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Postepy Dermatol Alergol
Postepy Dermatol Alergol
PDIA
Advances in Dermatology and Allergology/Postȩpy Dermatologii i Alergologii
1642-395X
2299-0046
Termedia Publishing House

54623
10.5114/ada.2024.142256
Letter to the Editor
Premature chondrodermatitis nodularis (adults < 61 years) and infection with human immunodeficiency virus: a matched multi-centre case-control study in North Spain
Martín Jimena Carrero 1
López Francisco Vazquez 1
Osuna Cristina Galache 1
de Castro Celia Gómez 1
Louzao Carla Díaz 2
López Marcos González 3
1 Dermatology Department, Central University Hospital of Asturias, Asturias, Spain
2 Health Research Institute Foundation, Clinic Hospital, Travesía da Choupana s/n. Santiago de Compostela, Galicia, Spain
3 Dermatoloy Department, Marqués de Valdecilla University Hospital, Cantabria, Spain
Address for correspondence: Jimena Carrero Martín, Dermatology Department, Central University Hospital of Asturias, Av Roma s/n. Oviedo, 33011, Asturias, Spain. e-mail: jimenacarrerom@gmail.com
14 8 2024
8 2024
41 4 426428
04 7 2023
19 4 2024
Copyright: © 2024 Termedia Sp. z o. o.
2024
https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
Funding No external funding.
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pmcChondrodermatitis nodularis helicis (CN) (Winkler’s disease) is a benign disease characterized by a tender nodule located on the helix or antihelix [1–3] (Figure 1). Its relevance is based on causing pain, and because its differentiation with skin cancer is crucial. CN has been reported to be associated with diseases with vascular injury [1, 2] but not yet with human immunodeficiency virus (HIV) infection. Nevertheless, we empirically observed in studies concerned with this disease [2, 3] that some patients with CN also suffer from HIV infection. Building on this empiric hypothesis, we constructed this multicentric study aimed to compare for the first time the frequency of individuals with a confirmed diagnosis of HIV infection (and treatment) in patients with CN and in a matched control population. The investigation was limited to adult patients with a premature onset of CN lesions (≤ 61 years), because only this age subsample showed differences in a preliminary, unpublished study.

Figure 1 A tender nodule located on the helix, clinically and dermoscopically compatible with chondrodermatitis nodularis helicis

With this aim, we investigated the frequency of a confirmed diagnosis of HIV infection (and specific treatment) in the digital charts of adult patients with a premature histopathological diagnosis of CN (18 to less than 61 years at diagnosis); and in a sex, age, year of diagnosis (±2 years), and date of birth (±2 years) 1-to-2 matched control population of individuals with a histopathological diagnosis of seborrheic keratosis (SK), in the same two hospitals from Spain (HUCA, Oviedo, Asturias; HUMV, Santander, Cantabria); and in the same period (1 January 2000–31 December 2022). The study was approved by the Hospital Ethics Committee (ref. 111/18 and 2021.340). Digital charts were investigated for this outcome (frequency of a confirmed HIV diagnosis) until the end of the study (31 December 2022), death, or the last available date when the patient had visited the clinician. The same index date was assigned to cases and paired controls (±2 years). Statistical analyses were carried out in the free statistical software R1, version 4.0.3. For the descriptive analysis, continuous variables were expressed as median (Me) and interquartile range (IQR), and categorical variables were defined by their absolute value and percentage. Differences between samples were assessed by means of Fisher’s exact test.

Regarding our results, the frequency of individuals with a confirmed diagnosis (and treatment) of HIV infection was higher among patients with a premature diagnosis of CN than in the control population (p = 0.045; OR = 8.081; CI: 1.0405–-197.7301) (Table 1). Two patients with CN and one control individual with HIV died during the study period (Table 2).

Table 1 Characteristics of samples and frequency of human immunodeficiency virus (HIV) infection in cases (chondrodermatitis nodularis, CN) and controls (seborrheic keratosis, SK)

Parameter	< 61 years(1-to-2 case-control ratio)	
CN	SK	
Number of individuals	131	259	
Female, n (%)	30 (22.9)	60 (23.2)	
Male, n (%)	101 (77.1)	199 (76.8)	
	p = 1.00	
Age [years] (Me [IQR])	52.7 [43.8–56.9]	52.6 [43.6–57.0]	
	p = 0.87	
Follow up time [years] (Me [IQR])	9.1 [4.3–12.7]	9.3 [4.5–13.0]	
	p = 0.84	
HIV infection, n (%)	4/131 (3.1)	1/259 (0.4)	
	p = 0.045	

Table 2 Characteristics of the 4 patients presenting human immunodeficiency virus (HIV) infection among patients with early-onset chondrodermatitis nodularis (CN)

Characteristics of CN patients	CN patients	
Patient 1	Patient 2	Patient 3	Patient 4	
Sex	Male	Male	Male	Female	
Ear lateralization	Right	Left	Left	Bilateral	
Age at diagnosis of CN lesion	46 years	54 years	59 years	59 years	
Year of diagnosis of CN lesion	2004	2014	2012	2012	
Year of diagnosis of HIV infection	1988	1993	2017	2009	
Time lapse	HIV: 16 years before CN diagnosis	HIV: 21 years before CN diagnosis	HIV: 5 years after CN diagnosis	HIV: 3 years before CN diagnosis	
HIV transmission mode	Injection drug use	Unknown	Sexual contact	Unknown	
Other risk factors	Injection drug user; tobacco smoking	Tobacco smoking; alcoholism	Tobacco smoking	Tobacco smoking. No drug user	
VHC coinfection	Yes	Yes	No	No	
Other comorbidities		Cirrhosis (alcoholic); severe COPD	COPD	Monoclonal gammopathy; aortic aneurysm	
Status at the end of study (2017)	Alive	Exitus (2015)	Alive	Exitus (2015)	
Cause of death	–	Sepsis	–	Ruptured aortic aneurysm	
HAART at diagnosis of lesion	Yes	Yes	No	Yes	
Histopathology:					
 Epidermal	+	+	+	+	
 Hyperplasia	+	+	+	+	
 Dermal necrobiosis	+	+	+	+	
 Peripheral	+	+	+	+	
 Vascularity	+	+	+	+	
 Inflammatory infiltrate	–	+	+	+	
 Cartilage damage	+	+	+	+	
COPD – chronic obstructive pulmonary disease, HAART – highly active antiretroviral therapy.

In this report, patients with a premature onset of CN lesions were more likely to be living with chronic HIV infection than a matched control population. Our findings are in line with the recent increase of diagnoses of benign lesions in patients with HIV infection after introduction of highly active antiretroviral therapies. CN is an idiopathic, exposome-induced, chronic, ischemic, degenerative and inflammatory disorder of the dermis/cartilage of the ear, with necrobiosis, transepidermal elimination and vasculopathy [1–3]. Age and chronic actinic damage favour its development [1–3]. CN is rare before 60 years of age at diagnosis (30%) and is rare in females (35%) [3]. This epidemiological study did not investigate causality, but different biologically plausible theories and pathomechanisms could explain this link: patients with HIV infection suffer from the premature occurrence of age-related comorbidities [4]. CN is an age-related disease and could be another one appearing earlier than usual in this context; tobacco smoking, more frequent among individuals with HIV, could favour both premature aging of patients [4] and premature development of CN lesions in HIV individuals [1]. In addition, CN is a vasculitis, and a relationship of CN with the spectrum of HIV vasculopathy (HIV-V) [5] could exist. In this way, a female patient with CN and HIV infection died from a ruptured thoracoabdominal aneurysm. Finally, therapy or the impact of other comorbidities, such as HCV coinfection, could be alternative pathomechanisms.

The strengths of this study were: multicentric design, confirmed histopathological diagnosis, the length of the study period, the size (it is the largest sample of CN patients evaluated to date); while limitations were: retrospective design, the small number of events; chance or bias cannot be excluded.

To conclude, in this pilot multi-centre study, adult patients with premature CN lesions were significantly more likely to be diagnosed with HIV infection than a matched control population. The importance of these findings for patients outweighs limitations and gives support for construction of larger, prospective, multicentric investigations.

Acknowledgments

Statistical analysis and interpretation were also completed with the assistance of the Scientific and Technical Services (Statistical Consultancy Unit) from the University of Oviedo (Tania Iglesias Cabo).

This investigation is performed In memoriam of Carmen Cadarso Suárez PhD (University of Santiago de Compostela, Spain). Without her great help and expert statistical guidance, this research would not have been possible. We remember her with gratitude.

Ethical approval

The study was approved by the Hospital Ethics Committee (ref. 111/18 and 2021.340).

Conflict of interest

The authors declare no conflict of interest.
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References

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