Treatment of cutaneous lupus erythematosus: current approaches and future strategies

Abstract

Purpose of Review

Cutaneous lupus erythematosus (CLE) is a highly heterogeneous autoimmune disease. No specific FDA-approved therapies for CLE-alone are available, and resistance to conventional treatments is common. This review will summarize current treatment approaches and pending treatment strategies.

Recent findings

Research into the pathogenesis of CLE is accelerating. A skewed type I interferon (IFN) production and response contribute to CLE lesions. The pathophysiology of lesions may be similar amongst the lesional subtypes, and patients with a more TLR9-driven disease pathology may have more benefit from HCQ. Case reports continue to support the use of dapsone for CLE, especially bullous LE. Rituximab and Belimumab have efficacy in patients with SLE and severe active CLE. The significant role for type I IFNs in CLE and encouraging clinical data suggest anifrolumab as a very promising agent for CLE. Dapirolizumab, BIIB059, Ustekinumab and JAK inhibitors also have supportive early data as promising new strategies for CLE treatment.

Summary

Continued research to understand the mechanisms driving CLE will facilitate the development and approval of new targets. The pipeline for new treatments is rich.

INTRODUCTION

Cutaneous lupus erythematosus (CLE) manifests in about 70% of all patients with systemic lupus erythematosus (SLE) and also can occur without associated SLE. Beyond generalized autoimmunity, more cases are now also being seen secondary to drug-induced CLE, especially as a side effect of novel cancer therapies [1,2]. CLE is divided into four different subsets: acute cutaneous LE (ACLE), subacute cutaneous LE (SCLE), intermittent cutaneous LE (ICLE) and chronic cutaneous LE (CCLE) including discoid LE (DLE), chilblain LE (CHLE) and LE panniculitis (LEP) [3]. The most common subset is CCLE, followed by SCLE and other subsets; 1/3 of patients have two or more different subsets [4]. The etiology for CLE is still under investigation, but a skewed type I interferon (IFN) production [5] and response [6] are contributing factors. Intriguingly, the pathophysiology of lesions may be similar amongst the lesional subtypes [5,7]. Although there are many management strategies available for CLE, the degrees of efficacy are varied. Resistance to conventional treatments is common, leading to an increased risk of scarring, disfigurement, and poor quality of life. Thus, our review aims to summarize current treatment approaches and the evolution of future strategies based on advances in the understanding of CLE pathogenesis. These will include topical treatment, antimalarials, synthetic DMARDs, and novel biologic therapies.

CURRENT TREATMENT OPTIONS

While systemic lupus erythematosus (SLE) has a meager 3 FDA-approved medications (corticosteroids, hydroxychloroquine, and belimumab), no specific FDA-approved medications for CLE itself have yet been approved. Despite this, established standard treatment of CLE includes pharmacological therapy ranging from topical to systemic therapy. Preventive measures, including sun protection, smoking cessation, elimination of photosensitizing drugs and vitamin D supplementation, are also important adjuncts for disease management [3]. Of note, a recent maximum usage trial demonstrated that all four chemical-based sunscreens tested showed systemic absorption >0.5 ng/mL, which is above FDA recommended limits [8]. The FDA has since recommended only barrier sunscreens containing zinc oxide or titanium dioxide as safe and effective. Because of the white residue from barrier sunscreens, tinted formulations can help adherence in patients with darker skin. Consideration of these changes when recommending sunscreen to patients should be made.

Topical treatments

Recent EULAR guideline recommended topical agents as the first-line treatment for CLE which mostly include topical corticosteroids and calcineurin inhibitors [9]. Multiple randomized controlled trials highlight that topical steroids are the mainstay treatment for CLE; high potency topical steroids are typically more effective (See Table 1 for steroid potency and body part recommendations). Because of well-known side effects such as atrophy, telangiectasias and steroid-induced rosacea-like dermatitis, topical corticosteroids should be intermittent and not exceed an application of more than a few weeks [3]; a common recommendation is use for two weeks then on weekends only for maintenance. Prolonged use of topical steroid may be necessary in patients with scalp DLE lesions. Intralesional injections of triamcinolone may be beneficial in patients with refractory localized DLE [10].

Table 1.

Potency ranking of commonly used topical steroids

Potency	Class	Example	Sites
Super-potent	I	Clobetasol propionate 0.05% Halobetasol 0.05%	Palms, soles, acral sites, trunk
High potency	II	Bethamethasone dipropionate 0.025% Desoximetasone 0.25% Halcinonide 0.1%	Palms, soles, acral sites, trunk
	III	Bethamethasone valerate 0.1% Fluticasone propionate 0.005%	Acral sites, trunk
Medium potency	IV	Triamcinolone 0.1% Desoximetasone 0.05%	Acral sites, trunk
	V	Hydrocortisone valerate 0.2% Hydrocortisone butyrate 0.1%	Acral sites, trunk
Low potency	VI	Fluocinolone acetonid 0.01% Desonide 0.05%	Face, intertriginous areas
	VII	Hydrocortisone acetate 1%	Face, intertriginous areas

Topical steroids come in many different formulations (ointments, creams, lotion, foam, solution, and gels) and potency may vary depending on the carrier vehicle. An ointment formulation is considered more potent than the same molecule in a cream or lotion base as it enhances percutaneous absorption. Most patients favor creams as they tend to be a more tolerable form of application. Foams and solutions are appropriate for lesions on the scalp.

Topical calcineurin inhibitors (CNIs) can be used as an alternative to, or in combination with if more efficacy is needed [11], topical corticosteroids, especially for thin skin areas or in skin damaged by chronic topical steroids. There are two available commercial preparations (pimecrolimus 1% cream and tacrolimus 0.03% or 0.1% ointment) [12]. A recent systematic review examined 13 studies (5 randomized controlled trials (RCT), 3 non-controlled clinical trials, 1 observational study and 4 case series) for topical CNI in patients with CLE. 6 studies included only patients with DLE whereas 7 studies included patients with a mixture of different subtypes of CLE. Among them, 8 studies used topical tacrolimus (0.03% or 0.1%), 4 studies topical pimecrolimus (1%) and one study a mixture of both. 6/13 studies involved a comparison group (mostly topical steroids). All studies demonstrated moderate improvement with topical CNI therapy with statistically significant improvement in patients with DLE, LET and ACLE. In a study of case series, those patients on topical tacrolimus lotion 0.3% achieved hair regrowth. Benefit was equivalent to topical steroids and the side effects were minor [13].

Other topical agents with reported use in CLE include topical R-Salbutamol 0.5% cream, retinoids, R333, clindamycin, and topical JAK inhibitors. Two studies (one RCT and one case series) investigated the use of topical R-salbutamol cream in 46 patients with CLE. The RCT only included patients with DLE lesions while the case series included patients with mixed subtypes. Both studies showed improvement [10]. Case reports of effective use of topical retinoids (tretinoid and tazarotene) and clindamycin have also been reported [14, 15]. JAK1 is overexpressed in the dermis of CLE patients and is critical to type I IFN signaling, which suggests JAK1 inhibitors, including topical formulas, may benefit CLE [16].

Systemic treatments

Antimalarials and systemic steroids are recommended as first-line systemic treatment of CLE [9]. Other immunosuppressive and immunomodulating agents that can be considered for refractory disease or for minimizing systemic steroid exposure. These agents include methotrexate, azathioprine, mycophenolate sodium, mycophenolate mofetil, dapsone, thalidomide and lenalidomide.

Antimalarials

Antimalarials include hydroxychloroquine (HCQ), chloroquine (CQ) and quinacrine (Q) and are administered according to actual body weight. HCQ is typically the treatment of choice, and it may have better efficacy than CQ [17]. A systematic review by Shipman et al. [18] included a total of 852 patients treated with HCQ from 10 studies (5 retrospective studies, 3 prospective, 2 case series, and 2 randomized controlled trials). It identified that a HCQ dosage up to 400 mg/day is effective for most CLE patients (range of effectiveness:50–97%), with few adverse effects, but the response rate declines over time such that long term HCQ response rate drop to 45%. More recently, in a retrospective study investigating the efficacy of HCQ on Japanese patients with CLE, complete improvement was observed at high rates for acute CLE (ACLE); partial or non-improvement rates were higher for chronic CLE (CCLE) at 16 weeks. Several patients with alopecia without scarring achieved complete improvement at 32 weeks. CCLE tended to take more time to improve than ACLE. Overall, 87% of patients had at least some beneficial response at 16 weeks. However, there were wide variations in complete improvement rates and duration for improvement among CLE subtypes [19]. Intriguingly, patients with a more TLR9-driven disease pathology may have more benefit from HCQ [20]. Currently, biomarkers are lacking to predict HCQ treatment response.

Retinal toxicity remains the most concerning complication of antimalarial use, especially HCQ and CQ; the risk of which is under 1% after 5 years but rises to ~20% after 20 years of antimalarial use [21]. More recent studies suggest that toxicity rates may be lower than previously thought: One recent study showed ~5% patients developed retinal complications over an average of 12.8 years [22], while another study demonstrated the prevalence of retinopathy was only 4.3% [23]. The elderly, high body mass index, duration of HCQ intake, renal insufficiency, concomitant use with tamoxifen and previous macular damage are major risk factors for retinal toxicity [22, 23]. Compared to HCQ, there was increased retinopathy risk with CQ and CQ-Q, but no retinopathy was seen with Q alone [24].

How to properly dose HCQ to mitigate side effects but maintain efficacy is a topic of debate. Monitoring of HCQ blood concentrations can be used to assess treatment compliance, with low blood levels indicative of poor adherence and very low blood HCQ concentrations (<200 ng/mL) indicating nonadherence to the treatment. This is an important consideration as blood levels of HCQ (>750 ng/mL) positively correlate with a significant decrease in CLE disease area and severity index (CLASI) [25]. Risk of retinal toxicity according to blood levels of HCQ is not known, but higher doses are associated with increased risk [26]. Thus dosing recommendations have been placed at 5mg/Kg/day, but how this impacts efficacy of the drug requires further study. If additional drug is needed once HCQ has been maxed out, one recommended strategy [3] is to add Q to HCQ in declining responders to achieve a synergic effect [17,27]. Unfortunately, a shortage of quinacrine has made this approach difficult in the United States.

Evolving therapeutic approaches of other DMARDs

Use of other DMARD therapies are supported primarily by case reports, which can lead to reporting bias for efficacy. Case reports continue to support the use of dapsone for CLE [28], and a recent literature review identified up to 90% efficacy for bullous lupus [29]. Similarly, a meta-analysis of 548 patients from 21 studies found the overall rate of response of multiple CLE subtypes to thalidomide was 90%. However, toxicity limits thalidomide use: the pooled rate of thalidomide withdrawal due to adverse events was 24% (peripheral neuropathy in 16% and thromboembolic events in 2%) and the pooled rate of relapse after thalidomide withdrawal was 71% [30]. Lenalidomide is a promising drug for severe refractory CLE with a lower frequency of nerve-related side effects [31]. In a translational study, iberdomide (CC-220), a related cereblon (CRBN) modulator, significantly reduced Ikaros and Aiolos protein levels in inflammatory cells and limited autoantibody production [32]. How iberdomide impacts CLE remains to be determined [33].

Emerging Novel Biologic Therapies

Recent advances in the pathogenesis of CLE link environmental factors, most notably ultraviolet (UV) light, with activation of innate immune responses, leading to subsequent generation of adaptive immune responses and the development of CLE skin lesions; this process is a self-amplification loop orchestrated by a large number of interferon (IFN)-regulated cytokines and chemokines [34]. All these findings have led to the testing of novel biologic agents targeting either immune cells (B cells, T cells and plasmacytoid dendritic cells) or pro-inflammatory mediators, such as type I IFNs, in SLE. Few recent trials are specific for CLE outcomes [35]. Thus, we summarize data from CLE and SLE trials with available data for CLE responses from the past two years.

Targeting B cells

Rituximab is a chimeric monoclonal antibody (mAb) against the protein CD20. Two phase III studies, LUNAR and EXPLORER investigated the efficacy of rituximab in SLE patients and did not meet the primary endpoints. However, a systematic review of efficacy and safety of rituximab in non-renal SLE patients included results from 7 cohort studies where SLE mucocutaneous manifestations were analyzed and found partial or complete response rates from 33% to 71%, (4 cohorts with SLE mucocutaneous manifestation in general; 3 cohorts with specific manifestations like urticarial vasculitis, small vessel vasculitis or rash); in addition, this study suggested that rituximab may benefit ACLE patients [36]. A retrospective study on 26 SLE patient with active mucocutaneous manifestations treated with rituximab identified improvement in British Isles Lupus Assessment Group Index (BILAG) mucocutaneous domain scores in 42.9% and 50% of patients with ACLE and SCLE respectively; no response was seen in CCLE [37]. In another retrospective cohort study, a total of 50 SLE patients with CLE were included (21 ACLE, 6 SCLE, 10 CCLE, 11 NSLE including 2 with concurrent ACLE and CCLE). 76% improvement was noted at 6 months and 61% of patients maintained this response at 12 months. Complete response was seen in 2/6 (33%) with SCLE at 6 and 12 months and 5/12 (42%) and 5/11 (45%) with CCLE at 6 months and 12 months respectively; 15 patients (30%) required further rituximab therapy within 12 months for cutaneous involvement. Thus, rituximab may have efficacy in patients with SLE and severe active CLE; however, outcomes were variable in those with SCLE and CCLE subtypes and may reflect the variation in co-medications, including administration of Cytoxan, in the various retrospective studies [36–38]. Prospective studies in which co-administered medications and steroid doses are controlled may be more useful for understanding the role of Rituximab in CLE treatment.

Belimumab

Belimumab is a fully humanized mAb against B cell activation factor (BAFF, also known as BlyS) which is the only biologic drug currently approved for SLE; no clinical trials have formally studied the effects of belimumab on cutaneous disease. In a post-hoc analysis of combined data from two phase III trials (BLISS-52 and BLISS-76), belimumab plus standard therapy showed significant improvement according to BILAG and SELENA-SLEDAI dermal component [39]. A retrospective study by Iaccarino et al [40] analyzed 188 active SLE patients from 11 Italian cohorts that were treated with belimumab; 62 patients had cutaneous lesions including 48 patients with refractory, prominent skin lesions. CLASI scores were low (average of 4 at baseline) but improved after 6, 12 and 18 months of follow up (1.5, 0 and 0, respectively). Thus, active SLE patients with acute mucocutaneous lesions may have improvement with belimumab [41].

Targeting T cells

Beyond generalized immunosuppressive measures, targeting T cells has not been successful or well-studied thus far for CLE. Abatacept, a fusion protein composed of the Fc region of the immunoglobulin IgG1 fused to the extracellular domain of CTLA-4, inhibits costimulatory T cell activation. Results from 3 studies (2 retrospective and one case series) showed that it may have some effects on nonspecific cutaneous lupus lesions (oral ulceration, facial erythema ad alopecia), but no effect on CCLE, and the efficacy was not assessed on ACLE and SCLE [42]. Another targeting approach with lupuzor (Rigerimod), a synthetic phosphopeptide (P140) that modulates the activation of autoreactive T cells by targeting MHC class II receptors, had a failed phase III trial in which there was a superior response rate over placebo in 202 patients including withdrawals who were considered non-responders, but did not reach statistical significance for the primary end point. No specific assessment of CLE was done in the trial [43]. Other T-cell approaches, such as the use of calcineurin inhibitors, have been used in SLE; a recent trial of voclosporin showed positive results for lupus nephritis, but skin metrics were not included in the trial [44].

Targeting plasmacytoid dendritic cells and interferon signaling

BIIB059 is a humanized IgG1 mAb that binds blood DC antigen 2 (BDCA2), a pDC-specific receptor that inhibits the production of type I interferons (IFNs) and other inflammatory mediators when ligated. In a recent phase I, randomized, double-blind, placebo-controlled clinical trial, 8 CLE patients were treated with one dose of BIIB059 (4 ACLE, 1 SCLE and 3 DLE); a reduction in CLASI-A scores was observed in 5/6 patients at week 4 and maintained at week 12, while no improvement was seen in 3 of 4 patient in the placebo group. In addition, decreased CLASI-A score was correlated with reduced level of IFN-response genes in blood, normalization of MxA expression and reduced immune infiltrates in skin lesions [45]. A phase 2 trial for the treatment of SLE and CLE is ongoing (NCT02847598) [46].

Anifrolumab is a fully humanized, IgG1κ monoclonal antibody that binds to IFN-α/β/ω receptor (IFNAR) and prevents signaling by all type I IFNs. A post hoc analysis of a phase IIb, comparing IV anifrolumab vs. placebo on rash and arthritis measures demonstrated significant improvement of cutaneous involvement in the high IFN gene signature subgroup [47]. Recently, results of the second phase 3 RCT of anifrolumab demonstrated improvement vs. placebo for multiple efficacy endpoints (overall disease activity, skin disease and OCS tapering), with CLASI response 49% vs 25%, p=0.039 [48]. In another phase II study on the efficacy of subcutaneous anifrolumab in SLE with type I IFN test-high and active skin disease, greater reductions in CLASI activity score were observed in anifrolumab groups [49]. These results suggest anifrolumab is a promising agent for CLE.

AMG 811 is a human anti-IFNγ antibody (IgG1 isotype) that selectively targets human IFNγ. A phase I RCT compared 15 DLE patients treated with AMG 811 with placebo group; there was no significant difference in CLASI score, but there were changes in biomarkers associated with IFNγ in the blood and skins of DLE patients [50]. Given that only a subset of CLE lesions demonstrates IFNγ overexpression [7], further subsetting of patients should be considered prior to additional treatment studies with AMG 811.

Targeting the JAK-STAT pathway

Baricitinib is a selective and reversible inhibitor of JAK1 and JAK2 that blocks type I IFN, IL-21 and IL-6 signaling. Results of a phase 2 trial in SLE of baricitinib met its primary endpoint and several secondary end points, but no difference in CLASI score was observed [51]. Overall CLASI scores were low at enrollment for this trial, so the performance of baricitinib in CLE remains debatable. Baricitinib, however, has shown significant improvement of skin lesions in patients with familial chilblain lupus and TREX1 mutation [52] and complete remission of a refractory papulosquamous rash in an SLE patient [53]. In addition to baricitinib, case reports support efficacy of tofacitinib for CLE [54] and several ongoing phase I and II clinical trials are investigating this [55,56].

Other therapies targeting Cytokines and their receptors

Consistent with previous results [57], a post-hoc analysis of a phase II RCT of ustekinumab, an IL-12/23 monoclonal antibody, demonstrated reduced the skin disease activity of patients with SLE who had a high CLASI score. The proportion of patients with ≥ 50% improvement in CLASI activity score stabilized at week 28 (67.7%) and then maintained through week 48 (68.6%) in the ustekinumab group [58]. Phase III trials are ongoing.

Conclusion and perspective

CLE encompasses several cutaneous diseases with common and unique pathogenesis. Current treatment approaches can improve CLE, but there are still several unmet needs, including more effective less toxic medications and a reliable supply of quinacrine. Ongoing research is driving the pipeline of possible therapies. Consideration of CLE as a disease entity worthy of individual study will be important for patients who suffer from CLE without associated SLE and for SLE patients with fairly good disease control but refractory skin lesions.

Key Points.

Topical corticosteroids, calcineurin inhibitors, antimalarials, and systemic steroids remain the first-line treatment for CLE.

Some targeted agents such as anifrolumab, ustekinumab, rituximab and belimumab show promise for CLE and SLE patients with skin manifestations.

Future research and ongoing clinical studies are needed for better, more targeted therapies for patients with refractory skin lesions.