saskatchewan.

Actinic prurigo is an idiopathic, familial photodermatosis seen especially in American Indians. Segregation analysis was performed on 12 Saskatchewan pedigrees with American Indian ancestry, comprising a total of 1,148 individuals, ascertained via probands diagnosed with actinic prurigo. Although a high degree of familial aggregation has been noted in the past and dominant inheritance has been suggested, no formal segregation analysis has been attempted. Actinic prurigo has a variable age of onset and, therefore, age at the time of censoring must be taken into account in the analysis. However, as these ages of 57% of the unaffected individuals were missing, an algorithm was devised to impute the missing ages from known birth years in the family based on the age differences among relatives and spouses. Using these imputed ages, simple dominant inheritance with incomplete penetrance and a single age of onset distribution was found. The method for imputing the ages at examination was evaluated, as was the correction for ascertainment, by using alternative methods and comparing the results. Regardless of the method used, a dominant mode of inheritance without any multifactorial component remained the best hypothesis.

A case of actinic prurigo in Thailand.

Actinic prurigo is a separate entity from the polymorphous light eruption that affects American Indians. It has been reported mainly from North and South America, with only few reported cases from Britain or Asia. We report a case of actinic prurigo in a Thai girl who showed cheilitis and pruritic papules on exposed areas for three years. We were able to induce populovesicular lesions by three consecutive irradiations with 100 J/cm2 UVA and 2 minimal erythematous dose of UVB. However, three weeks after irradiation, a prurigo papule developed at the UVB irradiated site.

Further evidence of the role of HLA-DR4 in the genetic susceptibility to actinic prurigo.

BACKGROUND: Actinic prurigo (AP) is triggered by sun exposure. Its prevalence in Mexicans seems to be particularly high, which suggests a genetic susceptibility. OBJECTIVE: Our purpose was to determine the role of major histocompatibility complex (MHC) genes in the genetic susceptibility to AP. METHODS: Fifty-six Mexican Mestizo patients with AP underwent serologic typing for HLA class I and class II antigens. Class II MHC genes were also studied by DNA analysis. Findings in patients were compared with 100 ethnically matched healthy controls. RESULTS: We found that 92.8% of patients with AP were HLA-DR4 positive (corrected p = 0.002; odds ratio [OR] = 10.1). The class I antigens HLA-A28 and HLA-B39 (B16) were also significantly increased (p < or = 0.000001, OR = 20.9 and p = 0.0001, OR = 6.7, respectively) compared with normal controls. Allele-specific oligonucleotide DR4 subtyping showed that 80.7% of HLA-DR4+ patients with AP were also positive for the DRB1*0407 allele. CONCLUSION: These results confirm the role of HLA-DR4 (DRB1*0407) in the genetic susceptibility to AP and raise the possibility of a role for class I MHC antigens HLA-A28 and B16 in Mexican patients.

Treatment of actinic prurigo in Chimila Indians.

BACKGROUND: Actinic prurigo has a high prevalence in women of child-bearing age. Its treatment has been, among others, with thalidomide. To avoid the deleterious effects of this drug on the embryo, therapeutic alternatives have been sought. Among these, tetracycline and vitamin E have been investigated as to their influence on the symptoms of actinic prurigo. Both these drugs affect superoxide radicals that are thought to be involved in the pathogenesis of actinic prurigo. MATERIALS AND METHODS: Patients (Chimila Indians with a high prevalence of actinic prurigo) received either (a) tetracycline, 500 mg three times daily, for 6 months, or (b) vitamin E, 100 IU daily, for 6 months. The patients were seen once monthly. There were eight patients in each group. RESULTS: Both drugs used were effective. Pruritus was remarkably improved by either treatment. None of the side effects were severe enough to lead to interruption of treatment, but the observation period posttreatment was relatively short, 4 months for tetracycline and 2 months for vitamin E. The improvement occurred in spite of the continuation of extensive exposure to the sun. CONCLUSIONS: Tetracycline and vitamin E are efficacious in relieving the pruritus of actinic prurigo. Preliminary trials of a combination treatment with these two drugs is a new avenue which has shown in preliminary trials to yield synergistic effects which might allow the dosage of tetracycline to be reduced.

HLA-DR4 may determine expression of actinic prurigo in British patients.

Human leukocyte antigen (HLA) associations have been reported in Amerindian patients with actinic prurigo. To determine if similar associations are present in the British Caucasoid population with actinic prurigo, 26 patients underwent serological typing for HLC Class I and II antigens. DNA analysis by both sequence-specific priming and group-specific amplification with single-stranded oligonucleotide probe hybridization was used to confirm the DR and DQ typing and to perform DR4 subtyping. All patients were DR4 positive, and 25 of 26 patients were DQ7 positive. DR4 subtyping revealed 12 of 20 patients tested to be DRB1*0407. A nonsignificant association was also found with HLA B55 that is in linkage disequilibrium with DRB1*0407. No HLA associations were found in 25 British Caucasoid patients with polymorphic light eruption. DRB1*0407 is rare in European Caucasoids without actinic prurigo, and HLA-DR4 may have an important role in determining expression of this disease.

Follicular cheilitis. A distinctive histopathologic finding in actinic prurigo.

Actinic prurigo (AP), a chronic skin disease caused by an abnormal reaction to sunlight, is commonly associated with cheilitis and conjunctivitis. Characteristic ethnic, genetic, environmental (occurs at high altitudes, above 1,500 m), clinical, and histopathologic features have been reported. AP occurs in American Indians of Canada and the United States and most commonly in Latin American countries, where Mestizos (mixed ancestry) are predominantly affected. The present study investigates AP involving the lips, where it is characterized by a dense lymphocytic infiltrate, often with well-formed lymphoid follicles; the latter feature we refer to as "follicular cheilitis" (FC). The histopathologic findings of FC are characteristic of and helpful in diagnosing actinic prurigo involving the lips.

Histopathology of actinic prurigo.

Actinic prurigo (AP) is an idiopathic familial photodermatosis seen in American Indians. We report on 17 patients; 16 had dermatitis and one had actinic cheilitis. Ten patients had acute dermatitis and six had chronic dermatitis. The histologies of acute AP and polymorphous light eruption (PLE; limited concept) are eczematous and indistinguishable. Both show spongiosis, superficial (and sometimes deep) perivascular lymphocytic infiltrates, and papillary dermal edema. Both also show vacuolar degeneration of the basal layer. In contrast, the chronic lichenified AP lesions are associated with marked hyperkeratosis, acanthosis, elongation of the rete ridges, and tissue repair. The large lymphoid germinal centers in the lamina propria are the main features of the lip histology. Seven biopsies were positive in the basal membrane zone on direct immunofluorescent testing, four were negative, and one was inconclusive. IgM was present in six and C3 in two. These immunofluorescent results are probably not significant. Immunofluorescent testing of the lip was negative. Although it is not possible to distinguish acute AP from PLE histologically, it is possible to differentiate the two conditions when chronic AP changes are present.

Patch testing in actinic prurigo.

42 out of 93 Saskatchewan Indians (32 female (F) and 10 male (M] with actinic prurigo were patch tested to standard series allergens between 1983 and 1987. Positive reactions were most frequently seen with nickel (3F:2M) and colophony. All 3 positive patch tests to colophony were in males. The same patients were also patch tested to extracts of 21 Saskatchewan plants and 3 Hollister-Stier plant extracts. Only 1 male and 2 females had positive patch tests. None of these 3 had rashes on the eyelids, behind the ears or under the chin. We conclude that plant contact dermatitis is unlikely to be mistaken for actinic prurigo in Saskatchewan.