Two different pathogenetic pathways in lichen amyloidosus and macular amyloidosis

Summary In lichen amyloidosus (LA) and macular amyloidosis (MA), small amyloid deposits occur in the upper papillary dermis. Previous electron-microscopic studies have indicated an epidermal origin of the amyloid, where degenerating keratinocytes drop into the dermis and undergo transformation to amyloid. While this mechanism seems possible at least in MA, we suggest an alternative pathogenetic pathway in LA, in which amyloid fibrils seem to form on the dermal surface of living basal keratinocytes. It is possible that the different morphology of the amyloid in LA and MA is explained by partially different pathogenetic mechanisms although the amyloid in both conditions may be chemically closely related.     

Cytokeratin expression in lichen amyloidosus and macular amyloidosis

AIM: To understand the role of epidermal cells in the pathogenesis of lichen amyloidosus (LA) and macular amyloidosis (MA). METHODS: We carried out immunohistochemical investigations on cytokeratins (CKs) in amyloid deposits in formalin-fixed and paraffin-embedded tissue specimens from eight persons with LA and 12 with MA. The primary antibodies of CK1-8 (AE3), CK10 (DEK-10), CK14 (LL002), CK17 (E3), CK18 (DC10), CK19 (KS19.1), CK5/6/18 (LP34) and CK8/18 (5D3) were used in the study. RESULTS: In amyloid deposits, immunoreactivity with only two monoclonal antibodies (CK1-8 and CK5/6/18) was observed in 14 cases (eight LA and six MA), confirming the hypothesis that epidermal cells participate in amyloid formation of LA and MA. COMMENTS: All of the CKs detected in amyloid deposits were basic type (type II). It seems plausible either that acidic CKs might be degraded faster than basic types in amyloidogenesis or that paraffin-embedded tissue specimens are less sensitive than frozen tissue sections. The results of our study suggest that when paraffin-embedded specimens are investigated by immunohistochemical methods, CK5 antibody is useful in the diagnosis of LA and MA.     

Clinical effect of tocoretinate on lichen and macular amyloidosis

Lichen amyloidosis and macular amyloidosis are commonly therapy-resistant. Tocoretinate is a hybrid compound of retinoic acid and tocopherol that is commonly used for the treatment of skin ulcers. Although beneficial effect of oral retinoic acid on lichen amyloidosis is reported, tocoretinate has not been reported to be useful for the treatment of lichen amyloidosis or macular amyloidosis. We evaluated the effects of topical tocoretinate on lichen amyloidosis and macular amyloidosis lesions. Tocoretinate was topically applied daily to the lesions and clinical improvement and histological changes were evaluated. The outcome was very good for four, good for two, moderate for two and poor for two of 10 treated patients. Epidermal hypertrophy was reduced and expression of involucrin, keratin 1 and keratin 10 was decreased by tocoretinate treatment, suggesting the normalization of epidermal differentiation. Amyloid deposits remained histologically detectable, even in clinically responsive patients. Together, topical application of tocoretinate reduced the clinical symptoms of lichen amyloidosis and macular amyloidosis, and normalized disturbed epidermal differentiation.     

Lokale DMSO-Behandlung der makulösen und papulösen Amyloidose

Zusammenfassung Makul?se Amyloidose (MA) und Lichen amyloidosus (LA) sind die zwei am h?ufigsten vorkommenden Varianten der prim?r kutanen Amyloidosen, bei denen ein heftiger Juckreiz im Vordergrund der klinischen Symptomatik steht. Leider zeigen aber die verschiedenen Therapiema?nahmen wie Antihistaminika, Kortikosteroide, UVB, Etretinat, Dermabrasion usw. wenig oder keinen Erfolg. In den letzten Jahren wurde in der Literatur über die erfolgreiche Therapie mit lokalem Dimethylsulphoxid (DMSO) berichtet. In unserer Studie haben wir Patienten mit MA, LA und biphasischer Amyloidose mit 50%iger DMSO-L?sung lokal behandelt. W?hrend einer Behandlungsdauer von 6–20 Wochen wurde bei 9 von insgesamt 10 Patienten klinische Besserung erzielt. Das schnelle Ansprechen des Juckreizes auf die Therapie innerhalb der ersten Woche ist auf den die Mastzelldegranulation bzw. -depletion f?rdernden Effekt von DMSO zurückzuführen. Mittels DMSO-Therapie wurde auch eine vollst?ndige Rückbildung der lichenoiden papul?sen Effloreszenzen innerhalb von durchschnittlich 11 Wochen erzielt, welche am ehesten durch das Abklingen des Juckreizes und des damit verbundenen Kratzeffektes erkl?rt werden kann. Trotz der guten klinischen Ergebnisse war histopathologisch kein Verschwinden der Amyloidmassen festzustellen. In den weiteren Verlaufskontrollen nach Ende der Therapie wurden Rezidive der klinischen Symptomatik beobachtet, wobei weitere prospektive Studien zur Bestimmung der optimalen Behandlungsdauer notwendig erscheinen. Eingegangen am 31. Januar 1996, Angenommen am 17. Juli 1996     

Unexpected diminished innervation of epidermis and dermoepidermal junction in lichen amyloidosus

Background  Lichen amyloidosus is a localized, chronic, pruritic skin disease characterized by deposition of amyloid in the papillary dermis. The pathogenesis of the pruritus of lichen amyloidosus is largely unknown.
Objectives  To determine any change in the nerve fibre density in lichen amyloidosus lesions as an explanation for itch.
Methods  Using an antibody to protein gene product (PGP) 9.5, the immunohistochemical analysis of the skin biopsies of 30 Hispanic patients with clinicopathologically proven lichen amyloidosus and of 11 healthy Hispanic controls matched for age, sex and site was performed.
Results  Unexpectedly, the mean amount of PGP9.5 stain, a measure for nerve fibre amount, for the healthy controls was higher than the lichen amyloidosus group both in the epidermis ( P  <   0·0019) and dermoepidermal junction ( P  <   0·0064). No change was observed in the papillary dermis. Furthermore, the proportion of area covered by PGP9.5 showed a significant decrease in the epidermis ( P  <   0·0024) and dermoepidermal junction ( P  <   0·0075) in lichen amyloidosus compared with healthy controls. Age, gender and body site were found not to be influencing factors in nerve fibre amounts in lichen amyloidosus samples.
Conclusions  We speculate that the severe pruritus observed in lichen amyloidosus might be the result of the hypersensitivity of the remaining nerve fibres as a response to an unexplained neurodegeneration of the absent nerve fibres.     

Cytokeratins in primary cutaneous amyloidosis

The expression of keratins was investigated immunohistochemically on formalin-fixed and snap-frozen primary cutaneous amyloidosis tissue with a panel of monospecific and polyspecific antikeratin antibodies which recognized keratins K1, K5, K6, K7, K8, K10, K14, K16, K17, K18, and K19. Amyloid deposits in frozen section of seven cases of macular amyloidosis and lichen amyloidosus always reacted with antibodies LP34 (labeling K5, K6 and K18) MNF (labeling K5, K6, K8, K10, K17 and K18) and RCK 102 (labeling K5 and K8); frozen section in one case each of the seven cases also reacted with antibodies LL001 (labeling K14), Lp1K (labeling K7 and K17), and LP2K (labeling K19), LP1K (labelling K7 and K17), and LP2K (labelling K19), In formalin fixed section of 13 cases of macular amyloidosis and lichen amyloidosus amyloid deposits were labeled with LP34 in three section LL020 ()labelling keratins K5 and K6) in one section and LP2K in two section. In nodular primary cutaneous amyloidosis amyloid deposits were not labeled with any antikeratin antibodies. These data confirm that amyloid in macular amyloidosis and lichen amyloidosus contains keratin epitopes, and suggests derivation of the fibrillar component from keratin intermediate filaments Several different keratins appear to undergo conversion to amyloid, LP34, MNF 116 and RCK 102 antibodies, which have in common the labelling of keratin K5, may be useful in the diagnosis of macular and popular amyloidosis with frozen tissue section.     

【开放获取】度普利尤单抗治疗泛发性苔藓状淀粉样变1例国内首报

【摘要】 国内报道首例度普利尤单抗治疗泛发性苔藓状皮肤淀粉样变。患者男,70岁,躯干、四肢广泛丘疹伴瘙痒23年。皮肤科检查：躯干、右胫前、双上臂外侧见弥漫性粟粒至绿豆大小褐色半球形丘疹,质硬。血常规嗜酸性粒细胞、血清IgE未见异常。下肢皮损组织病理：表皮角化过度,真皮乳头可见均一红染的团块状物质。免疫组化刚果红染色阳性。瘙痒数字量表评分10分。诊断：泛发性苔藓状皮肤淀粉样变。治疗：皮下注射度普利尤单抗,首次600 mg,之后每2周注射300 mg。治疗第2周时,瘙痒即明显缓解,14周时皮损开始明显消退,18周时前胸、腹部皮疹基本消退,腰背部、四肢皮疹明显消退。未见明显不良反应。     

Mucocutaneous bullous amyloidosis with an unusual mixed protein composition of amyloid deposits

We describe a case of fatal systemic amyloidosis presenting with mucocutaneous bullous lesions in a patient with IgA kappa monoclonal gammopathy. The amyloid plaques were composed of an unusual mixture of immunoglobulin kappa light chain and amyloid A proteins. Whereas oesophageal and oropharyngeal blisters are known to occur in several types of bullous dermatoses, to our knowledge this is the first report of oesophagopharyngeal blisters complicating bullous amyloidosis.     

Alitretinoin treatment of lichen amyloidosis

Lichen amyloidosis (LA) is characterized by the deposition of amyloid that may respond to chronic scratching that may be secondary to atopic dermatitis, stasis dermatitis, or interface dermatitis. Despite the development of several therapeutic strategies, including topical steroids, oral antihistamines, cyclosporine, and retinoids, an effective treatment for LA has not been established. A 49‐year‐old woman who has been treated irregularly for atopic dermatitis for 7 years presented with localized brownish papules on the left forearm and right elbow. They developed 3 months prior and were becoming more prominent despite of treatment with cyclosporine, oral antihistamines, and topical steroids for 5 months prior to presentation. A skin biopsy revealed amyloid deposition in the dermal papillae and the patient was diagnosed with LA associated with atopic dermatitis. A 6‐month course of daily oral alitretinoin 30 mg produced marked improvement in the thickness and color of the hyperkeratotic papules without aggravation of the patient's atopic dermatitis. Histologic evaluation showed clearance of amyloid deposition and almost normalization of the epidermal changes. Herein, we report a case of LA treated with alitretinoin and suggest that it could be a potential treatment option for LA, especially in patients with inflammatory skin diseases including atopic dermatitis.     

Therapeutic removal of amyloid deposits in cutaneous amyloidosis by localised intra‐lesional injections of anti‐amyloid antibodies

Please cite this paper as: Therapeutic removal of amyloid deposits in cutaneous amyloidosis by localised intra‐lesional injections of anti‐amyloid antibodies. Experimental Dermatology 2010; 19 : 904–911. Abstract: In the skin, amyloidosis can be found with or without systemic disease. Primary cutaneous amyloidosis defines those amyloidoses restricted to the skin without involvement of other systems. Here, we used conformation‐specific antibodies to characterise both fibrillar and oligomeric amyloid aggregates in the skin from patients with cutaneous amyloidosis. Localised cutaneous amyloidosis with different morphology was reproduced in mice by intra‐dermal (i.d.) and subdermal administration of amyloid‐enhancing factor. Moreover, we demonstrated that conformational antibodies were effective in clearing amyloid deposits caused by localised intra‐lesional injections without the necessity of an immune response. Given the accessibility and amyloid localization in this disease, direct i.d. injections of conformational antibodies could be a convenient and direct method for treatment.     

Transcutaneous electrical nerve stimulation for reduction of pruritus in macular amyloidosis and lichen simplex

Lichen simplex (LS) is characterized by circumscribed, lichenified, pruritic patches that may develop on any part of the body. Macular amyloidosis (MA) is the form of primary localized cutaneous amyloidosis. Transcutaneous electrical nerve stimulation (TENS) uses a pulsed electric current generated transcutaneously by a device to cause impulses to be carried along large-diameter afferent nerves. In this article, we report the effects of TENS on the Dermatology Life Quality Index (DLQI) measures and visual analogue scale (VAS) scores in patients with pruritus, in whom LS and MA were diagnosed. All patients with MA and six (75%) patients with LS had relief of their pruritus with TENS therapy. At week 2, there was a significant difference in median VAS scores between baseline in the group of LS (P = 0.007). At 4 weeks of therapy, statistically significant differences were observed compared with the baseline and week 2 in the median VAS scores in the group of MA (P < 0.001). There was also a statistically significant improvement in median DLQI total scores with respect to baseline, which was achieved as early as week 2 in patients with LS and MA who were on the TENS treatment (P = 0.006, P = 0.001, respectively).     

细胞角蛋白和波形蛋白在皮肤淀粉样变淀粉样蛋白中表达的研究

目的:探讨皮肤淀粉样变淀粉样蛋白的生物学来源.方法:应用免疫组化染色技术检测4种角蛋白(cytokeratins,CKs)及波形蛋白在20例斑状或苔藓样型皮肤淀粉样变淀粉样蛋白中的表达情况.结果:①CK3413E12和CK5/6在20例标本的淀粉样蛋白团块中均呈阳性表达:而AE1/AE3、CK10/13和波形蛋白在淀粉样蛋白团块中均呈阴性表达;②淀粉样蛋白团块中波形蛋白表达阳性的成纤维细胞明显增生.结论:淀粉样蛋白主要来源于凋亡的表皮基底细胞而非真皮组织.     

Cutaneous lymphatic amyloid deposits in "Hungarian-type" familial transthyretin amyloidosis: a case report

Multiple transthyretin (TTR) mutations have recently been identified and implicated in the development of familial systemic amyloidoses, but early diagnosis of these disorders is still largely unresolved. We investigated the presence and tissue distribution of TTR-derived amyloid in skin biopsies of a 59-year-old woman carrying the "Hungarian-type" mutation of TTR (Asp18Gly). Clinical symptoms involved severe central nervous system dysfunction without signs of polyneuropathy, also referred to as the "central form" of TTR-related systemic amyloidosis. Skin biopsy was also evaluated as a tool in order to diagnose this type of TTR amyloidosis. Biopsy samples were collected from the infra-axillary region. Light microscopy using Congo red and polarized light was used to diagnose amyloid deposits. Subsequently, electron microscopic analysis was performed to correlate the amyloid deposits with vicinal dermal structures. The amyloid class was determined by means of immunocytochemistry. TTR amyloid was primarily localized to lymphatic microvessels in the present case, whereas arterioles were devoid of TTR amyloid deposits. In addition, the well-known association of TTR amyloid with neural structures along the erector pilorum and around the sebaceous and serosal (sweat) glands was also evident. Electron microscopic analysis of amyloid deposits revealed characteristic amyloid fibrils that were irregular in shape, and exhibited a heterogeneous density and a random deposition pattern. Immunocytochemistry confirmed the cutaneous accumulation of TTR amyloid. In conclusion, amyloid deposits were abundantly present in the skin of a patient with "Hungarian-type" TTR amyloidosis; skin biopsy seems to be appropriate for the diagnosis of this disorder. We showed that besides the erector pilorum, sweat glands and nerve terminals, lymphatic microvessels are also severely infiltrated by TTR amyloid. Whether these pathological alterations can exclusively be found in "Hungarian-type" TTR amyloidosis should still be investigated. If such changes are not specific for the Asp18Gly mutation, they may be considered as diagnostic markers for "central" TTR amyloid disorders.     

结节、斑疹双相型皮肤淀粉样变一例

患者女,40岁,腰、腹部结节14年,无自觉症状,进行性加重;上背部色素性斑疹,痒十余年,于1989年来我院首诊,给予手术切除并行病理检查,诊断为结节型皮肤淀粉样变.最近因腰、腹部出现新的结节、斑块,背部出现褐色斑疹,痒,再次来我院就诊.既往体健,家族中无类似病史.皮肤科检查:双肩胛间见片状褐色斑疹,轻度肥厚(图1);腰、腹、臀部数个大小不等的结节、斑块,黄豆粒至红枣大小,呈黄红色,具蜡样光泽,部分区域有萎缩、紫癜及色素沉着,质硬,无触痛(图2).     

EB病毒蛋白对抗角蛋白自身抗体产生的影响

目的　研究EB病毒 (EBV)蛋白对B细胞产生抗角蛋白自身抗体 (AKautoAb)的影响。方法　用紫外线 (UV)灭活和热处理经EBV刺激培养的人脐带血B细胞 ,因ELISA法检测培养上清中AKautoAbIgG和IgM的水平。结果　UV灭活组IgG 18天以后各时间点有显著变化 (P <0 .0 5) ,IgM 2 6天与其它时间点有显著差异 (P <0 .0 5) ;热处理组IgG和IgM无明显变化 (P >0 .0 5)。结论　UV灭活EBV可诱导抗体的产生 ,而热处理EBV却不能 ,提示EBV蛋白成分可能是诱导抗体产生因素 ,这为深入研究影响AKautoAb产生的EBV功能蛋白奠定了基础     

Papules in the auricular concha: lichen amyloidosus in a case of biphasic amyloidosis.

We present a patient with lichen amyloidosus on the ears and macular amyloidosis on the back. These diagnoses were supported by histological, histochemical and immunohistochemical studies. This is to the best of our knowledge the first reported case of a biphasic form of amyloidosis whose lichenoid counterpart consists of papules on the ears. This suggests that primary cutaneous localized amyloidosis may have peculiar clinical manifestations depending on the location of the lesion.     

伴抗基底膜自身抗体的皮肤异色症样淀粉样变病1例

报道1例伴抗基底膜自身抗体阳性的皮肤异色症样淀粉样变病,并对相关文献进行复习.患者女,22岁.面颈部、躯干、四肢出现瘙痒性红斑、水疱及弥漫性网状色素沉着性斑片8年余.皮损组织病理示：表皮角化过度,基底细胞液化变性,真皮乳头均一化物质沉积,结晶紫染色阳性;直接免疫荧光（DIF）示：基底膜带及乳头IgG、IgM、IgA和C3沉积.     

Case of primary localized cutaneous amyloidosis with protean clinical manifestations: lichen, poikiloderma-like, dyschromic and bullous variants

Primary localized cutaneous amyloidosis (PLCA) commonly presents as macular and lichen variants. We present a case of a 27-year-old Chinese woman with cutaneous features of the rarely reported poikiloderma-like, dyschromic and bullous forms of PLCA, and the commoner lichen variant. There were no syndromic associations or systemic involvement, and the various morphological subtypes occurred in isolation from one another. We review the clinical spectrum of PLCA, highlight its protean clinical manifestations in this patient, and discuss its postulated pathogenesis in relation to its histopathological features.     

伴抗基膜自身抗体的皮肤异色病样淀粉样变病

报告1例伴抗基膜自身抗体的皮肤异色病样淀粉样变病.患者男,37岁.双上肢、上腰腹部及面颈部起丘疹、红斑、张力性水疱,色素沉着和色素减退相间,无自觉症状7年.皮损组织病理学检查示表皮基膜下有红色团块样物质,淋巴细胞呈带状浸润,可见噬黑素细胞,刚果红染色阳性.直接及间接免疫荧光示基膜带有IgG、C3沉积.