Lupus erythematosus (LE) is a typical autoimmune connective tissue disease and a disease-causing disease. One end of the spectrum is cutaneous lupus erythematosus (CLE), the lesion is mainly confined to the skin; the other end is systemic lupus erythematosus (SLE), in addition to skin damage, the lesion involves multiple organs and multiple systems.
CLE can manifest as individual skin lesions or some features within the SLE range. In addition to CLE-specific skin lesions, CLE patients may have other lesions that are not specific to the disease (ie, may be present in any autoimmune disease), such as vascular disease (including from single vascular dysfunction to vascular ulcers) Disease) or hair follicle disease (hair loss).
According to clinical manifestations and histopathological features, CLE can be divided into four subtypes: acute CLE (ACLE), subacute CLE (SCLE), intermittent CLE (ICLE), also known as swollen lupus erythematosus (LET) and chronic CLE (CCLE), the main variants are chronic discoid lupus erythematosus (CDLE), deep-onset lupus erythematosus (LEP), and frostbite-like lupus erythematosus (ChLE).
The incidence of system involvement depends on the subtype of CLE. For example, ACLE has the highest systemic involvement rate (~90%), while local CDLE has the lowest systemic involvement rate (<5%). But regardless of the subtype, the involvement of the internal organ system complicates CLE.
On August 9th, in a recent review published in Nature Reviews Rheumatology, Professor Joerg Wenzel from the University Hospital Bonn, Germany, introduced the established standard therapies for CLE, and discussed new developments in understanding the pathogenesis of CLE molecules, as well as New treatment strategies for these advances.
I. Molecular pathogenesis of CLE
In genetically susceptible individuals, different environmental factors (especially ultraviolet light) can activate the innate immune response. Activation of the innate immune system leads to the activation of a subsequent adaptive immune response, thereby inducing the onset of CLE skin lesions.
These skin lesions manifest as interfacial dermatitis, which promotes an inflammatory self-encoding cycle: cellular stress and cell death lead to the release of autoantigens and immunostimulatory endogenous nucleic acids, thereby re-activating the innate immune response through pattern recognition receptors.
Pro-inflammatory cycle of CLE lesions.
CLE is a multifactorial disease that often occurs within the family and between twins, suggesting that genetic factors play an important role. As shown in the table below, some genetic polymorphisms have been identified in different CLE patient populations. Most of these factors are functionally related to their involvement in innate or adaptive immune responses, including type I interferon pathways, cell death, clearance of cellular debris, antigen presentation, antibody production, and immune cell regulation.
CLE genetic link
Ultraviolet light is the most recognized CLE triggering factor. Approximately 60%–80% of patients with SLE have photosensitive skin lesions. Ultraviolet radiation induces cellular damage leading to proinflammatory responses, including cell death and reactive oxygen species release. In addition, ultraviolet light can stimulate mast cells to release pro-inflammatory factors. It is worth noting that only patients with SLE and non-healthy individuals develop CLE-like lesions with type I interferon characteristics after UV exposure. Moreover, UV irradiation can up-regulate interferon and MHC-related genes in the skin of CLE patients, but it cannot upregulate such genes in healthy human skin.
Smoking is another important environmental factor that leads to CLE. In CLE, smokers’ skin lupus erythematosus area and severity index (CLASI) scores were significantly higher than non-smokers, who required higher doses of immunomodulatory drugs to treat the disease. In addition, smoking promotes several pro-inflammatory processes in the pathogenesis of CLE (involving neutrophil activation, neutrophil extracellular trap formation, cellular stress, and apoptosis) to make the disease active.
Drug-induced SLE and CLE-like skin damage is a well-known drug side effect. Drugs traditionally associated with drug-induced lupus erythematosus (such as procainamide, hydralazine, quinidine, and omeprazole) have been reported to directly activate the innate immune system or indirectly activate by inhibiting autoantigen clearance. system. In addition, immunostimulants such as tumor necrosis factor antagonists, recombinant type I interferons, and checkpoint inhibitors can also induce CLE or SLE-like lesions.
Activation of the innate immune pathway
The immune complex activates the receptor of the innate immune system to promote CLE lesions. For example, immune complexes with RNA and/or DNA autoantibodies can be taken up by pDCs by CD32-mediated endocytosis, and the nucleic acid components of these immune complexes activate type I interferon production by binding to TLR7 or TLR9 in the endosomes.
CLE innate immune pathway reactivation model.
This mechanism can explain the adaptive immune mechanisms in CLE that allow the innate immune system in pDCs to be continuously activated, resulting in simultaneous activation of the “both arms” (both innate and adaptive) of the immune system.
Ultraviolet light upregulates the expression of autoantigens such as Ro52 in keratinocytes and activates a variety of pro-inflammatory pathways that promote keratinocyte death throughout the epidermal layer.
However, in established lesions, this pattern is completely altered: dead cells and pro-inflammatory chemical factors, particularly CXCL10, are found only at the dermal epidermal junction of the inflamed area, reflecting the typical interfacial dermatitis of CLE. These pro-inflammatory chemokines (including CXCR3 ligands: CXCL9, CXCL10, and CXCL11) mobilize cytotoxic type I immune cells to recruit lesions through CXCR3, resulting in necrotic apoptosis of keratinocytes. The fragments released by apoptotic cells contain endogenous immunostimulatory nucleic acids that activate the innate immune pathway in diseased keratinocytes via different pattern recognition receptors, including MDA5, RIG-I, and cGAS-STING.
In addition, immunostimulatory nucleic acid motifs derived from apoptotic keratinocytes accumulate due to DNase deficiency caused by genetic or drug-induced factors. These endogenous immunostimulatory nucleic acid motifs act as ligands for pattern recognition receptors, drive interferon responses and activate inflammatory bodies.
The identification of these pathological pathways and the molecular mechanisms of CLE helps to increase understanding of established CLE therapies and opens the door to targeted therapeutic strategies.
II. Established therapies
Since UV is one of the most important triggers for CLE skin lesions, effective sunscreens are essential. Broad-spectrum liposomal sunscreens prevent the development of skin lesions in patients with CLE. In addition, the use of sunscreens can also reduce the expression of type I and type III interferons in the skin and related cytokines and chemokines (such as CXCL10), thereby reducing systemic inflammation in these patients.
Local glucocorticoids are first-line drugs for the treatment of CLE lesions because of their anti-inflammatory effects. The primary indication for topical glucocorticoids is local CDLE, but patients with generalized CDLE and other CLE subgroups can also benefit from local immunosuppression beyond systemic therapy.
In the current guidelines, antimalarial drugs and glucocorticoids are recommended as first-line drugs for patients with highly active or generalized lesions.
Antimalarial drugs such as chloroquine, hydroxychloroquine and quinacrine are the most commonly used systemic drugs in CLE. The mode of action of these drugs is still under investigation, but it is certain that all of these antimalarial drugs inhibit the production of type I interferon by immune-activated peripheral blood mononuclear cells. For chloroquine and hydroxychloroquine, there is evidence that the two main mechanisms of therapeutic effects of these drugs in CLE are inhibition of antigen presentation by dendritic cells and direct binding to immunostimulatory nucleic acid motifs. Quinacrine inhibits Toll-like receptor-mediated production of TNF and IL-6.
Systemic glucocorticoids are recommended for severe or generalized and active CLE lesions, but should be gradually reduced as soon as possible to reduce adverse reactions.
For patients with long-term disease or high disease activity, other immunosuppressive and immunomodulatory drugs may be needed. Methotrexate, retinoic acid and dapsone are considered second-line drugs. Methotrexate is recommended for refractory CLE, primarily SCLE; dapsone is indicated for refractory CLE and bullous lupus erythematosus; retinoic acid is indicated for specific CLE patients who are not responding to other treatments (especially CDLE hypertrophy patients). Due to the lack of clinical studies in CLE, all other drugs, including mycophenolate mofetil and cyclosporin, are currently considered to be third-line drugs.
III. Targeted treatment strategies for CLE
In the past decade, while knowledge about the pathogenesis of CLE molecules has been enriched, some biopharmaceuticals and other targeted drugs have been introduced into the treatment of CLE, or are currently being tested in clinical and preclinical studies.
Drugs undergoing CLE clinical research
BAFF: B cell activating factor; JAK: Janus kinase; LILRA4: leukocyte immunoglobulin-like receptor subfamily A member 4; pDC: plasmacytoid dendritic cells; SLE: systemic lupus erythematosus; STAT: signal transduction and Transcriptional activator; SYK: spleen tyrosine kinase; TYK2: non-receptor tyrosine protein kinase 2.
These drugs can target immune cells, particularly B cells and T cells, as well as pDCs or proinflammatory mediators.
Therapy for B cells
B cells, plasma cells and their activation pathways are the early focus of CLE targeted therapeutic strategies because they play an important role in the production of autoantibodies.
Belimmab is a monoclonal antibody against B cell activating factor (BAFF, also known as BlyS) that was approved by the FDA in 2011 for the treatment of SLE. The initial registration trial for SLE did not include a specific skin score, but some case reports indicate that Belimmab has a positive effect in CLE and its efficacy on CLE is currently being studied in Phase III clinical trials.
Therapy for T cells
SLE has traditionally been classified as a B cell mediated disease due to its characteristic autoantibody production. However, B cells require T helper cells to be activated. Effector T cells cause most direct cell damage in SLE, whereas defects in regulatory T cells appear to be responsible for disease progression in many patients. These data indicate that T cells are potential targets for SLE.
Calcineurin inhibitors inhibit T cell activation. Among these inhibitors, cyclosporin has been used to treat refractory CLE for decades. However, factors such as side effects (nephrosis and hypertension) of the drug limit its use, and recent guidelines are not recommended for the treatment of patients with CLE without systemic involvement. Voclosporin is more metabolically stable than cyclosporin and is effective against lupus nephritis. It may also be a potential drug for future CLE clinical trials.
Targeting B cell and T cell costimulatory molecules
B cells and T cells are activated by pairwise stimulation receptors and their corresponding ligands. Several inhibitors of these receptors or ligands have been studied in clinical trials and may be effective in the treatment of CLE.
Abatacept is a CTLA4–IgGFc1 fusion protein that inhibits T cell activation and is beneficial for the treatment of patients with partially refractory SLE. However, it has been reported that this drug can also induce SCLE in individual cases. The mechanism behind this reversal is unclear, but it may be due to the formation of autoantibodies against CTLA4 in the Abatacept molecule during treatment, which directly stimulates T cells in the body and promotes the autoimmune process.
Plasmacytoid dendritic cells
pDCs are the most important cell type in the CLE innate immune system. These cells are the main producers of type I interferons in blood and skin lesions and can augment the pathological inflammation.
In tissues, pDCs can be recognized by the expression of their specific receptor, CD303. This receptor regulates the production of type I interferon and is the target structure of monoclonal antibody BIIB059 for the treatment of SLE. The efficacy of BIIB059 on CLE is currently undergoing clinical trials, and preliminary results indicate that the drug treatment resulted in a decrease in the area and severity index (CLASI) of the skin lupus erythematosus.
In addition, a new Phase I clinical trial is also investigating the efficacy of VIB7734 (formerly known as MEDI-7734) in targeting pDCs in CLE and related autoimmune diseases. VIB7734 is a monoclonal antibody against the leukocyte immunoglobulin-like receptor subfamily A member 4 (LILRA4, also known as ILT7), specific for pDCs.
Type I interferon system
Given that strong type I interferon signaling is a hallmark of SLE, interferons (especially IFNαs and IFNβ) and their co-receptors (IFNAR) have been the main targets of SLE drug development for the past decade. The initial study focused on IFNα, but specific anti-IFNα antibodies (eg, Sifalimumab and Rontalizumab) have limited therapeutic effects on CLE skin lesions, probably due to the high redundancy of different type I interferons. Targeting IFNAR appears to be more effective than targeting cytokine itself: in a Phase IIb clinical study, the anti-IFNAR1 antibody Anifrolumab reduced the CLASI score in patients with SLE.
Several proinflammatory cytokines (including TNF, IL-12 and IL-6) are up-regulated in lesioned skin of CLE patients compared to non-lesional or healthy human skin. Some case reports indicate that TNF inhibitors, including Infliximab and Etanercept, are effective in treating certain CLE patients, but these drugs can also induce CLE-like skin lesions [10–12]. Therefore, the efficacy of anti-TNF therapy in CLE remains controversial.
In phase II clinical trials published in 2018, treatment with IL-12 and the IL-23 inhibitor Ustekinumab reduced skin disease activity in SLE patients with a higher CLASI score (CLASI ≥ 4). This drug has been shown to be effective in treating SCLE patients and improving SLE skin mucosal disease characteristics.
An overview of the CLE skin lesion pro-inflammatory pathway and therapeutic targets for adaptive immune responses.
For the JAK-STAT pathway
The JAK-STAT pathway is critical for the autocrine loop of type I interferons and is located upstream of important CLE-associated pathogenic pro-inflammatory cytokines and chemokines. JAK inhibitors were originally developed for the treatment of hematological malignancies caused by JAK mutations, and these inhibitors (especially Ruxolitinib) have considerable immunosuppressive effects.
JAK1 and JAK2 inhibitors Ruxolitinib inhibits the expression of characteristic proinflammatory mediators of keratinocyte CLE in vitro and also treats skin lesions in patients with ChLE. JAK1 and JAK3 inhibitor Tofacitinib is also effective in patients with ChLE, which is currently being studied in a clinical trial for CDLE.
Spleen tyrosine kinase
Spleen tyrosine kinase (SYK) is a highly conserved tyrosine kinase that mediates a variety of biological functions, including the regulation of innate immune responses. For example, SYK is activated downstream of the pattern recognition receptor to regulate innate immune responses to some pathogens.
Phosphorylated SYK is strongly expressed in CLE skin lesions. The SYK inhibitor Fostamatinib (also known as R788) reduces skin disease that has developed in the mouse CLE141 model. Currently, the efficacy of a topical SYK inhibitor (GSK2646264) in CLE is being studied in Phase I clinical trials. In a phase II clinical study of women with moderate to severe CLE, the oral SYK inhibitor Lanraplenib (GS-9876) is being tested concurrently with Filgotinib.
Targeting other intracellular signaling pathways
Intracellular pathways may provide additional potential therapeutic targets for CLE, including the NF-κB signaling pathway and the mitogen-activated protein kinase (MAPK) signaling cascade.
Iguratimod is a synthetic anti-inflammatory small molecule drug that inhibits the activation of NF-κB and is currently being studied in the Phase I clinical trial for the treatment of lupus nephritis.
Some MAPK inhibitors have shown beneficial effects in the SLE mouse model (SB203580 and FR167653). Dimethyl fumarate, a drug that blocks NF-κB and MAPK signaling, reduced disease activity in some of the 11 patients with CLE in a phase II pilot study.
An overview of the CLE skin lesion pro-inflammatory pathway and therapeutic targets for downstream pathways.
The pathological mechanism of CLE is complex, especially in the context of the involvement of internal organ systems. A detailed understanding of the pathogenesis of CLE molecules, as well as new insights into the innate immune response pathway and its interaction with adaptive mechanisms, can help develop new CLE treatment strategies, such as regulating B cell and T cell activation, or by targeting pDCs, IFNAR or JAK-STAT signaling inhibit the type I interferon pathway. Some therapies for other pro-inflammatory pathway molecules are underway and are expected to provide more insights into the mechanisms of action in vivo.