Manejo de Las Manifestaciones-1-S2.0-S0049017219303737

Seminars in Arthritis and Rheumatism 50 (2020) 95 127
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Seminars in Arthritis and Rheumatism

journal homepage: www.elsevier.com/locate/semarthrit
Management of cutaneous manifestations of lupus erythematosus:

A systematic review
J.L. Fairleya,b, S. Oonc,d, A.M. Saracinoe, M. Nikpourc,d,*
a
School of Public Health and Population Medicine, Monash University, Melbourne, Australia
b
The Alfred Hospital, Melbourne, Australia
c
Department of Rheumatology, St Vincent’s Hospital, Melbourne, Australia
d
The University of Melbourne, Australia
e
Centre for Rheumatology and Connective Tissue Diseases, Division of Medicine, University College London, United Kingdom
A R T I C L E I N F O A B S T R A C T
Keywords: Background: Cutaneous lupus erythematosus (CLE), occurring with or without systemic lupus erythematosus
Cutaneous lupus erythematosus (SLE), is a group of inflammatory skin diseases that can be very debilitating, causing significant psychological
Discoid lupus distress, and sometimes scarring.
Subacute combined lupus erythematosus Objectives: We sought to comprehensively present the evidence for different treatment modalities in patients
Dermatology
with cutaneous manifestations of lupus erythematosus (LE).
Topical treatments
Methods: Medline, Embase, Scopus and Cochrane CENTRAL were searched electronically from 1990 to March
Biologic therapies
2019, using keywords related to cutaneous lupus and synonyms and treatment. Articles retrieved were
screened for relevance, including reference lists of retrieved reviews. We included clinical trials, observa-
tional studies or case series with 5 patients focussing on treatment of CLE, with or without SLE.
Results: The search identified 6637 studies, of which 107 were included. Each study commonly included a
heterogeneous mixture of CLE subtypes, with or without SLE. The 107 included studies investigated 11 differ-
ent categories of treatment in 7343 patients. Treatments included topical calcineurin inhibitors (13 studies),
sun protection (5 studies), R-salbutamol cream (2 studies), antimalarials (22 studies), synthetic DMARDs (10
studies), retinoids (2 studies), thalidomide/lenalidomide (22 studies), biologic therapies (15 studies), intrave-
nous immune globulin (3 studies), laser (6 studies) and other therapies (7 studies). General measures to be
considered include smoking cessation, sun protection measures and optimisation of vitamin D levels. Moder-
ate evidence exists for benefit with topical CNIs, particularly as a steroid sparing agent in areas at high risk of
steroid complications (e.g. facial skin). There is moderate evidence for hydroxychloroquine, which is first-
line in SLE patients, limited evidence to support other synthetic DMARDs, and moderate evidence supporting
thalidomide but with significant risk of toxicity. Of biologic therapies, there are moderate data to support
belimumab. Limited evidence exists for other therapies.
Conclusion: Many management options are available for CLE, including topical, systemic and biologic thera-
pies, with a variable balance of efficacy and toxicity. There is a paucity of high-quality clinical trial data. Fur-
ther trials are required to better understand optimal management of CLE, particularly in specific subgroups.
© 2019 Elsevier Inc. All rights reserved.
Introduction diverse skin diseases, with potentially different pathogenesis and

response to treatment. CLE can occur with or without SLE in a wide
Cutaneous lupus erythematosus (CLE), occurring with or without variety of different subtypes, including chronic CLE (CCLE; such as
systemic lupus erythematosus (SLE), is a group of inflammatory skin discoid (D)LE, lupus erythematosus tumidus and lupus profundus/
diseases [1 3] that can be debilitating, resulting in significant psy- panniculitis), subacute CLE (SCLE), acute CLE (ACLE; most commonly
chological distress, permanent scarring and disfigurement in many malar rash) and non-specific cutaneous involvement. The risk of SLE
[3]. These conditions are uncommon, with an increased risk in developing following onset of CLE has been estimated at 10 13% [1].
young-middle aged women [1]. CLE comprises a group of extremely There many potential management strategies available for those
affected by CLE, with varying degrees of efficacy [3]. These range from
topical therapies, including corticosteroids and more recently topical cal-
* Corresponding author at: The University of Melbourne at St. Vincent’s Hospital, 41
Victoria Parade, Fitzroy, Victoria 3065, Australia.
cineurin inhibitors, to systemic therapies including biologic disease mod-
E-mail address: m.nikpour@unimelb.edu.au (M. Nikpour). ifying anti-rheumatic drugs (DMARDs) [3,4]. Management can depend
https://doi.org/10.1016/j.semarthrit.2019.07.010
0049-0172/© 2019 Elsevier Inc. All rights reserved.
Descargado para Laura Daniela Murillo Villarreal (lauradmurillo@hotmail.com) en University of Rosario de ClinicalKey.es por Elsevier en febrero 09,
2022. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2022. Elsevier Inc. Todos los derechos reservados.
96 J.L. Fairley et al. / Seminars in Arthritis and Rheumatism 50 (2020) 95 127
on the presence of comorbid SLE [3]. In some cases, patients may be manifestations in SLE, studies were excluded when non-specific cuta-
refractory to many different therapies requiring significant immunosup- neous outcomes were presented (e.g. frequency of “rash” pre- and
pression to mitigate the risk of scarring and disfigurement [4]. post-treatment).
Despite the significant physical and psychosocial burden of these con-
ditions, no comprehensive and systematic summary of available evidence Secondary outcomes
exists to guide the treating physician. Thus, our review aims to compre- We also extracted data on adverse effects of treatment and patient
hensively present the evidence for different treatment modalities in satisfaction.
patients with cutaneous manifestations of lupus erythematosus (LE). We
have detailed, where possible, subgroup analyses to assist the practitioner Statistical analysis
in identifying the most effective treatments for specific CLE subtypes.
Highly heterogeneous results were anticipated due to large varia-
Methods tions in study design, treatments, study protocols and outcome meas-
ures. Data pertaining to treatment response were extracted; often
A detailed study protocol has been submitted to the PROSPERO these were a clinician-reported assessment of response. If any spe-
Register of systematic reviews. MEDLINE, EMBASE, Scopus and cific outcome score was used, scores were extracted and summarised.
CINAHL were searched from 1990 to March 2019. We used keywords We were unable to conduct meta-analysis due to the heterogeneity
and MeSH term related to cutaneous lupus, synonyms (such as DLE, of included studies in terms of study design and protocols, treat-
SCLE, lupus erythematous tumidus (LET), ACLE) and treatment ments, patient population and definitions of CLE subtypes, where
(including a comprehensive list of potential treatment options such these were recorded.
as topical corticosteroids, calcineurin inhibitors, biologic therapies)
(Fig. S1: Supplementary Digital Content). We hand-searched articles Risk of bias assessment
from reference lists of identified articles for additional studies of
potential relevance. The search was limited to English language stud- Risk of bias assessment was conducted for all included studies. By
ies in adult humans. Two review authors (JF and SO) independently definition, studies without a comparison or control group were
screened abstracts for potential relevance. If consensus was not deemed at “high” risk of bias. Studies with a comparison group were
reached, a third author (MN) was consulted. A single author (JF) per- assessed by the Cochrane Risk of Bias tool, which allowed stratification
formed data extraction. Studies were grouped by treatment modality, of risk of bias as “high”, “low”, “unclear” or “some concerns” in a num-
with the subgroup of lupus erythematosus reported where possible. ber of domains including risk of selection bias, reporting bias, perfor-
mance bias, detection bias and attrition bias. Any study which was
Inclusion/exclusion criteria assessed as “high” risk of bias in any one domain, or “some concerns”
in multiple domains, was considered “high” risk of bias overall. Any
We examined clinical trials and observational studies including study with multiple domains of “unclear” risk or one domain at “some
five or more patients investigating management of CLE, with or concern” of risk of bias was rated as “moderate” risk of bias overall.
without SLE. We included case series only where a standard treat- Studies at “low” risk of bias in all domains with at most one “unclear”
ment was used for five or more patients (i.e. we excluded those rating were deemed at “low” risk of bias. One author (JF) performed
studies seeking to provide descriptive epidemiology of a popula- risk of bias assessments, which were reviewed and uncertainties
tion). We reviewed and included articles involving cutaneous man- addressed by a second author (SO). Risk of bias assessments are avail-
ifestations in SLE only where specific cutaneous outcomes were able in Table 1 (detail in Supplementary Digital Content, Fig. S1).
mentioned, for example the response of malar or photosensitive
rash to treatment. Results
Population The search strategy identified 6637 papers, of which 1029 were
excluded as duplicates, and 5483 excluded for other reasons (See
We included studies looking at CLE (with or without SLE) in all Fig. 1: PRISMA Diagram). One-hundred and twenty-five articles were
forms (including ACLE, SCLE, CCLE subtypes including DLE, and non- retrieved, and 39 studies excluded (Fig. 1: PRISMA Diagram). Twenty-
specific cutaneous features). one were added post-search from screening reference lists of similar
reviews, resulting in a total of 107 studies included in this review.
Intervention These 107 studies examined 11 different categories of treatment
in 7343 patients (Table 1). Treatments included topical calcineurin
Any treatment strategy for cutaneous manifestations of lupus inhibitors (CNI) (13 studies; Table 2) [5 17], sun protection (5 stud-
erythematosus (LE), including topical, systemic (including biologic) ies; Table 3) [18 22], R-Salbutamol cream (2 studies; Table 4)
and physical (e.g. laser) therapies. [23,24], antimalarials (22 studies; Table 5) [25 47], synthetic
DMARDs including cyclophosphamide (10 studies; Table 6) [48 57],
Comparator/control retinoids (2 studies; Table 7) [58,59], thalidomide/lenalidomide (22
studies; Table 8) [60 78], biologic therapies (15 studies; Table 9)
No comparison or control group was required for inclusion in this [79 93], intravenous immune globulin (IVIG) (3 studies; Table 10)
review. [94 96], laser therapy (6 studies; Table 11) [97 102] and other ther-
apies (7 studies; Table 12) [28,103 108].
Outcomes
Topical CNIs
Primary outcomes
Studies were required to report specific mucocutaneous outcomes Thirteen studies involving 250 patients examined topical CNIs in
pre- and post-treatment. Ideally, studies used a skin outcome score CLE [5 17] (Table 2). Of these, there were 5 randomised controlled
(e.g. Cutaneous Lupus Erythematosus Disease Area and Severity trials (RCTs) [5 9], 3 non-controlled clinical trials(10 12), 1 obser-
Index (CLASI) or mucocutaneous component of British Isles Lupus vational study [14] and 4 case series [13,15 17]. Six studies
Assessment Group (BILAG)). In studies dealing with mucocutaneous included only patients with DLE [5,6,8,10,11,13], whilst 7 studies
Table 1
Summary of studies included in systematic review
Treatment modality Number of studies total: N = 107 Lupus subtype Risk of bias Recommendations
studies, 7343 patients
Summary/strength Subgroup data

of recommendation
Topical Calcineurin Inhibitors N = 13 studies, 250 patients Mixed: 7/13 High: 10/13 Moderate; large number of studies Conflicting data
(tacrolimus, pimecrolimus) RCT: 5 DLE: 6/13 Moderate: 2/13 with consistent results, plus some
Non-controlled trial: 3 Comorbid SLE: Yes 6/13, Low: 1/13 RCT data
Observational: 1 No 4/13, NR 3/13
Case series: 4
Sunscreen/Sun Protection N = 5 studies, 123 patients Mixed: 5/5 High: 4/5 Moderate; consistent data favour Limited data
RCT: 3 Comorbid SLE: Yes 2/5, NR 3/5 Low: 1/5 benefit in setting of photoprovoca-
Non-controlled clinical trial: 1 tion, limited data in “real world”
Case series: 1 circumstances
R-Salbutamol Cream N = 2 studies, 46 patients Mixed: 2/2 High: 1/2 Limited data support benefit Limited data
RCT: 1 Comorbid SLE: NR in 2/2 Low: 1/2
J.L. Fairley et al. / Seminars in Arthritis and Rheumatism 50 (2020) 95 127

Case series: 1
Antimalarials (HCQ, chloroquine, quinacrine) N = 22 studies, 2203 patients Mixed: 19/22 High: 20/22 Hydroxychloroquine: Low-moder- Limited data
RCT: 2 LET: 1/22 Moderate: 1/22 ate evidence for benefit (around
Non-controlled trial: 2 DLE: 2/22 Low: 1/22 50% response rates)
Observational: 16 Comorbid SLE: Included 17/22, Other antimalarials: limited data
Case series: 2 NR 4/22, No 1/22 support equivalence
Combination therapy: limited
data support improved response
rate with combination therapy
Synthetic DMARDs N = 10 studies, 170 patients Mixed: 7/10 High: 10/10 Methotrexate: limited evidence Limited data
(methotrexate, mycophenolate, RCT: 1 SLE/ACLE: 3/10 supports benefit, perhaps equiva-
cyclophosphamide, azathioprine) Non-controlled trial: 2 Comorbid SLE: Yes 8/10, lent to chloroquine
Observational: 4 No 1/10, NR 1/10 Mycophenolate mofetil: conflict-
Case series: 3 ing data
Azathioprine: limited data
Cyclophosphamide with dexa-
methasone: limited data favour
benefit (SLE only)
Retinoids (isotreinoin, acitretin) N = 2 studies, 64 patients Mixed: 22 High: 1/2 Limited data favour benefit Limited data
RCT: 1 Comorbid SLE: NR 2/2 Moderate: 1/2
Case series: 1
Thalidomide/Lenalidomide N = 22 studies, 629 patients DLE: 1/22 High: 22/22 Thalidomide: moderate data favour Thalidomide: limited data
Non-controlled trial: 7 Mixed: 21/22 benefit, although with significant favours improved response
Observational: 7 Included comorbid SLE: Yes 19/22, risk of adverse effects rate in SCLE than DLE
Case series: 8 No 1/22, NR 1/22 Lenalidomide: low-moderate con- Lenalidomide: limited data
sistent data favour benefit with less
adverse effects than thalidomide
Biologic therapies N = 15 studies, 3269 patients DLE: 2/15 High: 10/15 Belimumab (5 studies): moderate Limited data
(belimumab, rituximab, anifrolumab, RCT: 8 SLE/ACLE: 7/15 Moderate: 3/15 data support benefit
sirukumab, efalizumab, ustekinumab) Non-controlled trial: 2 Mixed: 7/15 Low: 2/15 Rituximab (3 studies): conflicting
Observational: 4 Included comorbid SLE: data only support benefit when
Case series: 1 Yes 14/15, NR 1/15 combined with cyclophosphamide
Other biologics: limited data
IVIG N = 3 studies, 35 patients Mixed: 3/3 High: 3/3 Conflicting data Limited data
Case series: 3 Comorbid SLE: Yes 2/3, NR 1/3
Laser Therapy N = 6 studies, 73 patients DLE: 2/6 High: 6/6 Laser therapy: low-moderate evi- Limited data
Non-controlled trial: 4 Mixed: 3/6 dence for pulsed dye laser therapy
Observational: 2 LET: 1/6 (wavelength usually 585 595 nm)
Comorbid SLE: Yes 5/6,
No 1/6, NR 1/6
(continued on next page)
97
included patients with a mixture of different subtypes of CLE
ble), RCT (randomised controlled trial), CR (complete response), PR (partial response), TDS (three times daily), BD (twice daily), AE (adverse effects), UVA (ultraviolet A), UVB (ultraviolet B), SPF (sun protection factor), CLASI (cutaneous
lupus erythematosus disease area and severity index), SLICC (Systemic Lupus Erythematosus International Collaborating Clinics), BILAG (British Isles Lupus assessment group), HCQ (hydroxychloroquine), mg (milligram), ms (millisec-
Abbreviations: SLE (systemic lupus erythematosus), CLE (cutaneous lupus erythematosus), LE (lupus erythematosus), DLE (discoid lupus erythematosus), ACLE (acute cutaneous lupus erythematosus), SCLE (Subacute cutaneous lupus
erythematosus), CCLE (chronic cutaneous lupus erythematosus), LET (lupus erythematosus tumidus), LEP (lupus erythematosus panniculitis/profondus), NSLE (non-specific lupus erythematosus), NR (not recorded), NA (not applica-
[7,9,12,14 17]. Patients with comorbid SLE were included in 6 stud-
ies [7,9,12,15 17]. Eight studies were deemed at high [5,9 17], two
moderate [6,8] and one at low risk of bias [7].
Eight studies used topical tacrolimus (0.03 or 0.1%)
[5 7,9,12,13,15,17], 4 studies topical pimecrolimus (1%) [8,10,11,16]
J (joules), cm (centimetre), nm (nanometre), kg (kilogram), RA (rheumatoid arthritis), PDL (pulsed dye laser), IPL (intense pulse laser), IFN (interferon), VAS (visual analogue scale), IVIG (intravenous immune globulin).
Subgroup data
Limited data
and one study included a mixture of both tacrolimus and pimecroli-

mus [14]. Six of thirteen studies involved a comparison group
[5 9,15], most commonly topical corticosteroids.
Recommendations
All studies demonstrated improvement with topical CNI therapy,

usually to a moderate extent. Benefit was equivalent to topical corti-
costeroid therapy [5,6,8,9,15]. There was a risk of relapse when treat-
ment was ceased [5,16]. Three studies presented conflicting data on
response of different lupus subtypes [7,12,14]. One showed a signifi-
cant improvement with tacrolimus in patients with DLE, LET and
ACLE, with no benefit of topical CNI versus placebo in SCLE [7]. An
of recommendation
Summary/strength
RCT showed similar improvements in DLE, SCLE and SLE with malar
rash [9]. One non-controlled trial showed similar improvements
Limited data
among subtypes, whereas one observational study showed equal

improvement in erythema and oedema in LET, SLE and SCLE [14].
Adverse effects were minor if noted, with pruritis, irritation or burn-
ing noted in some studies [6,14,15].
Sun protection and sunscreen

Risk of bias
High: 6/7
Low: 1/7
Five studies in 123 patients investigated sun protection and sun-

screen in the management of CLE [18 22] (Table 3). These included 3
RCTs [18,19,21], one non-controlled clinical trial [22] and one case
series [20]. All studies included patients with a mixture of CLE sub-
types, with one study including patients with comorbid SLE [20].
Four studies were deemed at high [18,20 22], and one study at low
Comorbid SLE: Yes 3/7,
risk of bias [19].

Four studies involved assessing the benefit of sunscreen in pre-
Lupus subtype
No 2/7, NR 2/7
venting LE lesions in response to photoprovocation testing [18 21],

Mixed: 4/6
while one study evaluated prolonged use of sunscreen in regular life

DLE: 2/6
[22]. In the studies analysing response to photoprovocation testing,

two studies [18,19] showed application of a high sun protection fac-
tor (SPF50-75) sunscreen completely prevented lesions, whilst the
remaining studies showed a significant reduction in lesion develop-
Number of studies total: N = 107
ment [20,21]. No difference across CLE subtypes was shown [18,20].

N = 7 studies, 481 patients
Another study showed a significant reduction in disease severity

Non-controlled trial: 3
studies, 7343 patients
with regular use of an SPF15+ sunscreen, despite only 54% adherence

[22]. Adverse effects were minimal in one study [19].
Observational: 2
Case series: 1
R-salbutamol cream
RCT: 1
Two studies in 46 patients investigated the use of R-salbutamol

cream to treat CLE [23,24] (Table 4). One study was a placebo-
controlled RCT [23], and another was a case series [24]. The RCT
included only patients with DLE [23], whilst the case series included
patients with mixed subtypes of CLE [24]. Neither study reported
whether patients with comorbid SLE were included. The case series
was deemed at high [24], and the RCT at low risk of bias [23].
Both studies showed improvement with R-Salbutamol cream. The
RCT showed significant reduction in scaling, hypertrophy, induration
and lesion size with improved patient satisfaction compared to pla-
cebo [23]. The case series showed a better response in SCLE than DLE,
with newer, non-hypertrophic DLE responding better than older,
hypertrophic lesions [24]. Adverse effects were minimal [23].
Treatment modality
Table 1 (Continued)
Other Therapies
Antimalarials
Twenty-two studies involving 2203 patients investigated the

use of antimalarials in patients with CLE [25 27,29 47] (Table 5).
ond),
These studies included 2 RCTs [25,27], 2 non-controlled trials

[39,109], 16 observational studies [26,29 38,40,41,43 47] and 3
J.L. Fairley et al. / Seminars in Arthritis and Rheumatism 50 (2020) 95 127 99
Fig. 1. PRISMA flowchart.
case series [38,40]. Nineteen studies included patients with mixed subtherapeutic levels [109]. Some adverse effects were noted but
subtypes of CLE [26,27,29 33,35,36,38,39,41,43 47], while two rarely required discontinuation of treatment [27,29,30].
studies included only patients with DLE [34,40] and one only Of the studies examining other antimalarials, one RCT showed
patients with LET [37]. Seventeen studies included patients with equivalence of chloroquine and clofazimine, an anti-lepromatous med-
comorbid SLE [25 27,29 34,36,38,41 44,46,47]. Twenty-one ication, in patients with mixed subtypes of CLE [25]. An observational
studies were deemed at high [26,29 41,43 47,109], one at mod- study showed inferior response to chloroquine, quinacrine or HCQ in
erate [25], and one at low risk of bias [27]. smokers than non-smokers [47]. One study showed equivalence of
Most commonly, studies examined use of hydroxychloroquine chloroquine and hydroxychloroquine in LET [37], while another study
(HCQ) [27,29 32,34,35,37,40 43,45 47], with fewer studies exam- showed switching from one antimalarial to an alternative may
ining other agents (chloroquine [25,37,41,45,47], quinacrine [47]) or improve response rate [41]. Adverse effects were generally mild [39],
combination therapy using hydroxychloroquine, chloroquine and although more frequent than with hydroxychloroquine [25,28].
quinacrine (also known as mepacrine) [26,33,36,38,39]. Combination therapy was generally implemented in those refrac-
Of the studies examining hydroxychloroquine monotherapy, one tory to monotherapy, with around half of patients responding
RCT [30] showed significant reduction in CLASI score with both pla- [26,33,36,38,39]. Rates of response by subtype were conflicting [26,36].
cebo and hydroxychloroquine, although with higher rates of
“marked” improvement with hydroxychloroquine. Among the obser- Synthetic DMARDs
vational studies, generally CLASI Activity scores improved with
response rates around 50% (partial or complete) [29 32,34,35,43,46]. Ten studies in 170 patients investigated synthetic DMARDs as
Two studies examining DLE alone showed similar results [34,40], treatment for CLE [48 57] (Table 6). This included one RCT [48], two
with one study identifying localised disease without SLE, and non- non-controlled trials [49,50], 4 observational studies [51 54] and
scarring alopecia, as predictors of response to hydroxychloroquine two case series [55 57]. Nine studies included patients with mixed
[34]. One further study identified absence of discoid lesions as a pre- cutaneous manifestations of lupus, while one study included SCLE
dictor of complete response [31]. No subgroup was identified as hav- only [49]. Eight studies included patients with SLE
ing a superior response to hydroxychloroquine, although smokers [48,50 53,55 57]. Three studies examined methotrexate [48,53,54],
were identified to be at higher risk of treatment failure [35,45] with three studies examined mycophenolate mofetil (MMF) [49,51,57],
higher CLASI scores [45]. One study showed improved response rates one azathioprine [50] and three pulse cyclophosphamide [52,55,56].
when HCQ levels were checked and doses increased in those with All studies were deemed at high risk of bias [48 57].
Fig. 2. Cutaneous lupus erythematosus: a suggested management algorithm.
One RCT [48] and two observational trials examined use of metho- good response of multiple different cutaneous manifestations includ-
trexate for cutaneous lupus [53,54]. The RCT demonstrated equiva- ing discoid and malar rashes, oral ulcers and alopecia [52,55]. Predict-
lence of methotrexate to chloroquine, with significant improvement ably, this regimen had significant adverse effects noted including
in skin disease in both groups with no difference between groups infection [52,55,56] and one death [52].
[48]. Both observational trials showed improvement in a majority of
patients (83 97%) [53,54]. One study suggested SCLE and more local- Retinoids
ised DLE responded better than generalised DLE [53]. Adverse effects
were frequent in all studies (including alopecia and transaminitis) Two studies in 64 patients examined retinoids to treat CLE [58,59]
but usually did not require treatment cessation [48,53,54]. (Table 7); one RCT studying acitretin [58] and one case series study-
Three studies examining MMF in CLE comprised one non-con- ing isotretinoin [59]. Both studies involved participants with mixed
trolled trial [49], one observational study [51] and one case series subtypes of cutaneous lupus. One study included participants with
[57]. While two studies showed improvement in skin disease [49,51], comorbid SLE [59]. One study was deemed at high [59], and the other
the case series showed partial response in 2/7 patients only [57]. at moderate risk of bias [58].
Adverse effects were common in all studies (including gastrointesti- The RCT comparing acitretin to HCQ did not show a significant dif-
nal disturbance and transaminitis), but usually did not require treat- ference between the two agents in patients with mixed subtypes of
ment cessation [49,51,57]. CLE, with around 50% of patients responding to each drug [58]. The
One non-controlled trial investigated azathioprine in cutaneous case series showed significant improvement in patients where iso-
lupus [50]. Two-thirds of participants experienced partial or com- tretinoin was used for CLE [59], although with frequent flares on
plete response to azathioprine, with 2/6 requiring cessation of treat- withdrawal. Adverse effects were mild [58,59].
ment due to serious adverse effects such as pancreatitis and fever.
One observational trial [52] and two case series [55,56] examined Thalidomide and lenalidomide
response of cutaneous manifestations of SLE to pulse cyclophospha-
mide therapy, combined with dexamethasone in two studies [52,55]. Twenty-two studies in 629 patients looked at thalidomide or lena-
Both studies combing cyclophosphamide and dexamethasone lidomide therapy in CLE [60 78,110 112] (Table 8). Fourteen studies
showed significant improvement, with two studies demonstrating looked at thalidomide therapy [60 73,112], and 5 investigated
Table 2
Topical CNIs
Population Intervention Comparator Results

RCTs
Wang et al. (2015) [5] N = 31 patients Tacrolimus 0.03% ointment Triamcinolone acetonide Response: no difference in rate of healing between tacrolimus and
DLE involving labia TDS then weaning for 0.1% cream triamcinolone.
Biopsy-proven at least 3 weeks Reduction in erosion, erythema and reticulation in both groups with treatment,
without differences between groups.
Relapse on treatment cessation in both groups.
Incomplete healing requiring additional therapy: 6/22 tacrolimus,
2/19 triamcinolone.
AE: none significant.
Pothinamthong N = 21 Tacrolimus 0.1% topical ointment 0.05% clobetasol propinoate Tacrolimus: significant reduction in CLASI activity score during
et al. (2012) [6] DLE with lesions on both (one side of body) daily (contralateral side of body) treatment only. No significant increase in CLASI Damage score during
right and left side of body, for 6 weeks treatment. Increase in both CLASI Activity and Damage scores when treatment
without SLE ceased. Significant reduction in patient satisfaction score, continuing to 4
Localised 12/21 weeks post treatment.

Generalised 9/21 Clobetasol: significant reduction in CLASI activity score post treatment, with no
Biopsy-proven significant increase in CLASI damage score. Improved patient satisfaction
scores. Significant difference in all scores
persisted to 4 weeks post treatment (unlike tacrolimus).
AE: pruritis/burning.
Kuhn et al. (2011) [7] N = 30 Tacrolimus 0.1% ointment Placebo (vehicle ointment) Significantly greater improvement in oedema in tacrolimus group at all
Refractory CLE, with 2 separate BD for 3 months timepoints, and total clinical score at Day 28 and 56 only. Significantly greater
comparable skin lesions improvement in erythema only at day 28.
required Response based on subtype of CLE
- DLE 14/30 - Greater improvement in LET vs. DLE (p = 0.0076)
- SCLE 4/30 - Significant improvement with tacrolimus in patients with DLE, ACLE and LET
- ACLE 1/30 - No significant improvement with tacrolimus vs. vehicle in SCLE patients
- LET 11/30 Response based on body site
- SLE 3/30 - Greater improvement at Day 28 in lesions on face compared with other body sites
Biopsy-proven Response based on duration of lesion
- Lesions persisting more than 6 months responded better to topical
tacrolimus
AE: none significant.
Barikbin et al. (2009) [8] N = 10 Pimecrolimus 1% cream Betamethasone valerate Significant reduction in clinical severity scores in both groups from
Moderate-severe facial DLE, twice daily 0.1% cream twice daily pre- to post-treatment scores; no significant difference between groups.
without SLE. AE: none.
Biopsy-proven
Tzung et al. (2007) [9] N = 20 Tacrolimus 0.1% ointment Clobetasol 0.05% propionate Erythema, Desquamation and Induration: significant reduction in both
Refractory CLE § SLE, facial to affected area on one ointment to contralateral tacrolimus and clobetasol from baseline to Week 8 (p < 0.05) and all other
involvement side of face side of face timepoints.
- SLE and malar rash 13/20 AE: significantly more telangiectasia with clobetasol than tacrolimus (none
- DLE 4/20 observed).
- SCLE 1/10
Biopsy: NR
Non-controlled clinical trials
Khondker et al. (2012) [10] N = 37 Pimecrolimus None Improvement: 26/37; excellent 0/26, good 23/26, fair 2/26, poor 1/26
DLE 1% cream BD Reduction in frequency and severity of erythema, infiltration,
Biopsy-proven for 6 weeks squamation.
No change in photosensitivity.
AE: NR.
Tlacuilo-Parra N = 10 Pimecrolimus None Response rate: 10/10 (>70% improvement in 3/10)
et al. (2005) [11] DLE, moderate severity 1% cream BD Patient reported response: marked clearing 5/10, moderate 4/10, slight 1/10
Biopsy-proven to affected areas Significant reduction in clinical severity scores and Skindex-29
for 8 weeks Histology: decreased hyperkeratosis, corneal plugging, infiltrate.
AE: pruritis, erythema.
101
102
Table 2 (Continued)
Lampropoulos N = 12 Tacrolimus 0.1% ointment None DLE significant improvement 2/5, mild 1/5, none 2/5
et al. (2004) [12] - CLE § SLE for at least 6 weeks SCLE: Significant improvement 2/4, none 2/4
- DLE 6/12 SLE: significant improvement in photosensitive rash 2/2

- SCLE 4/12 AE: usually minor (peeling, burning, itch), 1/12 requiring cessation.
- SLE 2/12
Biopsy: NR
Observational Studies
Avgerinou et al. N = 38 Topical tacrolimus None Significant reduction in erythema, desquamation and oedema pre- and
(2011) [14] - CLE or pimecrolimus post-treatment.
- DLE 20/38 Better results with topical CNI when combined with antimalarial.
- SCLE 9/38 DLE: significant reduction in erythema, desquamation and oedema.
- LET 9/38 SCLE: significant reduction in erythema, desquamation and oedema.
Biopsy: selected patients. LET: significant reduction in only erythema and oedema (no desquamation
present in any patient).
AE: skin irritation/pruritis only.

Case series
Madan et al. N = 18 Tacrolimus 0.1% Tacrolimus 0.1% ointment Combination therapy:
(2010) [15] Refractory CLE ointment alone combined with clobetasol - Excellent response: 6/13
- DLE 14/13 propionate 0.05% - Good response: 5/13
- SLE 3/13 - Slight improvement: 1/13
- SCLE 1/13 No response: 1/13
Biopsy: NR Response maintained for duration of follow up in those with good/excellent
response
Monotherapy
- Good response: 1/5
- Slight response: 2/5
AE: minor only, mainly in combined group; telangiectasia, acne, greasiness,
irritation.
Heffernan et N = 5 patients Topical tacrolimus ointment None Improvement in 3/3 patients who completed follow up (1 additional patient had
al. (2005)[13] DLE 0.1% to 2 target lesions BD significant improvement within 4 weeks then dropped out of study)
Biopsy-proven for 12 weeks Mild improvement 1/3, moderate 1/3, marked 1/3
AE: none.
Kreuter et N = 11 Topical pimecrolimus None Clinical score (composite of clinical assessment of erythema, squamation and
al. (2004) [16] CLE § SLE 1% cream BD on affected infiltration); significant reduction from baseline (6.45 § 0.80) to end of
- SCLE 2/11 area for 3 weeks therapy (2.73 § 1.00), p < 0.001
- DLE 4/11 Relapse: 2/11 prior to 8 weeks
- SLE 3/11 AE: minor 1/11.
- LET 2/11
Biopsy-proven
Yoshimasu N=7 Tacrolimus 0.1% daily None Clinical Response
et al. (2002) [17] SLE or DLE with facial for 4 weeks “Very effective” in 4/7
lesions. “No change” 3/7
- DLE 4/7 AE: minor (itch and burning).
- SLE 3/7
Biopsy: NR
Abbreviations: SLE (systemic lupus erythematosus), CLE (cutaneous lupus erythematosus), LE (lupus erythematosus), DLE (discoid lupus erythematosus), ACLE (acute cutaneous lupus erythematosus), SCLE (Subacute cutaneous lupus erythe-
matosus), CCLE (chronic cutaneous lupus erythematosus), LET (lupus erythematosus tumidus), LEP (lupus erythematosus panniculitis/profondus), NSLE (non-specific lupus erythematosus), NR (not recorded), NA (not applicable), RCT (rand-
omised controlled trial), CR (complete response), PR (partial response), TDS (three times daily), BD (twice daily), AE (adverse effects), UVA (ultraviolet A), UVB (ultraviolet B), SPF (sun protection factor), CLASI (cutaneous lupus
erythematosus disease area and severity index), SLICC (Systemic Lupus Erythematosus International Collaborating Clinics), BILAG (British Isles Lupus assessment group), HCQ (hydroxychloroquine), mg (milligram), ms (millisecond), J
(joules), cm (centimetre), nm (nanometre), kg (kilogram), RA (rheumatoid arthritis), PDL (pulsed dye laser), IPL (intense pulse laser), IFN (interferon), VAS (visual analogue scale), IVIG (intravenous immune globulin).
Table 3
Sunscreen/sun protection

RCTs
Patsinakidis et al. (2012) [18] N = 20 Sunscreen SPF50+ Untreated, exposed skin. Response to photoprovocation testing
Mixed CLE; undergoing photo- - 9/20 CLE patients developed lesions without sunscreen, 0/20 developed lesions with sunscreen
provocation testing R-CLASI: no significant difference in scores pre- and post-photoprovocation testing in CLE patients.
- DLE 8/20 AE: not recorded.
- LET 5/20
- SCLE 7/20
Biopsy-proven
Kuhn et al. (2011) [19] N = 25 Broad spectrum sunscreen Placebo Positive photoprovocation testing
Mixed CLE; photosensitive SPF60 (anti-UVA and UVB N = 25 (different site) - Untreated: 16/25
- LET 17/25 efficacy) - Vehicle-treated: 14/25
- DLE 5/25 N = 25 (different site) - Sunscreen-treated: 0/25 (p < 0.001 for both UVA and UVB)
- SCLE 3/25 AE: none.
Biopsy: NR

Stege et al. (2000) [21] N = 11 Sunscreen A: SPF60 Untreated, exposed skin. Photoprovocation testing positive in 11/11 (untreated area)
Mixed CLE; photosensitive Sunscreen B: SPF75 N = 11 (different site) Sunscreen A: complete protection 11/11
- SCLE: 8/11 Sunscreen C: SPF >35 Sunscreen B: complete protection 5/11
- Chronic DLE 3/11 N = 11 (different site) Sunscreen C: Complete protection 3/11
Biopsy-proven AE: not recorded.
Non-controlled clinical trial
Callen et al. (1991) [22] N = 15 Sunscreen SPF15+ None Significant reduction (p < 0.05) in severity of papules, hyperpigmentation, atrophy, scaling,
Mixed CLE 8 week treatment period telangiectases, erythema, plaques with sunscreen treatment. No significant reduction in pruritis,
- DLE 9/15 macules, vesicles
- SCLE 6/15 Overall disease severity changed from 2.7 (mod to severe) to 1.7 (mild to mod)
Biopsy: NR Adherence good to excellent in 54%
Investigator assessment: 10/13 “superior” or “far superior”
Patient assessment: 7/11 “superior” or “far superior”
AE: NR
Case series
Herzinger et al. (2004) [20] N = 52 Sunscreen SPF30 (anti UVA Untreated, exposed skin. Significant reduction in lesions post-photoprovocation testing with sunscreen application
Mixed CLE; undergoing photo- and UVB efficacy) No difference across lupus subtypes.
provocation testing AE: not recorded.
- Chronic DLE 33/66
- SLE 4/66
- SCLE 2/66
- LET: 12/66
- LEP 1/66
Biopsy: “selected” patients only
erythematosus), CCLE (chronic cutaneous lupus erythematosus), LET (lupus erythematosus tumidus), LEP (lupus erythematosus panniculitis/profondus), NSLE (non-specific lupus erythematosus), NR (not recorded), NA (not applicable),
RCT (randomised controlled trial), CR (complete response), PR (partial response), TDS (three times daily), BD (twice daily), AE (adverse effects), UVA (ultraviolet A), UVB (ultraviolet B), SPF (sun protection factor), CLASI (cutaneous lupus
(joules), cm (centimetre), nm (nanometre), kg (kilogram), RA (rheumatoid arthritis), PDL (pulsed dye laser), IPL (intense pulse laser), IFN (interferon), VAS (visual analogue scale),.
103
lenalidomide [74 78]. Seven studies were non-controlled trials
Patients reported greater reduction in pain and itching with R-salbutamol, also greater improvement in overall patient
[60 62,74 76,111], 7 observational studies [63 67,77,112] and 8
Significant reduction in R-salbutamol group compared to placebo in scaling/hypertrophy, induration, lesion size.
case series [68 73,78,110]. Twenty-one studies involved patients
with mixed subtypes of CLE [60,62 78,110,111], and one study
included DLE only [61]. Nineteen studies included patients with
comorbid SLE [60,62 73,75 78,110,111]. All studies were deemed
at high risk of bias.
Of the 17 studies investigating thalidomide therapy [60 73,110,111],
four non-controlled trials [60 62,111] showed high rates of response
(98 100%) in patients with mixed subtypes of CLE [60,62] and DLE [61].
Similarly, high response rates were found in data from observational
studies and case series (67 100%) [63 73,110]. However, studies
tended to show a high risk of relapse on cessation of treatment
- New/non-hypertrophic lesions responded better (but less well than SCLE)
[60 63,67,68]. Furthermore, adverse effects were common especially

neurological symptoms or nerve conduction study-confirmed neuropa-
thy in up to 50 70% of patients [60 66,69 71,73]. In terms of subgroup
AE: none deemed drug-related. R-Salbutamol 9/19, placebo 12/18.
analysis, data were conflicting. One study found that long term remission
was more common in SCLE with a lower cumulative dose of thalidomide
required, and DLE was predictive of relapse [60]. One case series showed
slightly lower rates of response in DLE than SCLE [110]. Another showed
lower response rates in SCLE than in DLE or SLE [65], and another
- Response: excellent in 2/5, no response in 2/5
- Minor effect only on hypertrophic elements
showed no major difference in response rates between subgroups [69].

Five studies assessed response of CLE to lenalidomide [74 78].
Three non-controlled trials in patients with mixed subtypes CLE
showed good response rates and significant reduction in CLASI Activ-
ity scores [74 76]. Similar response rates were found in one observa-
- Response: 4/4 responded
tional study [77] and one case series [78]. Overall there were lower
rates of adverse effects than with thalidomide, particularly neuropa-
thy which was infrequently reported. On subgroup analysis, one
AE: not recorded.
study found there was a lower time to complete response in DLE and
assessment.
SCLE compared to lupus profoundus [75]. One case series noted that
patients with lupus panniculitis failed to respond to treatment [78].
Results
SCLE
DLE
Biologic therapies
Comparator
Fifteen studies in 3269 patients investigated the effect of biologic

therapies in CLE [79 93] (Table 9). Five studies examined belimumab
Placebo
N = 18
None
[81,83 86], three examined rituximab [87 89], one anifrolumab

[91] and one each of ustekinumab [93], BIIB059 [92], AMG-811 [79],
sirukumab [82], efalizumab [90] and PD-0360324 [80]. There were
R-salbutamol 0.5% cream
ASF-1096: sulphate salt

of R-salbutamol 0.5%
eight RCTs [79 83,91 93], two non-controlled trials [84,85], four
observational studies [86 89] and one case series [90]. Thirteen
studies looked at patients with mixed subtypes of CLE, or SLE
for 8 weeks
Intervention
[80 89,91 93] with two studies examining DLE [79,90]. All studies
included patients with comorbid SLE except one, where presence of
N = 19
SLE was not specified [90]. Ten studies were deemed to be at high
risk of bias [79,82,84 90,92], three at moderate [80,81,91] and two
at low risk of bias [83,93].
not receiving systemic treatment
Five studies examined belimumab [81,83 86], a fully human

DLE (with at least 1 new lesion),
immunoglobulin-G1λ monoclonal antibody that inhibits the B cell

survival factor B-lymphocyte stimulator. In most studies, belimumab
was given at a dose of 10 mg/kg intravenously on day 1, 14, 28 and
Mixed CLE; refractory
then every 28 days thereafter. One RCT gave subcutaneous belimu-

mab at a dose of 200 mg weekly [81]. Two RCTs [81,83] showed
Biopsy-proven
- SCLE 4/9
- DLE 5/9
greater improvement in overall response rate and outcome scores

Population
Biopsy: NR
for SLE.
(mucocutaneous BILAG and SELENA-SLEDAI) in the belimumab com-

N = 37
N=9
pared with placebo group. Both of these trials showed similar fre-
quency of adverse effects with belimumab and placebo [81,83]. Three
non-controlled trials [84 86] showed significant improvement in
Jemec et al. (2009) [23]
Wulf et al. (2007) [24]
CLASI Activity scores, with two showing stable CLASI Damage scores
R-salbutamol cream
[85,86] and one showing a reduction in flares [84]. One study showed
better results in non-smokers treated with belimumab [86].
Case Series
Three observational studies investigated the use of rituximab, an

anti-CD20 monoclonal antibody, in cutaneous manifestations of lupus
Table 4
RCTs
[87 89]. All studies gave two 1000 mg doses 2 weeks apart, accompa-
nied by intravenous cyclophosphamide [87,89] or methylprednisolone
Table 5
Antimalarials.

RCTs
Yokogawa et al. (2017) [27] N = 103 HCQ 200 mg/day for ideal body Placebo CLASI: significant reduction in both HCQ and placebo groups at
Active CLE (CLASI score 4+) with weight <46 kg, 200 400 mg 16 weeks’ follow up, without significant difference between
or without SLE on alternate days if 46 61 kg, groups.
- SLE 58.3% (ACR criteria) 400 mg/day if >61 kg Clinical assessment: “marked” improvement 59.4% HCQ group,
Biopsy: NR 30.4% placebo
Skindex-29: non-significant trend to improvement in HCQ
group.
AE: 57/77 in HCQ (3/57 requiring discontinuation), 19/26 in pla-
cebo group
Bezerra et al. (2005) [25] N = 33 Chloroquine 250 mg/day Clofazimine 100 mg/day Response rate
Mixed; patients with SLE (ACR Criteria) for 6 months - CR: chloroquine 7/17, clofazimine 3/16
and cutaneous manifestations. - PR: chloroquine 14/17, Clofazimine 12/16
- Malar rash 9/33 - No significant difference between groups at any time point

- SCLE 7/33 AE: Chloroquine 12/17, chlofazimine 11/16
- DLE localised: 8/33
- DLE generalised: 18/33
Biopsy: only if diagnostic uncertainty
Chasset et al. (2015) [109] N = 32 HCQ; previous dosage increased None CLASI Score (Median)
Mixed CLE, refractory disease, low blood HCQ by 200 mg/day (according - Baseline: 8 (Range 2 30)
concentration (<750 ng/ml). to HCQ blood level). - After HCQ Dose increase: 1.5 (range 0 30), p < 0.001
- DLE 17/32 Subgroup analysis
- Chillblain lupus: 1/32 - SCLE higher median CLASI improvement than other
- LEP: 1/32 subtypes (8 (range 0 20) cf. 3 (range 0 9)), p < 0.003
- LET: 6/32 HCQ Blood concentration (ng/ml) (median)
- SCLE: 11/32 - Baseline: 638 (100-749)
- Multiple subtypes: 4/32 - After HCQ dose increase: 1187 (760 2095), p < 0.001
- SLE (SLICC Criteria): 17/32 HCQ Dose (median): 9.8 mg/kg (range 6.8 13.8) (real body
Biopsy-proven. weight)
Feldman et al. (1994) [39] N = 14 Combination treatment with None Response
Mixed CLE chloroquine and quinacrine - Significant improvement/total clearing
- 9/14: chronic DLE Chloroquine 100 mg 3x/day SCLE: 5/5
- 5/14 with SCLE and quinacrine 65 mg 3x/day DLE: 5/9
Biopsy: NR - No change
SCLE: 0/5
DLE: 4/9
AE: jaundice-like discolouration, photophobia/blurred vision,
GI, insomnia, electroretinographic abnormality requiring
withdrawal from treatment 1/14.
Observational Studies
Chasset et al. (2018) [41] N = 64 HCQ or chloroquine initiated None Response rate with switch of agent
Mixed CLE, either refractory to/toxicity after failure of/intolerance - Treatment inefficacy group
from first line antimalarial to either HCQ (52/64) Overall response at 3 months: 27/48 (AE 4/48, inefficacy
- ACLE 2/62 or chloroquine (12/64) 17/48)
- SCLE 12/64 Inefficacy 48/64 Overall response at 12 months: 19/45 (AE 1/45, inefficacy
- DLE 44/64 Intolerance 16/64 4/45, loss to follow up 3/45)
- Chillblain LE 5/64 - Treatment intolerance group
- LEP 3/64 Overall response at 3 months: 9/16 (Inefficacy 3/16,
- LET 14/64 AE 4/16)
- >1 type: 18/64 Overall response at 3 months: 9/16 (Inefficacy 3/16,
- SLE: 8/64 AE 4/16)
Biopsy-proven AE: increased risk in patients who switched due to
intolerance (31% vs. 12%). Generally minor.
105
106
Table 5 (Continued)
Kishi et al. (2018) [43] N = 31 HCQ None Response

Mixed CLE - CR/PR: 17/31
- SLE 20/31 (SLICC Criteria) - Non-responders: 6/31

- DLE: Localised 3/31, Generalised 6/31 - Premature cessation or addition of other treatment
- LEP 2/31 making efficacy of HCQ unclear: 8/31
Biopsy: NR No difference in response rates between smokers and
non-smokers.
Subgroup Analysis response rates
- SLE: 10/14
- Generalised DLE: 5/5
- Localised DLE: 1/3
- LEP: 1/1
AE: 12/31 patients.
Ugarte et al. (2018) [26] N = 46 (15/46 with skin disease) HCQ and quinacrine None Response (Global): CR 22/46, CR or PR 42/46
SLE (ACR or SLICC criteria), refractory skin combination therapy Skin disease only: CR 9/15, CR or PR 13/15

and/or joint disease, refractory Response by subtype
to HCQ monotherapy. - SCLE: CR 6/10, CR or PR 10/10
- SCLE 10/46 (43.5%) - DLE: CR 3/10, CR or PR 8/10
- DLE: 10/46 (43.5%) CLASI: significant improvement at all time points
- Other: 3/46 (13%) “Rash” Component of SLEDAI: improved in 8/15 patients
Biopsy: NR. AE: nil serious.
Benoit et al. (2015) [44] N = 10 Quinacrine (variable doses, None 10 patients underwent 11 treatment courses
Mixed CLE 100 200 mg daily) Response
- DLE: 5/10 - CR 1/10
- SCLE: 4/10 - CR with flares: 1/10
- LET: 1/10 - PR: 4/10
Biopsy: NR - Temporary improvement only: 3/10
- Not effective: 2/10
Subgroup analysis (number of treatment courses)
- DLE: PR 3/7, Transient response 2/7, No response 1/7, ceased
due to AE 1/7
- SCLE: CR 1/5, PR 1/5, Transient response 1/5, No response
1/5, not assessed due to AE 1/5
- LET: CR with flares 1/1
R-CLASI: Tended to reduce, numbers not presented.
AE: requiring cessation 2/10. Nil serious.
Kuhn et al. (2014)[45] N = 1002 HCQ or chloroquine None HCQ Treatment attempted/success
Mixed CLE - ACLE: Trialled: 63.9%, Success: 92.8%
- ACLE 304/1002 - SCLE: Trialled: 58.6%,Success: 86.1%
- SCLE 236/1002 - CCLE (DLE, Chillblain LE or LEP): Trialled: 64%, Success:
- LET: 65/1002 84.1%
- DLE 375/1002 - LET: Trialled: 58.3%, Success: 77.4%
- Chillblain LE 13/1002 Chloroquine Treatment attempted/success
- LEP: 9/1002 - ACLE: Trialled: 32.8%, Success: 88.6%
- 2+ subtypes 347/1002 - SCLE: Trialled: 37.3%, Success: 73.7%
Biopsy-proven - CCLE (DLE, Chillblain LE or LEP): Trialled: 33%, Success:
82.1%
- LET: Trialled: 35%, Success: 70.6%
Impact of smoking
- Higher CLASI activity + damage scores in “ever” smokers cf.
nonsmokers
- Higher efficacy of antimalarials amongst nonsmokers
(93.8%) than “ever” smokers (82.1%), p < 0.05
- HCQ: efficacy 95.8% in nonsmokers, 85.0% in “ever”
smokers (non-significant).

Table 5 (Continued)
Momose et al. (2013)[29] N=7 HCQ 200 400 mg per day None Response
Mixed CLE - Effective 3/7

- SLE 4/7 - Ineffective 2/7

- DLE 5/7 - Unable to judge 2/7
- SCLE 1/7 - Particular efficacy against telangiectasia and erythema
- LEP 1/7 CLASI Activity score shown to reduce in 1/3 patients, unchanged
- SLE-Dermatomyositis overlap 1/7 in 2/3 patients (missing data in 4/7 patients)
Biopsy: NR CLASI Damage score unchanged in 3/3 patients (missing data
4/7 patients)
AE: None.
Yokogawa et al. (2013)[30] N = 27 HCQ at <6.5 mg/kg/day None CLASI: significant reduction at 16 weeks.
Mixed CLE or SLE with significant (maximum 400 mg/day) CR in 6/27 patients
cutaneous disease AE: minor only in 6/27
- SLE 17/27
- Sjogren’s syndrome 6/27

- DLE 11/27
- ACLE 8/27
- SCLE 5/27
- Other CLE 6/27
- Annular erythema 5/27
Biopsy: NR
Frances et al. (2012)[31] N = 300 Hydroxychloroquine None CR negatively correlated with DLE (RR 0.57, 95%CI 0.37 0.91,
Mixed CLE for at least 3 months p = 0.02) and male sex (RR 0.38 95%CI, 0.18 0.81, p = 0.01).
- SCLE 86/300 CR positively associated with absence of discoid lesions (RR 0.48,
- DLE 160/300 95% CI, 0.29 0.79, p = 0.004) and increased blood HCQ
- LET 52/300 concentration
- LEP 16/300 Median blood HCQ concentration lower in men than women
- Chilblain lupus 26/300 (p = 0.007), in patients reporting missing tablets (p = 0.01) and in
- SLE 97/300 those with partial remission or treatment failure than in
Biopsy-proven complete remission (p = 0.007)
Higher risk of treatment failure in nonadherent patients, although
despite nonadherence, response rates: CR 8/30, PR 8/30,
nonresponse 14/30
Blood HCQ level correlated with mg/kg dose (p < 0.001), inversely
correlated with missing doses (p = 0.01), BMI (p = 0.03) and
weight (p = 0.003)
No difference between blood HCQ concentration between subtypes
Yokogawa et al. (2012)[46] N=7 HCQ None Response: 6/7
CLE with SLE CLASI Activity Score (median)
- SLE 7/7 Baseline: 8 (range2 22)
- SCLE 2/7 Post-treatment: 4 (range 2 10)
- ACLE 5/7 CLASI Damage Score: worsened in 4/7
- DLE 1/7 Median
- LEP: 2/7 Baseline: 1.0 (range 0 3)
Biopsy: NR. Post-treatment: 2.0 (range 0 2)
AE: nil serious.
Ikeda et al. (2012)[32] N=7 HCQ for 16 weeks None Response
Mixed CLE 200 mg if ideal weight <45 kg, 200 400 mg/day - Improvement: 4/7
- DLE 3/7 if ideal weight 45 60 kg, 400 mg/day if >60kg - Unchanged: 3/7
- LET 1/7 CLASI
- Livedo 2/7 - Activity score: significant decrease in mean CLASI score
- Annular erythema 1/7 (p < 0.05)
- Chillblain LE 1/7 - Damage index: decreased in 1/7, unchanged in 5/7
- Psoriasiform LE 1/7 AE: transient only in 2/7
- SLE 4/7
Biopsy: NR
107
108
Table 5 (Continued)
Chang et al. (2011)[33] N = 128 HCQ monotherapy: 11/128 None Variable response rates to different combinations of therapy
Mixed CLE and SLE with HCQ-Quinacrine combination: 15/128 Overall a proportion of patients responded at each time point to
cutaneous manifestations Chloroquine monotherapy: 3/128 each combination; combination treatment appeared to
Biopsy: NR Chloroquine-Quinacrine combination: 6/128 improve response rates.

AE: NR.
Wahie et al. (2011)[34] N = 200 HCQ None Response Rate
DLE - Response: 120/200 (60%)
- SLE 11/200 - Non-responders: 70/200 (35%)
- SCLE in addition to DLE: 2/200 - Withdrawn early: 8/200 (4%)
Biopsy-proven - Unclear if response due to co-administration of
quinacrine: n = 2/200 (1%)
Predictors of response: localised disease (OR = 7.29, 95%CI
3.16 16.79, p < 0.0001), no associated SLE (OR = 19.83, 95%CI
2.48 159, p = 0.005), non-scarring alopecia (OR = 2.13, 95%CI
1.17 3.88, p = 0.014)

Risk factors for non-response: increasing number of body sites
associated (test for trend; p = 1.78 £ 10 6)
AE: not recorded.
Jewell et al. (2000)[35] N = 61 HCQ 200 400 mg per day for at least 8 weeks, None Response
Mixed CLE or chloroquine 250mg+ per day for 5 weeks+ - Non-Smokers: 19/21; smokers: 16/40 (p < 0.0002 between
- DLE 47/61 (generalised 17/47, - HCQ 59/61 groups)
localised 30/47) - Chloroquine 2/61 - DLE patients: smokers: 38% response, non-smokers: 93%
- SCLE 14/61 (p < 0.0004 between groups)
Biopsy-proven - SCLE patients: smokers 50% response, non-smokers 83%
(p > 0.05)
Lowest response rate in patients who were the heaviest
smokers (packs per day)
AE: not recorded.
Cavazzana et al. (2009)[36] N = 34 HCQ (5 mg/Kg/d) and Quinacrine with two regimens: None Response
Mixed CLE 100 mg/day (29/34) and 50 mg/day (5/34) - Improvement in 25/34 CR 11/25, PR 14/25
- DLE 19/34 - None: 9/34
- SCLE 10/34 By subtype
- Acute lupus rash 6/34 - DLE 84.2%
- Chillblain 4/34 - SCLE 60%
- LEP 3/34 - Acute lupus rash 100%
- SLE 17/34 - Chilblains 50%
Biopsy-proven - Lupus profundus 0%
CLASI Score: significant reduction in all patients with
treatment. Significant reduction also in DLE, acute lupus rash
and chilblain lupus, but not in SCLE or LEP.
AE: 10/34, severe in 2/10
Kreuter et al. (2009)[37] N = 36 Antimalarial therapy None CLASI Score: significantly reduced with treatment.
LET - Chloroquine 26/36 Response
Biopsy-proven - HCQ 10/36 - Complete/near complete clearance: 22/36
- At 6 months: 29/35 had complete/near complete clearance
- Higher percentage of complete/near complete clearance in
nonsmokers (88%) vs. smokers (57%)
No difference in efficacy between chloroquine and HCQ p = 0.40
AE: only in patients treated with chloroquine (GI 5/36,
dizziness/headache 2/36).
Rahman et al. (1998)[47] N = 36 Antimalarial therapy: chloroquine None Response
Mixed CLE 28/36, HCQ 4/36, Quinacrine 4/36 - CR at 6 months: 3/17 smokers, 9/19 nonsmokers (p < 0.035)
- DLE 25/36 - CR at 12 months: 3/16 smokers, 9/17 nonsmokers
- SCLE 16/36 (p < 0.046)
- DLE + SCLE 5/36 AE: not recorded.
- SLE 36/36
Biopsy: NR.

100 mg intravenously [88,89]. Response rates were variable, with two
studies showing a response of 71 76% [87,89], with a third describing
AE: blurred vision in 1/15, electroretinographic abnormality 3/

only 35% response rate [88]. In this study, no patients with DLE
Clinical worsening + immunopathological improvement: 1/10

Good clinical but not immunopathologic response (same/
responded to rituximab [88]. While modest sample sizes (17 50
patients) limited conclusions about responses of different subgroups,
Good response both clinical + immunopathologic:

those with ACLE appeared to respond favourably while there is no evi-
dence to support a beneficial effect of rituximab on DLE, SCLE or new-
onset CLE [87,89]. In one study, 75% of patients required further B-cell
depleting therapy [89]. Adverse effects were generally mild [87,89].
One RCT [91] investigated use of anifrolumab in cutaneous mani-
festations of SLE, namely “rash” as measured by BILAG, SLEDAI-2K
and CLASI Activity scores. Anifrolumab, a monoclonal antibody
- Poor response: 3/15
which targets the type I interferon receptor (IFNAR) and neutralizes

all type I interferon (IFN) subtypes, was given at 300 mg or 1000 mg
AE: not recorded.
weekly for 48 weeks. Anifrolumab at a dose of 300 mg weekly was

6/10 patients
worse): 3/10
associated with a significantly higher frequency of 50% improve-

- CR: 8/15
- PR: 4/15
Response
ment in CLASI score (OR 4.49, 95% CI 1.67 12.12, p = 0.013), unlike
Results
15.
the 1000 mg dosing (OR 2.97, 95% CI 1.08 8.19, p = 0.077) [91]. In a
further subgroup analysis of these data, significantly higher rates of
improvement were seen in SLEDAI-2K and mucocutaneous BILAG
scores with anifrolumab than placebo [113]. There was no differ-
ence in rates of serious adverse effects or those requiring discontin-
uation of anifrolumab [91].
Comparator
One RCT examined the use of ustekinumab (monoclonal anti-

body targeting IL-12 and IL-23) in cutaneous manifestations of SLE
None
None
as measured by the CLASI activity score [93]. Patients were treated

with a weight-based intravenous loading dose following by 90 mg
subcutaneous injection administered every 8 weeks for 40 weeks.
Response rate (as measured by 50% or more reduction in CLASI
activity score) was significantly greater in those treated with usteki-
Hydroxychloroquine 600 mg daily for 10 days,
Combined chloroquine-Quinacrine treatment
numab than placebo. No significant difference in adverse events

was noted between groups.
One RCT examined the use of BIIB059 in patients with SLE and
followed by 400 mg for 20 days
active skin disease [92]. BIIB059 is a humanised monoclonal antibody

binding to blood DC2 antigen (BDCA2) [92]. This small RCT showed
- Chloroquine 300 mg/day
- Quinacrine 200 mg/day
higher frequency of improvement in CLASI activity scores in those

with SLE treated with a single dose of 20 mg/kg BIIB059 than placebo,
which was correlated with reduction in skin biopsy markers of IFN
pathway activation. There was one serious adverse effect in the
Intervention
BIIB059 group, with did not require cessation [92].

One RCT investigated the role of a subcutaneous dose of AMG811,
an anti-IFNg monoclonal antibody, in treating DLE with or without
comorbid SLE [79]. AMG811 was given on day 1 and day 85. No sig-
nificant benefit was seen, with no difference in response between
treatment and placebo groups, and no difference in CLASI scores.
Serious adverse effects were not frequent.
One additional RCT treated patients with mixed subtypes of CLE
with sirukumab [82], an anti-IL-6 monoclonal antibody which binds
selectively to the IL-6 cytokine. Four sirukumab infusions of 10 mg/kg
- SLE (ARA Criteria) 7/15
Mixed CLE/SLE, refractory
were given two weeks apart to patients with SLE, while those with CLE
received four fortnightly infusions of 1 mg/kg, 4 mg/kg or 10 mg/kg
- Generalised 4/10
- Localised 6/10
doses. Results were mixed; while SELENA-SLEDAI scores underwent

Biopsy-proven
Biopsy-proven
- DLE 14/15
greater reduction in the sirukumab group, no difference in CLASI activ-

- SCLE 3/15
Population
ity scores was seen in those treated with sirukumab or placebo.

Adverse effects were generally mild [82].
N = 15
N = 10
DLE
The last RCT examined the use of PD-0360324, a fully human

immunoglobulin-G2 monoclonal antibody against macrophage col-
Chieregato et al. (1990)[40]
ony-stimulating factor (M-CSF) as an IV infusion in patients with

Lipsker et al. (1995)[38]
mixed subtypes of CLE [80]. Compared to placebo, no improvement

was seen in CLASI scores.
Table 5 (Continued)
One case series investigated treatment of DLE patients with efali-

zumab [90], an anti-CD11a monoclonal antibody, now withdrawn
Case Series
from the market due to the risk of progressive multifocal leukoence-

phalopathy [114]. Patients were treated with efalizumab 1 mg/kg
subcutaneously weekly, with an initialisation dose of 0.7 mg/kg.
Good to excellent response was seen in 11/13 patients.
110
Table 6
Synthetic DMARDs
RCT
Islam et al. (2012) [48] N = 37 Methotrexate Chloroquine Response: significant improvement in both methotrexate and chloroquine
SLE with active cutaneous disease N = 13/37 N = 24/37 groups from baseline to week 24 with no significant difference between
- SLE 37/37 groups
Biopsy: NR AE: MTX 9/13 (GI, raised ALT), chloroquine 4/24 (GI)
Kreuter et al. (2007) [49] N = 10 Mycophenolate sodium 1440 mg None CLASI: significant improvement in activity score with treatment.
Refractory SCLE daily for 3 months AE: nil serious. GI + transaminitis noted.
- Papulosquamous SCLE lesions 4/10
- Annular SCLE lesions 6/10
Biopsy-proven
Callen et al. (1991) [50] N=6 Azathioprine 100 150 mg per day None Response rate
Mixed CLE - CR: 1/6
- SCLE 4/6 - PR: 3/6

- DLE (scarring) 2/6 - None: 2/6
Biopsy-proven Early cessation 2/6 (PR 1/6, No response 1/6)
AE: requiring cessation 2/6; pancreatitis 1/6, fever 1/6
Observational study
Gammon et al. (2011) [51] N = 24 Mycophenolate mofetil treatment None Response
Mixed CLE, refractory for at least 3 months; starting dose - CR 9/24
- DLE 19/24: Localised 9/19, generalised 10/19 500 1000 mg per day, then increased - CR with subsequent flare 6/24
- SCLE 3/24 as tolerated to 1500 3500 mg per day - PR: 9/24
- Overlap DLE/SCLE 1/24 - Time to initial response (mean): 2.76 months (some patients took up to 8
- LET 1/24 months to respond)
- SLE 15/24 - Control maintained in 9/24 with CR for 16.5 months
Biopsy-proven AE: 3/24 ceased due to AE (recurrent VZV/HSV infection)
Dhabhai et al. (2005) [52] N = 14 Dexamethasone: 100 mg intravenously None. Complete clinical recovery 7/14
SLE (ACR Criteria) on 3 consecutive days monthly - Oral ulceration improved after 1 3 pulses
- SLE 14/14 Cyclophosphamide: 500 mg monthly, - Malar rash improved after 2 5 pulses
Variety of manifestations with oral cyclophosphamide 50 mg - Discoid rash improved after 2 16 pulses
- Photosensitivity 13/14 daily given between infusions. - LEP: reduced by 50% after first pulse
- Malar rash 12/14 - Alopecia: improved after 2 6 pulses
- Hair loss 10/14 AE: infections, cardiac arrest and death during infusion 1/14, menstrual
- DLE 7/14 irregularity.
- Oral ulcers 6/14
- Chillblain lupus 1/14
- LEP 1/14
Biopsy: NR
Wenzel et al. (2005) [53] N = 43 Methotrexate: low dose intravenous None Response: significant improvement in 42/43
Mixed CLE (15 25 mg initially, then as maintenance - Significant reduction in composite activity score with MTX
- SCLE 16/43 7.5 15 mg IV or 10 20 mg PO) Subgroup analysis
- DLE 12/43; Localised 8/12, generalised 4/12 - SCLE/localised DLE more responsive than generalised DLE
- SLE 7/43 - Improvement in symptom score in all groups (SCLE and both local-
- LET 3/43 ised + generalised DLE)
- Chillblain lupus 4/43 - Clinical response seen after 2 8 weeks
- LEP 1/43 AE: 29/43; 7/29 requiring cessation. GI, fatigue, deranged LFTs, minor hair loss,
Biopsy-proven minor infections
Boehm et al. (1998) [54] N = 12 Methotrexate 10 25 mg weekly None Response
Mixed CLE - CR 6/12
- DLE 4/12 - PR 4/12
- SCLE 6/12 - Ineffective 2/12
- LEP 1/12 Ongoing steroid therapy required in 6/12
- CLE not otherwise specified 1/12 Long term remission of 5 24 months in 5/12
Biopsy-proven Only 1/12 patients experienced an exacerbation whilst on MTX
AE: mild LFT derangement, no cessation required.

Table 6 (Continued)
Case series
Swain et al. (2016) [55] N = 11 Dexamethasone IV 100 mg x 3 days per month, None Response rates (improvement)
SLE with mucocutaneous plus cyclophosphamide 500 mg IV monthly - Discoid rash: 3/6 (after 6 8 pulses)
manifestations (given Day 2), plus oral cyclophosphamide - Photosensitivity: 8/11 (after 2 4 pulses)
Biopsy: NR 50 mg and HCQ 200 mg daily in between. - Oral ulceration: 4/6 (after 1 3 pulses)
6 9 pulses given. - Alopecia: 4/9 (after 3 6 pulses)
AE: classical steroid AE uncommon. Infections (bacterial and fungal) common.
Raptopoulou N=6 Cyclophosphamide 1 g/m2 per month, plus None Response
et al. (2010) [56] Mixed CLE, refractory methylprednisolone 1 g/pulse. - CR 4/6
- DLE 2/6 Prednisolone 10 15 mg/day administered - PR 2/6
- SLE with cutaneous involvement 4/6 between infusions Treatment duration: 7.5 § 2.3 months (range 7 12 months)
Biopsy-proven in 4/6 Maintenance treatment: Azathioprine Cyclophosphamide dose (mean): 10.73 § 2.1 g
100 200 mg per day on remission CLASI: significant reduction from baseline to follow up.
Time to response (mean): 4.33 § 1.36 months (range 3 7 months)
Relapse after drug cessation: 0/6

AE: GI, alopecia.
Pisoni et al. (2005) [57] N=7 Mycophenolate mofetil None Response
Mixed CLE Dose (median): 2 g daily (range - PR 2/7
- SLE (ACR Criteria) 7/7, >1 type 2 3 g per day) - NR 5/7
of rash in 3/7 Relapse
- ACLE 4/7 - 1/2 whilst still on treatment
- SCLE 1/7 AE: 4/7, mild, none requiring cessation.
- DLE 3/7
- Vasculitis 2/7
- Chilblain lupus 1/7
Biopsy: 5/7
111
Table 7
Retinoids
RCT
Ruzicka et al. (1992) [58] N = 58 Acitretin 50 mg/day HCQ 400 mg/day Response
Mixed CLE (n = 28) (n = 30)
Localised DLE 31/58 Acitretin
Generalised DLE 8/58 CR: 5/28
SCLE 19/58 PR: 8/28
Biopsy: NR Slight improvement: 3/29
NR: 3/28
Deterioration: 6/28- HCQ
CR: 7/30
PR: 8/30
Slight improvement: 6/30
NR: 9/30
Deterioration: 0/30AE: mainly minor, acitretin
27/28, HCQ 17/30
Case series
Shornick et al. (1991) [59] N=6 Isotretinoin 1 mg/kg None Response
Mixed; refractory CLE or SLE with per day - Improvement 6/6
significant cutaneous involvement Relapse: Flare on withdrawal: 2/6
- DLE 5/6 AE: 1/6 required discontinuation.
- SLE 5/6
Biopsy: NR
Abbreviations: SLE (systemic lupus erythematosus), CLE (cutaneous lupus erythematosus), LE (lupus erythematosus), DLE (discoid lupus erythematosus), ACLE (acute cutane-
ous lupus erythematosus), SCLE (Subacute cutaneous lupus erythematosus), CCLE (chronic cutaneous lupus erythematosus), LET (lupus erythematosus tumidus), LEP (lupus
erythematosus panniculitis/profondus), NSLE (non-specific lupus erythematosus), NR (not recorded), NA (not applicable), RCT (randomised controlled trial), CR (complete
response), PR (partial response), TDS (three times daily), BD (twice daily), AE (adverse effects), UVA (ultraviolet A), UVB (ultraviolet B), SPF (sun protection factor), CLASI
(cutaneous lupus erythematosus disease area and severity index), SLICC (Systemic Lupus Erythematosus International Collaborating Clinics), BILAG (British Isles Lupus
assessment group), HCQ (hydroxychloroquine), mg (milligram), ms (millisecond), J (joules), cm (centimetre), nm (nanometre), kg (kilogram), RA (rheumatoid arthritis), PDL
(pulsed dye laser), IPL (intense pulse laser), IFN (interferon), VAS (visual analogue scale), IVIG (intravenous immune globulin).
IVIG [106], dapsone [28], vitamin D [107] and UV hardening therapy

[103]. Six studies were deemed at high risk of bias [28,103 107], and
Three case series involving 35 patients investigated intravenous one RCT at low risk of bias [116].
immunoglobulin (IVIG) in CLE [94 96]. All studies involved patients One RCT compared baricitinib, an oral selective Janus kinase (JAK)
with mixed subtypes of CLE, and two studies specified that patients with 1 and 2 inhibitor, in 2 mg or 4 mg daily doses to placebo in patients
SLE were included [95,96]. All studies were deemed at high risk of bias with SLE [115]. No significant benefit was seen in skin outcome meas-
[94 96]. Variable dosing regimens were used between the studies ures, with an increased risk of serious adverse events (especially
(Table 10). Results were variable; one study showed a 29% decrease in infection) in those on baricitinib 4 mg daily [115].
CLASI Activity score [94], another approximately 60% response rates One non-controlled trial investigated the role of fumaric acid
[95], while one case series showed no response [96]. Adverse effects esters in predominantly DLE patients [104]. CLASI Activity scores
were generally mild [94,95]. improved, whilst CLASI Damage scores did not worsen. Adverse
effects were minor.
Laser therapy One non-controlled trial investigated the use of apremilast, a
PDE4 inhibitor, in patients with DLE [105]. There was a marked
Six studies in 73 patients investigated laser therapy as a treatment reduction in disease activity in patients completing a full course of
modality for CLE [97 102] (Table 11). This comprised four non-con- therapy (85 days), with significant reduction in CLASI activity score
trolled trials [97 100] and two observational studies [101,102]. Four to day 85. CLASI damage scores did not increase.
studies involved patients with mixed subtypes of CLE [97,99,101,102], One non-controlled trial studied interferon alpha-2a in mixed
one with DLE [100], and one with LET [98]. Laser was specified as being subtypes of CLE [106]. Whilst 80% of patients responded, the fre-
used to treat active disease in 4 studies [98 101]. While disease activity quency of relapse was 100% on cessation of therapy and all patients
was not specified in two studies [97,102], it was implied that laser was experienced a flu-like syndrome.
used for active disease. All studies were deemed at high risk of bias. One case series showed around 50% of patients with mixed sub-
All six studies investigating laser therapy used pulsed dye lasers types of CLE responded to dapsone, but with 10% of patients
[97 102], with two studies also using intense pulsed laser [97,98]. Most experiencing exacerbations of disease or serious adverse effects such
showed significant improvement, with good response rates and high as drug reaction with eosinophilia and systemic symptoms (DRESS)
levels of satisfaction [97 102], including in studies specifying “active” syndrome and haemolytic anaemia [28].
lesions [98 101]. One study in LET identified a relapse rate of 50% over One observational study compared CLE patients recommended
6 months’ follow up [98]. Histology including inflammatory infiltrate vitamin D and calcium supplementation, with those not recom-
also tended to improve [98,99]. Adverse effects were common but mild, mended replacement [107]. CLASI Activity and Damage scores signifi-
including hyperpigmentation and transient pain [97 102]. cantly reduced in the vitamin D group, but not the control group,
with a trend to less exacerbations in the vitamin D-treated group.
Other therapies There was no correlation between vitamin D levels and CLASI activity
or damage scores.
Seven studies in 481 patients investigated other therapies includ- One observational study of UV hardening therapy in patients with
ing novel therapies [28,105,115], fumaric acid esters [104], interferon mixed subtypes of CLE showed improvement in only 5/35 patients [103].
Table 8
Thalidomide and lenalidomide


Wang et al. (2016) [111] N = 69 Thalidomide; commenced None Response

Mixed CLE; refractory 25 mg nocte, uptitrated - CR 56%
- SLE with malar rash: 48/69 as required. - PR 41%
- DLE: 9/69 - No response 3%
- Vasculitis: 12/69 Overall remission rate 97%
- Photosensitivity rash: 42/69 SLEDAI Score: significantly reduced with treatment
Biopsy: NR. AE: no peripheral neuropathy. All AE mild, none required cessation of
thalidomide
Braunstein et al. (2012) [74] N=5 Lenalidomide 5 mg daily None Response
Mixed CLE for 6 weeks - PR 5/5
- Localised DLE 2/5 - Insufficient (requiring change to other therapy) 1/5
- Generalised DLE 2/5 CLASI Score: significant decrease in activity score
- SCLE 2/5 AE: NR

- Hypertrophic LE 1/5
- LET 1/5
Biopsy: NR
Cortes-Hernandes N = 60 Thalidomide 100 mg daily None Mean treatment duration 6 months
et al. (2012) [60] Mixed CLE, refractory (weaned when CR achieved) Some clinical response: 58/59 (98%) noticeable at 2 weeks following
- DLE 25/60 (Generalised DLE 13/25) treatment
- SCLE 18/60 Response
- Acute LE 6/60 - CR: 50/59
- Lupus profonudus 5/60 - PR: 8/59
- Chillblain LE 3/60 - No response: 1/59
- LET 2/60 - Time to response (mean): 8 weeks (range 3 16 weeks)
- Pyoderma Gangrenosum 1/60 Relapse following CR: 35/50 (mean 5 months; range 2 60 months)
- SLE 35/60 Subgroup analysis
Biopsy-proven - Long term remission most common with SCLE (OR 30, 95% CI 5.82 154.63)
than DLE
- SCLE lower cumulative thalidomide dose p = 0.027 and duration p = 0.0002
- DLE predictive of relapse (OR 5.71, 95% CI 1.36 24.06)
CLASI Scores
- Activity (mean): significant reduction
- Damage (mean): trend to increase
AE: paraesthesia 11/59, confirmed neuropathy 5/11.
Cortes-Hernandes N = 15 Lenalidomide oral 5 mg per day None Response
et al. (2012) [75] Mixed; refractory CLE with for 4 weeks, then increased - CR or PR: 14/15
or without SLE to 10 mg/day ongoing - Premature cessation: 1/15
- DLE 60% Relapse: 9/12
- LEP 13% - Time to relapse (median): 4.4 weeks (range 2 8 weeks)
- SCLE 13% Subgroup analysis
Biopsy-proven - Lower time to CR in DLE and SCLE compared to LEP (median 6 weeks, range
2 12 weeks compared to median 13 weeks, range 4 32 weeks)
CLASI Scores
- Activity: significant reduction at 2 weeks
- Damage: no significant increase at 1 year
SLEDAI: No significant change during follow up
AE: 2/15, required cessation 1/2.
Okon et al. (2014) [130] N=5 Lenalidomide 5 mg daily for None CLASI Activity Score: significant reduction at baseline, week 6 and week 12
Mixed CLE with or without SLE. first 6 weeks (then weaned Personal skin scores: reduced at 12 weeks in all patients
Biopsy-proven if good/increased if poor clinical AE: 1/5 ceased treatment due to AE.
response)
113
114
Table 8 (Continued)
Kyriakis et al. (2000) [61] N = 17 patients Thalidomide None Response

Chronic DLE Dose (median): 100 mg/day - CR (90 100% improvement): 12/17 (at 65.4 § 30.5 days
Biopsy-proven (range 50 200 mg/day) (range 30 150 days))

- PR (70 80%): 5/17 at (68 § 19.2 days (range 50 100 days))

Relapse
- Time (mean) 39.4 § 21.4 days (range 15 90 days) post drug withdrawal
generally milder picture
- Relapse during observation period: 10/15 patients
- No relapse: 4/15
AE: requiring discontinuation 3/22, overall rate 16/22. No true neurotoxicity.
Drowsiness/somnolence common.
Ordi-Ros et al. (2000) [62] N = 22 Thalidomide initially 100 mg daily None Response
Mixed CLE, refractory. (weaned according to response) - CR 12/16 (75%)
- DLE 9/22 - PR 4/16 (25%)
- SCLE 7/22 - No response 3/19

- LEP 4/22 - Many noted improvements within 2 weeks; maximal benefit within 3
- Nonspecific rash 2/22 months
- SLE 7/22 Recurrence
Biopsy: NR - Post CR: 10/12
- DLE: 5/10
- SCLE 4/10
- LEP: 1/10
- Response to thalidomide on re-introduction: 10/10
- Time to recurrence 4 16 weeks post-cessation of thalidomide
AE: requiring discontinuation 3/22, sensory neuropathy 1/22, others
(amenorrhoea, drowsiness, constipation, vertigo etc.)
Observational study
Cesbron et al. (2018) [63] N = 139 Thalidomide therapy; variable None Response
Mixed CLE. starting dose (mean 100 mg/day, - CR: 98/139
- Acute LE 4/139 range 50 200 mg/day) - Treatment failure: 15/139
- SCLE: 36/139 AE: withdrawal due to AE 76/110
- CCLE 87/139
- LET: 12/139
- SLE: 59/139
Biopsy-proven
Fennira et al. (2016) [77] N = 16 Lenalidomide None Previously treated with thalidomide: 11/14
Mixed CLE, refractory Response
- DLE 50% - Response 14/16
- SCLE 46.7% - Successful taper without recurrence 13/14
- SLE 8/30 rCLASI Score: significant reduction with lenalidomide
Biopsy-proven AE: 12/16, including asthenia, insomnia, weight loss, dizziness, neutropenia,
SLE flare.
Baret et al. (2015) [112] N = 30 Thalidomide None Response (n = 24; 6/30 ceased prematurely)
Mixed CLE; refractory. - CR: 20/24
Biopsy-proven - PR: 4/24
Relapse 11/15: occurred 3 24 weeks post withdrawal
Permanent remission 4/30; ongoing therapy 10/30, side effects requiring
cessation 16/30
AE: 6/30 ceased early due to AE; ultimately 16.30 ceased due to AE.
Neuropathy 9/30.
Briani et al. (2005) [64] N = 14 Thalidomide 100 mg/day commenced None Response
Mixed CLE, or SLE with cutaneous (then weaned or increased based on - Improvement: 14/14
manifestations clinical response) AE: abnormal NCS 10/14, others including tremor, somnolence, amenorrhoea,
- CLE 3/14 constipation.
- SCLE 11/14
Biopsy-proven

Table 8 (Continued)
Cuadrado et al. (2005) [65] N = 48 Thalidomide, variable dose (50 mg alter- None Response Rate: 39/48 81%
Mixed CLE or SLE with cutaneous nate days to 100 mg daily) - CR: 29/48 (60%)
manifestations, refractory. - PR: 10/48 (21%)

- DLE 18/48 - No response: 9/48 (19%)
- SCLE 6/48 - No significant dose-response relationship observed
- SLE with skin involvement 24/48 Subgroup analysis: CR or PR
Biopsy-proven - SLE: 22/24 (92%)
- SCLE 3/6 (50%)
- DLE: 14/18 (78%)
- Significantly better response in those with SLE than SCLE (p < 0.05),
no difference with DLE (p = 0.37)
Relapse rate: 26/39 post-cessation.
AE: neuropathy sx (13/48), abnormal NCS (11/13), others (drowsiness, consti-
pation, abdominal pain, amenorrhoea).
Housman et al. (2003) [66] N = 29 Thalidomide 100 mg nocte (weaned None Response

Mixed CLE or SLE with cutaneous according to response) - CR 17/23
manifestations, refractory - PR 6/23
- SCLE 3/29 AE: abnormal NCS 5/23, paraesthessias 6/23 (2/6 with abnormal NCS),
- Chronic CLE 9/29 drowsiness/fatigue
- LEP 5/29
- SLE 14/29
Biopsy-proven
Thomson et al. (2001) [67] N = 27 Thalidomide started at 50 mg BD None Response
Mixed CLE, refractory (weaned with clinical response), usu- - CR 7/27
- DLE 20/27 ally with topical steroids - Good response 11/27
- SLE 5/27 - Slight improvement 2/27
- SCLE 2/27 - Worsening 1/27
Biopsy: NR - Lost to follow up 1/27
Relapse
- 16/20 relapsed on stopping treatment
AE: in 8/27 including tremor, sedation, dizziness, nausea. No neuropathy
noted. Ceased due to side effects 4/27.
Case series
Kindle et al. (2016) [78] N=9 Lenalidomide therapy None Response
Mixed CLE, refractory Variable dosing regimen; generally - CR 5/9
- DLE 6/9 started 5 10 mg daily, ranged from - PR 2/9
- LEP 2/9 2.5 20 mg daily - No response 2/9 (both LEP)
- SCLE 1/9 - Time to initial response 2 weeks 3 months; median time to CR 3 months
Biopsy-proven (range 3 6 months)
- Dose range at initial response 2.5 10 mg/day
- Both cutaneous and mucosal disease improved in responders
Duration of therapy (median): 12 months (range 2 67 months)
AE: mild cytopenias, DVT, pruritis, dyspepsia.
Frankel et al. (2013) [68] N=5 Thalidomide 50 mg/day starting dose None Response rate
Mixed CLE - CR: 3/5
- DLE 2/5 - PR: 1/5
- SCLE 3/5 - No response: 1/5
- Comorbid SLE 1/5 - Time to response (mean, weeks): 5.5 weeks (range 4 8 weeks)
Biopsy: NR Relapse: 4/4 (time to relapse (mean) 11.5 weeks (range 4 20))
AE: paraesthesias in 4/5
Doherty et al. (2008) [69] N = 15 Thalidomide 100 mg nocte None Response rates:
Mixed CLE or SLE with cutaneous manifestations (weaned with clinical response) - DLE (n = 6): CR 1/6, moderate 2/6, mild 2/6, none 1/6
(out of a larger cohort of 48 patients treated - LET (n = 3): CR 1/3, moderate 1/3, none 1/3
with thalidomide for a variety of indications) - SCLE (n = 3): CR 2/3, moderate 1/3
115
116
Table 8 (Continued)
- DLE 7/15 - SLE with Malar Rash (n = 1): CR 1/1

- LET 4/15 AE (whole cohort including CLE patients): numbness/paraesthesia 9/48,
- SCLE 3/12 others including constipation, sedation, drug eruption, leukopenia, arthral-
- SLE 1/15 gia, headache, dizziness, peripheral oedema.

Biopsy: NR
Coelho et al. (2005) [71] N = 65 Thalidomide 100 mg per day None Response
Mixed CLE or SLE with cutaneous (weaned with clinical response) - CR 60/65
manifestation, refractory - PR 3/65
- DLE 19/65 - No response 2/65 (both with LEP)
- DLE/SLE 15/65 - Duration of remission 2 12 weeks, mean 7 weeks
- SCLE 15/65 - Unable to reduce dose in 29/65
- SCLE/SLE 12/65 - Mean time to achieve minimum dose 48 weeks
- LEP: 3/65 AE: drowsiness, neuropathy (28/65).
- SLE 27/65
- Bullous lupus 1/65

Biopsy: NR
Gambini et al. (2004) [72] N=6 Thalidomide 100 mg/day None Response
Mixed CLE or SLE with hypertrophic/verrucous (weaned with clinical response) - CR 4/6
cutaneous manifestation - PR 2/6
- Chronic CLE 6/6 Duration of treatment (range): 4 25 months (some patients “ongoing” at time
- SLE 1/6 of study conclusion)
Biopsy-proven Relapse
- Ongoing thalidomide required in 3/6
- No relapse 2/6
AE: discontinued due to neurological symptoms 1/6, others including shakes,
dizziness, weight gain
Walchner et al. (2000) [73] N = 10 Thalidomide started at None Response
Mixed CLE or SLE with cutaneous manifestation 100 300 mg/day (weaned - Improvement 10/10 (within 2 3 weeks)
- SLE 5/10 with clinical response) - Stability to the point of cessation 4/10
- CLE 5/10; SCLE 1/5, DLE 4/5 AE: neuropathy 4/10, requiring cessation in 4/4, fatigue 10/10.
Biopsy: NR
Duong et al. (1999) [70] N=7 Thalidomide None Response
Mixed CLE, refractory - CR 2/6
- Chronic CLE 5/7 - PR 4/6
- SCLE 1/7 - Treatment withdrawn in 1/7
- Scleroderma-LE-LEP overlap 1/7 AE: neurological symptoms, weight gain, constipation, sedation
- SLE 3/7
Biopsy: NR
Stevens et al. (1997) [110] N = 16 Thalidomide 50 100 mg None Response
Mixed CLE, refractory. per day - Improvement 13/16
- SLE 8/16 - CR/near CR: 7/16
- DLE 10/16 - PR: 6/16
- SCLE 4/16 - No improvement: 3/16
Biopsy-proven: 11/16. Subgroup analysis
- SCLE: CR 2/4, PR 2/4
- DLE: CR 4/11, PR 4/11
- Mouth ulcers: resolved in all patients
- Alopecia: some improvement in loss, no hair re-growth noted
AE: ceased due to AE 1/16. Morning drowsiness contributing to dose reduction
2/16. Abnormal NCS 2/16, paraesthesias 1/16.
erythematosus), CCLE (chronic cutaneous lupus erythematosus), LET (lupus erythematosus tumidus), LEP (lupus erythematosus panniculitis/profondus), NSLE (non-specific lupus erythematosus), NR (not recorded), NA (not applica-
ble), RCT (randomised controlled trial), CR (complete response), PR (partial response), TDS (three times daily), BD (twice daily), AE (adverse effects), UVA (ultraviolet A), UVB (ultraviolet B), SPF (sun protection factor), CLASI (cutaneous
lupus erythematosus disease area and severity index), SLICC (Systemic Lupus Erythematosus International Collaborating Clinics), BILAG (British Isles Lupus assessment group), HCQ (hydroxychloroquine), mg (milligram), ms (millisec-
ond), J (joules), cm (centimetre), nm (nanometre), kg (kilogram), RA (rheumatoid arthritis), PDL (pulsed dye laser), IPL (intense pulse laser), IFN (interferon), VAS (visual analogue scale), IVIG (intravenous immune globulin).
Table 9
Biologic therapies

RCT
Furie et al. (2019) [92] N = 12 BIIB059 (mAB binding to blood dendritic Placebo Responders (significant reduction in CLASI Activity score
SLE and active skin disease cell antigen 2 (BDCA2)): single dose of of at least 4 points):
Of the 8/12 treated with BIIB059 20 mg/kg of intravenously - Week 4
- ACLE: 4/8 BIIB059: 6/8
- DLE: 3/8 Placebo: 1/4
- SCLE: 1/8 - Week 12
Biopsy: NR BIIB059: 5/8
Placebo: 1/4
- Improvement in CLASI Activity score correlated
with reduction in MxA protein expression (a marker
of interferon pathway activity in skin)
AE: 1/12 severe AE in BIIB059 group, no discontinuation
in BIIB059 or placebo group.

Van Vollenhoven N = 102 Ustekinumab (mAB targeting IL-12 and Placebo CLASI Score: 50% Improvement
et al. (2018) [93] SLE (SLICC criteria) IL-23): intravenous loading dose Ustekinumab: 17/32 (53%)
Biopsy: NR (weight-based; 35 55 kg 260 mg, Placebo: 6/17 (35%)
56 85 kg 390 mg, >85 kg 520 mg) at Difference between groups: 18% (95% CI 1 to 37%)
week 0, followed by subcutaneous Mean response rate
injection 90 mg 8-weekly thereafter up - Ustekinumab: 64.1% (95% CI 43 80.9%)
to week 40 - Placebo: 29¢9% (12¢0 to 57¢0%)
- p = 0.032 between groups
AE: ustekinumab 78%, placebo 67%. Serious AE
ustekinumab 8%, placebo 10%.
Furie et al. (2017) [91] N = 305 Anifrolumab (see above) intravenously Placebo CLASI Score: 50% Improvement
SLE (ACR Criteria) 300 mg or 1000 mg every 4 weeks for Placebo: 8/26
Biopsy: NR 48 weeks Anifrolumab 300mg: 17/27
Anifrolumab 1000mg: 14/24
OR (for 50% improvement in CLASI Score)
- Anifrolumab 300 mg vs. placebo: 4.49
(95% CI 1.67 12.12), p = 0.013
- Anifrolumab 1000 mg vs. placebo: 2.97
(95% CI 1.08 8.19), p = 0.077
AE: 77.2% of patients in placebo group vs. 85.3%
in combined anifrolumab groups. No difference
in serious AE or AE requiring discontinuation.
Stohl et al. (2017) [81] N = 836 Belimumab (anti-B lymphocyte stimula- Placebo Mucocutaneous SELENA-SLEDAI: significantly
SLE, ACR criteria tor) subcutaneously 200 mg weekly greater improvement in belimumab than placebo
Mucocutaneous manifestations Mucocutaneous BILAG domains: significantly
in 735/836 greater improvement in belimumab than placebo
Biopsy: NR AE: 65 patients withdrew due to AE
(40/65 receiving belimumab); serious AE 44
with placebo, 60 with belimumab
Werth et al. (2017) [79] N = 16 AMG811: anti-IFNg antibody; single dose Placebo Response
DLE with or without SLE, of 180 mg or placebo given subcutane- - No significant clinical benefit (patient or physician
refractory ously on days 1 and 85 assessment) seen in DLE patients after AMG811 treatment
- Comorbid SLE 88% CLASI-A Score: no significant improvement
Biopsy-proven or change with AMG811.
CLASI-D Score: no significant change with AMG811.
Histopathology: increased keratinocyte IFNg
RNA score in both lesional and nonlesional skin
in DLE patients compared to healthy controls.
AE: serious 3/16 (infection, gastroenteritis, migraine,
splenic infarction)
117
118
Table 9 (Continued)
Masek-Hammerman N = 28 PD-0360324 (fully human immunoglob- Placebo (n = 6) No significant difference in CLASI Score
et al. (2015) [80] Mixed CLE (SCLE or DLE), ulin G2 monoclonal antibody against or SLEDAI-2K scores at any timepoint
severe/ refractory. macrophage colony-stimulating AE: none serious, but significant increased
Biopsy-proven. factor); intravenous infusion 100 or risk in treatment group (100 mg group 3/12,
150 mg every 2 weeks for 3 months 150 mg group 6/10, placebo 1/6).
- 100mg: n = 12
- 150mg: n = 10
Szepietowski N = 46 patients in total Sirukumab (anti-IL6) Placebo CLASI Activity Score
et al. (2013) [82] Mixed; CLE or SLE with cutaneous N = 33 N = 13 - CLE patients: reduction in sirukumab and placebo groups
manifestations - CLE: 23/33 - CLE: 8/13 - SLE patients: sirukumab increased; placebo marginal decrease.
- CLE: 31/46 - SLE: 10/33 - SLE: 5/13 CLASI Damage Score: no significant increase during
- SLE: 15/46 CLE protocol: randomised to follow up (remained 0 at all times)
Biopsy-proven 4 £ 2-weekly infusions of 1, 4 or SELENA-SLEDAI (SLE patients only): greater reduction
10 mg/kg in sirkumab vs. placebo group
SLE protocol: 4 £ 2-weekly infusions of BILAG Score (SLE patients only): no difference in reduction

10 mg/kg in sirukumab and placebo groups.
Physician global assessment (SLE patients only): no difference
between sirukumab and placebo groups.
SF-36 MCS Score
- CLE: improved in sirukumab group; reduced in placebo group.
- SLE: no difference between groups.
SF-36 PCS Score
- CLE: no difference between change in sirukumab and placebo groups.
- SLE: greater increase in sirukumab than placebo group.
DLQI Score
- CLE and SLE: no difference between change in
sirukumab and placebo groups.
AE: 2/46 serious; 3/46 discontinued due to AE (neutropenia,
thrombocytopenia, nasopharyngitis).
Manzi et al. (2012) [83] N = 1684 (combined data from BLISS-52 Belimumab 10 mg/kg day 0, 14, 28, then Placebo SRI response rate (overall efficacy): combined data show
and BLISS-76) every 28 days to week 48 (BLISS-52) or significantly greater improvement in belimumab than placebo,
Seropositive SLE week 72 (BLISS-76) with 10 mg/kg group improving more than 1 mg/kg group.
Biopsy: NR
Mucocutaneous involvement
- BILAG: Significantly greater improvement in mucocutaneous
BILAG domains win belimumab (especially if highly serologically active)
- SELENA-SLEDAI: significantly more belimumab 10 mg/kg
treated patients had improvements in mucocutaneous domain
- SELENA-SLEDAI: improvement with belimumab noted for
alopecia, mucosal ulcers and rash
AE: equal rates between belimumab and placebo.
Iaccarino et al. (2017) [84] N = 67 Belimumab 10 mg/kg IV on day 1, 14, 28, None CLASI Activity score: significant reduction compared
Mixed CLE/SLE and then every 28 days. to baseline at 6, 12 and 24 months
- SLE 67/67 Disease flares: 6 mucocutaneous flares during follow up
- Mucocutaneous disease 19/67 - Significant reduction in flares with belimumab treatment
(refractory in 15/67) - Skin flares decreased from 69 flares/100 patient years
- Acute CLE 10/19 to 23 flares/100 patient years after belimumab initiation
- SCLE 9/19 Treatment failure: 1/19 with SCLE
Biospy: NR AE: 44/67 patients experienced mild AE, severe in 2/67
Vashisht et al. (2017) [85] N=5 Belimumab IV 10 mg/kg 2 weekly for 3 None Response: Significant improvement in 5/5
Mixed CLE, refractory doses, then 10 mg/kg 4 weekly - Clearing of the rash as early as 8 weeks
- SLE 5/5 thereafter - Mean time to improvement 4 § 1.8 months
- SCLE 3/5 - No cutaneous flares noted
- ACLE 2/5 SLEDAI: Improved in 5/5 (p = 0.025)

Table 9 (Continued)
- DLE 2/5 PGA: Improved 5/5 (p = 0.039)

Biopsy-proven CLASI Activity Score: dramatic improvement (p = 0.043)

CLASI Damage score: no worsening

Daily prednisolone dose reduced to mean
3 mg § 2.7 mg (p = 0.042)
AE: minor only
Observational study
Parodis et al. (2018) [86] N = 62 Belimumab 10 mg/kg at weeks 0, 2, 4, None Response: Mucocutaneous SLEDAI-2K
SLE, refractory then 10 mg/kg 4 weekly thereafter - Significant improvement compared to baseline
Biopsy: NR at both 6 and 12 months
- Higher rate of improvement (18/22 vs. 7/17) among
never smokers compared to current or former smokers
- Probability of poor response to belimumab higher
with previous tobacco exposure: OR 6.4, 95%CI 1.5 27.4, p = 0.012
CLASI Activity Score: significant improvement compared

to baseline at both 6 and 12 months
CLASI Damage score: no significant worsening compared
to baseline at both 6 and 12 months
AE: early discontinuation 4/62.
Quelhas da Costa N = 50 Rituximab IV None Response at 6 months
et al. (2018) [87] Mixed; SLE (all) with CLE Pre 2007: rituximab 1000 mg x 2 - Improvement in 38/50 (76%)
- ACLE 21/50 doses, - CR 20/50 (40%), PR 18/50 (36%), Stable
- SCLE 6/50 with cyclophosphamide 750 mg disease 8/10 (16%), Flare 0/50
- DLE: 8/50 (generalised 7/8, localised 1/8) IV day afterwards (x2 doses) Response at 6 months by subgroup
- LEP: 2/50 2007 onwards: single dose - ACLE: CR 8/23, PR 10/23, stable disease 3/23
- NSLE 11/50 (including 2 with concurrent cyclophosphamide only - SCLE: 2/6, PR 3/6, stable 0/6
ACLE + CCLE) - CCLE: CR 5/12, PR 5/12, Stable 2/12
- SLE 50/50 - NSLE: CR 5/11, PR 2/11, stable 3/11
Biopsy-proven: 14/50 Response at 12 months
- Response maintained in 28/46 patients (61%)
- CR 24/46 (52%), PR 4/46 (9%), Stable 1/46 (2%), Flare 2/46 (4%)
Response at 12 months by subgroup
- ACLE: CR 12/21, PR 2/21
- SCLE: CR 2/6, PR 1/6, Flare 2/6
- CCLE: CR 5/11, PR 2/11, Stable 1/11
- NSLE: CR 6/10.
Rate of requiring further rituximab for
cutaneous involvement
within 12 months: 15/50 (30%)
AE: serious 3/50.
Vital et al. (2015) [88] N = 26 Rituximab: 1000 mg IV twice daily on None Mucocutaneous response: 9/26 (35%)
Mixed; CLE or SLE with mucocutaneous days 1 and 15, each preceded by meth- - ACLE: response in 6/14 (42.9%)
manifestation ylprednisolone 100 mg - SCLE: Response in 1/2
- ACLE 14/26 - CCLE: response in 0/8
- SCLE 2/26 - Nonspecific lupus lesions: response in 2/2
- CCLE 8/26 AE: NR
- NSLE 2/26
Biopsy-proven
Hofman et al. (2013) [89] N = 17 Rituximab: 1000 mg and methylprednis- None Note additional immunosuppressants
Mixed; CLE or SLE with cutaneous olone 100 mg IV x2 doses 2 weeks withdrawn in 12/17 on commencing RTX
manifestation apart (remainder continued stable doses)
- SLE 14/17 Cyclophosphamide 750 mg IV day fol-
- SCLE 2/17 lowing first rituximab infusion
- DLE and RA 1/17
Biopsy status NR
119
(randomised controlled trial), CR (complete response), PR (partial response), TDS (three times daily), BD (twice daily), AE (adverse effects), UVA (ultraviolet A), UVB (ultraviolet B), SPF (sun protection factor), CLASI (cutaneous lupus erythe-
ematosus), CCLE (chronic cutaneous lupus erythematosus), LET (lupus erythematosus tumidus), LEP (lupus erythematosus panniculitis/profondus), NSLE (non-specific lupus erythematosus), NR (not recorded), NA (not applicable), RCT
matosus disease area and severity index), SLICC (Systemic Lupus Erythematosus International Collaborating Clinics), BILAG (British Isles Lupus assessment group), HCQ (hydroxychloroquine), mg (milligram), ms (millisecond), J (joules), cm
Abbreviations: SLE (systemic lupus erythematosus), CLE (cutaneous lupus erythematosus), LE (lupus erythematosus), DLE (discoid lupus erythematosus), ACLE (acute cutaneous lupus erythematosus), SCLE (Subacute cutaneous lupus eryth-
Discussion
(centimetre), nm (nanometre), kg (kilogram), RA (rheumatoid arthritis), PDL (pulsed dye laser), IPL (intense pulse laser), IFN (interferon), VAS (visual analogue scale), IVIG (intravenous immune globulin), mAB (monoclonal antibody).
CLASI Activity score reduced significantly: 12/13 patients (p = 0.002)
This review identified 107 studies that examined various treat-
ment modalities for CLE. Included studies were highly heteroge-
- Subsequent BCDT: 9/12 (CR or PR with re-treatment 7/9)

neous in study design, treatment outcome measures, treatments
- Relapse 12/17 (mean 10 § 1.8 months after first cycle)

- 2/17 slower response (in 4 5 months vs. <3 months)
and protocols, and usually involved patients with a mixture of CLE

- At 6 months: CR 5/17, PR 4/17, ongoing activity 8/17
subtypes rather than specific patient populations. While construct-

Subgroup Analysis: number in CR/PR at 6 months
Response Rate: Good to Excellent Response 11/13

ing firm recommendations is difficult, we have identified a wide
Response: 12/17 rapid response (improvement
range of potential therapies for patients suffering with CLE, with

variable levels of efficacy and toxicity, to help guide the physician in
AE: required treatment cessation 1/13.

managing these patients.
- Remission for >12 months in 6/17
in 50% of lesions within 3 months)
Several narrative reviews exist describing management of CLE

[3,117,118]. A systematic Cochrane review describes management of
- Non-specific lesions 2/3
DLE but lacks data on management of other CLE subtypes [4]. To our
knowledge this is the only systematic review to date to comprehen-
sively summarise treatment data relating to all cutaneous manifesta-
tions of LE.
AE: nil serious
Relapse Rates
This review has several strengths. It is the only review to date to

- ACLE 2/3
- CCLE 3/8
- SCLE 2/3
comprehensively and systematically describe management of cuta-

Results
neous manifestations of lupus erythematosus in all its forms. We

have sought to describe all possible practical management options,
and their evidence, for the physician treating patients with lupus.
Most studies included histopathologic diagnosis as part of their inclu-
Comparator
sion criteria. We have been able to clearly describe levels of evidence

for each management strategy, to aid the potential future develop-
None
ment of a treatment algorithm for CLE for use by treating physicians.

However, this review does have limitations. There was significant
clinical and methodological heterogeneity of included studies which
precluded quantitative synthesis of data. Generally speaking, studies
Efalizumab, 1 mg/kg subcutaneously
weekly, starting dose of 0.7 mg/kg
had small sample sizes, lacked a control group, and there was a pau-
city of standardised outcome measures. Most studies were at moder-
ate to high risk of bias; although this is reflective of the overall
quality of literature in this area, we believe it is important that these
studies are included to reflect the breadth of existing data. Generally,
studies included small numbers of patients. Finally, most studies
Intervention
included a mixture of CLE subtypes, which when combined with

small patient numbers, made attempting subgroup analysis difficult.
This has limited our ability to draw firm conclusions about optimal
treatment in individual groups, particularly where there was hetero-
geneity between studies in subclassification of patients.
On the basis of the results of this systematic review, summarised
in Fig. 2, we suggest that general measures with potential benefit and
low risk include routine recommendation of sun protection [22], and
also smoking cessation. Smoking was reported as a risk factor for
treatment failure with multiple therapies in our review [35,45,86],
and the wider literature [3,4]. Vitamin D supplementation to correct
deficiency may also be beneficial [107], which is a consideration
given that with sun protection measures, patients with CLE are at risk
Biopsy status NR
DLE, refractory
of deficiency [107].
Population
In practice, topical corticosteroids are routinely used either as first

N = 13
line monotherapy in mild localised CLE, or in combination with sys-

temic agents in more severe and widespread disease. However,
despite anecdotal evidence and expert opinion supporting this, there
is limited formal evidence and no studies to report in this review.
Topical therapy with CNIs however, has been formally studied
and these may be a good first-line topical steroid-sparing therapy for
CLE. This search has identified moderate consistent evidence to sup-
port topical CNI therapy to reduce dependence on topical steroids
Usmani et al. (2007) [90]
(Table 1) [5 17]. Furthermore, in sensitive areas such as facial skin,

these agents carry a lower risk of complications including telangiec-
Table 9 (Continued)
tasia and striae compared with topical corticosteroids [9]. Limited

data suggest a beneficial effect of R-salbutamol cream (Table 1)
Case Series
[23,24], although this drug has limited availability.

When considering systemic therapy, there is moderate evidence
for hydroxychloroquine (Table 1) [27,29,30,32,34,35,37,40], with
low level evidence favouring beneficial effects of other antimalarials
Table 10
IVIG
Case series
Ky et al. (2015) [94] N = 16 IVIG None Significant loss to follow up during study
Mixed CLE, refractory. 500 mg/kg/day on 4 consecutive days (5/16 completed all 9 follow up visits)
Biopsy-proven (up to a total of 2 g/kg/month) CLASI Activity score: mean score reduced
for 3 months by 29% by end of follow up
(all other therapies ceased) CLASI Damage score: no worsening dur-
ing follow up.
Relapse: 3/16
Physician Subjective Assessment of
Improvement (PSAI) and Severity
(PSAS): no significant change in either
scale during study period
Skindex-29: 8% decrease during study
period.
AE: nil serious. Mild anaemia, neutrope-
nia, headache, back aches, HTN, fever,
GI, infection
Goodfield et al. (2004) [95] N = 12 IVIG None Response
Mixed CLE or SLE with cutaneous 2 doses of 1 g/kg, followed by - CR (>75% clearing): 5/12
manifestations 400 mg/kg monthly - PR (>50% clearing): 2/12
- SCLE 5/12 until disease resolution or - Limited response: 3/12
- Generalised DLE 5/12 for 6 months - Premature cessation: 2/12
- Varied lesions 1/12 Relapse: 3/5 successfully re-treated
- Bullous LE 1/12 with IVIG in 2/3
Biopsy-proven AE: 1/12 requiring cessation (cutaneous
vasculitis), otherwise mild
De Pita et al. (1997) [96] N=7 IVIG None Response: no improvement 7/7
Mixed; SCLE or SLE with 300 mg/kg/day for 5 days per month for - Worsening infiltration after 12
cutaneous manifestations a 12 month period months in SCLE patients
- SCLE 2/7 Plus oral prednisolone 0.1 mg/kg/day AE: NR
- SLE (ACR Criteria) 5/7
Biopsy-proven
Abbreviations: SLE (systemic lupus erythematosus), CLE (cutaneous lupus erythematosus), LE (lupus erythematosus), DLE (discoid lupus erythematosus), ACLE (acute cutaneous
lupus erythematosus), SCLE (Subacute cutaneous lupus erythematosus), CCLE (chronic cutaneous lupus erythematosus), LET (lupus erythematosus tumidus), LEP (lupus erythe-
matosus panniculitis/profondus), NSLE (non-specific lupus erythematosus), NR (not recorded), NA (not applicable), RCT (randomised controlled trial), CR (complete response),
PR (partial response), TDS (three times daily), BD (twice daily), AE (adverse effects), UVA (ultraviolet A), UVB (ultraviolet B), SPF (sun protection factor), CLASI (cutaneous lupus
erythematosus disease area and severity index), SLICC (Systemic Lupus Erythematosus International Collaborating Clinics), BILAG (British Isles Lupus assessment group), HCQ
(hydroxychloroquine), mg (milligram), ms (millisecond), J (joules), cm (centimetre), nm (nanometre), kg (kilogram), RA (rheumatoid arthritis), PDL (pulsed dye laser), IPL
(intense pulse laser), IFN (interferon), VAS (visual analogue scale), IVIG (intravenous immune globulin).
such as quinacrine and chloroquine [25,37,47], or their use in com- it appears to have robust response rates without the risk of neurotox-
bination (Table 1) [26,33,36,38,39]. Quinacrine has a favourable side icity associated with thalidomide [74 78].
effect profile to chloroquine as a second-line antimalarial agent, and When considering biologic therapy, low-moderate evidence sup-
as such is often the first choice for combination therapy [33]. Discoid ports use of belimumab, with data largely derived from SLE patients
lesions may be a risk factor for non-response to hydroxychloroquine with CLE manifestations [83 86]. Additional trials have used belimu-
[31]. In the wider literature, one study showed treating patients mab with less defined cutaneous outcome measures but have tended
with SLE with HCQ may delay integument damage [119]. We there- to show efficacy in non-specific rash [123], with subcutaneous beli-
fore suggest hydroxychloroquine may be considered in patients mumab also on the horizon [124]. Rituximab may be beneficial
refractory to topical therapies. Trials of second line agents or combi- [87-89], although with limited data outside of ACLE, with case report
nation therapy may avoid escalation to more immunosuppressive data also of use for lupus panniculitis [125]. Limited evidence sug-
therapies. gests anifrolumab may be beneficial, while limited data exist for spe-
There are several potential options for disease refractory to HCQ. cific biologic agents otherwise (Table 1) [82,90,91,93,113]. It is
Limited data support a favourable effect of retinoids, however these important to note efalizumab has now been withdrawn from the
agents are contraindicated in women of child-bearing age which lim- market due to unacceptable risk of side effect [90].
its its suitability in many lupus patients (Table 1) [58,59]. In terms of Other possible options for treatment of CLE include laser therapy,
synthetic DMARD therapy, limited evidence supports a favourable with low-moderate evidence for pulsed dye laser [97 102]; how-
effect of methotrexate [48,53,54] with limited data also supporting ever, caution must be taken in light of the theoretical risk of disease
the use mycophenolate mofetil and azathioprine [49 51,57]. In the flare on exposure to laser light wavelengths. Importantly, no flares
wider literature there are case reports to support the use of cyclo- were noted with this treatment in the studies included in this review.
sporine [120,121] and rapamycin [122]. Cyclophosphamide and There are conflicting data to support the use of IVIG [94 96],
dexamethasone may be beneficial in select patients with SLE [52,56]. although a handful of case reports have shown evidence in refractory
Thalidomide and lenalidomide appear to have higher response rates manifestations, including lupus panniculitis [126]. There are limited
than other agents (Table 1) [60 78], although the frequent occur- data investigating other therapies [79,104,106], including apremilast,
rence of significant side effects including neuropathy and teratoge- anti-TNF-alpha, dapsone [28], anti-interferon-gamma [105,127], ata-
nicity may make the use of thalidomide less attractive cicept (a human recombinant fusion protein comprising binding por-
[60 66,69 71,73]. While there are less data to support lenalidomide, tions of two B cell survival factors, B-lymphocyte simulator and a
122
Table 11
Laser therapy

Ekback et al. (2013) [97] N = 16 Either Pulsed Dye Laser (PDL) or Intense None Satisfaction: very satisfied 14/16, unsatisfied 2/16
Mixed CLE/SLE chronic, refractory Pulse Laser (IPL) PDL: mean 5 treat- Relapse
lesions with scarring, activity unclear ments (range 1 11) - Maintenance therapy required in 2/16
- DLE 15/16 IPL: mean 4 treatments - Recurrent requiring additional therapy in 1/16
- SLE 2/16 Co-treatment: many treated with topi- - Additional other laser treatment required in 1/16 for scarring
- SCLE 3/16 cal Group IV glucocorticoid and sys- AE: cheek hyperpigmentation (1/2), long healing time (1/2)
Biopsy-proven temic antimalarial agents
Truchuelo et al. (2012) [98] N = 10 Pulsed dye laser; None Response: reduction in lesion size, erythema, oedema and pruritis
LET with at least one active lesion 595 nm at 0.5 ms pulse width, fluence Histology: reduction in lymphocytic infiltrate, with greater infiltrate reduction corre-
Biopsy-proven 8 J/cm2 sponded to greater clinical improvement
One session per lesion Relapse: new lesions in nearby or distant treated zones in 5/10
AE: pain, pigmentation, purpura
Diez et al. (2011) [99] N=9 Laser: 595 nm pulsed dye laser, fluence None Response

Mixed CLE, at least one active lesion of 11 J/cm2, single pulse of 2ms - Erythema/scaling reduced with treatment
Chronic DLE 6/9 Air cooling system set at level 6 used Satisfaction: 9/9 satisfied
- LET 2/9 with all patients Histopathology
- SCLE 1/9 - Reduction in inflammatory infiltrate, basal liquefactive degeneration and endothelial
- SLE 1/9 adhesion molecule markers (ICAM-1 and VCAM-2)
Biopsy-proven - Some improvement in mucin deposition
AE: 0/9
Erceg et al. (2009) [100] N = 12 Pulsed dye laser (585 nm, fluence 5.5 J/ None CLASI Total score: significant reduction cf. baseline.
DLE; chronic and active cm2, pulse duration 0.45 ms) 3 times CLASI Activity score: significant reduction cf. baseline.
Biopsy-proven with an interval of 6 weeks CLASI Erythema score: significant reduction cf. baseline.
Subsequent 6 week follow up period CLASI Desquamation score: significant reduction cf. baseline.
Overall cosmetic result rated as “fair”
AE: minimal pain, slight hyperpigmentation
Observational study
Baniandres et al. (2003) [101] N = 14 Laser treatment None Response
Mixed; CLE or SLE with cutaneous First 3/14 treated with flashlamp - Mean clearance >60%
manifestations, active lesions pulsed dye laser (585 nm, 450 micro- - Most benefit to lesions with telangiectasia or erythema
- DLE 8/14 seconds) with fluences in the range - Best results with higher fluences (10 13 J/cm2) and short pulse (1.5 ms) with epider-
- SLE 6/14 from 5 to 7.75 J/cm2) mal cooling
Biopsy-proven 11/14 treated with long pulsed dye - Relapse
laser (595 nm, - Partial relapse in 3/14 >1 year post treatment
1.5 10 ms) with fluences of 6 to AE: transient hyperpigmentation, mild atrophic scarring
13 J/cm2)
2 3 month intervals between sessions
Raulin et al. (1999) [102] N = 12 Pulsed Dye Laser (PDL): wavelength None Response
Mixed; CLE or SLE with cutaneous 585 nm, impulse duration - Median 70% clearance of lesions achieved for 9/12 patients after mean 5.1 laser sessions
manifestations, activity unclear. 0.3 0.45 ms, (1 10 treatments/patient)
- CLE 10/12 Treatment continued until no further - No response 1/12
- SLE 2/12 considerable visual improvement Relapse: 1/9
Biopsy-proven achieved AE: infrequent. Ceased due to AE in 2/12. No laser-induced scarring.
Table 12
Other therapies

RCTs
Wallace et al. (2018) [115] N = 314 Baricitinib Placebo Resolution of arthritis/rash (SLEDAI-2K) at week 24
SLE (SLICC criteria) 2 mg or 4 mg orally, daily for 24 weeks - Placebo: 56/105
Biopsy: NR - Baricitinib 2mg: 61/105; OR cf. placebo 1.3 (95% CI 0.7 2.3), p = 0.39
- Baricitinib 4mg: 70/104; OR cf. placebo 1.8 (95% CI 1.0 3.3), p = 0.0414
CLASI Activity Score: Least squares mean change from baseline at week 24
- Placebo: 2.8 § 0.4
- Baricitinib 2mg: 1.7 § 0.4; OR cf. placebo 1.1 (95% CI 0.1 2.2), p = 0.0371
- Baricitinib 4mg: 2.3 § 0.4; OR cf. placebo ( 0.5 1.6), p = 0.33
AE: similar rates of AE between baricitinib and placebo; discontinuation 4% in
placebo, 10% in baricitinib 2 mg and 11% in baricitinib 4 mg groups. Serious
AE 5% placebo, 10% baricitinib 2 mg and 10% baricitinib 4 mg. Most common
AE was infection.
Non-controlled

clinical trials
Kuhn et al. (2016) [104] - N = 11 Fumaderm (30 mg dimethylfumarate None R-CLASI Activity score: significantly improved from baseline at 12, 24 and 28
Predominantly DLE, refractory and 75 mg monoethylfumarate) weeks.
- DLE 11/11 (1/11 main diagnosis SCLE) starting dose one tablet daily, stepwise R-CLASI Damage score: no significant increase from baseline at 12, 24 or 28
- SCLE 1/11 increased to 6 tablets per day over 9 weeks.
Biopsy-proven weeks as tolerated VAS Score: improvement in pain and itch from baseline at 12 but not 24
weeks.
Subgroup analysis
- No clear relationship observed between efficacy and disease duration
- Quicker response in the SCLE lesions in a patient with combined SCLE + DLE
AE: none serious related to study drug. Other minor AEs (abdominal cramps,
headache, diarrhoea).
De Souza et al. (2012) [105] N = 8 patients Apremilast (PDE4 inhibitor) 20 mg BD for None Response
DLE 85 days - Marked reduction in CLE activity in patients in 4 patients who completed
Biopsy-proven full course (p = 0.03)
- Scalp lesions completely regressed in two patients
CLASI Activity scores: significantly reduced from baseline to day 85 but not at
day 57.
CLASI Damage score: significantly reduced from baseline to day 85.
AE: 2/8 ceased due to AE, neuropathy 1/8. Further 2/8 non-adherent.
Thivolet et al. (1990) [106] N = 10 Interferon alpha-2-a Response
Mixed CLE (DLE or SCLE) - Low/ intermediate dose in 8/10 - CR: 5/10
- DLE 6/10 (18 45 £ 106U/week) - PR (>50%): 3/10
- SCLE 4/10 - High dose 2/10 (100 120 £ 106U/ - Clearing of lesions rapid: occurred within 2 6 weeks of treatment
Biopsy-proven week) Relapse: 8/8 within 2 14 weeks of treatment cessation.
Treated for 4 13 weeks Subgroup analysis
- DLE: CR 3/10
- SCLE: CR 2/10
- Patients with DLE responded more rapidly/to a greater degree than
patients with SCLE
- Time to improvement (mean):
- DLE: 5.6 weeks (range 4 8 weeks)
- SCLE: 10 weeks (range 5 13 weeks)
- Dose required for improvement (mean):
- DLE: 35 (range 18 45) x106U/week
- SCLE: 80 (range 18 120) x106U/week
Histology: improvement correlated with clinical improvement. Reduced
dermal cellular infiltrate.
AE: flu-like syndrome 8/8 (dose-dependent, requiring dose reduction in 1/10),
deranged LFTs 3/10
123
124
Table 12 (Continued)
Observational study
Cutillas-Marco N = 60 Cholecalciferol 1400 units plus calcium Patients not recommended CLE patients more likely than healthy controls to have darker skin type
et al. (2014) [107] Mixed CLE (n = 60) and healthy carbonate 1250 mg for 40 days, fol- treatment (p = 0.001), shorter daily sun exposure (p = 0.03), higher rates of sunscreen
controls (n = 117) lowed by calcium carbonate use (p = 0.001) and smoking (p = 0.001).
Biopsy status NR 1250 mg + cholecalciferol 400 units Photosensitivity in 63%
twice daily for 1 year CLASI Activity Score: significant reduction in vitamin D group but not control
Control group: patients seen in June/ group.
July recommended supplementation, CLASI Damage Score: significant reduction in vitamin D group but not control
patients in August/September not rec- group.
ommended supplementation No correlation between serum 25(OH)D levels and CLASI activity or damage
scores (r= 0.04, p = 0.87)
Significantly lower number of days with active lesions in the vitamin D group
but not control group; trend to less exacerbations in vitamin D-treated
group.
Vitamin D Levels

- CLE patients: 20 § 9 vs. Controls: 26 § 8 (p = 0.001)
- Vitamin D levels in CLE patients improved with treatment
- Predictors of lower vitamin D levels in CLE group: increasing age (p = 0.02),
CLE for >5 years (OR 3.1, 95%CI 1.0 9.3), antimalarial treatment (21 § 9 vs.
14 § 6, p = 0.04)
- CLE associated with increased risk of having Vit D level <20 ng/ml (OR 3.5,
95%CI 1.8 6.7) (persisted despite adjustment for age, smoking, sun expo-
sure and sunscreen use)
Sanders et al. (2006) [103] N = 44 UVB hardening therapy: high pressure None 35/44 patients able to tolerate increasing monthly UVB doses
Mixed CLE mercury sunlamp (effective radiation Disease activity
- SLE 9/44 around 300 nm) - Stable 30/35
- DLE 21/44 At-home device used by patients - Improved 5/35
- SCLE 10/44 Starting dose 10% of 0.55mJ/cm2, AE: minor including skin irritation
- Not specified 4/44 increased gradually to final dose
Biopsy-proven 5.5mJ/cm2, gradual increase in expo-
sure time
Exposed 3 times weekly
Case Series
Klebes et al. (2016) [28] N = 34 Dapsone None CR 6/34
Mixed CLE PR 14/34
- DLE 19/34 No change 5/34
- SCLE 8/34 Exacerbation of skin lesions 3/34
- LET 4/34 Best improvement seen in SCLE; remission/improvement in 6/8 patients
- SLE 3/34 AE: serious 3/34 (4/34 required discontinuation including DRESS syndrome,
Biopsy: NR peripheral neuropathy, haemolytic anaemia.
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Seminars in Arthritis and Rheumatism 50 (2020) 95 127

Contents lists available at ScienceDirect

Seminars in Arthritis and Rheumatism

Management of cutaneous manifestations of lupus erythematosus:

Introduction diverse skin diseases, with potentially different pathogenesis and

Summary/strength Subgroup data

J.L. Fairley et al. / Seminars in Arthritis and Rheumatism 50 (2020) 95 127

(continued on next page)

included patients with a mixture of different subtypes of CLE

and one study included a mixture of both tacrolimus and pimecroli-

All studies demonstrated improvement with topical CNI therapy,

among subtypes, whereas one observational study showed equal

Sun protection and sunscreen

Five studies in 123 patients investigated sun protection and sun-

risk of bias [19].

venting LE lesions in response to photoprovocation testing [18 21],

while one study evaluated prolonged use of sunscreen in regular life

[22]. In the studies analysing response to photoprovocation testing,

ment [20,21]. No difference across CLE subtypes was shown [18,20].

Another study showed a signiﬁcant reduction in disease severity

with regular use of an SPF15+ sunscreen, despite only 54% adherence

Two studies in 46 patients investigated the use of R-salbutamol

Twenty-two studies involving 2203 patients investigated the

These studies included 2 RCTs [25,27], 2 non-controlled trials

Fig. 1. PRISMA ﬂowchart.

Fig. 2. Cutaneous lupus erythematosus: a suggested management algorithm.

Population Intervention Comparator Results

J.L. Fairley et al. / Seminars in Arthritis and Rheumatism 50 (2020) 95 127

Population Intervention Comparator Results

- DLE 6/12 SLE: signiﬁcant improvement in photosensitive rash 2/2

J.L. Fairley et al. / Seminars in Arthritis and Rheumatism 50 (2020) 95 127

Population Intervention Comparator Results

J.L. Fairley et al. / Seminars in Arthritis and Rheumatism 50 (2020) 95 127

[60 63,67,68]. Furthermore, adverse effects were common especially

- Minor effect only on hypertrophic elements

showed no major difference in response rates between subgroups [69].

Fifteen studies in 3269 patients investigated the effect of biologic

[81,83 86], three examined rituximab [87 89], one anifrolumab

ASF-1096: sulphate salt

Five studies examined belimumab [81,83 86], a fully human

immunoglobulin-G1λ monoclonal antibody that inhibits the B cell

then every 28 days thereafter. One RCT gave subcutaneous belimu-

greater improvement in overall response rate and outcome scores

(mucocutaneous BILAG and SELENA-SLEDAI) in the belimumab com-

Wulf et al. (2007) [24]

Three observational studies investigated the use of rituximab, an

Population Intervention Comparator Results

J.L. Fairley et al. / Seminars in Arthritis and Rheumatism 50 (2020) 95 127

Population Intervention Comparator Results

Kishi et al. (2018) [43] N = 31 HCQ None Response

- SLE 20/31 (SLICC Criteria) - Non-responders: 6/31

J.L. Fairley et al. / Seminars in Arthritis and Rheumatism 50 (2020) 95 127

(continued on next page)

Population Intervention Comparator Results

Mixed CLE - Effective 3/7

- SLE 4/7 - Ineffective 2/7

J.L. Fairley et al. / Seminars in Arthritis and Rheumatism 50 (2020) 95 127

Population Intervention Comparator Results

Biopsy: NR Chloroquine-Quinacrine combination: 6/128 improve response rates.

J.L. Fairley et al. / Seminars in Arthritis and Rheumatism 50 (2020) 95 127

(continued on next page)

100 mg intravenously [88,89]. Response rates were variable, with two

AE: blurred vision in 1/15, electroretinographic abnormality 3/