Medical Dermatology Practice Gaps: Insights from Mayo Clinic F021 - Wetter... · Increased...

©2015 MFMER | 3440206-1

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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slide-9

*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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slide-10

• 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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©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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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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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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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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• 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

Medical Dermatology Practice Gaps: Insights from Mayo Clinic F021 - Wetter... · Increased...

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