Barrier function and ultrastructure characteristics of epidermis in patients with primary cutaneous amyloidosis.

Previous studies on primary cutaneous amyloidosis (PCA) have mainly focused on exploring genetic mutation and components of amyloid in patients with PCA. However, studies on skin barrier function in PCA patients are scarce. Here, we detected the skin barrier function in PCA patients and healthy people by using noninvasive techniques and characterized ultrastructural features of PCA lesions compared with healthy people using transmission electron microscopy (TEM). The expression of proteins related to skin barrier function was examined by immunohistochemistry staining. A total of 191 patients with clinically diagnosed PCA and 168 healthy individuals were enrolled in the study. Our analysis revealed that all investigated lesion areas displayed higher transepidermal water loss and pH values, and lower Sebum levels and stratum corneum hydration levels in PCA patients compared with the same site area in healthy individuals. The TEM results showed that the intercellular spaces between the basal cells were enlarged and the number of hemidesmosomes decreased in PCA lesions. Immunohistochemical staining showed that the expression of integrin α6 and E-cadherin in PCA patients was less than that in healthy controls, while no differences in the expression of loricrin and filaggrin were observed. Our study revealed that individuals with PCA displayed skin barrier dysfunction, which may be related to alterations in epidermal ultrastructure and a decrease in the skin barrier-related protein E-cadherin. However, the molecular mechanisms underlying skin barrier dysfunction in PCA remain to be elucidated.

Immunoglobulin G4-Related Disease-Associated Dermatitis with Pruritus: A Positive Response to Dupilumab.

Immunoglobulin G4-related disease (IgG4-RD) is a rare fibro-inflammatory condition characterized by IgG4-expressing plasma cell infiltration of the skin and other organs, leading to profound itchiness. Oral corticosteroids are the first-line therapy for IgG4-RD but relapses and potential side effects are common. In this case, we discuss a patient with a hyperpigmented, scaling dermatitis on his arms, back, and chest with lichen amyloidosis (LA) that incompletely responded to corticosteroids. He had reduced quality of life secondary to chronic pruritus. Dupilumab, an IL-4 and IL-13 inhibitor, was initiated. He experienced a transient worsening, followed by complete resolution of his itch with remission of his rash. While the pathogenesis of IgG4-RD is not entirely understood, a T-helper 2 (Th2) immune response has been implicated, with interleukins (IL) 4, 5, 10, and 13 playing a role in IgG4 class switch, resulting in eosinophilia and elevated IgE. The strong response of dupilumab in this case may provide evidence in favor of the involvement of IL-4 and IL-13 in the pathogenesis of cutaneous IgG4-RD. Future clinical studies involving larger patient populations may be warranted.

Topical halometasone cream combined with fire needle pre-treatment for treatment of primary cutaneous amyloidosis: Two case reports.

BACKGROUND: Primary cutaneous amyloidosis (PCA) is a chronic metabolic skin disease that has a detrimental impact on physical and mental health. It appears as mossy papules and severe itching, which is long-term and recurrent. Traditional treatments are unsatisfactory, especially for refractory cases. Fire needle therapy, which is widely used in China, has shown good clinical efficacy, as well as advantages concerning safety and cost. Clinical reports about fire needle treatment of this disease are few at present. CASE SUMMARY: We report two older men who had developed maculopapules with itchiness on the trunk and arms for more than 10-15 years. Due to the dermatopathological findings, PCA was our primary consideration. They received topical halometasone cream and pretreatment with fire needle for 8-16 wk. Both patients showed significant improvement of lesions. Neither patient had recurrence with a minimum of 2 years of follow-up. CONCLUSION: Topical halometasone cream and pretreatment with fire needle could be a fast, safe, and economic treatment for PCA.

Lichen Amyloidosis on the Scalp: A Case Report.

Lichen amyloidosis (LA) is one form of primary cutaneous amyloidosis, presented as discrete, lichenoid papules with itching, commonly involving the extensor surfaces of extremities. Scalp involvement is rarely reported in the literature. In this study, we reported a case of LA over the crown and vertex areas of the scalp. The lesions subsided with topical clobetasol propionate/all-trans retinoic acid compound ointment treatment for 2 months and achieved significant improvement.

Multiple Indolent Asymptomatic Yellow-Orange Patches and Plaques.

An 83-year-old Caucasian male presented with a history of asymptomatic yellow-orange macules and plaques concentrated on his trunk and proximal extremities that have been slowly progressing for the past three years. A punch biopsy revealed the presence of eosinophilic amorphous and fissured material within the superficial and interstitial dermis consistent with nodular amyloidosis. With the lack of concurrent systemic symptoms and negative systemic laboratory workup, the patient was diagnosed with disseminated primary localized cutaneous nodular amyloidosis (PLCNA). Due to the possibility of developing systemic progression, serial monitoring was recommended. This case highlights an under-reported and unusual presentation of a widely distributed form of PLCNA compared to the more common localized nodular and plaque variants.

Diagnosis of Primary Cutaneous Amyloidosis by Rapid 4,6-Diamidino-2-Phenylindole Staining.

BACKGROUND: Quick and accurate diagnosis of primary cutaneous amyloidosis (PCA) may be difficult because its symptoms are often subtle and nonspecific. OBJECTIVE: We sought to review the literature on the roles of various staining methods in the diagnosis of amyloidosis and demonstrate added benefits of using rapid 4,6-diamidino-2-phenylindole (DAPI) staining in the diagnosis of PCA. METHODS: Three groups of cases, namely, PCA, neurodermatitis, and prurigo nodularis, were retrieved from a computerized pathology database for study, and their paraffin-embedded tissue blocks were cut following standard procedures. The tissue sections were stained with three stains: hematoxylin-eosin (HE), Congo red, and DAPI stains, and examined under the microscope to compare the staining patterns of these three methods. We also performed amyloid keratin and apolipoprotein E (APOE) staining on the sections of PCA in order to further support our conclusion. The PCA sections were read by junior and senior dermatopathologists for comparison. RESULTS: The sensitivity of DAPI staining for PCA was significantly higher than that of Congo red staining and HE staining (p < 0.001). This statement holds true whether the experiment was grouped in one sample or was divided into groups of junior and senior dermatopathologists (p < 0.001). The DAPI-positive staining areas, except for the nuclei, were consistent with the amyloid deposition areas. In this study, DAPI staining had a sensitivity of 98.6% and a specificity of 100%. CONCLUSION: DAPI staining could serve as a useful technique to establish the diagnosis of PCA, and its high efficacy in diagnosing PCA makes it less dependent on the experience levels of the evaluators. Additionally, the binding of DAPI to the A-T-rich sequence of double-stranded DNA suggests that amyloid may contain DNA or a similarly structured nucleic acid.

Dermoscopic Features of Lichen Amyloidosis in Caucasians-A Case Series and Literature Review.

Primary cutaneous amyloidosis (PCA) is characterized by the extracellular deposition of amyloid in the skin without systemic involvement. It comprises several clinical variants, the most common of which are macular amyloidosis (MA) and lichen amyloidosis (LA). PCA is frequently observed in Asians, while it is considered to be very rare in Caucasians. In the latter population, the condition often poses a diagnostic challenge. Dermoscopy has already been proved to be a useful, non-invasive diagnostic tool in various non-neoplastic skin diseases. In the paper, we present three Caucasian patients (skin phototypes I-II) with histologically confirmed LA. Under dermoscopy, central white hubs with grayish-brown dots and globules were observed in all three cases. Vascular structures were present in two cases and had the morphology of red globules and thick, unfocused branching lines intersecting the white hubs. A comprehensive review of the literature retrieved twelve papers presenting the dermoscopic features of PCA, including five articles on the dermoscopy of LA. The vast majority of these studies have been conducted on the Asian population, and there is a lack of data on the dermoscopic findings for patients with skin type I or II. The literature review revealed that MA and LA share several dermoscopic similarities (the presence of a white central hub and grayish dots), but also display distinct features. Compared to the dermoscopic features of LA in darker skin phototypes, our patients presented less pronounced pigmentation and more evident vascular structures. Nevertheless, further studies are needed in order to reliably evaluate the dermoscopic features of PCA in various ethnicities.

Fractional Carbon Dioxide Laser is Effective in Amelioration of Pruritus in Primary Cutaneous Amyloidosis: A Clinical and Biochemical Study.

BACKGROUND AND OBJECTIVES: Primary cutaneous amyloidosis (PCA) is a pruritic disease characterized by amyloid deposition in the skin. Interleukin-31 (IL-31) is a pruritus-mediating cytokine. Fractional carbon dioxide (CO2 ) laser has shown efficacy in the treatment of PCA regarding the clinical appearance, histological pattern, and pruritus. The aim of this study is to assess the effect of fractional CO2 laser on pruritus associated with PCA, and analyze whether this effect is related to IL-31 and IL-31 receptor (R) expression. STUDY DESIGN/MATERIALS AND METHODS: The study included 24 patients with PCA and 24 healthy controls. Each patient received four fractional CO2 laser sessions, 4 weeks apart, using the superficial ablative mode. Skin biopsies were taken from patients before and after treatment, as well as controls, for assessment of IL-31 and IL-31R by real-time polymerase chain reaction. RESULTS: Treatment resulted in significant improvement of all clinical parameters, including pruritus (P < 0.001). Patients before treatment had significantly higher IL-31 and IL-31R than controls (P = 0.000 for both). In addition, there was a statistically significant decrease in IL-31 and IL-31R after treatment than their values before treatment (P = 0.000 for both). CONCLUSION: This study confirms the therapeutic efficacy of fractional CO2 laser in treatment of PCA. Reduction of IL-31 and its receptor seems to be one of the involved mechanisms; however, its relation to improvement of pruritus is still not clear. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

Case Report: Diagnosis of Primary Cutaneous Amyloidosis Using Dermoscopy and Reflectance Confocal Microscopy.

The dermoscopy and reflectance confocal microscopy (RCM) can provide new insights for diagnosis disease as non-invasive and easy-to-use tool. We described the dermoscopy and RCM characteristics of two patients with primary cutaneous amyloidosis (PCA) respectively. The dermoscopy characteristics were as follows: brownish macules with brown or white centers surrounded by hyperpigmented blotches, and a whitish scar-like center encircled by irregular brownish hyperpigmented spots or patches. The RCM features were increased melanin deposition in the basal layer, highly refractive structures with various shapes in the enlarged papillary dermis, and the increased pleomorphic structure of the dermal papillary ring. This is the first report the dermoscopy and RCM characteristics of PCA. We hope the characteristic dermoscopy and RCM appearances would provide a basis for doctors to diagnose and intervene earlier.

Clinicopathological Study of Primary Cutaneous Amyloidosis in a Tertiary Care Center of Eastern India Reveals Insignificant Association with Friction, Scrubbing, and Photo-Exposure: How valid is the "Keratinocyte Hypothesis"?

INTRODUCTION: Primary cutaneous amyloidosis (PCA) can be classified into four principal categories: macular amyloidosis, lichen amyloidosis, biphasic, and nodular amyloidosis. Some unusual variants such as widespread diffuse hyperpigmentation without papules, poikiloderma like involvement, lesions following Blaschko's line, etc., have also been reported. However, not much data are available regarding the demography, epidemiology, clinical patterns, and distribution and histopathological findings, especially from the eastern part of India. AIMS: We conducted a cross-sectional, institution-based study to evaluate clinicopathological pattern and factors of PCA in eastern India. MATERIALS AND METHODS: We recorded clinical and histopathological findings of 100 consecutive patients of PCA presenting to a tertiary care institution of Kolkata in eastern India. RESULTS: We found female patients of PCA outnumber male (M:F =1:1.9) with majority of patients being young adults (56%) between 20 and 40 years of age. More than half (54%) of the patients were pruritic. The severity of pruritus is significantly more associated with lichenoid and biphasic variants over macular amyloidosis. Positive family history was recorded in 17% of cases. Macular variant was the most common variant constituting 48% of the total PCA. We also found that the association with history of friction and scrubbing and photo-exposure were statistically insignificant. However, duration of the disease has statistically significant association with the disease morphology. Congo red stain showed these deposits as reddish orange substance in 28 patients out of 64 patients' samples on which Congo red could be performed. CONCLUSION: Our study revealed that many concepts of pathogenesis of PCA including friction and photoexposure might have lesser importance. However, morphological types were significantly associated with the duration of the disease and symptom severity.

Comparative proteomics analysis of primary cutaneous amyloidosis.

Primary cutaneous amyloidosis (PCA) is a localized skin disorder that is characterized by the abnormal deposition of amyloid in the extracellular matrix (ECM) of the dermis. The pathogenesis of PCA is poorly understood. The objective of the present study was to survey proteome changes in PCA lesions in order to gain insight into the molecular basis and pathogenesis of PCA. Total protein from PCA lesions and normal skin tissue samples were extracted and analyzed using the isobaric tags for relative and absolute quantitation technique. The function of differentially expressed proteins in PCA were analyzed by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction analysis. The proteins that were most upregulated in PCA lesions were further analyzed by immunohistochemistry. A total of 1,032 proteins were identified in PCA lesions and control skin samples, with 51 proteins differentially expressed in PCA lesions, of which 27 were upregulated. In PCA lesions, the upregulated proteins were primarily extracellulary located. In addition, GO analysis indicated that the upregulated proteins were significantly enriched in the biological processes of epidermal development, collagen fiber organization and response to wounding (adjusted P<0.001). KEGG analysis indicated that the upregulated proteins were significantly enriched in the signaling pathways of cell communication, ECM receptor interaction and focal adhesion (adjusted P<0.001). Furthermore, the upregulated proteins were enriched in the molecular function of calcium ion binding, and the calcium binding proteins calmodulin-like protein 5, S100 calcium-binding protein A7 (S100A7)/fatty-acid binding protein and S100A8/A9 exhibited the highest levels of upregulation in PCA. This analysis of differentially expressed proteins in PCA suggests that increased focal adhesion, differentiation and wound healing is associated with the pathogenesis of PCA.

Dermoscopic features of primary cutaneous amyloidosis / 中华皮肤科杂志

Objective To describe common dermoscopic features of primary cutaneous amyloidosis (PCA),and to explore the application value of dermoscopy in assisting the diagnosis of PCA.Methods Seventeen patients with PCA were collected from Department of Dermatology of Peking Union Medical College Hospital between April 2014 and December 2016.A total of 45 skin lesions were subjected to dermoscopy,and their dermoscopic features were analyzed.Results The common dermoscopic features of PCA included central hubs,which could be white,brown or scar-like areas,various pigment structures and shiny white streaks.Dermoscopy showed that central hubs could be observed in all the lesions (100％),while white center hubs alone were observed in 14 (31％) lichenoid lesions,both white center hubs and scar -like areas in 5 (11％) lichenoid lesions,brown center hubs alone in 8 (18％) macular lesions,both white and brown center hubs in 6 (13％) lichenoid lesions and 17 (38％) macular lesions.All the lesions showed various pigment structures.Shiny white streaks were observed in 4 (9％) lichenoid lesions.Conclusion Dermoscopy has good application value in assisting the diagnosis of PCA.

Pathological Significance of CK5 Expression in Primary Cutaneous Amyloidosis / 华中科技大学学报(医学版)

Objective To analyze the pathological significance of CK5 expression in primary cutaneous amyloidosis(PCA).Methods The expression of CK5 in superficial dermis of PCA group and the control group[lichen planus(LP),lupus erythematosus(LE)]were detected by CK5 monoclonal antibody.The infiltration densities of CD3-positive T lymphocytes and CD68-positive macrophages in superficial dermis of PCA and control group were measured respectively by immunohistochemical staining using anti-CD3 antibodies and anti-CD68 antibodies.The skin lesions of PCA and control groups were analyzed by immunofluorescence to detect whether CK5 was phagocytosed by macrophages in superficial dermis.Results Totally,39 cases of PCA all were CK5-positive.Some control cases were positive.The number of CD3-positive T lymphocytes and CD68-positive macrophages in 8 cases of PCA group was lower than that of control group.The result of immunofluorescence colocalization of monoclonal anti-CK5 antibodies and anti-CD68 antibodies in 5 cases of PCA lesions was negative;that in 2 cases of LE lesions were both positive,and that in 2 cases of LP lesions were both negative.Conclusion Amyloid protein may be derived from the basal keratinocytes after interface damage.The amyloid protein deposits may be related to the number decrease or the functional defect of macrophages.

Efficacy of different modes of fractional CO2 laser in the treatment of primary cutaneous amyloidosis: A randomized clinical trial.

BACKGROUND: Primary cutaneous amyloidosis (PCA) comprises three main forms: macular, lichen, and nodular amyloidosis. The current available treatments are quite disappointing. OBJECTIVES: Assess and compare the clinical and histological changes induced by different modes of Fractional CO2 laser in treatment of PCA. PATIENTS AND METHODS: Twenty five patients with PCA (16 macular and 9 lichen amyloidosis) were treated by fractional CO2 using; superficial ablation (area A) and deep rejuvenation (area B). Each patient received 4 sessions with 4 weeks intervals. Skin biopsies were obtained from all patients at baseline and one month after the last session. Patients were assessed clinically and histologically (Congo red staining, polarized light). Patients were followed-up for 3 months after treatment. RESULTS: Both modes yielded significant reduction of pigmentation, thickness, itching, and amyloid deposits (P-value < 0.001). However, the percentage of reduction of pigmentation was significantly higher in area A (P-value = 0.003). Pain was significantly higher in area B. Significant reduction in dermal amyloid deposits denotes their trans-epidermal elimination induced by fractional photothermolysis. CONCLUSION: Both superficial and deep modes of fractional CO2 laser showed comparable efficacy in treatment of PCA. Superficial mode being better tolerated by patients, is recommended as a valid therapeutic option.