December 2011 Vol. 18 No.

12
From the publishers of
The New England Journal of Medicine

D ERMATOLOGY
Effects of Skin Disease on Numerous observations and limited
Quality of Life studies have suggested that psoriasis in-
Three recent studies examine the effects creases stress and depression. Kurd and col-
of skin disease on emotional health and leagues mined the British General Practice
vice versa. Research Database to assess the association
Skin diseases such as acne, psoriasis, and of psoriasis with depression, anxiety, and
eczema are associated with a significant suicidality in a large population. Compared
impairment in the quality of the patient’s with 766,950 patients without psoriasis,
daily life. Several instruments assess 149,998 psoriasis patients had significantly
quality-of-life (QoL) in adults and more clinically diagnosed psychiatric dis-
children with skin disease and help us orders. Additionally, among the psoriasis
understand its impact. Three groups of patients, those with most severe cutaneous
investigators have recently examined the disease were more likely to have depression,
psychosocial effects of skin disorders. anxiety, and suicidality diagnoses.
Smidt and colleagues developed and Evers and colleagues analyzed the ef-
tested a new instrument specifically de- fects of psychological stressors on skin dis-
signed to assess these issues in adoles- ease in patients with psoriasis. This report
cents, who are particularly vulnerable follows their earlier finding of clinical exac-
to issues of self-esteem. Skindex-Teen erbation of psoriasis in the month following
addresses such age-specific matters as stressful life events. The new longitudinal,
sports participation, peer relationships, prospective study assessed how stressors
and clothing choices. In the 200 patients affect serum levels of cortisol, a key compo-
studied, acne was the most common skin nent of the hypothalamic-pituitary-adrenal
condition. The reliability of the 21-item (HPA) axis, in psoriasis patients. They
scale was greater than 0.4, and test-retest found that peak levels of daily stressors were
reliability was supported by acceptable significantly associated with lower cortisol
intraclass correlation coefficients for the levels and that patients with persistent high
total score, physical symptoms scale score, stress had lower mean cortisol levels than
and psychosocial functioning scale score. patients with lower stress. The stress re-
sponse involves activation of both the HPA
CONTENTS
Effects of Skin Disease on Quality of Life ............... 89 Immune Responses in Polymorphic Light Eruption:
A Double-Edged Sword .......................................... 93
MelaFindings ................................................................ 90
Pneumocystis Prophylaxis
Bone Mineral Density in Children
with Atopic Dermatitis ............................................. 90 with Immunosuppressive Agents?........................ 93
A New Crop of Psoriasis Susceptibility Genes...... 91 Seeing the Light in Ocular Melanoma ..................... 94
Depressing News Relating to Oral Isotretinoin? ... 91 Filaggrin Signatures .................................................... 94
How Satisfied Are Residents with Congenital Epidermolysis Bullosa Acquisita ......... 95
Their Training in Procedural Dermatology? ........ 92 Second Malignancies in Lymphoma Patients ....... 95
axis and the autonomic nervous system,
both of which interact with the immune sys-
tem. Therefore, stressful events could exac-
erbate and prolong chronic inflammatory
diseases such as psoriasis. Other investiga-
tors have reported a blunting of the HPA
axis in some subjects with psoriasis, which
could account for inadequate secretion of
cortisol and a resulting exacerbation of
clinical disease.
COMMENT
These three articles demonstrate the in-
creased interest in psychological aspects of
skin diseases. Quality-of-life instruments
elucidate disease evolution and contribute
considerably to the selection of therapeutic
measures. For example, we have discovered
that the deleterious effects of psoriasis on
daily life quality are much greater than
previously assumed. Psoriasis is now con-
sidered “psoriatic disease,” a constellation
that can include rheumatologic, gastro-
intestinal, ophthalmologic, cardiac, meta-
bolic, and psychiatric manifestations.
The presence of depression and anxiety in
these patients is worthy of special attention,
because improvement of the cutaneous
component appears to improve depression
and vice versa. Numerous retrospective
studies have evaluated the impact of stress-
ors in patients with psoriasis; we are now
beginning to unravel the underlying
mechanisms of this phenomenon. Derma-
tologists must be aware of the complex
interactions among disease, therapeutics,
and patients’ quality of life.
— Francisco A. Tausk, MD
Dr. Tausk is Professor of Dermatology and Psychiatry,
University of Rochester School of Medicine and
Dentistry, Rochester, New York.

The Value of Patch Testing Methotrexate Recalled Because Smidt AC et al. Development and validation of
for Cosmetic Allergens ............................................ 92 of Glass Contamination ........................................... 95 Skindex-Teen, a quality-of-life instrument for
Populated Pustules ..................................................... 93 Nd:YAG Laser Treatment adolescents with skin disease. Arch Dermatol
of Hidradenitis Suppurativa.................................... 96 2010 Aug; 146:865.

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90
EDITOR-IN-CHIEF
Hensin Tsao, MD, PhD, Associate Professor
of Dermatology, Harvard Medical School;
Director, Melanoma Genetics Program and
the Melanoma and Pigmented Lesion Center,
Massachusetts General Hospital
EXECUTIVE EDITOR
Sharon S. Salinger
Massachusetts Medical Society
DEPUTY EDITOR
Jeffrey P. Callen, MD, Professor of Medicine
(Dermatology), and Chief, Division of Dermatology,
University of Louisville, Louisville, Kentucky
ASSOCIATE EDITORS
Murad Alam, MD, MSCI, Associate Professor
of Dermatology, Otolaryngology, and Surgery,
Chief of Cutaneous and Aesthetic Surgery,
Feinberg School of Medicine, Northwestern
University, Chicago
Mary Wu Chang, MD, Director, Pediatric
Dermatology of New England, West Hartford, CT;
Associate Clinical Professor of Dermatology and
Pediatrics, University of Connecticut School of
Medicine
Mark V. Dahl, MD, Professor, Department
of Dermatology, and Senior Consultant, College of
Medicine, Mayo Clinic, Scottsdale/Phoenix, Arizona
Craig A. Elmets, MD, Professor and Chair,
Department of Dermatology, and Director, Skin
Diseases Research Center, University of Alabama
School of Medicine, Birmingham
Jan V. Hirschmann, MD, Staff Physician, Puget
Sound VA Medical Center; Professor of Medicine,
University of Washington School of Medicine,
Seattle
George J. Hruza, MD, Clinical Associate Professor
of Dermatology and Otolaryngology, Saint Louis
University Medical School; Director, Laser &
Dermatologic Surgery Center, St. Louis
Angelica Selim, MD, Associate Professor
of Pathology and Dermatology; Duke University
Medical Center, Durham, North Carolina
Kenneth Y. Tsai, MD, PhD, Assistant Professor,
Departments of Dermatology and Immunology,
University of Texas MD Anderson Cancer Center,
Houston
FORMER EDITORS-IN-CHIEF
Jeffrey S. Dover, MD, FRCPC,
Founding Editor, 1993–2006
Lowell A. Goldsmith, MD, MPH,
2006–2010
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DERMATOLOGY
Kurd SK et al. The risk of depression, anxiety, and
suicidality in patients with psoriasis: A population-
based cohort study. Arch Dermatol 2010 Aug;
146:891.
Evers AWM et al. How stress gets under the
skin: Cortisol and stress reactivity in psoriasis.
Br J Dermatol 2010 Nov; 163:986.
MelaFindings
The MelaFind handheld multispectral
dermoscope assists in the evaluation of
pigmented lesions.
How useful are computer vision tools in
the diagnosis of pigmented lesions (PLs)?
Investigators conducted a prospective,
multicenter, blinded trial of MelaFind, a
multispectral imaging tool, for identifying
which PLs should be biopsied to rule out
melanoma. Patients with at least one suspi-
cious lesion targeted for biopsy were in-
cluded. Melanomas (invasive and in situ)
and borderline lesions, such as high-grade
dysplastic nevi (HGDN), atypical melano-
cytic proliferation (AMP), and atypical
melanocytic hyperplasia (AMH), were
evaluated; PLs with a prebiopsy melanoma
diagnosis were excluded.
Dermatopathology was used as the
reference standard for comparing the
diagnostic performance of MelaFind and
clinicians. Of 1632 eligible and evaluable
lesions, 143 (9%) required more than two
dermatopathology evaluations (i.e., exhib-
ited histologic discrepancy). MelaFind
produces one of two findings: The lesion
should be considered for biopsy to rule out
melanoma, or the lesion should be consid-
ered for later evaluation. MelaFind’s sensi-
tivity for appropriate recommendations
exceeded 95%; its specificity was 9.5%
(compared to 3.7% for clinicians, P<0.05).
It had a positive predictive value of about
10%, and a negative predictive value of
about 98%.
COMMENT
The study did not include clinically un-
suspected melanomas unlikely to be
biopsied. Thus, we do not know how many
melanomas would have been detected by
MelaFind but overlooked by clinicians. Be-
cause the histological designations HGDN,
AMP, and AMH are not universally used in
clinical practice, the reference standard may
have produced some bias. Nearly half of the
melanomas were in situ, and the median
thickness of the invasive melanomas was
Vol. 18 No. 12
only 0.36 mm; it is unlikely that a similar
trial will test survival benefit. Thus, the
theoretical benefit of MelaFind is that
melanomas would be identified and
removed at an earlier stage.
MelaFind was employed only for PLs
already targeted for removal, so a positive
finding would not much affect clinician
behavior, but a negative finding might have
dissuaded a physician from sampling the
lesion — and there’s the rub. How many
clinicians would back away from removing
a clinically suspicious PL, even given
MelaFind’s high negative predictive value?
An evaluation of randomly selected PLs
without regard to clinical suspicion would
get at the utility of MelaFind for melanoma
of benign appearance. Clinicians might
come to rely on this technology with great
confidence, but only after more studies and
some personal experience.
— Hensin Tsao, MD, PhD
Monheit G et al. The performance of MelaFind:
A prospective multicenter study. Arch Dermatol
2010 Oct 18; [e-pub ahead of print]. (http://dx
.doi.org/10.1001/archdermatol.2010.302)
Bone Mineral Density in
Children with Atopic Dermatitis
Use of topical corticosteroids in the previous
5 years was not associated with a decrease
in BMD.
Atopic dermatitis (AD) is a common,
chronic skin disease in children that is usu-
ally treated with courses of topical corti-
costeroid therapy. The risk for decreased
bone mineral density (BMD) with chronic
topical steroid use is unknown. Low BMD
has been reported in 30% of adult patients
with AD, although a causative role for
topical steroid use was not established.
Investigators from a Dutch children’s
hospital conducted a cross-sectional study
to determine the prevalence of low BMD
in children with AD. Sixty patients
(age range, 5–16 years) from the pediat-
ric dermatology outpatient clinic were
enrolled. Inclusion criteria were SCORing
Atopic Dermatitis (SCORAD) score >20;
more than four outpatient visits in 1 year;
hospital admission for AD; or prescription
for AD of potent topical steroids, systemic
prednisone, or cyclosporine. Pharmacy
records were used to calculate the 5-year
cumulative use of topical, inhaled, and
systemic corticosteroids. Lumbar spine
December 2011
BMD of these children was measured by
dual-energy X-ray absorptiometry
(DEXA).
Three children (5%) had low BMD;
one (1.7%) had osteoporosis, a prevalence
not statistically different from that ex-
pected in the general pediatric population.
Prior 5-year topical steroid use was not
associated with decreased BMD. Use of
oral corticosteroids or cyclosporine was
associated with a decrease in BMD, but this
was not statistically significant. Correction
for activity, diet, or sun exposure did not
change these associations.
COMMENT
Quantifying the risk for bone mineral
density loss in children associated with
long-term topical steroid use is difficult.
Moreover, adult BMD data cannot be ex-
trapolated, because bone metabolism dif-
fers in children. Still, these subjects were
well studied, and the data are reassuring.
It is worth noting that these children had
received relatively low amounts of topical
steroid. A trial in children with severe
AD who had received larger amounts of
corticosteroid might or might not produce
different results. — Mary Wu Chang, MD
van Velsen SGA et al. Bone mineral density in
children with moderate to severe atopic dermatitis.
J Am Acad Dermatol 2010 Nov; 63:824.
A New Crop of Psoriasis
Susceptibility Genes
Several research teams use genome-wide
association studies to identify new psoriasis
susceptibility loci in various populations.
Genetic predisposition to psoriasis has
been known for many years. Five new
genome-wide association studies (GWAS)
involving various refinements in technique
were conducted in distinct populations.
These studies confirm previously identified
loci with plausible immunologic impor-
tance, including the major histocompati-
bility complex (MHC) class I alleles, such
as HLA-C and the cytokines interleukin
(IL)-12 and IL-23, as well as identifying
new loci.
The Genetic Analysis of Psoriasis and
Wellcome Trust Case Control consortia
studied subjects of European ancestry in
the U.K. and Ireland (594,224 SNPs in
2622 cases and 5667 controls). They iden-
tified new loci, including TYK2, which
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regulates inflammatory cytokine produc-
tion, and ERAP1, which regulates antigen
presentation. In affected individuals, they
found ERAP1 variants associated with
high-risk alleles of HLA-C, suggesting that
peptide presentation to T cells is altered in
psoriasis.
Concentrating on German populations
(2,339,118 SNPs in 472 cases and 1146 con-
trols), Ellinghaus and colleagues identified
TRAF3IP2 as a psoriasis susceptibility
locus, while Hüffmeier and colleagues,
studying 609 cases and 990 controls, iden-
tified the same gene as a susceptibility lo-
cus for psoriatic arthritis. This gene func-
tions as a negative regulator of humoral
immunity and as a positive regulator of
IL-17–mediated inflammation. The ge-
netic variant in affected individuals ap-
pears to affect the ability of the encoded
protein to interact with other proteins.
Studying a variety of populations
(8312 cases and 12,919 controls in
China; 3293 cases and 4188 controls from
Germany and the U.S.; and 254 nuclear
families from the U.S.), Sun and colleagues
identified six psoriasis susceptibility loci,
including ERAP1 (also noted by the
Wellcome Trust consortium). They also
identified some genes expressed by kera-
tinocytes, including GBJ2 (which encodes
the connexin 26 protein).
Finally, in a meta-analysis incorporat-
ing German and North American subjects
(1831 cases and 2546 controls from
Michigan, Toronto, Newfoundland, and
Germany), Stuart and colleagues found
more loci involved in inflammation,
including NOS2 (inducible nitric oxide
synthase) and NFKBIA (also identified
by Ellinghaus and by the consortia), a
negative regulator of the NFkB trans-
cription factor, which in turn, regulates
multiple inflammatory pathways.
COMMENT
GWAS link genetic variation to disease
phenotypes, highlighting genes that may
determine susceptibility. Such insights are
important because they suggest pathoge-
netic mechanisms. These groups have iden-
tified new loci associated with psoriasis
and psoriatic arthritis, most of which are
involved in inflammatory cytokine regula-
tion or class I MHC/peptide processing
or presentation. Some of these genes are
91
expressed by keratinocytes, suggesting a
shared role for T cells and keratinocytes
in psoriasis pathogenesis. Interestingly, it
appears that the risk conferred by certain
genes may be modified by ethnogeographic
factors, suggesting yet another layer of
interaction. The hard work of clarifying the
functional relevance of these genetic varia-
tions and how they contribute to pathogen-
esis and treatment response has just begun.
— Kenneth Y. Tsai, MD, PhD
Genetic Analysis of Psoriasis Consortium and the
Wellcome Trust Case Control Consortium. A
genome-wide association study identifies new
psoriasis susceptibility loci and an interaction
between HLA-C and ERAP1. Nat Genet 2010
Oct 17; 42:985.
Ellinghaus E et al. Genome-wide association study
identifies a psoriasis susceptibility locus at
TRAF3IP2. Nat Genet 2010 Oct 17; 42:991.
Hüffmeier U et al. Common variants at TRAF3IP2
are associated with susceptibility to psoriatic arthri-
tis and psoriasis. Nat Genet 2010 Oct 17; 42:996.
Sun L-D et al. Association analyses identify six new
psoriasis susceptibility loci in the Chinese popula-
tion. Nat Genet 2010 Oct 17; 42:1005.
Stuart PE et al. Genome-wide association analysis
identifies three psoriasis susceptibility loci. Nat
Genet 2010 Oct 17; 42:1000.
Depressing News Relating
to Oral Isotretinoin?
Whether it is the acne, the therapy, or
multiple variables, patients with acne
should be monitored for depression and
suicidality.
The psychiatric risks of isotretinoin use for
treatment of acne are controversial. Most
studies have not shown a causal link be-
tween isotretinoin and depression, but
many of these studies had limitations.
In addition, the presence of acne vulgaris
itself may be associated with suicidal
ideation and other psychopathology.
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92
These authors conducted a large,
retrospective analysis in Sweden to assess
the risk for attempted suicide before,
during, and after treatment with iso -
t retinoin for severe acne. Among 5756
patients prescribed isotretinoin for severe
acne and observed for 17,197 person-
years before, 2,905 person-years during,
and 87,120 person-years after treatment,
128 were admitted to the hospital on at
least one occasion for attempted suicide.
The authors report an increase in at-
tempted suicides in this population in
the 3 years prior to therapy onset, which
was not statistically significant. The
standardized incidence ratio during
treatment and up to 6 months afterward
was 1.78 for all attempts and 1.93 for first
attempts. Risk peaked 6 months after the
end of treatment and then gradually re-
turned to the level predicted for the gen-
eral population. Compared with patients
whose first attempts occurred before
isotretinoin therapy, those whose first
attempts occurred during treatment or
within 6 months of cessation were sig-
nificantly more likely to make a second
attempt or die by suicide.
COMMENT
Adverse psychosocial effects are associat-
ed with acne itself, and in these study
patients, rates of suicide attempts were
already rising before isotretinoin therapy
began, which may reflect an association
with the disease rather than its therapy.
Whether later attempts were associated
with acne that failed to respond to thera-
py, a temporary worsening of acne with
initial isotretinoin use, or patients’ failure
to realize hoped-for benefits from suc-
cessful therapy is unknown. These au-
thors do not identify isotretinoin as a
cause of suicide. However, the bottom line
is that patients with acne, particularly
those with severe disease, need to be as-
sessed for suicidal ideation and depression
and referred for appropriate intervention.
— Jeffrey P. Callen, MD
Sundström A et al. Association of suicide attempts
with acne and treatment with isotretinoin: Retro-
spective Swedish cohort study. BMJ 2010 Nov 11;
341:c5812. (http://dx.doi.org/10.1136/bmj.c5812)
Magin P and Sullivan J. Suicide attempts in people
taking isotretinoin for acne. BMJ 2010 Nov 11;
341:c5866. (http://dx.doi.org/10.1136/bmj.c5866)
DERMATOLOGY
How Satisfied Are Residents
with Their Training
in Procedural Dermatology?
Residents are performing more hands-on
procedures than in the recent past, and
about half were very satisfied with their
experience.
Dermatology residents receive training in
a variety of procedures during residency.
Investigators surveyed third-year derma-
tology residents to find out how satisfied
they were with their training.
In all, 55% of the 240 respondents were
very satisfied with their residency training
in procedural dermatology. Overall, resi-
dents reported that they felt most compe-
tent in excisional surgery and some cos-
metic procedures, including botulinum
toxin injections and laser surgery. How-
ever, most had performed fewer than
10 of each of these procedures as the pri-
mary surgeon. They reported less hands-
on training in Mohs surgery — most had
only assisted in this procedure and did
not report proficiency. Experience with
advanced cosmetic procedures, such as
hair transplantation, liposuction, and
ambulatory phlebectomy, was described
as being mostly observational or book
knowledge, which respondents considered
to be sufficient.
COMMENT
Unsurprisingly, residents in programs with
a full-time surgical director (81% of pro-
grams) and more than 1 month of surgical
training per resident reported more com-
petence in basic cold steel surgery. What is
surprising, at least to this surgical director,
is that 78% of respondents believed them-
selves to be competent or very competent
in performing flap reconstructions.
This cohort performed hands-on pro-
cedures as the primary or assistant sur-
geon more often than residents have done
in the recent past, especially in cosmetic
procedures. Dermatology residents are
probably receiving as much as or more ex-
posure to minor cosmetic procedures as
most plastic surgery residents, who have
less clinic time and continue to focus on
operating room cases. One limitation of
this study was that self-reported compe-
tence was not confirmed by objective skill
assessment or the expert opinion of the
surgical directors. These results support
Vol. 18 No. 12
the argument that post-fellowship training
in Mohs may be useful.
— Murad Alam, MD, MSCI
Lee EH et al. Procedural dermatology training dur-
ing dermatology residency: A survey of third-year
dermatology residents. J Am Acad Dermatol 2010
Oct 4; [e-pub ahead of print]. (http://dx.doi.org/
10.1016/j.jaad.2010.05.044)
The Value of Patch Testing for
Cosmetic Allergens
Adding supplemental testing to the standard
patch test series increased the yield of posi-
tive reactions in patients with suspected
cosmetic contact allergy.
Individuals with suspected cutaneous reac-
tions to cosmetics are frequently evaluated
via patch testing. To determine the value of
adding supplemental testing with the cos-
metic series of reagents to the standard se-
ries, researchers retrospectively evaluated
results of patch tests conducted from 2000
to 2007 at one clinical center in 945 pa-
tients (age range, 6–91 years; mostly fe-
male) with a suspected cosmetic contact
allergy. All patients received a standard
screening series, including the thin-layer
rapid use epicutaneous (TRUE) test, and a
supplemental cosmetic series.
More than two thirds of the patients
had at least one positive reaction; nearly
half had two positive reactions; and almost
one third had three or more positive reac-
tions. Patients reacted most frequently to
preservatives (49.4% of tested patients),
followed by fragrances and botanicals
(31.2%). Positive reactions to vehicles
(19.0%) and sunscreens (10.3%) were also
common. Addition of the cosmetic series
enhanced the detection of positive reac-
tions to preservatives by 18% compared
with the standard series alone and by
22.5% compared with the TRUE test;
the cosmetic series similarly increased
discovery of contact allergies to fragrances/
botanicals, vehicles, and sunscreens. The
authors recommend expanding the TRUE
test series of contact allergens to include
amidoamine, benzalkonium chloride, ben-
zoic acid, cinnamic aldehyde, cocamido-
propyl betaine, DMDM hydantoin, dodecyl
gallate, 2-hydroxy-4-methoxybenzo-
phenone-5-sulfonic acid, jasmine absolute,
methyldibromo glutaronitrile/phenoxy-
ethanol, oleamidopropyl dimethylamine,
December 2011
propolis, propylene glycol, α-tocopherol
(vitamin E), triclosan, and ylang-ylang oil.
COMMENT
Because the composition of cosmetic
products is continually changing, it is
important to keep up with corresponding
changes in contact allergies. These findings
confirm previous observations that in-
creasing the number of patch test antigens
increases the likelihood of detecting a con-
tact allergy. When cosmetic allergy is sus-
pected, a broader spectrum of antigens
should be used at the time of the initial
patch testing procedure.
— Craig A. Elmets, MD
Wetter DA et al. Results of patch testing to personal
care product allergens in a standard series and a
supplemental cosmetic series: An analysis of 945 pa-
tients from the Mayo Clinic Contact Dermatitis
Group, 2000-2007. J Am Acad Dermatol 2010
Nov; 63:789.
Populated Pustules
A possible role for Staphylococcus
epidermidis in papulopustular rosacea
Bacteria may play a role in rosacea, par-
ticularly in the papulopustular variant.
Rosacea responds promptly and reliably
to many different antibiotics. However, no
nefarious bacteria are regularly isolated
from pustules.
Australian investigators incised rosacea
pustules in 15 patients with papulopustular
rosacea and swabbed the skin of the ipsilat-
eral cheek and eyelid margin of these pa-
tients and of 15 matched control subjects. A
pure growth of Staphylococcus epidermidis
was isolated from the pustules of nine of
the rosacea patients but not from the
ipsilateral cheek skin, a highly significant
difference. Eyelids of four patients, but
no controls, also yielded pure growths of
S. epidermidis, also a significant difference.
No pure cultures were isolated from the
cheeks of either group. The authors suggest
that S. epidermidis may play a role in the
pathogenesis of papulopustular rosacea.
COMMENT
In a trial of the role of temperature in
regulating bacterial protein production
(J Am Acad Dermatol 2004; 50:266) , my
colleagues and I found S. epidermidis in
four pustules of rosacea patients. More im-
portantly, in my view, all were hemolytic
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strains, whereas all S. epidermidis isolates
from swabs of the control subjects’ cheeks
were nonhemolytic. The “smoke” here sug-
gests that unique strains of S. epidermidis
may contribute to the fire of rosacea.
— Mark V. Dahl, MD
Whitfeld M et al. Staphylococcus epidermidis: A
possible role in the pustules of rosacea. J Am Acad
Dermatol 2010 Oct 12; [e-pub ahead of print].
(http://dx.doi.org/10.1016/j.jaad.2009.12.036)
Immune Responses in
Polymorphic Light Eruption:
A Double-Edged Sword
Ultraviolet radiation usually causes an
immunosuppressive response that is muted
in patients with PLE, which could protect
them from skin cancer.
Polymorphic light eruption (PLE) is the
most common cutaneous photosensitivity
disease, with an estimated prevalence of
10% to 15% in the U.S. The disease mani-
fests as a skin rash with variable character-
istics during the spring and summer
months following exposure to sunlight
or other sources of ultraviolet radiation.
Mechanisms of immunity have been pro-
posed to play a part in PLE pathogenesis.
In this study, investigators closely exam-
ined the immunosuppressive effects of UV
radiation in 24 patients with PLE and 24
healthy sex- and age-matched controls.
The researchers applied the sensitizing
agent diphenylcyclopropenone (DPCP) to
a localized area of skin preexposed to UV
radiation. About 80% to 90% of healthy
individuals develop a contact allergy when
nonirradiated skin is treated with DPCP.
Contact allergic reactions to DPCP de-
veloped in 37% of the healthy participants
and 50% of the PLE patients. Both groups
exhibited a suboptimal contact allergic re-
sponse, and the percentages of patients in
each group who failed to respond did not
differ significantly. However, when the
participants who initially had a suppressed
immune response were rechallenged with
DPCP 1 year later, 6 of 11 healthy indivi-
duals continued to have a suppressed re-
sponse, compared with only 1 of 13 PLE
patients, and this difference was statistical-
ly significant. Thus, the immunosuppres-
sive effects of UV radiation were much
more likely to endure long term in healthy
individuals than in PLE patients.
93
COMMENT
One theory of PLE pathogenesis proposes
that the T-cell–mediated immune re-
sponse to UV-induced endogenous anti-
gens is suppressed in healthy people but not
in those with PLE. As a result, a skin rash
follows UV exposure in PLE patients. The
findings support this theory. The report is
not definitive, as the investigators did not
test non–UV-suppressed and non–UV-
exposed subjects. Because suppressed im-
mune response following UV exposure is
thought to facilitate the growth and devel-
opment of UV-induced skin cancers, the
findings may explain why PLE patients
have a lower incidence of skin cancer than
the general population. If PLE patients are
less likely to develop suppressed immune
responses following UV exposure, they
may retain T-cell immunity to antigens on
UV-induced tumors, destroying cells that
could become clinically apparent skin
cancers. — Craig A. Elmets, MD
Koulu LM et al. UV-induced tolerance to a contact
allergen is impaired in polymorphic light eruption.
J Invest Dermatol 2010 Nov; 130:2578.
Pneumocystis Prophylaxis with
Immunosuppressive Agents?
PCP prophylaxis should not be adminis-
tered routinely to patients taking immuno-
suppressive medications.
Many clinicians routinely prescribe sulfa-
methoxazole-trimethoprim (SMX-TMP)
or another agent to prevent the develop-
ment of Pneumocystis jirovecii pneumonia
(PCP) in patients receiving immunosup-
pressive medications. Evidence justifying
such a policy is sparse. The authors of this
retrospective study examined the fre-
quency of PCP in 198 HIV-negative pa-
tients who received immunomodulatory
medications for dermatologic disorders,
such as psoriasis, dermatomyositis,
vasculitis, and pemphigoid.
Systemic corticosteroids, methotrexate,
antimalarials, and azathioprine were the
most common immunosuppressive medi-
cations used by these patients; approxi-
mately 25% received a biologic agent, such
as etanercept. About 25% were concur-
rently receiving a prophylactic medication
to prevent PCP. During an average follow-
up of 8 years, PCP developed in only one
patient not receiving PCP prophylaxis
94
(0.7% incidence). Serious reactions to the
PCP-preventive medication developed in
6% of SMX-TMP recipients and 37% of
dapsone recipients.
COMMENT
The very low risk for PCP is too small to
justify routine prophylaxis. In addition to
their expense, these medications are fre-
quently associated with adverse effects. The
authors sensibly recommend that clinicians
avoid routine prophylaxis in patients re-
ceiving immunosuppressive agents and
that we remain alert to the uncommon
possibility of PCP, especially in those
with apparent risk factors, which include
age >60, concurrent pulmonary disease,
leukopenia, hypoalbuminemia, and
CD4 counts <300/dL.
— Jan V. Hirschmann, MD
Lehman JS and Kalaaji AN. Role of primary pro-
phylaxis for pneumocystis pneumonia in patients
treated with systemic corticosteroids or other
immunosuppressive agents for immune-mediated
dermatologic conditions. J Am Acad Dermatol
2010 Nov; 63:815.
Seeing the Light in Ocular
Melanoma
Activation of a pathway involving two
similar genes appears to contribute to the
development of uveal melanoma.
The genetic basis for uveal melanoma for-
mation was unknown until a breakthrough
finding (Nature 2009; 457:599) document-
ed GNAQ mutations in 40% of uveal mela-
nomas. GNAQ encodes for the alpha sub-
unit of a class of G proteins that affect
intracellular signaling. The discovery of
activating oncogenic changes in GNAQ has
shed light on pathways involved in ocular
melanomas and raised the possibility of
novel therapeutic approaches to this treat-
ment-resistant form of melanoma.
Now, the same investigators have
sequenced exons 4 and 5 of GNAQ and
GNA11 (a paralogue of GNAQ) in various
types of melanocytic tumors, including
uveal melanomas and blue nevi. They
found inverse distribution patterns of
somatic mutations. In GNA11, mutations
affecting amino acid position 209 (Q209)
were present in 7% of blue nevi, 32% of
primary uveal melanomas, and 57% of
DERMATOLOGY
uveal melanoma metastases. Conversely,
in GNAQ, Q209 mutations were found in
55% of blue nevi, 45% of uveal melanomas,
and 22% of uveal melanoma metastases.
Mutations affecting the amino acid position
R183 were less prevalent than the Q209 mu-
tations (present in 2% of blue nevi and 6%
of uveal melanomas). Functional studies
showed that in mice, the GNA11 mutations
induced spontaneously metastasizing tu-
mors and activated the mitogen-activated
protein kinase pathway.
COMMENT
Strengths of this follow-up study of the
signaling pathway in ocular melanoma in-
clude the number and variety of melano-
cytic tumors studied and the thoroughness
of the molecular analysis. Both GNAQ and
GNA11 alterations were associated with oc-
ular melanomas, but in blue nevi, GNAQ
mutations were common and GNA11 mu-
tations were absent. The mutually exclusive
pattern of GNAQ and GNA11 mutations
suggests that either is sufficient to induce
cancer and that both are never needed; al-
ternatively, the presence of both mutations
might actually be toxic to cells. Mutational
differences did not significantly associate
with overall survival. The clinical implica-
tions of the GNAQ/GNA11 story lie in its
therapeutic potential: Having a key to the
ocular melanoma black box is the first step
to finding an effective drug.
— Hensin Tsao, MD, PhD
Van Raamsdonk CD et al. Mutations in GNA11
in uveal melanoma. N Engl J Med 2010 Dec 2;
363:2191)
Herlyn M and Nathanson KL. Taking the guesswork
out of uveal melanoma. N Engl J Med 2010 Dec 2;
363:2256)
Filaggrin Signatures
In patients with atopic dermatitis, non-
invasive Raman microspectroscopy can
reveal disturbances in skin barrier function
at the molecular level.
At least 50% of patients with atopic dermati-
tis (AD) harbor mutations in the complex
gene that regulates filaggrin production.
The filaggrin protein collapses the keratin
cytoskeleton, producing scaffolding for con-
struction of the optimal stratum corneum
barrier. Additionally, filaggrin degrades into
Vol. 18 No. 12
the so-called natural moisturizing factor,
which is actually a set of amino acids, such
as urocanic acid, pyrrolidone carboxylic
acid, and alanine. Mutations alter the ability
of filaggrin to perform these functions,
producing a “leaky” barrier that allows
increased transepidermal water loss and
encroachment by external irritants.
Identifying a filaggrin mutation in a
patient with eczema would be useful to the
clinician, not only by pointing to an AD
diagnosis but also by suggesting therapy
aimed at proper barrier maintenance and
moisturization. Genetic testing for filag-
grin gene mutations is very difficult, how-
ever, because tandem repeats in the gene
can mask a mutation in one of them. Ra-
man microspectroscopy uses the scattering
of monochromic light by molecular vibra-
tions to provide a noninvasive, real-time
picture of disturbances in skin at the mo-
lecular level. In AD, it can detect abnormal
filaggrin and thereby identify individuals
carrying filaggrin mutations.
Investigators monitored the composi-
tion and function of skin in 132 patients
with moderate-to-severe AD. The use of
Raman microspectroscopy to distinguish
patients with one or more gene mutations
from those with normal filaggrin geno-
types had a sensitivity of 99% and a speci-
ficity of 87%. Functional measurements
of transepidermal water loss, on the other
hand, were not very helpful.
COMMENT
This study’s primary importance lies in its
discovery of a clinical way to detect filag-
grin mutations without genotyping. In-
deed, a functional assay such as this may
be better than genotyping. Raman micro-
spectroscopy is theoretically cheaper and
noninvasive, with immediate readout. Ab-
normal results reflect abnormal genetic
expression (not just a genetic mutation).
In the patient with atopic dermatitis, detec-
tion of this functional abnormality of bar-
rier formation may be very relevant for
prevention and treatment decisions.
— Mark V. Dahl, MD
O’Regan GM et al. Raman profiles of the stratum
corneum define 3 filaggrin genotype–determined
atopic dermatitis endophenotypes. J Allergy Clin
Immunol 2010 Sep; 126:574.e1.
December 2011
Congenital Epidermolysis
Bullosa Acquisita
A first description of mother-to-infant
transfer of this autoimmune disorder
Epidermolysis bullosa acquisita (EBA)
is a rare autoimmune blistering disorder
in which autoantibodies against the
145-kDa NC1 domain of type VII collagen
result in a decrease in the anchoring fibrils
of the lamina densa. Typically presenting
in adulthood, EBA is characterized by
chronic skin fragility, with blistering of
the skin and mucosa, scarring, milia, and
dyspigmentation. EBA has rarely been re-
ported in children; authors now present the
first report of congenital EBA.
A 32-year-old woman (gravida 4,
para 3) with EBA delivered at 36 weeks’
gestation after labor was induced because
of a deficiency of amniotic fluid and intra-
uterine growth restriction. The newborn’s
Apgar scores were 9 at both 1 and 5 min-
utes; however, tense blisters and erosions
were noted at birth. At the time of delivery,
the mother had active EBA, with superfi-
cial erosions, crusting, hyper- and hypo-
pigmentation, and onychodystrophy. In
the past, she had suffered from esophageal
strictures and eye involvement and had re-
ceived cyclophosphamide and prednisone.
Her three other children, born before she
developed EBA, were healthy.
Congenital EBA was confirmed by his-
topathology, direct and indirect immuno-
fluorescence and enzyme-linked immuno-
sorbent assay (ELISA). Because the
physicians expected the circulating anti-
bodies to decrease spontaneously in the
infant, they deferred immunosuppressant
therapy and provided supportive care, in-
cluding nutritional support, pain manage-
ment, and topical wound care. No new bul-
lae developed after 10 days of life. Complete
healing occurred by age 2 months, leaving
scarring, milia, and dyspigmentation.
COMMENT
Transient autoimmune neonatal bullous
skin disorders are rare. This is the first
confirmed case of congenital EBA and
demonstrates the pathologic nature of EBA
antibodies. Mothers with pemphigus folia-
ceus, bullous pemphigoid, or pemphigus
vulgaris (even when in remission at time
of delivery) can transmit disease to the
JWatch.org
newborn via passive transfer of pathogenic
IgG antibodies across the placenta. Growth
retardation, extensive blistering, and fetal
death can occur prior to delivery in those
diseases. Postnatally, skin disease improves
as maternal IgG levels decline over time
in the infant. Once the diagnosis is con-
firmed, careful neonatal supportive care
(pain management, fluid and nutritional
support, and wound care) is usually suffi-
cient, and systemic immunosuppressant
therapy can be avoided. Further study of
additional cases of congenital EBA are
needed before we know if a similar clinical
prognosis holds true for this more rare
disease. — Mary Wu Chang, MD
Abrams ML et al. Congenital epidermolysis
bullosa acquisita: Vertical transfer of maternal auto-
antibody from mother to infant. Arch Dermatol
2010 Nov 15; [e-pub ahead of print]. (http://dx.doi
.org/10.1001/archdermatol.2010.317)
Second Malignancies
in Lymphoma Patients
Patients with small lymphocytic, follicular,
or diffuse large B-cell lymphomas had
excess risk for several second cancers.
Studies have shown that patients with
lymphoproliferative diseases have excess
risk for second cancers. To better quanti-
tate risks for specific lymphoma subtypes
in these patients and to identify the most
frequent second malignancies, investiga-
tors studied a large, population-based
cohort of lymphoma survivors who were
identified from Surveillance, Epidemiology,
and End Results (SEER) cancer registries.
The researchers evaluated 43,145 pa-
tients with a primary diagnosis of chronic
lymphocytic leukemia/small lymphocytic
lymphoma (CLL/SLL), follicular lymphoma
(FL), or diffuse large B-cell lymphoma
(DLBCL) who survived at least 1 year
after diagnosis. Of these patients, 42,213
were HIV negative; 932 were HIV positive.
Compared with the general population,
HIV-negative patients demonstrated higher
rates of lung cancer and melanoma after
CLL/SLL; acute myeloid leukemia (AML)
after FL and DLBCL; and Hodgkin lym-
phoma after CLL/SLL, FL, and DLBCL.
HIV-negative patients also experienced a
trend toward higher rates of salivary, colon,
anal, and thyroid cancers after CLL/SLL
95
and toward higher rates of breast and
pancreatic cancers after FL. HIV-positive
patients, most of whom had received a pri-
mary diagnosis of DLBCL, demonstrated
higher rates of anal cancer and Kaposi
sarcoma than those expected in the
general population.
COMMENT
These results confirm that survivors of
CLL/SLL, FL, and DLBCL have excess risk
for second cancers, which the authors pro-
pose arises from underlying defects in im-
munity, genetic predisposition to cancer,
treatment-related factors (such as chemo-
therapy-related AML), or, in the setting of
HIV infection, viral etiologies. Although
specific recommendations regarding
screening are not yet established for lymph-
oma survivors, a reasonable approach
would be to counsel patients about excess
risks for second malignancies, associated
risk factors (e.g., smoking and excessive
sun exposure), and age-appropriate
preventive measures.
— Michael E. Williams, MD, Journal
Watch Oncology and Hematology
Morton LM et al. Second malignancy risks after
non-Hodgkin’s lymphoma and chronic lymphocytic
leukemia: Differences by lymphoma subtype. J Clin
Oncol 2010 Nov 20;28: 4935.
Methotrexate Recalled Because
of Glass Contamination
Sandoz has recalled 24 lots of metho-
trexate — an injectable drug used to
treat rheumatoid arthritis, neoplasia,
and severe psoriasis — because flakes
of glass were found in some 50 mg/2 mL
and 250 mg/10 mL vials, the FDA
announced on Thursday, October 28.
For the complete list of recalled lots,
see the manufacturer’s news release (http://
www.fda.gov/Safety/Recalls/ucm231430.
htm) or the Sandoz U.S. website (www.us
.sandoz.com). No adverse events have been
reported so far.
NEJM’s Early Job Alert
Job Postings in Your Specialty
Fast. Useful. Free.
Check it out at
www.nejmjobs.org
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permission of the Massachusetts Medical Society. Printed in the USA. ISSN 1521-3595.

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Waltham, MA 02451-1413
JWatch.org

96 DERMATOLOGY Vol. 18 No. 12

Nd:YAG Laser Treatment
of Hidradenitis Suppurativa
Aggressive treatment with hair removal
laser had a positive effect on lesions of HS.
Hidradenitis suppurativa (HS) is very re-
sistant to both medical and surgical man-
agement — exacerbations, recurrence, and
progression are the norm. The observation
that HS may be related to follicular occlu-
sion has led to attempts to treat HS with
hair removal lasers. In this prospective,
controlled clinical and histologic study,
20 patients with Hurley stage II HS (skin
type, Fitzpatrick III or VI) underwent
treatment with a long-pulsed 1064-nm
Nd:YAG laser.
The patients received two treatments to
one affected area; untreated affected areas
served as controls. The patients were fol-
lowed clinically, with biopsy specimens
obtained before treatment and at 24 hours,
1 week, 1 month, and 2 months after treat-
ment. Laser parameters were adjusted
based on skin type and ranged from 25 to
50 J/cm2, with a 10-mm spot size and a
20- to 35-millisecond pulse duration.
Double pulse stacking was used at the first
treatment, and triple pulse stacking at the
second treatment on inflammatory lesions.
As measured by a Lesion Area and
Severity Index score modified for HS, pa-
tients realized a statistically significant im-
provement of 32% in treated areas 2 months
after the second treatment. No significant
adverse events were reported. Baseline and
24-hour biopsy specimens showed perifol-
licular inflammation, a superficial and deep
mixed infiltrate, and granulation. At 1 week,
inflammation and granulation had in-
creased. By 1 month, inflammation had de-
creased and broken hair shafts were noted.
At 2 months, the investigators found scar-
ring, fibrosis, and minimal inflammation.
These conditions correlated with the de-
gree of clinical improvement. Patients
with the greatest clinical response had the
least inflammation.
COMMENT
Laser hair removal seems to achieve
modest improvement in hidradenitis
suppurativa by destroying the offending
hair follicles. To be effective, the treatments
need to be quite aggressive, as evidenced by
the stacked pulses used in the study and
the histologic evidence of scarring and
fibrosis. Multiple treatments with a hair
removal laser will probably be needed to
achieve significant reduction in disease
activity. The duration of remission is yet
to be determined.
— George J. Hruza, MD
Xu LY et al. Histopathologic study of hidradenitis
suppurativa following long-pulsed 1064-nm
Nd:YAG laser treatment. Arch Dermatol 2010
Sep 20; [e-pub ahead of print]. (http://dx.doi
.org/10.1001/archdermatol.2010.245)