Cutaneous lupus erythematosus: new insights into pathogenesis and therapeutic strategies

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).

Introduction

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.

Fig. 1: Cutaneous lupus erythematosus subtypes.
figure1

Typical clinical and histological examples for the most common cutaneous lupus erythematosus (CLE) subsets: acute CLE (ACLE), subacute CLE (SCLE), intermittent CLE (ICLE) and chronic discoid lupus erythematosus (CDLE). a | Patients with ACLE typically have a butterfly rash on the face, and skin samples from these patients histologically show moderate interface dermatitis with some infiltrating neutrophils (magnification ×100). b | Non-scarring erythematosquamous lesions in sun-exposed skin are a typical feature of SCLE, which presents histologically as mild interface dermatitis (magnification ×100). c | ICLE presents clinically as non-scaling plaques in sun-exposed areas of the skin and histologically as patchy dermal infiltrates composed of lymphocytes and plasmacytoid dendritic cells (magnification ×50). d | Discoid lesions with central scarring are typically found in patients with CDLE, and histological samples show dense perifollicular and perivascular infiltrates combined with interface dermatitis and follicular plugging (magnification ×50).

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

Clinical classification

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).

Table 1 Subtypes of CLE

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.

Histological features

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.

Fig. 2: Pro-inflammatory cycle within CLE lesions.
figure2

Against the background of predisposing genetic factors, distinct environmental factors, most notably ultraviolet (UV) light, activate innate immune responses. Activation of the innate immune system leads to subsequent activation of adaptive immune responses and the development of cutaneous lupus erythematosus (CLE) skin lesions. These skin lesions are characterized by anti-epithelial cytotoxic inflammation, called interface dermatitis, which provides a self-amplification loop: cellular stress and cell death cause the release of autoantigens and immunostimulatory endogenous nucleic acids that reactivate innate immune responses via pattern recognition receptors.

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).

Genetic factors

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.

Table 2 Genetic associations with CLE

Environmental factors

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.

Fig. 3: Overview of pro-inflammatory pathways within CLE lesions.
figure3

Gene expression analyses have identified multiple immunological markers that are simultaneously expressed in different parts of the cutaneous lupus erythematosus (CLE) skin lesions during active inflammation21,58. The figure depicts the complex network of different immune cell types, including T cells, B cells, plasmacytoid dendritic cells and macrophages, highlighted by such analyses; interactions between these cells are orchestrated by a large number of interferon (IFN)-regulated cytokines and chemokines, particularly CXC-chemokine ligand 10 (CXCL10). These pro-inflammatory mediators regulate the adhesion of cells to skin vessel walls and their migration towards the epidermis via a chemokine gradient. Cytotoxic effector cells attack lesional keratinocytes, resulting in keratinocytic cell death as well as the expression of pro-inflammatory cytokines and the release of pro-inflammatory chemokines, overall fuelling the lesional inflammation.

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.

Fig. 4: Model for the reactivation of innate pathways in CLE.
figure4

Different mechanisms have been shown to be responsible for the chronic reactivation of the innate immune system in cutaneous lupus erythematosus (CLE). These mechanisms are not cell-type-specific and can involve classical immune cells as well as non-immune cells. Immune complexes of nucleic acid motifs and autoantibodies bind to cells via CD32 and activate type I and type III interferon-producing pathways via endosomal Toll-like receptors (such as TLR3, TLR7 and TLR9). This mechanism is particularly important for plasmacytoid dendritic cells. Endogenous nucleic acids, which are released following lesional cell death, can enter a cell by lipofection via natural compounds (such as via the cathelicidin antimicrobial peptide) and induce interferon-producing pathways by activating cytosolic pattern recognition receptor (PRRs), including the cGAS–STING pathway. In specific situations (for example, during cellular stress or DNase deficiency), nucleic acids can accumulate within the cytosol and activate cytosolic PRRs directly. This mechanism is most important in familial chilblain lupus systematosus, which is caused by deficiency in the cytosolic DNase TREX1. Signalling via ubiquitous cytosolic PRR pathways can activate keratinocytes in CLE.

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.

Lesional pathways

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).

Table 3 Ongoing clinical studies in CLE
Fig. 5: Therapeutic targets in CLE.
figure5

Overview of the pro-inflammatory pathways of cutaneous lupus erythematosus (CLE) skin lesions and potential therapeutic targets. a | Potential therapies include those that target adaptive immune responses, such as B cell-depleting drugs (such as rituximab and belimumab); T cell-targeting drugs (such as voclospririne); inhibitors of B cell and/or T cell activation (for example, the anti-CD40 antibody BI655064, the anti-CD40 ligand antibody dapirolizumab, the anti-ICOS ligand AMG 557 and anti-malarial drugs); proteasome inhibitors (such as bortezomib and ixazomib); drugs that inhibit effector T cells (for example, methotrexate); and plasmapheresis (removal of antibodies from the plasma). Drugs that target innate immune cells, including plasmacytoid dendritic cells (pDCs; for example, BIIB059), are also promising. Another strategy is to target cytokines, such as with anti-IFNα antibodies (for example, sifalimumab and rontalizumab), anti-IFNAR1 antibodies (such as anifrolumab), IL-12 and IL-23 inhibitors (such as ustekinumab), IL-6 inhibitors (such as PF-04236921, sirukumab, MRA003US and vobarilizumab) and TNF inhibitors (such as etanercept and infliximab). Some drugs can bind to DNA (such as antimalarial drugs), which might contribute to their efficacy. b | Downstream pathways can also be targeted, such as with inhibitors of the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway (such as ruxolitinib, baricitinib, tofacitinib, filgotinib, BMS-986165 and methotrexate); inhibitors of nuclear factor-κB (NF-κB) signalling (such as iguratimod); mitogen-activated protein kinase (MAPK) inhibitors (such as SB203580 and FR167653); and inhibitors of spleen tyrosine kinase (SYK; such as lanraplenib and GSK2646264). PRR, pattern recognition receptor; TLR, Toll-like receptor.

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.

Conclusions

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.

References

  1. 1.

    Kuhn, A., Wenzel, J. & Bijl, M. Lupus erythematosus revisited. Semin. Immunopathol. 38, 97–112 (2016).

    CAS  PubMed  Google Scholar 

  2. 2.

    Stannard, J. N. & Kahlenberg, J. M. Cutaneous lupus erythematosus: updates on pathogenesis and associations with systemic lupus. Curr. Opin. Rheumatol. 28, 453–459 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Hejazi, E. Z. & Werth, V. P. Cutaneous lupus erythematosus: an update on pathogenesis, diagnosis and treatment. Am. J. Clin. Dermatol. 17, 135–146 (2016).

    PubMed  Google Scholar 

  4. 4.

    Kuhn, A., Rondinone, R., Doria, A. & Shoenfeld, Y. 1st international conference on cutaneous lupus erythematosus Düsseldorf, Germany, September 1–5, 2004. Autoimmun. Rev. 4, 66–78 (2005).

    PubMed  Google Scholar 

  5. 5.

    Gilliam, J. N. & Sontheimer, R. D. Distinctive cutaneous subsets in the spectrum of lupus erythematosus. J. Am. Acad. Dermatol. 4, 471–475 (1981).

    CAS  PubMed  Google Scholar 

  6. 6.

    Grönhagen, C. M., Fored, C. M., Granath, F. & Nyberg, F. Cutaneous lupus erythematosus and the association with systemic lupus erythematosus: a population-based cohort of 1088 patients in Sweden. Br. J. Dermatol. 164, 1335–1341 (2011).

    PubMed  Google Scholar 

  7. 7.

    Biazar, C. et al. Cutaneous lupus erythematosus: first multicenter database analysis of 1002 patients from the European Society of Cutaneous Lupus Erythematosus (EUSCLE). Autoimmun. Rev. 12, 444–454 (2013).

    PubMed  Google Scholar 

  8. 8.

    Jarukitsopa, S. et al. Epidemiology of systemic lupus erythematosus and cutaneous lupus erythematosus in a predominantly white population in the United States. Arthritis Care Res. 67, 817–828 (2015).

    Google Scholar 

  9. 9.

    Durosaro, O., Davis, M. D. P., Reed, K. B. & Rohlinger, A. L. Incidence of cutaneous lupus erythematosus, 1965–2005: a population-based study. Arch. Dermatol. 145, 249–253 (2009).

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Patel, P. & Werth, V. Cutaneous lupus erythematosus: a review. Dermatol. Clin. 20, 373–385 (2002).

    PubMed  Google Scholar 

  11. 11.

    Lipsker, D. The need to revisit the nosology of cutaneous lupus erythematosus: the current terminology and morphologic classification of cutaneous LE: difficult, incomplete and not always applicable. Lupus 19, 1047–1049 (2010).

    CAS  PubMed  Google Scholar 

  12. 12.

    Lin, J. H., Dutz, J. P., Sontheimer, R. D. & Werth, V. P. Pathophysiology of cutaneous lupus erythematosus. Clin. Rev. Allergy Immunol. 33, 85–106 (2007).

    CAS  PubMed  Google Scholar 

  13. 13.

    Wieczorek, I. T., Propert, K. J., Okawa, J. & Werth, V. P. Systemic symptoms in the progression of cutaneous to systemic lupus erythematosus. JAMA Dermatol. 150, 291–296 (2014).

    PubMed  Google Scholar 

  14. 14.

    Sticherling, M. Kutaner lupus erythematodes und Hautveränderungen beim systemischen lupus erythematodes [German]. Z. Rheumatol. 72, 429–435 (2013).

    CAS  PubMed  Google Scholar 

  15. 15.

    Kuhn, A. & Landmann, A. The classification and diagnosis of cutaneous lupus erythematosus. J. Autoimmun. 48-49, 14–19 (2014).

    CAS  PubMed  Google Scholar 

  16. 16.

    Uva, L. et al. Cutaneous manifestations of systemic lupus erythematosus. Autoimmune Dis. 2012, 834291 (2012).

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Wenzel, J. et al. The expression pattern of interferon-inducible proteins reflects the characteristic histological distribution of infiltrating immune cells in different cutaneous lupus erythematosus subsets. Br. J. Dermatol. 157, 752–757 (2007).

    CAS  PubMed  Google Scholar 

  18. 18.

    Wenzel, J. & Tuting, T. An IFN-associated cytotoxic cellular immune response against viral, self-, or tumor antigens is a common pathogenetic feature in “interface dermatitis”. J. Invest. Dermatol. 128, 2392–2402 (2008).

    CAS  PubMed  Google Scholar 

  19. 19.

    Lauffer, F. et al. Type I immune response induces keratinocyte necroptosis and is associated with interface dermatitis. J. Invest. Dermatol. 38, 1785–1794 (2018).

    Google Scholar 

  20. 20.

    Obermoser, G., Sontheimer, R. D. & Zelger, B. Overview of common, rare and atypical manifestations of cutaneous lupus erythematosus and histopathological correlates. Lupus 19, 1050–1070 (2010).

    CAS  PubMed  Google Scholar 

  21. 21.

    Scholtissek, B. et al. Immunostimulatory endogenous nucleic acids drive the lesional inflammation in cutaneous lupus erythematosus. J. Invest. Dermatol. 137, 1484–1492 (2017).

    CAS  PubMed  Google Scholar 

  22. 22.

    Sarkar, M. K. et al. Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa. Ann. Rheum. Dis. 77, 1653–1664 (2018).

    CAS  PubMed  Google Scholar 

  23. 23.

    Zahn, S. et al. Evidence for a pathophysiological role of keratinocyte-derived type III interferon (IFNλ) in cutaneous lupus erythematosus. J. Invest. Dermatol. 131, 133–140 (2011).

    CAS  PubMed  Google Scholar 

  24. 24.

    Wenzel, J., Zahn, S., Bieber, T. & Tuting, T. Type I interferon-associated cytotoxic inflammation in cutaneous lupus erythematosus. Arch. Dermatol. Res. 301, 83–86 (2009).

    CAS  PubMed  Google Scholar 

  25. 25.

    Kuhn, A. et al. S2k guideline for treatment of cutaneous lupus erythematosus-guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV). J. Eur. Acad. Dermatol. Venereol. 31, 389–404 (2017).

    CAS  PubMed  Google Scholar 

  26. 26.

    Filotico, R. & Mastrandrea, V. Cutaneous lupus erythematosus: clinico-pathologic correlation. G. Ital. Dermatol. Venereol. 153, 216–229 (2018).

    PubMed  Google Scholar 

  27. 27.

    Sunderkötter, C. H. et al. Nomenclature of cutaneous vasculitis: dermatologic addendum to the 2012 revised International Chapel Hill Consensus Conference nomenclature of vasculitides. Arthritis Rheumatol. 70, 171–184 (2018).

    PubMed  Google Scholar 

  28. 28.

    Udompanich, S., Chanprapaph, K. & Suchonwanit, P. Hair and scalp changes in cutaneous and systemic lupus erythematosus. Am. J. Clin. Dermatol. 19, 679–694 (2018).

    PubMed  Google Scholar 

  29. 29.

    Reich, A., Meurer, M., Viehweg, A. & Muller, D. J. Narrow-band UVB-induced externalization of selected nuclear antigens in keratinocytes: implications for lupus erythematosus pathogenesis. Photochem. Photobiol. 85, 1–7 (2009).

    CAS  PubMed  Google Scholar 

  30. 30.

    Casciola-Rosen, L. & Rosen, A. Ultraviolet light-induced keratinocyte apoptosis: a potential mechanism for the induction of skin lesions and autoantibody production in LE. Lupus 6, 175–180 (1997).

    CAS  PubMed  Google Scholar 

  31. 31.

    Zhang, Y.-P., Wu, J., Han, Y.-F., Shi, Z.-R. & Wang, L. Pathogenesis of cutaneous lupus erythema associated with and without systemic lupus erythema. Autoimmun. Rev. 16, 735–742 (2017).

    CAS  PubMed  Google Scholar 

  32. 32.

    Wenzel, J. et al. Scarring skin lesions of discoid lupus erythematosus are characterized by high numbers of skin-homing cytotoxic lymphocytes associated with strong expression of the type I interferon-induced protein MxA. Br. J. Dermatol. 153, 1011–1015 (2005).

    CAS  PubMed  Google Scholar 

  33. 33.

    Mak, A. & Kow, N. Y. The pathology of T cells in systemic lupus erythematosus. J. Immunol. Res. 2014, 419029 (2014).

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Grassi, M., Capello, F., Bertolino, L., Seia, Z. & Pippione, M. Identification of granzyme B-expressing CD-8-positive T cells in lymphocytic inflammatory infiltrate in cutaneous lupus erythematosus and in dermatomyositis. Clin. Exp. Dermatol. 34, 910–914 (2009).

    CAS  PubMed  Google Scholar 

  35. 35.

    Herrada, A. A. et al. Innate immune cells’ contribution to systemic lupus erythematosus. Front. Immunol. 10, 772 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Sestak, A. L., Fürnrohr, B. G., Harley, J. B., Merrill, J. T. & Namjou, B. The genetics of systemic lupus erythematosus and implications for targeted therapy. Ann. Rheum. Dis. 70, i37–i43 (2011).

    CAS  PubMed  Google Scholar 

  37. 37.

    Peschke, K. et al. Deregulated type I IFN response in TREX1-associated familial chilblain lupus. J. Invest. Dermatol. 134, 1456–1459 (2014).

    CAS  PubMed  Google Scholar 

  38. 38.

    Hersh, A. O., Arkin, L. M. & Prahalad, S. Immunogenetics of cutaneous lupus erythematosus. Curr. Opin. Pediatr. 28, 470–475 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Foering, K. et al. Characterization of clinical photosensitivity in cutaneous lupus erythematosus. J. Am. Acad. Dermatol. 69, 205–213 (2013).

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Gehrke, N. et al. Oxidative damage of DNA confers resistance to cytosolic nuclease TREX1 degradation and potentiates STING-dependent immune sensing. Immunity 39, 482–495 (2013).

    CAS  PubMed  Google Scholar 

  41. 41.

    Kaczmarczyk-Sekuła, K. et al. Mast cells in systemic and cutaneous lupus erythematosus. Pol. J. Pathol. 4, 397–402 (2015).

    Google Scholar 

  42. 42.

    Gerl, V. et al. The intracellular 52-kd Ro/SSA autoantigen in keratinocytes is up-regulated by tumor necrosis factor α via tumor necrosis factor receptor I. Arthritis Rheum. 52, 531–538 (2005).

    CAS  PubMed  Google Scholar 

  43. 43.

    Patsinakidis, N. et al. Suppression of UV-induced damage by a liposomal sunscreen: a prospective, open-label study in patients with cutaneous lupus erythematosus and healthy controls. Exp. Dermatol. 21, 958–961 (2012).

    CAS  PubMed  Google Scholar 

  44. 44.

    Katayama, S. et al. Delineating the healthy human skin UV response and early induction of interferon pathway in cutaneous lupus erythematosus. J. Invest. Dermatol. https://doi.org/10.1016/j.jid.2019.02.035 (2019).

    Article  PubMed  Google Scholar 

  45. 45.

    Chang, J. & Werth, V. P. Therapeutic options for cutaneous lupus erythematosus: recent advances and future prospects. Expert Rev. Clin. Immunol. 12, 1109–1121 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Piette, E. W. et al. Impact of smoking in cutaneous lupus erythematosus. Arch. Dermatol. 148, 317–322 (2012).

    PubMed  Google Scholar 

  47. 47.

    White, P. C. et al. Cigarette smoke modifies neutrophil chemotaxis, neutrophil extracellular trap formation and inflammatory response-related gene expression. J. Periodont. Res. 53, 525–535 (2018).

    CAS  PubMed  Google Scholar 

  48. 48.

    Vaglio, A. et al. Drug-induced lupus: traditional and new concepts. Autoimmun. Rev. 17, 912–918 (2018).

    CAS  PubMed  Google Scholar 

  49. 49.

    Sandholdt, L. H., Laurinaviciene, R. & Bygum, A. Proton pump inhibitor-induced subacute cutaneous lupus erythematosus. Br. J. Dermatol. 170, 342–351 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Biermann, M. H. C. et al. The role of dead cell clearance in the etiology and pathogenesis of systemic lupus erythematosus: dendritic cells as potential targets. Expert Rev. Clin. Immunol. 10, 1151–1164 (2014).

    CAS  PubMed  Google Scholar 

  51. 51.

    Shovman, O., Tamar, S., Amital, H., Watad, A. & Shoenfeld, Y. Diverse patterns of anti-TNF-α-induced lupus: case series and review of the literature. Clin. Rheumatol. 37, 563–568 (2018).

    PubMed  Google Scholar 

  52. 52.

    Levine, D., Switlyk, S. A. & Gottlieb, A. Cutaneous lupus erythematosus and anti-TNF-α therapy: a case report with review of the literature. J. Drugs Dermatol. 9, 1283–1287 (2010).

    PubMed  Google Scholar 

  53. 53.

    Fiorentino, D. F. The Yin and Yang of TNF-α inhibition. Arch. Dermatol. 143, 233–236 (2007).

    CAS  PubMed  Google Scholar 

  54. 54.

    Arrue, I., Saiz, A., Ortiz-Romero, P. L. & Rodríguez-Peralto, J. L. Lupus-like reaction to interferon at the injection site: report of five cases. J. Cutan. Pathol. 34, 18–21 (2007).

    PubMed  Google Scholar 

  55. 55.

    Curran, C. S., Gupta, S., Sanz, I. & Sharon, E. PD-1 immunobiology in systemic lupus erythematosus. J. Autoimmun. 97, 1–9 (2018).

    PubMed  Google Scholar 

  56. 56.

    Sinha, A. A. & Dey-Rao, R. Genomic investigation of lupus in the skin. J. Invest. Dermatol. Symp. Proc. 18, S75–S80 (2017).

    Google Scholar 

  57. 57.

    Dey-Rao, R. & Sinha, A. A. Genome-wide transcriptional profiling data from skin of chronic cutaneous lupus erythematosus (CCLE) patients. Data Brief 4, 47–49 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Zahn, S. et al. Interferon-α stimulates TRAIL expression in human keratinocytes and peripheral blood mononuclear cells: implications for the pathogenesis of cutaneous lupus erythematosus. Br. J. Dermatol. 165, 1118–1123 (2011).

    CAS  PubMed  Google Scholar 

  59. 59.

    Muskardin, T. L. W. & Niewold, T. B. Type I interferon in rheumatic diseases. Nat. Rev. Rheumatol. 14, 214–228 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Yin, Q. et al. Ultraviolet B irradiation induces skin accumulation of plasmacytoid dendritic cells: a possible role for chemerin. Autoimmunity 47, 185–192 (2014).

    CAS  PubMed  Google Scholar 

  61. 61.

    Liu, L., Xu, G., Dou, H. & Deng, G.-M. The features of skin inflammation induced by lupus serum. Clin. Immunol. 165, 4–11 (2016).

    CAS  PubMed  Google Scholar 

  62. 62.

    Dudhgaonkar, S. et al. Selective IRAK4 inhibition attenuates disease in murine lupus models and demonstrates steroid sparing activity. J. Immunol. 198, 1308–1319 (2017).

    CAS  PubMed  Google Scholar 

  63. 63.

    Mande, P. et al. Fas ligand promotes an inducible TLR-dependent model of cutaneous lupus-like inflammation. J. Clin. Invest. 128, 2966–2978 (2018).

    PubMed  PubMed Central  Google Scholar 

  64. 64.

    König, N. et al. Familial chilblain lupus due to a gain-of-function mutation in STING. Ann. Rheum. Dis. 76, 468–472 (2017).

    PubMed  Google Scholar 

  65. 65.

    Sabrautzki, S. et al. An ENU mutagenesis-derived mouse model with a dominant Jak1 mutation resembling phenotypes of systemic autoimmune disease. Am. J. Pathol. 183, 352–368 (2013).

    CAS  PubMed  Google Scholar 

  66. 66.

    Means, T. K. et al. Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J. Clin. Invest. 115, 407–417 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Eloranta, M.-L. et al. Regulation of the interferon-α production induced by RNA-containing immune complexes in plasmacytoid dendritic cells. Arthritis Rheum. 60, 2418–2427 (2009).

    CAS  PubMed  Google Scholar 

  68. 68.

    Saadeh, D., Kurban, M. & Abbas, O. Update on the role of plasmacytoid dendritic cells in inflammatory/autoimmune skin diseases. Exp. Dermatol. 25, 415–421 (2016).

    PubMed  Google Scholar 

  69. 69.

    Liu, Z. & Davidson, A. Taming lupus — a new understanding of pathogenesis is leading to clinical advances. Nat. Med. 18, 871–882 (2012).

    PubMed  PubMed Central  Google Scholar 

  70. 70.

    Rönnblom, L. The type I interferon system in the etiopathogenesis of autoimmune diseases. Ups. J. Med. Sci. 116, 227–237 (2011).

    PubMed  PubMed Central  Google Scholar 

  71. 71.

    Kalali, B. N. et al. Double-stranded RNA induces an antiviral defense status in epidermal keratinocytes through TLR3-, PKR-, and MDA5/RIG-I-mediated differential signaling. J. Immunol. 181, 2694–2704 (2008).

    CAS  PubMed  Google Scholar 

  72. 72.

    Skouboe, M. K. et al. STING agonists enable antiviral cross-talk between human cells and confer protection against genital herpes in mice. PLOS Pathog. 14, e1006976 (2018).

    PubMed  PubMed Central  Google Scholar 

  73. 73.

    Stannard, J. N. et al. Lupus skin is primed for IL-6 inflammatory responses through a keratinocyte-mediated autocrine type I interferon loop. J. Invest. Dermatol. 137, 115–122 (2017).

    CAS  PubMed  Google Scholar 

  74. 74.

    Liu, Y. et al. TWEAK/Fn14 activation participates in Ro52-mediated photosensitization in cutaneous lupus erythematosus. Front. Immunol. 8, 651 (2017).

    PubMed  PubMed Central  Google Scholar 

  75. 75.

    Zahn, S. et al. Ultraviolet light protection by a sunscreen prevents interferon-driven skin inflammation in cutaneous lupus erythematosus. Exp. Dermatol. 23, 516–518 (2014).

    CAS  PubMed  Google Scholar 

  76. 76.

    Wenzel, J. et al. Enhanced type I interferon signalling promotes Th1-biased inflammation in cutaneous lupus erythematosus. J. Pathol. 205, 435–442 (2005).

    CAS  PubMed  Google Scholar 

  77. 77.

    Kuhn, A. et al. Accumulation of apoptotic cells in the epidermis of patients with cutaneous lupus erythematosus after ultraviolet irradiation. Arthritis Rheum. 54, 939–950 (2006).

    PubMed  Google Scholar 

  78. 78.

    Kuechle, M. K. & Elkon, K. B. Shining light on lupus and UV. Arthritis Res. Ther. 9, 101 (2007).

    PubMed  PubMed Central  Google Scholar 

  79. 79.

    Mistry, P. & Kaplan, M. J. Cell death in the pathogenesis of systemic lupus erythematosus and lupus nephritis. Clin. Immunol. 185, 59–73 (2017).

    CAS  PubMed  Google Scholar 

  80. 80.

    Wang, D., Drenker, M., Eiz-Vesper, B., Werfel, T. & Wittmann, M. Evidence for a pathogenetic role of interleukin-18 in cutaneous lupus erythematosus. Arthritis Rheum. 58, 3205–3215 (2008).

    CAS  PubMed  Google Scholar 

  81. 81.

    Caneparo, V., Landolfo, S., Gariglio, M. & De Andrea, M. The absent in melanoma 2-like receptor IFN-inducible protein 16 as an inflammasome regulator in systemic lupus erythematosus: the dark side of sensing microbes. Front. Immunol. 9, 1180 (2018).

    PubMed  PubMed Central  Google Scholar 

  82. 82.

    Kreuter, A. et al. Expression of antimicrobial peptides in different subtypes of cutaneous lupus erythematosus. J. Am. Acad. Dermatol. 65, 125–133 (2011).

    CAS  PubMed  Google Scholar 

  83. 83.

    Chamilos, G. et al. Cytosolic sensing of extracellular self-DNA transported into monocytes by the antimicrobial peptide LL37. Blood 120, 3699–3707 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Drake, L. A. et al. Guidelines of care for cutaneous lupus erythematosus. American Academy of Dermatology. J. Am. Acad. Dermatol. 34, 830–836 (1996).

    CAS  PubMed  Google Scholar 

  85. 85.

    Kuhn, A., Landmann, A. & Wenzel, J. Advances in the treatment of cutaneous lupus erythematosus. Lupus 25, 830–837 (2016).

    CAS  PubMed  Google Scholar 

  86. 86.

    Kuhn, A. et al. Photoprotective effects of a broad-spectrum sunscreen in ultraviolet-induced cutaneous lupus erythematosus: a randomized, vehicle-controlled, double-blind study. J. Am. Acad. Dermatol. 64, 37–48 (2011).

    CAS  PubMed  Google Scholar 

  87. 87.

    Kuhn, A. et al. Efficacy of tacrolimus 0.1% ointment in cutaneous lupus erythematosus: a multicenter, randomized, double-blind, vehicle-controlled trial. J. Am. Acad. Dermatol. 65, 54–64.e2 (2011).

    CAS  PubMed  Google Scholar 

  88. 88.

    Alves, P. et al. Quinacrine suppresses tumor necrosis factor-α and IFN-α in dermatomyositis and cutaneous lupus erythematosus. J. Investig. Dermatol. Symp. Proc. 18, S57–S63 (2017).

    PubMed  PubMed Central  Google Scholar 

  89. 89.

    Kuznik, A. et al. Mechanism of endosomal TLR inhibition by antimalarial drugs and imidazoquinolines. J. Immunol. 186, 4794–4804 (2011).

    CAS  PubMed  Google Scholar 

  90. 90.

    Yokogawa, N. et al. Effects of hydroxychloroquine in patients with cutaneous lupus erythematosus: a multicenter, double-blind, randomized, parallel-group trial. Arthritis Rheumatol. 69, 791–799 (2017).

    CAS  PubMed  Google Scholar 

  91. 91.

    Zeidi, M., Kim, H. J. & Werth, V. P. Increased myeloid dendritic cells and TNF-α expression predicts poor response to hydroxychloroquine in cutaneous lupus erythematosus. J. Invest. Dermatol. 139, 324–332 (2019).

    CAS  PubMed  Google Scholar 

  92. 92.

    Wenzel, J. Methotrexate in systemic lupus erythematosus. Lupus 14, 569 (2005).

    CAS  PubMed  Google Scholar 

  93. 93.

    Klebes, M., Wutte, N. & Aberer, E. Dapsone as second-line treatment for cutaneous lupus erythematosus? A retrospective analysis of 34 patients and a review of the literature. Dermatology 232, 91–96 (2016).

    CAS  PubMed  Google Scholar 

  94. 94.

    Shornick, J. K., Formica, N. & Parke, A. L. Isotretinoin for refractory lupus erythematosus. J. Am. Acad. Dermatol. 24, 49–52 (1991).

    CAS  PubMed  Google Scholar 

  95. 95.

    Chan, E. S. L. & Cronstein, B. N. Methotrexate—how does it really work? Nat. Rev. Rheumatol. 6, 175–178 (2010).

    CAS  PubMed  Google Scholar 

  96. 96.

    Thomas, S. et al. Methotrexate is a JAK/STAT pathway inhibitor. PLOS ONE 10, e0130078 (2015).

    PubMed  PubMed Central  Google Scholar 

  97. 97.

    Klaeschen, A. S. & Wenzel, J. Upcoming therapeutic targets in cutaneous lupus erythematous. Expert Rev. Clin. Pharmacol. 9, 567–578 (2016).

    CAS  PubMed  Google Scholar 

  98. 98.

    Felten, R. et al. The 2018 pipeline of targeted therapies under clinical development for systemic lupus erythematosus: a systematic review of trials. Autoimmun. Rev. 17, 781–790 (2018).

    PubMed  Google Scholar 

  99. 99.

    Presto, J. K., Hejazi, E. Z. & Werth, V. P. Biological therapies in the treatment of cutaneous lupus erythematosus. Lupus 26, 115–118 (2017).

    PubMed  Google Scholar 

  100. 100.

    Hofmann, S. C., Leandro, M. J., Morris, S. D. & Isenberg, D. A. Effects of rituximab-based B-cell depletion therapy on skin manifestations of lupus erythematosus—report of 17 cases and review of the literature. Lupus 22, 932–939 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Berghen, N., Vulsteke, J.-B., Westhovens, R., Lenaerts, J. & De Langhe, E. Rituximab in systemic autoimmune rheumatic diseases: indications and practical use. Acta Clin. Belg. 74, 272–279 (2018).

    PubMed  Google Scholar 

  102. 102.

    Vital, E. M. et al. Brief report: responses to rituximab suggest B cell-independent inflammation in cutaneous systemic lupus erythematosus. Arthritis Rheumatol. 67, 1586–1591 (2015).

    CAS  PubMed  Google Scholar 

  103. 103.

    Vashisht, P., Borghoff, K. & O’Dell, J. R. Hearth-Holmes, M. Belimumab for the treatment of recalcitrant cutaneous lupus. Lupus 26, 857–864 (2017).

    CAS  PubMed  Google Scholar 

  104. 104.

    Iaccarino, L. et al. Effects of belimumab on flare rate and expected damage progression in patients with active systemic lupus erythematosus. Arthritis Care Res. (Hoboken) 69, 115–123 (2017).

    CAS  Google Scholar 

  105. 105.

    European Medicines Agency. EU Clinical Trials Register https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-003051-35/DE (2018).

  106. 106.

    Wenzel, J., Landmann, A., Vorwerk, G. & Kuhn, A. High expression of B lymphocyte stimulator in lesional keratinocytes of patients with cutaneous lupus erythematosus. Exp. Dermatol. 27, 95–97 (2018).

    CAS  PubMed  Google Scholar 

  107. 107.

    Merrill, J. T. et al. Efficacy and safety of atacicept in patients with systemic lupus erythematosus: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled, parallel-arm, phase IIb study. Arthritis Rheumatol. 70, 266–276 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Kohler, S. et al. Bortezomib in antibody-mediated autoimmune diseases (TAVAB): study protocol for a unicentric, non-randomised, non-placebo controlled trial. BMJ Open 9, e024523 (2019).

    PubMed  PubMed Central  Google Scholar 

  109. 109.

    Shirley, M. Ixazomib: first global approval. Drugs 76, 405–411 (2016).

    CAS  PubMed  Google Scholar 

  110. 110.

    Alexander, T. et al. Proteasome inhibition with bortezomib induces a therapeutically relevant depletion of plasma cells in SLE but does not target their precursors. Eur. J. Immunol. 48, 1573–1579 (2018).

    CAS  PubMed  Google Scholar 

  111. 111.

    Aguayo-Leiva, I., Vano-Galvan, S., Carrillo-Gijon, R. & Jaén-Olasolo, P. Lupus tumidus induced by bortezomib not requiring discontinuation of the drug. J. Eur. Acad. Dermatol. Venereol. 24, 1363–1364 (2010).

    CAS  PubMed  Google Scholar 

  112. 112.

    Gensous, N. et al. T follicular helper cells in autoimmune disorders. Front. Immunol. 9, 1637 (2018).

    PubMed  PubMed Central  Google Scholar 

  113. 113.

    Katsuyama, T., Tsokos, G. C. & Moulton, V. R. Aberrant T cell signaling and subsets in systemic lupus erythematosus. Front. Immunol. 9, 1088 (2018).

    PubMed  PubMed Central  Google Scholar 

  114. 114.

    Dehesa, L., Abuchar, A., Nuno-Gonzalez, A., Vitiello, M. & Kerdel, F. A. The use of cyclosporine in dermatology. J. Drugs Dermatol. 11, 979–987 (2012).

    CAS  PubMed  Google Scholar 

  115. 115.

    Wu, Q. & Kuca, K. Metabolic pathway of cyclosporine A and its correlation with nephrotoxicity. Curr. Drug Metab. 20, 84–90 (2018).

    Google Scholar 

  116. 116.

    Sin, F. E. & Isenberg, D. An evaluation of voclosporin for the treatment of lupus nephritis. Expert Opin. Pharmacother. 19, 1613–1621 (2018).

    CAS  PubMed  Google Scholar 

  117. 117.

    Spee-Mayer, C. Von et al. Low-dose interleukin-2 selectively corrects regulatory T cell defects in patients with systemic lupus erythematosus. Ann. Rheum. Dis. 75, 1407–1415 (2016).

    Google Scholar 

  118. 118.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03312335 (2018).

  119. 119.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02770170 (2019).

  120. 120.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02804763 (2019).

  121. 121.

    Danion, F. et al. Efficacy of abatacept in systemic lupus erythematosus: a retrospective analysis of 11 patients with refractory disease. Lupus 25, 1440–1447 (2016).

    CAS  PubMed  Google Scholar 

  122. 122.

    Tarazi, M., Aiempanakit, K. & Werth, V. P. Subacute cutaneous lupus erythematosus and systemic lupus erythematosus associated with abatacept. JAAD Case Rep. 4, 698–700 (2018).

    PubMed  PubMed Central  Google Scholar 

  123. 123.

    Biliouris, K. et al. A pre-clinical quantitative model predicts the pharmacokinetics/pharmacodynamics of an anti-BDCA2 monoclonal antibody in humans. J. Pharmacokinet. Pharmacodyn. 45, 817–827 (2018).

    CAS  PubMed  Google Scholar 

  124. 124.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02847598 (2019).

  125. 125.

    Furie, R. et al. BIIB059, a monoclonal antibody targeting BDCA2, shows evidence of biological activity and early clinical proof of concept in subjects with active cutaneous LE. Ann. Rheum. Dis. 76, (Suppl. 2), 857 (2017).

    Google Scholar 

  126. 126.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03817424 (2019).

  127. 127.

    Kalunian, K. C. et al. A phase II study of the efficacy and safety of rontalizumab (rhuMAb interferon-α) in patients with systemic lupus erythematosus (ROSE). Ann. Rheum. Dis. 75, 196–202 (2016).

    PubMed  Google Scholar 

  128. 128.

    Merrill, J. T. et al. Safety profile and clinical activity of sifalimumab, a fully human anti-interferon α monoclonal antibody, in systemic lupus erythematosus: a phase I, multicentre, double-blind randomised study. Ann. Rheum. Dis. 70, 1905–1913 (2011).

    CAS  PubMed  Google Scholar 

  129. 129.

    Werth, V. P. et al. Brief report: pharmacodynamics, safety, and clinical efficacy of AMG 811, a human anti-interferon-γ antibody, in patients with discoid lupus erythematosus. Arthritis Rheumatol. 69, 1028–1034 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Furie, R. et al. Anifrolumab, an anti-interferon-α receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol. 69, 376–386 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Santos, F. P. S. & Verstovsek, S. Efficacy of ruxolitinib for myelofibrosis. Expert Opin. Pharmacother. 15, 1465–1473 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Spoerl, S. et al. Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood 123, 3832–3842 (2014).

    CAS  PubMed  Google Scholar 

  133. 133.

    Hornung, T. et al. Remission of recalcitrant dermatomyositis treated with ruxolitinib. N. Engl. J. Med. 371, 2537–2538 (2014).

    PubMed  Google Scholar 

  134. 134.

    Hornung, T., Wolf, D. & Wenzel, J. More on remission of recalcitrant dermatomyositis treated with ruxolitinib. N. Engl. J. Med. 372, 1273–1274 (2015).

    Google Scholar 

  135. 135.

    Klaeschen, A. S., Wolf, D., Brossart, P., Bieber, T. & Wenzel, J. JAK inhibitor ruxolitinib inhibits the expression of cytokines characteristic of cutaneous lupus erythematosus. Exp. Dermatol. 26, 728–730 (2017).

    CAS  PubMed  Google Scholar 

  136. 136.

    Wenzel, J. et al. JAK1/2 inhibitor ruxolitinib controls a case of chilblain lupus erythematosus. J. Invest. Dermatol. 136, 1281–1283 (2016).

    CAS  PubMed  Google Scholar 

  137. 137.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03159936 (2019).

  138. 138.

    Wallace, D. J. et al. Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 392, 222–231 (2018).

    CAS  PubMed  Google Scholar 

  139. 139.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03134222 (2019).

  140. 140.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03920267 (2019).

  141. 141.

    Deng, G.-M., Liu, L., Bahjat, F. R., Pine, P. R. & Tsokos, G. C. Suppression of skin and kidney disease by inhibition of spleen tyrosine kinase in lupus-prone mice. Arthritis Rheum. 62, 2086–2092 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Deng, G.-M. & Tsokos, G. C. The role of Syk in cutaneous lupus erythematosus. Exp. Dermatol. 25, 674–675 (2016).

    PubMed  Google Scholar 

  143. 143.

    Braegelmann, C. et al. Spleen tyrosine kinase (SYK) is a potential target for the treatment of cutaneous lupus erythematosus patients. Exp. Dermatol. 25, 375–379 (2016).

    CAS  PubMed  Google Scholar 

  144. 144.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02927457 (2019).

  145. 145.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02936375 (2018).

  146. 146.

    Iwata, Y. et al. p38 mitogen-activated protein kinase contributes to autoimmune renal injury in MRL-Fas lpr mice. J. Am. Soc. Nephrol. 14, 57–67 (2003).

    CAS  PubMed  Google Scholar 

  147. 147.

    Jin, N. et al. The selective p38 mitogen-activated protein kinase inhibitor, SB203580, improves renal disease in MRL/lpr mouse model of systemic lupus. Int. Immunopharmacol. 11, 1319–1326 (2011).

    CAS  PubMed  Google Scholar 

  148. 148.

    Kuhn, A. et al. Fumaric acid ester treatment in cutaneous lupus erythematosus (CLE): a prospective, open-label, phase II pilot study. Lupus 25, 1357–1364 (2016).

    CAS  PubMed  Google Scholar 

  149. 149.

    Dey-Rao, R., Smith, J. R., Chow, S. & Sinha, A. A. Differential gene expression analysis in CCLE lesions provides new insights regarding the genetics basis of skin vs. systemic disease. Genomics 104, 144–155 (2014).

    CAS  PubMed  Google Scholar 

  150. 150.

    Norman, R., Greenberg, R. G. & Jackson, J. M. Case reports of etanercept in inflammatory dermatoses. J. Am. Acad. Dermatol. 54, S139–S142 (2006).

    PubMed  Google Scholar 

  151. 151.

    Drosou, A., Kirsner, R. S., Welsh, E., Sullivan, T. P. & Kerdel, F. A. Use of infliximab, an anti-tumor necrosis α antibody, for inflammatory dermatoses. J. Cutan. Med. Surg. 7, 382–386 (2003).

    PubMed  Google Scholar 

  152. 152.

    Aringer, M. & Smolen, J. S. Efficacy and safety of TNF-blocker therapy in systemic lupus erythematosus. Expert Opin. Drug Saf. 7, 411–419 (2008).

    CAS  PubMed  Google Scholar 

  153. 153.

    European Medicines Agency. EU Clinical Trials Register https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-001602-33/GB (2015).

  154. 154.

    Van Vollenhoven, R. F. et al. Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study. Lancet 392, 1330–1339 (2018).

    PubMed  Google Scholar 

  155. 155.

    Souza, A., De Ali-Shaw, T., Strober, B. E. & Franks, A. G. Successful treatment of subacute lupus erythematosus with ustekinumab. Arch. Dermatol. 147, 896–898 (2011).

    PubMed  Google Scholar 

  156. 156.

    Tierney, E., Kirthi, S., Ramsay, B. & Ahmad, K. Ustekinumab-induced subacute cutaneous lupus. JAAD Case Rep. 5, 271–273 (2019).

    PubMed  PubMed Central  Google Scholar 

  157. 157.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01405196 (2017).

  158. 158.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01702740 (2012).

  159. 159.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02437890 (2019).

  160. 160.

    Kunz, M. et al. Genome-wide association study identifies new susceptibility loci for cutaneous lupus erythematosus. Exp. Dermatol. 24, 510–515 (2015).

    CAS  PubMed  Google Scholar 

  161. 161.

    Millard, T. P. et al. A candidate gene analysis of three related photosensitivity disorders: cutaneous lupus erythematosus, polymorphic light eruption and actinic prurigo. Br. J. Dermatol. 145, 229–236 (2001).

    CAS  PubMed  Google Scholar 

  162. 162.

    Ruiz-Larrañaga, O. et al. Genetic association study of systemic lupus erythematosus and disease subphenotypes in European populations. Clin. Rheumatol. 35, 1161–1168 (2016).

    PubMed  Google Scholar 

  163. 163.

    Järvinen, T. M. et al. Tyrosine kinase 2 and interferon regulatory factor 5 polymorphisms are associated with discoid and subacute cutaneous lupus erythematosus. Exp. Dermatol. 19, 123–131 (2010).

    PubMed  Google Scholar 

  164. 164.

    Skonieczna, K. et al. Genetic similarities and differences between discoid and systemic lupus erythematosus patients within the Polish population. Postepy Dermatol. Alergol. 34, 228–232 (2017).

    PubMed  PubMed Central  Google Scholar 

  165. 165.

    Levy, S. B., Pinnell, S. R., Meadows, L., Snyderman, R. & Ward, F. E. Hereditary C2 deficiency associated with cutaneous lupus erythematosus: clinical, laboratory, and genetic studies. Arch. Dermatol. 115, 57–61 (1979).

    CAS  PubMed  Google Scholar 

  166. 166.

    Agnello, V., Gell, J. & Tye, M. J. Partial genetic deficiency of the C4 component of complement in discoid lupus erythematosus and urticaria/angioedema. J. Am. Acad. Dermatol. 9, 894–898 (1983).

    CAS  PubMed  Google Scholar 

  167. 167.

    Racila, D. M. et al. Homozygous single nucleotide polymorphism of the complement C1QA gene is associated with decreased levels of C1q in patients with subacute cutaneous lupus erythematosus. Lupus 12, 124–132 (2003).

    CAS  PubMed  Google Scholar 

  168. 168.

    Lipsker, D. & Hauptmann, G. Cutaneous manifestations of complement deficiencies. Lupus 19, 1096–1106 (2010).

    CAS  PubMed  Google Scholar 

  169. 169.

    Sanchez, E. et al. Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus. Ann. Rheum. Dis. 70, 1752–1757 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 170.

    Järvinen, T. M. et al. Polymorphisms of the ITGAM gene confer higher risk of discoid cutaneous than of systemic lupus erythematosus. PLOS ONE 5, e14212 (2010).

    PubMed  PubMed Central  Google Scholar 

  171. 171.

    Da Silva Fonseca, A. M. et al. Polymorphisms in STK17A gene are associated with systemic lupus erythematosus and its clinical manifestations. Gene 527, 435–439 (2013).

    PubMed  Google Scholar 

  172. 172.

    Azevêdo Silva, J. De et al. Vitamin D receptor (VDR) gene polymorphisms and susceptibility to systemic lupus erythematosus clinical manifestations. Lupus 22, 1110–1117 (2013).

    PubMed  Google Scholar 

  173. 173.

    Zhong, H. et al. Replicated associations of TNFAIP3, TNIP1 and ETS1 with systemic lupus erythematosus in a southwestern Chinese population. Arthritis Res. Ther. 13, R186 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174.

    Vigato-Ferreira, I. C. C. et al. FcγRIIa and FcγRIIIb polymorphisms and associations with clinical manifestations in systemic lupus erythematosus patients. Autoimmunity 47, 451–458 (2014).

    CAS  PubMed  Google Scholar 

  175. 175.

    Harley, I. T. W. et al. The role of genetic variation near interferon-kappa in systemic lupus erythematosus. J. Biomed. Biotechnol. 2010, 706825 (2010).

    PubMed  PubMed Central  Google Scholar 

  176. 176.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03122431 (2018).

  177. 177.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02176148 (2018).

  178. 178.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03260166 (2017).

  179. 179.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02428309 (2019).

  180. 180.

    European Medicines Agency. EU Clinical Trials Register https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-001203-79/HU (2017).

  181. 181.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03288324 (2019).

  182. 182.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03517722 (2019).

  183. 183.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03866317 (2019).

  184. 184.

    European Medicines Agency. EU Clinical Trials Register https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-003246-93/PL (2016).

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Correspondence to Joerg Wenzel.

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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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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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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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