Cutaneous lupus erythematosus: new insights into pathogenesis and therapeutic strategies

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Abstract

Cutaneous lupus erythematosus (CLE) is an autoimmune disease that can present as an isolated skin disease or as a manifestation within the spectrum of systemic lupus erythematosus. The clinical spectrum of CLE is broad, ranging from isolated discoid plaques to widespread skin lesions. Histologically, skin lesions present as interface dermatitis (inflammation of the skin mediated by anti-epidermal responses), which is orchestrated by type I and type III interferon-regulated cytokines and chemokines. Both innate and adaptive immune pathways are strongly activated in the formation of skin lesions owing to continuous re-activation of innate pathways via pattern recognition receptors (PRRs). These insights into the molecular pathogenesis of skin lesions in CLE have improved our understanding of the mechanisms underlying established therapies and have triggered the development of targeted treatment strategies that focus on immune cells (for example, B cells, T cells or plasmacytoid dendritic cells), as well as immune response pathways (for example, PRR signalling, Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signalling and nuclear factor-κB signalling) and their cytokines and chemokines (for example, type I interferons, CXC-chemokine ligand 10 (CXCL10), IL-6 and IL-12).

Key points

  • Cutaneous lupus erythematosus (CLE) occurs as isolated skin disease or in the context of systemic lupus erythematosus.

  • Skin lesions in CLE are characterized by an interferon-orchestrated cytotoxic anti-epidermal immune response (known as interface dermatitis).

  • Genetic variations in immune-regulation genes (such as genes involved in the type I interferon pathway, cell death, clearance of cell debris, antigen presentation, antibody production and immune cell regulation) predispose individuals to CLE.

  • The chronic pathological cycle of CLE is fuelled by a continuous re-activation of innate immune pathways through adaptive effector mechanisms.

  • Pharmacological inhibition of both adaptive and innate immune responses can be effective in the treatment of patients with CLE.

  • New treatment strategies are being developed that mainly target type I interferon-producing cells (such as plasmacytoid dendritic cells) and their pathways (such as IFNAR or Janus kinase signalling).

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Fig. 1: Cutaneous lupus erythematosus subtypes.
Fig. 2: Pro-inflammatory cycle within CLE lesions.
Fig. 3: Overview of pro-inflammatory pathways within CLE lesions.
Fig. 4: Model for the reactivation of innate pathways in CLE.
Fig. 5: Therapeutic targets in CLE.

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Correspondence to Joerg Wenzel.

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Competing interests

J.W. declares that he has received financial support from GSK (for clinical studies, investigator-initiated trials and advisory board fees), Incyte (for investigator-initiated trials), Spirig (for an investigator-initiated trial), Medac (for advisory board fees), Actelion (for advisory board fees), Celgene (for advisory board fees), Biogen (for advisory board fees), Roche (for advisory board fees and clinical studies), Leo (for advisory board fees and clinical studies), Merck Serono (for clinical studies) and ArrayBio (for clinical studies).

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Nature Reviews Rheumatology thanks M. Caproni, F. Furukawa and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Interface dermatitis

Cytotoxic, anti-epithelial inflammation at the dermo-epidermal junction, characterized by hydropic degeneration, keratinocytic cell death and colloid bodies

Papulosquamous

A medium-sized (3–10 mm) elevated skin lesion with scaling

Psoriasiform

A ‘psoriasis-like’, well-circumscribed, elevated skin lesion with scaling

Annular

A ring-shaped skin lesion

Polycyclic

Skin lesions formed of several erythematous rings

Erythrosquamous

A red and scaling skin lesion

Bullae

Large blisters (>1 cm)

Target lesions

Annular skin lesions with similarity to an archer’s bullseye with a central papule or vesicle, surrounded by pale oedema, and a peripheral ring-shaped erythema

Colloid bodies

Pale, hyaline residue material derived from dead keratinocytes seen in the lower epidermis and the upper dermis (also known as Civatte bodies)

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