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Chronic eczematous dermatitis in patients with neurodegenerative diseases may be an early marker of bullous pemphigoid
Accepted Manuscript Chronic eczematous dermatitis in patients with neurodegenerative diseases may be an early marker of bullous pemphigoid Ping-Song Chou, Tsai-Ching Chou, Chung-Hsing Chang, Sebastian Yu, ChihHung Lee PII: DOI: Reference:
S0306-9877(17)30078-6 http://dx.doi.org/10.1016/j.mehy.2017.04.017 YMEHY 8542
To appear in:
Medical Hypotheses
Received Date: Accepted Date:
23 January 2017 21 April 2017
Please cite this article as: P-S. Chou, T-C. Chou, C-H. Chang, S. Yu, C-H. Lee, Chronic eczematous dermatitis in patients with neurodegenerative diseases may be an early marker of bullous pemphigoid, Medical Hypotheses (2017), doi: http://dx.doi.org/10.1016/j.mehy.2017.04.017
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Chronic eczematous dermatitis in patients with neurodegenerative diseases may be an early marker of bullous pemphigoid
Ping-Song Chou a,b, M.D, Tsai-Ching Chouc, M.D., Chung-Hsing Changd,e, M.D., Ph.D., Sebastian Yu d,f,*, M.D., M.S., Chih-Hung Leeg, , M.D. Ph.D. ＊
a
Department of Neurology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung
Medical University, Kaohsiung, Taiwan b
Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung
Medical University, Kaohsiung, Taiwan c
Department of Dermatology, Cathay General Hospital, Taipei, Taiwan
d
Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung
Medical University, Kaohsiung, Taiwan e
Department of Dermatology, College of Medicine, Kaohsiung Medical University,
Kaohsiung, Taiwan f
Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical
University, Kaohsiung, Taiwan g
Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital and Chang
Gung University College of Medicine, Kaohsiung, Taiwan ＊
These authors contribute equally.
Corresponding authors: Sebastian Yu 100, Shih-Chuan 1st Rd, Kaohsiung 80708 Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 1
email: [email protected] Tel: +886-7-3121101 ext 6103; Fax: +886-7-3118901 or Chih-Hung Lee 123 Dapi Rd, Kaohsiung 83301 Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan email: [email protected] Tel: +886-7-7317123 ext 2299; Fax: +886-7-7337612
Funding sources: none Conflict of interest: The authors have no conflict of interest to declare. Running head: pruritus and neurodegenerative diseases Word count:1825; Figure count:1; Table count:2
Keywords: dementia, Alzheimer's disease, stroke, Parkinson's disease, eosinophilia, neurodegenerative disease, pruritus
2
Abstract The number of elderly patients with chronic pruritus has been gradually increasing in aging countries. Bullous pemphigoid, a common autoimmune blister disease in the elderly, is always heralded by pruritic eczematous dermatitis and is often associated with neurodegenerative diseases. We hypothesized that chronic eczematous dermatitis in patients with neurodegenerative diseases may be an early marker of bullous pemphigoid. By conducting retrospective chart review, we found neurodegenerative diseases are more prevalent in elderly patients with chronic eczematous dermatitis. The mean time delay between the diagnosis of neurodegenerative diseases and onset of skin lesions is 4.17 years. In all 6 patients who received skin biopsy, eosinophils in the upper dermis or at the dermo-epidermal junction were obvious, which are remnant of the pathological finding of bullous pemphigoid. Together with the well-known association between bullous pemphigoid and neurodegenerative diseases, the results suggested that unlocalized eczematous dermatitis in the elderly may be an early manifestation of bullous pemphigoid. Interdiscipline communication among neurology, dermatology and geriatrics/gerontology is required to tailor specific managements for elderly patients with pruritus and neurodegenerative diseases.
3
Introduction With aging, chronic inflammatory state, decreased immunity to exogenous antigens, and increased autoimmunity to self antigens compromise one’s ability to sustain environmental insults. Chronic eczema and pruritus is increasingly reported in elderly patients.1,2Aging is associated with a loss of skin homeostasis, a decrease of skin hydration, altered epidermal barrier function, neuropathic changes in peripheral nerves and all these factors contribute to the development of senile pruritus.3 On the other hand, aging is associated with the increase of neurological deficit and neurodegenerative diseases such as Alzheimer's disease, stroke, and Parkinson’s disease.4 During several years of seeing senile patients developing severe chronic eczema, we noticed a proportion of elderly patients with chronic relapsing unlocalized pruritic eczematous dermatitis and sometimes erythroderma are associated with severe neurodegenerative diseases. These patients are characterized by high eosinophil percentage or elevated immunoglobulin E (IgE) in their peripheral bloods and tissue eosinophilia in skin. The potential explanations for association between neurodegenerative diseases and chronic pruritic skin lesions may be multifactorial. Central nervous system and the skin are functionally connected by various mechanisms.3 Animal studies gave evidences about the brain-skin connection. Pavlovic et al reported in 2008, in mice, stress raised the number of cutaneous nerve fibers containing the prototypic stress neuropeptide substance P in close contact with mast cells in mice and increased atopic dermatitis readout parameters by at least 30% of eosinophil infiltration. Stress in the brain also shifted the cytokine profile of CD4+ cells toward T helper 2 signaling in skin, increasing IL-4, IL-5, and tumor necrosis factor α (TNF-α) levels.5 In 2009, Ishiuji et al reported functional MRI studies support the hypothesis of brain-skin 4
connection. The results showed the activity in cortical areas in the brain involved in affect and emotion correlated to measures of disease severity of atopic dermatitis.6
The hypothesis Foureur et al proposed in 2001 that bullous pemphigoid could be considered to be a marker of neurological diseases.7 There are also at least seven reported hemiplegic bullous pemphigoid patients with unilateral skin lesions only on the paralyzed side.8 Several reports have proposed that bullous pemphigoid has a broad heterogeneous preclinical spectrum of presentations from eczematous or urticarial to papular or nodular lesions.9,10 Unlocalized eczematous dermatitis is among the manifestation of bullous pemphigoid, which is known to be associated with aging, tissue eosinophilia and associated neurodegenerative diseases.11 Given that non-bullous type bullous pemphigoid may account for pruritus in the elderly, we hypothesized that chronic pruritic dermatitis in patients with neurodegenerative diseases may be an herald of bullous pemphigoid..
Neurodegenerative diseases are more prevalent in elderly patients with chronic eczematous dermatitis To test this hypothesis, patients who received inpatient and/or outpatient care in Department of Dermatology in Kaohsiung Medical University Hospital or Department of Dermatology in Kaohsiung Municipal Hsiao-Kang Hospital were retrospectively reviewed from January, 2009 to December, 2011. Selection criteria included 1) patients who were over 60 years old, 2) presented with pruritic unlocalized eczematous dermatitis for more than two months, and 3) elevated 5
eosinophil percentage over 10% in total peripheral white blood cell counts or elevated IgE levels. Patients with other specific diagnosis known to cause eosinophilia such as scabies infestation were excluded. Age and gender-matched controls who received inpatient and/or outpatient care for other dermatologic diseases during the same period were randomly allocated to each patient. Three control subjects were matched to each case. Comorbid neurodegenerative diseases included ischemic stroke, dementia, and Parkinson's disease. By retrospective chart review, comorbid neurodegenerative diseases were identified in patients and controls and were ascertained by a neurologist. The proportion of comorbid neurodegenerative diseases in patient and control groups were compared using chi-square test. This study was approved by Institutional Review Board of Kaohsiung Medical University Hospital (KMUHIRB-E(II)-20150090). Thirty-two patients with unlocalized eczematous dermatitis met selection criteria. The ages ranged from 61 years to 89 years with a mean of 75.75 years. Twenty-six patients were male (81.25%) and six patients were female (18.75%).Among the 32 patients, 12 cases (37.5%) had comorbid neurodegenerative diseases. Compared with age and gender-matched control group, only 18 out of 93 control subjects had comorbid neurodegenerative diseases (18.8%). Neurodegenerative diseases are significantly more prevalent in cases than those in controls (P = 0.0301). The demographic characteristics of cases and controls were shown in Table 1.
Skin biopsy of elderly patients with unlocalized eczematous dermatitis showed characteristics reminiscent of bullous pemphigoid Next, we described cutaneous manifestation of the 12 elderly patients with chronic unlocalized eczematous dermatitis and comorbid neurodegenerative diseases(Table 2).
6
Physical examinations revealed generalized pruritic eczematous papules, confluent patches or plaques and sometime nodular lesions on trunk and limbs (Figure 1A-D). In some cases, the eczematous lesions progressed to erythroderma (case 1-4, 7). Regular complete blood counts examination disclosed markedly high percentage of eosinophils (mean, 12.2%; range, 7.3% to 48.2 %; reference range, 1% to 4%). Mean age at onset of symptoms was 80.7 years (range, 66-89 years). All twelve patients actually met the diagnostic criteria of atopic dermatitis.12Except for 1 patient (case 2, 66 years), all were older than 70 years. In all cases except case 6 and 7, the diagnosis of neurodegenerative diseases occurred prior to the onset of eczematous dermatitis, and the mean time delay is 4.17 years. In case 6 and 7, stroke occurred after the onset of skin eruptions by 1 and 4 years, respectively. The mean follow-up time was 4.2 years (range 1 year to 7 years). Histological examinations of the skin were performed for 6 patients. In case 1,2,3, and 6 the histological examinations showed chronic eczematous reaction with prominent hyperkeratosis and acanthosis. In case 7 and 9, there is mild hyperkeratosis and perivascular infiltrate. In all 6 cases who received skin biopsies, eosinophils in the upper dermis or at the dermo-epidermal junction are obvious (Figure 1E). In all patients, the treatment was started with a potent topical corticosteroid over the skin lesions. Prednisolone at a dose of 5 to 15 mg/day was given in all patients, and the eczema activity followed a chronic course.
Discussion Although bullous pemphigoid is considered to be a marker of neurological diseases, the association between chronic eczematous dermatitis and neurodegenerative disease 7
is less known. Chronic eczema and pruritus in elderly patients are often attributed to xerosis, impaired skin barrier function, and senile atopy. In our pilot study, we showed neurodegenerative diseases are common comorbidity in elderly patients with unlocalized eczematous dermatitis, indicating that neurodegenerative diseases may play a crucial role in the development of chronic pruritic skin lesions in the elderly. The epidemiological relationship between bullous pemphigoid and various neurological diseases has been well established. The mechanisms may involve and a simultaneous autoimmunization against bullous pmephigoid antigen 1 (BPAG1), also known as dystonin, in the skin and the neuronal isoform of BPAG1 in the brain, where the interaction between BPAG1 and dynactin is interrupted.11 In 1995, Guoet al reported disruption of the BPAG1 gene results in sensory ataxia and devastating sensory neurodegeneration in the null mice,13 suggesting its important role in maintaining sensory neuronfunction. Further studies by Liu et al in 2003 showed thatBPAG1 gene encodes multiple isoforms with BPAG1e expressed in the epidermis and the others (BPAG1n1, BPAG1n2, and BPAG1n3) expressed in neurons.14 Several clinical and experimental evidence suggested that senile pruritus may be linked to autoimmune events initiated by loss of self-tolerance against cutaneous autoantigens, which is facilitated by immune aging processes.3 Changes occurring in the immune system during aging, or immunosenescence, include an imbalance between inflammatory and anti-inflammatory networks, which results in the low grade chronic pro-inflammatory status.15 In addition, immune responses are tightly regulated in the healthy brain, such that antigens within the brain do not elicit immune responses but can only be targets of an immune response initiated in the periphery.16 8
We proposed that with immunosenescence, the self-antigens in the brain becomes targets of the aging immune system and their isoform self-antigen in the skin also be attacked by the autoaggressive peripheral T cells and resulted in the chronic unlocalized eczematous dermatitis in our patients. However, the mechanisms underlying these iso-antigens, loss of self-tolerance, and the induction of autoantibodies await further characterization. In this study, we also noticed an abnormally high eosinophilia in blood and in dermal tissue. Blood and tissue eosinophilia are commonly observed in the majority of bullous pemphigoid patients,17 and it plays an important role in the pathogenesis of bullous pempheoigd.11 92-kd gelatinase (matrix metalloproteinase 9), a protease secreted by eosinophils, has been shown to induce disruption of the basement membrane in vitro.18 The inhibition of eotaxin and the eosinophil chemoattractants IL-5 may improve the inflammation and blister formation in bullous pemphigoid, suggesting its major pathogenic role in the development of bullous pemphigoid.11 Eosinophil-derived neurotoxin are secreted by activated eosinophils during pathogenic stimulation and inflammatory process and is a powerful and important neurotoxin that causes neuronal and axonal damage and plays a crucial role in progressive neurodegenerative diseases.19 Population aging has become a transforming global issue. The demographic shift compels health care providers and government officials to consider the agingassociated skin problems. We propose that the pro-inflammation state and altered ‘immune-privilege’ in the brain during aging and neurodegeneration process had increased autoimmunity in the brain and affected the associated self-antigen in the skin. The cytokine imbalance during immunosenesence increased blood eosinophils
9
and resulted in chronic unlocalized eczematous dermatitis in the elderly. We proposed that the senile pruritus and bullous pemphigoid could likely both belong to one broad spectrum of disease presentations associated with neurodegeneration and aging. One of the strengths of our study is that the present study identifies the prevalence of neurodegenerative diseases is significantly higher in patients with pruritic unlocalized eczematous in the elderly. Furthermore, we proposed a new concept that pruritic unlocalized eczematous may be a early presentation of bullous pemphigoid. Based on this concept, we suggest a comprehensive survey, including potential risk of neurodegenerative diseases and specific dermatologic examinations for bullous pemphigoid, should be taken into consideration for these patients to tailor treatments. There are some limitations in this study. First, although the prevalence of neurodegenerative diseases is significantly different between cases and controls, the number of subjects was not large. Further investigation with larger sample size is needed to validate the results from this pilot study. Second, the definite diagnosis of bullous pemphigoid relies on direct immunofluorescence study. In the present study, we showed that eosinophils in the upper dermis or dermo-epidermal junction are suggestive of bullous pemphigoid. Further study with direct immunofluorescence examination will strengthen the concept that eczematous dermatitis in the elderly is a presentation of early bullous pemphigoid and may be an early marker of neurodegenerative diseases. In conclusion, neurodegenerative diseases are common in elderly patients with unlocalized eczematous dermatitis and eosinophilia. Non-bullous type bullous pemphigoid may account for a certain proportion of chronic pruritus in the elderly patients. As senile pruritus has been increasing in parallel with ageing of society, clarifying the exact mechanisms emerges as an important issue. Inter-discipline
10
collaboration among neurology, dermatology and geriatrics/gerontology is indicated to elucidate the mechanisms and to tailor specific treatment.
Conflict of interest statement The authors have no conflict of interest to declare.
11
References:
1.
Tanei R, Hasegawa Y, Sawabe M. Abundant immunoglobulin E-positive cells in skin lesions support an allergic etiology of atopic dermatitis in the elderly. J Eur Acad Dermatol Venereol. 2013;27(8):952-960.
2.
Garibyan L, Chiou AS, Elmariah SB. Advanced aging skin and itch: addressing an unmet need. Dermatol Ther. 2013;26(2):92-103.
3.
Schmidt T, Sitaru C, Amber K, Hertl M. BP180- and BP230-specific IgG autoantibodies in pruritic disorders of the elderly: a preclinical stage of bullous pemphigoid? The British journal of dermatology. 2014;171(2):212-219.
4.
Wajda DA, Mirelman A, Hausdorff JM, Sosnoff JJ. Intervention modalities for targeting cognitive-motor interference in individuals with neurodegenerative disease: a systematic review. Expert Rev Neurother. 2016.
5.
Pavlovic S, Daniltchenko M, Tobin DJ, et al. Further exploring the brain-skin connection: stress worsens dermatitis via substance P-dependent neurogenic inflammation in mice. The Journal of investigative dermatology. 2008;128(2):434-446.
6.
Ishiuji Y, Coghill RC, Patel TS, Oshiro Y, Kraft RA, Yosipovitch G. Distinct patterns of brain activity evoked by histamine-induced itch reveal an association with itch intensity and disease severity in atopic dermatitis. The British journal of dermatology. 2009;161(5):1072-1080.
7.
Foureur N, Descamps V, Lebrun-Vignes B, et al. Bullous pemphigoid in a leg affected with hemiparesia: a possible relation of neurological diseases with bullous pemphigoid? European journal of dermatology : EJD. 2001;11(3):230-233. 12
8.
Tsuruta D, Nishikawa T, Yamagami J, Hashimoto T. Unilateral bullous pemphigoid without erythema and eosinophil infiltration in a hemiplegic patient. The Journal of dermatology. 2012;39(9):787-789.
9.
Bakker CV, Terra JB, Pas HH, Jonkman MF. Bullous pemphigoid as pruritus in the elderly: a common presentation. JAMA dermatology. 2013;149(8):950953.
10.
Hertl M, Schmidt T. Underrecognition of the heterogeneous clinical spectrum of bullous pemphigoid. JAMA dermatology. 2013;149(8):954-955.
11.
Wakugawa M, Nakamura K, Hino H, et al. Elevated levels of eotaxin and interleukin-5 in blister fluid of bullous pemphigoid: correlation with tissue eosinophilia. The British journal of dermatology. 2000;143(1):112-116.
12.
Hanifin JM, Rajka G. Diagnostic Features of Atopic-Dermatitis. Acta DermVenereol. 1980:44-47.
13.
Guo L, Degenstein L, Dowling J, et al. Gene targeting of BPAG1: abnormalities in mechanical strength and cell migration in stratified epithelia and neurologic degeneration. Cell. 1995;81(2):233-243.
14.
Liu JJ, Ding J, Kowal AS, et al. BPAG1n4 is essential for retrograde axonal transport in sensory neurons. J Cell Biol. 2003;163(2):223-229.
15.
Franceschi C, Capri M, Monti D, et al. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mechanisms of ageing and development. 2007;128(1):92-105.
16.
Amor S, Peferoen LA, Vogel DY, et al. Inflammation in neurodegenerative diseases--an update. Immunology. 2014;142(2):151-166.
13
17.
Hurskainen T, Kokkonen N, Sormunen R, et al. Deletion of the major bullous pemphigoid epitope region of collagen XVII induces blistering, autoimmunization, and itching in mice. The Journal of investigative dermatology. 2015;135(5):1303-1310.
18.
Shimanovich I, Mihai S, Oostingh GJ, et al. Granulocyte-derived elastase and gelatinase B are required for dermal-epidermal separation induced by autoantibodies from patients with epidermolysis bullosa acquisita and bullous pemphigoid. The Journal of pathology. 2004;204(5):519-527.
19.
Liu GT, Hwang CS, Hsieh CH, et al. Eosinophil-derived neurotoxin is elevated in patients with amyotrophic lateral sclerosis. Mediators of inflammation. 2013;2013:421389.
14
Table 1.Demographic characteristics of patients with unlocalized eczematous dermatitis and their age- and gender-matched controls.
Patients
Controls
Number
32
96
Age (years), mean ± SD
75.75 ± 8.35
75.75 ± 8.44
Male/Female, n
26 (81.25%)/6 (18.75%)
78 (81.25%)/18 (18.75%)
Neurodegenerative diseases , n
12 (37.5%)
18 (18.75%)
Ischemic stroke
8 (25%)
11 (11.46%)
Dementia
8 (25%)
8 (8.33%)
Parkinson's disease
2 (6.25%)
2 (2.08%)
SD: standard deviation
15
Table 2. Ten elderly patients with unlocalized eczematous dermatitis and their neurologic manifestations Case
Age at Onset of Skin Lesions Skin Lesions /Gender
WBC (cell ⁄ mm3 ) ⁄ eosinophils (%)/IgE‡
Neurologic Manifestation
Time Delay Between Diagnosis of Neurodegenerative diseases and Onset of Skin Lesions (years)
1
89/male
Erythroderma
3500/22.0/NA
Ischemic stroke
4
2
66/male
Erythroderma
10165/48.2/129
Ischemic stroke
2
3
83 /male
Erythroderma
8600/12.1/3215
Ischemic stroke
3
4
78/male
Erythroderma; Pemphigoid 6600/10.3/9609
Senile dementia; Parkinsonism
12
5
82/female
Eczematous dermatitis
5400/15.3/NA
Ischemic stroke
2
6
80/male
Eczematous dermatitis
7000/25.5/36.7
Ischemia stroke
1*
7
74/male
Erythroderma
8400/12.2/2553
Ischemic stroke
4*
8
86/male
Eczematous dermatitis
4500/12.6/144
Dementia (Alzheimer's disease)
2
9
85/male
Eczematous dermatitis
8100/10.0/1409
Dementia
2
10
82/male
Eczematous dermatitis
9190/10.7/356
Ischemic stroke
12
11
84/female
Eczematous dermatitis
4700/7.3/391
Parkinsonism
2
12
79/male
Eczematous dermatitis
6750/12.0/NA
Ischemic stroke
14
16
‡Normal range: WBC, 4800–7500 /mm3; eosinophils, 1.0–4.0%; IgE< 100 IU/mL * Onset of skin lesions prior to stroke NA: not applicable
17
Figure 1.Clinical presentations and histologic examination of chronic unlocalized eczematous dermatitis in the elderly. (A,B,C ) Diffuse erythema and desquamation on chest, legs and face (Patient 3);(D) Close up view of the eczematous dermatitis (patient 10);(E) Histologic examination of the skin showed much eosinophilic dermal infiltration and epidermotropism of eosinophils (Patient 9)(Hematoxylin and eosin stain, 100X).
18
S0306-9877(17)30078-6 http://dx.doi.org/10.1016/j.mehy.2017.04.017 YMEHY 8542
To appear in:
Medical Hypotheses
Received Date: Accepted Date:
23 January 2017 21 April 2017
Please cite this article as: P-S. Chou, T-C. Chou, C-H. Chang, S. Yu, C-H. Lee, Chronic eczematous dermatitis in patients with neurodegenerative diseases may be an early marker of bullous pemphigoid, Medical Hypotheses (2017), doi: http://dx.doi.org/10.1016/j.mehy.2017.04.017
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Chronic eczematous dermatitis in patients with neurodegenerative diseases may be an early marker of bullous pemphigoid
Ping-Song Chou a,b, M.D, Tsai-Ching Chouc, M.D., Chung-Hsing Changd,e, M.D., Ph.D., Sebastian Yu d,f,*, M.D., M.S., Chih-Hung Leeg, , M.D. Ph.D. ＊
a
Department of Neurology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung
Medical University, Kaohsiung, Taiwan b
Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung
Medical University, Kaohsiung, Taiwan c
Department of Dermatology, Cathay General Hospital, Taipei, Taiwan
d
Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung
Medical University, Kaohsiung, Taiwan e
Department of Dermatology, College of Medicine, Kaohsiung Medical University,
Kaohsiung, Taiwan f
Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical
University, Kaohsiung, Taiwan g
Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital and Chang
Gung University College of Medicine, Kaohsiung, Taiwan ＊
These authors contribute equally.
Corresponding authors: Sebastian Yu 100, Shih-Chuan 1st Rd, Kaohsiung 80708 Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 1
email: [email protected] Tel: +886-7-3121101 ext 6103; Fax: +886-7-3118901 or Chih-Hung Lee 123 Dapi Rd, Kaohsiung 83301 Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan email: [email protected] Tel: +886-7-7317123 ext 2299; Fax: +886-7-7337612
Funding sources: none Conflict of interest: The authors have no conflict of interest to declare. Running head: pruritus and neurodegenerative diseases Word count:1825; Figure count:1; Table count:2
Keywords: dementia, Alzheimer's disease, stroke, Parkinson's disease, eosinophilia, neurodegenerative disease, pruritus
2
Abstract The number of elderly patients with chronic pruritus has been gradually increasing in aging countries. Bullous pemphigoid, a common autoimmune blister disease in the elderly, is always heralded by pruritic eczematous dermatitis and is often associated with neurodegenerative diseases. We hypothesized that chronic eczematous dermatitis in patients with neurodegenerative diseases may be an early marker of bullous pemphigoid. By conducting retrospective chart review, we found neurodegenerative diseases are more prevalent in elderly patients with chronic eczematous dermatitis. The mean time delay between the diagnosis of neurodegenerative diseases and onset of skin lesions is 4.17 years. In all 6 patients who received skin biopsy, eosinophils in the upper dermis or at the dermo-epidermal junction were obvious, which are remnant of the pathological finding of bullous pemphigoid. Together with the well-known association between bullous pemphigoid and neurodegenerative diseases, the results suggested that unlocalized eczematous dermatitis in the elderly may be an early manifestation of bullous pemphigoid. Interdiscipline communication among neurology, dermatology and geriatrics/gerontology is required to tailor specific managements for elderly patients with pruritus and neurodegenerative diseases.
3
Introduction With aging, chronic inflammatory state, decreased immunity to exogenous antigens, and increased autoimmunity to self antigens compromise one’s ability to sustain environmental insults. Chronic eczema and pruritus is increasingly reported in elderly patients.1,2Aging is associated with a loss of skin homeostasis, a decrease of skin hydration, altered epidermal barrier function, neuropathic changes in peripheral nerves and all these factors contribute to the development of senile pruritus.3 On the other hand, aging is associated with the increase of neurological deficit and neurodegenerative diseases such as Alzheimer's disease, stroke, and Parkinson’s disease.4 During several years of seeing senile patients developing severe chronic eczema, we noticed a proportion of elderly patients with chronic relapsing unlocalized pruritic eczematous dermatitis and sometimes erythroderma are associated with severe neurodegenerative diseases. These patients are characterized by high eosinophil percentage or elevated immunoglobulin E (IgE) in their peripheral bloods and tissue eosinophilia in skin. The potential explanations for association between neurodegenerative diseases and chronic pruritic skin lesions may be multifactorial. Central nervous system and the skin are functionally connected by various mechanisms.3 Animal studies gave evidences about the brain-skin connection. Pavlovic et al reported in 2008, in mice, stress raised the number of cutaneous nerve fibers containing the prototypic stress neuropeptide substance P in close contact with mast cells in mice and increased atopic dermatitis readout parameters by at least 30% of eosinophil infiltration. Stress in the brain also shifted the cytokine profile of CD4+ cells toward T helper 2 signaling in skin, increasing IL-4, IL-5, and tumor necrosis factor α (TNF-α) levels.5 In 2009, Ishiuji et al reported functional MRI studies support the hypothesis of brain-skin 4
connection. The results showed the activity in cortical areas in the brain involved in affect and emotion correlated to measures of disease severity of atopic dermatitis.6
The hypothesis Foureur et al proposed in 2001 that bullous pemphigoid could be considered to be a marker of neurological diseases.7 There are also at least seven reported hemiplegic bullous pemphigoid patients with unilateral skin lesions only on the paralyzed side.8 Several reports have proposed that bullous pemphigoid has a broad heterogeneous preclinical spectrum of presentations from eczematous or urticarial to papular or nodular lesions.9,10 Unlocalized eczematous dermatitis is among the manifestation of bullous pemphigoid, which is known to be associated with aging, tissue eosinophilia and associated neurodegenerative diseases.11 Given that non-bullous type bullous pemphigoid may account for pruritus in the elderly, we hypothesized that chronic pruritic dermatitis in patients with neurodegenerative diseases may be an herald of bullous pemphigoid..
Neurodegenerative diseases are more prevalent in elderly patients with chronic eczematous dermatitis To test this hypothesis, patients who received inpatient and/or outpatient care in Department of Dermatology in Kaohsiung Medical University Hospital or Department of Dermatology in Kaohsiung Municipal Hsiao-Kang Hospital were retrospectively reviewed from January, 2009 to December, 2011. Selection criteria included 1) patients who were over 60 years old, 2) presented with pruritic unlocalized eczematous dermatitis for more than two months, and 3) elevated 5
eosinophil percentage over 10% in total peripheral white blood cell counts or elevated IgE levels. Patients with other specific diagnosis known to cause eosinophilia such as scabies infestation were excluded. Age and gender-matched controls who received inpatient and/or outpatient care for other dermatologic diseases during the same period were randomly allocated to each patient. Three control subjects were matched to each case. Comorbid neurodegenerative diseases included ischemic stroke, dementia, and Parkinson's disease. By retrospective chart review, comorbid neurodegenerative diseases were identified in patients and controls and were ascertained by a neurologist. The proportion of comorbid neurodegenerative diseases in patient and control groups were compared using chi-square test. This study was approved by Institutional Review Board of Kaohsiung Medical University Hospital (KMUHIRB-E(II)-20150090). Thirty-two patients with unlocalized eczematous dermatitis met selection criteria. The ages ranged from 61 years to 89 years with a mean of 75.75 years. Twenty-six patients were male (81.25%) and six patients were female (18.75%).Among the 32 patients, 12 cases (37.5%) had comorbid neurodegenerative diseases. Compared with age and gender-matched control group, only 18 out of 93 control subjects had comorbid neurodegenerative diseases (18.8%). Neurodegenerative diseases are significantly more prevalent in cases than those in controls (P = 0.0301). The demographic characteristics of cases and controls were shown in Table 1.
Skin biopsy of elderly patients with unlocalized eczematous dermatitis showed characteristics reminiscent of bullous pemphigoid Next, we described cutaneous manifestation of the 12 elderly patients with chronic unlocalized eczematous dermatitis and comorbid neurodegenerative diseases(Table 2).
6
Physical examinations revealed generalized pruritic eczematous papules, confluent patches or plaques and sometime nodular lesions on trunk and limbs (Figure 1A-D). In some cases, the eczematous lesions progressed to erythroderma (case 1-4, 7). Regular complete blood counts examination disclosed markedly high percentage of eosinophils (mean, 12.2%; range, 7.3% to 48.2 %; reference range, 1% to 4%). Mean age at onset of symptoms was 80.7 years (range, 66-89 years). All twelve patients actually met the diagnostic criteria of atopic dermatitis.12Except for 1 patient (case 2, 66 years), all were older than 70 years. In all cases except case 6 and 7, the diagnosis of neurodegenerative diseases occurred prior to the onset of eczematous dermatitis, and the mean time delay is 4.17 years. In case 6 and 7, stroke occurred after the onset of skin eruptions by 1 and 4 years, respectively. The mean follow-up time was 4.2 years (range 1 year to 7 years). Histological examinations of the skin were performed for 6 patients. In case 1,2,3, and 6 the histological examinations showed chronic eczematous reaction with prominent hyperkeratosis and acanthosis. In case 7 and 9, there is mild hyperkeratosis and perivascular infiltrate. In all 6 cases who received skin biopsies, eosinophils in the upper dermis or at the dermo-epidermal junction are obvious (Figure 1E). In all patients, the treatment was started with a potent topical corticosteroid over the skin lesions. Prednisolone at a dose of 5 to 15 mg/day was given in all patients, and the eczema activity followed a chronic course.
Discussion Although bullous pemphigoid is considered to be a marker of neurological diseases, the association between chronic eczematous dermatitis and neurodegenerative disease 7
is less known. Chronic eczema and pruritus in elderly patients are often attributed to xerosis, impaired skin barrier function, and senile atopy. In our pilot study, we showed neurodegenerative diseases are common comorbidity in elderly patients with unlocalized eczematous dermatitis, indicating that neurodegenerative diseases may play a crucial role in the development of chronic pruritic skin lesions in the elderly. The epidemiological relationship between bullous pemphigoid and various neurological diseases has been well established. The mechanisms may involve and a simultaneous autoimmunization against bullous pmephigoid antigen 1 (BPAG1), also known as dystonin, in the skin and the neuronal isoform of BPAG1 in the brain, where the interaction between BPAG1 and dynactin is interrupted.11 In 1995, Guoet al reported disruption of the BPAG1 gene results in sensory ataxia and devastating sensory neurodegeneration in the null mice,13 suggesting its important role in maintaining sensory neuronfunction. Further studies by Liu et al in 2003 showed thatBPAG1 gene encodes multiple isoforms with BPAG1e expressed in the epidermis and the others (BPAG1n1, BPAG1n2, and BPAG1n3) expressed in neurons.14 Several clinical and experimental evidence suggested that senile pruritus may be linked to autoimmune events initiated by loss of self-tolerance against cutaneous autoantigens, which is facilitated by immune aging processes.3 Changes occurring in the immune system during aging, or immunosenescence, include an imbalance between inflammatory and anti-inflammatory networks, which results in the low grade chronic pro-inflammatory status.15 In addition, immune responses are tightly regulated in the healthy brain, such that antigens within the brain do not elicit immune responses but can only be targets of an immune response initiated in the periphery.16 8
We proposed that with immunosenescence, the self-antigens in the brain becomes targets of the aging immune system and their isoform self-antigen in the skin also be attacked by the autoaggressive peripheral T cells and resulted in the chronic unlocalized eczematous dermatitis in our patients. However, the mechanisms underlying these iso-antigens, loss of self-tolerance, and the induction of autoantibodies await further characterization. In this study, we also noticed an abnormally high eosinophilia in blood and in dermal tissue. Blood and tissue eosinophilia are commonly observed in the majority of bullous pemphigoid patients,17 and it plays an important role in the pathogenesis of bullous pempheoigd.11 92-kd gelatinase (matrix metalloproteinase 9), a protease secreted by eosinophils, has been shown to induce disruption of the basement membrane in vitro.18 The inhibition of eotaxin and the eosinophil chemoattractants IL-5 may improve the inflammation and blister formation in bullous pemphigoid, suggesting its major pathogenic role in the development of bullous pemphigoid.11 Eosinophil-derived neurotoxin are secreted by activated eosinophils during pathogenic stimulation and inflammatory process and is a powerful and important neurotoxin that causes neuronal and axonal damage and plays a crucial role in progressive neurodegenerative diseases.19 Population aging has become a transforming global issue. The demographic shift compels health care providers and government officials to consider the agingassociated skin problems. We propose that the pro-inflammation state and altered ‘immune-privilege’ in the brain during aging and neurodegeneration process had increased autoimmunity in the brain and affected the associated self-antigen in the skin. The cytokine imbalance during immunosenesence increased blood eosinophils
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and resulted in chronic unlocalized eczematous dermatitis in the elderly. We proposed that the senile pruritus and bullous pemphigoid could likely both belong to one broad spectrum of disease presentations associated with neurodegeneration and aging. One of the strengths of our study is that the present study identifies the prevalence of neurodegenerative diseases is significantly higher in patients with pruritic unlocalized eczematous in the elderly. Furthermore, we proposed a new concept that pruritic unlocalized eczematous may be a early presentation of bullous pemphigoid. Based on this concept, we suggest a comprehensive survey, including potential risk of neurodegenerative diseases and specific dermatologic examinations for bullous pemphigoid, should be taken into consideration for these patients to tailor treatments. There are some limitations in this study. First, although the prevalence of neurodegenerative diseases is significantly different between cases and controls, the number of subjects was not large. Further investigation with larger sample size is needed to validate the results from this pilot study. Second, the definite diagnosis of bullous pemphigoid relies on direct immunofluorescence study. In the present study, we showed that eosinophils in the upper dermis or dermo-epidermal junction are suggestive of bullous pemphigoid. Further study with direct immunofluorescence examination will strengthen the concept that eczematous dermatitis in the elderly is a presentation of early bullous pemphigoid and may be an early marker of neurodegenerative diseases. In conclusion, neurodegenerative diseases are common in elderly patients with unlocalized eczematous dermatitis and eosinophilia. Non-bullous type bullous pemphigoid may account for a certain proportion of chronic pruritus in the elderly patients. As senile pruritus has been increasing in parallel with ageing of society, clarifying the exact mechanisms emerges as an important issue. Inter-discipline
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collaboration among neurology, dermatology and geriatrics/gerontology is indicated to elucidate the mechanisms and to tailor specific treatment.
Conflict of interest statement The authors have no conflict of interest to declare.
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Table 1.Demographic characteristics of patients with unlocalized eczematous dermatitis and their age- and gender-matched controls.
Patients
Controls
Number
32
96
Age (years), mean ± SD
75.75 ± 8.35
75.75 ± 8.44
Male/Female, n
26 (81.25%)/6 (18.75%)
78 (81.25%)/18 (18.75%)
Neurodegenerative diseases , n
12 (37.5%)
18 (18.75%)
Ischemic stroke
8 (25%)
11 (11.46%)
Dementia
8 (25%)
8 (8.33%)
Parkinson's disease
2 (6.25%)
2 (2.08%)
SD: standard deviation
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Table 2. Ten elderly patients with unlocalized eczematous dermatitis and their neurologic manifestations Case
Age at Onset of Skin Lesions Skin Lesions /Gender
WBC (cell ⁄ mm3 ) ⁄ eosinophils (%)/IgE‡
Neurologic Manifestation
Time Delay Between Diagnosis of Neurodegenerative diseases and Onset of Skin Lesions (years)
1
89/male
Erythroderma
3500/22.0/NA
Ischemic stroke
4
2
66/male
Erythroderma
10165/48.2/129
Ischemic stroke
2
3
83 /male
Erythroderma
8600/12.1/3215
Ischemic stroke
3
4
78/male
Erythroderma; Pemphigoid 6600/10.3/9609
Senile dementia; Parkinsonism
12
5
82/female
Eczematous dermatitis
5400/15.3/NA
Ischemic stroke
2
6
80/male
Eczematous dermatitis
7000/25.5/36.7
Ischemia stroke
1*
7
74/male
Erythroderma
8400/12.2/2553
Ischemic stroke
4*
8
86/male
Eczematous dermatitis
4500/12.6/144
Dementia (Alzheimer's disease)
2
9
85/male
Eczematous dermatitis
8100/10.0/1409
Dementia
2
10
82/male
Eczematous dermatitis
9190/10.7/356
Ischemic stroke
12
11
84/female
Eczematous dermatitis
4700/7.3/391
Parkinsonism
2
12
79/male
Eczematous dermatitis
6750/12.0/NA
Ischemic stroke
14
16
‡Normal range: WBC, 4800–7500 /mm3; eosinophils, 1.0–4.0%; IgE< 100 IU/mL * Onset of skin lesions prior to stroke NA: not applicable
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Figure 1.Clinical presentations and histologic examination of chronic unlocalized eczematous dermatitis in the elderly. (A,B,C ) Diffuse erythema and desquamation on chest, legs and face (Patient 3);(D) Close up view of the eczematous dermatitis (patient 10);(E) Histologic examination of the skin showed much eosinophilic dermal infiltration and epidermotropism of eosinophils (Patient 9)(Hematoxylin and eosin stain, 100X).
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