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3.8 Xanthomas
mainly cholesterol ester core and B-100 on
surface)
Uptake into hepatocytes by apo B-100/E
♦ High-density lipoprotein (HDL): removes
• Tuberous xanthomas: yellow-pink indurated nodules
cholesterol from tissues
Free cholesterol esteried by lecithin:
• Tendinous xanthomas: rm nodules on Achilles tendon
cholesterol acyltransferase
Requires apoprotein A-I on HDL
• Hyperlipidemias have a variety of clinical ndings
(Table 3.25)
Cutaneous xanthoma types
• Plane xanthomas: may be localized or diffuse
• Eruptive xanthomas: numerous red-yellow papules on
extensor surfaces, buttocks, intertriginous areas, and
orally (Fig. 3.72)
■
Triglycerides usually . 3000 mg/dL
■
Pathogenesis: may be primary or secondary
Primary: type I, IV, and V hyperlipidemias
Secondary: obesity, diabetes, alcohol abuse,
medication-induced (oral retinoids, protease
Table 3.25 Important Hyperlipoproteinemias
Type Pathogenesis Laboratory Findings
Type I (familial LPL
deficiency, familial
hyperchylomicronemia)
Type II (familial
hypercholesterolemia
or familial defective apo
B-100)
Type III (familial
dysbetalipoproteinemia,
remnant removal disease,
broad beta disease, apo E
deficiency)
Type IV (endogenous familial
hypertriglyceridemia)
Type V Elevated chylomicrons and
a
Gain-of-function mutations cause autosomal dominant hypercholesterolemia, whereas loss-of-function mutations (most prevalent in African Americans) result in
low LDL levels.
b
Said to be pathognomonic for homozygous state.
Apo, Apolipoprotein; HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LPL, lipoprotein lipase; PCSK9,
proprotein convertase subtilisin/kexin type 9; VLDL, very-low-density lipoprotein.
Modied from Massengale WT. Xanthomas. In: Bolognia JL, Schaffer JV, Cerroni L. Dermatology. 4th ed. Philadelphia: Elsevier; 2018:1634–1643.
Deficient or abnormal LPL Slow chylomicron
Apo C-II deficiency Reduced LDL and HDL
Deficient glycosyl-
phosphatidylinositol-anchored
HDL-binding protein
LDL receptor defect
Reduced afnity of LDL for LDL
receptor due to dysfunction of
apo B-100 (ligand)
Accelerated degradation of LDL
receptor due to missense
PCSK9 mutations
Defective LDL receptor adaptor
protein 1 (required for receptor
internalization)
Hepatic remnant clearance
impaired due to apo E
abnormality; patients only
express the apo E
interacts poorly with the apo E
receptor
Elevated production of
VLDL associated with
glucose intolerance and
hyperinsulinemia
VLDLs; subset related to apo
A-V defect
a
isoform that
2
clearance
levels
Hypertriglyceridemia
Reduced LDL clearance
Hypercholesterolemia
Elevated levels of chylomi-
cron remnants and IDLs
Hypercholesterolemia
Hypertriglyceridemia
Increased VLDLs
Hypertriglyceridemia
Decreased LDLs and HDLs
Hypertriglyceridemia
inhibitors, olanzapine, and estrogen
replacement)
mainly on elbows and knees
■
Most strongly a/w type II and III
and extensor tendons of ngers/hands that develop in
third decade
■
Usually seen in type II hyperlipidemia (.type III)
■
Occurrence on palmar/nger creases (xanthoma
striatum palmare) nearly pathognomonic for
dysbetalipoproteinemia (Fig. 3.73)
■
Occurrence in intertriginous areas and web spaces of
ngers usually diagnostic of homozygous familial
hypercholesterolemia (type II hyperlipidemia)
(Fig. 3.74)
■
May occur in monoclonal gammopathy (plasma cell
dyscrasia usually) with no lipid abnormalities; favors
neck, upper trunk, intertriginous and periocular areas
Clinical Findings
Skin (Types of
Xanthoma) Systemic
Eruptive No increased risk of
Tendinous,
tuberoeruptive,
tuberous, plane
(xanthelasma,
intertriginous areas,
interdigital web spaces
Tuberoeruptive,
tuberous, plane
(palmar creases
5 strongly a/w
dysbetalipoproteinemia)
Tendinous
Eruptive Frequently associated
Eruptive Diabetes mellitus
coronary artery disease
Atherosclerosis of
peripheral and coronary
arteries
b
)
Atherosclerosis of
peripheral and coronary
arteries
with type 2 non-insulindependent diabetes
mellitus, obesity, alcoholism
165
CHAPTER 3 • General Dermatology
Fig. 3.72 Eruptive xanthomas (due to hypertriglyceridemia) typically occur on the
extensor surface of the lower extremities, particularly the knees. (From Ko CJ,
Cowper SE. Dermatologic conditions in kidney disease. In: Yu ASL, Chertwo
GM, Luyckx VA, Marsden PA, Skorecki K, Taal MW, eds. Brenner & Rector’s the
Kidney. 11th ed. Philadelphia: Elsevier; 2020:1932–1944. Courtesy Yale Residents’ Collection.)
Fig. 3.73 Xanthomas of palmar striae. (From James WD, Elston DM, Treat JR,
Rosenbach MA, Neuhaus IM. Pruritis and neurocutaneous dermatoses. In: An-
drews’ Diseases of the Skin. 13th ed. Philadelphia: Elsevier; 2020:46–62.)
• Xanthelasma 5 plane xanthoma on eyelids
■
Only 50% have hyperlipidemia
■
Surgical treatment is best option
• Verruciform xanthoma:
■
Benign verrucous plaque(s) typically occurring in
mouth or genital area
■
Often confused for warts clinically and histologically
■
Not a/w hyperlipidemia
■
May be a/w CHILD (congenital hemidysplasia with
ichthyosiform erythroderma and limb defects) syndrome
and any disorder that causes epidermal damage
(epidermolysis bullosa, GVHD, LS&A, and pemphigus)
■
Unique histology: papillomatous epidermal
hyperplasia w/ foam cells in dermal papillae
Pathology
• Foam cells (macrophages w/ lipidized cytoplasm) in dermis
■
Foam cells located more supercially in plane
xanthomas, and deeper in dermis/subcutaneous tissue
in tuberous and tendinous xanthomas
Fig. 3.74 Plane xanthoma. (From James WD, Berger TG, Elston DM, Neuhaus
IM. Errors in metabolism. In: Andrews’ Diseases of the Skin. 12th ed. Philadelphia: Elsevier; 2016:509–541.)
Treatment
• Determine underlying lipoprotein disorder and
contributing factors, correct via various interventions
(dietary modications, lipid-lowering medications,
surgical excision, and chemotherapy in certain
monoclonal gammopathies)
3.9 URTICARIA AND ANGIOEDEMA
Urticaria
Epidemiology
• Up to 20% of population will have acute urticaria
(duration , 6 weeks)
■
1% may develop into chronic urticaria (duration
$ 6 weeks)
• F . M overall, and for chronic urticaria,
dermatographism, and cold urticaria
■
M . F for delayed pressure urticaria
Pathogenesis
• Many cases of urticaria are idiopathic and causes vary
(e.g., allergy, autoimmune, infections, and drugs)
• In children, the most common cause is viral or
idiopathic, but other causes include:
■
Infectious (assess for symptoms of UTI, URI, or GI
infection)
166
3.9 Urticaria and Angioedema
■
Allergic: foods, meds, and other environmental allergens
■
Physical stimuli: pressure, solar, cholinergic, cold
■
Arthropod bite reactions (“papular urticaria”)
■
Malignancy (most commonly lymphoma)
• Mast cell is the primary cell responsible for urticaria
(though basophils and eosinophils play role)
■
Contains proinammatory mediators:
Preformed: histamine, proteases, and heparin
Newly-formed: prostaglandin D2, leukotrienes C4/
D4/E4, platelet-activating factor, and cytokines
(TNF-a, IL-1, IL-4, IL-5, IL-6, and IL-8)
■
Degranulating stimuli → release of mediators by mast
cells
Immunologic mechanisms: autoantibodies against
FcRI (seen in up to 30% of chronic urticaria
patients; occurs via autoimmune cross-linking of
receptors) or IgE; IgE-dependent allergic response
(e.g., to food, med, latex, or infection); ↑ frequency
of HLA-DR4 and -DQ8
♦ Drug-induced immunologic urticaria: PCN and
cephalosporins (.TMP-SMX, and minocycline),
latex gloves, or medical devices
Non-immunologic mechanisms: opiate-mediated
release of mast cell contents, C5a anaphylatoxin, stem
cell factor, neuropeptides (e.g., substance P and
vasoactive intestinal peptide)
• Other causes of urticaria include immune complex
deposition (i.e., urticarial vasculitis), vasoactive stimuli
like nettle, ASA/NSAIDs, radiocontrast media,
polymyxin B, ACE inhibitors (due to ↑ bradykinin), and
dietary pseudoallergens
■
ASA → exacerbation of chronic urticaria in 30%
Clinical features
• Characterized by wheals: swelling and erythema of skin
from plasma leakage in supercial dermis
■
May have “are” of erythema surrounding them
■
Intensely itchy
■
Individual lesions last , 24 hours
• “Acute” versus “chronic” urticaria:
■
Acute:
Most common causes: idiopathic (#1) . URIs (#2)
. drugs (b-lactams most common) and foods
Typically fast-onset (exception: drug-induced acute
urticaria may start days after triggering agent)
■
Chronic:
Most common causes: “ordinary” (60%; consists of
idiopathic and autoimmune autoantibodies against
FcRI or Fc portion of IgE, infection-related, and
pseudoallergic) . physical (35%) . vasculitic (5%)
Autoimmune etiology in up to 50%
a/w Autoimmune thyroid disease, vitiligo, IDDM,
RA, Helicobacter pylori gastritis, and parasitic infections
Mean duration: 3 to 5 years
• Physical urticaria: induced by physical stimuli
■
Dermatographism: urticaria develops at sites of
friction/scratching/stroking
Most common physical urticaria
Reproducible by scratching back—occurs seconds to
minutes after provocation
Worse in evening
■
Delayed pressure urticaria: deep red swelling
(angioedema) at anatomic areas of high friction/pressure
(e.g., waistline after wearing tight-tting clothes)
May be quite delayed, up to 12 hours after stimulus
Painful, itchy, and possibly long lasting (72 hours)
→ ↓ QoL
May be a/w arthralgias, malaise, and u-like
symptoms
■
Heat-induced: very rare; urticaria after just a few
minutes of heat contact
■
Cold urticaria: rapid itch, erythema, and swelling after
exposure; triggers include cold weather, air
conditioners, aquatic activity, and holding cold
objects; “ice cube” test can aid in diagnosis (positive in
primary cold contact urticaria [PCCU], negative in
reex cold and familial cold urticaria); patients should
never swim alone as massive mediator release can
→ hypotension
PCCU: usually idiopathic; young adults; acute or
chronic; can have systemic symptoms like syncope;
positive ice cube test
Secondary cold CU: may be due to
cryoglobulinemia, cryobrinogenemia, hepatitis
B/C, lymphoproliferative disease, or mononucleosis
Reex cold urticaria: widespread urticaria after
generalized cooling of body
Familial cold urticaria: cryopyrin-associated periodic
syndromes (CAPS), PLAID (see Chapter 4)
■
Cholinergic urticaria: distinct lesions (multiple 2–3 mm
slightly papular wheals with pronounced large are)
occurring after sweating/↑ body temperature in young
adults (e.g., after exercise, hot bath, spicy foods, and
strong emotions)
May be due to hypersensitivity to sweat components
May have systemic symptoms (e.g., faintness and
wheezing) and be chronic
■
Adrenergic urticaria: blanched vasoconstricted halos
around pink wheal
Responds better to propranolol than to
antihistamines
Can reproduce lesions by intradermal
norepinephrine injections
■
Solar urticaria: discussed in Section 3.15
■
Aquagenic urticaria: lesions similar to cholinergic,
response to water exposure (independent of
temperature)
Can be seen in cystic brosis
• Urticarial vasculitis: lesions that resemble urticaria but last
. 24 hours, burn/hurt rather than itch and often bruise;
histology shows mild LCV (1/– eosinophils)
■
Typically middle-aged women
■
Pain/burning . itch
■
Usually chronic
■
Angioedema in one third of patients
■
Arthralgias (50%), GI involvement (20%), obstructive
pulmonary disease (20%), and others (renal, ocular,
cardiac, livedo, and intracranial HTN)
■
May be a/w autoimmune CTDs and infections
■
Can have ↑ ESR, ↓ complement, and (1)ANA
■
NSAIDs rst line, but may need other agents (e.g.,
colchicine, dapsone, MTX, or steroids)
167
CHAPTER 3 • General Dermatology
• Schnitzler’s syndrome: chronic urticaria (burn . itch), fevers,
bone pain, arthralgia/arthritis, ↑ ESR, and IgM gammopathy
■
Neutrophilic inltrate on histopathology; anakinra is a
good treatment
Histopathology
• Supercial dermal edema, vasodilation, scant perivascular
and interstitial inltrate predominantly composed of
neutrophils (. eosinophils, lymphocytes)
■
Also see marginated neutrophils in vessel lumens
• Dermal neutrophilia seen 1 hour into process
Testing
• RAST and skin prick (intradermal) testing can help
identify environmental allergens in acute urticaria
■
Most helpful to determine etiology of acute urticaria to
foods, venom, and medications
■
RAST has 20% false-negative rate
• For recalcitrant chronic urticaria, consider CBC w/
differential, ESR/CRP, thyroid antibodies, thyroid function
tests, anti-FcRI and anti-IgE antibodies, immunoassays,
functional assays (e.g., histamine release assay), and
autoreactivity (e.g., autologous serum skin test)
Treatment/clinical course
• Soothing lotions (e.g., containing pramoxine and/or
menthol); avoidance of triggers (e.g., overheating, cold
exposure, and vibratory stimuli)
• May need to avoid ASA, NSAIDs, and opiates
• Exclusion diets/low-pseudoallergen diets may be helpful
in some cases
• First-line treatment 5 H1 antihistamines (sedating and
non-sedating; up to 43 dosing of non-sedating
antihistamines is acceptable); can consider adding H2
antihistamine
• For more recalcitrant cases, consider doxepin, short
courses of systemic steroids, montelukast (mixed results,
second line), phototherapy, sulfasalazine, cyclosporine,
colchicine, dapsone, antimalarials, MTX, MMF, and
omalizumab (FDA approved for chronic idiopathic
urticaria in patients 12 yo and older - monthly dosing)
Angioedema
Epidemiology
• Causes: idiopathic (#1 cause), physical stimuli
(temperature, vibration), type I hypersensitivity reactions
(drugs other than ACE inhibitors, arthropod bites, food
allergies), “pseudoallergic” (NSAIDs, ASA, IV contrast), C1
inhibitor deciency syndromes (hereditary angioedema
[HAE], acquired angioedema [AAE]), and ACE inhibitorinduced angioedema
• HAE in 1:10,000–1:50,000; starts in rst to second decade
and more severe in adolescence
■
Type I HAE most common (80%–85% of HAE cases)
■
Sex predilections: types I and II (M 5 F); type III (F . M)
• AAE starts in middle age
Pathogenesis
• Similar to urticaria for majority of cases with urticaria 1
angioedema; for cases of angioedema LACKING urticaria
(HAE, AAE) and ACE inhibitor-induced angioedema,
excess bradykinin is the cause
• Must rule out C1 esterase inhibitor (C1 inh) deciency in
cases of angioedema without urticaria
• HAE:
■
Types I and II due to mutations in C1 inh (type I has
↓ C1 inh levels; type II has ↓ C1 inh function)
■
Type III due to an activating mutation in Hageman
factor (FXII)
■
All forms of HAE are autosomal dominant
• AAE:
■
May be type I (consumption of C1 inh) or type II
(inhibitory autoantibodies against C1 inh)
■
May be due to B-cell lymphoproliferative disorders,
plasma cell dyscrasias, or autoimmune CTDs
• Acquired and hereditary forms result in ↑ bradykinin
levels and ↓ C4 levels (screening test of choice)
■
↓ C1q levels → seen in AAE only!
■
C1 inh levels → helps distinguish between types I and
II HAE
↓ C1 inh in type I HAE
Normal/↑ C1 inh levels in type II (but decreased C1
inh function)
• Drug-induced angioedema
■
Most commonly ACE inhibitors (lisinopril, enalapril
. captopril): occurs in 0.2% of all new users; 53 ↑
risk in Blacks; 77% occur within rst 3 weeks, and
almost all within rst year; ACE inhibitors block kinase
II → ↑ bradykinin
■
Others causes (NOT bradykinin-induced): PCN,
cephalosporins, NSAIDs, radiocontrast media, and
monoclonal antibodies (biologics)
Clinical features
• Characterized by deep swellings of skin/mucosa (in
deeper dermis and subcutaneous/submucosa)
■
Painful, non-erythematous
■
Non-pitting, non-pruritic (but may burn or cause
pain)
■
Commonly lasts 2–5 days (worst in rst 36 hours)
■
Face most commonly affected (lips, eyelids, throat,
ears, and nose)
■
May → anaphylaxis if throat involved (laryngeal or
epiglottic edema → stridor)
■
Associated symptoms: GI pain, N/V/diarrhea (edema of
bowel wall), and urinary retention
■
Up to 50% of patients w/ chronic urticaria will also
have angioedema at some point; however, if see
angioedema in absence of urticaria, must consider HAE
and AAE!
• Vibratory angioedema: vibration → localized swelling/
itching lasting about half an hour
■
Causes include running, motorcycling, biking and
operating machinery (e.g., lawnmower)
■
Familial form (activating mutation in ADGRE2) has
systemic symptoms
• HAE:
■
Type I and II: estrogens and trauma can → attacks
Episodes last 2 to 3 days
Avoid ACE inhibitors (can trigger attacks)
■
Type III: later age of onset (in teens), ↑ facial edema
168
3.10 Neutrophilic Dermatoses
Table 3.26 Complement Alterations in Angioedema Due to C1INH Deciency
Antigenic C1INH Functional C1INH C4 C1q
HAE type I
HAE type II
AAE type I
AAE type II
a
In AAE, normal values of antigenic C1INH are due to elevated levels of its cleaved form of 96 kDa.
AAE, acquired angioedema; C1INH, C1 inhibitor; HAE, hereditary angioedema; N, normal.
From Guilarte M, Luengo O, Nogueiras C, Labrador-Horrillo M, Muñoz E, López A, et al. Acquired angioedema associated with hereditary angioedema due to
C1 inhibitor deciency. J Investig Allergol Clin Immunol. 2008;18(2):126-130. Data from Bowen T, Cicardi M, Farkas H, Bork K, Kreuz W, Zingale L, et al.
Canadian 2003 international consensus algorithm for the diagnosis, therapy, and management of hereditary angioedema. J Allergy Clin Immunol.
2004;114(3):629-637.
↓ ↓ ↓ N
↑/N ↓ ↓/N ↓
↓ ↓ ↓ ↓
a
↓/N
↓ ↓ ↓
Diagnosis
• If HAE or AAE are suspected, check C4, C1 inh
(quantication and function), and C1q Table 3.26
Treatment/clinical course
• Similar to treatments for urticaria
• Intensive support (e.g., intubation and tracheostomy) may
be needed
• Should carry epi-pen in case of angioedema in
oropharynx
• For C1 inh deciency, oral danazol is ToC for prophylaxis,
and C1 inh concentrate is ToC for acute attacks
■
Danazol and C1 inh concentrate can be used
prophylactically prior to surgical procedures
■
Another option is icatibant, a synthetic bradykinin B2
receptor antagonist
• Anaphylaxis: life-threatening reaction to drugs that p/w
both skin (urticaria/angioedema) and systemic
(hypotension and tachycardia) ndings; occurs within
minutes of parenteral (. oral) administration of drugs;
most common drugs: PCN (1/5000 patients), latex
(especially mucosal contact), topical antibiotic use
(bacitracin, Neosporin, and rifamycin); and radiocontrast
media (anaphylactoid); Rx: hospitalization for serious
cases 1 systemic steroids 1 subcutaneous epinephrine
3.10 NEUTROPHILIC DERMATOSES
Sweet’s syndrome (Acute febrile
neutrophilic dermatosis)
Epidemiology
• Usually middle-aged
• F . M (3:1 for classic Sweet’s)
■
M 5 F for cancer-associated Sweet’s
• Five major subtypes: classic (60%–70%), cancer-associated
(10%–20%), inammatory disease-related (10%–15%),
drug-induced (5%), and pregnancy (2%)
Fig. 3.75 Sweet’s syndrome. Markedly edematous lesions on the upper arm.
(Courtesy of Christopher Sayed, MD.)
■
Favors head/neck and upper extremities
■
Rapid onset
■
May become vesiculobullous or pustular, and may have
a targetoid appearance
■
In drug-induced Sweet’s, lesions occur 1–2 weeks after
drug administration
■
Ulcerative, bullous and oral lesions → stronger a/w
hematologic disorders/malignancy
• Extracutaneous features: fever (50%–80%), malaise,
preceding URI or u-like symptoms, leukocytosis (70%),
arthralgias/arthritis, ocular involvement (conjunctivitis,
episcleritis, scleritis, retinal vasculitis, and iridioyclitis),
cardiac involvement (aortitis, cardiomegaly, coronary
artery occlusion)
• Lab abnormalities:
■
↑ ESR/CRP (90%)
■
Leukocytosis: neutrophilia w/ ↑ band forms (“left
shift”)
• Various triggers:
Pathogenesis
• Unknown; may have (1) pathergy
Clinical features
• Tender/burning, red, well-demarcated, expanding,
edematous/“juicy” papules/plaques (Fig. 3.75)
■
Infections: mainly streptococcus and yersiniosis; HIV,
hepatitis C
■
Cancer: especially acute myeloid leukemia (AML;
M2 and M4 subtypes), but also other hematologic
malignancies and myeloproliferative disorders (e.g.,
MDS)
169
CHAPTER 3 • General Dermatology
■
Consider screening all patients without obvious causes
with peripheral blood smear and bone marrow biopsy
if the smear is abnormal
■
IBD
■
Drugs: G-CSF, GM-CSF, ATRA, TMP-SMX, minocycline,
OCPs, furosemide, and hydralazine
■
Other: autoimmune CTDs, pregnancy, vaccines (e.g.,
BCG, smallpox)
Histopathology
• Diffuse dermal neutrophilic inltrate w/ karyorrhexis 1
massive papillary dermal edema
■
Generally lacks LCV (although some “bystander”
damage is done to vessels within inammatory soup)
■
Massive papillary dermal edema is responsible for
“pseudovesicular” clinical morphology
• Variants:
■
Subcutaneous Sweet’s: neutrophils involve subcutis in a
lobular pattern; p/w deep-seated red nodules on
extremities
■
Cryptococcoid Sweet’s: presence of degenerated
lymphocytes w/ vacuolization/acellular basophilic
bodies mimicking Cryptococcus on H&E
■
Histiocytoid Sweet’s (variant): deep dermal inltrate of
CD1631 macrophages (myeloid lineage), often
associated with myeloproliferative disease
(myelodysplasia . AML) or NSAIDs
Treatment/clinical course
• Resolves within 2–3 months without scarring (vs. PG)
• Recurs in up to one third of classical patients, but up to
69% of malignancy-associated cases
• ToC 5 systemic steroids (prednisone 0.5–1.0 mg/kg daily
for 4–6 weeks; WORKS FAST!)
■
Others: saturated solution of potassium iodide (SSKI),
dapsone (100–200 mg/day), and colchicine (1.5 mg/day)
• Increased malignancy risk: histiocytoid/lymphocytic
subcutaneous histology, age, bullous morphology,
leukopenia/anemia/thrombocytopenia, ↑ ESR, NO arthralgias
• Half have an associated systemic inammatory disorder
(IBD most common, up to 30%), hematologic disorder
(e.g., IgA monoclonal gammopathy, AML, chronic
myeloid leukemia [CML], hairy cell leukemia,
polycythemia vera), or inammatory arthritis
Pathogenesis
• Likely immunologic disorder
• Genetic: some cases are caused by a mutation in CD2-
binding protein 1 (PAPA syndrome)
• Pathergy (30%): minor trauma (e.g., incisions, needle
sticks) may initiate and/or aggravate disease; may recur
with surgical procedures in 15% of patients
Clinical features
• Major types include classic (ulcerative), bullous (less
destructive than ulcerative type; strongly a/w
myeloproliferative disorders), pustular, peristomal, and
supercial granulomatous (aka vegetative; cribriform
supercial ulcers on trunk)
• Classic (ulcerative) PG
■
Starts as inamed papulopustule/bulla → painful
undermining ulcer w/ overhanging, irregular,
violaceous border and purulent/vegetative base;
satellite lesions arise at the periphery of ulcer → break
down and fuse with central ulcer (Fig 3.76)
a/w IBD, RA, and IgA gammopathies
Heals with atrophic cribriform scar
Most commonly on lower extremities (pretibial)
■
Related variants:
Pyostomatitis vegetans: chronic vegetative pyoderma
of oral mucosa associated w/ IBD
Peristomal PG: painful, undermined lesions around
ostomy; a/w IBD
Classic PG in kids (rare): most common on head
and anogenital region; usually a/w IBD or
leukemia
Mimickers of Sweet’s syndrome
• CANDLE syndrome (Chronic Atypical Neutrophilic
Dermatosis with Lipoatrophy and Elevated temperature):
autoinammatory disorder of children with mutations in
PSMB8 gene that can mimic Sweet’s
• Marshall syndrome: rare childhood disease that has Sweet’s-
like lesions that resolve w/ acquired cutis laxa at affected sites
Neutrophilic dermatosis
of the dorsal hands
• Features of PG 1 Sweet’s
• Ulcerative red-violaceous plaques on dorsal hands
• a/w Hematological disorders, infection, solid organ
tumors, and IBD
• Rx: prednisone, dapsone, colchicine
Pyoderma gangrenosum
Epidemiology
• Adults (20–60 yo); F . M
170
Fig. 3.76 Pyoderma gangrenosum. Ulcer with purulent exudate and violaceous,
undermined border on the lower leg in a patient with ulcerative colitis. (Courtesy
of Christopher Sayed, MD.)
3.10 Neutrophilic Dermatoses
• Pustular PG
■
Multiple small pustules that do not progress to ulcers
■
a/w IBD in most cases
• Bullous PG
■
More supercial, less destructive than classic PG
■
More widespread distribution (face, dorsal hands)
→ overlaps w/ bullous Sweet’s disease
■
More strongly a/w hematologic malignancy (AML,
CML, MDS, polycythemia vera)
• Vegetative PG
■
Least aggressive form
■
p/w supercial, painless cribriform ulcers w/
verrucous growths on trunk; responds well to
conservative treatment
■
Usually arises as result of trauma (e.g., surgery)
■
NOT a/w underlying systemic diseases
Histopathology
• Epidermal ulceration w/ dense underlying supercial and
deep dermal neutrophilic inltrate (inammation
deeper than Sweet’s), leukocytoclasis, epidermal pustules,
and dermal edema
■
Neutrophilic inltrate extends laterally beyond
overlying ulcer (“undermining inltrate”)
• PG is a diagnosis of exclusion!!!
■
Histologic features are not entirely specic
■
Must rule out infection, vasculitis, vasculopathy, and
malignancy
Treatment/clinical course
• Course varies depending on type of PG
• Good wound care is essential for all patients
• Must search for underlying diseases
■
GI: colonoscopy, stool studies, particularly in patients
, 65 yo
■
Heme: CBC, peripheral smear, serum protein
electrophoresis (SPEP), 1/– bone marrow biopsy
especially in patients . 65 yo
• Treatment:
■
Wound care is important (DO NOT surgically debride
due to pathergy)
■
Initial: topical/intralesional steroids (mild disease); TCIs
■
Recalcitrant/severe disease: systemic steroids (1 mg/kg/day
avg; rst line); cyclosporine (rst line); TNF-a inhibitors
(iniximab has best data); other options (e.g., MMF,
MTX, dapsone, minocycline, clindamycin/rifampin)
Clinical features
• Recurrent oral ulcerations (aphthous stomatitis 5 rst
and most common symptom) (Fig 3.77) at least three
times in a year 1 two of the following:
■
Recurrent genital ulceration: large, irregular aphthae
on scrotum (#1), penis, and vulva (labia majora #1)
that heal with scarring
■
Ocular lesions: panuveitis is most common, and posterior
. anterior when isolated also may have conjunctivitis,
iridocyclitis, and retinal vasculitis (may → blindness)
■
Cutaneous lesions: pseudofolliculitis papulopustules
or acneiform nodules, purpura, EN-like lesions on
legs/buttocks, positive pathergy test
Pathergy test: needle stick or intradermal injection
of saline → papulopustule at site of trauma within
24 to 48 hours
• Oral ulcerations can occur anywhere in oral cavity/lips, be
single or multiple, painful, large in diameter, recurrent,
and have a gray base w/ surrounding erythema
• Can affect all organs w/ unpredictable course:
■
Ocular (90%)
#1 cause of morbidity, including blindness
■
Vascular: supercial migratory thrombophlebitis (30%)
and less frequently superior vena cava thrombosis
■
Other: joints (50% develop arthritis), neurologic
(meningoencephalitis, multiple sclerosis-like
symptoms), cardiopulmonary (cardiomyopathy,
myocarditis, MVP), renal (glomerulonephritis), and GI
(ileocecal inammation/ulceration)
Histopathology
• Classically neutrophilic inltrate around vessels w/ LCV
■
Lymphocytic vasculitis may be seen in older lesions
Treatment/clinical course
• Important to treat because of systemic involvement, but
difcult to control (no ToC exists)
■
Options: mild (topical steroids, TCIs); moderate-severe
(colchicine [rst line for EN-like lesions and rst line
Behçet’s disease
Epidemiology
• Japanese, Middle Eastern, and Mediterranean (highest
prevalence in Turkey)
• Usually 20–35 years
• F . M in the United States and Japan; M . F in Middle
East and Mediterranean
• May be familial in subset of cases
Pathogenesis
• Multifactorial (infectious trigger?); circulating immune
complexes and neutrophil dysregulation → vascular injury
• Strongly a/w HLA-B51 allele
Fig. 3.77 Behçet’s disease: oral aphthae on the gingiva and palate. (Courtesy of
Christopher Sayed, MD.)
171
CHAPTER 3 • General Dermatology
for mucocutaneous disease], dapsone [rst line for
mucocutaneous disease], minocycline, thalidomide,
prednisone, IFN-γ, MTX, TNF-a inhibitors, anakinra/
canakinumab, alemtuzumab, apremilast, AZA)
• Symptomatic relief (e.g., mild mouthwashes and
sucralfate suspension, lidocaine gel, chlorhexidine)
important
Additional information
• MAGIC syndrome 5 features of Behçet’s and relapsing
polychondritis
Bowel-associated dermatosis arthritis
syndrome (Bowel bypass syndrome)
Epidemiology/pathogenesis
• Classically patients with jejunoileal bypass surgery and
blind loops of bowel
■
Occurs 1–6 years after bowel surgery
■
Other causes: biliopancreatic diversion, gastric
resection, IBD, peptic ulcer disease, and diverticulitis
• Bacteria in blind loop of bowel → immune complexes
w/ bacterial antigens are deposited in skin/synovium
Clinical features
• Constitutional and serum-sickness like symptoms (e.g.,
malaise, fever, chills, arthralgias/myalgias) usually precede rash
• Classic rash 5 red to purpuric papulopustules over
proximal extremities and trunk
■
May also have tender subcutaneous nodules (trunk,
extremities; due to lobular panniculitis; heals w/
depressed scars) or EN-like lesions (lower legs; nonscarring)
• Diarrhea/malabsorption, hepatic failure, kidney stones,
and gallstones
Histopathology
• Classic papulopustules: nodular or perivascular dermal
neutrophilic inammation
• Tender, scarring subcutaneous nodules: lobular
neutrophilic panniculitis (→ loss of fat lobules and scar)
• EN-like lesions: resembles EN
Treatment/clinical course
• Skin lesions may last up to 1 month and recur
frequently
• Antibiotics (e.g., tetracyclines) and immunosuppressive
agents (prednisone, dapsone) → temporary
improvement
• Surgical correction of blind bowel loop or revision of
bypass is curative
Amicrobial pustulosis of the folds
• Chronic, relapsing disorder of grouped aseptic pustular
lesions involving intertriginous sites
• May be due to immune-complex complement activation
→ neutrophil activation
• Commonly associated with autoimmune conditions (e.g.,
undifferentiated CTD, lupus, SjS, Hashimoto thyroiditis,
APLS, IBD)
3.11 EOSINOPHILIC DISORDERS
• Various disorders can have signicant numbers of eosinophils
histologically, including: arthropod bites, urticaria, allergic
contact and AD, drug reactions, and autoimmune blistering
disorders (e.g., BP, PV, inammatory EBA)
Granuloma faciale
• Discussed in Section 3.22
Eosinophilic folliculitis
• Discussed in Section 3.13
Papuloerythroderma of Ofuji
• Elderly Japanese men most commonly
• Generalized pruritic red-brown papules → erythroderma
sparing skin folds (“deck chair sign”); lesions can
become superinfected → cellulitis, erysipelas
• Eosinophilia, lymphopenia, ↑ IgE, lymphadenopathy
common; can be a/w gastric carcinoma, hepatocellular
carcinoma, CLL, B-cell lymphoma, T-cell lymphoma,
hepatitis C, HIV
• Chronic, indolent course (remitting over several years)
but responsive to systemic steroids (ToC), PUVA,
cyclosporine, retinoids; treat underlying cause if possible
Wells’ syndrome (Eosinophilic cellulitis)
• Unknown etiology, but can be triggered by
myeloproliferative diseases, infections, drugs, arthropod
bites, and Churg-Strauss syndrome
• Exaggerated lymphocyte response to mosquito salivary
gland extract may be present
• Recurrent tender/itchy erythematous indurated cellulitis-
like plaques (occasionally arcuate)
■
Extremities . trunk
■
Malaise and eosinophilia typically present
■
Lesions resolve over 1 to 2 months
• Histology: striking eosinophilic inltrate in interstitial
dermis w/ classic “ame gures”
■
Flame gures 5 collagen bers coated with eosinophil
granule proteins (most importantly, major basic protein)
• Systemic steroids are ToC → quick improvement;
alternatives include dapsone, colchicine, cyclosporine,
minocycline
Hypereosinophilic syndrome (HES)
• Criteria:
■
Peripheral blood eosinophilia (eosinophils .1500/
mm3 and/or tissue hypereosinophilia (e.g., eosinophils
. 20% of cells in bone marrow)
■
No evidence of infectious, allergic, or other underlying
causes
■
Symptoms/signs of end-organ involvement (due to
eosinophil products)
• HES divided into primary (neoplastic; 75% cases) versus
secondary (reactive; 25% cases)
172
■
Primary HES (neoplastic):
Due to malignancy of stem cells/myeloid cells/
eosinophils (usually chronic eosinophilic
leukemia)
Patients typically have FIP1L1-PDGFRA fusion gene
→ constitutively activated tyrosine kinase (rarely
PDGFRB or FGFR1 fusion genes)
100% of cases are men
Systemic symptoms: fever, cough, malaise, and
myalgias
May have ↑ serum tryptase and vitamin B12,
endomyocardial brosis, cardiomyopathy,
hepatosplenomegaly, CD251 atypical mast cells on
bone marrow biopsies, and constitutional
symptoms (on presentation)
■
Secondary HES (reactive):
Due to inammatory, neoplastic, or other disorder
Clonal T-cell proliferation → ↑ Th2 cytokines
(especially IL-5) → eosinophil activation/
hypereosinophilia)
Lymphocytic subtype of secondary (reactive) HES:
itch, erythroderma, angioedema w/ ↑ IgE (due to
↑ IL-4/-13), eosinophilia, and lymphadenopathy
Generally benign course (when compared with
primary HES):
♦ Rarely develop cardiac complications
♦ However, there is ↑ risk of T-cell lymphoma
• Mucocutaneous lesions in . 50% HES
■
Most commonly p/w itchy red papules/nodules,
urticaria, angioedema
■
Mucosal ulcers (a/w primary HES 1 more aggressive
course; responsive to imatinib)
• Treatment: successful treatment correlates w/ decreasing
eosinophil count
■
Primary HES (neoplastic)
Imatinib (if fusion gene present) 1 prednisone (for
possible cardiac issues), nilotinib/dasatinib/
sorafenib (other tyrosine kinase inhibitors),
hydroxyurea, IFN-a, and mepolizumab/reslizumab
(anti-IL-5 antibodies)
■
Secondary HES (reactive)
Treat underlying disorder
Prednisone (rst line—1 mg/kg/day), IFN-a,
hyroxyurea, mepolizumab/reslizumab; imatinib can
be considered as some patients may have occult
PDGFRA/-B mutations
■
#1 cause of death 5 congestive heart failure (5-year
survival 5 80%)—patients need regular
echocardiograms!
3.12 FIGURATE ERYTHEMAS
Erythema annulare centrifugum (EAC)
3.12 Figurate Erythemas
viruses, parasites), drug, pregnancy, malignancies (usually
lymphoproliferative)
Clinical features
• Start as rm pink papule → erythematous annular lesions
that migrate centrifugally (outward; up to 6 cm diameter
in 2 weeks)
• Trailing scale (inner margin desquamation) is common
in supercial lesions, but not deep lesions
• Most commonly on thighs/hips, but can become more
generalized
Histopathology
• Supercial EAC: mild spongiosis, focal parakeratosis, and
perivascular lymphohistiocytic inltration, which is tight
and dense (“coat sleeve”)
• Deep EAC: deep and tight perivascular lymphohistiocytic
inammation
Treatment
• Treat underlying disorder if present; otherwise topical steroids
Prognosis/clinical course
• Lesions last days to months
Erythema marginatum
Epidemiology
• Primarily seen in children 5 to 15 years old who are NOT
treated for group A b-hemolytic Streptococcus infections
of pharynx (3% of untreated patients)
• More prevalent in underdeveloped countries
Pathogenesis
• Seen in setting of rheumatic fever (aberrant humoral/
cellular immune response to group A b-hemolytic strep
infection; may be related to cross-reacting epitopes)
■
Rheumatic fever: starts 2–5 weeks after infection; two
major or one major 1 two minor criteria, in addition
to evidence of group A strep infection (culture, antiDnase B titer, and antistreptolysin O [ASO])
Jones major criteria: carditis, migratory polyarthritis,
erythema marginatum, subcutaneous nodules, or
Sydenham’s chorea
Jones minor criteria: fever, arthralgias, or abnormal
laboratory ndings (↑ ESR, ↑ CRP, and ↑ PR interval)
Clinical features
• Migratory expanding annular/polycyclic patches/plaques
starting as macules
■
Can migrate 2 to 12 mm in half day
■
Usually trunk, axillae, and proximal extremities
• Typically resolves in a few weeks and is seen in active
phase of rheumatic fever (in conjunction w/ carditis)
Epidemiology
• Peaks in fth decade
Pathogenesis
• Unknown, but may be immune reaction to antigen (e.g.,
tinea pedis, other dermatophyte infections, other fungi,
Histopathology
• Perivascular inltrate of neutrophils and sometimes
eosinophils without vasculitis
Treatment/clinical course
• No treatment shown to alter natural disease course
173
CHAPTER 3 • General Dermatology
Erythema migrans
Epidemiology
• Most commonly seen in the United States (southern New
England, SE NY, NJ, Eastern PA, Eastern MD, Delaware,
and certain parts of MN/WI/MI) and Europe (particularly
central Europe)
• White-footed mice and white-tailed deer are natural hosts
for Borrelia
Pathogenesis
• Due to Borrelia burgdorferi (a spirochete) that is
inoculated by Ixodes tick bites
■
Note: these ticks can also transmit babesiosis and
human granulocytic anaplasmosis
■
Borrelia mayonii recently identied in Midwestern
United States with higher spirochete burden and more
severe disease
• Tick MUST be attached for . 1 day (and usually .
48 hours) to transmit disease
Clinical features
• Large annular red expanding patch ($5 cm) at the site
of Borrelia-infected tick bite 7–15 days after tick
detachment lasting up to 6 weeks without treatment
■
Trunk and intertriginous areas
• Initial manifestation of Lyme disease (up to 90% of
infected patients have erythema migrans)
■
Smaller secondary lesions possibly due to lymphatic/
hematologic spread or multiple tick bites
■
History of tick bite is not required for diagnosis
• Lyme disease has different symptoms in various phases
■
Early localized disease: u-like symptoms and
lymphadenopathy
■
Early disseminated disease: Bell’s palsy, arthralgias, AV
block, iritis
■
Chronic disease: chronic arthritis (usually monoarticular
of large joints), encephalopathy, acrodermatitis chronica
atrophicans (chronic sclerosing dermatitis)
• Jarisch-Herxheimer reaction with increased inammation
of erythema migrans may occur in up to 15% with start of
treatment
Prognosis/clinical course
• If left untreated:
■
Erythema migrans lesions self-resolve in 6 weeks
■
60% develop arthritis (usually knee)
■
10% develop neurologic issues (usually Bell’s palsy)
■
5% develop cardiac issues (usually AV block)
Erythema gyratum repens
• Paraneoplastic disorder likely due to immune reaction
against tumor-associated antigens, and subsequently
cutaneous antigens (due to similarities/cross-reaction
between tumor-associated antigen and cutaneous antigens)
■
Most common malignancies: lung (most common) .
breast and GI (especially esophagus/stomach)
• Multiple lesions w/ “wood grain” (polycyclic and
serpiginous) appearance of erythema in concentric rings
(Fig. 3.78); rapid expansion (1 cm/d) with itch and
trailing scale; hands and feet are spared
• M . F
• Lesions develop 1 year pre-cancer to 1 year post-cancer
diagnosis, and resolve once cancer treated
Flushing
• Not a gurate erythema, but still an erythema (change in
skin color due to dilation of blood vessels in dermis)
• Wide differential (Box 3.7), which includes common and
serious medical issues, as well as medications and alcohol
use; Table 3.27 discusses clinical ndings and laboratory
markers in malignancy-associated ushing
Laboratory testing
• Conrmed diagnosis requires erythema migrans 1
either known exposure or laboratory evidence of
exposure (positive tissue/uid culture, tissue/uid PCR,
and anti-Borrelia antibodies via ELISA and Western
blot—peak IgM response occurs 3 to 6 weeks into
infection); agar for Borrelia 5 Barbour-Stoenner-Kelly
medium
• ,50% will have positive antibodies in the acute phase or
in the convalescent phase after receiving treatment
• Histology: plasma cell-rich perivascular and interstitial
pattern, though a signicant minority may have GA-like
or lichenoid features
Treatment
• Depends on stage of disease, age, and pregnancy status
• Typically doxycycline in early localized disease and mild
early disseminated or chronic disease for non-pregnant
adults and children $ 8 years
■
Amoxicillin in children , 8 years or pregnant women
• Ceftriaxone is best IV treatment (usually for Lyme
meningitis)
174
Fig. 3.78 Erythematous gyratum repens. (From James WD, Elston DM, Treat JR,
Rosenbach MA, Neuhaus IM. Dermal and subcutaneous tumors. In: Andrews’
Diseases of the Skin . 13th ed. Philadelphia: Elsevier; 2020:587–635.)