Journal of Dermatological Treatment

ISSN: 0954-6634 (Print) 1471-1753 (Online) Journal homepage: http://www.tandfonline.com/loi/ijdt20

Pustular psoriasis eruption with dabrafenib, a

BRAF inhibitor

Bilal Fawaz, Lauren Dickson & Alan Menter

To cite this article: Bilal Fawaz, Lauren Dickson & Alan Menter (2016): Pustular psoriasis
eruption with dabrafenib, a BRAF inhibitor, Journal of Dermatological Treatment, DOI:
10.3109/09546634.2016.1157258

To link to this article: http://dx.doi.org/10.3109/09546634.2016.1157258

Published online: 14 Apr 2016.

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 JOURNAL OF DERMATOLOGICAL TREATMENT, 2016
http://dx.doi.org/10.3109/09546634.2016.1157258

CASE REPORT

Pustular psoriasis eruption with dabrafenib, a BRAF inhibitor

Bilal Fawaz, Lauren Dickson and Alan Menter
Department of Dermatology, Baylor University Medical Center, Dallas, TX, USA

ABSTRACT ARTICLE HISTORY

Targeted BRAF inhibition with vemurafenib and dabrafenib has dramatically improved the survival rate in Received 12 November 2015
metastatic melanoma. These agents are now being tested for their efficacy against other tumors with BRAF Accepted 14 January 2016
mutations, including lung adenocarcinoma. While cutaneous adverse events are prevalent with BRAF inhib- Published online 13 April
ition, our patient, to our knowledge, is the first to develop a psoriatic eruption with BRAF inhibitors. We 2016
postulate that the elevation of tumor necrosis factor-alpha (TNF-a) and the paradoxical activation of the
Downloaded by [USC University of Southern California] at 18:44 17 April 2016

KEYWORDS
mitogen-activated protein kinase (MAPK) pathway due to BRAF inhibition may be responsible for the erup- cutaneous; toxicity;
tion. More studies are needed to further elucidate the immunopathogenic mechanisms behind this adverse medication; adverse;
event. The response to MEK inhibitors and/or increased TNF-a inhibition may help support or debunk our reaction
hypothesis.

Introduction regimen consisting of paclitaxel-carboplatin and bevacizumab,

Targeted BRAF inhibition with vemurafenib and dabrafenib has
recently transformed the treatment of stage IV metastatic melan-
oma. BRAF is a serine-threonine kinase involved in the mitogen-
activated protein kinase (MAPK) pathway – a signaling cascade
that promotes cell growth and proliferation (1). Activation of the
MAPK pathway by growth factors leads to sequential phosphoryl-
ation of several kinases, including BRAF, ultimately resulting in
increased gene transcription and cell proliferation (1). A mutation
in BRAF, observed in up to 15% of human cancer, results in a con-
stitutively active MAPK pathway, leading to uncontrolled cell
growth (2).
BRAF mutations have been identified in various types of cancer,
most notably in melanoma and papillary thyroid cancer, but also
in colorectal, lung, ovarian and breast cancer (2,3). They are well
known for their role in melanoma, as they compromise 50% of
the malignancy’s mutations (2,3). Specifically, the BRAF V600E
mutation, which involves a valine to glutamate substitution at
codon 600, accounts for over 90% of the melanoma mutations
(2,3). Dabrafenib and vemurafenib, both selective BRAF V600E
inhibitors, were thus developed for the treatment of advanced
melanoma (4,5). To date, they both have been shown to prolong
survival and improve response rates in this patient population
(4,5).
These agents are now being tested for use in other BRAF-
mutant tumors. Specifically, phase II trials are now underway to
test dabrafenib’s efficacy in lung adenocarcinomas with the V600E
BRAF mutation. Our patient was undergoing treatment with dabra-
fenib for a recently diagnosed lung adenocarcinoma and devel-
oped an unexpected side effect – pustular psoriasis.
Case report
A 54-year-old woman with a history of chronic plaque psoriasis,
stable on etanercept for 15 years, was diagnosed with stage IV
lung adenocarcinoma. She was placed on a chemotherapy
with discontinuation of her etanercept while undergoing chemo-
therapy. However, the patient failed to respond to the treatment,
and intractable psoriatic arthritis drove her to resume etanercept
therapy six months after its discontinuation. She was subsequently
placed on dabrafenib, 100 mg twice daily, as part of a clinical trial
seeking to assess the efficacy of dabrafenib in treating lung
adenocarcinomas.
Two weeks after therapy initiation, the patient developed mul-
tiple erythematous, scaly plaques with overlying 1–3 mm tender
pustules in her axillary, breast and inguinal folds (Figure 1a). In
addition, she displayed multiple pink, scaly, erythematous papules
and plaques on the scalp, ears, lower back and buttocks (Figure
1b), with tender, yellow, hyperkeratotic calluses on the soles of her
feet bilaterally. Her psoriasis was previously well controlled for 15
years on etanercept, 25 mg biweekly plus topical steroids.
Throughout her treatment, the patient only had minimal involve-
ment of her scalp and ears, with no history of pustular psoriasis or
psoriasis involving the intertriginous areas. However, not only did
her condition progressively deteriorate once dabrafenib was initi-
ated, but the lesions were also refractory to treatment with her
traditional therapy.
Biopsies of the mid-lower back and the right axilla both dem-
onstrated hyperkeratosis, parakeratosis, and aggregation of neutro-
phils forming Munro microabscesses (Figure 2). There was also loss
of the granular layer, regular acanthosis with elongation of rete
ridges, and lymphohistiocytic infiltration in the dermis (Figure 2).
PAS stain was negative for hyphae. These findings are most con-
sistent with the follicular variant of psoriasis. The patient was pre-
scribed CLN washes three times a week (containing water, sodium
laureth sulfate, cocamidopropryl betaine, cocamide mea, disodium
EDTA, sodium hypochlorite), in addition to mometasone furoate
0.1% ointment and Greer’s Goo (a compounded medication con-
sisting of hydrocortisone, zinc oxide and nystatin) every morning.
After nine months of dabrafenib therapy, elevated liver
function tests resulted in the discontinuation of both dabrafenib

CONTACT Dr Alan Menter, MD amderm@gmail.com Department of Dermatology, Baylor University Medical Center, 3900 Junius St, #145, Dallas, TX 75246, USA
ß 2016 Informa UK Limited, trading as Taylor & Francis Group
 2 B. FAWAZ ET AL.
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Figure 1. Clinical images. (a) Multiple erythematous, scaly plaques with overlying tender pustules in the left axillary fold. (b) Multiple pink, scaly, erythematous papules
and plaques on the lower back and upper buttocks.

Figure 2. Histopathological images of the axillary biopsy specimen. (a) Hyperkeratosis, parakeratosis, elongation of rete ridges and dermal lymphohistiocytic infiltration
(hematoxylin-eosin stain, original magnification 10). (b) Loss of the granular layer with aggregation of neutrophils forming Munro microabscesses (hematoxylin-eosin
stain, original magnification 20).

and etanercept. Two weeks following therapy withdrawal, the
patient noted a marked improvement in her psoriasis, despite the
discontinuation of etanercept. On physical exam, she displayed
mild erythema with associated scale on her scalp, in addition to
resolving plaques in the axillae and lower back.
Discussion
Cutaneous toxicities are the most common adverse effects of dab-
rafenib and vemurafenib, occurring in a significant proportion of
patients receiving BRAF inhibitors (4–6). The most frequently
reported cutaneous effects are verruciform, keratotic, squamoproli-
ferative lesions or verrucal keratoses, Grover’s disease, cutaneous
squamous cell carcinoma, actinic keratoses, non-specific exan-
thema, photosensitivity, keratoacanthoma and plantar hyperkera-
tosis (4–6). To our knowledge, the present case is the first to
describe an association between the induction of psoriasis and
BRAF inhibitors. Interestingly, there have been multiple reports of
Dupuytren’s contractures (DP) developing secondary to BRAF
inhibitors (7,8), which offers some insight into the possible patho-
physiologic mechanisms behind these complications, as psoriasis
and Dupuytren’s have been recently linked in a statistically

controlled study (9). This association was noted especially with
intertriginous and palmoplantar psoriasis (9). The authors postu-
lated that an increase in platelet-derived growth factor and Wnt
signaling, found in both diseases, may explain the association
between the two (9). In addition, as tumor necrosis factor-alpha
(TNF-a) is known to drive Wnt signaling, an increase in its level
may explain the link between the two conditions and illuminate
their association with BRAF inhibitors (10).
TNF-a has long been implicated in the pathogenesis of psoria-
sis and psoriatic arthritis. The impressive efficacy of TNF-a inhibi-
tors, including etanercept, in the treatment of psoriasis further
highlights the cytokine’s pivotal role in disease development; TNF-
a has a wide range of immunomodulatory effects that ultimately
result in inflammation and keratinocyte hyperproliferation (10).
Similarly, elevated TNF-a levels play a crucial role in DP develop-
ment, particularly by inducing the differentiation of dermal fibro-
blasts into myofibroblasts, the cells responsible for DP (11).
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Moreover, anti-TNF-a antibodies inhibit the contractility of the
myofibroblasts, resulting in the disassembly of the contractile
apparatus (11). This provides further evidence for the notion of
TNF-a-driven DP development.
Particularly pertinent to our discussion, recent studies have
shown that BRAF inhibitors increase levels of TNF-a, IFN-c and
CCL4, due to their induction of an immune response against tumor
cells (12). The elevation in TNF-a, similar to its role in DP develop-
ment as postulated by Chan et al. (7), may be responsible for the
development and/or exacerbation of psoriasis. The fact that our
patient was already on etanercept does not discredit this hypoth-
esis; BRAF inhibition could have led to overwhelming levels of
TNF-a, rendering etanercept less effective. Moreover, we must con-
sider that on restarting etanercept, the drug demonstrated
decreased efficacy due to the diminished response rates known to
occur after biologic holidays, usually associated with antibody for-
mation. However, etanercept is a fusion protein consisting of a
TNF-alpha receptor linked to the Fc portion of human IgG1 and is
therefore highly less likely to result in the formation of anti-drug
antibodies compared to the other TNF-alpha inhibitors.
Another plausible explanation to our patient’s condition may
relate to the paradoxical activation of the MAPK pathway by BRAF
inhibitors (13). In wild-type BRAF cells, the agents are known to
hyperactivate the MAPK pathway through CRAF and the formation
of RAF dimers (13). This paradoxical activation has been proposed
as the mechanism behind the development of squamous cell car-
cinomas and keratoacanthomas observed with BRAF inhibitors
(6,13). Interestingly, MAPK hyperactivity has also been implicated
in psoriasis pathogenesis, specifically p38 MAPK (14). Although p38
and ERK are two distinct groups within the MAPK family, signifi-
cant interactions between the two groups occur, and they are
each capable of activating one another (15). It is thus reasonable
to postulate that MAPK activation may have also played a role in
our patient. The mechanisms are also not mutually exclusive, and
the onset of pustular psoriasis in this case may have been a com-
bined effect of both elevated TNF-a levels and increased activation
of the MAPK pathway.
In conclusion, TNF-a has been proven to be elevated in the set-
ting of BRAF inhibition (12). This cytokine is capable of triggering a
potent immunostimulatory effect, increasing the risk of developing
TNF-a-related cutaneous events, such as psoriasis and Dupuytren’s
contractures. MAPK in wild-type BRAF cells has also been shown
to be hyperactive, suggesting a possible role for it in our patient’s
eruption (13). Physicians should be aware of these associations
and adjust the treatment regimen accordingly. It would be inter-
esting to see if psoriasis in the setting of BRAF inhibition improves
with MEK inhibitors or with increased TNF-a inhibition. This would
JOURNAL OF DERMATOLOGICAL TREATMENT 3
allow us to determine which of TNF-a or MAPK played a more sig-
nificant role in this setting. Because the immunopathogenic mech-
anisms are still largely unclear, more investigative studies are
needed to further elucidate the involved pathways and allow for
the development of targeted therapies.
Disclosure statement
Dr Menter has served as an investigator for AbbVie, Allergan,
Amgen, Boehringer Ingelheim, Celgene, Eli-Lilly, Genentech,
Janssen Biotech Inc., LEO Pharma, Merck, Novartis, Pfizer, Symbio/
Maruho, Syntrix, Wyeth; a consultant for AbbVie, Allergan, Amgen,
Convoy Therapeutics Inc., Eli-Lilly, Janssen Biotech Inc., LEO
Pharma, Novartis, Pfizer, Syntrix, Vitae, Wyeth, XenoPort; and a
speaker for AbbVie, Amgen, Janssen Biotech Inc., LEO Pharma,
Wyeth; has received honoraria from AbbVie, Allergan, Amgen,
Boehringer Ingelheim, Convoy Therapeutics Inc., Eli-Lilly,
Genentech, Janssen Biotech Inc., LEO Pharma, Novartis, Pfizer,
Syntrix, Vitae, Wyeth, XenoPort; grants from AbbVie, Allergan,
Amgen, Boehringer Ingelheim, Celgene, Genentech, Janssen
Biotech Inc., LEO Pharma, Merck, Novartis, Pfizer, Symbio/Maruho,
Syntrix; and has sat on advisory boards for AbbVie, Allergan,
Amgen, Boehringer Ingelheim, Eli-Lilly, Genentech, Janssen Biotech
Inc., LEO Pharma, and Pfizer. No other conflicts of interest to
declare. No funding organization or sponsor was involved in this
study.
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