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British Journal of Dermatology 2004; 151: 731736.

DOI: 10.1111/j.1365-2133.2004.06196.x

TOPICAL REVIEW

Update on the management of cutaneous lupus erythematosus


J.P.CALLEN
Division of Dermatology, University of Louisville School of Medicine, Louisville, KY 40292, U.S.A.

Accepted for publication 9 March 2004

Summary

This paper reviews the latest treatments for cutaneous lupus erythematosus. It focuses on evidencebased guidance for the management of cutaneous lupus erythematosus, with identification of the
strength of evidence available at this time. In addition, I have briefly reviewed the epidemiological
aspects, diagnosis and evaluation of patients with cutaneous lupus erythematosus. This review
reflects data available from the Cochrane Library, Medline, literature searches, and the experience
of the author managing patients with cutaneous lupus erythematosus for over 25 years.

Definition

ing are useful only as suggestive tests and must be


considered only in appropriate circumstances. Serological findings are neither diagnostic nor exclusionary.
Once a diagnosis of cutaneous LE has been established,
the patient should be evaluated thoroughly to assess
the presence of systemic disease associated with LE.
In the absence of severe systemic disease, which is often
the case, the focus of therapy may then be upon the
skin.

Cutaneous lupus erythematosus (LE) is an acquired


autoimmune disorder that may manifest a variety of
clinical presentations. Gilliam and Sontheimer were
among the first to classify lesions based upon the
presence or absence of the characteristic histopathology, the interface dermatitis.1 In this paper I will
concentrate on the clinical syndromes associated with
the interface dermatitis, including primarily chronic
cutaneous LE and SCLE.

Epidemiology
The prevalence of cutaneous lupus varies from 146 to
68 per 100 000 people.2 The rate may be increasing or
the recognition of LE may be increasing. Regardless, it
appears that more cases are diagnosed now than in the
past. Systemic LE is more common in women, and most
cutaneous subsets of LE also are more prevalent in
women, but the ratio is not as high. All races are
affected.

Diagnosis
The diagnosis of cutaneous LE is based upon the
presence of compatible clinical lesions which on biopsy
demonstrate a characteristic pathological picture.
Immunofluorescence microscopy and serological testCorrespondence: Professor Jeffrey P. Callen, MD, 310 East Broadway,
Suite 200, Louisville, KY 40202, U.S.A.
E-mail: jefca@aol.com
 2004 British Association of Dermatologists

Treatment
The therapy of cutaneous lesions of LE involves both an
empirical as well as a scientific approach.3 Unfortunately, there are few double-blind, placebo-controlled
trials of drugs used in the treatment of cutaneous LE.4
The author generally approaches patients with specific
cutaneous lesions of LE [e.g. subacute cutaneous LE
(SCLE), discoid LE (DLE) or lupus panniculitis] in a
similar manner (Table 1). The annotated table includes
levels of evidence for each of the therapies which will
not be repeated within the body of the article because
although there are several randomized, controlled
trials, they involve small numbers of patients.
The goals of management of the patient with DLE or
SCLE are to improve the patients appearance and to
prevent the development of deforming scars, atrophy or
dyspigmentation. In addition, the majority of patients
with chronic cutaneous LE (CCLE) or SCLE have disease
that primarily affects their skin and may be reassured
that their prognosis is relatively benign. A complete list
of the patients medications will assist in the exclusion
of drug-induced cutaneous LE.510 Also, patients who
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732

J.P.CALLEN

Table 1. Therapy for cutaneous lupus erythematosus and weight of


evidence
Standard therapy
Thorough evaluation
Is the patient on any drug that might exacerbate the disease?
(B, III)
Is the patient a smoker? (B, II-iii)
Reassurance and education
Sunscreens (A, I-i), sun-protective clothing and life-style alterations
Topical agents: corticosteroids (A, I-i), retinoids (C, III)
Intralesional corticosteroids (B, III)
Antimalarial agentsHydroxychloroquine, chloroquine,
quinacrine (A, II-ii)
When standard therapy fails
Is the patient utilizing the therapy appropriately?
Dapsone (C, III)
Auranofin (C, III)
Thalidomide (B, II-iii)
Retinoidsisotretinoin (B, III), acitretin (A, I)
Immunosuppressive cytotoxic agents (C, III)azathioprine,
methotrexate, mycophenolate mofetil, ciclosporin, other
Intravenous immune globulin
Cytokinesalfa interferon, chimeric CD4 monoclonal antibody
(C, III)
Systemic corticosteroids (C, III)
Strength of recommendations
A there is good evidence to support the use of the
procedure agent
B there is fair evidence to support the use of the
procedure agent
C there is poor evidence to support the use of the
procedure agent
D there is fair evidence to support the rejection of the use
of the procedure agent
E there is good evidence to support the rejection of the use
of the procedure agent
Quality of evidence
I evidence obtained from at least one properly designed,
randomized controlled trial
II-i evidence obtained from well-designed controlled trials without
randomization
II-ii evidence obtained from well-designed cohort of casecontrol
analytical studies, preferably from more than one centre or
research group
II-iii evidence obtained from multiple time series with or without
intervention. Dramatic results in uncontrolled experiments
(such as results of the introduction of penicillin treatment in
the 1940s) could be regarded as this type of evidence.
III opinions of respected authorities based on clinical experience,
descriptive studies or reports of expert committees.
IV evidence inadequate due to problems of methodology, e.g.
sample size, or length of comprehensiveness of follow-up or
conflicts in the evidence.

smoke may have more severe clinical disease than


nonsmokers.11
Cosmetic problems are often of major importance to
the patient with cutaneous LE. Dyspigmentation may
follow both DLE and SCLE and may be effectively
hidden by agents such as CovermarkTM (Epiderm,

Market Rasen, U.K.) or DermablendTM (Brodie and


Stone, London, U.K.). Scarred lesions may be excised if
they are inactive; however, the possibility of reactivation resulting from manipulation exists because the
Koebner phenomenon has been reported to occur in
some patients with LE.12,13
Photosensitivity is generally prevalent in patients
with cutaneous LE.14 Patients with SLE have a history
of photosensitivity in 5773%, whereas those with
SCLE report photosensitivity in 7090% and those
patients with DLE are estimated at 50%. The action
spectrum has been defined by photoprovocation testing
and includes ultraviolet (UV) A, UVB and occasionally
visible light. Phototesting does not reproduce lesions in
all or even a majority of patients and should be
reserved for investigations or in individual circumstances where it is necessary for workers compensation or other medicolegal circumstances.
Sunscreens are a cornerstone of therapy. They
should be applied daily to all exposed surfaces. The
ideal sunscreen would be broad in its spectrum and
water resistant. Unfortunately, no sunscreen is able to
block all UV radiation (UVR) that might exacerbate
cutaneous LE in any patient and therefore patients
should also be encouraged to alter their sun-related
behaviour and to use sun-protective measures including sun-protective clothing. In a recent study, Stege
et al.15 in a randomized, controlled trial, examined the
capacity of three sunscreens to prevent the development of skin lesions after provocative phototesting.
Although each of the three sunscreens tested prevented
lesions, the extent to which they did so varied greatly.
The sunscreen that was most effective contained
octocrylene as the UVB protectant, Mexoryl SX, Mexoryl XL and Parsol 1789 as UVA protectants and
titanium oxide. This sunscreens sun protection factor
(SPF) was 60. Their study was of only 11 patients (nine
men and two women) of whom eight had SCLE and
three had DLE. This preparation is not available in the
U.S.A. at the present time, but is available in many
other countries including France, Great Britain, and
Canada (AntheliosTM, LOreal, Clichy, France).
Topical corticosteroids are usually prescribed for
patients with cutaneous LE and were one of the
therapies tested in a randomized placebo-controlled
trial.4 An appropriate topical corticosteroid is selected
for the area of the body being treated as well as the type
of lesions that are present. Facial lesions should be
treated with low- to mid-potency agents. Lesions on the
trunk and arms may be treated with mid-potency
agents. Lesions on the palms or soles and hypertrophic

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UPDATE ON MANAGEMENT OF CUTANEOUS LE

lesions often require superpotent corticosteroids. The


prescribing physician should consider the total amount
of corticosteroid that the patient applies, as it is possible
to cause hypothalamicpituitaryadrenal axis suppression with use of even as little as 60 g per day of the
superpotent corticosteroids.
Several other topical agents might be of use in
individual patients with cutaneous LE. However, none
of these agents have been tested in any systematic
manner. Retinoids, specifically tretinoin, might be
effective and have primarily been used in patients with
DLE and hypertrophic LE. A topical retinoid tazarotene
(TazoracTM, Allergan Inc., Irvine, CA, U.S.A.) might
also be used.
Several recent reports have detailed the effectiveness
of topical tacrolimus for erythematous facial lesions.16,17 These reports are all open label use of
tacrolimus in small numbers of patients. Pimecrolimus
has also been reported to be useful in one patient.18
Finally, as it has been demonstrated that systemically
administered interferon alfa-2a is effective for cutaneous LE,19 one group has used topically applied imiquimod effectively in a patient.20 Intralesional injections of
corticosteroids are often effective in patients with
lesions that are refractory to topical corticosteroids;
however, these agents are useful only when combined
with other therapy that is aimed at control of the
disease.
When existing lesions are not controlled with topical
agents or intralesional corticosteroids, systemic therapy
is often indicated. The first line therapy is the use of an
antimalarial drug. Antimalarials seem to work less well
in patients who smoke.21,22 Hydroxychloroquine sulphate (PlaquenilTM, Sanofi-Synthelabo, Guildford, U.K.)
is associated with less ocular toxicity than chloroquine,
although it may be less potent. It is my initial choice,
but when patients do not respond after at least a
2-month trial, chloroquine phosphate (AvlachlorTM
AstraZenaca, Luton, U.K. or NivaquineTM, Aventis
Pharma, West Malling, U.K., or in the U.SA., AralenTM,
Sanofi-Synthelabo, New York, U.S.A.) may be used.
The dosage for these agents should be 65 mg kg)1
lean body weight day)1 or less for hydroxychloroquine
and 4 mg kg)1 day)1 for chloroquine. Both of these
agents may be associated with ophthalmological toxicity, and monitoring guidelines vary from country to
country; however, in the U.K. there are published
guidelines.23 Another antimalarial that is available is
quinacrine HCl (also known as mepacrine outside the
U.S.A.). This agent has been used alone in some cases,
but is more useful when combined with either

733

hydroxychloroquine or chloroquine.24 It is not associated with ocular toxicity, but has other toxicity
associated with antimalarial use.
In difficult cases, many other approaches have been
advocated for the treatment of cutaneous LE. In the
authors experience, low-dose systemic corticosteroids
(< 1 mg prednisone per day or its equivalent) are
rarely effective for DLE, and only partially effective for
SCLE lesions. Corticosteroids are effective for the acute
lesions of photosensitivity, the malar rash, or for the
vasculitic lesions that may complicate LE. The chronic
use of oral or intramuscular corticosteroids for patients
with cutaneous disease should be avoided.
Dapsone, given in doses of 25200 mg daily, has
been useful for patients with the vasculitic lesions that
may accompany LE, SCLE lesions, bullous LE and oral
ulceration.25 In open-label clinical trials, dapsone has
resulted in improvement in some patients with DLE or
SCLE; however, the level of benefit has been judged as
excellent in only about 25% of patients. In contradistinction, clofazimine failed to demonstrate efficacy in all
but one report.26 There are several special circumstances in which dapsone may be useful. The first is
bullous LE. In addition, those patients with urticarial
vasculitis in combination with SCLE lesions may benefit
from the use of dapsone. The author has only once
observed benefit from dapsone therapy, and therefore it
is only the first line of therapy for a minority of patients.
A variety of other antibiotics have been used for the
treatment of cutaneous LE. Recently, Rudnicka et al.27
reported that the antibiotic cefuroxime axetil resulted
in the clearing of skin lesions in three patients with
SCLE at a dose of 500 mg daily. Cefuroxime axetil is a
second-generation b-lactamase oral cephalosporin.
Others must replicate this observation before it can be
recommended for widespread use; however, it is a
relatively benign form of treatment. Another group has
reported the successful use of sulfasalazine in eight of
11 patients.28 Sulfasalazine is used for inflammatory
bowel disease and various forms of arthritis. These
authors administered 2 g daily, but noted that the
minimal effective daily dose was 15 g. The eight
patients who responded were all rapid acetylators,
while the three who failed to respond were all slow
acetylators. No serious toxicity was noted in this small
open-label case series. In contrast, Lagrange et al. noted
a drug eruption in five of six patients whom they
treated with sulfasalazine and in only two patients did
they feel that there was a beneficial effect.29
Auranofin (RidauraTM, Yamanouchi, West Byfleet,
U.K.), an oral form of gold, has been used in cutaneous

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734

J.P.CALLEN

LE.30 Complete remission occurred in a minority of


patients, about 15%, while a partial response was
noted in about two-thirds of those treated. The authors
personal experience has been encouraging in a small
number of patients. Responsiveness may be best in
patients with nonscarring forms of cutaneous LE.
Auranofin is given orally beginning with one 3-mg
dose daily and, if tolerated, increased to 3 mg twice
daily within 12 weeks. It is generally well tolerated.
Oral gold is less likely than parenteral therapy to result
in toxicity, but monitoring with blood counts for
haematological toxicity and urinalyses for proteinuria
is necessary. One patient within my practice developed
a lichenoid drug eruption that resolved when auranofin
was discontinued.
Thalidomide has recently become more available
and is being used for patients with cutaneous LE with
some regularity.3135 Its mechanism of action is
believed to involve a decrease in inflammatory mediators, particularly tumour necrosis factor (TNF)-a and
Fas-ligand. Open-label trials suggest that it is highly
effective, and may result in an increase in the
lymphocyte count and a decrease in the C-reactive
protein level. Induction with 100300 mg daily at
bedtime results in improvement in 90% of the patients
who are able to tolerate the drug. Toxicity commonly
associated with thalidomide use includes drowsiness,
headache, weight gain, amenorrhoea and dizziness.
Drowsiness and dizziness may persist during the
following day. Neuropathy, usually sensory, may limit
the ability of patients to continue thalidomide on a
long-term basis. Neuropathy may be reversible, but
there are patients whose neuropathy has progressed
despite stopping the drug. Whether nerve conduction
studies should be performed at the onset of therapy
and periodically is not known. A recent prospective
study of patients treated with thalidomide for a variety
of conditions suggested that the only safe dose was
equal to or less than 25 mg per day.36 Thalidomide is
a potent teratogen and accordingly the manufacturers
have developed a programme to prevent the chance of
pregnancy in patients exposed to the drug. Unfortunately the response to thalidomide is not durable in
most patients, therefore long-term, low-dose maintenance therapy may be necessary. In the future an
analogue of thalidomide that separates its effects from
its toxicity may become available, but currently there
are no studies of any such agents that have been
reported or even presented in abstract form.
Rodriguez-Castellanos and coworkers37 treated 93
patients with cutaneous LE with oral phenytoin (up to

300 mg per day) and observed excellent results in 90%.


Relapse occurred in at least one-third of the patients in
whom follow-up data were available, but prolonged
remission of 612 months was noted in 33 patients.
Toxicity was minimal in prevalence and severity. These
observations have not been replicated.
Oral retinoids are effective in many patients who
have failed to respond to previous less toxic therapies.
Isotretinoin (RoaccutaneTM, Roche, Welwyn Garden
City, U.K.) and acitretin (NeotigasonTM, Roche) have
both been used in doses similar to those used for acne
vulgaris or psoriasis, respectively.38,39 The response is
not durable and after short courses the patient will still
need further suppressive therapy. These agents are
particularly helpful in patients with hypertrophic
lesions, or those with lesions on the palms and or
soles.
Several cytotoxic agents have been reported to be
beneficial for the control of cutaneous LE lesions.
Azathioprine,40 methotrexate41,42 and mycophenolate
mofetil43,44 have been reported to benefit patients with
recalcitrant disease. The author has treated six patients
with refractory cutaneous disease with azathioprine
2 mg kg)1 day)1 and five of these improved within a
period of 48 weeks. Relapse occurred following discontinuation of the therapy and control occurred with
reinstitution. Little acute toxicity was noted, but longterm use in one of the patients was associated with
multiple warts and squamous cell carcinomas. Continued therapy is required to maintain the remission.
Methotrexate has been reported to be successful in
roughly 19 patients.41,42 Doses and monitoring should
be similar to that utilized for psoriasis with the
exception that liver biopsy may only be required in
selected patients, i.e. those who are obese, diabetic,
drink excessive amounts of alcohol and or have
abnormal tests of liver function. Mycophenolate mofetil
has been reported to be useful in eight patients with
cutaneous LE (three with SCLE, three with DLE and one
each with lupus tumidus and lupus panniculitis).4345
Mycophenolate mofetil is administered orally in a dose
of 23 g daily. It is generally well tolerated, but
gastrointestinal side-effects may limit its use in some
patients. Other cytotoxic or immunosuppressive agents
that have been reported to be successful within
individual reports include cytarabine, cyclophosphamide and ciclosporin.
High-dose intravenous immune globulin has been
effective in small series.46 Goodfield et al.47 treated 12
patients in an open-label study using 1 gm kg)1 day)1
on two consecutive days followed by 400 mg kg)1 on a

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UPDATE ON MANAGEMENT OF CUTANEOUS LE

monthly basis. They noted complete or near clearing of


disease in five patients, partial response in two while
three had a limited response. The remaining two
patients did not complete 6 months of therapy because
of pregnancy in one and the development of vasculitis in
the second.
The use of cytokine therapy has been reported. As
thalidomide may be effective through its effects on
TNF-a, it might be possible that infliximab or etanercept might also prove to be of benefit to patients with
cutaneous LE. However, at least one patient developed
SCLE while on etanercept,9 and several others on
etanercept have developed what appears to be druginduced SLE.48 Interferon alfa has been used successfully;19,49 however, all patients on this regimen develop
toxicity and long-term remission is rarely achieved. In
contrast, Prinz and colleagues have used chimeric CD4
monoclonal antibody infusions in five patients with
severe, refractory cutaneous LE.50 Long-lasting
improvement was noted, with a restoration of responsiveness to conventional treatments. If other cytokines
can be administered and result in the restoration of
response with less toxic therapy, then perhaps we will
be able to induce remission with one agent and
maintain it with another.

Recommendations
Cutaneous LE is a chronic or recurrent disease that may
occur at any age. It is more common in women, but men
are also affected. It may be induced or exacerbated by
drugs and therefore a careful history and intervention
such as discontinuation or substitution of a drug may
induce a remission. Tobacco smoking seems to worsen
the disease or render antimalarial therapy less effective
and when possible this behaviour should be stopped. DLE
and SCLE are exacerbated by sunlight and appropriate
sun-protective measures should be used on a daily basis.
Topical corticosteroids, intralesional corticosteroids and
oral antimalarial therapies are the standard therapies
and are effective in a majority of patients. Alternative
topical therapies while available are not proven. Various
systemic therapies beyond antimalarial agents are based
on anecdotal reports or small case series. The approach
to therapy should follow a course as outlined: (i) remove
any exacerbating factors; (ii) photoprotection; (iii) topical corticosteroids or other immunomodulating agents;
(iv) oral antimalarialhydroxychloroquine with or
without quinacrine or chloroquine with or without
quinacrine; (v) consider thalidomide, with careful monitoring to prevent pregnancy and monitoring for neur-

735

opathy in those patients who fail to respond to the above


therapy; and (vi) consider immunomodulatory agents in
those who still have not responded.

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