BJD

GUI DEL IN ES British Journal of Dermatology

British Association of Dermatologists guidelines for the

management of people with cutaneous lupus
erythematosus 2021
D. O’Kane iD ,1 C. McCourt iD ,1 S. Meggitt,2 D.P. D’Cruz iD ,3 C.H. Orteu,4 E. Benton,5 S. Wahie,6 S. Utton,7
M. Hashme,8 M.F. Mohd Mustapa iD ,8 L.S. Exton iD 8 and the British Association of Dermatologists’
Clinical Standards Unit

Correspondence Linked Comment: B.F. Chong. Br J Dermatol 2021; 185:1084.

Donal O’Kane.
Emails: donal.okane@belfasttrust.hscni.net; guidelines@bad.org.uk

Accepted for publication

1. Purpose and scope
17 June 2021 The overall objective of the guideline is to provide up-to-
date, evidence-based recommendations for the management of
The author affiliations can be found in the Appendix.
cutaneous lupus erythematosus (CLE) in the presence or
absence of systemic lupus erythematosus (SLE) in adults,
Funding sources
young people and children. The document aims to:
None.
• offer an appraisal of all relevant literature up to December
Conflicts of interest 2020, focusing on any key developments
D.O’K. has received sponsorship to attend meetings from Janssen, Galderma and Novartis
• address important, practical clinical questions relating to
(nonspecific) and invited speaker fees from Janssen (nonspecific), and has participated in
the primary guideline objective
advisory boards for AbbVie, Janssen and Novartis (nonspecific). C.M. has received travel
and accommodation expenses from AbbVie, Almirall and Janssen (nonspecific) and • provide guideline recommendations and, if appropriate,
invited speaker fees from Almirall (nonspecific). S.W. has received travel and accommo-
research recommendations.
dation expenses from AbbVie, Almirall, Janssen and Novartis (nonspecific), and has been The guideline is presented as a detailed review with high-
awarded a research grant from Lupus UK (specific). D.D’C. has participated in advisory lighted recommendations for practical use in primary care and
boards for Eli Lilly (specific), has received sponsorship to attend meetings from Eli Lilly
secondary care (see section 3.0), in addition to an updated
and GSK/Human Genome Sciences (specific), has received departmental grant support
patient information leaflet (available on the BAD Skin Health
from Aspreval/Vifor Pharma (specific), is a British Society for Rheumatology Heberden
Committee member (specific), a British Society for Rheumatology GDG for SLE mem-
Information website, https://www.skinhealthinfo.org.uk/a-z-
ber (specific) and a Clinical Reference Group for Specialised Rheumatology representing conditions-treatments/).
London member (specific). C.H.O. is Chair of the Clinical Reference Group for Spe-
cialised Dermatology (specific). 1.1. Exclusions
Produced in 2021 by the British Association of Dermatologists The guideline does not cover Jessner lymphocytic infiltrate or
nonspecific cutaneous manifestations of lupus such as vasculi-
This is a new guideline prepared for the British Association of Dermatologists (BAD) tis and Raynaud phenomenon.
Clinical Standards Unit, which includes the Therapy & Guidelines subcommittee. Mem-
bers of the Clinical Standards Unit who have been involved are N.J. Levell (Chair,
Therapy & Guidelines subcommittee), B. McDonald (BAD Assistant Honorary Secre- 2. Methodology
tary), A. Bardhan, S.L. Chua, A. Daunton, H. Frow, P. Laws, I. Nasr, G. Petrof, A.
This set of guidelines has been developed using the BAD’s rec-
Salim, M.C. Ezejimofor (BAD Guideline Research Fellow), M. Hashme (BAD Informa-
ommended methodology.1 Further information can be found
tion Scientist), L.S. Exton (BAD Senior Guideline Research Fellow) and M.F. Mohd
in Appendix M (see Supporting Information) with reference
Mustapa (Director Clinical Standards).
to the Appraisal of Guidelines Research and Evaluation (AGREE
DOI 10.1111/bjd.20597 II) instrument (www.agreetrust.org)2 and the Grading of Rec-
ommendations Assessment, Development and Evaluation
NICE has renewed accreditation of the process used
by the British Association of Dermatologists to pro- (GRADE; http://www.gradeworkinggroup.org/). Recommen-
duce clinical guidelines. The renewed accreditation is
valid until 31 May 2026 and applies to guidance dations were developed for implementation in the UK
produced using the processes described in Updated
guidance for writing a British Association of Derma- National Health Service (NHS).
tologists clinical guideline – the adoption of the
GRADE methodology 2016. The original accredita- The Guideline Development Group (GDG), which consisted
tion term began on 12 May 2010. More information on accreditation can be viewed at www.nice.org.uk/
accreditation. of six consultant dermatologists, a consultant rheumatologist,

1112 British Journal of Dermatology (2021) 185, pp1112–1123 © 2021 British Association of Dermatologists
 BAD guidelines for the management of people with CLE 2021, D. O’Kane et al. 1113
summary of included studies (Appendices F and G), narrative
two patient representatives and a technical team (consisting of an
findings for within-patients studies (Appendix H) and non-
information scientist, a guideline research fellow and a project
comparative studies (Appendix I), PRISMA flow diagram
manager providing methodological and technical support),
(Appendix J), critical appraisal of included systematic reviews
established several clinical questions pertinent to the scope of the
(Appendix K) and list of excluded studies (Appendix L). The
guideline and a set of outcome measures of importance to
strength of recommendation is expressed by the wording and
patients, ranked according to the GRADE methodology (see sec-
symbols as shown in Table 1.
tion 2.1 and Appendix A; see Supporting Information).
A systematic literature search of PubMed, MEDLINE, Embase
and the Cochrane databases was conducted by the technical 2.1. Clinical questions and outcomes
team to identify key articles on CLE up to December 2020; The GDG established a number of clinical questions pertinent to
search terms and strategies are detailed in Appendix N (see the scope of the guideline; see Appendix A for the full review
Supporting Information). Additional references relevant to the protocol. The GDG also established a set of outcome measures of
topic were also isolated from citations in reviewed literature. importance to patients for each clinical question, which were
Data extraction and critical appraisal for question 1 were car- agreed with and ranked according to the GRADE methodology
ried out by two clinicians and for questions 2 and 3 by the by the patient representatives.3 This uses a 9-point scale, with
technical team. Data synthesis, evidence summaries, lists of outcomes that the patient representatives considered most impor-
excluded studies and the PRISMA diagram were prepared by tant ranked 9. Outcomes ranked 9, 8 or 7 are critical for decision
the technical team. Overall certainty of the evidence from making; those ranked 6, 5 or 4 are important but not critical for
included studies was rated according to the GRADE system decision making, and those ranked 3, 2 or 1 are the least impor-
(high, moderate, low or very low). tant for decision making. Data on these outcome measures were
The recommendations are based on the evidence drawn extracted from included studies (Appendices B, C, E and G).
from systematic reviews of the literature pertaining to the clini- The GDG decided that an initial review of the available lit-
cal questions identified following discussions with the entire erature was needed to define a change in Cutaneous Lupus
GDG and factoring in all four factors that would affect its Erythematosus Disease Area and Severity Index (CLASI) that is
strength rating according to the GRADE approach (i.e. balance clinically relevant in order to inform the outcomes for the
between desirable and undesirable effects, overall certainty of other two clinical questions.4
the evidence, patient values and preferences and resource allo-
cation). All GDG members contributed towards drafting and Review question 1: CLASI
reviewing the guideline and supporting information. Where In people with CLE how effective is the CLASI score in
there was insufficient evidence from the literature, informal determining the impact of therapy on disease activity and
consensus was reached based on the experience of the GDG. damage?
The Supporting Information contains the summary of find- Critical
ings with forest plots (Appendix B), clinical evidence sum-
mary (Appendix C), tables Linking the Evidence To the •
Sensitive and specific for disease activity/damage severity
Recommendations (Appendix D), GRADE evidence profiles •
Sensitive and specific to clinically relevant changes in
disease activity/damage
indicating the overall certainty of the evidence (Appendix E),

Table 1 Strength of recommendation ratings

Strength Wording Symbols Definition

Strong recommendation for ‘Offer’ (or similar, e.g. ‘use’, ↑↑ Benefits of the intervention outweigh the risks; most patients
the use of an ‘provide’, ‘take’, would choose the intervention while only a small proportion
intervention ‘Investigate’, etc.) would not; for clinicians, most of their patients would receive the
intervention; for policymakers, it would be a useful performance
indicator
Weak recommendation for ‘Consider’ ↑ Risks and benefits of the intervention are finely balanced; most
the use of an patients would choose the intervention, but many would not;
intervention clinicians would need to consider the pros and cons for the
patient in the context of the evidence; for policymakers it would
be a poor performance indicator where variability in practice is
expected
No recommendation Θ Insufficient evidence to support any recommendation
Strong recommendation ‘Do not offer’ ↓↓ Risks of the intervention outweigh the benefits; most patients
against the use of an would not choose the intervention whilst only a small proportion
intervention would; for clinicians, most of their patients would not receive the
intervention

© 2021 British Association of Dermatologists British Journal of Dermatology (2021) 185, pp1112–1123
1114 BAD guidelines for the management of people with CLE 2021, D. O’Kane et al.

Important • Improvement in QoL measures (e.g. DLQI – mean change

from baseline)
• Correlation with physician-assessed disease measures
• CLASI-50 (proportion of participants achieving at least a
• Correlation with patient-reported health outcomes 50% reduction in CLASI score)
After a review of the literature (see Appendices D and F) • Drug withdrawal due to serious adverse event (e.g. ocular
the following outcomes were agreed. toxicity)
(↑↑) Use CLASI-50 (proportion of participants achieving atImportant
least a 50% reduction in the CLASI score) as a critical outcome
(for decision making) in the systematic reviews Q2 and Q3. • Improvement in the skin component of a validated lupus
(↑↑) Use CLASI-20 (proportion of participants achieving at least activity score (e.g. BILAG, SLEDAI, SLAM, ECLAM, SLICC/
a 20% reduction in the CLASI score) as an important outcome ACR-DI and SLEDAI-2K)
(for decision making) in the systematic reviews Q2 and Q3. • CLASI-20 (proportion of participants achieving at least a
20% reduction in CLASI score)
Review question 2: local and systemic therapies
In people with CLE what is the clinical effectiveness and
• Improvement in disease severity (PGA and PGSA)
safety of local and systemic therapies compared with each
• Time to flare
other and/or placebo?
• Reduction in number of flares
Less important
Critical
• Mild adverse event (e.g. gastrointestinal upset)
• Clear/nearly clear (proportion of participants with com-
plete resolution of skin lesions)
• Improvement in quality of life (QoL) measures [e.g. Der-3. Summary of recommendations
matology Life Quality Index (DLQI) – mean change from
The following recommendations and ratings were agreed
baseline]
upon unanimously by the core members of the GDG and
• CLASI-50 (proportion of participants achieving at least apatient representatives. For further information on the word-
50% reduction in the CLASI score)
ing used for recommendations and strength of recommenda-
• Drug withdrawal due to serious adverse event (e.g. oculartion ratings, see Table 1. The evidence for recommendations
toxicity)
is based on the studies as listed (for details and discussion of
Important the evidence see Appendices B–I). Good practice point (GPP)
recommendations are derived from informal consensus. The
• Improvement in the skin component of a validated lupusGDG acknowledges that a number of the recommended treat-
activity score [e.g. British Isles Lupus Assessment Group
ment options are used off licence in CLE.
(BILAG) index; Systemic Lupus Erythematosus Disease Activity
Where recommendations relate to specific subtypes of CLE:
Index (SLEDAI); Systemic Lupus Activity Measure (SLAM);
acute (ACLE), subacute (SCLE) or chronic [CCLE, which
European Consensus Lupus Activity Measurement (ECLAM);
includes discoid (DLE)], this has been indicated.
Systematic Lupus International Collaborating Clinics/American
There is a paucity of evidence relating to the treatment of
College of Rheumatology-Damage index (SLICC/ACR-DI);
CLE in young people and children. The GDG is mindful that
and SLE Disease Activity Index-2000 (SLEDAI-2K)]
the presentation of CLE before adulthood is rare and therefore
• CLASI-20 (proportion of participants achieving at least atreatment decisions are typically based on available evidence
20% reduction in CLASI score)
in adults and physicians’ own experience in children and
• Improvement in disease severity [Physician Global Assess-young people with CLE or other inflammatory diseases (see
ment (PGA), Patients’ Global Self-Assessment (PGSA)]
section 8). Throughout this guideline, drug doses refer to
• Time to flare adults and adjustment of all systemic drugs is required in
• Reduction in number of flares children.
Less important
General
• Mild adverse event (e.g. gastrointestinal upset)
R1 (↑) Consider the presence of SLE in people with CLE using
Review question 3: other interventions history, examination and targeted laboratory investigations.
In people with CLE, what is the clinical effectiveness andR2 (GPP) People with CLE in the setting of SLE should be
safety of other interventions compared with each other and/or managed jointly with rheumatology.
placebo? R3 (GPP) Where the psychological impact of CLE on an indi-
Critical vidual patient is significant, consider referral to available psy-
chological support services (such as a psychiatrist, clinical
• Clear/nearly clear (proportion of participants with com-psychologist or patient support group).
plete resolution of skin lesions)
British Journal of Dermatology (2021) 185, pp1112–1123
© 2021 British Association of Dermatologists
 BAD guidelines for the management of people with CLE 2021, D. O’Kane et al. 1115
R4 (↑) Consider the possibility of drug-induced CLE (particu-
R17 (GPP) Consider intralesional triamcinolone (0.1 mL per
larly in people with SCLE) and discontinue any potential cau-
1 cm2 field, starting at 2.5–5 mg mL–1 for sites at higher risk
sative drug.
of atrophy including the face and 10 mg mL–1 for other sites)
R5 (↑↑) Discuss with people with CLE the importance of life-
as a local treatment option in people with localized DLE or as
style changes on disease activity and treatment response, such
an adjunctive therapy for persistent lesions.
as smoking cessation and the need for a range of photoprotec-
Θ There is insufficient evidence to support the use of pulsed
tive measures, including the use of a broad-spectrum sun-
dye laser in CLE.
screen.
R6 (↑) Consider vitamin D supplementation in people with Systemic therapies
CLE.5 Antimalarials
R7 (GPP) Caution people with CLE against herbal supple- R18 (↑↑) Offer antimalarials, either alone or with adjunctive
ments and traditional medicines as some may contain corticos- topical corticosteroids (see R13–R17), as the first-line sys-
teroids or induce disease exacerbation by immune stimulation. temic treatment option to people with CLE (see R22–R39).
R8 (↑↑) Offer those of child-bearing potential a pregnancy R19 (GPP) Consider higher, initial antimalarial doses in peo-
test prior to commencing methotrexate, mycophenolate mofe- ple with severe or disseminated CLE, or subtypes at the great-
til, acitretin, rituximab, belimumab, cyclophosphamide, est risk of scarring (e.g. DLE and lupus profundus).
thalidomide or lenalidomide therapy for their CLE (see indi- R20 (GPP) Consider concomitant systemic corticosteroids ini-
vidual drug’s summary of product characteristics).6–8 Counsel tially in people with severe or disseminated CLE, or subtypes
them regarding the risk of teratogenicity, advise pregnancy at the greatest risk of scarring (see R32–R33).
prevention and instigate the pregnancy prevention pro- R21 (GPP) Consider intermittent use of antimalarials in peo-
gramme. ple with seasonal CLE (e.g. summer flares in photosensitive
R9 (↑↑) As a precautionary measure, advise sexually active lupus erythematosus and winter flares in chilblain lupus ery-
males to use reliable contraception during methotrexate, thematosus) (see R22–R31).
mycophenolate mofetil, thalidomide and lenalidomide therapy Hydroxychloroquine
for their CLE, during dose interruption (where applicable) and R22 (↑↑) Offer HCQ at doses of 200–400 mg daily to people
for periods of time following the cessation of treatment (see with CLE. The daily maintenance dose of HCQ should not
individual drug’s summary of product characteristics).6 exceed 5 mg kg–1 (actual body weight).
R10 (GPP) Additional monitoring by the obstetric team is R23 (↑↑) Screen people with CLE receiving HCQ for retinopa-
required to identify congenital heart block in the fetuses of thy, following current guidelines by the Royal College of
females with CLE with anti-Ro/SSA and/or anti-La/SSB anti- Ophthalmologists:9
bodies who become pregnant. • Annual screening is recommended in all patients who have
R11 (GPP) Consider hydroxychloroquine (HCQ) at standard taken HCQ for > 5 years. This should include spectral
dosing (see R22) as a first-line systemic therapy for CLE dur- domain optical coherence tomography and fundus autoflu-
ing pregnancy. orescence imaging photography.
R12 (GPP) Consider dapsone as a second-line systemic agent • Annual screening may be commenced after 1 year of treat-
for CLE during pregnancy when the response to HCQ is sub- ment if additional risk factors for retinal toxicity exist, such
optimal. Co-prescription of folic acid 5 mg daily is necessary. as concomitant tamoxifen therapy or impaired renal func-
tion (estimated glomerular filtration rate < 60 mL min–1
Local therapies 1.73 m–2) or if the daily dose of HCQ is > 5 mg kg–1.
Topical therapy
Mepacrine
R13 (↑↑) Offer very potent/potent topical corticosteroids as a
R24 (↑) Consider mepacrine (50–100 mg daily) as an alterna-
first-line monotherapy option to people with localized CLE
tive, first-line antimalarial option in people with CLE in whom
(including the face) for up to 4 weeks, and as an adjuvant to
retinal toxicity may be a concern.
systemic therapy when there is widespread cutaneous and/or
R25 (GPP) Consider mepacrine (up to 200 mg daily) in people
SLE involvement.
with CLE resistant to standard dosing (see R24), when combina-
R14 (↑↑) Offer topical calcineurin inhibitors as a first-line
tion antimalarials or other therapies are contraindicated.
monotherapy option to people with localized CLE for up to
Chloroquine
12 weeks, and as an adjuvant to systemic therapy when there
R26 (↑) Consider chloroquine (CQ) as a third-line antimalar-
is widespread cutaneous and/or SLE involvement.
ial option in people with CLE.
R15 (GPP) Consider reducing to a twice-weekly dose for
R27 (↑↑) Conduct an annual retinal assessment in all people
maintenance in people with CLE who respond to topical corti-
with CLE on CQ after 1 year of therapy, following the current
costeroids or calcineurin inhibitors, reviewing the effectiveness
Royal College of Ophthalmologists guidelines.9
after 3–6 months.
R28 (GPP) Take care when prescribing CQ as the dosing
R16 (↑) Consider the early addition of systemic therapy to
depends on the salt used and is generally expressed in refer-
topical therapy in people with severe or disseminated CLE.
ence to chloroquine base, for example chloroquine phosphate

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 1116 BAD guidelines for the management of people with CLE 2021, D. O’Kane et al.

R43 (↑↑) Monitor for signs and symptoms of haemolytic

250 mg is approximately equivalent to chloroquine sulfate
anaemia, methaemoglobinaemia and agranulocytosis in people
200 mg and to chloroquine base 155 mg.
with CLE receiving dapsone, particularly in the first 3 months
Combination antimalarials
of treatment.
R29 (↑) Consider mepacrine in combination with HCQ as a
Retinoids
second-line antimalarial option in patients with CLE refractory
R44 (↑) Consider acitretin (25–50 mg daily) as a second-
to HCQ monotherapy.
line systemic treatment option in people with CLE
R30 (↑↑) Do not offer HCQ in combination with CQ owing
(see R8).
to the combined risk of retinopathy.
R45 (GPP) Consider acitretin in people with hyperkeratotic
R31 (GPP) Exercise caution when using maximum doses of
DLE resistant to topical therapy and antimalarials (see R8).
HCQ/CQ, and when used in combination with mepacrine,
R46 (↑↑) Only offer acitretin in those of child-bearing
due to the uncertainty around the retinal safety of antimalarial
potential in exceptional circumstances owing to the risk of
combinations.
teratogenicity during and up to 3 years after treatment (see
Oral/intravenous corticosteroids
R8).8
R32 (GPP) Consider concomitant tapering courses of oral or
Θ There is insufficient evidence to support the use of alitreti-
intravenous corticosteroids, e.g. methylprednisolone, in people
noin in CLE.
with severe or disseminated CLE, or subtypes with the greatest
Biologics
risk of scarring (e.g. patients with DLE with a high risk of
Θ While rituximab has shown benefit in the management of
permanent damage, high disease burden, etc.).
SLE, there is insufficient evidence to support its routine use in
R33 (GPP) Ensure people receiving long-term oral corticos-
CLE.
teroids (> 3 weeks’ duration) and those needing frequent
R47 (↑) Consider rituximab on a case-by-case basis in people
courses (three or four per year) are regularly monitored during
with treatment-resistant CLE where conventional systemic
the course of corticosteroid treatment to identify and help pre-
therapies have failed (see R8). (Rituximab is approved by
vent steroid-induced osteoporosis and adrenal insufficiency.10,11
NHS England for use in SLE.)
R34 (GPP) Consider comorbidities in people with CLE and
Θ There is insufficient evidence to support the use of beli-
the risk/benefit ratio prior to commencing systemic corticos-
mumab in people with CLE.
teroids.
R48 (↑) Consider belimumab in eligible people with SLE with
Methotrexate
cutaneous involvement where conventional systemic therapies
R35 (↑) Consider methotrexate (up to 25 mg once weekly) in
have failed (see R8). [Belimumab is currently restricted by
people with CLE with an inadequate response to topical ther-
NHS England to people with active seropositive SLE (SLEDAI
apy and antimalarials (see R8 and R9).
score > 10, with positive anti-double-stranded (ds)DNA anti-
R36 (GPP) Consider methotrexate in combination with anti-
bodies and low complement)].
malarials in people with CLE with partial response to topical
Intravenous immunoglobulins
therapy and antimalarials (see R8 and R9).
R49 (↑) Only consider intravenous immunoglobulins (IVIg)
R37 (GPP) Consider switching from an oral to a subcuta-
on a case-by-case basis in people with treatment-resistant CLE
neous preparation of methotrexate when the treatment
where conventional systemic therapies have failed (see treat-
response is suboptimal or in the event of significant gastroin-
ment algorithm). Individual funding requests to the NHS will
testinal side-effects.
be required as IVIg are not approved by the National Institute
Mycophenolate
for Health and Care Excellence (NICE) for the treatment of
R38 (↑) Consider oral mycophenolate mofetil (typically com-
SLE or CLE.
menced at 500 mg twice daily and escalated to 1.5 g twice
Azathioprine and ciclosporin
daily, dependent on response and tolerability) in people with
Θ There is insufficient evidence to support the use of azathio-
CLE with an inadequate response to topical therapy and anti-
prine or ciclosporin in the treatment of CLE.
malarials (see R8 and R9).
Cyclophosphamide
R39 (GPP) Consider mycophenolate mofetil in combination
Θ While cyclophosphamide has robust evidence for use in the
with antimalarials in people with CLE with a partial response
management of severe SLE with major organ involvement,
to topical therapy and antimalarials (see R8 and R9).
there is insufficient evidence to support its use in the treat-
R40 (GGP) Consider a switch to enteric-coated mycopheno-
ment of CLE specifically. However, if it is used, see R8 and
late sodium (360 mg equivalent to 500 mg of mycophenolate
provide additional counselling on the risk of infertility.
mofetil) in the event of significant gastrointestinal side-effects.
Clofazimine
Dapsone
R50 (↑) Consider clofazimine (100 mg daily) as a third-line
R41 (GPP) Consider dapsone (typically commenced at 50 mg
systemic treatment option in people with CLE with or without
daily and escalated to 150 mg daily, depending on response
SLE.
and tolerability) as a first-line systemic treatment option in
R51 (GPP) Avoid co-prescription of clofazimine and anti-
people with SCLE and bullous SLE.
malarials in people with CLE as both drugs can independently
R42 (↑) Consider dapsone as a second-line systemic treatment
cause skin discoloration.
option in people with CLE.
© 2021 British Association of Dermatologists
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 BAD guidelines for the management of people with CLE 2021, D. O’Kane et al. 1117

Thalidomide
R52 (↑) Consider thalidomide in people with CLE as a third-line 5.1. Classification
treatment option for treatment-resistant disease (see R8 and R9). The most commonly used classification system for CLE divides
R53 (GPP) Consider the addition of short courses of thalido- lupus-specific skin disease into three subtypes: ACLE, SCLE and
mide to antimalarial therapy in people with CLE as a third-line CCLE.12 CCLE encompasses the most common subtype, DLE,
therapy for treatment-resistant disease (see R8 and R9). as well as lupus profundus/panniculitis and chilblain lupus. A
R54 (↑↑) Use thalidomide with caution in people with fourth subtype – intermittent (ICLE) – has been proposed for
increased risk of thromboembolic events and other comorbidi- lupus tumidus, which displays distinct clinical and histological
ties (see R8 and R9). features and follows a relatively benign clinical course.13
R55 (↑↑) Monitor for signs and symptoms of peripheral neu-
ropathy in people with CLE receiving thalidomide (see R8
and R9). 5.2. Aetiology
Lenalidomide
R56 (↑) Consider lenalidomide in people with CLE as a third- 5.2.1. Endogenous factors
line treatment option for treatment-resistant disease. Availabil- Major histocompatibility complex alleles conferring increased
ity may be restricted due to cost (see R8 and R9). risk of CLE include human leucocyte antigen (HLA)-B8, HLA-
DR3, HLA-DQA1 and HLA-DRB1. HLA-DR3 is associated with
Summary of future research recommendations
anti-Ro/SSA antibody positivity, the tumour necrosis factor
The following list outlines future research recommendations
(TNF)-a promoter polymorphism –308A and SCLE, whereas
(FRRs).
HLA-DQA1 increases the risk of DLE. IRF5, TYK2 and CTLA4,
FRR1 Head-to-head randomized controlled trials (RCTs) to
single nucleotide polymorphisms previously implicated in SLE,
compare the safety and efficacy of established and emerging
are also associated with CLE.14 The pattern of inflammation in
therapies in CLE (e.g. baricitinib).
CLE is T helper cell 1 predominant and an upregulation of
FRR2 Establish a validated patient-reported outcome measure
cytokines including interleukin (IL)-6 and IL-17 in affected
(PROM) for CLE.
skin has been demonstrated. Several autoantibodies can be
FRR3 Trials involving SLE should include CLE as a primary/
overexpressed in CLE, although their contribution to disease
secondary stratum and with stratification of the cutaneous
onset and severity is poorly understood. Anti-Ro/SSA positiv-
results using CLASI and a validated PROM to determine the
ity is seen in approximately 80% of patients with SCLE and its
minimal clinically important difference.
presence in ACLE appears to confer increased risk of photosen-
FRR4 Trials involving CLE using treatments with proven efficacy
sitivity. Keratinocytes within the epidermis in CLE demonstrate
to help identify what constitutes a minimum clinically important
increased susceptibility to ultraviolet (UV)-induced apopto-
difference as measured by CLASI and a validated PROM.
sis.15 Increased generation and reduced clearance of apoptotic
FRR5 Assessment of the effectiveness of CLASI in measuring
keratinocytes that express Ro/SSA on their surface, and UV-in-
disease severity and response to treatment in the different sub-
duction of proinflammatory cytokines, chemokines and adhe-
types of disease.
sion molecules, may represent the triggers necessary for UV-
FRR6 Optimal and standardized core patient- and physician-
induced autoimmunity. Subsequently, recruitment and activa-
reported outcome measures in CLE to reduce heterogeneity of
tion of effector memory T cells and plasmacytoid dendritic
reported data and allow comparisons and pooling of data.
cells amplifying the inflammatory immune response may lead
FRR7 A UK-wide disease registry capturing real-world safety
to UV-induced cutaneous LE lesions.16,17 Anti-La/SSB antibod-
and efficacy of treatments for CLE.
ies are also more commonly seen in SCLE than in ACLE and
CCLE. Importantly, anti-Ro/SSA and/or anti-La/SSB positivity
4. Algorithm in pregnant people confers a risk of neonatal lupus and con-
The recommendations, discussions in the Linking Evidence To genital heart block.17 The presence of other antibodies includ-
Recommendations (see Appendix D) and consensus specialist ing anti-dsDNA and anti-Sm are associated with an increased
experience were used to inform the algorithm/pathway of risk of SLE.
care (Figure 1).
5.2.2. Environmental
5. Background
5.2.2.1. Smoking
CLE refers to a spectrum of cutaneous disorders that share
Cigarette smoking is more common in patients with CLE than
common clinical, laboratory and histological findings. The
healthy controls, with a prevalence of 60–80%. Current smok-
pathogenesis is multifactorial, with genetics, autoantibodies
ers demonstrate increased disease activity and damage, and a
and environmental exposures contributing to disease onset
more pronounced effect on QoL.18 Despite previous reports
and severity. CLE can occur independently or in association
that smoking interferes with antimalarial efficacy in CLE, it is
with SLE with different CLE subtypes conferring differing
more likely that this reflects increased disease activity in this
levels of risk of systemic disease.
group.19

© 2021 British Association of Dermatologists British Journal of Dermatology (2021) 185, pp1112–1123
Figure 1 Patient management pathway – cutaneous lupus erythematosus (CLE).
 typically more aggressive in darker skin types. Of the CLE sub-
5.2.2.2. Ultraviolet radiation types, DLE is the most common (68%), followed by SCLE
(18%) and ACLE (6%). CLE is rare in childhood and < 3% of
The ability of UV radiation (UVR) to induce or exacerbate
cases of DLE present before 10 years of age.27
CLE is widely recognized, with varying susceptibility depen-
dent on CLE subtype (more common in SCLE and ACLE than
DLE).20 Photoprovocation studies have demonstrated that the 5.5. Emotional impact
culpable UVR wavelength can differ between patients (UVA,
The impact of CLE on emotional well-being is greater than
UVB or both). UVA and UVB may also have distinct roles in
other common dermatological conditions (including acne and
the disease pathogenesis.21 In addition, UVR not only aggra-
alopecia), with equivalent or worse scores of mental health
vates cutaneous involvement in CLE, but also exacerbates sys-
status than hypertension, diabetes and congestive cardiac fail-
temic symptoms, including joint pains, fatigue and QoL
ure.28 Patients with CLE describe pressures conforming to
scores.
societal norms, distress regarding their appearance and a feel-
Flares of CLE can be reduced by effective photoprotection
ing of helplessness aggravated by the chronicity of their dis-
measures. In one RCT, a broad-spectrum (UVA and UVB) sun-
ease. All of these factors contribute to social isolation. A recent
screen prevented flares of CLE in response to UVA and UVB
publication provides in-depth insight into the disruption and
photoprovocation on three consecutive days, whereas typical
additional burden that CLE and the required photoprotective
CLE lesions developed in the same patients at sites of vehicle
practices place on individuals with CLE on a daily basis.24
application (n = 14/25 to UVA and n = 14/25 to UVB).22
Despite this, adherence to photoprotective measures (including
applying suitable sunscreen, avoiding sun exposure and wearing 6. Diagnosis and investigation
appropriate clothing) are often suboptimal in CLE. Importantly,
the latency period between UV exposure and a CLE flare can be 6.1. Diagnosing cutaneous lupus erythematosus
several weeks, resulting in the impact of UV on disease flares
The diagnosis of CLE is clinical and based on a characteristic
being underappreciated.23 In one study, CLE lesions developed
appearance, particularly in the setting of underlying SLE.
following photoprovocation in 71% of patients with CLE who
Where there is diagnostic uncertainty or overlap with other
denied any contribution of sun exposure to activity of their dis-
dermatoses, serum autoantibodies (see section 6.2) and skin
ease. Additional barriers to adequate photoprotection identified
biopsy can be useful. On routine histology, an interface der-
in a recent study include unclear advice from clinicians, cost,
matitis characterized by varying degrees of basal layer degen-
tolerability, time constraints and conforming to social norms.24
eration (keratinocyte apoptosis and vacuolization) is seen in
all types of CLE where there is epidermal involvement. Histol-
5.3. Clinical features ogy in early lesions, particularly in ACLE, can be nonspecific,
whereas in established DLE hyperkeratosis, basement mem-
Each subtype of CLE has characteristic clinical features. ACLE
brane zone thickening, follicular plugging, and perivascular
typically presents as a macular erythematous rash involving the
and periadnexal inflammation are typically seen. Direct
malar region of the face. Less commonly, more generalized
immunofluorescence (DIF; historically termed the ‘lupus band
involvement is seen. ACLE is frequently accompanied by oral
test’) can demonstrate linear or granular deposits of
ulceration. ACLE is strongly correlated with flares of SLE and
immunoglobulin (IgG, IgM and IgA) and complement at the
activity is typically transient, resolving without scarring. DLE
dermal–epidermal junction in lesional skin in isolated CLE and
characteristically presents as erythematous, indurated plaques
in both lesional and nonlesional skin in SLE.29 However, these
with overlying scale extending into hair follicles (follicular plug-
changes are nonspecific and DIF is therefore not routinely rec-
ging) on the face, ears, scalp (resulting in scarring alopecia) and
ommended in CLE.
neck (localized DLE; 70%) with concurrent involvement below
the neck less commonly (generalized DLE). Central atrophic
scarring and dyspigmentation are characteristic. SCLE is typically 6.2. Diagnosing systemic lupus erythematosus in
highly photosensitive and usually presents as annular and/or patients with cutaneous lupus erythematosus
psoriasiform plaques on the upper torso, neck and arms. Lesions
Approximately 80% of patients with SLE will develop CLE at
heal without scarring, but dyspigmentation often persists.
some stage. The risk of SLE differs based on the CLE subtype.
Despite the contrasting appearance of the different subtypes,
For example, ACLE is regarded as a cutaneous manifestation of
two or more CLE subtypes coexist in up to 30% of patients.25
SLE and therefore 90–100% of patients with ACLE have sys-
temic disease.30 Approximately 50% of patients with SCLE
5.4. Epidemiology meet the 1997 American College of Rheumatologists (ACR)
classification criteria for SLE; however, only 10% will develop
The incidence of CLE as an independent disease is similar to
clinically significant systemic disease.31 The risk of SLE in
SLE and approximately 4–5 per 100 000.26 There is a peak
patients with DLE is lower and dependent on the extent of
age of onset in the fourth decade of life, and CLE is twice as
disease (5% for localized and 15% for generalized
common in females. Overall, CLE is more prevalent and

© 2021 British Association of Dermatologists British Journal of Dermatology (2021) 185, pp1112–1123
 1120 BAD guidelines for the management of people with CLE 2021, D. O’Kane et al.

disease).32,33 The risk of progression to SLE appears to be

than that of the general population, particularly when the dis-
greater in children with CCLE (25–40%).34 The risk in lupus
ease is active at time of conception or in the presence of
profundus/panniculitis is similar to localized DLE, whereas the
antiphospholipid antibodies.44 The impact of pregnancy on CLE
risk in lupus erythematosus tumidus is negligible.
specifically, whether as an independent disease or in association
There are no diagnostic criteria for SLE and classification
with SLE, is less clearly defined. One review of 31 patients with
criteria should not be used to diagnose SLE.
DLE reported a flare of disease (skin and joints being the most
When assessing a patient with CLE for the development of
common) in 21%.45 Another small study identified comparable
SLE, a number of factors can be considered.35 The most
obstetric outcomes in people with CLE and those in the general
important is a full clinical evaluation with a detailed history
population.46 Importantly, anti-Ro/SSA and/or anti-La/SSB pos-
and physical examination, searching for evidence of internal
itivity in pregnant females confers a risk of neonatal lupus and
organ involvement. Women with DLE, especially of African or
congenital heart block.17 Thus, additional vigilance is necessary
Asian ancestry, are more likely than men to develop SLE, espe-
to ensure the safety of both the mother and fetus. Owing to
cially if the skin lesions are below the head and neck. The
understandable caution from manufacturers and regulatory bod-
presence of nailfold lesions and periungual telangiectasias are
ies, the use of topical and systemic medications during preg-
associated with progression to SLE. The development of muco-
nancy is generally informed by data from retrospective case
cutaneous and inflammatory musculoskeletal symptoms, and
series and animal studies. The UK Teratology Information Ser-
systemic features such as malaise, fevers and new proteinuria
vice (UKTIS, www.uktis.org/index.html) and its Best Use of
strongly suggest systemic disease. Laboratory abnormalities
Medicines in Pregnancy (bumps, www.medicinesinpregnancy.
such as raised erythrocyte sedimentation rate, especially with a
org) are useful resources for healthcare professionals and
low C-reactive protein, cytopenias and the development of
patients on the safety of medications during pregnancy. Where
autoantibodies, including antinuclear, anti-dsDNA and extrac-
safety data are lacking, an individual decision should be made
table nuclear antibodies, especially Sm antibodies, which are
based on the risk vs. benefit of continuing medication vs. a
highly specific for SLE, and low complement levels, should
switch to an alternative treatment. Where medications are
prompt a referral to a rheumatologist or other specialist,
stopped owing to concerns about teratogenicity, UKTIS advise –
depending on the clinical presentation.
as a general rule – to wait five half-lives before trying to con-
ceive while taking any drug.
6.3. Drug-induced lupus A 2015 Cochrane review on the safety of topical corticos-
teroids in pregnancy identified no association between mater-
Drug-induced (DI) CLE should be distinguished from DI-SLE
nal use of topical corticosteroids of any potency and adverse
where cutaneous findings (as well as severe renal and haema-
pregnancy outcomes.47 There is a probable association
tological sequelae) are much less common than idiopathic
between low birth rates and potent-to-very potent topical cor-
SLE.36 Almost all reported cases of DI-CLE are DI-SCLE.
ticosteroids. High-dose systemic corticosteroid administration
Approximately one-quarter of SCLE cases have been attributed
in pregnancy is associated with an increased risk of diabetes,
to a drug trigger and the frequency of DI-SCLE has increased
hypertension, pre-eclampsia and premature rupture of
in recent years as a result of new therapeutics and increased
membranes.48 Where systemic corticosteroids are required for
awareness of DI-SCLE.37 There are a wide range of reported
severe/active CLE in pregnancy, control with the lowest possi-
triggers of DI-SCLE, including antihypertensives (including cal-
ble dose of prednisolone is recommended (i.e. < 10 mg
cium channel blockers, beta blockers and angiotensin-convert-
daily).
ing enzyme inhibitors), diuretics (including loop and
Based on studies of around 750 women taking HCQ in preg-
thiazide), terbinafine, proton pump inhibitors, statins, several
nancy, there is no evidence that HCQ causes birth defects.
chemotherapy agents, monoclonal antibodies and antihis-
Therefore, HCQ is considered a first-line systemic medication to
tamines.38 In patients with SCLE (particularly when it is wide-
treat active CLE or maintain remission in patients with a history
spread) a DI trigger should be considered,39,40 particularly
of severe CLE in pregnancy (including when cessation of other
when an implicated drug has recently been introduced.36 In
potentially teratogenic systemic agents is required). Regarding
most cases DI-SCLE is reversible on stopping the offending
other antimalarial medications, there is no evidence to suggest
drug, although resolution can take up to 3 months and con-
that CQ is harmful in pregnancy, based on limited data. As there
current therapies may be required during this time.41 Potential
is insufficient literature regarding the use of mepacrine in preg-
triggers of DI-SCLE include antifungals, calcium channel block-
nancy, avoidance during pregnancy is advised. Of the other sys-
ers, diuretics and antihistamines. DI-DLE is rare and usually
temic medications used to treat CLE, dapsone is considered safe
associated with anti-TNF inhibitors and fluorouracil.42
for use in active disease in pregnancy, although co-administra-
tion of folic acid at 5 mg daily is required.
7. Pregnancy
It has been estimated that approximately 25% of females may8. Children and young people
experience a flare of their SLE during pregnancy.43 Additionally,
When present in children, CCLE and SCLE appear to confer a
obstetric complications are more common in people with SLE
higher risk of SLE progression (estimated to be 25–40% for

British Journal of Dermatology (2021) 185, pp1112–1123

© 2021 British Association of Dermatologists
 BAD guidelines for the management of people with CLE 2021, D. O’Kane et al. 1121

○ Measurement of disease severity (e.g. CLASI, PGA and

CCLE).49 Both idiopathic and drug-induced SCLE are rare in
clinical photography)
children. Neonatal LE is considered a subtype of SCLE and is
observed in 1–2% of anti-Ro/SSA antibody positive mothers• Appropriate clinical assessment for SLE, and, if suspected,
due to transplacental transfer of antibodies. Neonatal LE is referral to a rheumatologist?
associated with a spectrum of systemic complications, includ-• Drug history (in patients with SCLE, in particular)?
ing congenital heart block. • Body weight, drug dose, additional retinopathy risk factors
Childhood SLE has a similar pathogenesis to adult-onset dis- and plan for ocular screening in those on HCQ or chloro-
ease but is associated with a more severe clinical phenotype quine?
50
(lupus nephritis in up to 80%) and higher rate of cumula-
The audit recommendation of 20 cases per department is to
tive damage. Atypical manifestations are also more common.
reduce variation in the results due to a single patient and to
Modifications may be required to the classification criteria
allow for benchmarking between different units. However,
used in adults [such as the 2019 ACR/European League
departments unable to achieve this recommendation may
Against Rheumatism (EULAR) criteria] to increase early sensi-
choose to audit all cases seen in the preceding 12 months. See
tivity and specificity in children.
Appendix O in Supporting Information.
The Single Hub and Access point for paediatric Rheumatol-
ogy in Europe (SHARE) initiative has published consensus
guidelines to help the diagnosis and management of SLE in10. Stakeholder involvement and peer review
children.51 The guidelines acknowledge the absence of evi-
The draft document was made available to the BAD member-
dence regarding treatment of SLE in children, and no specific
ship, the British Dermatological Nursing Group (BDNG), the
recommendations, other than photoprotection, are made in
Primary Care Dermatological Society (PCDS), the British Soci-
the guidelines regarding the management of CLE in children
ety for Rheumatology (BSR), the British Health for Profession-
and young people.
als in Rheumatology (BHPR), the British Society for
Based on consensus opinion and evidence extrapolated from
Immunology (BSI), the Royal College of Obstetricians and
adult disease, the SHARE guidelines recommend that all chil-
Gynaecologists (RCOG), the Royal College of Paediatrics and
dren with SLE should be treated with HCQ. Where systemic
Child Health (PCPCH), the Royal College of Ophthalmologists
corticosteroids are required along with HCQ and clinical activ-
(RCOphth), the Royal College of General Practitioners (PCGP),
ity restricts tapering of corticosteroids, the addition of other
the British Society for Medical Dermatology (BSMD), the Bri-
disease-modifying treatments should be considered.
tish Society of Paediatric Dermatology (BSPD), the Lupus UK
The increased risk of HCQ-induced retinopathy with a
Nursing Group, LUPUS UK, the British Isles Lupus Assessment
cumulative dose in adult patients is well established. In con-
Group (BILAG) and St Thomas’ Lupus Trust for comments,
trast, there are no reports of HCQ retinopathy in children and
which were actively considered by the GDG. Following further
evidence for monitoring paediatric patients for drug toxicity is
review, the finalized version was sent for peer review by the
lacking. Throughout this guideline, drug doses refer to adults
Clinical Standards Unit of the BAD (made up of the Therapy &
and adjustment of all recommended systemic drugs is required
Guidelines subcommittee) prior to submission for publication.
in children.
In view of the paucity of published literature on CLE in
children and young people, treatment should ideally involve11. Limitations of the guideline
assessment by a multidisciplinary team with experience of
This document has been prepared on behalf of the BAD and is
managing lupus in children. Treatment decisions should aim
based on the best data available when the document was pre-
to control disease and minimize systemic toxicity, which is
pared. It is recognized that under certain conditions it may be
particularly relevant with systemic corticosteroid prescription
necessary to deviate from the guidelines and that the results of
in children.
future studies may require some of the recommendations
herein to be changed. Failure to adhere to these guidelines
9. Recommended audit points should not necessarily be considered negligent, nor should
adherence to these recommendations constitute a defence
In the last 20 consecutive patients with CLE, is there clear doc-
against a claim of negligence. Limiting the review to English-
umentation of:
language references was a pragmatic decision, but the authors
• Disease subtype? recognize this may exclude some important information pub-
• Provision of a patient information leaflet (e.g. https://lished in other languages.
www.skinhealthinfo.org.uk/a-z-conditions-treatments/)?
• Disease site, extent and severity during the initial assess-12. Plans for guideline revision
ment and as part of evaluating treatment response, where
applicable? The proposed revision date for this set of recommendations is
scheduled for 2026; where necessary, important interim
○ Above/below neck
changes will be updated on the BAD website.
○ Limited/disseminated

© 2021 British Association of Dermatologists British Journal of Dermatology (2021) 185, pp1112–1123
1122 BAD guidelines for the management of people with CLE 2021, D. O’Kane et al.

Acknowledgements systemic lupus erythematosus: the SHARE initiative. Ann Rheum Dis
2017; 76:1788–96.
We are very grateful to Victoria Werth, Professor of Dermatology,
University of Pennsylvania, PA, USA, for her advice on CLASI
score, and to both the patient representatives – Ms Sandie UttonSupporting Information
and Miss Samantha Murphy – for their input in formulating theAdditional Supporting Information may be found in the online
clinical questions, ranking of the outcomes, reviewing the evi-version of this article at the publisher’s website:
dence and formulating the recommendations, as well as all those
who commented on the draft during the consultation period. Appendix A Review protocol.
Appendix B Forest plots.
Appendix C Clinical evidence summary.
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