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Cutaneous lupus erythematosus: Update of therapeutic

options
Part II
Annegret Kuhn, MD, Vincent Ruland, and Gisela Bonsmann, MD
Munster, Germany
In the rst part of the review, topical agents and rst-line systemic treatment options for cutaneous lupus
erythematosus were discussed whereas in the second part, recent information on efcacy, dosage, and side
effects for further systemic treatment options are described in detail. In contrast to other immunosuppressive
agents, such as azathioprine, cyclophosphamide, and cyclosporine, methotrexate has recently received more
attention in the treatment of the disease. Further second-line treatment includes retinoids, dapsone, and
mycophenolate mofetil. Because of severe side effects or high costs, other agents, such as thalidomide or high-
dose intravenous immunoglobulins, are reserved for severe recalcitrant CLE. Biologics, ie, rituximab, have been
used to treat systemic lupus erythematosus; however, in CLE, most biologics have only been applied in single
cases. In addition to successful treatment, induction of CLE subtypes by biologics has been reported. In
conclusion, many treatment options exist for CLE, but not many are supported by evidence from randomized
controlled trials. ( J Am Acad Dermatol 2011;65:e195-213.)
Key words: biologics; dapsone; lupus erythematosus; methotrexate; mycophenolate mofetil; retinoids;
second-line treatment; skin.
T
opical agents and rst-line systemic treat-
ment options for patients with cutaneous
lupus erythematosus (CLE) were discussed
in the rst part of this review. A structured overview
of further systemic treatment options is given in this
second part of the review, by summarizing recent
information on therapeutic strategies and substances
available for the treatment of the different disease
subtypes. However, no medication has been
approved particularly for the treatment of CLE,
although several agents are licensed for systemic
lupus erythematosus (SLE) and other immunologic
diseases. Moreover, only a few randomized, double-
blind, placebo-controlled multicenter trials are avail-
able and in most cases, off-label-use of systemic
agents is applied in CLE. In this review, we have
included a treatment algorithm for practicing derma-
tologists (Fig 1).
SECOND-LINE SYSTEMIC TREATMENT
Methotrexate
Methotrexate (MTX), a folic acid analog, inhibits
dihydrofolate reductase responsible for conversion of
From the Department of Dermatology, University of Mu nster.
Supported by a Heisenberg scholarship from the German
Research Foundation to Dr Kuhn (KU 1559/1-2).
Conflicts of interest: None declared.
Reprint requests: Annegret Kuhn, MD, Department of
Dermatology, University of Mu nster, Von-Esmarch-Strasse 58,
D-48149 Mu nster, Germany. E-mail: kuhnan@uni-muenster.de.
Published online August 30, 2010.
0190-9622/$36.00
2010 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2010.06.017
Abbreviations used:
ACLE: acute cutaneous lupus erythematosus
CHLE: chilblain lupus erythematosus
CLE: cutaneous lupus erythematosus
DILE: drug-induced lupus erythematosus
DLE: discoid lupus erythematosus
dsDNA: double-stranded DNA
EC-MPS: mycophenolate sodium
ECP: extracorporeal photopheresis
IL: interleukin
IV: intravenous
IVIG: intravenous immunoglobulins
LE: lupus erythematosus
LEP: lupus erythematosus panniculitis
LET: lupus erythematosus tumidus
MMF: mycophenolate mofetil
MTX: methotrexate
sc: subcutaneous
SCLE: subacute cutaneous lupus
erythematosus
SLE: systemic lupus erythematosus
TNF: tumor necrosis factor
TPMT: thiopurine methyltransferase
e195
dihydrofolate to tetrahydrofolate, which is necessary
for several key enzymes involved in the synthesis of
pyrimidine and purine nucleotides. The folic acid
pathway explains the antineoplastic effects of MTX,
whereas it has been supposed that the anti-
inammatory effects of MTX are mediated via the
inhibition of lymphocyte proliferation.
1
Recent stud-
ies have linked the anti-
inflammatory properties of
MTX to the effects on adeno-
sine, a purine nucleoside that
has potent anti-inflammatory
effects on different target cells
(inhibition of the oxidative
burst in neutrophils and mon-
ocytes; prevention of leuko-
cyte chemotaxis; inhibition of
monocyte and macrophage
secretion of multiple cyto-
kines, eg, tumor necrosis
factor [TNF]-alfa, interferon-
gamma, and interleukin [IL]-
12 and -6). Furthermore, MTX
selectively induces apoptosis
in activated, proliferating
CD4
1
T cells and has also
been shown to inhibit IL-1
activity.
MTX has been used for
the treatment of therapy-refractory subacute CLE
(SCLE)
2-5
and discoid lupus erythematosus (DLE).
5-8
In a retrospective study from 1998, 12 patients with
different subtypes of CLE (6 SCLE, 4 DLE, 1 lupus
erythematosus [LE] panniculitis [LEP], and1chilblainLE
[CHLE]) were analyzed. All patients received weekly
low-dose administration of 10 to 25 mg MTX orally or
intravenously (IV), and 10 patients improved.
5
In 6 of
these 10 patients, CLE disappeared completely, and 4
patients showedpartial remission; intwopatients, MTX
administration was ineffective. Of the 10, 5 patients
showed long-term remission of 5 to 24 months.
In a study of 43 patients with various subtypes of
recalcitrant CLE (16 SCLE, 12 DLE, 3 LE tumidus
[LET], 1 LEP, 4 CHLE, and 7 SLE with cutaneous
manifestations), low-dose MTX was administered
either orally or IV.
4
Nearly all patients (98%) showed
improvement of skin lesions; the best clinical im-
provement was seen in patients with SCLE and
localized DLE, whereas treatment of disseminated
DLE was less effective. Discontinuation of treatment
after significant side effects, such as extraordinary
increase in liver enzymes (n = 4), nausea (n = 2), and
panleukocytopenia (n = 1), was recorded in 7
patients; however, side effects resolved after cessa-
tion of MTX. In this study, IV application was
tolerated better than oral administration. In 15 of
these 43 patients with CLE, who had received MTX
IV, the administration was changed to subcutaneous
(sc) application in a follow-up study.
9
This sc
route of MTX was well tolerated, and it was appre-
ciated by the patients because of easier and
self-administered application, while maintaining a
similar efficacy.
In addition to the recom-
mended sc injection of 7.5 to
25mgMTXonceweekly, folic
acid supplementation is
given up to 5 days a week,
excluding the day of MTX
applicationandthedaythere-
after. This can alleviate gas-
trointestinal side effects;
however, many different
schemes of protective folic
acid supplementation exist.
For example, one-time ad-
ministration 24 hours after
MTX application is advised
by many rheumatologists.
10
MTX is further known for
its bone-marrow toxicity,
which calls for regular hemo-
grams, but also for nephro-
toxicity and hepatotoxicity.
Moreover, it is important to rule out tuberculosis and
hepatitis before MTX treatment. Long-term applica-
tionof MTXcanleadtoliver fibrosis, cirrhosis, or both.
Therefore, liver and kidney function tests should be
carried out before and during MTX treatment; how-
ever, the risk of liver disease in patients with LE seems
less than in patients with psoriasis. In patients with
psoriasis, it has beensuggestedthat serial destinations
of the aminoterminal propeptide of type III procolla-
gen may decrease the need for liver biopsies.
11
Signs
of mucositis appear rarely with low-dose MTX ther-
apy. MTX-induced interstitial pneumonitis (acute hy-
persensitivity reaction) is a potentially fatal but
reversible complication. Therefore, MTX treatment
is to be discontinued at signs of dry nonproductive
cough, dyspnea, fever, and peripheral eosinophilia,
and a chest x-ray should be arranged immediately.
The recommended therapeutic approach includes
administration of high-dose corticosteroid (CS) ther-
apy and respiratory support together with broad-
spectrum antibiotics until an infectious cause is ex-
cluded.
12
However, MTXpneumonitis is anextremely
rare side effect in dermatologic diseases. In conclu-
sion, we consider MTX a second-line treatment for
patients with CLE who are refractory to antimalarials,
especiallythosepatients withSCLEandlocalizedDLE,
CAPSULE SUMMARY
d
Second-line treatment of cutaneous
lupus erythematosus includes
methotrexate, retinoids, dapsone, and
mycophenolate mofetil.
d
Because of severe side effects or high
costs, other agents, such as thalidomide
or high-dose intravenous
immunoglobulins, are reserved for
patients with severe recalcitrant
cutaneous lupus erythematosus.
d
Biologics have been used to treat
systemic lupus erythematosus; however,
in cutaneous lupus erythematosus, most
biologics have only been applied in
single cases and induction of the disease
by biologics has also been reported.
J AM ACAD DERMATOL
DECEMBER 2011
e196 Kuhn, Ruland, and Bonsmann
or those who cannot tolerate antimalarials (Table I).
Moreover, a combination of MTX with antimalarials is
possible.
Retinoids
Retinoids comprise a family of compounds with
structures and mechanisms of action that resemble
those of vitamin A (retinol), an essential nutrient that
plays a role in cell growth and differentiation. The
aromatic retinoid etretinate (no longer available) and
its major metabolite acitretin are used for psoriasis
and keratinization disorders. Meanwhile, acitretin
has replaced etretinate because of its shorter serum
half-life. Isotretinoin is approved for the treatment of
acne. In addition, acitretin and isotretinoin are listed
as second-line substances for CLE in the American
Academy of Dermatology guidelines,
13
because
of their relatively innocuous side-effect profile
(Table I). Etretinate was first used in 1985 in an
open prospective trial by Ruzicka et al
14
in 19
patients with localized and disseminated DLE,
SCLE, and one patient with cutaneous manifestations
Fig 1. Algorithm of treatment for cutaneous lupus erythematosus (CLE).
1
Systemic treatment is
usually initiated with hydroxychloroquine (HCQ), if no response, chloroquine (CQ) can be
used.
2
If there is partial response with quinacrine, methotrexate (MTX) may be added; if there
is no response with antimalarials, these drugs are discontinued and MTX is started.
3
Retinoids
are primarily used in hypertrophic discoid lupus erythematosus (LE), refractory subacute CLE
(SCLE), and CLE/lichen planus overlap (discontinue MTX).
4
Thalidomide should only be
applied in severe refractory CLE as remission-inducing agent (discontinue MTX).
5
Dapsone is
recommended for urticarial vasculitis, LE panniculitis, SCLE, and oral ulcers (discontinue MTX).
6
Mycophenolate mofetil (MMF ) or mycophenolate sodium (EC-MPS ) are primarily indicated in
refractory SCLE (discontinue MTX).
7
Note that maintain only refers to a certain period of time
depending on agent, efficacy, and CLE subtype. After clearing of skin lesions, agents should be
reduced to minimum effective dose or discontinued; however, sunscreens should be used for
prevention of skin lesions. CI, Calcineurin inhibitors; CS, Corticosteroids.
J AM ACAD DERMATOL
VOLUME 65, NUMBER 6
Kuhn, Ruland, and Bonsmann e197
of SLE. The dose of etretinate was 50 mg per day
given in two separate oral doses. A complete or
almost complete clearing of CLE skin lesions was
seen in 11 patients within 2 to 6 weeks of treatment;
moderate response or treatment failure was ob-
served in 8 patients. The best treatment results with
etretinate were obtained in male patients with DLE.
In 1988, acitretin was administered to 20 patients
with CLE; 5 showed unsatisfactory results, whereas
the rest demonstrated complete clearing or marked
improvement of all lesions.
15
A further study con-
ducted by Ruzicka et al
16
in 1992 was a double-blind,
randomized, multicenter trial, comparing efficacy of
acitretin (50 mg per day) with hydroxychloroquine
(400 mg per day) in 28 and 30 patients with CLE,
respectively. Up to now, this is the only randomized
controlled trial in CLE using two systemic drugs.
Overall improvement occurred in 13 of the 28
patients (46%) treated with acitretin and 15 of the
30 patients (50%) treated with hydroxychloroquine.
In the following years, isotretinoin was applied in
approximately 50 patients, particularly with DLE and
SCLE, in open studies and case reports; favorable
responses were documented in up to 86.9% of the
patients.
17-21
Acitretin was especially useful in treat-
ing hyperkeratotic verrucous forms of DLE on hands,
feet, and legs.
22
In CLE, the recommended dose for acitretin and
isotretinoin is 0.2 to 1.0 mg/kg body weight per day.
Both retinoids are teratogenic; therefore, effective
contraception is essential during and after treatment
(isotretinoin: 1 month; acitretin: 2 years). Therefore,
isotretinoin is preferable in female patients of child-
bearing potential because of the shorter half-life.
Most common side effects of retinoids include
dryness of skin and mucous membranes (xeroph-
thalmia, xerostomia), less common are gastrointesti-
nal disturbances and skeletal toxicity, as well as
muscle pain and arthralgia.
23
Because of pre-existing
keratoconjunctivitis sicca, treatment with retinoids is
a relative contraindication in SCLE-associated
Sjogren syndrome. Retinoid therapy may cause hy-
perlipidemia and alter liver function tests, but severe
hepatotoxic reactions are rare. Reversible hair loss
can be recorded in up to 50% of patients, mainly
during treatment with acitretin. Psychiatric disorders
such as depression have been reported in patients
during and after isotretinoin therapy. Despite the
known side effects, retinoids are part of second-line
treatment for CLE refractory to antimalarials.
Dapsone
In addition to its known antibacterial activity,
dapsone, which inhibits the synthesis of dihydrofolic
acid through competition with para-aminobenzoate,
exhibits signicant anti-inammatory activity and
has been used in many neutrophilic dermatoses.
It protects cells from neutrophil-mediated auto-
oxidative tissue injury by converting myeloperoxi-
dase to an inactive compound, thus suppressing the
formation of toxic oxygen intermediates; it has been
shown to block neutrophil chemotaxis.
24
Dapsone
has been reported to be effective in SCLE, LEP,
urticarial vasculitis, oral ulcerations, and bullous
eruptions complicating SLE.
23,25
Seven patients
(4 with DLE, 3 with widespread rash of SLE) were
treated with dapsone, resulting in resolution of
urticarial vasculitis in SLE, discoid lesions, and oral
ulcerations in DLE. However, widespread eruptions
of SLE and disseminated DLE were unresponsive to
dapsone.
26
In 1982, 11 patients with DLE received dapsone
with moderate effect in 4 and appreciable improve-
ment in another 4 patients.
27
Lindskov and
Reymann
28
treated 33 patients with DLE and dap-
sone showing excellent results in 8 patients (24%),
some effect in 8 patients (24%), and no response in
17 patients (52%). Of the 6 patients who received a
combination of dapsone and hydroxychloroquine,
two responded well and no effect was seen in the
one patient with hypertrophic lesions. Six patients
terminated dapsone because of side effects, such as
dyspepsia (n = 3), exanthema (n = 2), fever (n = 2),
methemoglobinemia (n = 1), and vertigo (n = 1). The
authors suggested that dapsone might be an alterna-
tive or supplement to antimalarials in the treatment
of DLE, when the latter cause adverse reactions or fail
to be effective. Single case reports of successful
treatment of SCLE and LEP with dapsone have also
been described in the literature.
29-33
Ujiie et al
34
Table I. Second-line systemic treatment in
cutaneous lupus erythematosus
MTX
7.5-25 mg (0.2 mg/kg body weight)
once weekly per os, sc, IV, or IM (preferred sc)
Acitretin
0.2-1.0 mg/kg body weight per day
Isotretinoin
0.5-1.0 mg/kg body weight per day
Dapsone
50-150 (maximum 200) mg per day
MMF/EC-MPS
2 3 1000 mg MMF per day
2 3 720 mg EC-MPS per day
Agents for first-line treatment can be combined with agents for
second-line treatment.
EC-MPS, Mycophenolate sodium; IM, intramuscular; IV,
intravenous; MMF, mycophenolate mofetil; MTX, methotrexate;
os, orally; sc, subcutaneous.
J AM ACAD DERMATOL
DECEMBER 2011
e198 Kuhn, Ruland, and Bonsmann
reported a further case of LEP successfully treated
with dapsone and reviewed 10 previously published
Japanese cases with LEP. The initial dose of dapsone
was between 25 and 75 mg per day, and disease
remission was obtained in all patients between 1 and
8 weeks (mean 4.6 weeks).
Therapeutic dosages of dapsone range from 25 to
150 (maximum 200) mg per day; it is recommended
to start with a low dose and to increase the dose
gradually (Table I). A maintenance dose of 25 to 50
mg per day may be necessary, the lowest effective
dose should be applied to minimize possible side
effects.
35
Because hemolysis and methemoglobine-
mia are known dose-dependent side effects of
dapsone, glucose-6-phosphate dehydrogenase defi-
ciency must be excluded before therapy. During
the first month of dapsone treatment blood cell
counts need to be obtained weekly, and, if stable,
every 2 weeks for 2 months thereafter, along with
liver function tests. After the initial 3 months of
treatment with dapsone, blood cell counts and liver
function tests should be obtained every 3 months.
Methemoglobin levels should be monitored in case
of severe anemia and clinical symptoms of cyanosis
and dyspnea, especially in patients with cardiopul-
monary disease.
24,36
Oxygen radicals are thought to
be involved in dapsone-induced hemolytic anemia.
Antioxidants, such as vitamins C and E, or cimetidine
have been described to reduce methemoglobin
levels and are therefore protective against this ad-
verse event. A severe side effect is the dapsone
hypersensitivity syndrome, which usually occurs 1 to
6 weeks (on average 27 days) after the start of
therapy and shows an infectious mononucleosis-like
picture with fever, malaise, rash (ie, exfoliative
dermatitis), lymphadenopathy, jaundice with hepa-
tic dysfunction, atypical lymphocytosis, and eosino-
philia.
24
Another rare, severe, and unpredictable
idiosyncratic reaction is dapsone-mediated poten-
tially fatal agranulocytosis; the risk is highest within
the first 3 months of treatment.
37
If symptoms,
such as fever and stomatitis, occur, dapsone must
be discontinued and blood cell count checked
immediately.
Mycophenolate mofetil and mycophenolate
sodium
Another immunosuppressive drug not approved
for treatment of LE is mycophenolate mofetil (MMF),
a mycophenolic acid ester, which is reabsorbed
quickly and transformed to mycophenolic acid after
oral administration. Mycophenolic acid is a specific,
noncompetitive, reversible inhibitor of inosine
monophosphate dehydrogenase, a key enzyme of
the guanosine nucleotide synthesis specifically
within T and B lymphocytes. Beyond inhibition of
lymphocyte proliferation, MMF is able to directly
induce apoptosis of activated T lymphocytes; in
addition, antibody production by activated B cells
is also inhibited by MMF.
38
MMF has multiple effects
on other cell types of the immune system, such as
dendritic cells. In addition, MMF affects the expres-
sion and processing of various adhesion molecules
and appears to have a role in limiting oxidative stress
associated with immunologic driven inflammatory
reactions by suppressing the production of the
inducible nitric oxide synthase.
MMF should be administered in doses between
1 and 3 g per day (Table I). The best clinical results
are achieved with 2 to 3 g per day; however, it can
take 1 to 2 months for clinical effects to become
visible. Recently, MMF has shown good efficacy in
bullous autoimmune dermatoses in two prospective
multicenter, randomized, nonblinded clinical
trials.
39,40
In patients with SLE, lupus nephritis has
been successfully treated with MMF.
41,42
In single
case reports, MMF also proved successful in one
patient with CHLE,
43
two patients with refractory
palmoplantar DLE,
44
and 4 patients with SCLE.
45,46
Moreover, Hanjani and Nousari
47
reported the treat-
ment of MMF in 4 patients with various manifesta-
tions of CLE (LEP, DLE, lupus perniosis, SCLE, and
LET) and smoldering systemic involvement resistant
to conventional therapy. All patients achieved a
complete remission within 3 months of starting
MMF; it is noteworthy that 3 of the patients were
treated with 3 g per day. In contrast, the lack of a
response was reported in 5 of 7 patients with various
LE-specific and nonspecific skin diseases in the
context of SLE including acute CLE (ACLE), SCLE,
DLE, CHLE, vasculitis, and urticarial rash.
48
In general, MMF is well tolerated. Typical side
effects include gastrointestinal symptoms, such as
diarrhea, nausea, and vomiting, as well as infections
of the urinary system and viral infections, such as
herpes simplex and herpes zoster. Before therapy,
chronic infections should be ruled out, and liver and
kidney function tests as well as regular hemograms
are to be performed and continued during ther-
apy.
49,50
With the common dose of 2 g of MMF,
hematologic side effects are extremely rare and less
common than with azathioprine.
The enteric-coated form of MMF, mycophenolate
sodium (EC-MPS), is associated with fewer gastroin-
testinal side effects. EC-MPS was recently used in a
nonrandomized, open-pilot study to treat 10 patients
with active SCLE resistant to at least one standard
therapy (Table I).
51
The substance led to significant
improvement of the skin lesions, while no serious
side effects were recorded. However, randomized
J AM ACAD DERMATOL
VOLUME 65, NUMBER 6
Kuhn, Ruland, and Bonsmann e199
controlled trials with a larger number of patients are
needed to further evaluate efficacy and safety of
MMF or EC-MPS in CLE.
SYSTEMIC TREATMENT OPTIONS FOR
PATIENTS WITH REFRACTORY DISEASE
Thalidomide and lenalidomide
Thalidomide (alpha-N-phthalimido-glutarimide)
is thought to inhibit synthesis of TNF-alfa and to
modify the expression of TNF-alfainduced adhe-
sion molecules on endothelial cells and human leu-
kocytes. It has further been demonstrated in a murine
system that thalidomide inhibits ultraviolet (UV)
Beinduced keratinocyte apoptosis; moreover, these
observations were extended to patients with CLE and
SLE, suggesting that inhibition of UVBeinduced
inflammation may, in part, explain the therapeutic
benefits of this agent on photosensitive disease.
52,53
In addition, thalidomide may have several other
modes of action.
54
In 1953, thalidomide was synthe-
sized in Germany and was commonly used as a mild
sedative to treat insomnia, until it was phased out in
1961 because of its teratogenic effect. Hence, thalid-
omide should only be prescribed to women of
childbearing potential with severe and refractory
CLE, and with highly effective contraceptive mea-
sures.
55
Particularly in patients with DLE, successful
therapy with a high number of cases has been
reported as a result of the agents immunomodulatory
and anti-inflammatory characteristics.
The rst large series of thalidomide in DLE was a
study of 60 patients treated initially with 400 mg per
day subdivided in two equal doses.
56
After marked
clinical response, the dosage was reduced every
month until a maintenance dosage of 50 to 100 mg
per day was reached. This dosage was maintained
for 3 to 5 months or longer, resulting in a 90%
complete or marked response. Thirty of 41 patients
(71%) relapsed after stopping thalidomide; however,
most of the skin lesions were not as severe as they
were before thalidomide treatment. Sixteen of the
relapsing patients again responded well while un-
dergoing a second course of treatment with
thalidomide. Various side effects were reported; all
patients reported drowsiness, 31.6% constipation,
and 11.6% rash, which resulted in discontinuation in
one patient with DLE. Other side effects included
edema and xerostomia; however, most importantly,
peripheral polyneuropathy appeared in 25% of the
patients (Table II). This side effect, which may be
irreversible, makes close neurologic monitoring ab-
solutely mandatory; baseline nerve conduction stud-
ies should be performed before therapy and
periodically thereafter.
57
In addition to neurologic
symptoms, electromyogram abnormalities may oc-
cur during thalidomide treatment, as may signs of
muscle weakness and changes.
58
The characteristic
neurologic presentation is a sensory rather than a
motor axonal polyneuropathy that presents with
symmetric painful distal paresthesias or numbness.
Electrophysiologic alterations may persist and even
worsen after thalidomide discontinuation, suggest-
ing a prolonged neurotoxic effect.
59
Aside from strict
precautions for the use of this drug in women of
childbearing potential (appropriate contraception),
polyneuropathy is the major limiting toxicity of
thalidomide. The manufacturer has developed a
comprehensive program to control prescribing, dis-
pensing, and use of this drug, known as the System
for Thalidomide Education and Prescribing Safety
(S.T.E.P.S.).
60
Aside from thrombotic events, second-
ary amenorrhea is a well-recognized side effect in
patients with CLE treated with thalidomide, begin-
ning 4 to 5 months after onset of the drug and
resolving 2 to 3 months after withdrawal.
58,61
This
emphasizes the importance of performing preg-
nancy tests regularly.
Recently, Cuadrado et al
58
demonstrated in a
retrospective study of 48 patients with therapy-
refractory CLE (18 DLE, 4 SCLE, 2 LEP, 24 SLE with
skin involvement) an overall clinical response rate of
81%. However, there were no clear dose-dependent
effects of thalidomide, as determined by administer-
ing 3 different dosages (100, 50, and 50 mg/d on
alternate days). The relapse rate after discontinua-
tion of the drug was 67% in the 39 patients who
received remission. In patients with SLE, no changes
were noticed in other clinical features, such as
arthralgia, Raynaud phenomenon, renal function,
leukopenia, anti-double-stranded DNA (dsDNA) an-
tibody level, or thrombocytopenia. The high inci-
dence (27%) of polyneuropathy, even at low doses,
suggests that it may be most useful as a remission-
inducing agenteif applicable in combination with
antimalarialseto minimize the high incidence of
relapse observed after stopping thalidomide.
Recent studies of approximately 100 patients with
CLE (mostly DLE, but also SCLE and LEP) and SLE
Table II. Further systemic treatment options for
refractory cutaneous lupus erythematosus
Thalidomide High risk of
polyneuropathy
50-200 mg per day
IVIG High costs
1-2 g/kg body weight monthly
Clofazimine Only one recent study
100-200 mg per day
IVIG, Intravenous immunoglobulins.
J AM ACAD DERMATOL
DECEMBER 2011
e200 Kuhn, Ruland, and Bonsmann
with cutaneous manifestations treated with thalido-
mide confirmed the efficacy of this drug, but also the
high relapse rate, the known side effects, and most
importantly the high risk of potential irreversible
polyneuropathy.
59,62,63
Therefore, thalidomide
should only be used to treat severe refractory CLE,
and the lowest dose possible is advised; however,
even at low doses, there is a high incidence of
neurotoxicity.
58
Notwithstanding its great efficacy in
refractory DLE, thalidomide should only be applied
in appropriately selected patients after intensive
consideration of the risk-benefit ratio.
Lenalidomide is a structural derivative of thalido-
mide introduced in 2004; it was initially intended as a
treatment for multiple myeloma, but has also shown
efcacy in the class of hematologic disorders known
as myelodysplastic syndromes. Similar to thalido-
mide, lenalidomide has complex immunomodula-
tory, antiangiogenic, antiproliferative, and
proapoptotic effects.
64
Recently, two patients with
severe refractory disseminated DLEwere treatedwith
lenalidomide, 5 to 10 mg per day.
65
In one patient,
improvement of skin lesions was noted within
1 month at a dosage of 5 mg per day. This dosage
was maintained for 10 months before it was doubled
to 10 mg per day for another 12 months because of a
slight worsening of symptoms. The patients showed
a good clinical response and the dosage of 60 mg of
prednisolone per day was tapered and discontinued.
The second patient failed to show clinical improve-
ment on 5 mg per day of lenalidomide, which was
stopped after 6 months. Both patients had failed to
respond to several therapies including topical corti-
costeroids, antimalarials, dapsone, MTX, azathio-
prine, MMF, rituximab, IV immunoglobulins (IVIG),
and cyclosporine. The first patient was previously
treated successfully with thalidomide, which had
to be discontinued secondary to neuropathy.
Interestingly, in this patient thalidomide-induced
peripheral neuropathy symptoms resolved during
lenalidomide therapy. The second patient had
previously failed to respond to thalidomide.
The same strict precautions used for thalidomide
have to be applied for lenalidomide; the risk of
neurotoxicity seems to be lower for lenalido-
mide.
64,66
A prospective noncontrolled, open-
labeled pilot study is being conducted to evaluate
the safety and effectiveness of lenalidomide in
patients with CLE (clinicaltrials.gov).
IV immunoglobulins
The mechanism of action of IVIG is complex and
not fully understood, although numerous immuno-
modulatory mechanisms have been suggested.
Clinical efcacy has been shown in the treatment
of skin diseases, despite the lack of evidence from
randomized, double-blind, placebo-controlled
trials.
67
Therapy with IVIG has been reported to
show beneficial effects in a 2-day course (1 g/kg per
day) every 4 weeks in 5 patients with refractory
extensive long-lasting DLE with major face involve-
ment.
68
IVIG failed in two patients; in 3 others, all
active skin lesions disappeared between 3 weeks
and 3 months after institution of IVIG. Relapses
occurred 2 to 10 months after IVIG withdrawal and
skin lesions were controlled again with IVIG in one
patient with DLE. In another case report, one patient
with both antimalarial-resistant SCLE and ACLE was
treated with IVIG (2 g/kg per month) and showed
dramatic improvement within 3 months and almost
complete resolution after 6 months.
69
More recently,
3 patients with SCLE unresponsive to previous anti-
malarial and immunosuppressive therapy were trea-
ted with IVIG, which achieved good response of
their skin lesions.
70
Twelve patients with histologi-
cally confirmed CLE of various subtypes were given
IVIG with starting doses of 1 g/kg per day on 2
consecutive days, followed by 400 mg/kg per month
for 6 months or until disease resolution.
71
Five
patients had complete or near complete clearing of
their skin disease ([75% clearing), two had partial
improvement ([50% clearing), and 3 had limited
response (\50% clearing). Two patients received no
further treatment because of pregnancy and devel-
opment of acute cutaneous vasculitis, respectively.
In 2005, Kreuter et al
72
reported a female patient with
highly recalcitrant SCLE who responded very well to
treatment with IVIG(1 g/kg per day on 3 consecutive
days per month). Amelioration was observed after
the first cycle and an almost complete clearing of skin
lesions was achieved after 3 cycles of IVIG. At this
time, IVIG was reduced to 0.5 g/kg per month. In
1997, de Pita et al
73
described 5 female patients with
SLE and two with SCLE treated with IVIG at a dosage
of 300 mg/kg per day for 5 consecutive days each
month for a 12-month period. Although some clinical
symptoms, such as asthenia, arthromyalgia, and
fever, disappeared in the patients with SLE and
immunologic parameters improved (eg, decrease
of antinuclear antibodies, negativity of anti-dsDNA
antibodies, slight increase of C3, and reduction of
immunoglobulin sediments in the dermal papillae
analyzed by direct immunofluorescence), IVIG was
not able to improve the cutaneous manifestations.
Moreover, skin lesions in SCLE worsened. Recently, a
case of LEP successfully treated with IVIG was
reported after other therapy modalities failed.
74
The majority of adverse reactions with IVIG are
mild; of these, headache is most common. Rare
serious side effects include urticarial rash and
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Kuhn, Ruland, and Bonsmann e201
cutaneous vasculitis with vascular occlusion, protein-
uria, acute renal failure, deep venous thrombosis,
embolia, myocardial infarction, stroke, and anaphy-
lactic reactions in IgA-decient patients.
67
Overall,
although IVIGmay be a useful and promising therapy
for highly resistant and severe CLE, it is very expen-
sive, and additional controlled clinical trials are
needed to investigate its efficacy in this disease
(Table II).
Clofazimine
Clofazimine is a lipophilic rimino-phenazine
dye with antimicrobial, anti-inammatory, and
immunosuppressive activity, which is not only
taken up by macrophages but is also deposited in
the subcutaneous fat.
75
The resulting reddish-
brown discoloration of the skin and body secre-
tions is the most frequent but reversible side effect
and more marked with high dosages. Other side
effects include dry skin, occasional nausea and
diarrhea, and in rare cases, eosinophilic enteritis
and splenic infarction (only after high-dose and
long-term use of clofazimine).
In 1974, clofazimine was rst used in different
dosages for the treatment of 26 patients with long-
standing DLE (3 months-27 years, mean: 8.6 years) by
Mackey andBarnes.
76
The dose of 200 mg per day was
more effective than 100 mg per day, and 17 of the 26
patients with DLE, many of whom had failed to
respond to chloroquine and other treatments, went
into remission. In the following years, only a few case
reports were published describing the treatment of
CLE (mostly DLE) with clofazimine.
77-80
In 2005, a
randomized, double-blind, controlled trial compared
clofazimine (100 mg per day) with chloroquine (250
mg per day) in 33 patients with SLE and active skin
lesions (ACLE, SCLE, localized and disseminated
DLE).
81
At the end of the 6-month study, a complete
response was seen in 18.8% of patients treated with
clofazimine as compared with 41.2% of patients
treated with chloroquine, but the difference was not
significant. A good response was observed in 12 of 16
patients (75%) fromthe clofazimine groupandin14 of
17 patients (82.4%) from the chloroquine group.
These findings suggest that clofazimine is equally
effective as chloroquine in controlling cutaneous
lesions in patients with SLE; however, 5 patients
who were treated with clofazimine and one who
was treated with chloroquine were withdrawn from
the study because of development of a serious flare.
The authors could not exclude the possibility that
clofazimine itself could have been the cause of these
flares or that the difference in frequency of flares
between the groups might have been a result of the
known effect of chloroquine in reducing disease
activity. Clofazimine should therefore only be recom-
mended for patients who have exclusively cutaneous
manifestations of the disease (Table II).
FURTHER TREATMENT OPTIONS
Azathioprine
The mechanism of azathioprine, a prodrug of
6-mercaptopurine, is still not fully understood al-
though it was introduced approximately 50 years
ago. Azathioprine is a purine antimetabolite and
classically has been described as a cell-cycle specic
drug, an s-phase inhibitor. The active metabolites of
azathioprine disrupt the function of endogenous
purines; the generally accepted mechanism of its
cytotoxic and immunosuppressive activity is the
disruption of nucleic acids. Lymphocytes rely on de
novo synthesis of purines, and accordingly, azathi-
oprine is thought to be relatively specic for lym-
phocytes. It is more selective for T lymphocytes than
for B lymphocytes.
82
Before initiation of azathio-
prine therapy the activity of the enzyme thiopurine
methyltransferase (TPMT) should be determined, as
TPMT deficiency results in significant accumulation
of thioguanine nucleotides with increased hemato-
poietic toxicity. Interestingly, one of 300 individuals
are homozygous for very low TPMT activity. In a
recent report, one of 220 individuals had no detect-
able activity.
83
Therefore, testing for TPMT levels
would be helpful to achieve proper dosing.
The dosage of azathioprine should range between
1 and 2.5 mg/kg body weight per day, usually
around 100 to 150 mg, and clinical effects can be
expected 1 to 2 months after starting therapy. This
immunosuppressive drug has been used since the
early 1960s to treat SLE, eg, lupus nephritis. In 1991, 6
patients with different subtypes of refractory CLE (4
SCLE, 2 DLE) were treated with 100 to 150 mg of
azathioprine and 20 to 30 mg of prednisone per
day.
84
The 4 patients with SCLE exhibited partial or
complete clearing of skin lesions and the prednisone
dose could be decreased; but one of these patients
had to discontinue therapy secondary to pancreatitis.
One patient with erosive palmar DLE did not re-
spond to azathioprine and the other patient with DLE
had a short duration of therapy as a result of
development of drug-induced fever. In 1988,
Ashinoff et al
85
also reported successful treatment
of two patients with resistant DLE on the palms and
soles. Two further reports in the literature showed
successful treatment of generalized discoid lesions,
unresponsive to conventional therapies.
86,87
Moreover, skin lesions in a patient given the diag-
nosis of so-called Rowell syndrome (SCLE with
erythema multiforme-like eruption) were success-
fully treated with prednisolone and azathioprine.
88
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e202 Kuhn, Ruland, and Bonsmann
The main side effects of azathioprine include
bone-marrow toxicity, hepatotoxicity, and gastroin-
testinal symptoms; rarely, a hypersensitivity reaction
with fever, nausea, vomiting, diarrhea, rash, and
occasionally shock occurs.
89
Considering the side
effects of azathioprine and the drugs inconclusive
efficacy in the treatment of CLE, this immunosup-
pressive drug should be primarily reserved for
patients with SLE.
Cyclophosphamide
Cyclophosphamide is an inactive mechloreth-
amine derivate, which is metabolized by mitochon-
drial cytochrome P-450 enzymes in the liver to a
variety of active metabolites with both therapeutic
and toxic actions. Aside from the liver, other tissues
such as transitional epithelial cells in the bladder and
lymphocytes, may metabolize the drug, resulting in
local toxicity, immunosuppression, or both. Direct
effects of cyclophosphamide on DNAresulting in cell
death have been identied as being the major effect
of this drug. The onset of therapeutic efcacy is rapid
(within 2-4 days) in contrast to azathioprine.
90,91
Cyclophosphamide is used in lupus nephritis in
conjunction with IV prednisolone, particularly as
pulse IV therapy, which has signicantly less toxicity
than continuous oral application.
92
In a study from
2003, high-dose IV cyclophosphamide (50 mg/kg)
for 4 consecutive days without stem cell transplanta-
tion and without pulse prednisolone was used
in refractory SLE.
93
Among these patients, two were
successfully treated for severe skin lesions, one with
severe refractory cutaneous lupus and one with
pyoderma gangrenosum. In an explorative trial
with 9 patients, DLE and subacute LE were treated
with cyclophosphamide at a dosage of 50 to 200 mg
per day.
94
Clinical improvement was excellent in
5 patients, moderate in 3 patients, and negligible in
one patient; in two patients, in whom cyclophospha-
mide has been stopped, there was no recurrence
after 6 and 23 months, respectively.
Close monitoring of blood cell counts and
liver enzymes is mandatory during therapy with
cyclophosphamide. Because of its impact on repro-
duction (ovarian failure), the risk of hemorrhagic
cystitis/urothelial toxicity, and secondary malignan-
cies (bladder cancer, myeloproliferative disorders,
eg, leukemia, especially after a cumulative dose
[80 g),
95
cyclophosphamide can no longer be
recommended for treatment of CLE.
Cyclosporine
Cyclosporine is derived from a soil fungus,
Tolypocladium inflatum, and is a prodrug that
becomes active after forming complexes with an
intracytoplasmatic protein called cyclophilin. This
binding results in inhibition of T-cell function by
preventing the dephosphorylation of nuclear factors
and blocking this path to gene transcription.
96
Oral doses of 2.5 to 5 mg/kg body weight per day
are usually applied to achieve clinical effects and can
be tapered after 4 weeks to the minimal effective
maintenance dose. Application of cyclosporine in
SLE has been the subject of only a few reports, and
large multicenter controlled trials in this area are
lacking; however, a steroid-sparing effect is evi-
dent.
97
Although skin disease was not a primary
outcome measure of many studies in SLE, malar
rash and LE-nonspecific manifestations, such as
vasculitis, have been reported to improve with
cyclosporine.
98
Treatment of a patient with coexisting SCLE and
extensive generalized lichen planus with hydroxy-
chloroquine (200 mg per day) and cyclosporine
(2.5 mg/kg per day) led to signicant remission of
skin lesions.
99
In this patient, only marginal improve-
ment had been observed after treatment with 400 mg
of hydroxychloroquine per day for 10 weeks as
single therapy. In a young female patient with SLE
and recurrent lesions of LEP, which were therapy
refractory to various drugs such as dapsone, low-
dose corticosteroids, azathioprine, and cyclophos-
phamide, only 4 mg/kg of cyclosporine per day
maintained remission of LEP.
100
A 27-year-old female
patient with severe mutilating, progressive, therapy-
refractory DLE relapsed repeatedly after decrease of
prednisone to less than 40 mg per day.
101
However,
addition of 5.3 mg/kg of cyclosporine per day did
not improve the skin lesions despite reliable thera-
peutic trough blood concentrations. Cyclosporine at
4 to 5 mg/kg per day was also not effective in the
treatment of two patients with long-standing recal-
citrant DLE.
102
In two patients with psoriasis and in a
patient with liver transplantation for primary biliary
cirrhosis, the first manifestation of DLE developed
despite treatment with cyclosporine at a dose of 3
mg/kg per day.
103,104
Because of contradictory re-
ports, its poor efficacy, and the well-known side
effects, especially nephrotoxicity, hypertension, and
the risk of malignancy, cyclosporine should not be
regarded as treatment for CLE.
Antibiotics
Sulfasalazine is used for the treatment of inam-
matory bowel disease and different forms of arthritis;
however, the mode of action remains unclear. It is
suggested that the anti-inammatory activity of sul-
fasalazine may rely on inhibition of the transcription
factor nuclear factor-kB.
105
Aside from two single
case reports of DLE responsive to sulfasalazine,
106,107
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Kuhn, Ruland, and Bonsmann e203
one small open-label case series with 11 patients
with DLE exists. In this study, sulfasalazine at a dose
of 2 mg per day was administered and showed
complete response in 7 patients, partial response in
one patient, and 3 failures.
108
Efficacy in these
patients could be explained by drug metabolism
because all responders except one were rapid
acetylators whereas nonresponders were of the
slow acetylator phenotype. Although there were no
serious side effects in this case series, Callen
109
cited
a study (abstract only) of 6 patients treated with
sulfasalazine that showed beneficial effects in only
two patients; remarkably, 5 of these patients expe-
rienced a drug eruption. Moreover, drug-induced
lupus by sulfasalazine has been reported.
110
Cefuroxime axetil, a second-generation oral ceph-
alosporin, is rapidly hydrolyzed in vivo to the active
compound cefuroxime and has a wide spectrum of
antibacterial activity. The clinical effect of cefurox-
ime axetil was investigated in 3 patients with SCLE at
a daily dose of 500 mg.
111
In all patients, complete
clearance of skin lesions was achieved within 30 to
45 days without side effects; one patient relapsed
after follow-up of 7 months and obtained major
improvement again after a 30-day treatment with
cefuroxime axetil. It is hypothesized that the mech-
anism of action of cefuroxime axetil in CLE might be
based on its immunomodulatory activity. No further
studies exist evaluating the efficacy of these antibi-
otics in CLE.
Danazol
Hormonal factors have been strongly suggested to
inuence the clinical expression of LE; moreover,
some female patients report premenstrual exacerba-
tions of their disease. Danazol is a heterocyclic steroid
that has weak androgenic properties, and it is related
chemically to 17 alpha-ethinyltestosterone (ethister-
one). Two patients with DLE and premenstrual exac-
erbations of skinlesions resistant to antimalarials were
treatedsuccessfully withdanazol at anoral dose of 200
to 400 mg per day.
112,113
Afterward, the dose of
danazol was reduced and subsequently interrupted
in both patients with DLE. In one of these patients, a
47-year-old woman, the skin lesions flared again in
parallel with her recommencing menstruation 3
months after ceasing danazol. The skin lesions
responded again dramatically after reinstitution of
danazol.
113
Afurther case report describes the onset of
DLE 6 years after manifestation of hereditary angio-
neurotic edema; treatment with danazol showed
efficacy in hereditary angioneurotic edema and the
associated DLE skin lesions markedly improved.
114
Treatment with dehydroepiandrosterone, another
steroid hormone, has shown favorable effects in 7
randomized controlled trials involving 842 patients
with SLE; however, no reports of dehydroepiandros-
terone exist in the therapy of CLE.
115
In addition,
cyproterone acetate, which is a synthetic hydroxy-
progesterone derivative, has also been shown to
reduce the frequency of SLE flares as well as the
frequency and severity of oral and vulva
ulcerations.
116
Extracorporeal photopheresis
Extracorporeal photopheresis (ECP) is a
leukapheresis-based therapy that uses 8-methoxyp-
soralen and ultraviolet-A irradiation.
117
In advanced
cutaneous T-cell lymphoma, ECP is an established
and effective therapy and has shown promising
efficacy in a number of other severe and difficult-
to-treat conditions, such as systemic sclerosis, graft-
versus-host disease, and prevention and treatment of
rejection in solid organ transplantation. In a single
patient with disseminated DLE, who did not respond
to conventional therapy, monthly cycles of ECP
showed nearly complete regression of the discoid
lesions within a period of 3 to 14 months.
118
In
another case report, a female patient with refractory
SCLE first responded dramatically to ECP, but after 9
months of ECP, the cutaneous lesions relapsed and
treatment was discontinued.
119
Two female patients
with therapy-resistant CLE, one with SCLE and the
other with DLE, were treated with ECP; after 6 and 8
cycles of ECP, patients went into prolonged remis-
sion of 18 and 11 months, respectively.
120
In a recent
report, a patient with Sjogren syndrome and anti-
Ro/SSA and anti-La/SSB antibodies developed a
terbinafine-induced flare of widespread SCLE.
121
Despite topical steroids and 100 mg per day of
chloroquine, the rash progressed within 2 months
and ECP was started. Three days after each cycle of
ECP the patient noted improvement and complete
clearance occurred after 4 cycles without relapse.
Therapeutic plasmapheresis in combination with
dexamethasone and azathioprine has been success-
fully used in one case report for the prevention of
congenital complete heart block associated with
anti-Ro/SSA and anti-La/SSB antibodies.
122
EXPERIMENTAL THERAPIES WITHOUT
PROVEN EFFICACY AND/OR
UNFAVORABLE RISK-BENEFIT RATIO
Anti-CD4 antibody
The recombinant chimeric CD4 monoclonal anti-
body binds specically to a conformational epitope
in the extracellular V1/V2 domains of the CD4
receptor protein and blocks in vitro helper T-cell
functions. One report describes successful treatment
of 5 patients with severe cutaneous manifestations of
J AM ACAD DERMATOL
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e204 Kuhn, Ruland, and Bonsmann
DLE, SCLE, and SLE with monoclonal anti-CD4
antibodies. After receiving total doses of 275, 400,
or 475 mg in single administrations of 20 to 50 mg
during a period of 5 to 8 weeks, patients showed
lasting decreases in disease activity and healing of LE
skin lesions.
123
As an immediate response, all pa-
tients showed a nearly complete loss of cutaneous
inflammatory activity, and as a long-term effect anti-
CD4 antibody treatment restored the responsiveness
to conventional therapies. No further reports exist on
treatment with anti-CD4 antibodies, possibly be-
cause of the high costs of this therapy.
Interferon alfa
Interferon alfa has antiviral, antiproliferative, and
immunomodulating properties and is used for the
treatment of tumors, viral infections, and inamma-
tory conditions. In one study, 6 patients with DLE
and 4 patients with SCLE received recombinant
interferon alfa-2a.
124,125
Patients had been pretreated
with hydroxychloroquine, systemic or topical corti-
costeroids, or thalidomide, with or without clinical
improvement. In DLE, average treatment duration
was 5.6 weeks at a mean dose of 35 3 10
6
IU per
week. Improvement was experienced in 5 patients
with DLE, whereas 3 patients with SCLE obtained
similar improvement but required longer time until
remission (10 weeks) and a higher mean weekly
dose of 80 3 10
6
IU of recombinant interferon alfa-
2a. However, the response to interferon alfa-2a was
only temporary with a rapid relapse a few weeks
after withdrawal of therapy in all patients who were
improved or cleared. Exacerbation of skin lesions
was observed in one patient with SCLE, and one
patient with DLE was unchanged after 4 weeks of
treatment. In 1992, Tebbe et al
126
described a 43-
year-old female patient with SCLE resistant to several
standard therapies, who was treated with recombi-
nant interferon alfa-2a (3 3 9 3 10
6
IU weekly).
Prednisolone was initially continued at 25 mg per
day. After some weeks the prednisolone dose was
tapered down to 7.5 mg per day as a result of partial
remission. Ten months after starting therapy with
interferon alfa-2a the patient demonstrated more
than 90% improvement of the skin lesions and
maintained a clinically stable condition. However,
induction of an SLE-like syndrome in a patient
receiving interferon alfa treatment has been re-
ported.
127
Recently, 5 cases of cutaneous reactions
at the injection site of interferon beta-1b with histo-
logic findings mimicking CLE were reported.
128
Side
effects of interferon therapy include flu-like syn-
drome, headache, fever, depression, and hair loss.
Martinez et al
129,130
reported on intralesional
injection of interferon alfa in 3 patients with
refractory DLE on the face and scalp (two patients
with 6 310
6
IU interferon alfa-2b twice weekly, one
patient with 5 3 10
6
IU interferon alfaenot further
specifiedetwice weekly). An excellent improvement
was seen after repeated injections in all 3 patients
with DLE, and follow-up was reported in two of
these patients with no recurrence within 12 months
after withdrawal of interferon therapy.
Leunomide
The active metabolite of leunomide, A771726, is
an inhibitor of dihydroorotate dehydrogenase, a key
mitochondrial enzyme of the de novo pyrimidine
synthesis in immune cells, particularly in activated
T and B lymphocytes.
131
It has been suggested to be
effective in the management of SLE; in a double-
blind, placebo-controlled pilot study of 12 patients
with SLE and mild to moderate disease activity,
leflunomide was more effective than placebo and
was safe and well tolerated.
132
Furthermore, leflu-
nomide was efficacious and safe after 2 to 3 months
of therapy in an open-label pilot study of a cohort of
18 female patients with SLE.
133
However, in 3 pa-
tients taking leflunomide for rheumatoid arthritis
SCLE occurred, resolving several months after
discontinuation of the drug.
134-136
Goeb et al
137
reported induction of SCLE with leflunomide in
two other patients with rheumatoid arthritis. In one
patient, skin lesions completely cleared after 3 weeks
of discontinuation of leflunomide and anti-Ro/SSA
antibodies reverted to normal after 2 years, support-
ing more clearly the induction of SCLE by the drug.
Furthermore, SCLE did not reappear within a follow-
up period of 2 and 3 years in either patient. In a
female patient with ankylosing spondylitis, a drug
reaction to leflunomide was recently described,
consistent with an erythematous annular/bullous
variant of SCLE over the trunk in association with a
malar rash and erythema multiforme-like lesions
involving hands and feet as well as conjunctival,
oral, and genital mucous membranes.
138
Induction
of SCLE by leflunomide was reported in a female
patient with primary Sjogren syndrome; the skin
lesions showed resolution when leflunomide was
stopped and reappeared with reintroduction of the
drug.
139
This outcome might have been favored by
the genetic disease background (HLA-B8, -DR3 pre-
disposition) in Sjogren syndrome, which is identical
to that observed in patients with SCLE. A recent case
report describes two patients with pre-existing
SCLE.
140
The female patient with a history of rheu-
matoid arthritis and SCLE experienced rapid im-
provement of arthritis, but severe deterioration of
her cutaneous disease. In contrast, the second male
patient experienced a complete clinical remission of
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Kuhn, Ruland, and Bonsmann e205
arthralgia and SCLE lesions with leflunomide. In
conclusion, the data in the literature demonstrate
a higher risk of CLE induction by leflunomide
(8 patients) than warranted by the level of disease
improvement (one patient with SCLE). The most
prominent side effects of leflunomide include gas-
trointestinal symptoms, such as nausea, rash, tran-
sient elevation of transaminases, and leukopenia.
TNF-alfa antagonists
TNF-alfa is a mediator of inammation and is
involved in many cutaneous and systemic inamma-
tory diseases.
141
The development of biologics that
block the effects of TNF-alfa has increased therapeu-
tic possibilities for treatment of several autoimmune
diseases, such as rheumatoid arthritis and psoriasis.
However, final conclusions about the efficacy and
safety of TNF-alfa antagonists can only be made with
growing experience and after conduction of ran-
domized controlled multicenter trials. Although the
similarity of biologics compared with human pro-
teins results in good compatibility, severe infections
can appear when applying TNF-alfa antagonists.
Cytokines play a significant role in immune defense
and, therefore, application of these agents in patients
with apparent infections is contraindicated. Since the
introduction of TNF-alfa antagonists, an increase in
the incidence of tuberculosis has been observed.
142
Therefore, a chest x-ray and an intracutaneous
tuberculin skin test (also called PPD or Mendel-
Mantoux test) is required in every patient before
therapy with TNF-alfa antagonists. If the patient has a
positive PPD test result and has never been treated
for tuberculosis or shows signs of previous infection
of tuberculosis on chest x-ray, therapy with isoniazid
should be initiated at least 1 month before therapy
with TNF-alfa antagonists. In cases where BCG
vaccination is not documented, the same therapeutic
procedure is indicated.
143
Recent blood tests based
on antigen-specific T-cell response measuring pro-
duction of interferon-gamma, so called interferon-
gamma release assays (eg, enzyme linked immuno
spot technique [ELISPOT]), are a major advance in
screening for tuberculosis. These assays seem to be
more sensitive and specific than the tuberculin skin
test and are unaffected by BCG vaccination.
144,145
Furthermore, it is well-known that TNF-alfa
blockade leads to the formation of antinuclear anti-
bodies including anti-dsDNA antibodies, which are
usually of the IgM- and not of the pathogenic IgG-
isotype.
146,147
However, drug-induced LE (DILE) is
relatively rare. In a recent review, 33 cases of DILE
secondary to anti-TNF-alfa therapy have been sum-
marized and compared with classic DILE.
148
In
contrast to classic DILE induced by more traditional
agents such as hydralazine and procainamide, DILE
secondary to TNF-alfa antagonist therapy shows a
high incidence of skin lesions (72%), nephritis (9%),
antinuclear antibodies (100%), and hypocomple-
mentemia (59%). In most cases, the symptoms are
reversible after discontinuation of the drug.
149
Less
frequent cutaneous findings (malar rash, discoid
rash, or photosensitivity) (29%) and more frequent
arthritis (93%) were seen in 14 patients with Crohn
disease or rheumatoid arthritis, who developed a
lupuslike syndrome after treatment with infliximab
(n = 13) or adalimumab (n = 1).
150
In a MEDLINE
search of articles published between January 1990
and December 2006, 233 patients with autoimmune
diseases induced by TNF-targeted therapies were
analyzed (including 92 cases of LE induced by
infliximab in 40, etanercept in 37, and adalimumab
in 15 cases).
151
Iniximab. Iniximab is a chimeric monoclonal
antibody against TNF-alfa, which blocks and inacti-
vates soluble and possibly membrane-bound TNF-
alfa by creating stable antigen-antibody complexes.
To date, there are no reports on the treatment of CLE
with iniximab; however, TNF-alfa antagonists have
been successfully used in the treatment of 6 patients
with SLE and kidney involvement.
152
Disease activity
of arthritis and lupus nephritis decreased signifi-
cantly during therapy; anti-dsDNA antibodies and
anticardiolipin antibodies increased in 4 patients, but
the increase of these autoantibodies was transient
and not associated with a decrease in serum com-
plement levels, with vascular events, or with disease
flares.
153
However, induction of CLE subtypes (SCLE-
and DLE-like eruption, CHLE) and worsening of
SCLE through infliximab have been reported.
154-158
Moreover, in a patient with rheumatoid arthritis,
induction of LET by infliximab has recently been
described. LET completely resolved after discontinu-
ing therapy and, interestingly, did not relapse after
administering another TNF-alfa antagonist (etaner-
cept).
159
In another study, 4 of 5 patients with
infliximab-induced lupus-like syndrome tolerated
an alternative TNF-alfa inhibitor (3 patients, adali-
mumab; 1 patient, etanercept).
150
Etanercept. Etanercept is a fully human dimeric
fusion protein composed of a TNF-alfa type II
receptor and the Fc portion of IgG-1. In contrast to
the monoclonal antibodies iniximab and adalimu-
mab, the receptor blocker etanercept has a single
binding site for TNF-alfa. In 2002, Fautrel et al
160
described a complete resolution of SCLE in a patient
treated with etanercept for rheumatoid arthritis. After
6 months of therapy the rheumatoid arthritis re-
mained controlled and there were no signs of SCLE
lesions. In a recent report, a 42-year-old patient with
J AM ACAD DERMATOL
DECEMBER 2011
e206 Kuhn, Ruland, and Bonsmann
SCLE failed to respond to other therapeutic options
(MTX, hydroxychloroquine, prednisone) and was
treated with 25 mg of etanercept sc twice a week.
161
After 3 doses of etanercept, flaring of the cutaneous
lesions was noted and therapy was discontinued.
However, the patient reported that flaring had al-
ready occurred before etanercept treatment.
Etanercept was restarted without adverse events,
leading to clearing of SCLE after 3 months and to
discontinuation of other therapies.
There is also one case report about the induction
of SCLE by etanercept in a 54-year-old woman with
rheumatoid arthritis.
162
The patient was treated with
betamethasone cream and, at the time of the last
follow-up 5 months later, the skin lesions of SCLE
had resolved despite continuation of etanercept. In
this article, the authors documented reports of the
Dutch Inspectorate for Healthcare including 3 other
cases of etanercept-induced CLE (2 acute DLE,
1 SCLE), which resolved after discontinuation of the
TNF-alfa antagonist.
Adalimumab. Adalimumab is a fully human
monoclonal antibody composed of the constant
and variable regions of human IgG-1 targeted toward
TNF-alfa. So far, there are no reports on the treatment
of CLE with adalimumab in the literature. However,
10 days after starting adalimumab for rheumatoid
arthritis, a 51-year-old Caucasian woman developed
SCLE in a photosensitive distribution with positive
antinuclear antibodies in a homogeneous pattern.
163
Two weeks after stopping adalimumab the rash
resolved without treatment and antinuclear anti-
bodies became negative again. Seven days after a
second injection of adalimumab for rheumatoid
arthritis, a 40-year-old African American woman
presented with DLE lesions on the scalp and later
on the eyebrow and forehead.
164
After discontinua-
tion of adalimumab and topical therapy with high-
potency steroids the DLE lesions resolved after 4
weeks and did not reoccur despite the initiation of
treatment with etanercept. A further case of acute
lupus-like skin rash (edematous and annular skin
lesions, clinical picture not typical for ACLE) was
reported in a 49-year-old woman with rheumatoid
arthritis treated with adalimumab and lefluno-
mide.
165
After discontinuation of adalimumab and
treatment with 30 mg of prednisone per day, the
lesions faded over the following 3 weeks (with
continued leflunomide administration).
Three case reports of DILE caused by adalimumab
have been published; in two of these cases, the
development of SLE followed treatment conversion
of iniximab to adalimumab in patients with rheu-
matoid arthritis.
164,166
Therefore, caution may have
to be taken when anti-dsDNA antibodies are present
after infliximab therapy (even without clinical signs
of SLE) and before conversion to adalimumab. The
third 52-year-old female patient with rheumatoid
arthritis and previously negative antinuclear and
anti-dsDNA antibodies and normal serum creatinine
developed class III focal proliferative lupus nephritis
1 week after receiving her third monthly dose of
adalimumab.
167
In summary, because of the reported inductions
of SLE and different subtypes of CLE, therapy with
TNF-alfa antagonists cannot be recommended in the
treatment of CLE up to now.
Other biologics
Other biologics, such as rituximab and efalizu-
mab, have been used in SLE treatment. However, in
CLE most biologics have only been applied in single
cases.
Rituximab is a chimeric monoclonal antibody that
selectively depletes B cells for a median of 6 months
by targeting CD20, a surface molecule expressed
exclusively on B cells.
168
Rituximab has been used
successfully in adults and children for refractory SLE,
usually in conjunction with corticosteroids, other
immunosuppressive agents, antimalarials, or a com-
bination of these.
169
In a case report, two patients
with SLE and cutaneous lesions (urticarial vasculitis
and diffuse generalized rash with painful erythema
on feet and hands) were treated with 2 3 1000
mg/m
2
IV rituximab in combination with 100 mg IV
methylprednisolone at an interval of 2 weeks.
170
The
patients had previously been treated with various
combinations of therapeutic agents, such as antima-
larials, thalidomide, immunosuppressive drugs, and
high-dose IVIG, with no significant impact or serious
adverse events; however, skin lesions cleared com-
pletely and persistently in both patients with ritux-
imab treatment. Recently, a 44-year-old male patient
with therapy-resistant SLE, who presented with pso-
riasiform SCLE skin lesions and bullous lesions on
the palms, was successfully treated with rituximab
(two doses of IV rituximab, 1000 mg each, 1 week
apart).
171
The patient had already failed on hydroxy-
chloroquine in addition to 60 mg per day prednisone
and azathioprine, which was later substituted by
MMF. The skin lesions improved partially, but pred-
nisone could not be lowered under 40 mg per day.
After initiation of treatment with rituximab, predni-
sone could be discontinued 6 weeks after the second
infusion and follow-up after 6 months showed only
minimal residual lesions.
A recent case report described a 44-year-old
patient with refractory SCLE who was successfully
treated with IV rituximab (375 mg/m
2
) weekly for
4 weeks, remaining on oral hydroxychloroquine at
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VOLUME 65, NUMBER 6
Kuhn, Ruland, and Bonsmann e207
600 mg per day and clobetasol propionate 0.05%
with regression of skin lesions at 16 weeks. At 11
months of follow-up SCLE recurred and the same
rituximab regimen was repeated with maintenance
therapy every 8 weeks for 2 years, with ongoing
disease remission.
172
Efalizumab is a recombinant monoclonal anti-
body that binds to CD11a, a subunit of leukocyte
function antigen-1. The agent blocks the interaction
between leukocyte function antigen-1 and intercel-
lular adhesion molecule-1 (inhibiting the rm attach-
ment of lymphocytes to endothelial cells and
impeding the recruitment of lymphocytes to the
skin).
173
Efalizumab is administered sc once weekly.
It has been reported to be effective in a single case
report in a patient with extremely therapy-refractory
SCLE (including a high number of first- to third-line
treatments) at a dose of 1 to 1.25 mg/kg sc per
week.
174
The cutaneous lesions improved dramati-
cally within 6 weeks, while efalizumab was well
tolerated and side effects were not observed. In a
recent retrospective study, 13 patients with severe
recalcitrant DLE were treated with efalizumab
(1 mg/kg sc weekly; initialization dose 0.7 mg/kg)
and 12 of them showed good to excellent results.
175
All patients had severe DLE, which had failed to
respond to a wide range of systemic therapies. The
mean time of treatment response to efalizumab was
5.5 weeks (mean treatment duration 14.1 months). In
this case series, adverse events were noted in 9
patients, such as superficial erosions, generalized
rash, arthralgia, and gastrointestinal symptoms.
Furthermore, two patients experienced a mild flare
of DLE 2 months after starting treatment. There was a
decrease in the titer of antinuclear antibodies in some
patients with DLE; however, an increase of the
antinuclear antibody titer was seen in other
patients. Hamprecht et al
176
reported successful
treatment of recalcitrant malar rash in a patient
with a 10-year history of a biopsy-proven LET with
positive anti-Ro/SSA antibodies and marginally
raised anti-dsDNA antibodies. Six weeks after the
initiation of treatment with efalizumab (0.7 mg/kg
per week) in addition to 5 mg of prednisolone per
day, the patient developed systemic exacerbation of
the disease with high anti-dsDNA antibodies and
biopsy-proven lupus nephritis, despite substantial
improvement of the skin lesions. Obviously, this
patient had mild SLE before therapy with efalizumab.
Furthermore, a 65-year-old woman, who was
treated for oral and cutaneous lichen planus with
efalizumab, developed photodistributed SCLE 8
weeks after the initial injection.
177
Aside from anti-
nuclear antibodies (titer 1:160) with speckled pattern
and anti-Ro/SSA antibodies, anti-dsDNA antibodies
were positive without clinical symptoms of SLE;
however, the test for anti-dsDNA antibodies was not
specified (in case of positive anti-dsDNA antibodies
the antinuclear antibodies usually show a homoge-
nous pattern; possibly, the anti-dsDNA antibodies in
this patient were not of the pathogenic IgG-isotype).
In a recent case report, two cases of recalcitrant SCLE
were treated with efalizumab at a dose of 100 mg per
week sc.
178
In one patient, complete response was
seen after 16 weeks; however, in the second patient
the response was incomplete with initial dramatic
improvement but a flare after 2 months.
Efalizumab was approved for plaque psoriasis;
however, the European Medicines Agency recom-
mended withdrawal of its marketing authorization
and by June 8, 2009, efalizumab was no longer
available in the United States because of the in-
creased risk of progressive multifocal leukoenceph-
alopathy. It has been concluded that the benets of
efalizumab no longer outweigh its risks.
179
HISTORICAL MEDICATIONS
Phenytoin
Phenytoin(diphenylhydantoin) is a highlyeffective
and widely prescribed anticonvulsant agent used in
the treatment of grandmal andpsychomotor epilepsy.
Ina single opentrial fromMexico, phenytoinhas been
applied for the treatment of 93 patients with DLE (76
women and 17 men).
180
In 74 patients (79.5%), DLE
was localized, andin19 cases (20.5%) the lesions were
disseminated. The treatment consisted exclusively of
100 mg of phenytoin administered orally 3 times per
day the mean time of treatment was 4 to 5 months
(range 2-12 months). The response was excellent in
90%of patients withdisseminatedDLEandin87.5%of
patients with localized DLE. Improvement was visible
after 4 to 6 weeks of treatment; 8.3% of patients
discontinued phenytoin because of adverse events,
such as erythema multiforme, urticarial reactions,
muscle weakness, or paresthesia. Within a follow-up
period of 6 to 12 months, 32.9% of the patients
remained without relapse, 15.7% had a relapse, and
in the remaining patients, follow-up data were not
available beforepublication. The mechanismof action
with phenytoin in the treatment of DLE is unclear.
Phenytoin can induce a variety of generalized erup-
tions and systemic complications, such as erythema
multiforme/Stevens-Johnson syndrome; toxic epider-
mal necrolysis; generalized exfoliative dermatitis;
vasculitis; and a hypersensitivity syndrome with fever,
rash, lymphadenopathy, hepatitis with elevated liver
enzymes, eosinophilia, and other organ involve-
ment.
181
Similar toseveral other anticonvulsants phen-
ytoin is associated with a lowbut significant incidence
of DILE (SLE-like).
182
One case of phenytoin-induced
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DECEMBER 2011
e208 Kuhn, Ruland, and Bonsmann
SCLE has beendescribed ina 73-year-old woman with
detectable antibodies to Ro/SSA, La/SSB, and his-
tones.
183
Despite the promising data from a single
study, no further trials with phenytoin in CLE have
been published since 1995, which might be a result of
the growing evidence of severe side effects.
Gold
Auranon, an oral form of gold, was developed
for the treatment of rheumatoid arthritis and has also
been used in DLE at a dose of 3 mg per day.
184
If
there was little or no beneficial response after 3
months, the dose was elevated to a maximum of 9
mg per day. In 23 patients with severe long-standing
DLE unresponsive to conventional treatment, auran-
ofin showed improvement in 15 patients and reso-
lution of skin lesions in 4 patients; one patient
worsened and in 3 patients DLE was unchanged. In
another study, 8 patients with long-standing disfig-
uring refractory DLE were treated with auranofin (3
mg twice daily).
185
Three patients improved and in
one of these a complete resolution of skin lesions
occurred. However, the potential toxicity of gold
compounds limits their use. Side effects, such as
diarrhea, nausea, headache, pruritus, rash, and he-
matologic and renal abnormalities can appear so that
monitoring with regular complete blood cell counts
and urinalysis is mandatory. Treatment with gold is
historic and no longer used in DLE because of its
wide spectrum of side effects.
CONCLUSION
In conclusion, many treatment options exist for
CLE, but most are not supported by evidence from
randomized controlled trials. This is also the case for
antimalarials, although long-term experience shows
high efcacy of these agents, which are still consid-
ered rst-line therapy in the different subtypes of CLE.
However, new molecules, such as chemokines
(ie, CXCR3), will possibly provide new therapeutic
alternatives based on recent research activities in CLE.
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