EDITORIALS

Clinically Relevant Information

About Cutaneous Lupus Erythematosus

ARCHIVES THERE ARE 6 ARticles on the subject of cutaneous lupus erythematosus (CLE) that provide dermatologists
with new insights and offer us practical advice
about the manner in which we might care for
patients who present to our clinics and offices with cutaneous lesions of lupus erythematosus (LE). I reached
out to several of the authors for answers to some of the
questions that developed as I reviewed this group of articles systemically rather than individually. The answers that I received to some of my questions are within
this editorial. As part of the process of preparing this editorial, I have included some practical information about
how I evaluate and treat patients with CLE in my clinical practice and conclude with what I see are unanswered questions that remain for future study.

The topics and questions that I will address within this

editorial are as follows: Which types of CLE lesions are
most commonly seen? How often and which drugs are
involved in exacerbation of, or induction of, CLE? What
is the role of smoking in patients with CLE, and are smoking cessation programs effective as part of the treatment
of patients with CLE? What is the risk of developing SLE
for a patient with cutaneous lesions, and does our therapy
lower the chance of progression? What impact does the
presence of CLE have on a patients quality of life, and
does treatment have an effect on improving the health
of patients whose disease has had an impact on their lives?
And, last, is TLE a misnomer?

See also pages 244, 249,

255, 303, 340, and 343

Review articles and book chapters have suggested that DLE

is more common than SCLE. In my practice, I have felt that
they were equally distributed, but my practice has become a referral practice and the patients are likely selected because of recalcitrant cutaneous disease or systemic manifestations. In the studies by Durosaro et al4 and
Moghadam-Kia et al,5 patients with DLE represented the
vast majority of patients with CLE. Durosaro et al4 did not
include TLE among their patients, whereas MoghadamKia et al5 reported that 13 of their 77 patients with chronic
CLE had TLE. Even if one eliminates these 13 patients,
CCLE still remains 3-fold more prevalent than SCLE.

N THIS ISSUE OF THE

In 2000, Ackerman et al1(p336) wrote, Perhaps no subject

in dermatology, . . . , is as confusing to students as that of
lupus erythematosus. In the discussion offered after this
statement, the authors attempt to equate all cutaneous manifestations as variations on the same pathologic theme and
suggest the term lupus dermatitis/panniculitis as a unifying concept. They included tumidus lupus erythematosus (TLE) within this concept. This approach failed to recognizetheworkofGilliamandSontheimer,2 who,intheearly
1970s, proposed a classification system that divided cutaneous lesions that occur in patients with LE into 2 broad subsets: those characterized histopathologically by an interface
dermatitis and those not represented by said changes. Furthermore, the patients with an interface dermatitis can be
subdivided into those whose lesions result in scarring or atrophy (chronic cutaneous lupus erythematosus [CCLE]),
those patients with annular lesions or papulosquamous lesions that may resolve with dyspigmentation but without
atrophy or scarring (subacute cutaneous lupus erythematosus [SCLE]), and patients with lesions that are more transient, such as the malar rash (acute CLE). Dermatologists
in practice are primarily confronted with patients in the first
2 categories whose disease manifests as discoid LE (DLE)
lesions as part of CCLE or who have SCLE. It is not clear
howfrequentlyeachofthesubsetsoccur,buttraditionalviews
suggest that patients with CCLE whose disease manifests
as DLE are more frequent than those with SCLE, and there
is controversy about the frequency of progression from
primarily cutaneous disease to cutaneous disease as part of
systemic lupus erythematosus (SLE). In addition, although
there is a classification schema for SLE,3 the fact that a patient may fulfill 4 of these 11 criteria does not inform us about
the severity of the systemic disease.

WHICH TYPES OF CLE LESIONS

ARE MOST COMMONLY SEEN?

WHAT IS THE RISK OF DEVELOPING SLE

FOR A PATIENT WITH CUTANEOUS LESIONS,
AND DOES OUR THERAPY LOWER
THE CHANCE OF PROGRESSION?
Diagrams produced by Gilliam and Sontheimer,2 as they
proposed their classification system, suggested that patients with CCLE and SLE were at either end of a continuous spectrum that spanned from a benign cutaneous only disease to a severe systemic disease. It has been
suggested that patients with disease localized to their head
and neck (termed localized DLE) have little risk of developing SLE.6,7 The observations of the populationbased study suggest that, perhaps, this teaching is not true
because over a prolonged follow-up period, the disease
of 23% of the patients progressed to SLE, which included 13 with DLE, 4 with SCLE, and 2 with lupus panniculitis. Furthermore, of the patients with DLE whose
disease progressed to SLE, 9 had localized DLE and 4 had
widespread disease. It should be further noted that patients with SLE at the time of their initial examination
were excluded from this study, so the fact that the disease of the patients in this cohort progressed over a period of years is of clinical significance.

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Although none of the studies reported in this issue address the second part of the question posed, there is at
least 1 observation that suggests that the use of antimalarial therapy will possibly prevent the progression to SLE.
In a study of military recruits,8 it was demonstrated that
the development of SLE was preceded by a progressive
development of autoantibodies. As an extension of this
study, the same authors analyzed whether the time from
first symptom to development of SLE was altered by the
use of antimalarial therapy.9 One hundred thirty military recruits who eventually developed SLE were included in this analysis. There were 26 patients in whom
antimalarial drug therapy, primarily hydroxychloroquine, was started before classification of SLE, and they
were compared with those who did not have therapy prior
to classification. In addition, the authors9 compared these
patients with those treated with nonsteroidal antiinflammatory drugs (NSAIDs) and systemic corticosteroids. The use of corticosteroids or hydroxychloroquine was associated with a longer lag time from the first
symptom of SLE to the development of 4 criteria (only 1
patient was treated prior to any symptom). In addition,
the combination of hydroxychloroquine with corticosteroids was statistically associated with a longer lag time
than corticosteroids alone. There was no increase in the
lag time for NSAID therapy. Hydroxychloroquinetreated patients also had less frequent leukopenia, lymphopenia, and proteinuria. Although the symptom that
led to therapy in most patients was arthritis, there were
several patients in whom CLE (discoid rash) was the reason for therapy. Thus, it is possible that early use of antimalarial therapy might delay the development of SLE.
HOW DOES THE PRESENCE OF CLE HAVE
AN IMPACT ON A PATIENTS QUALITY OF LIFE,
AND DOES TREATMENT HAVE AN EFFECT
ON IMPROVING PATIENTS WHOSE DISEASE
HAS HAD AN IMPACT ON THEIR LIVES?
There are ample studies that document the impact of various skin diseases on the quality of life, but few have dealt
with the impact of CLE. The investigators5 at the University of Pennsylvania and University of Texas have clearly
shown that the presence of cutaneous disease is associated with an effect on patients quality of life and, further,
that the impact is greatest for patients with widespread DLE.5
In addition, their use of a validated scoring system will allow documentation of improvement in future studies of
therapies that might be developed for CLE. This was applied to the observation herein detailing the use of lenalidomide for the treatment of patients with recalcitrant LE10
and has also been used in several previous studies of newer
agents or new uses of existing agents.11,12
HOW OFTEN AND WHICH DRUGS ARE
INVOLVED IN EXACERBATION OF,
OR INDUCTION OF, CLE?
In 1985, Reed et al13 published the first case series of SCLE
that was linked to the administration of a drug. In their report, the onset of the cutaneous eruption occurred during
the administration of hydrochlorothiazide and resolved with

its discontinuation. In addition, one of their patients had

a second administration of hydrochlorothiazide that was
followed by a reappearance of the eruption, which then
cleared again with discontinuation of treatment with the
offending drug. Their patients were positive for anti-Ro/
SS-A antibodies, and in 1 of the 3 patients who was subsequently tested, the antibody had disappeared.
In 1986, my colleagues and I reported our experience with SCLE.14 Following the initial review of our article, we were asked to assess the potential occurrence
of drug-induced disease in our group of patients by one
of the reviewers. We did not find that any of our patients at that time had disease that was seemingly induced or worsened by a drug. In a follow-up report15 that
included 88 patients, we again failed to note any relationship between a drug and SCLE. However, in a subsequent study16 of SCLE, we found 3 patients with druginduced SCLE among 76 patients with SCLE. In my
practice, drugs as a cause of SCLE has seemingly increased in prevalence. There seem to be new drugs that
awaken or exacerbate SCLE, and, although most of the
drugs have been either associated with photosensitivity
or lichenoid eruptions, not all of the drugs that are associated with SCLE are photosensitizers. In this issue of
the Archives, yet another drug has been implicated in the
class of chemotherapy for malignant neoplasms.17 Previous reports have associated COL-318 and docetaxel19 as
causes of SCLE, and now we can add capecitabine as a
possible causative agent. In addition, our group has recently observed SCLE due to doxorubicin hydrochloride (personal observations).
Srivastava et al,20 in an article published in the Archives,
found that 15 of 70 patients with anti-Ro/SS-A positive CLE
had a potential drug induction. This frequency is striking
and suggests that in the population referred for tertiary medical care to Johns Hopkins Medical Institutions there might
be an overrepresentation of drug-induced disease compared with community-based practices. Among the patients reported in the study by Durosaro et al,4 there were
14 with drug-induced SCLE who were excluded from the
analysis compared with 23 patients with SCLE included
in the study. This might suggest that perhaps 25% to 30%
of patients with SCLE have disease induced by drugs. Therefore, as suggested in the editorial that I wrote21 to accompany the Srivastava et al20 study, it remains important to
assess all patients with new-onset SCLE for a drug that might
have triggered the disease.
WHAT IS THE ROLE OF SMOKING IN PATIENTS
WITH CLE, AND ARE SMOKING CESSATION
PROGRAMS EFFECTIVE AS PART OF THE
TREATMENT OF PATIENTS WITH CLE?
Previous observations have suggested that smoking interferes with the effectiveness of antimalarial therapy.22,23 What
has not been known is whether this observation relates to
interference with the mechanism of action of the antimalarial drugs or to the possibility that the disease is more severe in smokers. Two of the studies in this issue add additional data to these observations. Smoking was
significantly more prevalent among the patients considered refractory to treatment in the report of Moghadam-

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Kia et al.5 This observation suggests that the disease is more

severe because the refractory patients were not defined only
by being refractory to antimalarial therapy. In a large cohort from Finland, smoking seemed to be a triggering factor for CLE.24 Kreuter et al25 have confirmed previous observations regarding antimalarial therapy for patients with
TLE, specifically that antimalarial drugs are effective but
that they work less well in patients who smoke tobacco.
Whether smoking cessation programs will have an impact on CLE has not been well studied; however, in my practice it does seem that those patients who drastically decrease their level of smoking or who stop smoking often
have disease that becomes easier to treat. While we await
future studies to confirm this clinical observation, it seems
reasonable for dermatologists to encourage patients with
CLE to stop smoking and to involve primary care physicians in programs that lead to smoking cessation as well.
IS TLE A MISNOMER?
Tumid lupus erythematosus was first described in 1930.26
It was generally a neglected diagnosis until the publication by Kuhn et al27 in 2000. Subsequently, multiple articles have appeared regarding this entity. Most authorities classify TLE as a form of CCLE because it is either
chronic or recurrent, few patients have any serologic abnormalities, and few, if any, patients have systemic manifestations of LE. A new observation regarding TLE is published in this issue, namely, that patients with TLE might
demonstrate a Koebner phenomenon.28 However, the skin
lesions in these patients do not scar or cause atrophy, and
they are not characterized by an interface dermatitis. Therefore, although these patients have a photosensitive disease process that responds to antimalarial therapy (albeit
that smoking interferes with responsiveness), it does not
seem reasonable to me to classify this disorder anywhere
within the LE spectrum. It does not belong in the subsets
characterized by an interface dermatitis, and it does not belong among the cutaneous lesions observed in SLE. This
is an important point for patients because inclusion within
an LE classification has implications for insurability.

seldorf, Germany, the second in Kyoto, Japan) will include this issue as they plan their meeting.
The development of systemic disease in patients with
what seems to be a strictly cutaneous disease at diagnosis has been highlighted in this issue of the Archives. What
is needed is a clear statement of how to monitor patients
for this possibility. Is there predictive value of obtaining
immunofluorescence microscopic findings on patients at
diagnosis? Should we be performing repeated serologic
testing in our patients, or should we only follow patients with a careful clinical history along with complete blood cell counts and urinalyses?
We need more information about whether the early onset of therapy, specifically with an antimalarial drug, might
delay the onset of systemic disease. We also need to prove
that smoking cessation is an effective adjunct to traditional therapy. Last, because there is a seemingly growing
body of patients with recalcitrant disease, we need to develop new therapies, particularly ones that are effective, safe,
and economical because many of the therapies we now consider (eg, mycophenolate mofetil, efalizumab, thalidomide, and lenalidomide) have potential toxic effects and
cost in the range of $1500 to $3000 per month. Bottom line:
although the work presented herein is clinically relevant,
and practical information for the care of our patients is available, there remain a number of unanswered questions.
Jeffrey P. Callen, MD
Correspondence: Dr Callen, Division of Dermatology,
University of Louisville School of Medicine, 310 E Broadway, Louisville, KY 40202 (jefca@aol.com).
Financial Disclosure: Dr Callen has received honoraria
from Amgen, Abbott Immunology, Genentech, Centocor, Electrical Optical Sciences, Medicis, and Steifel. He
serves on a safety monitoring committee for Genmab.
Additional Contributions: Carol Kulp-Shorten, MD, provided critical comments.
Disclaimer: Dr Callen is associate editor of the Archives
of Dermatology, but he was not involved in any of the decisions regarding review of the manuscript or its acceptance.

CONCLUSIONS AND FUTURE QUESTIONS

The careful description and appropriate nomenclature for
cutaneous lesions of LE should be clarifying and not confusing, as suggested by Ackerman et al.1 However, those
of us who have a special interest in this nomenclature
have not been clear, as noted by the difference in the inclusion of TLE in 1 of the 2 large cohorts4,5 reported in
this issue. In addition, careful analysis, along with the
development of reliable measures of activity and damage, will give future studies the ability to prove effectiveness of therapies that we use currently or might use in
the future. Therefore, in my opinion, we need a consensus conference aimed at international agreement on nomenclature along with the use of a scoring system to assess activity and damage. Such a consensus conference
should include all stake holders, including those in rheumatology and, perhaps, hematology and nephrology. Perhaps the organizers of the next International Congress
for Cutaneous Lupus Erythematosus (the first was in Dus-

REFERENCES
1. Ackerman AB, Kerl H, Sanchez J, et al. Lupus erythematosus. In: Guo Y, Hofer
A, Kelly P, et al, eds. A Clinical Atlas of 101 Common Skin Diseases. New York,
NY: Ardor Scribendi; 2000:326-338.
2. Gilliam JN, Sontheimer RD. Distinctive cutaneous subsets in the spectrum of
lupus erythematosus. J Am Acad Dermatol. 1981;4(4):471-475.
3. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25(11):12711277.
4. Durosaro O, Davis MDP, Reed KB, Rohlinger AL. Incidence of cutaneous lupus
erythematosus, 1965-2005: a population-based study. Arch Dermatol. 2009;
145(3):249-253.
5. Moghadam-Kia S, Chilek K, Gaines E, et al. Cross-sectional analysis of a collaborative Web-based database for lupus erythematosusassociated skin
lesions: prospective enrollment of 114 patients. Arch Dermatol. 2009;145
(3):255-260.
6. Prystowsky SD, Herndon JH Jr, Gilliam JN. Chronic cutaneous lupus erythematosus (DLE): a clinical and laboratory investigation of 80 patients. Medicine
(Baltimore). 1976;55(2):183-191.
7. Callen JP. Chronic cutaneous lupus erythematosus: clinical, laboratory, therapeutic, and prognostic examination of 62 patients. Arch Dermatol. 1982;118
(6):412-416.
8. Arbuckle MR, McClain MT, Rubertone MV, et al. Development of autoantibodies

(REPRINTED) ARCH DERMATOL/ VOL 145 (NO. 3), MAR 2009

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WWW.ARCHDERMATOL.COM

2009 American Medical Association. All rights reserved.

Downloaded From: http://archderm.jamanetwork.com/ by a J H Quillen College User on 05/26/2015

9.

10.
11.
12.

13.

14.

15.

16.

17.

before the clinical onset of systemic lupus erythematosus. N Engl J Med. 2003;
349(16):1526-1533.
James JA, Kim-Howard XR, Bruner BF, et al. Hydroxychloroquine sulfate treatment is associated with later onset of systemic lupus erythematosus. Lupus. 2007;
16(6):401-409.
Shah A, Albrecht J, Bonilla-Martinez Z, et al. Lenalidomide for the treatment of
resistant discoid lupus erythematosus. Arch Dermatol. 2009;145(3):303-306.
Usmani N, Goodfield M. Efalizumab in the treatment of discoid lupus erythematosus.
Arch Dermatol. 2007;143(7):873-877.
Kreuter A, Tomi NS, Weiner SM, Huger M, Altmeyer P, Gambichler T. Mycophenolate sodium for subacute cutaneous lupus erythematosus resistant to standard therapy [published online April 4, 2007]. Br J Dermatol. 2007;156(6):
1321-1327.
Reed BR, Huff JC, Jones SK, Orton PW, Lee LA, Norris DA. Subacute cutaneous
lupus erythematosus associated with hydrochlorothiazide therapy. Ann Intern
Med. 1985;103(1):49-51.
Callen JP, Kulick KB, Stelzer G, Fowler JF. Subacute cutaneous lupus erythematosus: clinical, serologic, and immunogenetic studies of 49 patients seen in a
non-referral setting. J Am Acad Dermatol. 1986;15(6):1227-1237.
Callen JP, Klein J. Subacute cutaneous lupus erythematosus: clinical, serologic,
immunogenetic and therapeutic considerations. Arthritis Rheum. 1988;31(8):
1007-1013.
Black DR, Hornung CA, Schneider PD, Callen JP. Frequency and severity of systemic disease in patients with subacute cutaneous lupus erythematosus. Arch
Dermatol. 2002;138(9):1175-1178.
Fernandes NF, Rosenbach M, Elenitsas R, Kist JM. Subacute cutaneous lupus
erythematosus associated with capecitabine monotherapy. Arch Dermatol. 2009;
145(3):340-341.

18. Ghate JV, Turner M, Rudek M, et al. Drug-induced lupus associated with COL-3:
report of 3 cases. Arch Dermatol. 2001;137(4):471-474.
19. Chen M, Crowson A, Woofter M, Luca M, Magro C. Docetaxel (taxotere) induced subacute cutaneous lupus erythematosus: report of 4 cases. J Rheumatol.
2004;31(4):818-820.
20. Srivastava M, Rencic A, Diglio G, et al. Drug-induced Ro/SS-A positive cutaneous lupus erythematosus. Arch Dermatol. 2003;139(1):45-49.
21. Callen JP. How frequently are drugs associated with the development or exacerbation of subacute cutaneous lupus? Arch Dermatol. 2003;139(1):89-90.
22. Rahman P, Gladman DD, Urowitz MB. Smoking interferes with efficacy of antimalarial therapy in cutaneous lupus. J Rheumatol. 1998;25(9):1716-1719.
23. Jewell ML, McCauliffe DP. Patients with cutaneous lupus erythematosus who
smoke are less responsive to antimalarial treatment. J Am Acad Dermatol. 2000;
42(6):983-987.
24. Koskenmies S, Jrvinen TM, Onkamo P, et al. Clinical and laboratory characteristics of Finnish lupus erythematosus patients with cutaneous manifestations.
Lupus. 2008;17(4):337-347.
25. Kreuter A, Galfullina R, Tigges C, et al. Lupus erythematosus tumidus: response
to antimalarial treatment in 36 patients with emphasis on smoking. Arch Dermatol.
2009;145(3):244-248.
26. Gougerot H, Burnier R. Lupus erythemateux tumidus. Bull Soc Fr Dermatol
Syphiligr. 1930;37:1291-1292.
27. Kuhn A, Richter-Hintz D, Oslislo C, Ruzicka T, Megahed M, Lehmann P. Lupus
erythematosus tumidus: a neglected subset of cutaneous lupus erythematosus:
report of 40 cases. Arch Dermatol. 2000;136(8):1033-1041.
28. Perez G, Kowalczyk JP, Montie D, Nousari CH. Tumid lupus erythematosus at
the site of a scar. Arch Dermatol. 2009;145(3):343-344.

Hypothalamic-Pituitary-Adrenal Axis
Suppression in Systemic Glucocorticoid-Treated
Infantile Hemangiomas
Putting the Risk Into Context

EMANGIOMAS OF INFANCY (IH) ARE THE

most common benign tumor of childhood.1 When small and located in nonvital areas, IH may be safely observed;
however, approximately 10% to 20% become problematic and require intervention (Figure).2
The gold standard therapy is systemic glucocorticoids
(GCs). 3 Glucocorticoids have the following wellrecognized adverse effects in infants4: irritability, gastrointestinal tract upset, appetite change, decreased growth
while receiving treatment, fungal skin infection, hirsutism, cushingoid facies, hypertension, pneumocystis pneumonia, and hypothalamic-pituitary-adrenal (HPA) axis suppression, a potentially devastating adverse effect, which in
the appropriate clinical setting may lead to adrenal crisis.

See also page 262

There is a paucity of information about GC-induced
HPA axis suppression in the setting of problematic IH.
Any information gap, particularly one that pertains to a
medically significant risk of standard therapy, is regrettable; however, the situation becomes alarming when new,
untested, potentially harmful therapies are judged against
this imperfect standard. The risk to benefit ratio of any
novel treatment is predicated on that of the existing standard of care. It is precisely this dynamic that makes the
study by Lomenick et al5 so timely.

Ulceration

Visual compromise

Infection

Pyschosocial stigmatization

Bleeding

High-output heart failure

Pain

Hypothyroidism

Tissue distortion and/or

cosmetic deformity

Coagulopathy
Laryngospasm

Figure. Complications of infantile hemangiomas. *Typically in the setting of

large liver hemangiomas and/or multiple cutaneous hemangiomas.
Kasabach-Merritt phenomenon, typically in the setting of proliferative
vascular tumors of infancy other than infantile hemangiomas (eg, kaposiform
hemangioendothelioma). Typically in the setting of a subglottic
hemangioma often with cutaneous involvement in a beard distribution.

The recent serendipitous discovery of incidental IH improvement in infants treated with propranolol hydrochloride for cardiac concerns is very exciting.6 In their small cohort, Leaute-Labrze et al6 demonstrated that propranolol
not only appeared to stop hemangioma growth but to dramatically hasten involution. Propranolol is a relatively safe
agent that has a long track record. It is, however, typically
used in a very different patient population, who are often
observed in hospital during the initial dosing and followed
carefully. The idea that propranolol could be haphazardly
adopted as a first-line treatment for problematic IH on account of extraordinary but premature results gives pause and
redoubles the need for good safety data on the standard of
care and systemic GCs that propranolol might challenge.

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