An unusual presentation of Sweet syndrome in a patient with
ulcerative colitis treated with a tumor necrosis factor alpha inhibitor:
a case report
Author: Yung-Chun Chang1,2, Hui-Ju
Yang3,4
1 Institute of Medicine, China Medical University,
Taichung, Taiwan
2 Changhua Christian Hospital, Changhua, Taiwan
3 Institute of Medicine, Chung Shan Medical
University, Taichung, Taiwan
4 Department of Dermatology, Changhua Christian
Hospital, Changhua, Taiwan
Running Head: Unusual presentation of Sweet syndrome
- [Corresponding Author]: Hui-Ju Yang
- [Institution]: Department of Dermatology, Changhua Christian
Hospital, Changhua, Taiwan
- [Institution Address]: No. 135, Nanxiao St., Changhua City,
Changhua County 500054, Taiwan (R.O.C.)
- [Author e-mail address]:u103001425@cmu.edu.tw
- [Corresponding Author E-mail address]:149777@cch.org.tw
- [Tel]: area code (Taiwan/886) -4-7238595 (extend number 4361)
- [Fax]: area code (Taiwan/886) -4-7232942
(b) Key clinical message
When distinguishing between extra-intestinal cutaneous manifestation
flare-ups and drug-induced skin lesions, anti-TNF agents should be
withheld, and steroid doses increased in cases of suspected
anti-TNF-agent-induced Sweet syndrome.
(c) Abstract
Tumor necrosis factor (TNF) alpha inhibitors are widely used to treat
inflammatory bowel disease (IBD) and Sweet syndrome is known as an
extra-intestinal cutaneous manifestation of IBD. We wish to highlight a
paradoxical case and successful management of anti-TNF-agent-induced
Sweet syndrome compared with Sweet syndrome treated by anti-TNF agents.
Keyword: Sweet syndrome, ulcerative colitis, tumor necrosis factor alpha
inhibitor, adverse event, cytokine dysregulation
(d) Main text
Introduction
Sweet syndrome, also known as acute febrile neutrophilic dermatosis,
is characterized by sudden-onset fever, neutrophilia, and erythematous
painful macules, papules, and nodules on the whole body. This condition
is a characteristic neutrophilic dermatoses, and its histopathologic
presentation demonstrates dense diffuse infiltrate of neutrophils and
massive edema of the papillary dermis.1 The
pathogenesis is unclear and multifocal but is associated with cytokine
dysregulation caused by infection, malignancy, or
medication.2
Sweet syndrome is also a rare extraintestinal manifestation (EIM) of
inflammatory bowel disease (IBD) that can be controlled by anti-tumor
necrosis factor (TNF) agents.3-5 Interestingly, some
studies have reported that Sweet syndrome can develop in patients with
IBD being treated with anti-TNF therapy.6, 7 The
objective of this clinical case study is to compare
anti-TNF-agent-induced Sweet syndrome with EIMs of IBD. This case may
aid medical physicians in determining whether to discontinue anti-TNF
agents when facing the dilemma of this differential diagnosis. We also
review articles about the anti-TNF-agent-induced paradoxical effect
compared with our case.
Case presentation
A 62-year-old male patient with ulcerative colitis presented with
diffuse generalized skin rashes and a low-grade fever after one month of
adalimumab therapy. He was concurrently receiving systemic prednisone
and mesalazine.
Three months prior, the patient presented to a gastroenterology
outpatient department with a one-week history of frequent bloody
diarrhea (>20 times per day), severe abdominal cramps, and
fever. Examination revealed tenderness and guarding in the left lower
abdominal quadrant. Colonoscopy revealed ulceration involving the
rectum, entire sigmoid, and left to ascending colon. Multiple biopsies
of the colon revealed neutrophilic infiltration in the lamina propria
with cryptitis. He responded well to prednisolone and mesalazine for
ulcerative colitis. However, prednisolone was not weaned to 10 mg daily,
and he was re-admitted to the hospital due to flare-up bowel symptoms.
He responded well to high-dose steroids (40 mg of intravenous
methylprednisolone every 12 hours). After discharge, adalimumab (initial
dose of 160mg on September 21, 2020, 2nd dose of 80 mg
2 weeks later, and 3rd dose of 40 mg one month later)
was added to his treatment with daily prednisolone (20 mg) and
mesalazine (2400 mg). After one month of these concurrent treatments
(with prednisolone tapered from 20 mg to 5 mg to 2.5 mg), he suffered
from diffuse generalized rashes, malaise, and a low-grade fever
(37.8°C).
Physical examination revealed multiple tender erythematous papules,
macules, and plaques involving his face, back, upper and lower
extremities, palms, and soles (Fig. 1). Laboratory investigations
revealed a leukocytosis with 10,200/uL leukocytes, peripheral
neutrophilia with 75.6% neutrophils, and elevated inflammatory markers
with positive C-reactive protein. Skin biopsy of his left hand revealed
edematous change on the dermal papillae and diffuse inflammatory
infiltration in the upper dermis, perivascular and periadnexal areas,
and deep dermis, predominantly composed of neutrophils (Fig. 2). A few
scattered eosinophils in the interstitial tissue were noted. No definite
leukocytoclastic vasculitis was seen. Direct immunofluorescence for IgG,
IgA and C3 were negative, and no pathogens were detected by periodic
acid-Schiff (PAS) stain.
Based on the diagnostic criteria, a definitive diagnosis of
neutrophilic dermatosis (Sweet syndrome) was made. After increasing the
steroid dose and discontinuing adalimumab, he had marked symptom
improvement in five days (Fig. 3). No recurrent symptoms of skin or IBD
occurred within 6 months after weaning the prednisolone dose to 2.5 mg.
Discussion
Sweet syndrome is known as an EIM and a rare natural course of
IBD.8 With increasing use of anti-TNF agents to treat
IBD, more cutaneous adverse events have been reported, of which the
prevalence among patients with IBD ranges between 5% and
10%.9 Some cases of anti-TNF-induced Sweet syndrome
have been reported, while some cases of Sweet syndrome as an EIM of IBD
treated with anti-TNF agents have been reported.3-7Considering that Sweet syndrome is treated or triggered by anti-TNF
agents, medical physicians must decide whether discontinue anti-TNF
agents.
The origin of Sweet syndrome in this case was unclear, and the
probable causes included EIMs of IBD or medication (adalimumab).
Prednisolone could not be tapered to 10 mg daily, and the patient was
admitted due to a flare of ulcerative colitis at the first
hospitalization. After discharge, he responded well to prednisolone,
mesalazine, and adalimumab, which was newly added. Unfortunately, when
prednisolone was tapered to 2.5 mg, he presented with multiple
polymorphic skin rashes on the whole body. With the previous failure to
taper prednisolone, an EIM and flare of ulcerative colitis was suspected
initially because cutaneous manifestations parallel IBD
activity.8 However, drug-induced skin lesions were
probable owing to the temporal relationship between the adalimumab
treatment and clinical presentation. A marked improvement in skin
lesions was observed by increasing the steroid dose and discontinuing
adalimumab. Furthermore, he did not suffer from bowel symptoms and skin
manifestations for 2 months after weaning prednisolone to 2.5 mg without
adalimumab. According to the diagnostic criteria for drug-induced Sweet
syndrome, adalimumab-induced Sweet syndrome was suspected because all
five of the following criteria were met: abrupt onset of painful skin
lesions, histopathologic evidence, pyrexia, temporal relationship
between drug ingestion and clinical presentation, and improvement in
skin lesions after treatment with corticosteroids and drug
withdrawal.10
Among reported cases of adalimumab-induced Sweet syndrome, the period
from adalimumab administration to skin lesion appearance ranged from 3
to 14 months; thus, differential diagnosis by presentation and
resolution alone is difficult.6, 7 Anti-TNF agents
should be discontinued and steroid doses increased in cases of probable
anti-TNF-agent-induced Sweet syndrome.
TNFα is a proinflammatory cytokines, and anti-TNF agents are
breakthrough therapeutic treatments for inflammatory disease. However,
numerous paradoxical effects including psoriasiform skin lesions have
been reported.9 he mechanisms of these paradoxical
reactions remain controversial. One hypothesis is that inhibiting TNF
induces interferon (IFN) production, which might lead to
psoriasis.11, 12 Another is that TNF blockade has an
immunoregulatory role in decreasing expansion of Treg cells and
increasing Th17 function, leading to exacerbated skin
inflammation.2, 13 These mechanisms are associated
with cytokine imbalance under anti-TNF treatment. There are few cases of
adalimumab-induced Sweet syndrome.6, 7 The molecular
and cellular mechanisms and pathogenesis of Sweet syndrome are
unclear;2 however, cytokine dysregulation is
suspected.14 In summary, Sweet syndrome may be
triggered in some patients with cytokine dysregulation caused by
anti-TNF agents; in other patients, Sweet syndrome may be an EIM
controlled by anti-TNF agents.
A limitation of this study is that the histopathologic evidence was
atypical. Skin biopsy revealed characteristic edematous change of the
dermal papillae and diffuse inflammatory infiltration in the dermis.
However, the neutrophilic infiltration was not as dense as typical
patterns. Even though clinicopathological presentations in different
categories of Sweet syndrome are similar, there are slight variations
owing to the different underlying etiologies including infection,
medication, and malignancy.10 A significant increase
in Th1 cytokines in classic Sweet syndrome leads to neutrophil
activation and localization, while a remarkable presence of Th17
cytokines in anti-TNF-agent-induced Sweet syndrome creates an
inflammatory response and localizes neutrophils by producing multiple
inflammatory molecules and inducing adhesion
molecules.2, 13 Moreover, neutrophilia is uncommonly
present in drug-induced Sweet syndrome.15 The
intensity of neutrophilic infiltration and adhesion formation may be
related to different immunologic pathways leading to the same endpoint
of leukocytosis. The study of different pathological patterns including
classical, malignancy-associated, and drug-induced Sweet syndrome is
limited, and further study should be conducted for differential
diagnosis.
When distinguishing between EIM flare-ups and drug-induced skin
lesions, anti-TNF agents should be withheld, and steroid doses increased
in cases of suspected anti-TNF-agent-induced Sweet syndrome. In
addition, determining the temporal relationship between drug ingestion
and clinical presentation is pivotal. In appropriate situations,
patients can be re-challenged to confirm a definitive diagnosis
drug-induced Sweet syndrome. Further studies should be conducted to
clarify the relationship of cytokine dysregulation between Sweet
syndrome and the paradoxical effects of anti-TNF agents to elucidate
which patients are vulnerable to Sweet syndrome during anti-TNF
therapy.
(e) Acknowledgments
We sincerely thank the patient. We thank all the nursing staff, who
provided expertise and care for patients. This study received no
specific funding. Both authors are the patients’ doctors. All Authors
read and approved the manuscript
(f) Conflict of interest statement
The authors declare no conflict of interest.
(g) ORCID number (Yung-Chun Chang): 0000-0001-9658-7923
Corresponding Author (Hui-Ju Yang): 0000-0002-0193-4687
(h) Funding source: no specific funding
(i) Data sharing statement: All data are available to facilitate
research reproducibility
(j) Authorship
YCC: primary author of the final manuscript, writing the manuscript and
reviewing it; YCC, HJY: involved in study concept; HJY: contributed with
pathological expertise and images and revised the manuscript, involved
in critical revision
(k) Ethical statement
An informed consent was obtained. All procedures performed in this study
were following the ethical standards of the national research committee.
(m) References
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(l) Figure legends
- Figure 1: Initial clinical presentation. Multiple painful erythematous
papules, macules, and plaques involving the (a) back, (b) palm, and
(c) lower extremities after adalimumab therapy.
- Figure 2: Histopathological presentation. (a) A low magnification
shows diffuse inflammatory infiltrate in the upper dermis and deep
dermis. (hematoxylin and eosin stain [H&E], x40 magnification)
(b) An intermediate magnification shows prominent papillary dermal
edematous change. (H&E, x100 magnification) (c) A high magnification
view shows perivascular and periadnexal lymphocytic infiltrate,
predominantly composed of neutrophils. A few scattered eosinophils are
noted and no definite leukocytoclastic vasculitis is found. (H&E,
x400 magnification)
- Figure 3: (a-c) Marked lesion improvement after two days of
withholding adalimumab and increasing the steroid dose.