Cutaneous Sarcoidosis as a Predictor of Cardiac Sarcoidosis

Yuta Norimatsu^1,2, Ayumi Yoshizaki^1*, Yuki Ohno², Yuka Mizuno^1,2, Haruka Watanabe², Hirohito Kotani¹, Kazuki M Matsuda¹, Maiko Fukayama¹, Ai Kuzumi¹, Satoshi Ebata¹, Takemichi Fukasawa¹, Asako Yoshizaki-Ogawa¹, Shinichi Sato¹

¹Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan

²Department of Dermatology, JR Tokyo General Hospital, Tokyo, Japan

^*Corresponding author: Ayumi Yoshizaki, Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan

Received: 19 April 2021; Accepted: 30 April 2021; Published: 13 May 2021

Abbreviations

FDG-PET-18F-fluorodeoxyglucose positron emission tomography; MRI - magnetic resonance imaging

1. Introduction

Sarcoidosis is a relatively rare, unexplained systemic granulomatous disease that occurs in 1-40 per 100,000 individuals [1-4]. It affects various organs, including the skin [5], and may be associated with a poor prognosis. Cardiac sarcoidosis is a serious complication that accounts for 77% of deaths in Japanese patients with sarcoidosis [6]. Moreover, two-thirds of sudden deaths in patients with sarcoidosis is attributable to undiagnosed cardiac sarcoidosis [7].

In these patients, cardiac sarcoidosis is often diagnosed only upon autopsy. As such, diagnosing cardiac sarcoidosis early is integral to decreasing disease-related morbidity and mortality. However, patients with cardiac sarcoidosis may present with normal electrocardiograms, so diagnosis through this method is often inadequate [8].

Comparatively, gadolinium-enhanced cardiovascular magnetic resonance imaging (MRI) and/or 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) can detect cardiac sarcoidosis well, but these tests are considered highly invasiveness and expensive [9].

A landmark study on Japanese patients demonstrated that four of out five patients with cardiac sarcoidosis also had cutaneous sarcoidosis that presented with lesions on the face [10].

However, no prior report has investigated whether the presence of facial skin sarcoidosis poses a risk for cardiac sarcoidosis. Cutaneous sarcoidosis occurs in approximately 25% of patients with sarcoidosis [11], and most commonly presents in the lower extremities [12, 13]. Therefore, because cutaneous sarcoidosis is less likely to occur on the face, the presence of facial lesions in cutaneous sarcoidosis may be considered a characteristic index.

If an association between cutaneous sarcoidosis on the face and cardiac sarcoidosis can be established, the dermatologist may play a greater role in diagnosing cardiac sarcoidosis through skin biopsy of similar lesions. We examined whether cutaneous sarcoidosis of the face increased the risk for cardiac sarcoidosis.

2. Method

2.1 Study design

This was a retrospective cohort study. This study was approved by the Ethics Committee of the University of Tokyo Hospital and JR Tokyo General Hospital.

2.2 Patient selection and data classification

Patients with pathologically diagnosed cutaneous sarcoidosis who visited the Department of Dermatology at JR Tokyo General Hospital or the Department of Dermatology at the University of Tokyo Hospital between April 1, 2005, and March 31, 2019, were included in our study. Sarcoidosis was diagnosed in accordance with the data in the joint statement on sarcoidosis given by the American Thoracic Society, European Respiratory Society, and World Association of Sarcoidosis and Other Granulomatous Disorders [14]. All patients underwent electrocardiography and echocardiography. Gadolinium-enhanced cardiovascular (MRI) and/or FDG-PET was performed at least once in all patients.

The eruption site of cutaneous sarcoidosis in each patient was recorded and classified as being on the face, trunk, or extremities. Patients with multiple eruption sites were excluded from our study. The presence or absence of concomitant cardiac sarcoidosis was also collected from the medical records.

2.3 Analysis

For statistical analysis, we used the Mann-Whitney U test and Fisher's exact test. Statistical significance was set at P < 0.05. Prism 8 (GraphPad Software Inc.) was used for the statistical analyses.

3. Results

We identified 58 patients with cutaneous sarcoidosis. Seventeen cases were excluded from the study because the eruption spanned multiple areas. Table 1 shows the characteristics of the 41 patients included in our study.

We examined the association between lesions in the face, trunk, and extremities, and cardiac sarcoidosis. We found that facial rashes increased the risk for cardiac sarcoidosis (p = 0.0090, Odds ratio 20) (Table 2); there was no association between truncal rash and cardiac sarcoidosis (p> 0.9999) (Table 3); and the absence of lesions on the extremities slightly decreased the risk for cardiac sarcoidosis (p = 0.0387, Odds ratio 0.0961). (Table 4).There was no correlation between angiotensin-1-converting enzyme and the soluble interleukin-2 receptor (Table 5). The types of cutaneous sarcoidosis are summarized in Table 6.

Fisher’s exact test or Mann–Whitney U test was used for statistical analysis.

^† standard deviation (SD)

Table 1: Patient characteristics.

Fisher’s chi-square test (for categorical variables): p-value = 0.0090

Odds ratio: 20

Table 2: Relationship between cutaneous sarcoidosis (face) and cardiac sarcoidosis.

Fisher’s chi-square test (for categorical variables): p-value > 0.9999

Odds ratio: not assessed

Table 3: Relationship between cutaneous sarcoidosis (trunk) and cardiac sarcoidosis.

Fisher’s chi-square test (for categorical variables): p-value = 0.0387

Odds ratio: 0.096

Table 4: Relationship between cutaneous sarcoidosis (upper or lower extremity) and cardiac sarcoidosis.

Fisher's exact test or the Mann-Whitney U test was used for statistics.

SD; standard deviation

Table 5: Patient blood test results.

Table 6: Type of lesion in patients with cutaneous sarcoidosis.

4. Discussion

Our results suggest that cutaneous sarcoidosis of the face increases the risk for cardiac sarcoidosis, while cutaneous sarcoidosis of the extremities reduces the risk for cardiac sarcoidosis. The association between cutaneous sarcoidosis of the face and cardiac sarcoidosis was first reported by Okamoto et al. [10] in their study of five Japanese patients. Another report examined 12 Japanese patients with cutaneous sarcoidosis. Four of the twelve patients also had cardiac sarcoidosis. Among the four patients with cutaneous sarcoidosis and cardiac sarcoidosis, three patients had facial plaque-type cutaneous sarcoidosis [15]. As such, the association between cutaneous sarcoidosis of the face and cardiac sarcoidosis has been documented in existing reports, as well as in our study.

Our study showed that cutaneous sarcoidosis of the face statistically increased the risk for cardiac sarcoidosis. In our study, there were four patients with cutaneous sarcoidosis of the face and cardiac sarcoidosis. Two of these patients had nodule-type cutaneous lesions, whereas the other two patients had no available data (Table 6). Comparatively, previous reports have only suggested an association between cutaneous sarcoidosis with plaque-type facial lesions and cardiac sarcoidosis [15]. While our results are inconsistent with these reports, the combined data also suggest that cutaneous sarcoidosis of the face, regardless of the lesion type, is an important factor.

On the other hand, in a study of 13 Caucasian patients with cutaneous sarcoidosis, only one case had cardiac sarcoidosis [16]. From this report, it was unclear whether the cutaneous lesions in these patients were located on the face, trunk, or extremities. However, racial differences in sarcoidosis do exist. In Japan, the proportion of cardiac sarcoidosis and ocular sarcoidosis is higher than in other regions. Cardiomyopathy is also the most common cause of death in patients with sarcoidosis in Japan [6, 17, 18], whereas respiratory failure is the most common cause of death for patients in other regions [19, 20].

 As such, in light of these known data and considering the study that examined 12 Japanese patients and ours, it may be concluded that Caucasians patients with cutaneous sarcoidosis are less likely than Japanese patients with cutaneous sarcoidosis to develop cardiac sarcoidosis [15].

It is also noteworthy that our study showed that cardiac sarcoidosis was less likely to develop when cutaneous sarcoidosis is observed in the extremities. Doherty and Rosen examined 12 cases of cutaneous sarcoidosis, of which eight, three, and one case had lesions in the face, lower extremities, and entire body, respectively. In their study, cardiac sarcoidosis was observed in 1 of the 3 cases with cutaneous sarcoidosis of the lower extremities [15]. Cutaneous sarcoidosis of the lower extremities is relatively common in Japan. In our study, 25 of the 41 cases showed involvement of the lower limbs and comprised the majority [12, 13]. It is possible that some cases of cutaneous sarcoidosis of the lower extremities have been overlooked, especially because it is difficult or time-consuming to diagnose [21]. Therefore, it is highly likely that the number of cases, particularly in the study by Doherty and Rosen, are also underestimated.

Various causes for cutaneous sarcoidosis of the face have been considered, but none have been confirmed [22, 23]. Propionibacterium acne and pine pollen are often cited as examples, because they easily come into contact with the face. However, Propionibacterium acne and pine pollen may just as easily come into contact with the palms and lower limbs. It is unknown whether any of the patients in our study had a previous history of acne vulgaris.

Cutaneous sarcoidosis has also been studied as possible sequelae of malignant tumors [24]. However, this association may have been identified due to a reporting bias, because the study that identified it was a retrospective review. This study also examined non-Japanese patients, so its findings may not be applicable to Japanese patients. In our study, there was only one patient with a malignant tumor.

In contrast, the studies by Okamoto et al. and Nakamura et al. all involved Japanese patients [10, 15]. Diffuse infiltrative erythema of the face and cardiac sarcoidosis are generally more common in Japanese patients with sarcoidosis than in other races. As such, this result may be peculiar only to Japanese patients [25, 26]. We were unable to analyze cutaneous sarcoidosis in terms of its different skin lesion types, because these data were usually not reported.

Our study followed a retrospective design. Future prospective studies may shed more light on sarcoidosis as a whole. We also recommend examining patients with cutaneous sarcoidosis with lesions in multiple parts of the body, because we excluded these patients in the current study. In conclusion, among Japanese patients with cutaneous sarcoidosis, lesions on the face and limbs may increase and reduce the risk for cardiac sarcoidosis, respectively.

Acknowledgements

No funding was received from private, public, or not-for-profit agencies.

Conflicts of Interest

The authors declare no conflicts of interest.

References

1. Yamamoto M, Sharma OP, Hosoda Y. Special Report: The 1991 Descriptive Definition of Sarcoidosis. Sarcoidosis (1992): 33-34.
2. Henke CE, Henke G, Elveback LR, Beard CM, Ballard DJ, et al. The Epidemiology of Sarcoidosis in Rochester, Minnesota: A Population-based Study of Incidence and Survival. American Journal of Epidemiology (1986): 840-845.
3. Rybicki BA, Major M, Popovich Y, Jr. Maliarik MJ, Iannuzzi MC. Racial Differences in Sarcoidosis Incidence: a 5-year Study in a Health Maintenance Organization. American Journal of Epidemiology (1997): 234-241.
4. Bresnitz EA, Strom BL. Epidemiology of Sarcoidosis. Epidemiology Review (1983): 124-156.
5. Haimovic A, Sanchez M, Judson MA, Prystowsky S. Sarcoidosis: A Comprehensive Review and Update for the Dermatologist: Part I. Cutaneous Disease. Journal of American Academic Dermatology 699 (2012): e1-e18; quiz 717-718.
6. Iwai K, Sekiguchi M, Hosoda Y, DeTemee RA, Tzelaar HD, et al. Racial Difference in Cardiac Sarcoidosis Incidence Observed at Autopsy. Sarcoidosis (1994): 26-31.
7. Ekström K, Lehtonen J, Nordenswan HK, Mäyränpää MI, Räisänen-Sokolowski A, et al. Sudden Death in Cardiac Sarcoidosis: An Analysis of Nationwide Clinical and Cause-of-death Registries. European Heart Journal (2019): 3121-3128. 
8. Fahy GJ, Marwick T, McCreery CJ, Quigley PJ, Maurer BJ. Doppler Echocardiographic Detection of Left Ventricular Diastolic Dysfunction in Patients with Pulmonary Sarcoidosis. Chest (1996): 62-66.
9. Okasha O, Kazmirczak F, Chen KA, Farzaneh-Far A, Shenoy C. Myocardial Involvement in Patients with Histologically Diagnosed Cardiac Sarcoidosis: A Systematic Review and Meta-Analysis of Gross Pathological Images from Autopsy or Cardiac Transplantation Cases. Journal of the American Heart Association (2019): e011253. 
10. Okamoto H, Mizuno K, Ohtoshi E. Cutaneous Sarcoidosis with Cardiac Involvement. European Journal of Dermatology (1999): 466-469.
11. Sharma OP. Cutaneous Sarcoidosis: Clinical Measures and Management. Chest (1972): 320-325.
12. Doherty CB, Rosen T. Evidence-based Therapy for Cutaneous Sarcoidosis. Drugs (2008): 1361-1383.
13. Baughman RP, Lower EE. Evidence-based Therapy for Cutaneous Sarcoidosis. Clinical Dermatology (2007): 334-340.
14. Statement on Sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS), the World Association of Sarcoidosis and other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. American Journal of Critical Care Medicine (1999): 736-755.
15. Nakamura S, Hashimoto Y, Nishi K, Takeda K, Mizumoto T, et al. High Rate of Cardiac Sarcoidosis Presenting with Cutaneous Plaque Type Sarcoidosis in 18F-fluorodeoxyglucose Positron Emission Tomography-computed Tomography: A Case Series. Journal of Medical Case Reports (2014): 8-17.
16. Drago F, Ciccarese G, Cittadini G, Drago F, Rosa GM, et al. Cardiac Involvement in Cutaneous Sarcoidosis. Giornale Italiano di Dermatologia e Venereologia (2019): 352-356. 
17. Iwai K, Tachibana T, Takemura T, Matsui Y, Kitaichi M, et al. Pathological Studies on Sarcoidosis Autopsy. I. Epidemiological Features of 320 Cases in Japan. Acta Pathologica Japonica (1993): 372-376.
18. Iwai K, Takemura T, Kitaichi M, Kawabata Y, Matsui Y: Pathological Studies on Sarcoidosis Autopsy. II. Early Change, Mode of Progression and Death Pattern. Acta Pathologica Japonica (1993): 377-385.
19. Keller AZ. Hospital, Age, Racial, Occupational, Geographical, Clinical and Survivorship Characteristics in the Epidemiology of Sarcoidosis. American Journal of Epidemiology (1971): 222-230.
20. Gideon NM, Mannino DM. Sarcoidosis Mortality in the United States 1979-1991: An Analysis of Multiple-cause Mortality Data. American Journal of Medicine (1996): 423-427.
21. Tchernev G, Cardoso JC, Chokoeva AA, Verma SB, Tana C, et al. The Mystery of Cutaneous Sarcoidosis: Facts and Controversies. International Journal of Immunopathology and Pharmacology (2014): 321-330. 
22. Mitchell DN, Rees RJ. A Transmissible Agent from Sarcoid Tissue. Lancet (1969): 81-74
23. Almenoff PL, Johnson A, Lesser M, Mattman LH. Growth of Acid Fast L Forms from the Blood of Patients with Sarcoidosis. Thorax (1996): 530-533.
24. Alexandrescu DT, Kauffman CL, Ichim TE, Riordan NH, Kabigting F, et al. Cutaneous Sarcoidosis and Malignancy: An Association between Sarcoidosis with Skin Manifestations and Systemic Neoplasia. Dermatology Online Journal (2011): 2. 
25. James DG. Seminars in Respiratory and Critical Care Medicine (1992): 422-441.
26. Morimoto T, Azuma A, Abe S, Usuki J, Sugisaki K, et al. Epidemiology of Sarcoidosis in Japan. The European Respiratory Journal (2008): 372-379.