MD François Chasset
email: francois.chasset@aphp.fr

Camille Francès

Current concepts and future approaches in the treatment of cutaneous lupus erythematosus: a comprehensive review Running heading: Treatment of cutaneous lupus erythematosus

Standard treatment of cutaneous lupus erythematosus (CLE) includes preventive measures such as smoking cessation and photoprotection associated with topical therapies and antimalarial agents, which are recommended as first-line systemic treatment. In more severe disease, alternative therapeutic options include immunosuppressive and immunomodulatory drugs. Recently, the development of specific tools to assess CLE activity and the publication of European CLE guidelines have improved the management of CLE. Moreover, several biologic agents are currently studied specifically in CLE or in systemic lupus erythematosus with assessment of skin involvement and may be promising therapies. However, improvement of the management of CLE remains a major unmet need. In this review, we summarize current concepts in the management of CLE as well as future approaches for more targeted treatments.

Key points:

 Some targeted agents that have shown some promise in skin manifestations with systemic lupus erythematosus.

 Future studies are needed specifically for cutaneous lupus erythematosus (CLE), with responses for each of the CLE subtypes reported separately.

Introduction 1.1 Cutaneous lupus erythematosus (CLE) subtype classification

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of auto-antibodies to nuclear antigens and a broad spectrum of clinical manifestations, including specific cutaneous findings in 75% to 80% of patients [START_REF] Cervera | Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1,000 patients. The European Working Party on Systemic Lupus Erythematosus[END_REF]. Cutaneous lupus erythematosus (CLE) may be associated with SLE or present as a separate entity with isolated cutaneous manifestations. Currently, we have no uniform definition of cutaneous CLE, and different grouping schemes have been discussed on the basis of clinical findings, duration of lesions, pathological findings, direct immunofluorescence results and immunological laboratory abnormalities [START_REF] Lipsker | 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[END_REF][START_REF] Kuhn | The classification and diagnosis of cutaneous lupus erythematosus[END_REF]. CLE is generally subdivided into different subtypes including acute CLE (ACLE), subacute CLE (SCLE) and chronic CLE (CCLE) [START_REF] Gilliam | Distinctive cutaneous subsets in the spectrum of lupus erythematosus[END_REF].

CCLE includes discoid CLE (DLE), chilblain lupus, lupus panniculitis and lupus tumidus (LET). Some groups suggest classifying LET as a separate entity of CLE, namely intermittent CLE subtype (ICLE), because of its better course and prognosis [START_REF] Kuhn | The classification and diagnosis of cutaneous lupus erythematosus[END_REF][START_REF] Schmitt | Lupus erythematosus tumidus is a separate subtype of cutaneous lupus erythematosus[END_REF].

Epidemiology

The incidence of CLE ranges from 2.59 to 4.3 cases per 100,000 persons per year [START_REF] Durosaro | Incidence of cutaneous lupus erythematosus, 1965-2005: a population-based study[END_REF][START_REF] Deligny | Incidence of chronic cutaneous lupus erythematosus in French Guiana: a retrospective population-based study[END_REF][START_REF] Grönhagen | Cutaneous lupus erythematosus and the association with systemic lupus erythematosus: a population-based cohort of 1088 patients in Sweden[END_REF] and is globally similar to that of SLE ranging from 3.32 to 9.11 cases per 100,000 persons per year [START_REF] Arnaud | Prevalence and incidence of systemic lupus erythematosus in France: a 2010 nation-wide population-based study[END_REF]. Considering the epidemiology of CLE subtypes, a large population-based cohort of 1088 patients in Sweden found that the most common subset was DLE (80%), followed by SCLE (15.7%) and other subtypes [START_REF] Grönhagen | Cutaneous lupus erythematosus and the association with systemic lupus erythematosus: a population-based cohort of 1088 patients in Sweden[END_REF]. However, a study of 1002 CLE patients of the European Society of Cutaneous Lupus Erythematosus (EUSCLE) cohort reported a prevalence of CCLE of 47%, followed by SCLE (24%), ACLE (22%) and ICLE (7%). In this study, 347 (34.6%) patients presented two or more different CLE subtypes [START_REF] Biazar | Cutaneous lupus erythematosus: first multicenter database analysis of 1002 patients from the European Society of Cutaneous Lupus Erythematosus (EUSCLE)[END_REF]. Recent advances in the pathogenesis of CLE emphasize a multifactorial disease involving genetic susceptibility [START_REF] Kunz | Genome-wide association study identifies new susceptibility loci for cutaneous lupus erythematosus[END_REF]; environmental factors such as UV exposure, drugs, smoking, radiotherapy [START_REF] Szczęch | Trigger factors of cutaneous lupus erythematosus: a review of current literature[END_REF]; and induction of deregulated innate and adaptive immune responses [START_REF] Yu | Immunologic and genetic considerations of cutaneous lupus erythematosus: a comprehensive review[END_REF].

CLE treatment generalities

Standard treatment of CLE includes preventive measures such as smoking cessation and photoprotection associated with topical therapy especially for mild disease. Antimalarials (AMs), including hydroxychloroquine (HCQ), chloroquine (CQ) and quinacrine/mepacrine (QC), are recommended as first-line systemic treatment of CLE. In more severe disease, alternative therapeutic options include immunosuppressive and immunomodulatory drugs.

More recently, several biologic agents have been developed for SLE and may be promising for CLE [START_REF] Felten | The 2018 pipeline of targeted therapies under clinical development for Systemic Lupus Erythematosus: a systematic review of trials[END_REF]. Recently, the management of CLE has been improved with the development of European guidelines for CLE treatment [START_REF] Kuhn | S2k Guideline for Treatment of Cutaneous Lupus Erythematosus[END_REF]. However, improvement in the management of CLE remains a major unmet need. Indeed, most published studies of CLE are of poor-quality randomized studies are difficult to perform in rare diseases. In this review, we summarize current concepts in the management of CLE as well as future approaches for more targeted treatments in CLE.

Literature search

This review summarizes several systematic reviews and meta-analyses performed by our group using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist [START_REF] Liberati | The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses of Studies That Evaluate Health Care Interventions: Explanation and Elaboration[END_REF] focusing on AMs [START_REF] Chasset | Influence of smoking on the efficacy of antimalarials in cutaneous lupus: a meta-analysis of the literature[END_REF][START_REF] Chasset | Efficacy and comparison of antimalarials in cutaneous lupus erythematosus subtypes: a systematic review and meta-analysis[END_REF] and thalidomide [START_REF] Chasset | Efficacy and tolerance profile of thalidomide in cutaneous lupus erythematosus: A systematic review and metaanalysis[END_REF] use in CLE. For other immunosuppressive/immunomodulatory drugs and biological therapies, we searched MEDLINE/PubMed until March 2019 by using the MeSH terms "Lupus Erythematosus, Cutaneous" and "Lupus Erythematosus, Systemic" and reviewed studies assessing cutaneous response in lupus patients with a focus on CLE subtypes when available. For biological therapies, we also searched studies specifically designed for CLE identified in ClinicalTrials.gov.

Assessment of CLE activity and damage

The Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) [START_REF] Petri | Combined oral contraceptives in women with systemic lupus erythematosus[END_REF] and British Isles Lupus Assessment Group (BILAG) scale [START_REF] Romero-Diaz | Measures of adult systemic lupus erythematosus: updated version of British Isles Lupus Assessment Group (BILAG 2004), European Consensus Lupus Activity Measurements (ECLAM), Systemic Lupus Activity Measure, Revised (SLAM-R), Systemic Lupus Activity Questionnaire for Population Studies (SLAQ), Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI)[END_REF] are currently used to assess activity and response to treatment in SLE patients. These scores include cutaneous components; however, they do not accurately reflect disease severity or cutaneous improvement of CLE. Recently, a quantitative scoring tool, the CLE Disease Area and Severity Index (CLASI), was specifically developed to assess CLE activity and damage [START_REF] Albrecht | The CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index): an outcome instrument for cutaneous lupus erythematosus[END_REF]. A 4-point or 20% decrease in activity score has been associated with an objective clinical improvement [START_REF] Bein | Evaluation of disease activity and damage in different subtypes of cutaneous lupus erythematosus using the CLASI[END_REF]. However, a 50% decrease in activity score is considered an appropriate definition for cutaneous improvement and has been used in several recent phase II trials [START_REF] Furie | Anifrolumab, an Anti-Interferon-α Receptor Monoclonal Antibody, in Moderate-to-Severe Systemic Lupus Erythematosus[END_REF][START_REF] Van Vollenhoven | 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[END_REF]. Moreover, CLASI activity allows for classifying CLE severity: mild (CLASI activity score 0 to 9), moderate (score 10 to 20) and severe (score 21 to 70) [START_REF] Bein | Evaluation of disease activity and damage in different subtypes of cutaneous lupus erythematosus using the CLASI[END_REF].

 The CLE Disease Area and Severity Index (CLASI) is an appropriate tool to assess CLE severity or cutaneous improvement in clinical trials. SELENA-SLEDAI and BILAG skin components should not be used to assess skin improvement.

Preventive non-pharmaceutical measures

Smoking cessation

A meta-analysis showed an increased risk of developing SLE among smoking patients as compared with non-smokers (pooled odds ratio [OR] 1.56 [95% confidence interval (CI) 1.26-1.95]) [START_REF] Jiang | Smoking and the risk of systemic lupus erythematosus: an updated systematic review and cumulative meta-analysis[END_REF]. Moreover, several studies showed increased CLE activity, cutaneous damage index, and scarring scores in CLE among smokers as compared with non-smokers [START_REF] Turchin | Cigarette smoking and cutaneous damage in systemic lupus erythematosus[END_REF][START_REF] Bourré-Tessier | Association of smoking with cutaneous manifestations in systemic lupus erythematosus[END_REF]. In a retrospective study of 218 patients, current smokers had higher median CLASI scores than never smokers (9.5 vs 7, p=0.02) [START_REF] Piette | Impact of smoking in cutaneous lupus erythematosus[END_REF] and were more likely to receive a combination of HCQ and QC, thereby suggesting refractory disease [START_REF] Piette | Impact of smoking in cutaneous lupus erythematosus[END_REF]. Also, an interaction between smoking and efficacy of AMs has been suggested. Indeed, a meta-analysis from our group showed that smoking is associated with a 2-fold decrease in the proportion of patients with CLE achieving cutaneous improvement with AMs [START_REF] Chasset | Influence of smoking on the efficacy of antimalarials in cutaneous lupus: a meta-analysis of the literature[END_REF]. Moreover, smoking has been found associated with decreased efficacy among SLE patients receiving belimumab [START_REF] Parodis | Smoking and pre-existing organ damage reduce the efficacy of belimumab in systemic lupus erythematosus[END_REF].

 The smoking status of patients with CLE should be assessed systematically and appropriate intervention offered to those who smoke, especially those with refractory CLE.

Photoprotection:

In a study of 431 CLE patients, 61.7% exhibited positive photoprovocation with ultraviolet (UV) B (or UVA). The frequency of positive photoprovocation varied by CLE subtype, with ICLE and SCLE the most photosensitive (74.8% and 67.5%) [START_REF] Ruland | Updated analysis of standardized photoprovocation in patients with cutaneous lupus erythematosus[END_REF]. UVB exposure plays a central role in CLE pathogenesis. In mice and human CLE lesions, UVB irradiation has been shown to induce a recruitment of inflammatory cells and production of pro-inflammatory cytokines including interleukin (IL) IL-1β, IL-6 and tumor necrosis factor alpha (TNF-α) and type I interferon (IFN) [START_REF] Wozniacka | The influence of antimalarial treatment on IL-1beta, IL-6 and TNF-alpha mRNA expression on UVB-irradiated skin in systemic lupus erythematosus[END_REF][START_REF] Sontheimer | Ultraviolet B Irradiation Causes Stimulator of Interferon Genes-Dependent Production of Protective Type I Interferon in Mouse Skin by Recruited Inflammatory Monocytes[END_REF]. UVB irradiation is responsible for apoptosis of keratinocytes [START_REF] Kuhn | Accumulation of apoptotic cells in the epidermis of patients with cutaneous lupus erythematosus after ultraviolet irradiation[END_REF]. Keratinocytic apoptosis results in the release of endogenous nucleic acids that can induce a type I IFN response in keratinocytes via pathogen recognition receptors [START_REF] Scholtissek | Immunostimulatory Endogenous Nucleic Acids Drive the Lesional Inflammation in Cutaneous Lupus Erythematosus[END_REF]. The LE-prone MRL/lpr mouse showed a recruitment of plasmacytoid dendritic cells (pDCs) and an increase in the type I IFN response after UVB irradiation [START_REF] Yin | Ultraviolet B irradiation induces skin accumulation of plasmacytoid dendritic cells: a possible role for chemerin[END_REF]. pDCs are the main IFN-α producer and are thought to play a central role in SLE pathogenesis [START_REF] Chasset | Targeting interferons and their pathways in systemic lupus erythematosus[END_REF]. Previous studies showed that pDCs accumulate in CLE lesions and their density correlated well with the number of cells expressing the IFNα/β-inducible protein MxA, which suggests that they produce IFNα locally [START_REF] Farkas | Plasmacytoid dendritic cells (natural interferon-alpha/beta-producing cells) accumulate in cutaneous lupus erythematosus lesions[END_REF]. However, recent studies suggested that pDCs could not be the only producer of type I IFN in CLE lesions. Indeed, keratinocyteproduced IFN-κ has been found the source of basal type I IFN activity in healthy skin [START_REF] Sarkar | Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa[END_REF].

Moreover, IFN-κ secretion can activate DCs/pDCs and may participate in recruiting pDCs in skin and IFN-α and initiate a deregulated immune response in CLE lesions [START_REF] Sarkar | Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa[END_REF].

All these data support the crucial role of UV exposure in the pathogenesis of CLE lesions and the need for photoprotection in the management of CLE. Photoprotection should include protective clothing and chemical methods. Indeed, a randomized controlled trial (RCT) demonstrated that the application of a broad-spectrum sunscreen (UVB and UVA) with a high protection factor (SPF 60) could prevent UV-induced skin lesions in CLE patients [START_REF] Kuhn | Photoprotective effects of a broad-spectrum sunscreen in ultraviolet-induced cutaneous lupus erythematosus: a randomized, vehicle-controlled, double-blind study[END_REF].

Moreover, a study showed that applying a broad-spectrum liposomal sunscreen 20 min before combined standardized UVA/UVB irradiation could reduce lesional tissue damage and inhibit the typical IFN-driven inflammatory response in CLE lesions [START_REF] Zahn | Ultraviolet light protection by a sunscreen prevents interferon-driven skin inflammation in cutaneous lupus erythematosus[END_REF]. Also, vitamin D supplementation may be included in photoprotective methods. Indeed, data suggested that patients with CLE show vitamin D deficiency throughout the year [START_REF] Heine | Vitamin D deficiency in patients with cutaneous lupus erythematosus is prevalent throughout the year[END_REF]. Moreover, an RCT of healthy adults found vitamin D supplementation associated with reduced expression of proinflammatory mediators such as TNF-α and increased skin expression of the antiinflammatory mediator arginase-1 as well as genes related to skin barrier repair [START_REF] Scott | Oral Vitamin D Rapidly Attenuates Inflammation from Sunburn: An Interventional Study[END_REF]. Finally, a retrospective study showed that treating vitamin D deficiency improved CLASI activity in CLE patients [START_REF] Cutillas-Marco | Vitamin D and cutaneous lupus erythematosus: effect of vitamin D replacement on disease severity[END_REF].

 RCTs support the use of photoprotection to prevent UV-induced skin lesions in CLE patients.

 Photoprotection should include protective clothing and broad-spectrum sunscreen (UVB and UVA) as well as vitamin D supplementation.

Drug-induced cutaneous lupus and drug withdrawal

Drug-induced CLE (DILE) should be suspected with SCLE. Indeed, among a cohort of 90 SCLE patients, 11 (12%) had DILE [START_REF] Marzano | Drug-induced subacute cutaneous lupus erythematosus: evidence for differences from its idiopathic counterpart[END_REF]. Subacute DILE more frequently exhibited widespread cutaneous involvement with malar rash and was more frequently bullous or erythema multiforme-like as compared with idiopathic SCLE [START_REF] Marzano | Drug-induced subacute cutaneous lupus erythematosus: evidence for differences from its idiopathic counterpart[END_REF]. However, in a recent multicentric study of 232 patients, including 67 (29%) with subacute DILE, the presentation pattern or serology did not differ, except that people with subacute DILE were older than those with idiopathic SCLE [START_REF] Guicciardi | Are there distinct clinical and pathological features distinguishing Idiopathic from Drug-Induced Subacute Cutaneous Lupus Erythematosus? A European retrospective multicenter study[END_REF]. A case-control study of 234 SCLE patients found subacute DILE frequently associated with use of the drugs terbinafine (OR 52.9, 95% CI 6.6-∞), TNFα inhibitors (OR 8.0, 95% CI 1.6-37.2), antiepileptics (OR 3.4, 95% CI 1.9-5.8) and proton pump inhibitors (OR 2.9, 95% CI 2.0-4.0) [START_REF] Grönhagen | Subacute cutaneous lupus erythematosus and its association with drugs: a population-based matched case-control study of 234 patients in Sweden[END_REF]. This study showed that subacute DILE is reversible once the drug is discontinued, which indicates the importance of screening patients with SCLE for potentially triggering drugs [START_REF] Grönhagen | Subacute cutaneous lupus erythematosus and its association with drugs: a population-based matched case-control study of 234 patients in Sweden[END_REF].

 Drug-induced CLE (DILE) should be suspected particularly with SCLE.

 Treatment discontinuation leads to resolution of DILE lesions in most cases.

Topical treatments

Recent European guidelines for CLE treatments recommended topical therapy as first-line treatment for localized CLE and/or mild disease [START_REF] Kuhn | S2k Guideline for Treatment of Cutaneous Lupus Erythematosus[END_REF]. Topical treatments mostly include topical corticosteroids and calcineurin inhibitors.

Topical corticosteroids

Potent topical corticosteroids are more effective than less potent ones in treating DLE lesions. Indeed, in an RCT enrolling 37 DLE patients, 0.05% fluocinonide (a potent corticosteroid cream) conferred a better cutaneous improvement at 6 weeks as compared with 1% hydrocortisone (a low-potency corticosteroid cream) [START_REF] Roenigk | Discoid lupus erythematosus. Diagnostic features and evaluation of topical corticosteroid therapy[END_REF]. Because of cutaneous side effects, including atrophy, telangiectasia, and steroid-induced rosacea-like dermatitis, it is recommended that treatment with topical corticosteroids be intermittent and not exceed a treatment duration of a few weeks [START_REF] Kuhn | S2k Guideline for Treatment of Cutaneous Lupus Erythematosus[END_REF]. However, for scarring alopecia of DLE, prolonged use may be necessary to achieve satisfactory results.

Intralesional corticosteroids

Intralesional corticosteroids have been used only in retrospective case series. Intralesional therapy showed interesting results particularly for hyperkeratotic DLE lesions, which are often unresponsive to topical treatments [START_REF] Spann | Clinical, serologic and immunogenetic studies in patients with chronic cutaneous (discoid) lupus erythematosus who have verrucous and/or hypertrophic skin lesions[END_REF]. Injections of triamcinolone acetonide suspension 2.5 to 10 mg/ml (depending on the site) may be repeated at 4-to 6-week intervals, and some authors suggested that this may be useful in preventing further hair loss in DLE lesions of the scalp [START_REF] Ting | Local therapy for cutaneous and systemic lupus erythematosus: practical and theoretical considerations[END_REF].

Topical calcineurin inhibitors

Topical calcineurin inhibitors represent a good alternative to topical corticosteroids. Indeed, an RCT found similar efficacy between pimecrolimus 1% cream and betamethasone valerate 0.1% cream in treating facial DLE lesions [START_REF] Barikbin | Pimecrolimus 1% cream versus betamethasone 17-valerate 0.1% cream in the treatment of facial discoid lupus erythematosus: a double-blind, randomized pilot study[END_REF]. Moreover, in an RCT, both twice-daily 0.1% topical tacrolimus and once-daily 0.05% clobetasol propionate conferred significant improvement in DLE lesions. Better improvement was observed with 0.05% clobetasol propionate in this study but with a higher rate of cutaneous adverse events [START_REF] Pothinamthong | A comparative study in efficacy and safety of 0.1% tacrolimus and 0.05% clobetasol propionate ointment in discoid lupus erythematosus by modified cutaneous lupus erythematosus disease area and severity index[END_REF]. In another RCT, CLE patients receiving tacrolimus 0.1% ointment showed significant improvement of skin lesions after 28 and 56 days but not after 84 days as compared with skin lesions treated with vehicle, which suggests transient efficacy or short-term adherence. In this trial, patients with LET had the most improvement [START_REF] Kuhn | Efficacy of tacrolimus 0.1% ointment in cutaneous lupus erythematosus: a multicenter, randomized, double-blind, vehicle-controlled trial[END_REF]. Furthermore, in a case series of 3 patients, topical tacrolimus lotion, 0.3%, in an alcohol base demonstrated improvement in lesion severity and hair regrowth after 3 months for treating AM-refractory scarring alopecia in DLE patients [START_REF] Milam | Treatment of Scarring Alopecia in Discoid Variant of Chronic Cutaneous Lupus Erythematosus With Tacrolimus Lotion, 0.3[END_REF].

Other topical treatments

Among other topical agents that may be used in CLE, 0.5% R-salbutamol, a β2-adrenergic receptor agonist, showed promising results in a double-blind, phase II RCT of 37 DLE patients [START_REF] Jemec | A randomized controlled trial of R-salbutamol for topical treatment of discoid lupus erythematosus[END_REF]. However, topical R-salbutamol is not currently commercially available. Topical retinoids have been found effective in CLE lesions in a few case reports [START_REF] Seiger | Cutaneous lupus treated with topical tretinoin: a case report[END_REF][START_REF] Terao | Two cases of refractory discoid lupus erythematosus successfully treated with topical tocoretinate[END_REF]. Recently, a case report suggested that topical clindamycin may be a potential treatment for refractory CLE lesions [START_REF] Newman | Chronic cutaneous lupus erythematosus and topical clindamycin[END_REF].

 RCTs support the use of topical corticosteroids and topical calcineurin inhibitors for treating CLE lesions.

 Because of cutaneous side effects, the use of topical corticosteroids should not exceed a treatment duration of few weeks except for use in scalp DLE lesions.

Systemic treatments

Antimalarials

Antimalarial efficacy in CLE

AMs including HCQ, CQ and QC are recommended as first-line systemic treatment for CLE [START_REF] Kuhn | S2k Guideline for Treatment of Cutaneous Lupus Erythematosus[END_REF]. In 1965, a randomized placebo-controlled trial suggested the efficacy of HCQ in chronic CLE [START_REF] Kraak | The value of hydroxychloroquine (plaquenil) for the treatment of chronic discoid lupus erythematosus; a double blind triaL[END_REF]. More recently, in a randomized placebo-controlled trial of 103 Japanese CLE patients, the mean CLASI activity score at week 16 did not significantly differ between HCQ and placebo treatment. However, the investigator's global assessment demonstrated a greater proportion of "improved" and "remarkably improved" patients in the HCQ group (51.4% vs 8.7% in the placebo group, p = 0.0002) [START_REF] Yokogawa | Response to hydroxychloroquine in Japanese patients with lupus-related skin disease using the cutaneous lupus erythematosus disease area and severity index (CLASI)[END_REF]. In a systematic review and metaanalysis, among 1990 courses of treatment with AMs from 31 included studies, the overall response to AMs was 63% (95% CI [START_REF] Jemec | A randomized controlled trial of R-salbutamol for topical treatment of discoid lupus erythematosus[END_REF][START_REF] Seiger | Cutaneous lupus treated with topical tretinoin: a case report[END_REF][START_REF] Terao | Two cases of refractory discoid lupus erythematosus successfully treated with topical tocoretinate[END_REF][START_REF] Newman | Chronic cutaneous lupus erythematosus and topical clindamycin[END_REF][START_REF] Kraak | The value of hydroxychloroquine (plaquenil) for the treatment of chronic discoid lupus erythematosus; a double blind triaL[END_REF][START_REF] Yokogawa | Response to hydroxychloroquine in Japanese patients with lupus-related skin disease using the cutaneous lupus erythematosus disease area and severity index (CLASI)[END_REF][START_REF] Ruiz-Irastorza | Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review[END_REF][START_REF] Mittal | Antimalarial drug toxicities in patients with cutaneous lupus and dermatomyositis: A retrospective cohort study[END_REF][START_REF] Costedoat-Chalumeau | Very low blood hydroxychloroquine concentration as an objective marker of poor adherence to treatment of systemic lupus erythematosus[END_REF][START_REF] Francès | Low blood concentration of hydroxychloroquine in patients with refractory cutaneous lupus erythematosus: a French multicenter prospective study[END_REF][START_REF] Chasset | The effect of increasing the dose of hydroxychloroquine (HCQ) in patients with refractory cutaneous lupus erythematosus (CLE): An open-label prospective pilot study[END_REF][START_REF] Chasset | Changing antimalarial agents after inefficacy or intolerance in patients with cutaneous lupus erythematosus: A multicenter observational study[END_REF][START_REF] Zeidi | Increased Myeloid Dendritic Cells and TNF-α Expression Predicts Poor Response to Hydroxychloroquine in Cutaneous Lupus Erythematosus[END_REF][START_REF] Marmor | Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy[END_REF][START_REF] Melles | The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy[END_REF][START_REF] Marmor | Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision)[END_REF]. The response to AMs differed between CLE subtypes, ranging from 31% (95% CI for chilblain lupus to 91% (95% CI 87-93) for acute CLE [START_REF] Chasset | Efficacy and comparison of antimalarials in cutaneous lupus erythematosus subtypes: a systematic review and meta-analysis[END_REF]. In this study, HCQ had higher overall efficacy than CQ but not significantly (OR 1.48, 95% CI 0.98-2.23).

HCQ is usually prescribed as a first-line AM agent because of its better safety profile as compared with chloroquine. Indeed, in a meta-analysis, the prevalence of retinopathy was 2.5% with CQ versus 0.1% with HCQ [START_REF] Ruiz-Irastorza | Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review[END_REF]. Moreover, in a recent study of 534 patients, the risk of retinopathy was higher with CQ than HCQ (hazard ratio 30.35 [95% CI 1.50-613.30]) [START_REF] Mittal | Antimalarial drug toxicities in patients with cutaneous lupus and dermatomyositis: A retrospective cohort study[END_REF].

HCQ blood concentration measurement

Measuring HCQ blood concentration is recommended with persistent CLE activity. Indeed, a very low blood concentration of HCQ < 200 ng/ml is a good marker of poor adherence and may be useful to discriminate between failure of HCQ and non-adherence [START_REF] Costedoat-Chalumeau | Very low blood hydroxychloroquine concentration as an objective marker of poor adherence to treatment of systemic lupus erythematosus[END_REF]. Moreover, a threshold of 750 ng/ml is associated with cutaneous response in CLE patients receiving HCQ [START_REF] Francès | Low blood concentration of hydroxychloroquine in patients with refractory cutaneous lupus erythematosus: a French multicenter prospective study[END_REF]. In a prospective study, 26/32 (81%) CLE patients showed a significant decrease in CLASI activity after increasing HCQ doses to reach blood concentrations > 750 ng/ml. In all, 50% of responders achieved a decrease in HCQ doses without further CLE flare (median follow-up 15.8 months [range 3.06-77.4]) [START_REF] Chasset | The effect of increasing the dose of hydroxychloroquine (HCQ) in patients with refractory cutaneous lupus erythematosus (CLE): An open-label prospective pilot study[END_REF].

Switch of AM agent or addition of QC

In a retrospective study of 63 patients, in case of inefficacy of a first AM agent, 56% of responders had a switch to another agent (CQ > HCQ or HCQ > CQ) at 3 months. However, the median duration before failure of the second AM agent was 9 months (95% CI 6-24). For patients with a switch because of adverse events, the second AM agent was well tolerated in 69% of cases [START_REF] Chasset | Changing antimalarial agents after inefficacy or intolerance in patients with cutaneous lupus erythematosus: A multicenter observational study[END_REF]. In case of failure of HCQ or CQ, the addition of QC is useful in about two thirds of patients [START_REF] Chasset | Efficacy and comparison of antimalarials in cutaneous lupus erythematosus subtypes: a systematic review and meta-analysis[END_REF] and is recommended in European CLE guidelines [START_REF] Kuhn | S2k Guideline for Treatment of Cutaneous Lupus Erythematosus[END_REF]. QC has recently been shown to inhibit both IFN-α and TNF-α, whereas HCQ inhibited only IFN-α, which may explain the synergic association of both molecules [START_REF] Zeidi | Increased Myeloid Dendritic Cells and TNF-α Expression Predicts Poor Response to Hydroxychloroquine in Cutaneous Lupus Erythematosus[END_REF]. However, QC is not available in most European countries because of reports of aplastic anemia. Of note, in the study of Mittal et al., no severe anemia or retinopathy was observed with QC [START_REF] Mittal | Antimalarial drug toxicities in patients with cutaneous lupus and dermatomyositis: A retrospective cohort study[END_REF].

Dosage of HCQ and CQ and risk of retinopathy

The dosage of HCQ and CQ is an important parameter in reducing the risk of retinopathy.

Initially, daily doses of HCQ ≤ 6.5 mg/kg and CQ ≤ 4mg/kg ideal body weight were the highest advocated by the American Academy of Ophthalmology in 2002. Later, the risk of toxicity was found to increase sharply after 5 to 7 years, or a cumulative dose of 1000 g and a dose of 400 mg/day HCQ and 250 mg/day CQ were considered acceptable by the 2011 revised recommendations of the American Academy of Ophthalmology [START_REF] Marmor | Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy[END_REF]. Finally, in a large series of 2361 patients, real body weight predicted risk of retinopathy better than ideal body weight. In this study, daily doses delivered by pharmacists (not prescribed dose) ≥ 5 mg/kg real body weight for HCQ were associated with increased risk of retinopathy [START_REF] Melles | The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy[END_REF] and were used in the latest revisions of the recommendations on screening for CQ and HCQ retinopathy [START_REF] Marmor | Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision)[END_REF].

 RCTs support the use of AMs (mostly HCQ) as a first-line systemic agent for

CLE.

 HCQ blood concentration measurement is useful to discriminate between failure of HCQ and non-adherence and a threshold of 750 ng/ml is associated with cutaneous response.

 With failure of a first AM agent, a switch to another agent or the addition of QC may be useful.

Systemic corticosteroids

Systemic corticosteroids remain the mainstay of SLE treatment and have led to improved survival among high-risk patients [START_REF] Albert | Does corticosteroid therapy affect the survival of patients with systemic lupus erythematosus?[END_REF]. Systemic corticosteroids 0.5 to 1 mg/kg are recommended as first-line treatment in addition to AMs in severe or widespread active CLE lesions by European CLE guidelines. Systemic corticosteroids should be used for 2 to 4 weeks followed by a tapering of the dose to a minimum (≤7.5 mg/day) with the aim of discontinuing the treatment [START_REF] Kuhn | S2k Guideline for Treatment of Cutaneous Lupus Erythematosus[END_REF]. These recommendations are based on the results of the EUSCLE study showing 94.3% of 413 CLE patients with cutaneous improvement [START_REF] Sigges | Therapeutic strategies evaluated by the European Society of Cutaneous Lupus Erythematosus (EUSCLE) Core Set Questionnaire in more than 1000 patients with cutaneous lupus erythematosus[END_REF]. However, in this study, response was obtained by a questionnaire and therefore results should be interpreted with caution [START_REF] Sigges | Therapeutic strategies evaluated by the European Society of Cutaneous Lupus Erythematosus (EUSCLE) Core Set Questionnaire in more than 1000 patients with cutaneous lupus erythematosus[END_REF]. Moreover, the use of systemic corticosteroids is associated with significant side effects, including infections, hypertension, hyperglycemia, osteoporosis, avascular necrosis, myopathy, cataracts, and glaucoma in lupus patients [START_REF] Sawah | Effect of corticosteroid use by dose on the risk of developing organ damage over time in systemic lupus erythematosus-the Hopkins Lupus Cohort[END_REF][START_REF] Rúa-Figueroa | Bacteremia in systemic lupus erythematosus patients from RELESSER: risk factors, clinical and microbiological characteristics and outcomes[END_REF].

 In the absence of associated SLE, the benefit-risk balance of the use of systemic corticosteroids in CLE remains uncertain and long-term use should be strictly avoided.

Methotrexate

Methotrexate efficacy in CLE

Methotrexate is an antimetabolite agent, inhibiting the enzyme dihydrofolate reductase.

Dihydrofolate reduces folic acid to tetrahydrofolic acid, which plays an important role in the synthesis of purine nucleotides and thymidylate. Mechanisms of action are thought to relate to antagonism of folate-dependent processes, stimulation of adenosine signalling, inhibition of methyl-donor production, generation of reactive oxygen species, downregulation of adhesionmolecule expression, and modification of cytokine profiles [START_REF] Brown | Mechanism of action of methotrexate in rheumatoid arthritis, and the search for biomarkers[END_REF]. Indeed, methotrexate induces apoptosis of inflammatory cells [START_REF] Nakazawa | Methotrexate inhibits rheumatoid synovitis by inducing apoptosis[END_REF]. It also reduces levels of inflammatory cytokines, particularly IL-1, IL-6 and TNF-α. It increases IL-10 and IL-4 levels, which promotes Thelper 2 (Th2) cytokine effects that may be protective against autoimmune manifestations [START_REF] Barrera | Circulating soluble tumor necrosis factor receptors, interleukin-2 receptors, tumor necrosis factor alpha, and interleukin-6 levels in rheumatoid arthritis. Longitudinal evaluation during methotrexate and azathioprine therapy[END_REF]. Methotrexate is recommended as the preferred second-line agent by the European CLE guidelines [START_REF] Kuhn | S2k Guideline for Treatment of Cutaneous Lupus Erythematosus[END_REF]. In a small RCT, results were similar for 10 mg methotrexate weekly and 150 mg/day CQ for skin manifestations in SLE [START_REF] Islam | Efficacy and safety of methotrexate in articular and cutaneous manifestations of systemic lupus erythematosus[END_REF]. Moreover, in a retrospective study of 12 CLE patients who were refractory to AMs and/or low-dose oral glucocorticosteroids, 10 showed cutaneous improvement, including 6 with complete response with methotrexate 10 to 25 mg weekly [START_REF] Boehm | Management of cutaneous lupus erythematosus with low-dose methotrexate: indication for modulation of inflammatory mechanisms[END_REF]. In a retrospective study of 43 CLE patients receiving methotrexate 15 to 25 mg per week, 98%, particularly DLE and SCLE patients, showed improvement of cutaneous lesions [START_REF] Wenzel | Efficacy and safety of methotrexate in recalcitrant cutaneous lupus erythematosus: results of a retrospective study in 43 patients[END_REF]. In the large retrospective EUSCLE study, the response rate to methotrexate was 50% for ICLE, 57.1% for DLE, 68.8% for SCLE and 72.7% for ACLE [START_REF] Sigges | Therapeutic strategies evaluated by the European Society of Cutaneous Lupus Erythematosus (EUSCLE) Core Set Questionnaire in more than 1000 patients with cutaneous lupus erythematosus[END_REF]. However, again, in this study, cutaneous response was obtained by a questionnaire and thus results should be interpreted with caution [START_REF] Sigges | Therapeutic strategies evaluated by the European Society of Cutaneous Lupus Erythematosus (EUSCLE) Core Set Questionnaire in more than 1000 patients with cutaneous lupus erythematosus[END_REF].

Methotrexate safety profile

The safety profile of methotrexate is favorable. Methotrexate is teratogenic, and adequate contraception should be used. The most common adverse events include nausea/vomiting, elevated transaminase levels, mucosal ulcerations, leucopenia, thrombocytopenia and infectious events. In a recent meta-analysis including 68 trials and 6938 participants receiving methotrexate ≤ 30 mg/week for any condition, the risk of serious adverse events or death was not increased with low-dose methotrexate as compared with placebo [START_REF] Mazaud | Relative risk of and determinants for adverse events of methotrexate prescribed at a low dose: a systematic review and meta-analysis of randomized placebocontrolled trials[END_REF]. The concomitant prescription of folic/folinic acid is recommended to reduce adverse events, particularly nausea and vomiting. Moreover, methotrexate prescribed subcutaneously or by intramuscular injection has been found associated with reduced risk of abdominal pain as compared with oral prescription [START_REF] Mazaud | Relative risk of and determinants for adverse events of methotrexate prescribed at a low dose: a systematic review and meta-analysis of randomized placebocontrolled trials[END_REF].

 A small RCT of SLE with a focus on skin involvement and observational studies support the use of methotrexate as a second-line agent in CLE.

 The safety profile of methotrexate is favorable and the concomitant prescription of folic/folinic acid is recommended to reduce adverse events.

Retinoids

Retinoids, vitamin-A derivates, have been used in CLE or refractory cutaneous manifestation in SLE. European CLE guidelines recommended retinoids as second-line systemic treatment associated with AMs, particularly for hypertrophic CLE lesions [START_REF] Kuhn | S2k Guideline for Treatment of Cutaneous Lupus Erythematosus[END_REF]. In a double-blind RCT, acitretin 50 mg/day showed similar efficacy as HCQ 400 mg/day at 8 weeks, with marked improvement or clearing of CLE lesions in 50% of patients receiving HCQ and 46% using acitretin. However, tolerance was better for patients receiving HCQ [START_REF] Ruzicka | Treatment of cutaneous lupus erythematosus with acitretin and hydroxychloroquine[END_REF]. Other retinoids, isotretinoin and alitretinoin, have shown efficacy in CLE in small case series [START_REF] Kuhn | Alitretinoin for cutaneous lupus erythematosus[END_REF]. All retinoids are teratogenic; therefore, effective contraception is essential during and after treatment (isotretinoin: 1 month; acitretin: 3 years). Thus, acitretin should not be used in females of childbearing potential because of the longer half-life. The most common side effects of retinoids include skin and mucous membrane dryness, gastrointestinal disturbance, muscle pain and arthralgia. Psychiatric disorders such as depression and suicidal ideation have been reported in patients during and after isotretinoin therapy. However, data for patients receiving isotretinoin for acne are reassuring [START_REF] Huang | Isotretinoin treatment for acne and risk of depression: A systematic review and meta-analysis[END_REF].

 An RCT supported the use of acitretin as a second-line systemic agent in CLE.

 Small case series suggested that isotretinoin or alitretinoin may be potential alternatives.

Dapsone

Dapsone has both antimicrobial/antiprotozoal properties and anti-inflammatory effects.

Particularly, it has been shown to block neutrophil chemotaxis and suppress neutrophilmediated auto-oxidative tissue injury [START_REF] Wozel | Dapsone in dermatology and beyond[END_REF]. Dapsone is recommended as a second-line agent for CLE by European CLE guidelines. Of note, dapsone is the only second-line agent recommended during pregnancy or breastfeeding [START_REF] Kuhn | S2k Guideline for Treatment of Cutaneous Lupus Erythematosus[END_REF]. From the results of retrospective studies, dapsone may be more efficacious in SCLE than DLE. Indeed, in a retrospective study of 34 CLE patients, response (improvement) was 75% for SCLE and 60% for DLE patients [START_REF] Klebes | Dapsone as Second-Line Treatment for Cutaneous Lupus Erythematosus? A Retrospective Analysis of 34 Patients and a Review of the Literature[END_REF]. Moreover, in a retrospective study of 33 DLE patients, excellent results were observed in only 8 (24%) [START_REF] Lindskov | Dapsone in the treatment of cutaneous lupus erythematosus[END_REF]. Furthermore, dapsone may be discussed as a first-line agent in neutrophilic bullous lupus. Indeed, a recent literature review of 128 published cases found a response of 90% [START_REF] De Risi-Pugliese | Clinical, histological, immunological presentations and outcomes of bullous systemic lupus erythematosus: 10 New cases and a literature review of 118 cases[END_REF]. A low starting dose of 50 mg/day is recommended, then the dose could be increased to usually about 100 to 150 mg/day (maximum 400 mg/day or 2 mg/day/kg in children) [START_REF] Begon | Disulone][END_REF]. Before starting dapsone, laboratory tests should include G6PD activity, complete blood count including reticulocyte count, methemoglobin level, liver and renal function. During follow-up, some authors recommended only complete blood count with reticulocytes [START_REF] Begon | Disulone][END_REF], but others suggest assessing liver and renal function as well as haptoglobin every 2 weeks for 3 months and then every 3 months [START_REF] Kuhn | S2k Guideline for Treatment of Cutaneous Lupus Erythematosus[END_REF][START_REF] Wozel | Dapsone in dermatology and beyond[END_REF]. Methemoglobin level should be monitored between 8 to 14 days after treatment initiation and may be useful later to determine adherence [START_REF] Wozel | Dapsone in dermatology and beyond[END_REF][START_REF] Begon | Disulone][END_REF]. Then, checking methemoglobin levels is unnecessary in the absence of symptoms. The main adverse effects are hemolysis and methemoglobulinemia. Others include a mononucleosis-like hypersensitivity syndrome, occurring usually during the first month of treatment; neuropathy; and agranulocytosis [START_REF] Klebes | Dapsone as Second-Line Treatment for Cutaneous Lupus Erythematosus? A Retrospective Analysis of 34 Patients and a Review of the Literature[END_REF].

 Dapsone may be considered a first-line systemic agent in neutrophilic bullous lupus.

 Several observational studies suggest the use of dapsone as second-line systemic treatment for CLE.

Thalidomide

Thalidomide (alpha-N-phthalimido-glutarimide) was originally introduced as a nonbarbiturate hypnotic but was withdrawn from the market in 1961 because of teratogenic effects. Thalidomide has immunosuppressive and anti-angiogenic activity. It inhibits the release of TNF-α from monocytes and modulates the action of other cytokines. Moreover, thalidomide has photoprotective properties and can inhibit UVB-induced keratinocyte apoptosis [START_REF] Cummins | Photoprotection by thalidomide in patients with chronic cutaneous and systemic lupus erythematosus: discordant effects on minimal erythema dose and sunburn cell formation[END_REF]. In 1983, Knop et al. reported a series of 60 DLE patients receiving high-dose thalidomide 400 mg/day; complete response or marked improvement was noted in 90% of patients [START_REF] Knop | Thalidomide in the treatment of sixty cases of chronic discoid lupus erythematosus[END_REF]. Thereafter, other case series found similar results with a lower dose of 100 or 50 mg/day thalidomide [START_REF] Cuadrado | Thalidomide for the treatment of resistant cutaneous lupus: efficacy and safety of different therapeutic regimens[END_REF]. In a recent systematic review from our group, among 548 patients from 21 included studies, the overall response to thalidomide was 90% (95% CI 85-94), with similar response rates between CLE subtypes [START_REF] Chasset | Efficacy and tolerance profile of thalidomide in cutaneous lupus erythematosus: A systematic review and metaanalysis[END_REF]. Moreover, the clinical benefits need to be balanced against potential adverse events such as high teratogenicity, peripheral neuropathy [START_REF] Cortés-Hernández | Thalidomide in the treatment of refractory cutaneous lupus erythematosus: prognostic factors of clinical outcome[END_REF][START_REF] Briani | Positive and negative effects of thalidomide on refractory cutaneous lupus erythematosus[END_REF] (which is sometimes only partially reversible after treatment cessation [START_REF] Chaudhry | Thalidomide-induced neuropathy[END_REF]) and thromboembolic events. Indeed, in our meta-analysis, the pooled rate of thalidomide withdrawal related to adverse events was 24% (95% CI 14-35), including confirmed peripheral neuropathy in 16% (95% CI 9-25) and thromboembolic events in 2% (95% CI 1-3).

The efficacy of thalidomide is only suppressive with a rate of relapse of 71% (95% CI [START_REF] Chasset | The effect of increasing the dose of hydroxychloroquine (HCQ) in patients with refractory cutaneous lupus erythematosus (CLE): An open-label prospective pilot study[END_REF][START_REF] Chasset | Changing antimalarial agents after inefficacy or intolerance in patients with cutaneous lupus erythematosus: A multicenter observational study[END_REF][START_REF] Zeidi | Increased Myeloid Dendritic Cells and TNF-α Expression Predicts Poor Response to Hydroxychloroquine in Cutaneous Lupus Erythematosus[END_REF][START_REF] Marmor | Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy[END_REF][START_REF] Melles | The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy[END_REF][START_REF] Marmor | Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision)[END_REF][START_REF] Albert | Does corticosteroid therapy affect the survival of patients with systemic lupus erythematosus?[END_REF][START_REF] Sigges | Therapeutic strategies evaluated by the European Society of Cutaneous Lupus Erythematosus (EUSCLE) Core Set Questionnaire in more than 1000 patients with cutaneous lupus erythematosus[END_REF][START_REF] Sawah | Effect of corticosteroid use by dose on the risk of developing organ damage over time in systemic lupus erythematosus-the Hopkins Lupus Cohort[END_REF][START_REF] Rúa-Figueroa | Bacteremia in systemic lupus erythematosus patients from RELESSER: risk factors, clinical and microbiological characteristics and outcomes[END_REF][START_REF] Brown | Mechanism of action of methotrexate in rheumatoid arthritis, and the search for biomarkers[END_REF][START_REF] Nakazawa | Methotrexate inhibits rheumatoid synovitis by inducing apoptosis[END_REF][START_REF] Barrera | Circulating soluble tumor necrosis factor receptors, interleukin-2 receptors, tumor necrosis factor alpha, and interleukin-6 levels in rheumatoid arthritis. Longitudinal evaluation during methotrexate and azathioprine therapy[END_REF] after thalidomide withdrawal. Therefore, a minimal maintenance dose should be used to avoid relapse. Of note, a prospective study showed no peripheral neuropathy with daily doses ≤ 25 mg per day, which supports the use of a minimal maintenance dose [START_REF] Bastuji-Garin | Incidence and risk factors for thalidomide neuropathy: a prospective study of 135 dermatologic patients[END_REF]. Considering the occurrence of thromboembolic events, in a retrospective study of 139 CLE patients receiving thalidomide, the risk of overall thrombosis was 2.74 for 100 patient-years, whereas the risk of arterial thrombosis was 1.72 and that of venous thrombosis was 1.03 for 100 patientyears [START_REF] Cesbron | Risk of thromboembolic events in patients treated with thalidomide for cutaneous lupus erythematosus: a multicenter-retrospective study[END_REF]. The risk of all thromboembolic events was higher for patients with a history of previous arterial thrombosis and those with hypercholesterolemia. Conversely, the risk was lower with a starting dose of thalidomide of 50 mg/day as compared with 100 mg/day and with HCQ associated with thalidomide. The risk of thromboembolic events did not significantly differ according to antiphospholipid syndrome or significant antiphospholipid antibody (aPL) titers [START_REF] Cesbron | Risk of thromboembolic events in patients treated with thalidomide for cutaneous lupus erythematosus: a multicenter-retrospective study[END_REF]. Therefore, the benefit-risk balance should be careful examined before prescribing thalidomide in patients with high cardiovascular risk. Overall, thalidomide is recommended as a third-line agent in European CLE guidelines [START_REF] Kuhn | S2k Guideline for Treatment of Cutaneous Lupus Erythematosus[END_REF]. Since 2015, thalidomide has received a temporary recommendation for use in France for CLE patients. In our opinion, thalidomide should be used as a second-line agent for severe, refractory CLE with high scarring risk. We suggest a starting dose of 50 mg/day thalidomide associated with HCQ because it is has similar efficacy and reduced adverse events rate as compared with ≥ 100 mg/day [START_REF] Chasset | Efficacy and tolerance profile of thalidomide in cutaneous lupus erythematosus: A systematic review and metaanalysis[END_REF][START_REF] Cesbron | Risk of thromboembolic events in patients treated with thalidomide for cutaneous lupus erythematosus: a multicenter-retrospective study[END_REF]. In France, given the high teratogenicity rate, adequate contraception for at least 4 weeks before and until 4 weeks after completion is mandatory, and plasma beta human chorionic gonadotropin level should be measured monthly under treatment [98]. In the United States, sexually active females of childbearing potential must use two methods of birth control before, during and after treatment [START_REF] Uhl | Thalidomide use in the US : experience with pregnancy testing in the S[END_REF]. The usefulness of a systematic prescription of low-dose aspirin to reduce thromboembolic events in CLE treated with thalidomide has not been proven but should be advised, at least in patients with substantial aPL titers[100,101].

 A recent systematic review and meta-analysis of 548 patients found that the response to thalidomide was 90% (95% CI 85-94), with similar response rates between CLE subtypes.  However, the rate of thalidomide withdrawal related to adverse events was 24% (95% CI 14-35), which limits thalidomide prescription to refractory CLE with high scarring risk.

 The efficacy of thalidomide is only suppressive, and a minimal maintenance dose should be used to avoid relapse.

 The benefit-risk balance should be carefully examined before prescribing thalidomide in patients with high cardiovascular risk because of increased risk of thromboembolic events.

Lenalidomide

Lenalidomide is a 4-amino-glutamyl analogue of thalidomide. The drug has immunomodulatory, antiangiogenic and anti-inflammatory properties by inhibiting the secretion of the pro-inflammatory cytokines such as TNF-α, IL-1, IL-6, and IL-12 by monocytes. Lenalidomide immunomodulatory effects have been found 100 to 2,000 times more potent than those of thalidomide, in particular for inhibiting TNF-α However, in a prospective phase II study of 15 patients, lenalidomide did not affect doublestranded DNA (dsDNA) antibody titers and complement levels of SLE patients receiving lenalidomide, and no SLE flare was observed [104]. In this study, 12 patients showed complete response defined by CLASI activity score = 0 after 6 weeks, but a relapse rate of 75% was observed after lenalidomide withdrawal. In a retrospective study of 16 CLE patients receiving lenalidomide, including 14 who previously received thalidomide, 88% of patients were responders with a starting dose of 5 mg/day with no cases of new or worsening peripheral neuropathy [105]. No relapse was observed after the dose was tapered to reach a minimum effective dose. In this study, two patients with previous SLE experienced SLE flare according to SLEDAI criteria, after 36 and 26 months of lenalidomide treatment. No patient without initial SLE showed SLE flare. Overall, in our opinion, lenalidomide is currently one of the best therapeutic options for severe refractory CLE. However, it is approved for only haematological diseases and should be prescribed only for very severe diseases because of its high cost. No peripheral neuropathy has been reported with low-dose lenalidomide in CLE patients. Lenalidomide should be started at a dose of 5 mg/day. The co-prescription of lowdose aspirin and the continuation of HCQ should be discussed regarding the risk of thromboembolic events [105]. As for thalidomide, the efficacy of lenalidomide is only suppressive and the dose should be tapered to reach a minimum effective dose. Also, as for thalidomide, adequate contraception is required for at least 4 weeks before and until 4 weeks after completion of treatment.

 Some observational studies suggested that lenalidomide may be a promising alternative treatment for severe refractory CLE.

 The high cost and the tolerance profile limit the prescription of lenalidomide in CLE.

Iberdomide

Recently, thalidomide and its analogues were found to induce the degradation of the zinc  Some observational studies suggest the use of MMF and MPA for severe refractory CLE.

Azathioprine

Azathioprine is a derivative of 6-mercaptopurine that acts as an antimetabolite agent by affecting purine nucleotide synthesis and metabolism. Data on CLE are scarce. In a retrospective study of 6 CLE patients, 3 showed an excellent response to azathioprine [114].

Moreover, in the EUSCLE study, the response to azathioprine was 29/40 (72%) for ACLE, 10/12 (83%) for SCLE and 8/15 (53%) for DLE [START_REF] Sigges | Therapeutic strategies evaluated by the European Society of Cutaneous Lupus Erythematosus (EUSCLE) Core Set Questionnaire in more than 1000 patients with cutaneous lupus erythematosus[END_REF]. The use of azathioprine is not recommended by European CLE guidelines [START_REF] Kuhn | S2k Guideline for Treatment of Cutaneous Lupus Erythematosus[END_REF] in the absence of associated SLE 15 . Of note, azathioprine is considered to have an acceptable benefit-risk profile in controlling SLE activity during pregnancy [115].

 Data regarding the use of azathioprine in CLE are scarce.

 Azathioprine has an acceptable benefit-risk profile in controlling SLE activity during pregnancy and could therefore be used to treat active CLE lesions associated with SLE during pregnancy.

Intravenous immunoglobulin (IVIg)

IVIg is a therapeutic preparation of human polyspecific IgG derived from the plasma of healthy donors. IVIg was initially used, in the early 1980s, as replacement therapy in patients with primary or secondary immunodeficiencies. To date, three case series assessing the efficacy of IVIg involving ≥ 5 CLE patients have been reported. In a case series of 5 DLE patients, 3 showed significant improvement with IVIg 1g/kg/day for 2 days monthly [116].

Moreover, in a retrospective study of 12 patients, 5 showed complete response and 3 partial response with IVIg 1g/kg/day for 2 days followed by 400 mg/kg/day for a maximum of 6 months [117]. Finally, in a case series of 16 CLE patients, 5 (31%) showed significantly improved CLASI activity with IVIg 500 mg/kg/day for 4 days monthly for 3 months [118].

 Data on the efficacy of IVIg are limited. Given its high cost, we do not suggest the use of IVIg in CLE.

Pulsed dye laser (PDL)

PDL has a wavelength of 585 nm or 595 nm, which corresponds to one of the oxyhaemoglobin absorption peaks. This causes selective thermal damage to dermal microvessels, which play an important role in the pathogenesis of CLE. PDL was used in a prospective study of 10 patients with lupus tumidus, with an overall response of 90% without  Some observational studies suggested the use of PDL in CLE, but a recent RCT failed to demonstrate clinical efficacy.

Extracorporeal photopheresis (ECP)

ECP is a leukapheresis-based therapy that uses 8-methoxypsoralen and UVA irradiation. ECP is frequently used for mycosis fungoides/Sézary syndrome[122] and graft-versus host disease [123]. Some case reports or small case series suggested that ECP may be a therapeutic alternative for refractory CLE [124,125], but data are limited.

 Data regarding the use of ECP in CLE are limited and further studies are needed to determine its potential interest. IFNs (n=7), pDCs (n=3), and other targets (n=12). Some targeted therapies are being developed specifically for CLE (Table 2). Among available targeted therapies or those currently under development, we detail below the drugs with available data for CLE.

Targeted therapies

Improvement in the comprehension

Targeting B cells

Rituximab

Rituximab is a chimeric monoclonal antibody (mAb) against the protein CD20. CD20 is expressed from early pre-B cells to those later in differentiation, but it is absent on terminally differentiated plasma cells. The Fc portion of rituximab mediates antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, inducing apoptosis of CD20 + cells.

Rituximab has been investigated in two phase III RCTs of SLE, LUNAR 113 and EXPLORER, that did not meet their primary endpoint [128]. However, the off-label use of rituximab is recommended by international consensus for severe kidney disease,

Anifrolumab

Anifrolumab is a fully human mAb that binds to subunit 1 of the type I IFN receptor, blocking the activity of all type I IFNs. In a phase II, randomized, placebo-controlled study comparing intravenous anifrolumab (300 mg or 1,000 mg) or placebo in addition to standard therapy, anifrolumab showed promising results in several clinical endpoints including SLE Responder Index [START_REF] Gilliam | Distinctive cutaneous subsets in the spectrum of lupus erythematosus[END_REF] response at week 24 with sustained reduction of oral corticosteroids [START_REF] Furie | Anifrolumab, an Anti-Interferon-α Receptor Monoclonal Antibody, in Moderate-to-Severe Systemic Lupus Erythematosus[END_REF].

Considering cutaneous involvement, among patients with CLASI activity score ≥ 10 at baseline, a 50% decrease at week 52 was significantly greater in patients receiving anifrolumab (63% for 300 mg and 58.3% for 1000 mg) as compared with placebo (30.8%) (p=0.013 and 0.077, respectively). Of note, in a post-hoc analysis, patients receiving anifrolumab showed significantly improved cutaneous involvement as compared with placebo in the high IFN gene signature subgroup only, which suggests that IFN signature may be a biomarker of response to anifrolumab [137]. Although no results have been published yet, results of TULIP1, the first phase III trial of anifrolumab, failed to demonstrate superiority as compared with placebo[138].

Janus kinase (JAK) inhibitors

Baricitinib is an orally administered selective and reversible inhibitor of JAK1 and JAK2, which inhibit type I IFN but also IL-

Conclusions and perspectives

Overall, recent improvements in the management of CLE have included the development and validation of specific tools to assess skin activity (CLASI [START_REF] Albrecht | The CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index): an outcome instrument for cutaneous lupus erythematosus[END_REF], RCLASI[157]) as well as the publication of European CLE guidelines [START_REF] Kuhn | S2k Guideline for Treatment of Cutaneous Lupus Erythematosus[END_REF]. However, there are still several unmet needs.

-Most current therapeutic trials are designed for only SLE, with skin assessment as secondary outcomes. For example, belimumab is not approved for isolated CLE.

Therefore, future treatments, particularly biological therapies, should include specific trials of isolated patients in their development plan.

-Second, although some recent trials used CLASI to assess skin improvement, this is not always the case. For example, the recent baricitinib phase II studies focused on skin lesions and articular involvement. However, resolution of SLEDAI-2K arthritis or rash were primary outcomes instead of CLASI score [140]. Among dermatologists and rheumatologists who were present at the recent 2018 international CLE meeting, there was 100% agreement that the CLASI should be used in evaluating the skin in CLE [158]. Moreover, CLE subtypes are never reported. Of note, we and others reported that response to treatment is widely heterogeneous among CLE subtypes [START_REF] Chasset | Efficacy and tolerance profile of thalidomide in cutaneous lupus erythematosus: A systematic review and metaanalysis[END_REF]159].

Therefore, future trials with a specific design for CLE and a focus on CLE subtypes are needed to improve management of CLE.

  [102]. In a prospective, open-label study of 5 patients, 4/5 patients showed significant improvement in CLASI activity score [103]. Of note, clinical response was also associated with increased circulating T regulatory cells (Tregs) and decreased circulating pDCs[103]. However, one patient with isolated CLE had new-onset proteinuria after 20 weeks of treatment and therefore the authors suggested that lenalidomide may trigger systemic disease in CLE patients[103].

5 . 9

 59 finger transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). IKZF1 and IKZF3 are susceptibility loci for SLE and play a role in B-cell, T-cell and monocyte regulation[106,107]. IKZF1 and IKZF3 mRNA levels were increased in SLE patients as compared with healthy volunteers. Recently, CC-220 (iberdomide), a cereblon modulator targeting Ikaros and Aiolos, has been developed and may be a promising therapeutic option in CLE and SLE[108].  Targeting Ikaros (IKZF1) and Aiolos (IKZF3) may be a promising therapeutic strategy in CLE. Mycophenolate mofetil (MMF) and mycophenolic acid (MPA) MPA was first discovered in 1913 and first used clinically in the 1970s as an immunosuppressant to prevent organ transplantation rejection. Several RCTs have established the efficacy of MMF for induction treatment[109,110] and maintenance regimen[111] for lupus nephritis. MMF and MPA are recommended as third-line treatment in refractory CLE patients by European CLE guidelines. Indeed, in a retrospective study of 24 CLE patients refractory to AMs, every patient experienced at least partial response to MMF, including 9 (37%) with complete response[112]. Moreover, in the EUSCLE study, 47/52 (90%) CLE patients receiving MMF showed clinical improvement[72]. Adverse events including gastrointestinal, cytopenic, hepatotoxic and hypersensitivity reactions are usually mild and mainly dose-dependent. Monthly laboratory monitoring is mandatory for hematological, hepatic and renal toxicities[15]. MMF and MPA are teratogenic, and adequate contraception should be used. Considering MPA, in a prospective, open-label study of 10 SCLE patients refractory to AMs, MPA 1440 mg daily was given for a total of 3 months and resulted in cutaneous improvement in 9/10 patients[113].

  flare of CLE lesions after treatment[119]. Moreover, in a prospective study of 12 DLE patients with mild disease (baseline CLASI activity score 3-5), baseline CLASI activity significantly decreased after PDL, from a mean (SEM) of 4.4 ± 0.2 to 1.3 ± 0.3 after followup (p < 0.001)[120]. However, in a recent RCT involving 48 lesions in 9 DLE patients, no difference was seen in CLASI improvement with PDL as compared with the control[121].

  of the pathogenesis of SLE and CLE has led to the development of several targeted treatments. Most targeted therapies have been developed for SLE, but recently CLASI has been used in SLE studies to assess cutaneous improvement as secondary outcomes, which has allowed for insights into the potential effect on CLE. Recently, a recent systematic review of targeted therapies under clinical development in SLE [126] in 17 main online registries of clinical trials identified 74 targeted therapies for SLE among 1140 trials. Treatment strategies under current clinical development for SLE target B cells or plasma cells (n=17), inflammatory cytokines or chemokines and their receptors (n=17), intracellular signalling pathways (n=10), T/B-cell co-stimulation molecules (n=8),

regarding the use of rituximab in CLE are limited.  Observational studies suggested that rituximab may benefit mostly ACLE patients versus SCLE and CCLE patients.

  central nervous system involvement or severe autoimmune thrombocytopenia[129]. Considering CLE, some data suggested that rituximab might benefit mostly ACLE patients. Indeed, in a retrospective study of 26 SLE patients with CLE lesions treated with rituximab, only 9 were responders,

	including those with ACLE (6/14) and SCLE (1/2) but not CCLE (0/8)[130]. Moreover, in a
	recent retrospective study of 50 SLE patients with CLE, 76% showed cutaneous improvement
	after 6 months of rituximab, but complete response was observed in only 2/6 (33%) with
	SCLE and 5/12 (42%) with CCLE [131].
	6.1.2 Belimumab
	Belimumab is a fully humanized mAb against B lymphocyte stimulator (BLyS) also called B-
	cell-activation factor (BAFF) that belongs to the TNF family. Administration of belimumab
	leads to depletion of naive, activated and plasmacytoid CD20 + B cells, and a reduction in anti-
	dsDNA titers. Belimumab demonstrated efficacy versus placebo in reducing SLE disease
	activity and the time to lupus flares in addition to standard care in two phase III RCTs
	(BLISS-52 and BLISS-76 [132,133]). It is currently the only biological therapy approved by
	the US Food and Drug Administration and European Medicines Agency for SLE. Recently,
	Wenzel et al. showed high expression of BAFF, BAFF receptor and B-cell maturation antigen
	(BCMA) on immunohistochemistry of CLE lesions, which suggested a potential interest of
	belimumab in CLE[134]. Data regarding the efficacy of belimumab of CLE are scarce.
	Indeed, most SLE patients included in the phase III clinical trials[132,133] had skin
	involvement; however improvement was assessed by the BILAG or SLEDAI and therefore no
	conclusion can be drawn. In a retrospective study of 67 patients including 19 with CLE
	involvement, median CLASI activity score was decreased from 5 (range 1-14) to 0.5 (0-6) at
	24 months[135].

 Data

 Belimumab

is currently the only biological therapy approved by the US Food and Drug Administration and European Medicines Agency for SLE.  Although most SLE patients included in phase III trials had skin involvement, specific assessment of CLE improvement using the CLASI is limited and no conclusions can be drawn.

	6.2 Targeting IFN and pDCs
	6.2.1 Sifalimumab
	Sifalimumab is a fully human IgG1 mAb that neutralizes IFN-α. In a randomised, double
	blind, placebo-controlled study, the proportion of patients achieving the SRI-4 response index
	at week 52 was significantly higher in the three treatment groups as compared with placebo.
	Moreover, among patients with CLASI activity score ≥10 at baseline, sifalimumab conferred
	a significantly greater 4-point decrease as with compared with placebo: 73.1% for 1200 mg
	versus 48.6% for placebo, p=0.049[136]. However, development of sifalimumab has been
	stopped by Astra-Zeneca © .

  21 and IL-6[139] playing a central role in the pathogenesis of SLE. In a recent double-blind, placebo-controlled phase II trial, baricitinib at 4 mg but not 2 mg (in addition to standard treatment) significantly improved the symptoms of active SLE[140]. However, baricitinib and placebo did not differ in CLASI activity score decrease at week 24: mean decrease -1.7 for baricitinib 2 mg, -2.3 for baricitinib 4 mg and -Ustekinumab is an mAb targeting IL-12 and IL-23 and is approved for treating plaque psoriasis, psoriatic arthritis, and Crohn's disease[150,151]. Recently, in a phase II RCT, ustekinumab in addition to standard of care treatment resulted in better efficacy in clinical and laboratory parameters than placebo in the treatment of SLE. In this study, among patients with A loss of the healthy balance of activity between effector and regulatory CD4+ T cells is associated with the development of SLE[154]. In mice and humans, IL-2 can enhance Treg cell development and suppress the differentiation of T follicular helper and T helper 17

	2.8 for placebo[140]. However, familial chilblain lupus associated with three prime repair a baseline CLASI activity score ≥4, the proportion with at least 50% improvement in CLASI
	exonuclease 1 (TREX1) mutation and Aicardi-Goutières syndrome was significantly activity score from baseline was 17/32 (53%) with ustekinumab versus 6/17 (35%) with
	improved with baricitinib 4 and 2 mg/day, respectively[141,142]. Filgotinib is an oral placebo (p=0.032)[25]. Moreover, the efficacy of ustekinumab for treating SCLE[152] and
	selective JAK1 inhibitor that has shown promising results in two-phase II studies of active DLE[153] has been suggested in some case reports. Results of the phase III study will be
	ankylosing spondylitis and psoriatic arthritis with acceptable safety profile[143,144]. A important to assess the potential role of ustekinumab in CLE treatment.
	randomized placebo-controlled study is ongoing in CLE patients. Ruxolitinib is an oral
	JAK1/2 inhibitor originally developed for treating JAK2-mutated primary myelofibrosis[145]. 6.3.2 Low-dose IL-2
	Ruxolitinib 20 mg/day twice daily conferred rapid improvement of chilblain lupus associated
	with primary myelofibrosis[146]. Moreover, in vitro studies demonstrated that ruxolitinib
	significantly decreased the production of CLE associated with cytokine (C-X-C motif) ligand
	10 (CXCL10), CXCL9, and MxA[147]. Finally, in an RCT, the topical R333 inhibitor of
	γc/JAK1/3-dependent cytokines did not significantly improve lesion activity after 4
	weeks[148].
	6.2.4 Anti-BDCA2
	BIIB059 is a humanized IgG1 mAb that specifically recognizes blood DC antigen 2
	(BDCA2), which is uniquely expressed on the surface of human pDCs. Recently, in a phase I,
	randomized, double blind, placebo-controlled clinical trial, anti-BDCA2 showed potential
	efficacy in SLE patients with active CLE lesions. Among the 8 CLE patients who received
	BIIB059, with ACLE (n=4), SCLE (n=1), and DLE (n=3), after 4 weeks of one dose of 20
	mg/kg, all patients with ACLE (4/4) and SCLE (1/1) but only 1 of 3 with DLE showed a
	decrease in CLASI activity score ≥ 4 points. Of note, improvement in CLASI activity was
	statistically correlated with reduced level of type I IFN inducible protein MxA, which
	suggests that type I IFN expression in skin lesions reflects cutaneous disease
	activity[149][149]. Further studies are needed to assess whether anti-BDCA2 mAb may be a
	promising drug in CLE.
	6.3 Targeting cytokines and their receptors
	6.3.1 Ustekinumab

cells

[154,155]

. In a recent phase II study of 40 SLE Chinese patients receiving 3 cycles of low-dose IL-2 at a dose of 1 million IU every other day for 2 weeks followed by a 2-week break, an improvement in skin lesions (20/24) and alopecia (13/14) was observed at week 12.

Of note, CLASI activity score was not used in this study, and other studies are needed to assess the role of low-dose IL-2 as potential treatment of CLE

[156]

.

Table 1 . Systemic treatments available for cutaneous lupus erythematosus (CLE) with focus on dosage and monitoring of adverse events

 1 CQ: chloroquine, QC: quinacrine, AAO: American Academy of Ophthalmology, PIIINP: N-terminal propeptide of type III Collagen, MMF: mycophenolate mofetil, MPA: mycophenolic acid, IVIgs: intravenous immunoglobulins * Delivered dose by pharmacists (not prescribed dose) of ≥ 5 mg/kg of real body weight[START_REF] Melles | The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy[END_REF] is associated with an increased risk of retinopathy ** by analogy regarding bioequivalence between HCQ and CQ † used as second-line agent in France

	First-line treatment
	Drugs	Dosage


V Bulanin

E Gusakov

V Gusev

S Heuraux

C Lechte

V Minaev

A Petrov

Yu Petrov

A Yashin

N Sakharov

F Da Silva

N Teplova

G Zadvitskiy

Globus-M Team

Simulation of Doppler backscattering off filaments in the Globus-M spherical tokamak

In this paper we present the results of two-dimensional full wave simulations of Doppler backscattering (DBS) from filaments in slab geometry. For simulation we have used a substitutional model of a filament of a Gaussian cross-section. The comparison of the simulation results and experimental data obtained at the tokamak Globus-M was performed.

Introduction. Filamentary-like plasma perturbations are routinely observed in many tokamaks. They are the result of non-linear development of some peripheral MHD instabilities in the region of the maximum plasma pressure gradient [1]. As soon as filaments can play a key role in the anomalous transport of particles and energy at plasma periphery studies of filaments are actively continuing in various tokamak experiments for better understanding of filament physics and extrapolating of filament parameters to the tokamaks of ITER scale [2]. Recently, authors proposed to use the Doppler backscattering method for filaments investigation [3,4]. The results of backscattering from filaments can be easily interpreted within the framework of the linear backscattering or Born approximation.

However, the description of the experimental data under the transition from linear to nonlinear backscattering is a rather complicated task that could be solved with the help of fullwave simulations.

Numerical analysis. Instead of using complicated non-linear MHD codes for filament description we have used relatively simple model of a filament with a Gaussian cross-section that allows freedom in choosing the shape, size, amplitude and position of a filament. Twodimensional full wave simulations were done with finite-difference time-domain code IPF-FD3D [5] in slab geometry. The goal was to calculate the DBS responses depending on various filament amplitudes (0.1%, 1%, 5%, 50%, 100% and 150% of density at cut off of the probing wave). This dependence was calculated for various filament positions in relation to the cut off and filament shapes (circle and elongated ellipse in radial direction). The parameters of the computations are as following: antenna tilt angle 13°, antenna horn mouth 5.5 cm, Gaussian beam with flat wave front in the antenna mouth. Computations have been performed for the frequencies 16GHz, 24 GHz, 32GHz, 40GHz, 48GHz, 56GHz, 64GHz in O-mode that corresponds to the frequency range used in the Globus-M tokamak DBS diagnostics (20GHz, 29GHz, 40Ghz and 48GHz). Experimental plasma density profile used information on filament size in radial direction when using multiple-frequency probing. Such a technique is used in Globus-M tokamak. In figure 4(a) the DBS signals obtained in Globus-M experiment (shot #36569) are shown. It is seen that there is no DBS signal at f=29GHz and f=20GHz. The radial size of the filament can be estimated as ≈2cm (distance between cut offs for f=48GHz and f=40GHz). The BQF at f=40GHz is shifted comparing to the BQF at f=48GHz, the same effect can be observed in figure 4(b) showing the result of numerical simulation for filament size 3cm in radial direction. To obtain precise information on filament size in radial direction more probing frequencies for DBS signals measurements needed.

Conclusions. Full-wave calculations have shown that similar BQFs are formed in case of scattering off from filament either in case of linear or non-linear regimes. As soon as the signal amplitude is measured in experiment in arbitrary units it is not possible to extract information on filament amplitude from experimental data. Nevertheless it is possible to determine the filament size in radial direction in case of multi-frequency probing. As it was expected the signal amplitude decreases with growing filament size in linear regime and in non-linear regime the signal amplitude is independent on filament size.

The calculations have been performed in O-mode using simple slab model and have not taken into account complicated magnetic field configuration taking place in real experiment. Such a task that is difficult even in the optical approximation is particularly relevant for tokamaks with a low aspect ratio. Moreover in presented computation turbulence effects are not taken into account as well. Despite the difficulties described above the comparison of the simulation result and experimental data obtained at the tokamak Globus-M was performed and has shown in particular the amplitude at which transition to the non-linear regime occurs. Also the preliminary calculations using full-wave finite-difference time-domain code REFMULF [START_REF] Da Silva | Proc of the 13th International reflectometry workshop[END_REF] are being processed currently.

Figure 1 .

 1 Figure 1. Electric field distribution for linear (a) and non-linear (b) regime.

Figure 2 .Figure 4 .Figure 3 .

 243 Figure 2. (a) Calculated Q(t) signals for linear (blue) and nonlinear(red regimes; (b) normalized calculated signals; (c) I(t) and Q(t) DBS signals measured in Globus-M shot#36537, f=48GHz.

th EPS Conference on Plasma Physics P4.1009

P4.1009

Acknowledgements. The work is supported by RSCF grant 18-72-10028 and the maintenance of Globus-M tokamak and standard discharge diagnostics systems was supported by the Ioffe Institute.