Scratching below the surface for the etiology of lichen amyloidosis — no sweat?
July 10, 2017
We have all confronted patients with maddeningly pruritic, recalcitrant cases of lichen amyloidosis (LA). Establishing the diagnosis is easier than treating the disorder; understanding its pathogenesis is even more confounding.
LA is part of the spectrum of primary localized cutaneous amyloidosis (PLCA) comprised of macular amyloidosis, LA, nodular amyloidosis, and amyloidosis cutis dyschromica. Atypical variants include bullous, biphasic (macular and LA), poikilodermic, and familial forms. By definition, amyloid deposition is skin-limited, without any concern for systemic amyloidosis (as distinguished from systemic amyloidosis that may present with plaques and nodules). (1)
LA characteristically presents as multiple pruritic, firm, hyperpigmented, hyperkeratotic papules on the shins that may coalesce to a rippled pattern. With time, the papules can form thickened plaques. The differential diagnosis includes lichen simplex chronicus, lichen sclerosis et atrophicus, and prurigo nodularis. The diagnosis can usually be made clinically, particularly in patients with the classical presentation; biopsies demonstrating amyloid are confirmatory. (2)
The amyloid of LA is derived from degenerated epidermal keratinocytes, as demonstrated by immunhistochemical stains with antikeratin antibodies. (3) In certain circumstances, there may be genetic influences in the development of LA. Filaggrin (FLG) mutations are common in patients with atopic dermatitis. A novel FLG mutation has been reported in a case of LA with a rippled appearance. (4) Autosomal dominant familial forms of PLCA have been associated with mutations of the oncostatin M receptor gene and the interleukin-31 receptor RA gene. (1) Cutaneous LA may be found in up to one-third of patients with MEN2, particularly with mutations involving codon 634 of the RET gene. (5)
For most patients with LA the driving factor causing LA is intense pruritus, with the deposition of keratin-derived amyloid being a consequence, not cause, of the itch. What incites the initial itch? Shimoda et al note that according to recent studies, follicular structures are usually spared in serial histological sections of LA, and deposits of amyloid are likely to be confined to areas that display xerosis, suggesting that decreases in skin wetness by sweating disturbance seem to initiate LA. They investigated whether sweating disturbances could represent early events that trigger LA, and whether LA could be improved by resolving these. Utilizing the impression mould technique, which allowed accurate quantification of individual sweat glands/ducts actively delivering sweat, the authors examined sweat responses to a thermal stimulus (immersion of both legs below the knee in a hot water bath) in LA lesions before and after treatment with a moisturizer. The found that the sweating disturbance was most profound in the ‘hub’ structure of the LA papule, and this disturbance due to leakage of sweat, at the acrosyringeal and dermal levels, could be restored by short-term treatment with a moisturizer, particularly when used under occlusion. (6)
This is a fascinating and thought-provoking study. According to Weidner et al, therapies for PLCA have been limited predominantly to case reports or small case series. The few clinical trials have lacked control groups. A variety of treatment options for PLCA reported include retinoids, corticosteroids, cyclophosphamide, cyclosporine, amitriptyline, colchicine, cepharanthine, tacrolimus, dimethyl sulfoxide, vitamin D3 analogs, capsaicin, menthol, hydrocolloid dressings, surgical modalities, laser treatment, and phototherapy. The authors concluded that to date, no definitive recommendation of preferred therapy based on the analyzed literature can be offered. (7)
These treatments have been administered in established cases of LA. What if patients could be recognized at the earliest onset of their disease, before the presumed keratinocytic injury transforms into LA? Could the use of confocal microscopy or optical coherence tomography recognize subtle changes in the eccrine ducts of patients with dry shins who begin to itch? Only further study will answer those questions, but I congratulate Shimoda et al for opening up a new area of inquiry that may yield therapeutic benefit for those afflicted with this recalcitrant disease.
1. Suranagi VV, et al. Bullous variant of familial biphasic lichen amyloidosis: A unique combination of three rare presentations. Indian J Dermatol 2015; 60: 105.
2. Ladizinski B, Lee KC. Lichen amyloidosis. CMAJ 2014; 186: 532.
3. Oiso N, et al. Successful treatment of lichen amyloidosis associated with atopic dermatitis using a combination of narrow band ultraviolet B phototherapy, topical corticosteroids, and an antihistamine. Clin Exp Dermatol 2009; e833-6.
4. Kono M, et al. Ripple-pattern lichen amyloidosis in a case of icthhyosis vulgaris with a novel FLG mutation. J Eur Acad Dermatol Venereol 2017; 31: e130-2.
5. DeSousa SMC, McCormack AI. Cutaneous lichen amyloidosis in multiple endocrine neoplasia. Intern Med J 2016; 46: 116-7.
6. Shimoda Y, et al. Lichen amyloidosis as a sweat gland/duct-related disorder: resolution associated with restoration of sweating disturbance. Br J Dermatol 2017; 176: 1308-15.
7. Weidner T, et al. Primary localized cutaneous amyloidosis: A systematic treatment review. Am J Clin Dermatol 2017; Mar 24 [Epub ahead of print]
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