Cutaneous amyloidoses and pruritus

The relationship between cutaneous amyloidosis and itching works both ways:

• Chronic itching can contribute to the development of cutaneous amyloidosis (friction amyloidosis).
• Conversely, amyloidosis can sustain or exacerbate the itching.

This creates a self-perpetuating neuroepidermal cycle.

The pathogenic process begins with amyloid formation in keratinocytes

In cutaneous amyloidoses, particularly lichen amyloidosus and macular cutaneous amyloidosis, the amyloid deposited in the dermis originates predominantly from degenerated epidermal keratinocytes. The pathogenetic process can be reconstructed as follows: 

• Chronic pruritus leads to repeated scratching and rubbing.
• This mechanical stress damages basal keratinocytes and promotes their apoptosis.
• Keratin components enter the papillary dermis.
• There, keratin-associated amyloid fibrils (amyloid K) are formed and deposited extracellularly.

These amyloid deposits may be associated with changes in cutaneous nerve fibers and persistent pruritus.

The Pathogenic Vicious Cycle

• Pruritus
• Neuroepidermal dysregulation
• Chronic scratching and rubbing
• Mechanical damage to basal keratinocytes
• Keratinocyte degeneration
• Release and transformation of keratin-associated proteins
• Amyloid deposition in the papillary dermis
• Neuroepidermal changes
• Possible exacerbation of pruritus and renewed scratching
• Feedback loop leading to pruritus

Why does cutaneous amyloidosis cause itching?

Several mechanisms are under discussion.

• A. Neuropathic component: Changes in the intraepidermal nerve fibers have been described in cutaneous amyloidosis. These include a reduced nerve fiber density and structural changes in epidermal nerve endings. Such damage may be associated with neuropathic pruritus. However, it has not been conclusively determined to what extent these changes are the cause or the consequence of chronic scratching.
• B. Genetics:IL-31 and neuroimmunological signaling: Genetic studies of familial forms of primary localized cutaneous amyloidosis are particularly revealing. Mutations in two genes have been identified:
  • OSMR: encodes the oncostatin M receptor β subunit.
  • IL31RA: encodes the α subunit of the interleukin-31 receptor.
  • Both receptor components are involved in the signaling of IL-31, an important pruritogenic cytokine. The functional IL-31 receptor consists of IL-31RA and OSMRβ. IL-31 can activate sensory neurons via this receptor complex and mediate itching. It is noteworthy that certain disease-associated mutations impair receptor function. Itch cannot therefore be explained simply by increased IL-31 signaling. Changes in epidermal homeostasis and neuroepidermal communication likely play an additional role.

Epidermal Damage and Inflammation:

• Repeated scratching causes a mechanical disruption of the skin barrier. This can result in secondary inflammatory reactions and the release of pruritogenic mediators. These processes promote further sensitization of cutaneous nerve endings and thus the chronicity of pruritus.

Lichen amyloidosus: Usually marked, chronic itching; frequently pruritic papules on the lower legs

Macular cutaneous amyloidosis: Variable pruritus; frequently in the interscapular region

Nodular cutaneous amyloidosis: Often no pruritus or only mild pruritus; different amyloid composition, predominantly immunoglobulin light chains.

Secondary cutaneous amyloid deposits: Pruritus depends on the underlying dermatosis

Notalgia paresthetica: Notalgia paresthetica is characterized by primarily neuropathic pruritus, usually in the interscapular region. Chronic scratching and rubbing can lead to localized hyperpigmentation and, occasionally, to secondary cutaneous amyloid deposits. Thus, notalgia paraesthetica serves as a clear example of how neuropathic itching can precede amyloid formation rather than being triggered by it.

1. Arita K et al. (2008) Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis. American Journal of Human Genetics 82:73–80.
2. Soriano LF et al. (2018) An intensely pruritic pebbled presentation. Dermatol Online J 24:13030/qt6tp6f9c4.
3. Tanaka A et al. (2009) Oncostatin M receptor-beta mutations in familial primary cutaneous amyloidosis. American Journal of Human Genetics. 2009;85:542–548.
4. Tey HL et al. (2011) Targeted treatment of pruritus: a look into the future. British Journal of Dermatology 165:5–17.