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).
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).
Lupus erythematosus is an autoimmune disease that has a large spectrum of manifestations ranging from skin lesions to systemic manifestations (systemic lupus erythematosus (SLE)). Cutaneous lupus erythematosus (CLE) can present as an isolated skin disease or as a manifestation within the spectrum of SLE1,2,3. CLE-specific cutaneous manifestations are characterized by clinical features (for example, a butterfly rash and ultraviolet (UV) light-induced skin lesions), serological features (for example, antinuclear antibodies (ANAs), particularly anti-SSA/Ro and anti-SSB/La antibodies) and histological features (for example, interface dermatitis alongside the expression of interferon-regulated chemokines)1,3. CLE-specific skin lesions can be subdivided into four subsets, based on clinical and histological features: acute CLE (ACLE), subacute CLE (SCLE), intermittent CLE (ICLE) and chronic CLE (CCLE)4 (Fig. 1; Supplementary Fig. 1). In addition to these CLE-specific skin lesions, patients with CLE might also have other skin lesions that are not specific to this disease and that can present in any autoimmune disease, such as alopecia or vascular disorders5.
In Europe and the USA, the incidence of isolated CLE is ~4 cases per 100,000 persons per year, which is slightly higher than the incidence of SLE (~3 cases per 100,000 persons per year)6,7,8,9. Skin involvement occurs in 70–80% of all patients with SLE during the course of their disease and skin lesions are the first disease manifestation to present in 20–25% of patients with SLE8. The involvement of internal organ systems can complicate CLE, irrespective of subtype. The rate of systemic manifestations depends on the underlying subtype of CLE; for example, ACLE has the highest rate of systemic involvement (~90%), whereas localized chronic discoid lupus erythematosus (CDLE) has the lowest (<5%)7,10.
This Review provides an overview of the characteristic clinical and pathological findings in CLE and introduces the established standard therapies. Also discussed are new advances in our understanding of the molecular pathogenesis of CLE, as well as the emerging therapeutic strategies based on these new findings.
Skin lesions in CLE
The clinical features and prognosis of CLE-specific skin lesions vary4 (Table 1). ACLE can manifest as two main distinct forms: ACLE with localized, indurated erythematous lesions in the malar areas of the face (known as butterfly rash) or ACLE with widespread erythema, predominantly in sun-exposed areas of the skin (known as maculopapular rash). ACLE has a very close association with SLE (in that many patients develop systemic disease) and is often accompanied by typical type I interferon-mediated general symptoms such as fever and fatigue. The close association of ACLE with SLE is also reflected by the high proportion of patients with ANAs (~80%) or anti-double-stranded DNA antibodies (30–40%)7 (the distribution of subtypes are shown in Supplementary Figure 1).
SCLE can also occur as two major clinical forms: one characterized by papulosquamous or psoriasiform skin lesions, and the other by annular or polycyclic lesions. In both SCLE variants, skin lesions occur mainly in sun-exposed skin areas of the neck, shoulders, arms and/or legs, but not often the face. A high proportion of patients with SCLE have UV-associated autoantibodies (anti-SSA/Ro antibodies in 70–80% of patients and anti-SSB/La antibodies in 30–40% of patients), and between 20% and 30% of all patients with SCLE meet the criteria for systemic disease, for which the presence of nephritis and arthritis is common1,7.
ICLE (also known as lupus erythematosus tumidus (LET)) is characterized by non-scarring and non-scaling skin lesions in sun-exposed areas of the skin, which present histologically with large clusters of plasmacytoid dendritic cells (pDCs) and mucin deposition11. Despite the high photosensitivity of patients with ICLE, anti-SSA/Ro and anti-SSB/La antibodies are rare (10–20% of patients) and patients with ICLE rarely develop systemic features of SLE (<5%)7. The classification of this subtype as a separate CLE subset is still under debate and ICLE has also been regarded as a subset of CCLE12.
CCLE is characterized by a chronic clinical course (month to years) and a slow progression. The main CCLE variants are CDLE (which is the largest group (~50% of patients with CCLE)), lupus erythematosus profundus (also known as lupus erythematosus panniculitis or Kaposi–Irgang) and chilblain lupus erythematosus (ChLE). CDLE skin lesions are characterized by scarring erythrosquamous plaques accompanied by adherent scale formation, often with a disc-like (discoid) shape. CDLE can be localized (localized CDLE: affecting the skin of the head and face) or disseminated (disseminated CDLE: affecting the skin above and below the neck). CDLE might also present with extensive hyperkeratosis (hypertrophic CDLE). Only ~50% of all patients with CDLE are ANA-positive, and many patients develop systemic features of SLE (5–18% of patients)1,6,7,13. Lupus erythematosus profundus is a rare subtype of CCLE and involves lesions of the subcutaneous fat tissue1,7 whereas ChLE is a rare acral variant of CCLE that typically affects the fingers, toes, ears and nose1,7.
Other rare variants of CLE include bullous acute lupus erythematosus (characterized by subepidermal bullae), Rowell syndrome (with erythema multiforme-like target lesions), neonatal CLE (in newborn children) and mucocutaneous lupus erythematosus (with oral ulcers, plaques and/or discoid lesions)14,15,16.
CLE-specific skin lesions usually have a typical histological pattern, called interface dermatitis, which presents as an anti-epidermal immune reaction that includes the presence of cytotoxic CXC-chemokine receptor 3-positive (CXCR3+) lymphocytes17 and apoptotic or necroptotic keratinocytes (colloid bodies)18,19. In combination with clinical findings, histology therefore helps to establish the exact diagnosis in individual cases20. CLE skin lesions are characterized by a strong expression of interferon-regulated cytokines and chemokines17, as well as the presence of two major type I and type III interferon producers: pDCs and keratinocytes21,22,23. Cytotoxic CXCR3+ lymphocytes are recruited to the lesion via the corresponding chemokine CXC-chemokine ligand 10 (CXCL10), which is specifically expressed in the lower epidermis of active skin lesions, promoting keratinocytic cell death24 (the main immunohistological features of CLE-specific skin lesions are shown in Supplementary Figure 2). The detection of a band of localized granular deposits of C3 and immunoglobulins (particularly IgG), known as a ‘lupus band’, by direct immunofluorescence can help to confirm a diagnosis of CLE in unclear clinical cases25.
Other skin lesions
A large spectrum of cutaneous disorders exist that can occur in CLE as well as in the context of other autoimmune diseases (Box 1; examples of these other skin lesions are shown in Supplementary Figure 3). In general, these lesions can be subdivided into two groups: vascular disorders, which include a wide spectrum of disorders ranging from dysfunction of single vessels to vascular ulcers, and disorders of the hair follicle (alopecia). Typical clinical manifestations are livedo racemosa, leukocytoclastic vasculitis, urticarial vasculitis, Raynaud phenomenon, vasculopathy, thrombophlebitis, periungual erythema and telangiectasia, fingertip necrosis and skin ulcers26,27. Diseases of the hair follicle include alopecia areata and telogen effluvium (known as lupus hair)28.
Molecular pathogenesis of CLE
In genetically susceptible individuals, different environmental factors can activate innate and adaptive immune responses and induce the development of CLE skin lesions. In patients with CLE, skin lesions are characterized by an anti-epithelial cytotoxic immune response, which promotes the release of cell debris and in turn re-activates innate immune pathways, leading to a pro-inflammatory self-amplifying cycle (Fig. 2). At first, autoantibodies were proposed to make a major contribution to this pathway; in this model, a primary trigger, such as UV light, causes keratinocytes to undergo cell death and present nuclear antigens on their surface, which are subsequently recognized by circulating autoantibodies29. This model explains the development of skin lesions and the photosensitivity in patients with pre-existing autoantibodies, but it is based on the assumption of pre-existing autoantibodies and fails to explain the pathogenesis in autoantibody-negative patients3,30.
Particularly in solitary CDLE, which is characterized by a high proportion of autoantibody-negative patients, the pathogenetic function of autoantibodies and B cells is under discussion31. There is, however, strong evidence for a function of cytotoxic T cell-mediated immune reaction directed against the epidermis, as these cells can cause keratinocytic cell death and release of nuclear antigens32,33,34. In this context, B cells might function primarily as antigen-presenting cells that prime autoreactive T cell activation35. Moreover, some evidence suggests that keratinocytes themselves participate in the lesional self-perpetuating cycle by producing type I and III interferons and interferon-regulated pro-inflammatory cytokines and chemokines21,22,31. These observations have led to a broader pathogenetic model encompassing both adaptive and innate mechanisms (Fig. 2).
CLE is a multifactorial disease that occurs within families and between twins, suggesting that genetic factors have a strong contribution36. To date, only one monogenetic variant of CLE has been identified: a rare familial ChLE variant characterized by a mutation in TREX1. TREX1 is a cytosolic DNase and deficiency of TREX1 leads to chronic hyperactivation of the type I interferon system via cytosolic DNA recognition pathways37. Moreover, several additional genetic associations, mutations and gene polymorphisms have been identified in different CLE populations38 (Table 2). Most of these factors are functionally relevant, as they are involved in innate or adaptive immune responses, including the type I interferon pathway, cell death, clearance of cell debris, antigen presentation, antibody production and immune cell regulation.
UV light is the most well-established provocation factor for CLE. Approximately 60–80% of patients with SLE have photosensitive skin lesions7,39. UV irradiation induces cellular damage resulting in pro-inflammatory responses, including cell death, the release of reactive oxygen species and distinct DNA modifications (such as an increase in the level of pro-inflammatory 8-hydroxyguanine (8-OHG), a marker of oxidative damage in DNA)40. In addition, UV light stimulates the release of pro-inflammatory factors from mast cells, which are increased in number within CLE skin lesions41,42. A disease-associated genetic background seems to be crucial for the development of skin lesions following UV exposure: in a prospective analysis, only patients with SLE and not healthy individuals developed CLE-like skin disease with a lesional type I interferon signature after UV provocation43 and, importantly, UV irradiation upregulated interferon-related and MHC-related genes in the skin of patients with CLE but not in that of healthy individuals in a prospective gene expression study44.
Cigarette smoke is another important environmental factor for CLE45. In CLE, smokers have notably higher Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) scores than non-smokers, and they need higher doses of immunoregulatory drugs to treat their disease46. Cigarette smoke can promote several pro-inflammatory processes involved in the pathogenesis of CLE, including neutrophil activation, neutrophil extracellular trap formation, cellular stress and apoptosis, thus fuelling disease activity47.
Drug-induced SLE, which includes induction of CLE-like skin lesions, is a well-known adverse effect of several agents. Drugs traditionally associated with drug-induced SLE (for example, procainamide, hydralazine, quinidine and omeprazole) have been reported to directly activate the innate immune system or indirectly activate this system by inhibiting the clearance of autoantigens48,49,50. TNF-blocking agents can also induce SLE-like adverse effects (including the induction of CLE-like lesions)51,52, which is probably because of the inhibition of the TNF-mediated regulation of the interferon system, leading to upregulation of interferon-associated pro-inflammatory factors and interferon-driven disease53. Recombinant type I interferons can also induce CLE-like skin lesions at the injection site, supporting a direct pathophysiological function of type I interferons in CLE54. Finally, immune stimulators such as checkpoint inhibitors have also been added to the list of potentially SLE-inducing drugs55.
Gene expression patterns
The expression of type I interferon-regulated pro-inflammatory cytokines is a hallmark of CLE skin lesions22,56. Gene expression analyses have helped to form a detailed picture of the functional pathways activated in CLE skin lesions21,22,57. These analyses have revealed simultaneous activation of innate and adaptive immune pathways in the skin of patients with CLE21,58 (Fig. 3). Genes encoding pro-inflammatory cytokines and chemokines are the most prominent subset within the innate pathways in CLE skin lesions. These pathways also include a large number of genes involved in DNA recognition and RNA recognition accompanied by genes involved in cell death pathways and complement activation. Genes relating to adaptive immune pathways include those involved in leukocyte migration, T cell and B cell activation, and antigen presentation. Gene expression signatures of CLE are also closely associated with not only other autoimmune diseases (such as SLE, rheumatoid arthritis, thyroid disease and inflammatory bowel disease) but also with type I interferon-mediated anti-viral responses (for example, responses to herpes simplex or influenza) and anti-epithelial disorders (for example, graft-versus-host disease and allograft reaction)21, supporting the classification of CLE as an interferon-driven, cytotoxic autoimmune disease59.
Molecular insights from mouse models
The contribution of cytotoxic interferon-associated inflammation, driven by innate immune mechanisms, in the pathogenesis of CLE is supported by findings in mouse models. The number of type I interferon-producing pDCs is increased in UV-induced skin lesions in lupus-prone MRL/lpr mice compared with non-lesional skin60. The mice also develop skin lesions after injection of IgG immune complexes61. Furthermore, activation of the innate immune response via Toll-like receptor 7 (TLR7) agonists aggravates skin disease in these mice, whereas inhibitors of the downstream pathway molecule MyD88 improve the skin condition62.
In Tlr9–/– mice, the pro-apoptotic FAS ligand promotes CLE-like, interferon-driven skin inflammation, which notably improves following treatment with the anti-IFNAR1 antibody MAR1-5A3 (ref.63). CLE-like skin inflammation is also increased in Trex1–/– mice21,64, and in mice with a mutated form of Janus kinase 1 (JAK1) that leads to increased activation of the JAK–signal transducer and activator of transcription (STAT) pathway65.
Activation of innate immune pathways
Immune complexes can activate receptors of the innate immune system and can contribute to CLE pathogenesis. For example, immune complexes of autoantibodies with RNA and/or DNA can be taken up by pDCs via CD32-mediated endocytosis66; the nucleic acid components of these immune complexes activate type I interferon production via binding to TLR7 or TLR9 in the endosome66,67,68 (Fig. 4). This mechanism could explain the continuous reactivation of the innate immune system in pDCs by adaptive immune mechanisms in CLE, which leads to the parallel activation of both arms of the immune system69.
This hyperactivation of the innate immune pathways promotes lesional inflammation and also induces upregulation of CLE-typical autoimmune nuclear autoantigens, including SSA/Ro52 (which are interferon-inducible proteins)70. These autoantigens are recognized by adaptive immune mechanisms, resulting in the induction of autoantigen-specific cytotoxic T cells and autoantibodies produced by plasma cells. This process, however, might not explain how keratinocytes (which are crucial to the development of CLE skin lesions) contribute to the development of CLE skin lesions, and many patients with CLE lack autoantibodies7. Moreover, keratinocytes, as classical non-immune cells, have a different expression pattern of pattern recognition receptors (PRRs) and respond particularly to (TLR-independent) ligands that bind to cytosolic PRRs71,72.
Keratinocytes participate in lesional inflammation in CLE by producing type I and type III interferons, particularly IFNκ and IFNλ, and interferon-regulated pro-inflammatory cytokines and chemokines (such as CXCL10)21,22,23. These interferons promote an autocrine feedback loop that increases the capacity of lesional keratinocytes to produce pro-inflammatory cytokines, including IL-6 (ref.73). UV light upregulates the expression of autoantigens such as Ro52 in keratinocytes and activates several pro-inflammatory pathways2,74. Morphologically, UV irradiation induces the expression of immunogenic 8-OHG nucleic acid motifs, together with the expression of pro-inflammatory cytokines, and promotes keratinocytic cell death within the whole epidermal layer75. In established lesions, however, this morphological pattern changes completely: dying cells and pro-inflammatory chemokines, particularly CXCL10, are found exclusively at the dermo-epidermal junction in inflamed areas, reflecting CLE-typical interface dermatitis17. These pro-inflammatory chemokines (including the CXCR3 ligands CXCL9, CXCL10 and CXCL11) initiate the recruitment of cytotoxic type I immune cells to the lesion via CXCR3 (ref.76), which supports lesional keratinocytic cell death, most probably via keratinocyte necroptosis19. The dying cells release debris including endogenous immunostimulatory nucleic acids, which can activate innate immune pathways in lesional keratinocytes via different PRRs (including MDA5, RIG-I and cGAS–STING)21. Immunostimulatory nucleic acid motifs from dying keratinocytes can accumulate within CLE lesions because of defects in phagocytic or enzymatic DNA clearance (for example, because of genetic or pharmaceutical predisposing factors)50,77. These endogenous immunostimulatory nucleic acid motifs can function as ligands for PRRs, and can drive interferon responses (for example, via the cGAS–STING pathway)21,40,78,79 and activate the inflammasome (most probably via AIM2)80,81. 8-OHG-DNA and other DNA motifs are detectable in the cytosol of keratinocytes of patients with CLE, supporting the function of non-TLR cytosolic receptors in these cells in CLE21. Extracellular nucleic acid motifs are able to reach the cytosol by lipofection mediated by the antimicrobial peptide cathelicidin, which is present in CLE skin lesions and can function as an endogenous lipofection vector21,82,83. The identification of these lesional pathways and the molecular mechanisms of CLE increases the understanding of the function of established treatments in CLE and opens the door to targeted therapy strategies.
Treatment of CLE
Established therapies and guidelines
To date, no drug has been approved specifically for the treatment of CLE. Therefore, established therapeutic strategies are mainly based on a low level of evidence. Existing guidelines focus on the use of topical agents, anti-malarial drugs, glucocorticoids and classic immunosuppressive drugs for the treatment of CLE25,84,85.
Topical treatment: sunscreen and topical immunosuppressive drugs
As UV light is one of the most important triggers for CLE skin lesions7, effective sunscreen is vital. Broad-spectrum liposomal sunscreen can prevent the development of skin lesions in patients with CLE43,86. Moreover, the use of sun-blocking agents also decreases the expression of type I and type III interferons and associated cytokines and chemokines (such as CXCL10) in the skin, thus reducing systemic inflammation in these patients75.
Topical glucocorticoids are the first-line treatment for CLE lesions because of their anti-inflammatory properties25,45. The primary indication for topical glucocorticoids is a localized CDLE, but patients with widespread CDLE lesions and other CLE subsets also benefit from topical immunosuppression as an add-on to systemic treatment85. Topical calcineurin inhibitors (such as tacrolimus ointment and pimecrolimus cream) are not approved for the treatment of CLE, but are the most established therapeutic alternative to corticosteroids in CLE25,45. Unlike corticosteroids, these inhibitors do not induce skin atrophy as an adverse effect, but they are also less effective than corticosteroids87.
Established systemic treatment in CLE
In current guidelines, antimalarial drugs and glucocorticoids are both recommended as first-line treatment in patients with highly active or widespread lesions25,84,85. Antimalarial drugs (such as chloroquine, hydroxychloroquine and quinacrine) are the most frequently used systemic drugs in CLE: about 80% of all patients with active CLE were reported to receive either chloroquine or hydroxychloroquine in a large European cohort of >1,000 patients64. The mode of action of antimalarial drugs is still under investigation, but all of these antimalarial drugs inhibit type I interferon production by immune-activated peripheral blood mononuclear cells88. For chloroquine and hydrochloroquine, evidence suggests two main mechanisms underlying the therapeutic effects of these drugs in CLE: the inhibition of antigen presentation by dendritic cells and the direct binding of immunostimulatory nucleic acid motifs89,90. By contrast, quinacrine inhibits TLR-mediated production of TNF and IL-6 by immune cells88,91.
The use of systemic glucocorticoids is recommended in severe or widespread active CLE lesions, but should be tapered as soon as possible to minimalize adverse effects25. Because of the adverse effects of sun protection (decreased vitamin D production) and corticosteroids (enhanced risk of osteoporosis), the European Academy of Dermatology and Venereology guidelines recommend vitamin D supplementation for all patients with CLE25.
In patients with long-standing disease or high disease activity the use of other immunosuppressive and immunomodulatory drugs might be indicated45. Methotrexate, retinoids and dapsone are considered as second-line treatments25. Methotrexate is recommended for use in refractory CLE, primarily SCLE92, dapsone for recalcitrant CLE and bullous lupus erythematosus93, and retinoids for selected patients with CLE (particularly patients with hypertrophic CDLE) when they are unresponsive to other treatments94. All other drugs, including mycophenolate mofetil and cyclosporine, are currently regarded as third-line therapies because of the lack of clinical studies in CLE25.
Most of the second-line and third-line therapies are corticosteroid-sparing drugs and inhibit the proliferation of T cells and B cells, but these drugs also have additional effects that might support their efficacy in CLE45,85. For example, methotrexate not only downregulates the expression of several adhesion molecules that promote lymphocyte migration into the skin but also reduces antigen presentation, blocks activation of neutrophilic granulocytes95 and inhibits the JAK–STAT pathway96.
Targeted therapy strategies in CLE
In parallel to the growing knowledge about the molecular mechanisms within the past decade, several biologic drugs and other targeted drugs have been introduced into the treatment of CLE or are currently being tested in clinical and preclinical studies (Table 3). These drugs target either immune cells, particularly B cells and T cells but also pDCs, or pro-inflammatory mediators97,98,99 (Fig. 5).
Therapies targeting B cells
B cells, plasma cells and their activation pathways were an early focus of targeted treatment strategies in CLE because of their function in the production of autoantibodies99. The first of these studies was performed with rituximab, an anti-CD20 B cell-depleting antibody. Despite rituximab showing some effect on CLE disease activity in initial studies100, larger studies failed to support the efficacy of this drug in most subtypes of CLE101. In specific CLE subsets (including ACLE and bullous lupus erythematosus), rituximab was reported to be effective99, but the drug also induced new-onset CDLE and SCLE in patients with SLE102.
Belimumab is a monoclonal antibody against B cell-activating factor (BAFF, also known as BlyS) that was approved for the treatment of SLE by the FDA in 2011 (ref.99). The original registration trial in SLE did not include a specific skin score as an outcome, but several case reports and case series have suggested a positive effect of belimumab in CLE103,104. The efficacy of belimumab in CLE is also currently being investigated in a phase III clinical trial105. BAFF is one of the interferon-regulated cytokines produced by keratinocytes in CLE after stimulation of PRRs and might therefore have an important function in the feedback loop between innate and adaptive immune systems in lesional skin106.
Atacicept, a TACI-Fc fusion protein that binds to BAFF and TACI, can reduce the severity of flares in patients with SLE and high disease activity, but data on CLE are still lacking107. Several other agents that deplete B cells (for example, the humanized anti-CD19 antibody obexelimab (also known as XmAb5871); the anti-CD20 antibodies obinutuzumab and ocrelizumab; and the anti-CD22 antibody epratuzumab) or inhibit B cell activation (for example, the anti-BAFF antibody tabalumab; the bispecific molecule AMG 570 that targets both ICOSL and BAFF; and the TACI antibody fusion protein RC18) are currently under investigation in clinical trials for SLE and might also provide new insights for the treatment of skin lesions98.
Proteasome inhibitors target plasma cells, which are the source of autoantibodies in SLE and CLE. Two of these drugs, bortezomib and ixazomib, have been investigated in recent clinical trials on SLE and are still under investigation108,109. These drugs might be an option for refractory SLE, but need to be combined with targeted B cell therapies for sustained responses110. The potential benefit of these drugs in CLE is controversial, as some evidence suggests that a possible adverse effect of bortezomib might be the development of CLE-like lesions111.
Therapies targeting T cells
SLE has traditionally been classified as a B cell-mediated disease because of its characteristic autoantibody production33. B cells, however, need T helper cells to become activated112. Effector T cells are responsible for most of the direct cell damage in SLE, and defects of regulatory T cells seem to be responsible for disease progression in many patients33. These data suggest T cells as potential targets in SLE99,113.
Calcineurin inhibitors suppress T cell activation and among these inhibitors, cyclosporine has been used to treat recalcitrant CLE for decades114. However, placebo-controlled studies are not available and the use of this drug is limited by its adverse effects (for example, nephrotoxicity and hypertension) and pharmacodynamical variabilities115. Cyclosporin is therefore not recommended for the treatment of patients with CLE without systemic organ involvement in current guidelines25. Voclosporin, a calcineurin inhibitor with greater metabolic stability than cyclosporin, is effective in treating lupus nephritis, and could also be a potential drug to test in future trials of CLE116. In SLE, defects in regulatory T cells lead to unchecked immune responses113. The administration of low-dose IL-2 might have the capacity to correct these regulatory T cell defects117 and is currently under investigation for the treatment of SLE118 (although the relevance for CLE is as yet unclear).
Targeting B cell and T cell costimulatory molecules
B cells and T cells are co-activated by distinct pairs of stimulatory receptors and their corresponding ligands. Several inhibitors of these receptors or ligands have been investigated in clinical trials or are still under investigation in SLE (for example, BI655064 (an anti-CD40 antibody)119 and dapirolizumab pegol120 (a pegylated anti-CD40 ligand Fab′ fragment))98, and might also be effective in CLE. Abatacept is a CTLA4–IgGFc1 fusion protein that inhibits T cell activation, and is beneficial in treating some patients with refractory SLE121. This drug, however, is also reported to induce SCLE in individual cases122. The mechanisms behind this reverse phenomenon are unclear, but it might be because of the formation of autoantibodies against the CTLA4 portion of the abatacept molecule during treatment, which directly stimulates T cells in vivo and promotes the autoimmune process122.
Targeting plasmacytoid dendritic cells
pDCs are the most important cell type of the innate immune system in CLE. These cells are the main producers of type I interferons in the blood and skin lesions and amplify lesional inflammation68. In the tissue, pDCs can be identified by the expression of their specific receptor CD303 (also known as BDCA2). This receptor, which regulates the production of type I interferons, is the target structure of BIIB059, a monoclonal antibody developed for the treatment of SLE123. The efficacy of this drug in CLE is currently under investigation in an ongoing clinical trial124, with initial results indicating that BIIB059 treatment results in a decline in CLASI activity score125. A new phase I trial is also investigating the efficacy of targeting pDCs in CLE and related autoimmune diseases using VIB7734 (formerly known as MEDI-7734)126. VIB7734 is a monoclonal antibody against leukocyte immunoglobulin-like receptor subfamily A member 4 (LILRA4, also known as ILT7) that specifically targets pDCs.
Targeting the type I interferon system
Given that a strong type I interferon signature is a hallmark of SLE, interferons (especially IFNαs and IFNβ) and their common receptor (IFNAR) have been a major target in SLE drug development over the past decade. Initial studies focused on targeting IFNα, but the specific anti-IFNα antibodies (for example, sifalimumab and rontalizumab) had only a limited effect on CLE skin lesions, possibly because of the high redundancy of the different type I interferons22,127,128. The anti-IFNγ antibody AMG 811 had no notable clinical effect on patients with CDLE129. Targeting IFNAR seems to be more effective than targeting the cytokines themselves: the anti-IFNAR1 antibody anifrolumab reduced the CLASI score in patients with SLE in a phase IIb clinical study130.
Targeting the JAK–STAT pathway
The JAK–STAT pathway is crucial for the autocrine loop of type I interferons and is located upstream of important CLE-associated pathogenic pro-inflammatory cytokines and chemokines, including CXCL10 (Fig. 5). JAK inhibitors were initially developed for the treatment of haemato-oncological diseases caused by JAK mutations, in which these inhibitors (particularly ruxolitinib) had considerable immunosuppressive effects131. First clinical observations suggesting a potential efficacy of JAK inhibitors in immunological diseases closely related to CLE were reported for graft-versus-host disease132 and dermatomyositis133,134. The JAK1 and JAK2 inhibitor ruxolitinib improved skin lesions in both conditions. Ruxolitinib inhibits the expression of pro-inflammatory mediators characteristic of CLE (such as CXCl10 and CXCL11) in vitro in keratinocytes and was also effective in treating skin lesions of a patient with ChLE135,136. The JAK1 and JAK3 inhibitor tofacitinib was also effective in the treatment of another patient with ChLE64, and this inhibitor is now under investigation in a clinical trial for the treatment of CDLE137. Treatment with baricitinib, another JAK1 and JAK2 inhibitor, improved the proportion of patients with SLE achieving resolution of arthritis or rash, as measured by the SLE Disease Activity Index 2000 score, in a phase II trial; however, this effect was mainly caused by amelioration of arthritis, whereas skin severity (as measured by the CLASI) did not improve138. Currently, the JAK1 inhibitor filgotinib is under investigation in a phase II clinical trial for the treatment of female patients with active CLE139. The non-receptor tyrosine-protein kinase TYK2 (TYK2) inhibitor BMS-986165 is also being investigated for the treatment of SLE140.
Targeting spleen tyrosine kinase
Spleen tyrosine kinase (SYK) is a highly conserved tyrosine kinase that mediates several biological functions, including the regulation of innate immune responses141. For example, SYK is activated downstream of PRRs to regulate innate immune responses against several pathogens, and is also important for triggering cellular cytotoxicity in lymphocytes and in nuclear factor-κB (NF-κB) signalling-mediated expression of pro-inflammatory cytokines and chemokines142. Phosphorylated SYK is strongly expressed in CLE skin lesions143. In functional studies, the anti-SYK antibody GSK143 inhibited the expression of CLE-typical pro-inflammatory mediators, including OAS2, CXCL9 and CXCL10, in in vitro models of CLE involving 3D epidermis constructs or keratinocyte cultures143. Treatment with another SYK inhibitor, fostamatinib (also known as R788), reduced established skin disease in mouse models of CLE141. The efficacy of a topical SYK inhibitor (GSK2646264) in CLE is currently under investigation in a phase I clinical trial144, and the oral SYK-inhibitor lanraplenib (GS-9876) is being tested in parallel with filgotinib in a phase II study in female patients with moderate-to-severe CLE139.
Targeting other intracellular signalling pathways
Intracellular pathways might provide several additional potential therapeutic targets in CLE. These include the NF-κB signalling pathway and the mitogen-activated protein kinase (MAPK) signalling cascade. Iguratimod is a synthetic anti-inflammatory small-molecule drug that inhibits the activation of NF-κB and is currently under investigation for the treatment of lupus nephritis in a phase I clinical trial145. Some MAPK inhibitors have beneficial effects in mouse models of SLE (SB203580 and FR167653)146,147. Finally, dimethyl fumarate, a drug that blocks NF-κB and MAPK signalling, decreased disease activity in a small cohort of 11 patients with CLE in a phase II pilot study148.
Targeting pro-inflammatory cytokines
Several pro-inflammatory cytokines, including TNF, IL-12 and IL-6, are upregulated in the lesional skin of patients with CLE compared with non-lesional skin or the skin of healthy individuals21,149. A few case reports have suggested that TNF inhibitors, including infliximab and etanercept, can be efficacious in treating some patients with CLE150,151, but these drugs can also induce CLE-like skin lesions152. Therefore, the efficacy of anti-TNF treatment strategies in CLE is still under debate and is being investigated in a clinical trial with etanercept153. Treatment with the IL-12 and IL-23 inhibitor ustekinumab reduced the skin disease activity of patients with SLE who had a high CLASI score (CLASI ≥ 4) in a phase II clinical trial published in 2018 (ref.154). This drug has been shown to be effective in treating patients with SCLE155 and to improve mucocutaneous disease features of SLE154. However, another study has reported a case of ustekinumab-induced SCLE in a patient with pre-existing psoriasis156. Two IL-6 inhibitors (PF-04236921 (ref.157) and sirukumab158) and two inhibitors of the IL-6-receptor (MRA003US and vobarilizumab) have been tested in SLE and/or CLE without success98,159.
Detailed insights into the molecular landscape of CLE, in combination with new advances in the understanding of innate immune response pathways and their interaction with adaptive mechanisms, have revolutionized our understanding of the pathological mechanisms underlying this disease. This new insight has informed the development of new therapeutic strategies such as the modulation of B cell and T cell activation, or the inhibition of the type I interferon pathway by targeting pDCs, IFNAR or JAK–STAT signalling. Several studies of therapies that target other pro-inflammatory pathway molecules are underway and will hopefully provide more in vivo insights. From a dermatological point of view, the development of small molecules with the capacity to penetrate the skin barrier is of particular interest. These drugs might be effective as topical treatment strategies and might thus reduce systemic adverse effects in patients with CLE. Moreover, interdisciplinary cooperation might not only be able to address problems such as the systemic effects of cutaneous inflammation but will also be able to further improve the possibilities for personalized targeted therapies.
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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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- Interface dermatitis
Cytotoxic, anti-epithelial inflammation at the dermo-epidermal junction, characterized by hydropic degeneration, keratinocytic cell death and colloid bodies
A medium-sized (3–10 mm) elevated skin lesion with scaling
A ‘psoriasis-like’, well-circumscribed, elevated skin lesion with scaling
A ring-shaped skin lesion
Skin lesions formed of several erythematous rings
A red and scaling skin lesion
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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Wenzel, J. Cutaneous lupus erythematosus: new insights into pathogenesis and therapeutic strategies. Nat Rev Rheumatol 15, 519–532 (2019). https://doi.org/10.1038/s41584-019-0272-0
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