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Medical Dermatology Practice Gaps: Insights from Mayo Clinic
David A. Wetter, M.D. Professor of Dermatology, Mayo Clinic (Rochester, MN)
American Academy of Dermatology, Summer Meeting, Chicago, IL Forum F020: Practice Gaps in Adult and Pediatric Dermatology: Illustrative Cases
July 28, 2018
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Disclosure
• I have no conflicts of interest
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Overview
•Discuss 3 clinical insights from medical dermatology based on Mayo Clinic research that addresses practice gaps
•Take home messages
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CLINICAL INSIGHTS – PART 1
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What would be the most appropriate radiologic
study to obtain in order to non-invasively
diagnose calcinosis cutis associated with
autoimmune connective tissue disease (ACTD)?
a. Bone scan
b. Computed tomography (CT) scan
c. Magnetic resonance imaging (MRI)
d. Plain radiograph (x-ray)
e. Ultrasound
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• 46 year-old woman with overlap connective tissue
disease (systemic sclerosis + rheumatoid arthritis)
• Past ACTD treatments: prednisone, methotrexate,
mycophenolate mofetil, azathioprine, adalimumab,
rituximab, and cyclophosphamide
• 14 year history of painful and ulcerative calcinosis
cutis of elbows, buttocks, and sacrum
Even dermatologists can recognize calcinosis cutis on x-ray!
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• Diagnosis:
• Consider labs, skin biopsy, imaging in cases in which diagnosis and/or extent of
calcinosis is unclear
• Management:
• No universally effective treatment – focus on control rather than “cure”
• Surgical excision of symptomatic, discrete lesions; often in conjunction with calcium
channel blocker (diltiazem)
• Don’t forget about wound care and physical therapy
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*37 patients with calcinosis cutis in
association with ACTD
*Imaging studies assessing for
calcinosis cutis formally reviewed in a
blinded fashion by 2 radiologists
*Plain radiography detected
calcinosis in all patients – thus
recommended for initial imaging of
calcinosis associated with ACTD
*5 distinct morphological patterns of
calcinosis were found:
-Nodular (most common)
-Sheet-like
-Reticular
-Amorphous
-Linear
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• When to consider imaging of calcinosis cutis
in association with ACTD?
• If diagnosis is uncertain
• To assess for presence of deep involvement
(i.e. below fat)
• Confirm diagnosis noninvasively without
skin biopsy
• Assess for presence of subclinical calcinosis
• Determine extent of calcinosis (if clinically
unclear)
• Assess for radiologic improvement in
calcinosis after starting treatment
• Document radiologic progression (or
regression) of calcinosis over time
• Note: Diagnosis can often be made on
clinical exam findings alone
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*Learning point 1 (calcinosis cutis)*
•Plain radiography (x-ray) should be the initial imaging modality for calcinosis cutis associated with ACTD
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Which of the following would be the most
appropriate treatment for calcinosis cutis
associated with autoimmune connective tissue
disease (ACTD)?
a. Dapsone
b. Isotretinoin
c. Itraconazole
d. Prednisone
e. Sodium thiosulfate
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The treatment challenge. . .
• “Calcinosis cutis is a vexatious clinical problem that is difficult to study due to the rarity of the condition.”*
• Definition of “vexatious,” according to online Merriam-Webster dictionary:
• (1a) causing vexation: distressing
• (1b) intended to harass
• (2) full of disorder or stress: troubled
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*Opening line of peer-reviewer comments to our manuscript, Sept 2011
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“Fix my arms” (chief complaint of 31 year-old woman I saw in October
2017 with longstanding dermatomyositis and associated calcinosis cutis)
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Scope of problem: Lots of reported treatments, but none uniformly effective
Gutierrez Jr and Wetter, Dermatologic Therapy 2012;25:195-206
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• This is on Mayo formulary (“topical 25% sodium thiosulfate compounded in
zinc oxide ointment”)
• Authors applied twice daily to wound base and periwound skin
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Mayo study (in press; Clin Exp Dermatol. June 2018)
19 of 28 (68%) patients had
improvement in calcinosis cutis
with topical sodium thiosulfate
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*Injected (intradermally) 0.1 mL of 12.5 g/50 mL sodium
thiosulfate into 3 mm exophytic calcinosis cutis nodule
on the fingertip
*Complete healing noted 3 weeks after initial injection
(which was repeated one week later)
J Am Acad Dermatol. 2013 Sep;69(3):e146-7
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• In addition to using topical sodium thiosulfate, the authors used
intravenous sodium thiosulfate 10 grams three times weekly for 2
weeks, then 15 grams two times weekly for 3 months
• (Note: in dermatology we typically use 25 grams intravenously three
times weekly for calciphylaxis)
Intravenous sodium thiosulfate
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Recent study showing lack of benefit with intravenous sodium thiosulfate
Used 25 grams intravenously 1-3 times weekly
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*Learning point 2 (calcinosis cutis)*
•Sodium thiosulfate (topical, intralesional, intravenous) has been reported (with varying success) for the treatment of calcinosis cutis associated with ACTD
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CLINICAL INSIGHTS – PART 2
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Which of the following conditions is most
likely to be associated with pruritus and
cutaneous dysesthesias?
a. ANCA-associated vasculitis
b. Autoimmune uveitis
c. Fibromyalgia
d. Inflammatory bowel disease
e. Rheumatoid arthritis
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Genesis of a research idea. . .
1. Many research ideas begin from a patient encounter (as this idea did)
2. Our trainees (residents, medical students) constantly teach us (while we are simultaneously teaching them)
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Patient Vignette
• 76-year-old woman with fibromyalgia
• Seen in dermatology on several occasions for nearly 2 years of intermittent (non-generalized) skin itching/burning
• Sometimes associated with “rash”
• Skin exam
• Mild dermatographism
• Mildly dry skin
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Patient Vignette (continued)
• Skin biopsy
• “Urticarial tissue reaction” (routine microscopy)
• Direct immunofluorescence (DIF) - negative
• Normal/negative labs
• BP 180/230
• Indirect immunofluorescence
• Anti-tissue transglutaminase antibodies
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Patient Vignette (continued)
• Otherwise in good health, followed regularly by her general internist
• Treatments for skin
• Dry skin care
• Discontinuation of aspirin (only “new” medication prior to her itching)
• Topical corticosteroids
• Topical camphor/menthol
• Mirtazapine
• Multiple antihistamines (doxepin, cetirizine, ranitidine, fexofenadine)
• Gabapentin (prescribed, but patient did not take)
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Daily Itch Score Diary Quantified by Patient as “Large, Minimal, None”
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But You Need to Listen to Your Patients...
• On several occasions the patient brought me information from the Internet and asked
• “Do you think my skin itching could be related to my fibromyalgia?”
• My response: “That is very interesting, but I am not sure” (Sadly, I did not even review the literature despite her astute insight!)
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And You Also Need to Listen to Your Students!
• Several months later I saw the patient with one of our first-year dermatology residents, and the patient again asked
• “Do you think my skin itching could be related to my fibromyalgia?”
• This time I didn’t make the same mistake (but only because I was working with a bright and curious dermatology resident!)
• The resident asked me: “Do you think her itching and fibromyalgia might be related? Should we explore the literature?”
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The Culmination of our Inquiry...
Abstract The aim of this study was to determine the common dermatologic diagnoses and skin-related symptoms in a cohort of patients with fibromyalgia seen in a tertiary referral center. A retrospective chart review was performed of all patients with a fibromyalgia diagnosis from January 1 to December 31, 2008, whose diagnosis was confirmed in the Fibromyalgia and Chronic Fatigue Clinic at Mayo Clinic in Rochester, Minnesota. Charts were reviewed for dermatologic conditions and cutaneous symptoms. Demographic and clinical data were collected to assess the frequency of skin-related issues in patients with fibromyalgia. Of 2,233 patients screened, 845 patients met the inclusion criteria of having a confirmed diagnosis of fibromyalgia. Among these fibromyalgia patients, various dermatologic conditions and cutaneous problems were identified, including hyperhidrosis in 270 (32.0 %), burning sensation of the skin or mucous membranes in 29 (3.4 %), and various unusual cutaneous sensations in 14 (1.7 %). Pruritus without identified cause was noted by 28 patients (3.3 %), with another 16 patients (1.9 %) reporting neurotic excoriations, prurigo nodules, or lichen simplex chronicus. Some form of dermatitis other than neurodermatitis was found in 77 patients (9.1 %). Patients with fibromyalgia may have skin-related symptoms associated with their fibromyalgia. No single dermatologic diagnosis appears to be overrepresented in this population, with the exception of a subjective increase in sweating.
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Abnormal Skin Findings in Fibromyalgia
Authors, year
Fibromyalgia
patients, no.
Controls,
no. Findings in skin biopsy specimens
Beritze et al, 2010 63 49 Increased mast cells
Cordero et al, 2010 2 2 CoQ10 deficiency, mitochondrial dysfunction, increased
oxidative stress
Kim et al, 2008 13 5 Peripheral localization of axons within unmyelinated Schwann
cell sheaths
Salemi et al, 2007 25 10 Increased interleukin δ and κ opioid receptor expression
Salemi et al, 2003 53 10 Increased interleukin-1β, interleukin-6, and tumor necrosis
factor α
Jeschonneck et al,
2000 20 20
Vasoconstriction and decreased temperature within tender
points
Enestrom et al, 1997 25 22 Increased mast cell degranulation and intradermal IgG deposits
Skin Biopsy Findings of Patients With Fibromyalgia Compared With Controls in the Literature, Listed in Order of Publication Date
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Number and Percentage of Patients With Fibromyalgia Who Had Various Dermatologic Diseases and Symptoms, Listed in Order of Frequency
Condition Patients affected, no (%)
Increased sweating 270 (32.0)
Dermatitis excluding neurodermatitis 77 (9.1)
Pruritus 28 (3.3)
Raynaud phenomenon 22 (2.6)
Psoriasis 19 (2.2)
Acne, other 18 (2.1)
Rosacea 18 (2.1)
Burining skin sensation 17 (2.0)
Cutaneous pain/odd sensations 14 (1.7)
Folliculitis 14 (1.7)
Urtcarial 13 (1.5)
Burning/painful mouth/tounge 12 (1.4)
Hair loss/telogen effuvium 12 (1.4)
Rash, other 10 (1.2)
Neurodermatitis/excoriations 8 (0.9)
Oral ulcers 7 (0.8)
Cutaneous lupus 6 (0.7)
Prurigo nodules 4 (0.5)
Lichen simplex chronicus 4 (0.5)
Lichen planus 4 (0.5)
Vasculitis 3 (0.4)
Acne excoriée 3 (0.4)
Lichen sclerosus 2 (0.2)
Hidradenitis suppurativa 2 (0.2)
Livedo reticularis 2 (0.2)
Systemic sclerosis (limited) 1 (0.1)
Morphea 1 (0.1)
Dermatitis herpetiformis 1 (0.1)
Darier disease 1 (0.1)
Trichotillomania 1 (0.1)
Calcinosis cutis 1 (0.1)
Erythromelalgia 1 (0.1)
Our Mayo Clinic Study Retrospective Review
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• Demographics (845 total patients)
• 766 female (90.7%)
• Median age, 49 years (range, 17-84)
• Dermatologic diseases and symptoms [n (%)]
• Increased sweating – 270 (32.0%)
• Itchy/burning dermatoses – 87 (10.4%)
• Pruritus – 28 (3.3)
• Burning skin sensation – 17 (2.0)
• Cutaneous pain/odd sensations – 14 (1.7)
• Burning/painful mouth/tongue – 12 (1.4)
• Neurodermatitis/excoriations – 8 (0.9)
• Prurigo nodules – 4 (0.5)
• Lichen simplex chronicus – 4 (0.5)
• Erythromelalgia – 1 (0.1)
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• Other “neurodermatoses” – 4 patients
• Acne excoriée – 3
• Trichotillomania – 1
• Other notable diseases
• Dermatitis (excluding neurodermatitis) – 77 (9.1)
• Psoriasis – 19 (2.2)
• Urticarial – 13 (1.5)
• Cutaneous lupus – 6 (0.7)
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Brief Thoughts on Clinical Findings
• “Itchy/burning dermatoses” – 10.4% of Mayo cohort
• Supports previous study showing increased neurotic excoriations in fibromyalgia compared to controls
• Highlights skin and mucosal symptoms may occur as a result of the fibromyalgia itself
• Should be a diagnosis of exclusion
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Could some fibromyalgia patients have a small-fiber neuropathy leading to abnormal skin sensations
(which in turn could be detected by TST)?
Thermoregulatory
sweat testing (TST)
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Skin Itching and Burning in Fibromyalgia Indicative of a Bigger Knowledge Gap in Dermatology?
Pruritus was one of 3 areas
selected by the American
Academy of Dermatology
(AAD) as a research gap
that needs to be filled
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Chronic pruritus
Primary skin lesions with or without chronically scratched lesions present
Dermatologic cause
• Atopic eczema
• Psoriasis
• Xerosis
• Scabies
• Contact dermatitis
• Insect bite
• Lichen planus
No primary skin lesions; chronically scratched lesions present or absent
Nondermatologic cause
Systemic cause
• Chronic kidney disease
• Cholestasis
• Hodgkin’s lymphoma
• Polycythemia vera
• HIV infection
• Hyperthyroidism
Neuropathic cause
• Brachioradial pruritus
• Notalgia paresthetica
• Postherpetic itch
Psychogenic cause
• Obsessive-compulsive
disorder
• Delusions of parasiotsis
• Substance abuse
• Complete blood count and differential count
• Creatinine level
• Liver-function test
• Thyroid-function test
• Erthrocyte sedimentation rate
• HIV serologic analysis
• Chest radiography
• Drug history
Based on Mayo study and other
research, should fibromyalgia be
added as a “neuropathic cause”
of pruritus?
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Melding Basic Science With Clinical Practice in Fibromyalgia...
Medication Common dose Side effects Medical condition Comments
Anticonvulsants
Gabapentin 100 to 200 mg orally
three times daily
Drowsiness, constipation, leg
swelling
Neuropathic itch (high dose, up to
3600 mg daily); pruritus from chronic
kidney disease (low dose, 100 to 300
mg three times a week after dialysis)
Pregabalin 25 to 200 mg orally twice
daily
Drowsiness, leg swelling
Antidepressants
Paroxetine 10 to 40 mg orally once
daily
Insomnia, dry mouth, sexual
dysfunction
Generalized pruritus, paraneoplastic
itch, psychogenic pruritus
Mirtazapine 7.5 to 15 mg orally once
daily
Drowsiness, dry mouth,
increase in appetite, weight
gain
Generalized pruritus, nocturnal itch
Amitriptyline 25 to 150 mg once daily
or up to 3 divided doses
Drowsiness, dizziness,
constipation, dry mouth,
blurred vision
Neuropathic itch Urinary retention, heart palpitations, low
blood pressure, confusion in elderly
Opioids
Mu antagonist Naltrexone, 12.5 to 50
mg orally once daily
Nausea and vomiting,
abdominal cramps, diarrhea,
hepatoticity
Intractable itch, cholestatic pruritus,
possibly pruritus from chronic kidney
disease
Kappa agonist and
mu antagonist
Butorphanol, 1 to 4 mg
inhaled at bedtime
Drowsiness, dizziness,
nausea, vomiting
Intractable itch
NEJM 368:17, 2013
Commonly Used Topical and Systemic Medications for Chronic Pruritus
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Melding Basic Science With Clinical Practice in Fibromyalgia...
Abnormalities found in skin biopsies of fibromyalgia patients provide rationale for pursuing certain classes of pruritus treatments in those with fibromyalgia AND pruritus or skin dysesthesias
• Anticonvulsants (“neuropathic” itch)
• Antidepressants
• Opioid (antagonists)
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*Learning Points (Fibromyalgia and Skin)*
• Dermatologic symptoms and findings are common in fibromyalgia patients, including: A subjective increase in sweating, and dermatoses manifesting as itching or burning of the skin
• Cutaneous symptoms can occur directly as a result of fibromyalgia (but this is a diagnosis of exclusion)
• Further studies are needed to determine if traditional fibromyalgia treatments may have a beneficial effect on cutaneous problems in patients with fibromyalgia
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CLINICAL INSIGHTS – PART 3
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A 73 year-old man
developed painful
ulcerations nine days
after bilateral knee
replacement surgery.
Which of the following is
the most appropriate
treatment?
a. Arterial revascularization
b. Cephalexin
c. Fluconazole
d. Prednisone
e. Surgical debridement
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We were consulted Saturday morning and received
many concerned messages from General Internal
Medicine service, Infectious Diseases, and
Orthopedics:
• Will this erode into the patellar tendon?
• Will prednisone inhibit wound healing?
• Should this be surgically debrided?
• Should this patient be immobilized to protect his
knees?
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Diagnosis: postoperative pyoderma
gangrenosum (PG)
• Note violaceous and undermined
borders
Workup was negative for:
• Infection
• Systemic diseases typically
associated with PG:
• Inflammatory bowel disease
• Hematologic malignancy
• Rheumatoid arthritis
• Monoclonal gammopathy
Prednisone 90 mg daily (1 mg/kg) was
initiated and tapered by 10 mg each
week
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12 days after initiation of prednisone
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2 months after initiation of prednisone
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Initial patient that prompted us to analyze
our Mayo experience with postoperative PG
(urgent Saturday morning hospital consult)
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• 18 patients with postoperative PG from Mayo Clinic-Rochester
• 3 patients had a previous history of PG
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• 34% had an associated
systemic disease
• Approximately 4% had
a previous history of PG
• Approximately 4% had
a family history of PG
140 published cases from 1978-2012
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• Usually occurs 1 week postoperatively
• Often misdiagnosed as infection;
surgical debridement often erroneously
performed prior to dermatologic
consultation (which worsens PG)
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Recent article found 5.5% of procedures in patients with history of PG led
to postoperative PG or exacerbation of pre-existing PG
• Higher risk with (1) more invasive procedures and (2) chronically-
present PG (present for > 1 year duration)
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Which of the following
strategies most effectively
reduces the risk of
recurrence of the depicted
peristomal ulceration after
surgical treatment?
a. Concomitant perioperative immunomodulator/immunosuppressive treatment
b. Mupirocin ointment to the wound base until healed
c. Postoperative use of vacuum-assisted closure (wound VAC)
d. Prophylactic intravenous antibiotics for one week postoperatively
e. Ultrasonic (ultrasound) mist therapy to the postoperative wound
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• 44 patients with peristomal
pyoderma gangrenosum
(PPG) from Mayo Clinic-
Rochester
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• 41 patients (93%) had
underlying inflammatory
bowel disease (IBD)
• PPG developed 5.2 months
(mean) or 1.5 months
(median) after stoma
surgery
• Only 2 patients (5%) had a
previous history of PG
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• Variety of treatments
employed for PPG
• Remission (disease-
free for at least 2 years)
was commonly
achieved (29 of 31 with
follow-up data [94%])
• Mean time of 10.7
weeks to achieve
complete response
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Can Stoma Surgery be an
Effective Treatment for PPG?
• Stoma closure: Definitive surgical take down of
a stoma (with excision of PPG) without creation
of a new stoma
• Stoma revision: Surgical take down of a stoma
(with excision of PPG) and reconstruction of a
stoma at the same site
• Stoma relocation: Surgical take down of a
stoma (with excision of PPG) and reconstruction
of a stoma at a different site
• Recurrence of PPG: Development of PPG at the
new (relocation) or revised (revision) stoma site
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• 26 stoma surgeries in 20 patients
• 16 patients had stoma revision/relocation
• 11 had one procedure; 5 had two
procedures
• 4 patients had stoma closure
• 1 had two closure operations (stomas
created and closed 2 years apart)
• 4 of 5 procedures performed while on
concomitant medical therapy
• STOMA CLOSURE
• 100% complete response
• 0% recurrence
• STOMA REVISION/RELOCATION
• 100% complete response
• 60% recurrence (12 of 20 procedures)
**Stoma relocation/revision:
• If not receiving
concomitant medical
therapy: 60% PPG
recurrence rate
• If receiving concomitant
medical therapy: 33%
PPG recurrence rate
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Stoma surgery in IBD
usually performed for a
variety of reasons
Most of our patients had
stoma surgery due to their
underlying IBD or stoma-
related complications
• 7 of 26 (27%) had PPG
listed as an indication
for stoma surgery
*Our study supports that surgical treatment of PPG
may be effective and can be considered for select
patients, particularly those receiving concomitant
immunomodulators/immunosuppressives for their
underlying IBD and/or PPG (as this may decrease
PPG recurrence)
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Recent systematic review that highlights:
• Clinical features of PPG
• Surgical intervention (such as stoma closure, resection of active IBD) may be
effective for PPG (in contrast to classic ulcerative PG)
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*Learning Points (Pyoderma Gangrenosum [PG])*
• Recognition and management of two distinct variants of PG
• Postoperative PG
• Peristomal PG
• (See upcoming “SUMMARY” slide for additional details)
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**SUMMARY (TAKE HOME MESSAGES)** • Consider imaging in the (1) evaluation of calcinosis cutis and (2)
assessment of therapeutic response
• Plain radiography is the imaging modality of choice
• Sodium thiosulfate (including topical) can be successfully used to treat calcinosis cutis
• Fibromyalgia may be associated with pruritic dermatoses and dysesthesias – treatment directed at fibromyalgia and/or neuropathic itch mechanisms may be helpful in such patients
• Be aware of postoperative PG – prompt recognition with treatment with prednisone (and avoidance of surgical debridement) substantially decreases morbidity
• Surgical intervention (stoma closure, relocation/revision) can be effective for peristomal PPG
• Concomitant immunomodulatory agents can decrease recurrence risk