The role of cytokines in the pathogenesis of cutaneous lupus erythematosus

Cytokine 73 (2015) 326–334

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The role of cytokines in the pathogenesis of cutaneous lupus erythematosus E.S. Robinson, V.P. Werth ⇑ Veteran Affairs Medical Center, Philadelphia, PA, United States Department of Dermatology, University of Pennsylvania, Philadelphia, PA, United States

a r t i c l e

i n f o

Article history: Received 11 September 2014 Received in revised form 24 January 2015 Accepted 28 January 2015 Available online 9 March 2015 Keywords: Cutaneous lupus erythematous Ultraviolet light Interferon Interleukin Tumor necrosis factor-alpha

a b s t r a c t Cutaneous lupus erythematosus (CLE) is an inflammatory disease with a broad range of cutaneous manifestations that may be accompanied by systemic symptoms. The pathogenesis of CLE is complex, multifactorial and incompletely defined. Below we review the current understanding of the cytokines involved in these processes. Ultraviolet (UV) light plays a central role in the pathogenesis of CLE, triggering keratinocyte apoptosis, transport of nucleoprotein autoantigens to the keratinocyte cell surface and the release of inflammatory cytokines (including interferons (IFNs), tumor necrosis factor (TNF)-a, interleukin (IL)-1, IL-6, IL-8, IL-10 and IL-17). Increased IFN, particularly type I IFN, is central to the development of CLE lesions. In CLE, type I IFN is produced in response to nuclear antigens, immune complexes and UV light. Type I IFN increases leukocyte recruitment to the skin via inflammatory cytokines, chemokines, and adhesion molecules, thereby inducing a cycle of cutaneous inflammation. Increased TNFa in CLE may also cause inflammation. However, decreasing TNFa with an anti-TNFa agent can induce CLE-like lesions. TNFa regulates B cells, increases the production of inflammatory molecules and inhibits the production of IFN-a. An increase in the inflammatory cytokines IL-1, IL-6, IL-10, IL-17 and IL-18 and a decrease in the anti-inflammatory cytokine IL-12 also act to amplify inflammation in CLE. Specific gene mutations may increase the levels of these inflammatory cytokines in some CLE patients. New drugs targeting various aspects of these cytokine pathways are being developed to treat CLE and systemic lupus erythematosus (SLE). Published by Elsevier Ltd.

1. Introduction to cutaneous lupus erythematosus Lupus erythematosus (LE) encompasses a broad range of cutaneous symptoms including malar rash, discoid rash, photosensitivity and oral ulcers as well as systemic symptoms such as arthritis, renal disease, abnormal serologies and hematologic disease. Patients may have cutaneous lupus erythematosus (CLE), systemic lupus erythematosus (SLE) or both. The American College of Rheumatology defines SLE as the presence of at least four of eleven diagnostic criteria. The prevalence of SLE varies worldwide from 17 to 48 per 100,000 people. The prevalence of CLE is approximately equal to that of SLE [1]. CLE is a heterogeneous disease that includes a wide variety of cutaneous symptoms. Gilliam and Sontheimer’s classification of CLE identifies three types of histopathologic LE-specific lesions:

⇑ Corresponding author at: Department of Dermatology, Perelman Center for Advanced Medicine, Suite 1-330A, 3400 Civic Center Boulevard, Philadelphia, PA 19104, United States. Tel.: +1 215 823 4208; fax: +1 866 755 0625. E-mail address: [email protected] (V.P. Werth). http://dx.doi.org/10.1016/j.cyto.2015.01.031 1043-4666/Published by Elsevier Ltd.

acute CLE (ACLE), subacute CLE (SCLE) and chronic CLE (CCLE) [2]. ACLE most commonly presents with erythematous macules and papules classically in a malar (‘‘butterfly’’) distribution along with positive antinuclear, anti-double stranded deoxyribonucleic acid (dsDNA) and anti-Smith (Sm) antibodies. ACLE is often associated with systemic symptoms. SCLE presents with annular or papulosquamous morphologies. Patients with SCLE are highly photosensitive. Seventy percent of SCLE patients have anti-Ro/SSA antibodies, 70–80% have antinuclear antibodies and 5% have antidsDNA antibodies [3,4]. Fifty percent of SCLE patients meet criteria for SLE, although they often have mild SLE symptoms [5]. CCLE includes tumid lupus, lupus panniculitis, chilblain lupus and discoid lupus erythematosus (DLE). CCLE patients, less frequently those with localized discoid lupus and tumid lupus, develop SLE, but when they meet SLE criteria it is frequently with non-organthreatening criteria [6]. However, patients with SLE can develop CCLE-type lesions. Patients with CCLE rarely have positive antinuclear, anti-dsDNA or anti-Sm antibodies. They may have low-titer anti-Ro/SSA antibodies [7]. In addition to the LE-specific lesions of ACLE, SCLE and CCLE described above, Gilliam and

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Sontheimer identified non-specific LE lesions. These non-specific LE lesions include Raynaud’s phenomenon, vasculopathy, leukocytoclastic vasculitis, livedo reticularis and alopecia. CLE can cause significant disability and decreased quality of life. CLE patients have equivalent or worse mental health than patients with recent myocardial infarctions, congestive heart failure, type 2 diabetes or chronic hypertension [8]. Quality of life in CLE is particularly impaired for women and patients with a generalized distribution of CLE lesions or severe disease. Improvement of CLE skin disease activity as measured by the CLE Disease Area and Severity Index (CLASI) correlates with an improvement in skin-specific quality of life [9].

63% of SCLE, 60% of SLE and 45% of DLE subjects developed skin lesions after exposure to UV irradiation [12]. Forty-two percent of lesions were induced by UVB alone and 34% by UVA alone. In the patients irradiated with combined UVA and UVB, 53% developed skin lesions. UV light produces CLE lesions through multiple pathways. UV light induces cytokine and chemokine production, keratinocyte apoptosis and necrosis, expression of autoantigens on keratinocytes, recruitment of activated immune cells and increased antibody binding to keratinocytes (Table 1). Through these actions UV light causes CLE lesions and can aggravate systemic symptoms in SLE.

2. The pathogenesis of CLE

3.2. UV light-induced production of cytokines and chemokines

The pathogenesis of CLE is multifactorial and incompletely understood. It involves ultraviolet (UV) light, keratinocyte apoptosis, cytokine release, B cell hyperactivity, and activation of T cells and dendritic cells. Cytokines play an important role in the pathogenesis of CLE. Cytokines induce and inhibit immune cells and each other. Their roles may be different in the various CLE subtypes. Cytokines are grouped into two functional classes: T-helper 1 (Th1) cell-produced cytokines and T-helper 2 (Th2) cell-produced cytokines. The Th1 group includes interleukin (IL)-2, IL-12, tumor necrosis factor (TNF)-a and interferon (IFN)-c. These cytokines stimulate cell-mediated immunity. The Th2 group consists of IL-4, IL5, IL-6 and IL-10. These cytokines increase humoral immunity. Abnormal expression of both Th1 and Th2 cytokines are important in the pathogenesis of tissue injury in lupus. In one study, the peripheral blood mononuclear cells (PBMC) of CLE patients had increased expression of the C–C chemokine receptor (CCR) 5 (characteristic of Th1 cells) and decreased expression of CCR3 (characteristic of Th2 cells) when compared to healthy controls [10]. Chemokines are proteins involved in the recruitment of inflammatory cells and play an important role in executing the cytokine pathways. The increased ratio of CCR5 to CCR3 in this study suggests a predominantly Th1 immune response in CLE. However, in another study, UVB irradiation induced a predominantly Th2 cytokine response [11]. It is now thought that both Th1 and Th2 cytokines play important roles in CLE. Below we review the current understanding of the role of cytokines in the development of CLE, particularly IFNs, TNFa, and ILs. However, first, we review the role of UV in the production of these cytokines and the pathogenesis of CLE.

UV light directly induces cytokine synthesis and release. UV light triggers keratinocyte and immune cell production of IFN, TNFa, transforming growth factor (TGF)-b, IL-1a/b, IL-6, IL-8, IL10 and IL-17 [13–15]. These cytokines, particularly IL-1a and TNFa, then trigger the release of additional inflammatory epidermal cytokines, inflammatory chemokines and adhesion molecules. These factors recruit inflammatory cells into the skin and cause tissue inflammation. The pathways of these cytokines are described in detail shortly. Chemokine (CXC motif) ligand (CXCL) 9, CXCL10 and CXCL11 are the most highly expressed chemokines in CLE [16]. More recently, the finding of chemokine (C–C motif) ligand (CCL) 27 ‘‘leakage’’ from the basal epidermis into the papillary dermis in the skin of LE subjects after UV irradiation points to a new chemokine involved in the development of CLE lesions [16]. CCL27 is a chemokine that recruits memory T cells into the skin.

3. Ultraviolet light-induced cytokine production and keratinocyte apoptosis 3.1. Key points  UV light directly increases the levels of TNFa and certain types of interferon and interleukin. These cytokines are important in the pathogenesis of CLE. They mediate the immune cell dysfunction, tissue inflammation and tissue injury present in CLE.  UV light induces keratinocyte apoptosis, which may increase the release of cytokines and autoantigens.  Keratinocyte necrosis and the action of UV light on keratinocytes displace nucleoproteins from inside the cell to the cell surface. Antibodies bind to these nucleoproteins causing further inflammation and tissue injury. UV light plays a significant role in the production of cytokines in CLE and causes typical CLE lesions and photosensitivity. UV light, particularly UVB (290–320 nm), can induce new CLE lesions and exacerbate existing CLE disease. Seventy-six percent of tumid LE,

3.3. UV light-induced keratinocyte apoptosis and necrosis In addition to triggering cytokine release, UV light also induces keratinocyte apoptosis. The keratinocytes of CLE patients are prone to apoptosis after UV irradiation. In one study DLE lesions had increased apoptotic keratinocytes in the basal zone and SCLE lesions had increased apoptotic keratinocytes in the suprabasal zone compared to controls [17]. Another study found that CLE lesions had increased p53 expression, a tumor suppressor that is associated with apoptosis and is upregulated by UV light, TNFa and IFN-c [18]. DLE lesions, but not healthy control skin, also had increased expression of Fas and the Fas ligand [19]. The Fas ligand binds to Fas, a cell surface receptor, to trigger apoptosis.

Table 1 The role of UV light in the pathogenesis of CLE. CCL27 = Chemokine (C–C motif) ligand 27. CLE = Cutaneous lupus erythematosus. IFN = Interferon. IL = Interleukin. TNFa = Tumor necrosis factor-a. UV = Ultraviolet. Potential CLE pathogenic factors

Primary source(s)

Primary function

UV light

Sun Artificial lights

Proinflammatory

Primary role(s) in the pathogenesis of CLE

 Increases production of inflammatory cytokines and chemokines such as IFN, TNFa, IL and CCL27, which recruit activated immune cells and cause tissue inflammation  Triggers keratinocyte apoptosis and necrosis  Increases expression of autoantigens on keratinocytes and antibody binding to keratinocytes

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These studies describe multiple mechanisms for increased keratinocyte apoptosis in CLE. There may also be impaired clearance of these apoptotic cells in CLE. In one study, a high number of apoptotic keratinocytes were still present in CLE lesions 72 h after UV-irradiation, while in healthy control skin the apoptotic cells which were visible at 24 h had significantly decreased by 72 h [20]. This accumulation of apoptotic keratinocytes can result in secondary necrosis, and the release of proinflammatory cytokines and potential autoantigens [21]. However, other studies found that the number of apoptotic cells, clearance rate of apoptotic cells and level of secondary necrosis after UV irradiation were not significantly different in the skin of SLE patients compared to controls [22,23]. 3.4. UV light-induced autoantigens Keratinocyte apoptosis and necrosis as well as UV irradiation alone increase the presence of autoantigens in the skin. Both UV irradiation and keratinocyte apoptosis increase the translocation of nucleoproteins via blebs to the keratinocyte surface. These nucleoproteins include CLE-associated autoantigens such as Ro/ SSA (Ro52 and Ro60) [24]. High-mobility group protein B1 (HMGB1), a proinflammatory and immunogenic cytokine, is also released from apoptotic or necrotic keratinocytes and acts as an autoantigen [25,26]. These autoantigens are then targeted by autoantibodies, resulting in the release of additional cytokines and skin inflammation [27]. Minimizing sun exposure and maximizing sun protection are critical in the treatment of LE to block the multiple UV-induced inflammatory pathways. 4. Interferon 4.1. Key points  Increased IFN, especially type I IFN, plays an important role in the pathogenesis of CLE.  In CLE, plasmacytoid dendritic cells (pDCs) produce type I IFN in response to nuclear antigens, immune complexes and UV light. Type I IFN increases leukocyte recruitment to the skin via inflammatory cytokines, chemokines and adhesion molecules. Type I IFN also upregulates the production of cytotoxic proteins. In total, these actions induce and propagate cutaneous inflammation.  Mutations in the IFN regulatory factor 5 (IRF5), tyrosine kinase 2 (TYK2) and three prime repair exonuclease 1 (TREX1) genes increase type I IFN production in some people with CLE.  Like type I IFN, type II IFN increases the production of chemokines and adhesion molecules that recruit inflammatory cells into the skin. Type II IFN also increases the production of TNFa. Increased levels of type II IFN are found in SLE. Type II IFN’s role in CLE is unclear.  Increased type III IFN in the lesions and serum of CLE subjects points to a potential role for this cytokine in the pathogenesis of CLE. Like the other types of IFN, type III IFN increases the production of inflammatory cytokines.  Many new drugs are being developed to treat CLE and SLE that target various aspects of the IFN pathway. IFNs are important modulators of the immune system. Increased IFN production was first identified as a central factor in the pathogenesis of lupus in 1979 [28]. IFN-a and IFN-b are classified as type I IFNs, while IFN-c is a type II IFN. Type I IFN is involved in the early activation of innate and adaptive immunity as well as autoimmunity. It has wide-ranging effects including: stimulating proliferation and differentiation of B cells into plasma cells, and

monocytes into antigen presenting cells; activating the Th1 pathway; stimulating dendritic cells; suppressing regulatory T cells; and modifying cytokine effects. Type II IFN inhibits viral replication to fight infections, activates macrophages, monocytes and tumor surveillance, and both stimulates and modulates inflammation. Increased IFN, particularly type I IFN, plays an important role in the development of cutaneous inflammation in CLE (Table 2). 4.2. Type I interferon Type I IFN is elevated in the serum and lesional skin of lupus patients. In CLE, pDCs residing in the dermis are the primary type I IFN producing cells. PDCs produce type I IFN in response to nuclear antigens released through apoptosis or necrosis and to autoantibodies in immune complexes (such as anti-dsDNA and anti-U1ribonucleoprotein [RNP] antibodies) via the toll-like receptor (TLR) 7 or TLR9 as well as through TLR-independent mechanisms [29]. TLR7 and TLR9 are expressed on pDCs. Other stimulating factors for type I IFN remain poorly defined, but include UV light, medications, trauma and infection. IFN-a is composed of 13 subtypes with pleiotropic functions. IFN-a binds the type I IFN receptor (IFNAR) to activate Janus-activated kinases (JAKs) including TYK2 and JAK1. JAK phosphorylates signal transducers and activators of transcription (STAT) 1 and STAT2, which form a complex with other factors. This complex translocates into the nucleus to initiate gene transcription of IFNstimulated genes. These genes increase IFN signaling, rapidly stimulate further cytokine release and increase leukocyte recruitment into the skin (including memory T cells, cytotoxic T cells and pDCs) via the proinflammatory chemokines CXCL9, CXCL10 and CXCL11 [16]. In particular, CXCL9 on dendritic cells and endothelial cells of the superficial dermal plexus as well as CXCL10 in the basal epidermis and perivascular leukocytes recruit chemokine (CXC motif) receptor

Table 2 The role of interferon (IFN) in the pathogenesis of CLE. CD95 = Cluster of differentiation 95. CLE = Cutaneous lupus erythematosus. CXCL = Chemokine (CXC motif) ligand. IFN = Interferon. JAK = Janus-activated kinase. NK = Natural killer. pDC = Plasmacytoid dendritic cell. STAT = Signal transducers and activators of transcription. Th1 = T-helper 1. TNFa = Tumor necrosis factor-a. TRAIL = TNF-related apoptosis-inducing ligand. Potential CLE pathogenic factors

Primary source(s)

Primary function

Type I IFN

pDCs

Proinflammatory

Type II IFN

Th1 cells NK cells

Proinflammatory

Type III IFN

Keratinocytes

Proinflammatory

Primary role(s) in the pathogenesis of CLE

 Activates transcription of type I IFN-stimulated genes via the JAK/ STAT pathway, which recruit leukocytes to the skin via inflammatory cytokines, chemokines (particularly CXCL9 and CXCL10) and adhesion molecules  Increases the level of cytotoxic proteins (perforin and granzyme B) and mediators of apoptosis (CD95 and TRAIL)  Enhances production of TNFa, inflammatory chemokines and adhesion molecules  Increases the level of the inflammatory chemokine CXCL9

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(CXCR) 3-positive effector cells [16]. PDCs also express CXCR3, allowing pDC-produced IFN to recruit new pDCs into the skin and further increase the production of IFN from pDCs. Additionally, type I IFN upregulates cytotoxic proteins, such as perforin and granzyme B via IFN-c in T cells, the apoptosis receptor cluster of differentiation 95 (CD95) and TNF-related apoptosis-inducing ligand (TRAIL) [30– 32]. TRAIL is a keratinocyte-produced IFN-dependent chemokine (Fig. 1). TRAIL is upregulated in the blood of CLE patients [32]. TRAIL’s proapoptotic receptor is found on keratinocytes in CLE lesions and TRAIL’s production is increased when keratinocytes are treated with IFN-a [32]. The ultimate result of these processes is the induction and perpetuation of CLE inflammation and disease. Type I IFNs are also associated with SLE systemic symptoms such as fever, fatigue, myalgias and arthralgias. The presence of increased type I IFN in CLE has been reported in many studies. The type I IFN signature is upregulated in the PBMC of patients with SCLE and DLE compared to controls, but not subjects with tumid lupus [33]. An increased type I IFN score in CLE correlated with an increased CLASI activity score, a measure of CLE disease activity [33]. The presence of IFN-a-inducible genes such as IRF7 and myxovirus resistance protein A (MxA) in cutaneous LE lesions suggests the presence of IFN-a in CLE [16,34]. PDCs producing IFN-a have been found to infiltrate cutaneous LE lesions, but not normal skin, with the number of pDCs correlating with MxA, implicating them in local type I IFN production [35]. The localization of MxA in CLE lesions is the same as the areas of CXCR3 + T cell accumulation [36]. Wenzel et al. found that the distribution pattern of MxA, CXCL9 and CXCL10 corresponded to the histological distribution of lymphocytes in different types of CLE [34]. In DLE and SCLE MxA and CXCL9 were observed in the epidermis and papillary dermis, consistent with interface dermatitis, while in lupus panniculitis CXCL9 and CXCL10 were predominately present in the fat in a lobular distribution. Some genetic mutations that increase type I IFN are implicated in the pathogenesis of CLE. A genetic polymorphism in IRF5, an IFN-a-inducible gene that increases type I IFN production, was present in six SCLE, eight DLE and eight SLE subjects out of a total of 219 subjects studied [37]. A polymorphism in TYK2, a JAK that binds to the IFNAR, is also associated with DLE [37]. Case reports of a genetic mutation in TREX1, a DNA exonuclease, in SLE and a familial form of chilblain lupus point to another genetic cause of LE [38]. Abnormal DNA repair in TREX1-deficient cells may result in DNA accumulation, thereby stimulating IFN-a and, through this pathway, triggering LE. Although rare, patients with diseases such as chronic hepatitis, leukemias, lymphomas and other cancers requiring treatment with IFN-a can develop SLE- or CLE-like symptoms. These LE-like symptoms include abnormal lupus serologies, a malar rash, a discoid rash, photosensitivity and renal disease. CLE-like lesions may also develop at the IFN injection site [39].

4.3. Type II interferon The role of type II IFN (IFN-c) in the pathogenesis of CLE is still being determined. Like IFN-a, IFN-c is increased in the serum of SLE patients, but not all studies found that the serum level of IFN-c correlated with SLE disease activity [40]. Th1 cells and natural killer (NK) cells stimulated by specific antigens secrete type II IFN. Type II IFN induces the production of the chemokines CXCL9, CXCL10 and CXCL11 [16]. Additionally, IFN-c stimulates the production of intracellular adhesion molecule 1 (ICAM-1) in human keratinocytes and increases T lymphoblast-keratinocyte adhesion [41]. IFN-c also induces TNFa production in a dose-dependent manner in unirradiated human keratinocytes [42]. Combining IL-1a with IFN-c synergistically increases TNFa production from these cells. Neither IFN-a nor IFN-b upregulates TNFa expression in unirradiated human keratinocytes. Because type II IFN is increased in SLE patients, and it increases the production of chemokines, adhesion molecules and TNFa, it likely plays a role in the inflammation of SLE and possibly CLE. 4.4. Type III interferon Recent evidence points to type III IFN, IFN-k, as a pathogenic factor in CLE [43]. Keratinocytes produce high levels of IFN-k in response to nucleic acids, but not type I or type II IFNs. In turn, IFN-k produces the chemokine CXCL9. Like type I IFN, type III IFN functions through the JAK/STAT pathway to induce inflammatory pathways, but it does not target the IFNAR. Instead, type III IFN binds to a receptor found on epithelial cells [44]. In one study, high levels of IFN-k and the IFN-k receptor were found using immunohistochemistry in the epidermis of CLE lesions of eight SCLE and eight DLE subjects compared to weak expression of both in six healthy controls [43]. Additionally, 28 CLE subjects with active lesions had increased serum levels of IFN-k. These results point to a potential role for type III IFN in the pathogenesis of CLE. 4.5. Treatments targeting the interferon pathways Many available drugs as well as drugs currently undergoing clinical trials for LE target the IFN pathway. Antimalarial drugs used for the treatment of CLE, including hydroxychloroquine and chloroquine, are thought to reduce pDC production of IFN by preventing nucleic acids from acting on TLRs [45]. Early trials for the treatment of SLE are underway for anti-IFN-a antibodies including sifalimumab (MEDI-545) and rontalizumab (RG7415). In phase I and II studies sifalimumab, a human anti-IFN-a monoclonal antibody, decreased expression of type I IFN-induced messenger ribonucleic acid (mRNA) in whole blood and type I IFN proteins in skin in a dose-dependent manner as well as improved the clinical disease activity of treated subjects in the phase I study only

TRAIL

Smulated pDC

TRAIL R1 receptor

IFN-α Keranocyte

Apoptoc cell

Fig. 1. IFN-a induced apoptosis via TRAIL in the skin in CLE. IFN = interferon. pDC = plasmacytoid dendritic cell. TRAIL = TNF-related apoptosis-inducing ligand.

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[46,47]. The clinical studies of rontalizumab, a humanized immunoglobulin G1 anti-IFN-a monoclonal antibody, found a significant decrease in IFN-regulated gene expression in whole blood-derived RNA, but not in anti-dsDNA antibody levels [48]. The primary endpoint of the phase II study for rontalizumab, the British Isles Lupus Assessment Group (BILAG) response index, was not significantly different between the treatment and placebo groups [49]. Amgen’s drug AMG 811, an anti-IFN-c monoclonal antibody, is also currently undergoing clinical trials for the treatment of SLE.

5. Tumor necrosis factor-alpha 5.1. Key points  TNFa is increased in the serum and skin of CLE patients.  Keratinocytes produce TNFa in response to UV light and inflammatory cytokines, particularly IL-1a, IL-18 and IFN-c.  In CLE, high levels of TNFa increase the production of inflammatory cytokines, chemokines and adhesion molecules, which recruit inflammatory cells into the skin.  TNFa also activates B cells to produce antibodies and increases the expression of nuclear antigens on the keratinocyte surface.  The 308A TNFa promoter polymorphism is associated with increased production of TNFa in SCLE compared to healthy controls [50].  Although increased levels of TNFa cause CLE, decreasing levels of TNFa with a TNFa inhibitor can also produce CLE-like symptoms. TNFa is an inflammatory cytokine involved in the mechanism of many autoimmune diseases such as rheumatoid arthritis, psoriasis and inflammatory bowel disease as well as lupus. Both the serum and skin of CLE patients have high levels of TNFa, which may cause inflammation in LE skin lesions [51,52]. However, the role of TNFa in CLE is unclear because use of a therapeutic TNFa inhibitor is associated with the appearance of SCLE-like lesions. TNFa is involved in cytokine production, B cell regulation and inhibition of IFN-a production from pDCs. TNFa may have both inflammatory and immunomodulatory roles in CLE (Table 3). In the skin, keratinocytes, dermal fibroblasts and mast cells produce TNFa. UV irradiation, IL-1a, IL-18 and IFN-c increase these cells’ production of TNFa [42,53–56]. Within hours after exposure to UVB, the keratinocytes, dermal fibroblasts and mast cells release TNFa triggering an inflammatory cascade and photosensitivity [55]. This effect of UV on TNFa production is mediated through the TNFa promoter, which contains four nuclear factor kappa B (NFjB) binding sites and one activator protein 1 (AP-1) binding site, both of which are UV-stimulated transcription factors [57,58]. Studies suggest that AP-1 mediates the UVB effect, while IL-1 mediates through NFjB a synergistic increase in TNFa production by UVB-irradiated fibroblasts and keratinocytes [59]. As an inflammatory molecule TNFa induces the production of cytokines, chemokines and adhesion molecules such as IL-1, IL-6, CXCL8, CCL20, selectins, vascular cell adhesion molecule 1 (VCAM-1) and ICAM-1. The selectins and adhesion molecules enable leukocyte rolling, attachment and chemotaxis through dermal blood vessels into the skin. In total, these factors create a positive feedback loop for TNFa in which TNFa upregulates its own production and release from UVB irradiated human keratinocytes. In addition to the above functions, TNFa activates Langerhans cells by binding the TNF p75 receptor [60]; acts as a growth factor for B cells and increases the production of antibodies; acts as a B cell regulator; and reduces the release of IFN-a from pDCs [61]. Finally, TNFa upregulates the production of 52-kd Ro/SSA mRNA and protein, the surface expression of Ro/SSA and La/SSB on

Table 3 The role of tumor necrosis factor-a (TNFa) in the pathogenesis of CLE. CCL = Chemokine (C-C motif) ligand. CLE = Cutaneous lupus erythematosus. CXCL = Chemokine (CXC motif) ligand. ICAM-1 = Intracellular adhesion molecule 1. IFN = Interferon. IL = Interleukin. pDC = Plasmacytoid dendritic cell. TNFa = Tumor necrosis factor-a. VCAM-1 = Vascular cell adhesion molecule 1. Potential CLE pathogenic factors

Primary source(s)

Primary function

TNFa

Keratinocytes Fibroblasts Mast cells

Proinflammatory and antiinflammatory

Primary role(s) in the pathogenesis of CLE

 Stimulates production of inflammatory cytokines, chemokines and adhesion molecules such as IL-1, IL-6, CXCL8, CCL20, VCAM-1 and ICAM-1  Activates B cells antibody production  Upregulates keratinocyte surface expression of lupus antibodies  Reduces the release of IFN-a from pDCs, which may cause TNFa inhibitor-induced lupus

keratinocytes and the binding of anti-Ro/SSA antibodies to keratinocytes [62,63]. These findings emphasize multiple potential roles for TNFa in the pathogenesis of CLE. Increased levels of TNFa have been found in many studies of CLE and SLE patients. Refractory skin lesions in SCLE, the most photosensitive type of lupus, are strongly positive for TNFa in the epidermis [52]. The prevalence of the 308A TNFa promoter polymorphism, which is associated with increased TNFa production, is higher in SCLE compared to healthy controls [50]. Circulating levels of TNFa are elevated in SLE and the levels of the TNF soluble receptors (TNF-sR) TNF-sR55 and TNF-sR75 correlate with the Systemic Lupus Activity Measure (SLAM) index [64]. One study though had contradictory findings with increased TNFa levels in patients with inactive SLE (Systemic Lupus Erythematosus Disease Activity Index [SLEDAI] 6 2) compared to patients with very active SLE (SLEDAI P 13) and control patients, possibly suggesting that TNFa is a protective factor in SLE [65]. Despite this evidence for the influence of increased TNFa in the pathogenesis of LE, medications that inhibit TNFa and TNFa’s actions also induce lupus. One study reported the incidence of TNFa inhibitor-induced lupus to be 0.93% (25/2682) for infliximab, 0.81% (9/1110) for adalimumab and 0.37% (5/1360) for etanercept [66]. Anti-TNFa agents can produce a myriad of systemic symptoms and cutaneous symptoms equivalent to those found in idiopathic LE such as fever, arthritis and rashes. TNFa inhibitors can also induce lupus antibodies. Positive anti-dsDNA antibodies were found in 20% of infliximab, 10–12% of adalimumab, 15% of etanercept and 4% of certolizumab pegol treated patients who had previously tested negative for anti-dsDNA antibodies [67]. Antiphospholipid antibodies may also be present in TNFa inhibitor-induced lupus. Antihistone antibodies are found in some types of drug-induced lupus, but are uncommon in TNFa inhibitor-induced lupus. In cases of TNFa inhibitor-induced lupus, once the offending TNFa inhibitor causing lupus-like symptoms is stopped the patient usually improves over days to weeks with antibodies normalizing over months. Treatment with topical steroids, topical non-steroidal immunomodulators or oral antimalarials may be needed. Rarely, systemic steroids or steroid-sparing agents must be used.

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It is unclear if the TNFa inhibitor unmasks underlying lupus or truly induces lupus. The interaction of TNFa with IFN-a may explain the mechanism of TNFa inhibitor-induced lupus. TNFa inhibits the release of IFN-a from pDCs [61]. When endogenous TNFa is eliminated, as it is with an anti-TNFa agent, pDC production of IFN-a increases [61]. As previously described, increased IFN-a triggers an inflammatory cascade resulting in tissue inflammation. Interestingly, although TNFa inhibitors are well characterized as causing lupus-like symptoms, short-term anti-TNF therapy may improve some manifestations of LE, particularly nephritis [68]. 6. Interleukins 6.1. Key points  Many inflammatory interleukins play important roles in the pathogenesis of CLE.  Increased levels of IL-6 and IL-10 in CLE may cause B cell hyperactivity.  Decreased IL-12 levels in LE enable increased humoral immune responses and UV-induced keratinocyte apoptosis.  IL-17 likely contributes to the increased production of inflammatory cytokines and chemokines in CLE.  High levels of IL-18 and the IL-18 receptor in CLE increase TNFa production, decrease IL-12 production and trigger keratinocyte death.  New drugs for CLE and SLE are being developed that act along the interleukin pathway. 6.2. IL-1 IL-1 is an inflammatory cytokine central to the regulation of the immune system. IL-1 release from keratinocytes is markedly increased after UV irradiation, and there is a synergistic increase in TNFa release from keratinocytes and fibroblasts when IL-1a is added to UVB-irradiated cells [53]. IL-1 stimulates the production of TNFa and the inflammatory chemokines CCL5, CCL20, CCL22 and CXCL8 in epidermal keratinocytes [16]. IL-1 is increased in the serum of patients with SLE and correlates with SLE disease activity [69]. 6.3. IL-6 and IL-10 Increased IL-6 and IL-10 in CLE may induce B cell hyperactivity. IL-6 may have anti- and pro-inflammatory functions. IL-6 stimulates B cell maturation and immunoglobulin secretion as well as cytotoxic T cell production and differentiation. In the skin, UVB irradiation increases keratinocyte expression of IL-6 mRNA [70,71]. In SLE, monocytes and B cells also produce IL-6 [72]. IL-6 serum levels are significantly higher in SLE than in healthy controls, and IL-6 serum levels correlate with the SLEDAI score, erythrocyte sedimentation rate and C-reactive protein level [72,73]. Multiple cells including B cells, monocytes, CD4 + T cells and CD8 + T cells produce IL-10 [72,73]. IL-10 is largely regarded as an anti-inflammatory cytokine, but may also stimulate B cells. IL10 suppresses Th1 cells, macrophages and dendritic cells as well as increases B cell proliferation, maturation and immunoglobulin production. Like IL-6, IL-10 serum levels are increased in SLE and the IL-10 levels correlate with SLE disease activity and the antidsDNA antibody levels, and negatively with C3, C4 and lymphocyte counts [72–74]. Increased levels of IL-6 and IL-10 in LE, resulting in B cell hyperactivation, may contribute to the development of CLE. 6.4. IL-12 IL-12 is an anti-inflammatory cytokine that is reduced in LE. B cells, dendritic cells and macrophages produce IL-12. IL-12 is a

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Th1 cytokine that regulates T lymphocytes via IFN-c, inhibits humoral immune responses (including the production of antidsDNA antibodies) and protects keratinocytes from UVB- and TNFa-induced apoptosis [75,76]. In one study, the addition of IL12 to the PBMC of lupus patients reduced IL-10 levels [76]. More importantly, IL-12 reduced anti-dsDNA antibody production independently from this change to IL-10. An imbalance between IL-12 and IL-10 contributes to the pathogenesis of SLE and potentially to the pathogenesis of CLE. 6.5. IL-17 IL-17 is increased in lesional LE skin [77]. Th17 cells produce IL17, an inflammatory cytokine family consisting of six members, IL17A-F. IL-23 enhances the production of IL-17 [78]. IL-17 stimulates T cells and increases the production of autoantibodies, inflammatory cytokines (IL-1 and IL-6) and chemokines (CCL2, CCL7, CCL20, CXCL1 and CXCL5) [79,80]. A study of IL-17 levels in the serum and skin of subjects with SLE (n = 23), DLE (n = 26) and SCLE (n = 17) found higher lesional concentrations of IL-17A and higher IL-17 serum levels in all lupus groups compared to controls [81]. However, a different study of seven DLE patients did not find IL-17 producing Th17 cells or an increase in IL-17-associated genes in the lesional skin [82]. In SLE, an increased serum IL-17 level and the number of Th17 cells correlated with a higher SLEDAI score and CXCL10 level [78]. These results indicate a possible role for IL-17 in the development of inflammation in CLE and SLE. 6.6. IL-18 IL-18, another inflammatory cytokine increased in CLE, is a member of the IL-1 superfamily produced by macrophages and other immune cells. IL-18 helps immune cells to migrate into tissue, stimulates the production of inflammatory cytokines including IFN-c, TNFa and IL-1b, and potentiates IFN-c induced production of CXCL9, CXCL10 and CXCL11 [83]. IL-18 is increased in the serum [84,85] and kidney tissue [86] of SLE patients as well as in CLE keratinocytes [56]. Serum levels of IL-18 correlate with SLE disease activity [84,85]. A study of hair follicle keratinocytes from CLE patients had a higher cell surface level of the IL-18 receptor than controls [56]. In this study, the addition of TNFa and IFN-c further increased keratinocyte surface expression of the IL-18 receptor. The addition of IL-18 to these cells stimulated the keratinocytes to increase TNFa production and inhibit IL-12 production, resulting in keratinocyte death. In total, IL-18’s multiple actions contribute to the inflammatory cascade that causes CLE. 6.7. Treatments targeting the interleukin pathways LE treatments target many of these interleukin pathways (Table 4). Chloroquine inhibits UVB irradiation-induced production of IL-1b and IL-6 [71]. Hydroxychloroquine reduces IL-1a production from monocytes and IL-6 production from T cells and monocytes, but does not impact IL-2 or IL-4 [87]. Recent studies of tocilizumab, an anti-IL-6 receptor antibody currently approved for the treatment of rheumatoid arthritis, found decreased SLE disease activity in the treatment group as well as success in a case of refractory CLE [88,89]. A placebo-controlled clinical trial for sirukumab, a human IL-6 monoclonal antibody, in CLE and SLE patients found no clinically significant change in the clinical disease activity scores of the treated patients as measured by the CLASI, BILAG or safety of estrogen in lupus erythematosus national assessment (SELENA)-SLEDAI [90]. In another trial, an anti-IL-10 monoclonal antibody decreased cutaneous lesions, joint symptoms and SLEDAI scores of SLE subjects [91].

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Table 4 The role of interleukin (IL) in the pathogenesis of CLE. CCL = Chemokine (C–C motif) ligand. CD = Cluster of differentiation. CLE = Cutaneous lupus erythematosus. CXCL = Chemokine (CXC motif) ligand. IFN = Interferon. IL = Interleukin. Th1 = Thelper 1 cell. Th17 = T-helper 17 cell. TNFa = Tumor necrosis factor-a. UV = Ultraviolet. Potential CLE pathogenic factors

Primary source(s)

Primary function

IL-1

Keratinocytes

Proinflammatory

IL-6

Keratinocytes

Proinflammatory and antiinflammatory

IL-10

B cells Monocytes CD4 + T cells CD8 + T cells

Proinflammatory and antiinflammatory

IL-12

B cells Dendritic cells Macrophages

Antiinflammatory

IL-17

Th17 cells

Proinflammatory

IL-18

Macrophages

Proinflammatory

Primary role(s) in the pathogenesis of CLE

 Amplifies production of TNFa and the inflammatory chemokines CCL5, CCL20, CCL22 and CXCL8  Triggers B cell maturation and immunoglobulin secretion  Increases cytotoxic T cell production and differentiation  Suppresses Th1 cells, macrophages and dendritic cells  Stimulates B cell hyperactivity  Regulates T cell function  Reduces immunoglobulin production  Protects keratinocytes from UVinduced apoptosis  Stimulates T cells  Increases the production of autoantibodies  Triggers the production of inflammatory cytokines and chemokines including IL-1, IL-6, CCL2, CCL7, CCL20, CXCL1 and CXCL5  Stimulates the production of the inflammatory cytokines IFN-c, TNFa and IL-1b  Potentiates IFN-c-induced production of CXCL9, CXCL10 and CXCL11

7. Conclusions Many studies point to cytokines as important factors in the pathogenesis of CLE. IFNs, TNFa and ILs all play significant roles. The actions and interactions of these cytokines in CLE are complex. The cytokine pathways are impacted by UV light, genetic and other environmental factors. They are further complicated in that they may vary with CLE subtype. Current research is continuing to expand our knowledge of these pathways and identify potential targets for the treatment of CLE.

Acknowledgements This material is supported by the Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development and a VA Merit Review grant to VPW.

References [1] Durosaro O, Davis MD, Reed KB, Rohlinger AL. Incidence of cutaneous lupus erythematosus, 1965–2005: a population-based study. Arch Dermatol 2009;145(3):249–53. [2] Gilliam JN, Sontheimer RD. Distinctive cutaneous subsets in the spectrum of lupus erythematosus. J Am Acad Dermatol 1981;4(4):471–5. [3] Tebbe B, Mansmann U, Wollina U, et al. Markers in cutaneous lupus erythematosus indicating systemic involvement. A multicenter study on 296 patients. Acta Dermato-venereologica 1997;77(4):305–8. [4] Lee LA, Werth VP. Lupus Erythematosus. In: JL B, editor. Dermatology. 3rd ed. London: Elsevier Ltd; 2012, p. 601. [5] Cohen MR, Crosby D. Systemic disease in subacute cutaneous lupus erythematosus: a controlled comparison with systemic lupus erythematosus. J Rheumatol 1994;21(9):1665–9. [6] Wieczorek IT, Propert KJ, Okawa J, Werth VP. Systemic symptoms in the progression of cutaneous to systemic lupus erythematosus. JAMA Dermatol 2014;150(3):291–6. [7] Lee LA, Roberts CM, Frank MB, McCubbin VR, Reichlin M. The autoantibody response to Ro/SSA in cutaneous lupus erythematosus. Arch Dermatol 1994;130(10):1262–8. [8] Klein R, Moghadam-Kia S, Taylor L, et al. Quality of life in cutaneous lupus erythematosus. J Am Acad Dermatol 2011;64(5):849–58. [9] Chang AY, Ghazi E, Okawa J, Werth VP. Quality of life differences between responders and nonresponders in the treatment of cutaneous lupus erythematosus. JAMA Dermatol 2013;149(1):104–6. [10] Freutel S, Gaffal E, Zahn S, Bieber T, Tuting T, Wenzel J. Enhanced CCR5+/CCR3+ T helper cell ratio in patients with active cutaneous lupus erythematosus. Lupus 2011;20(12):1300–4. [11] Ullrich SE. Does exposure to UV radiation induce a shift to a Th-2-like immune reaction? Photochem Photobiol 1996;64(2):254–8. [12] Kuhn A, Sonntag M, Richter-Hintz D, et al. Phototesting in lupus erythematosus: a 15-year experience. J Am Acad Dermatol 2001;45(1):86–95. [13] Kock A, Schwarz T, Kirnbauer R, et al. Human keratinocytes are a source for tumor necrosis factor alpha: evidence for synthesis and release upon stimulation with endotoxin or ultraviolet light. J Exp Med 1990;172(6):1609–14. [14] Takashima A, Bergstresser PR. Impact of UVB radiation on the epidermal cytokine network. Photochem Photobiol 1996;63(4):397–400. [15] Kuhn A, Sontheimer RD. Cutaneous lupus erythematosus: molecular and cellular basis of clinical findings. Curr Direct Autoimmunity 2008;10:119–40. [16] Meller S, Winterberg F, Gilliet M, et al. Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: an amplification cycle triggering cutaneous lupus erythematosus. Arthritis Rheum 2005;52(5):1504–16. [17] Norris DA, Whang K, David-Bajar K, Bennion SD. The influence of ultraviolet light on immunological cytotoxicity in the skin. Photochem Photobiol 1997;65(4):636–46. [18] Chung JH, Kwon OS, Eun HC, et al. Apoptosis in the pathogenesis of cutaneous lupus erythematosus. Am J Dermatopathol 1998;20(3):233–41. [19] Zhang M, Zhang Y, Wang L, Li F. [Expression of Fas and Fas ligand in lesions of patients with discoid lupus erythematosus]. Hua xi yi ke da xue xue bao = Journal of West China University of Medical Sciences = Huaxi yike daxue xuebao/[bian ji zhe, Hua xi yi ke da xue xue bao bian wei hui]. December 2001;32(4):513–515. [20] Kuhn A, Herrmann M, Kleber S, et al. Accumulation of apoptotic cells in the epidermis of patients with cutaneous lupus erythematosus after ultraviolet irradiation. Arthritis Rheum 2006;54(3):939–50. [21] Munoz LE, Lauber K, Schiller M, Manfredi AA, Herrmann M. The role of defective clearance of apoptotic cells in systemic autoimmunity. Nat Rev Rheumatol 2010;6(5):280–9. [22] Reefman E, de Jong MC, Kuiper H, et al. Is disturbed clearance of apoptotic keratinocytes responsible for UVB-induced inflammatory skin lesions in systemic lupus erythematosus? Arthrit Res Therapy 2006;8(6):R156. [23] Reefman E, Kuiper H, Jonkman MF, Limburg PC, Kallenberg CG, Bijl M. Skin sensitivity to UVB irradiation in systemic lupus erythematosus is not related to the level of apoptosis induction in keratinocytes. Rheumatology 2006;45(5):538–44. [24] Oke V, Vassilaki I, Espinosa A, et al. High Ro52 expression in spontaneous and UV-induced cutaneous inflammation. J Invest Dermatol 2009;129(8): 2000–10. [25] Barkauskaite V, Ek M, Popovic K, Harris HE, Wahren-Herlenius M, Nyberg F. Translocation of the novel cytokine HMGB1 to the cytoplasm and extracellular space coincides with the peak of clinical activity in experimentally UVinduced lesions of cutaneous lupus erythematosus. Lupus 2007;16(10):794–802. [26] Urbonaviciute V, Furnrohr BG, Meister S, et al. Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE. J Exp Med 2008;205(13):3007–18. [27] Caricchio R, McPhie L, Cohen PL. Ultraviolet B radiation-induced cell death: critical role of ultraviolet dose in inflammation and lupus autoantigen redistribution. J Immunol 2003;171(11):5778–86. [28] Hooks JJ, Moutsopoulos HM, Geis SA, Stahl NI, Decker JL, Notkins AL. Immune interferon in the circulation of patients with autoimmune disease. New England J Med 1979;301(1):5–8.

E.S. Robinson, V.P. Werth / Cytokine 73 (2015) 326–334 [29] Savarese E, Chae OW, Trowitzsch S, et al. U1 small nuclear ribonucleoprotein immune complexes induce type I interferon in plasmacytoid dendritic cells through TLR7. Blood 2006;107(8):3229–34. [30] Bose A, Baral R. IFNalpha2b stimulated release of IFNgamma differentially regulates T cell and NK cell mediated tumor cell cytotoxicity. Immunol Lett 2007;108(1):68–77. [31] Zella D, Barabitskaja O, Casareto L, et al. Recombinant IFN-alpha (2b) increases the expression of apoptosis receptor CD95 and chemokine receptors CCR1 and CCR3 in monocytoid cells. J Immunol 1999;163(6):3169–75. [32] Zahn S, Rehkamper C, Ferring-Schmitt S, Bieber T, Tuting T, Wenzel J. Interferon-alpha stimulates TRAIL expression in human keratinocytes and peripheral blood mononuclear cells: implications for the pathogenesis of cutaneous lupus erythematosus. British J Dermatol 2011;165(5):1118–23. [33] Braunstein I, Klein R, Okawa J, Werth VP. The interferon-regulated gene signature is elevated in subacute cutaneous lupus erythematosus and discoid lupus erythematosus and correlates with the cutaneous lupus area and severity index score. British J Dermatol 2012;166(5):971–5. [34] Wenzel J, Zahn S, Mikus S, Wiechert A, Bieber T, Tuting T. The expression pattern of interferon-inducible proteins reflects the characteristic histological distribution of infiltrating immune cells in different cutaneous lupus erythematosus subsets. British J Dermatol 2007;157(4):752–7. [35] Farkas L, Beiske K, Lund-Johansen F, Brandtzaeg P, Jahnsen FL. Plasmacytoid dendritic cells (natural interferon- alpha/beta-producing cells) accumulate in cutaneous lupus erythematosus lesions. Am J Pathol 2001;159(1):237–43. [36] Wenzel J, Worenkamper E, Freutel S, et al. Enhanced type I interferon signalling promotes Th1-biased inflammation in cutaneous lupus erythematosus. J Pathol 2005;205(4):435–42. [37] Jarvinen TM, Hellquist A, Koskenmies S, et al. Tyrosine kinase 2 and interferon regulatory factor 5 polymorphisms are associated with discoid and subacute cutaneous lupus erythematosus. Exp Dermatol 2010;19(2):123–31. [38] Rice G, Newman WG, Dean J, et al. Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome. Am J Hum Genet 2007;80(4):811–5. [39] Arrue I, Saiz A, Ortiz-Romero PL, Rodriguez-Peralto JL. Lupus-like reaction to interferon at the injection site: report of five cases. J Cutan Pathol 2007;34(Suppl 1):18–21. [40] Kim T, Kanayama Y, Negoro N, Okamura M, Takeda T, Inoue T. Serum levels of interferons in patients with systemic lupus erythematosus. Clin Exp Immunol 1987;70(3):562–9. [41] Dustin ML, Singer KH, Tuck DT, Springer TA. Adhesion of T lymphoblasts to epidermal keratinocytes is regulated by interferon gamma and is mediated by intercellular adhesion molecule 1 (ICAM-1). J Exp Med 1988;167(4):1323–40. [42] Matsuura K, Otsuka F, Fujisawa H. Effects of interferons on tumour necrosis factor alpha production from human keratinocytes. Cytokine 1998;10(7):500–5. [43] Zahn S, Rehkamper C, Kummerer BM, et al. Evidence for a pathophysiological role of keratinocyte-derived type III interferon (IFNlambda) in cutaneous lupus erythematosus. J Invest Dermatol 2011;131(1):133–40. [44] Sommereyns C, Paul S, Staeheli P, Michiels T. IFN-lambda (IFN-lambda) is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo. PLoS Pathog 2008;4(3):e1000017. [45] Kuznik A, Bencina M, Svajger U, Jeras M, Rozman B, Jerala R. Mechanism of endosomal TLR inhibition by antimalarial drugs and imidazoquinolines. J Immunol 2011;186(8):4794–804. [46] Merrill JT, Wallace DJ, Petri M, et al. Safety profile and clinical activity of sifalimumab, a fully human anti-interferon alpha monoclonal antibody, in systemic lupus erythematosus: a phase I, multicentre, double-blind randomised study. Ann Rheum Dis 2011;70(11):1905–13. [47] Merrill JCV, Box J, et al. Results of a randomized, placebo-controlled, phase 2A study of sifalimumab, an anti-interferon-alpha monoclonal antibody, administered subcutaneously in subjects with systemic lupus erythematosus. Ann Rheum Dis 2011;70(Suppl 3):314. [48] McBride JM, Jiang J, Abbas AR, et al. Safety and pharmacodynamics of rontalizumab in patients with systemic lupus erythematosus: results of a phase I, placebo-controlled, double-blind, dose-escalation study. Arthritis Rheum 2012;64(11):3666–76. [49] Kalunian K, Merrill JT, Maciuca R, Ouyang W, McBride JM, Townsend MJ. Efficacy and safety of rontalizumab (Anti-Interferon Alpha) in SLE subjects with restricted immunosuppressant use: results of a randomized, doubleblind, placebo-controlled phase 2 study. [abstract]. Arthritis Rheum 2012;64(Suppl 10):2622. [50] Werth VP, Zhang W, Dortzbach K, Sullivan K. Association of a promoter polymorphism of tumor necrosis factor-alpha with subacute cutaneous lupus erythematosus and distinct photoregulation of transcription. J Invest Dermatol 2000;115(4):726–30. [51] Maczynska I, Millo B, Ratajczak-Stefanska V, et al. Proinflammatory cytokine (IL-1beta, IL-6, IL-12, IL-18 and TNF-alpha) levels in sera of patients with subacute cutaneous lupus erythematosus (SCLE). Immunol Lett 2006;102(1):79–82. [52] Zampieri S, Alaibac M, Iaccarino L, et al. Tumour necrosis factor alpha is expressed in refractory skin lesions from patients with subacute cutaneous lupus erythematosus. Ann Rheum Dis 2006;65(4):545–8. [53] Werth VP, Zhang W. Wavelength-specific synergy between ultraviolet radiation and interleukin-1 alpha in the regulation of matrix-related genes: mechanistic role for tumor necrosis factor-alpha. J Invest Dermatol 1999;113(2):196–201.

333

[54] Fujisawa H, Wang B, Kondo S, Shivji GM, Sauder DN. Costimulation with ultraviolet B and interleukin-1 alpha dramatically increase tumor necrosis factor-alpha production in human dermal fibroblasts. J Interferon Cytokine Res: Offic J Int Soc Interferon Cytokine Res 1997;17(5):307–13. [55] Bashir MM, Sharma MR, Werth VP. UVB and proinflammatory cytokines synergistically activate TNF-alpha production in keratinocytes through enhanced gene transcription. J Invest Dermatol 2009;129(4):994–1001. [56] 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 2008;58(10):3205–15. [57] Fisher GJ, Datta SC, Talwar HS, et al. Molecular basis of sun-induced premature skin ageing and retinoid antagonism. Nature 1996;379(6563):335–9. [58] Bazzoni F, Kruys V, Shakhov A, Jongeneel CV, Beutler B. Analysis of tumor necrosis factor promoter responses to ultraviolet light. J Clin Investig 1994;93(1):56–62. [59] Bashir MM, Sharma MR, Werth VP. TNF-alpha production in the skin. Arch Dermatol Res 2009;301(1):87–91. [60] Wang B, Fujisawa H, Zhuang L, et al. Depressed Langerhans cell migration and reduced contact hypersensitivity response in mice lacking TNF receptor p75. J Immunol 1997;159(12):6148–55. [61] Palucka AK, Blanck JP, Bennett L, Pascual V, Banchereau J. Cross-regulation of TNF and IFN-alpha in autoimmune diseases. Proc Natl Acad Sci USA 2005;102(9):3372–7. [62] Gerl V, Hostmann B, Johnen C, et al. The intracellular 52-kd Ro/SSA autoantigen in keratinocytes is up-regulated by tumor necrosis factor alpha via tumor necrosis factor receptor I. Arthrit Rheum 2005;52(2):531–8. [63] Dorner T, Hucko M, Mayet WJ, Trefzer U, Burmester GR, Hiepe F. Enhanced membrane expression of the 52 kDa Ro(SS-A) and La(SS-B) antigens by human keratinocytes induced by TNF alpha. Ann Rheum Dis 1995;54(11):904–9. [64] Gabay C, Cakir N, Moral F, et al. Circulating levels of tumor necrosis factor soluble receptors in systemic lupus erythematosus are significantly higher than in other rheumatic diseases and correlate with disease activity. J Rheumatol 1997;24(2):303–8. [65] Gomez D, Correa PA, Gomez LM, Cadena J, Molina JF, Anaya JM. Th1/Th2 cytokines in patients with systemic lupus erythematosus: is tumor necrosis factor alpha protective? Semin Arthrit Rheum 2004;33(6):404–13. [66] Moulis G, Sommet A, Lapeyre-Mestre M, Montastruc JL, on behalf of the Association Francaise des Centres Regionaux de P. Is the risk of tumour necrosis factor inhibitor-induced lupus or lupus-like syndrome the same with monoclonal antibodies and soluble receptor? A case/non-case study in a nationwide pharmacovigilance database. Rheumatology 2014. Jun 4. [67] Kerbleski JF, Gottlieb AB. Dermatological complications and safety of anti-TNF treatments. Gut 2009;58(8):1033–9. [68] Aringer M, Smolen JS. Efficacy and safety of TNF-blocker therapy in systemic lupus erythematosus. Exp Opin Drug Safety 2008;7(4):411–9. [69] McCarthy EM, Smith S, Lee RZ, et al. The association of cytokines with disease activity and damage scores in systemic lupus erythematosus patients. Rheumatology 2014. Apr 4. [70] Urbanski A, Schwarz T, Neuner P, et al. Ultraviolet light induces increased circulating interleukin-6 in humans. J Invest Dermatol 1990;94(6): 808–11. [71] Wozniacka A, Lesiak A, Boncela J, Smolarczyk K, McCauliffe DP, SysaJedrzejowska A. The influence of antimalarial treatment on IL-1beta, IL-6 and TNF-alpha mRNA expression on UVB-irradiated skin in systemic lupus erythematosus. British J Dermatol 2008;159(5):1124–30. [72] Mellor-Pita S, Citores MJ, Castejon R, et al. Monocytes and T lymphocytes contribute to a predominance of interleukin 6 and interleukin 10 in systemic lupus erythematosus. Cytomet. Part B, Clin Cytomet 2009;76(4):261–70. [73] Chun HY, Chung JW, Kim HA, et al. Cytokine IL-6 and IL-10 as biomarkers in systemic lupus erythematosus. J Clin Immunol 2007;27(5):461–6. [74] Grondal G, Gunnarsson I, Ronnelid J, Rogberg S, Klareskog L, Lundberg I. Cytokine production, serum levels and disease activity in systemic lupus erythematosus. Clin Exp Rheumatol 2000;18(5):565–70. [75] Werth VP, Bashir MM, Zhang W. IL-12 completely blocks ultraviolet-induced secretion of tumor necrosis factor alpha from cultured skin fibroblasts and keratinocytes. J Invest Dermatol 2003;120(1):116–22. [76] Houssiau FA, Mascart-Lemone F, Stevens M, et al. IL-12 inhibits in vitro immunoglobulin production by human lupus peripheral blood mononuclear cells (PBMC). Clin Exp Immunol 1997;108(2):375–80. [77] Yang J, Chu Y, Yang X, et al. Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthrit Rheum 2009;60(5):1472–83. [78] Wong CK, Lit LC, Tam LS, Li EK, Wong PT, Lam CW. Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity. Clin Immunol 2008;127(3):385–93. [79] Dong G, Ye R, Shi W, et al. IL-17 induces autoantibody overproduction and peripheral blood mononuclear cell overexpression of IL-6 in lupus nephritis patients. Chin Med J 2003;116(4):543–8. [80] Chang SH, Dong C. Signaling of interleukin-17 family cytokines in immunity and inflammation. Cell Signal 2011;23(7):1069–75. [81] Tanasescu C, Balanescu E, Balanescu P, et al. IL-17 in cutaneous lupus erythematosus. Eur J Int Med 2010;21(3):202–7. [82] Jabbari A, Suarez-Farinas M, Fuentes-Duculan J, et al. Dominant Th1 and minimal Th17 skewing in discoid lupus revealed by transcriptomic comparison with psoriasis. J Invest Dermatol 2014;134(1):87–95.

334

E.S. Robinson, V.P. Werth / Cytokine 73 (2015) 326–334

[83] Kanda N, Shimizu T, Tada Y, Watanabe S. IL-18 enhances IFN-gamma-induced production of CXCL9, CXCL10, and CXCL11 in human keratinocytes. Eur J Immunol 2007;37(2):338–50. [84] Wong CK, Li EK, Ho CY, Lam CW. Elevation of plasma interleukin-18 concentration is correlated with disease activity in systemic lupus erythematosus. Rheumatology 2000;39(10):1078–81. [85] Park MC, Park YB, Lee SK. Elevated interleukin-18 levels correlated with disease activity in systemic lupus erythematosus. Clin Rheumatol 2004;23(3):225–9. [86] Calvani N, Richards HB, Tucci M, Pannarale G, Silvestris F. Up-regulation of IL18 and predominance of a Th1 immune response is a hallmark of lupus nephritis. Clin Exp Immunol 2004;138(1):171–8. [87] Sperber K, Quraishi H, Kalb TH, Panja A, Stecher V, Mayer L. Selective regulation of cytokine secretion by hydroxychloroquine: inhibition of interleukin 1 alpha (IL-1-alpha) and IL-6 in human monocytes and T cells. J Rheumatol 1993;20(5):803–8.

[88] Illei GG, Shirota Y, Yarboro CH, et al. Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthrit Rheum 2010;62(2):542–52. [89] Makol A, Gibson LE, Michet CJ. Successful use of interleukin 6 antagonist tocilizumab in a patient with refractory cutaneous lupus and urticarial vasculitis. J Clin Rheumatol: Pract Rep Rheum Musculoskeletal Diseases 2012;18(2):92–5. [90] Szepietowski JC, Nilganuwong S, Wozniacka A, et al. Phase I, randomized, double-blind, placebo-controlled, multiple intravenous, dose-ascending study of sirukumab in cutaneous or systemic lupus erythematosus. Arthrit Rheum 2013;65(10):2661–71. [91] Llorente L, Richaud-Patin Y, Garcia-Padilla C, et al. Clinical and biologic effects of anti-interleukin-10 monoclonal antibody administration in systemic lupus erythematosus. Arthrit Rheum 2000;43(8):1790–800.