The long-term prognosis of patients with chondrodermatitis nodularis (CN) has never been investigated. We developed the empirical hypothesis that the survival of these patients could present differences with controls, based in our own previous experience. Our objective is to assess for the first time whether survival in CN patients and matched controls is similar. We investigated the number of natural deaths and survival in patients with histopathologically diagnosed early-onset (EO) (< 61 years at diagnosis) and late onset (LO) CN lesions (= > 61 years at diagnosis); and in matched age, gender and year of diagnosis controls in a Hospital in Asturias, North Spain (years 2000-2017). We have found a small, non-significant excess of mortality in the total CN sample (p= 0.14), but this excess was significant in patients with an early-onset (EO) (< 61 years at diagnosis) of CN lesions in: a) univariate analysis: OR = 6.3; IC: 1.1-44.4; p=0.02; b) Kaplan- Meier survival curve (log-rank test, p=0.02; c) and Cox proportional hazard model (HR for mortality, 5.93; p=0.03; CI: 1.20-29.41). In this pilot, empirical hypothesis - driven, matched, single-centre, case-control study, patients with EO CN lesions (before the age of 61 years) had a decreased survival respect to matched controls. The potential importance for patients of these results outweighs limitations (retrospective and single Hospital design; small number of events); and gives support for construction of multicentric investigations.
Study protocol
Possible association of early - onset chondrodermatitis nodularis and risk of mortality. Results of a pilot retrospective case-control single-hospital study in Asturias, Northen Spain.
https://doi.org/10.21203/rs.3.rs-1496471/v1
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There is no evidence of systemic associations of Chondrodermatitis nodularis helicis (CN) (Winkler disease), but the lack of investigation on this topic could have biased our thought about this [4,5,7,12,16]. Some case reports suggested associations with diseases with vascular injury and autoimmune diseases [2,6,13]; and with atopy [11] and we recently suggested the hypothesis of a role of tobacco smoking in the development of this disease, because the accumulation of different tobacco strongly related diseases in a sample of patients with CN lesions [15]. Surprisingly, a further in deep review of the medical records of these patients, allowed us to unexpectedly observe that the number of deceased patients could be higher than expected, especially in those patients with an onset earlier than usual.
Considering the potential interest of this empiric observation, we considered it would be of value to perform this pilot, retrospective, case-control study, comparing 215 patients with CN and sex and age paired controls of the same hospital and period of diagnosis. Our aim was to assess for the first time whether survival in CN patients and controls is similar.
This retrospective study included 215 patients histopathologically diagnosed with CN at the Central University Hospital of Asturias, Northern Spain, from year 2000 to 2017. The number of natural deaths was registered in CN patients and compared with the number in controls. Traumatic deaths were not scored. Controls were matched to index CN patients by sex, age, year of diagnosis (±2 years), and year of birth (±2 years) and randomly selected from the histopathological register of seborrheic keratosis (SK) of the same Hospital (Huca) and period (from 2000 to 2017). This comparison was performed in the overall sample and in a further age sub analysis differentiating between early-onset (<61 years-old) (EO) and late-onset (≥ 61 years-old) (LO) patients. Controls were matched in a 1:1 ratio in the overall and in the late-onset sub sample; but, because CN patients with an early-onset (EO) were a minority, controls were matched in a 1:2 Case-Control Ratio in this sub sample. The study was approved by the Principado de Asturias ethics and investigation committee. Patients were investigated from year 2000 until death, end of study (31st December 2017), or the last available visit of the patient to a clinician. The length of follow-up was potentially similar for both samples; information regarding immunosuppression and cancer prone syndromes was recorded. The study was approved by the Hospital’s ethics committee. Histologic diagnosis of CN was based on these criteria: 1) a central ulcer of the epidermis, surrounded by an acanthotic epidermis; 2) central necrobiotic degeneration of dermal collagen below the ulcer; 3) peripheral granulation tissue; 4) variable chronic inflammatory cell infiltrate (1).
Statistical analyses were carried out in the free statistical software R1, version 4.0.3, using the exact 2x2, survival, mgcv and survminer packages. Continuous variables were expressed as median (Me) and interquartile range (IQR); categorical variables were defined by their absolute value and percentage. Differences in the survival time were checked using a Kaplan-Meier plot estimator with log-rank test. A multivariate analysis of the survival time (including diagnosis and age) was fitted using a Cox proportional hazards regression model. Results are presented as Hazard Ratio (HR) with 95% confidence intervals (CI).
Characteristics of patients and results (total sample and age sub analysis) are shown in TABLE 1. Overall, there was a small excess of mortality in the total CN sample and in the LO CN sub sample, but this excess was highly significant in the EO sub sample in: a) univariate analysis: OR=6.3; IC: 1.1-44.4; (p=0.02) (Table 1); b) The Kaplan- Meier survival curve was significantly lower in CN than in controls (log-rank test, p=0.02 (Figure 1); c) The Cox proportional hazard model disclosed a 5.93-fold increase in the adjusted HR for mortality in CN patients with respect to controls (p=0.03; CI: 1.20-29.41), after adjusting for age but not for sex (all deceased patients were men). Age was not significant in the same model (p=0.23) (Table 2). The causes of death in the six patients with EO CN lesions were: visceral cancer (four patients); sepsis (one patient living with human immunodeficiency virus infection); and acute cardiovascular event (one patient with Buerger´s disease). Cancer was the only cause of death of two control patients who deceased. None of deceased patients or controls had an organ transplant.
Table 1. Demographic data and number of deceased persons in the total sample and in the age subanalysis. Patients with chondrodermatitis nodularis (CN) versus controls.
|
|
AGE SUBANALYSIS |
TOTAL SAMPLE (1:1 case-control Ratio) |
||||
|
|
<61 years (2:1 case-control Ratio) |
≥61 years (1:1 case-control Ratio) |
||||
|
|
CN |
Controls |
CN |
Controls |
CN |
Controls |
|
Number of individuals |
N = 62 |
N = 121 |
N = 153 |
N = 154 |
N = 215 |
N = 215 |
|
Female (n, %) |
13 (21.0%) |
26 (21.5%) |
62 (40.5%) |
62 (40.3%) |
75 (34.9%) |
75 (34.9%) |
|
Male (n, %) |
49 (79.0%) |
95 (78.5%) |
91 (59.5%) |
92 (59.7%) |
140 (65.1%) |
140 (65.1%) |
|
|
P = 1.00 |
P = 1.00 |
P = 1.00 |
|||
|
Age (years) (Me [IQR]) |
54.1 [48.8-57.9] |
55.1 [48.8-58.0] |
74.9 [68.0-80.8] |
75.6 [68.2-80.9] |
69.6 [59.4 -77.7] |
69.7 [60.0-78.2] |
|
|
P = 0.78 |
P = 0.70 |
P = 0.72 |
|||
|
Follow up time (years) (Me [IQR]) |
10.0 [4.6-13.6] |
9.8 [4.7-13.5] |
5.9 [3.0-8.7] |
5.7 [3.4-9.2] |
6.5 [3.2-10.7] |
6.5 [3.7-10.4] |
|
|
P = 0.85 |
P = 0.73 |
P = 0.80 |
|||
|
Deceased persons (n, %) |
6 (9.7%) |
2 (1.7%) |
42 (27.5%) |
34 (22.1%) |
48 (22.3%) |
35 (16.2%) |
|
|
P= 0.02 |
P = 0.29 |
P= 0.14 |
|||
Table 2. Results of the Cox regression model. Statistically significant p-value is marked in red.
Chondrodermatitis nodularis chronica helicis (CN) (Winkler disease) is a benign dermatosis that affects the skin/cartilage of the ear. It clinically appears as a round, usually isolated, centrally crusted/eroded papule, on the protruding areas of the helix or antehelicis of the ear [4,5,7,12,16]. Its relevance is based on causing pain, and because differentiation with skin carcinoma is important, especially in elderly patients [4]. Diagnosis of CN lesions is based on pain, clinical - dermoscopic features, and biopsy for doubtful lesions [3]. There is no evidence of association of CN with systemic diseases [4,5,7,12,16], but a few of case reports suggested associations with diseases with vascular injury, including those of immune-based etiology [2,6,13]; and atopy [11]; in addition, we recently reported the association with different disorders closely related to tobacco smoking [15], and suggested the hypothesis that tobacco smoking could have a role in the development of CN lesions. CN is idiopathic but thought to be an ischemic, degenerative, and inflammatory skin disorder of the external ear, with transepidermal elimination and necrobiosis [1,10]. CN lesions seems to be a complex interplay of altered wound-healing, tissue hypoxia, and microangiopathy [6], and secondary to environmental exposure [12]. CN is triggered by external microtrauma [4], cold exposure, damage from contact with cell phone [8] and, rarely, surgery. Changes related to ageing and chronic actinic damage favour its development [[4,5,7,12,16]: most patients with CN (70%) have more than 60 years at diagnosis and most patients are men (65%) [14].
In this pilot, empirical hypothesis - driven, matched, single-centre, case-control study, we would like to remark that patients with EO CN lesions (before the age of 61 years) had a decreased survival respect to matched controls. The Kaplan- Meier survival curve was significantly lower (log-rank test, p=0.02) in EO CN patients; and the adjusted Cox proportional hazards model confirmed this finding (aHR 5.93; CI: 1.20-29.41; p=0.03).
Limitations of the study were: it was a retrospective, single hospital study; the number of events was small; extrapolation to other populations cannot be properly performed and limits the generalizability of these findings; possibility of lost events must be considered; risk factors were not assessed; methodological biases are possible; all patients were surgically treated/biopsied and they could represent a subgroup with a worse prognosis; a comparison with other studies was not possible because this topic has never been investigated.
Strengths of the study were: all diagnoses were histopathologically confirmed; the length of the study period (17 years); information regarding immunosupression and cancer prone syndromes was recorded; the small number of events made it difficult to obtain samples powered to provide meaningful data, but controls were extended in a 1x2 Ratio in the EO sub sample, increasing the statistic power of the study.
This epidemiologic study was unable to assess causality, but we can hypothesize that the link between two conditions that are so different (EO CN development and risk of death), could be the lifestyle of the patients. In this way, both conditions could be different pleiotropic consequences of the same underlying risk factors. Among them, the possible association of CN with diseases strongly related to tobacco smoking [15], such as Buerger disease (BD) or pulmonary Langerhans cell histiocytosis (PLCH), suggests a role for this carcinogen in this association. This hypothesis is biologically plausible. Tobacco can increase skin ageing, induce actinic and vascular damage, delay healing and affect the inflammatory response [9]; and it is known that both ageing and chronic actinic damage favor CN development [4]. In this way, our results make possible to propose for the first time the hypothesis that there could be a subgroup of patients presenting with an earlier diagnosis of CN and an earlier decline of health, and that it could be related with an inadequate lifestyle. In the case that our results could be confirmed, these patients could benefit from prevention and early changes in lifestyle.
To conclude, in this empirical hypothesis – driven pilot study, the survival of patients with early development of CN lesions (< 61years) decreased respect to matched controls. Our results present limitations but give support for the construction of larger multicentric investigations concerned with this topic. In the meantime, reassuring younger patients with CN of the importance of a healthy lifestyle always will be of value.
Competing interests: authors don´t have financial or non-financial interests that are directly or indirectly related to the work
Funding sources: none
Francisco Vázquez López and Cristina Galache Osuna contributed to study conception, design and writing and editing.
Borja Gómez Vila and Celia Gómez de Castro contributed to material preparation and rewiew the text.
Carmen Cadarso and Carla Díaz contributed to formal análisis and investigation.
All authors rea and approved the final manuscript
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No competing interests reported.