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3.22 Vasculitides, Vasculopathies, and Other Vascular Disorders
Table 3.32 Depositional and Calcication Disorders Not Previously Discussed—cont'd
Disorder Histopathology Clinical Findings Pearls
Idiopathic
calcification
Osteoma
cutis
MTP, metatarsophalangeal joint; PTH, parathyroid hormone; PAS, periodic acid-Schiff; AICTD, autoimmune connective tissue disease; DM, dermatomyositis;
PXE, psuedoxanthoma elasticum; PCT, porphyria cutanea tarda; RFs, risk factors; DM2, type 2 diabetes; STS, sodium thiosulfate; TPA, tissue plasminogen
activator.
Table 3.33 Key Features of Cutaneous Ulcers
Ulcer Types Clinical Presentation Useful Pearls
Venous Irregular borders with shallow yellow brinous
Lymphedema Classically starts as pitting edema of dorsal foot
Arterial (peripheral
arterial dz)
Diabetic/neuropathic
(“mal perforans”)
Decubitus/pressure
Diffuse dermal
angiomatosis
Arteriosclerotic ulcer of
Martorell
Idiopathic calcified nodules
of the scrotum: may see
calcification in the setting
of an epidermal cyst within
scrotal skin
Bone formation within
dermis/SQ
base
Classically above medial malleolus (2° to
Cockett’s perforating veins)
Usually in background of venous stasis
changes (brown hemosiderin deposits 1 pinpoint purpura, LDS, edema) and varicosities
→ moves to leg
Skin changes: induration, ulceration, 2° infection
Elephantiasis nostras verrucosa : chronic
lymphedema of feet/legs → brosis of dermis
and subcutis → verrucous, hyperkeratotic,
cobblestone-like, papillomatous appearance
Painful ulcer w/ well-dened borders with round,
“punched out” dry, necrotic base
Classically at pressure points (e.g., lateral mal-
leolus, rst and fth metatarsal heads)
Usually in background of atrophic skin w/
↓ hair
Claudication
“Punched out,” smelly, moist base with cal-
lused borders
Classically at pressure points (e.g., metatarsal
heads, great toes, heels)
Usually in setting of peripheral neuropathy
1/– foot deformity (e.g., hammer toes)
Ulcer due to prolonged pressure from ↓ ambu-
lation/mobility → pressure to soft tissue from
bony prominence and external surface
Common sites: sacrum, heel, ischial tuberosities,
greater trochanters, malleoli (lateral . medial)
Four stages: I) non-blanchable erythema; II)
skin loss of epidermis 1/– dermis 5 erosion/
shallow ulcer; III) skin loss 1 subcutis damage, but not fascia; and IV) tissue necrosis to
muscle, bone or supporting structures
Violaceous/erythematous patches/plaques with
ulceration on legs, breasts, forearms
Painful red blister → blue purpuric lesion → ul-
ceration; ulceration is preceded by pigmented
pretibial patches
Anterior or medial lower leg
Usually supercial ulcer w/ necrotic base and vi-
olaceous-erythematous edges, but may be
deep and enlarging
Idiopathic calcied nodules of the scrotum: multiple white small
nodules of scrotum
Tumor calcinosis: large painful calcium-phosphate subcutaneous
nodules around joints → ulceration
Genetic causes: brodysplasia ossicans progressiva (process is en-
dochondral; autosomal dominant; mutation in ACVR1 gene which
encodes activin A receptor; may have malformed great toes), progressive osseous heteroplasia, plate-like osteoma cutis, Albright
hereditary osteodystrophy
Miliary osteomas of the face: white-skin colored tiny papules on
faces of adults, common; a/w prior acne and tetracyclines
Other causes include milia-like
calcinosis (typically on dorsal
hands/face in Down syndrome)
and subepidermal calcified nodule
RFs: ↑ age, F . M, obesity, pregnancy, prolonged standing, ↑ height
Due to venous HTN and insufciency
Duplex ultrasound 1 /– venography may help characterize dz
Treatment: moisture/occlusion, debridement, dressings (create moist environ-
ment but absorb excess exudate), treatment of infection, compression (do
NOT use in arterial insufciency pts), negative pressure therapy, manual lymphatic drainage, pentoxifylline, ASA, G-CSF
Due to ↑ interstitial lymph uid due to poor drainage
1° (e.g., Nonne-Milroy dz, Meige dz, lymphedema tarda) vs. 2° (malignancy, radi-
ation, LN dissection, CVI, recurrent cellulitis, obesity, liriasis)
↓ Pedal pulses w/ ↑ capillary rell time and pallor w/ elevation
Diagnosis via ABIs; may need CTA, MRA, invasive digital subtraction
angiography
Due to lack of blood perfusion (peripheral arterial dz)
RFs: tobacco, DM2, HTN, hyperhomocysteinemia, HLD
Do NOT use VAC treatment or sharp debridement
May need surgical reconstruction and/or angioplasty
May have underlying osteomyelitis (MRI best for dx) which may require bone bx/cx
15% of DM2 pts with foot ulcer → lower extremity amputation
Treatments: off-loading measures (e.g., total contact casting, therapeutic shoes),
wound healing measures (e.g., debridement), treatment of infection, hyperbaric
oxygen, negative pressure therapy, exogenous growth factors (e.g., becaplermin
gel), skin substitutes, dressings, G-CSF
RFs: immobility, sensory decit, poor nutrition, circulation issues
Treatment: relief of pressure (e.g., position changes, support surfaces like foam
wedges), good wound care
Stage IV ulcers will likely need surgical treatment
Strongly a/w vascular atherosclerosis and smoking
May need surgical intervention
Isotretinoin recently described as treatment option
Women 50–70 yo
Poor healing and slow wound healing
Typically a/w HTN
Histology: impressive thickening of arteriole media and intima, 1/–
hyalinosis/calcinosis of media , 1/– periarteritis, 1/– endarterial proliferation
Treatment involves multiple modalities (e.g., VAC, HTN control, compression
stockings)
Continued
195
CHAPTER 3 • General Dermatology
Table 3.33 Key Features of Cutaneous Ulcers—cont'd
Ulcer Types Clinical Presentation Useful Pearls
Hematologic causes Anemia, particularly hemoglobinopathies
Inflammatory Consider vasculitis, PAN, RA/Felty’s syndrome, pyoderma gangrenosum and nec-
Infectious When suspected, culture broadly to r/o bacterial (e.g., anthrax), mycobacterial,
Neoplastic
Metabolic Ulcers can occur in depositional disorders (e.g., calcinosis cutis, gout) adjacent to
Genetic Ulcers can be seen in Adams-Oliver syndrome (from aplasia cutis on scalp),
Drugs Hydroxyurea is a common culprit (malleolus, tibial crest; painful)
Other Dermatitis artefacta, illegal drug use, burns, frostbite, radiation-induced,
RFs, risk factors; HTN, hypertension; ASA, aspirin; LDS, lipodermatosclerosus; LN, lymph node; CVI, chronic venous insufciency; ABIs, ankle-brachial index;
CTA, computed tomography angiogram; MRA, magnetic resinance angiogram; DM2, type 2 diabetes; HLD, hyperlipidemia; VAC, vacuum-assisted closure;
MRI, magnetic resonance imaging; IV, intravenous; APLS, antiphospholipid syndrome; PAN, polyarteritis nodosa; RA, rheumatoid arthritis; LP, lichen planus;
SCC, squamous cell carcinoma; HSV, herpes simplex virus; LS&A, lichen sclerosus et atrophica; MTX, methotrexate; HIT, heparin-induced thrombocytopenia.
Hematologic malignancy associations: pyoderma gangrenosum, vasculitis, type I
cryoglobulinemia
Clotting abnormalities: factor V Leiden deciency, protein C/S deciency, anti-
thrombin III deciency, prothrombin G20210A mutation, APLS, hyperhomocysteinemia, plasminogen activator inhibitor deciency/increase
robiosis lipoidica, Behçet’s—lower extremity common site in aforementioned
Ulcerative LP, ulcerative sarcoid, livedoid vasculopathy
Consider panniculitides (pancreatic, a
viral (esp. HSV), fungal, parasitic (acanthamoeba, amebiasis)
Almost all cutaneous malignancies can → ulcer (SCC most common, but also
BCC, lymphomas, Kaposi’s, angiosarcoma)
SCC can develop in chronic ulcers, scars, sites of chronic inammation
(e.g., in hidradenitis suppurative or LS&A)
joints, and higher fat areas in disorders like calciphylaxis
prolidase deficiency (leg ulcers), familial tumor calcinosis, Werner syndrome
(leg ulcers), Flynn-Aird syndrome, Klinefelter syndrome (leg ulcers)
Other culprits are interferon (injection sites), MTX in psoriasis pts, anticoagulants
(warfarin [2° to acquired protein C deficiency] and heparin necrosis [2° to HIT])
chemical etching
-antitrypsin, erythema induratum)
1
Cutaneous small vessel vasculitis
Epidemiology
• Adults . children
Pathophysiology
• Immune complex deposition in post-capillary venules
→ activates complement → neutrophilic inammatory
response → vessel damage, hemorrhage, and tissue ischemia
■
Fibrinoid necrosis of blood vessels arises via lysosomal
enzymes (collagenases and elastases) and reactive
oxidative species
• Various triggers exist (Table 3.35)
Clinical presentation
• Crops of partially blanchable, symmetric, palpable
purpura on the lower extremities, dependent areas, and
under tight clothing or areas with pressure
■
Other manifestations: erythematous papules, urticaria,
vesicles, pustules, and livedo reticularis
■
Rarely occurs on the face, palms, soles, or mucous
membranes
• Timing: appears 7–10 days after exposure and resolves
within 3–4 weeks with transient hyperpigmentation and/
or atrophy
• Cutaneous symptoms: asymptomatic, pruritus, burning,
or pain
• Systemic symptoms: 30% may have fever, malaise,
arthralgias, myalgias, and GI/GU symptoms
Table 3.34 Categories of Vasculitis by Vessel Size
Clinical Features Examples
Small vessel
vasculitis
Mixed
small and
medium
vessel
vasculitis
Medium
vessel
vasculitis
Large vessel
vasculitis
LE, lower extremity; UE, upper extremity.
Palpable purpura
Petechiae
Vesicles
Pustules
Mixture of features from
small and medium vessel
vasculitis
Livedo reticularis
Retiform purpura
Ulcers
Subcutaneous nodules
Specic per disease
Temporal arteritis: ery-
thematous tender nodules or ulceration on the
frontotemporal scalp
Takayasu’s arteritis: ery-
thematous subcutaneous nodules, PG-like lesions on LE . UE
Henoch-Schonlein purpura
Acute hemorrhagic edema
of infancy
Urticarial vasculitis
Erythema elevatum diutinum
Granuloma faciale
Secondary vasculitis
Drug
Infection
Malignancy
Autoimmune
Mixed cryoglobulinemia
(II and III)
ANCA-associated:
Microscopic polyangiitis
Wegener’s granulomatosis
Churg-Strauss syndrome
Polyarteritis nodosa
Kawasaki disease
Temporal arteritis
Takayasu’s arteritis
196
3.22 Vasculitides, Vasculopathies, and Other Vascular Disorders
Table 3.35 Triggers of Cutaneous Small Vessel Vasculitis
Triggers Examples
Primary cutaneous small vessel vasculitis
Idiopathic (50%)
Secondary cutaneous small vessel vasculitis
Infection (15%–20%)
Inflammatory
disorders (15%–
20%): can present
as a small and/
or medium vessel
vasculitis
Drug (10%–15%):
onset is 1–3 weeks
after drug initiation,
third most common
cutaneous drug
eruption (2%)
Neoplasm (,5%)
Other Thrombotic
Bacterial: group A b-hemolytic Streptococci,
Staphylococcus aureus, Chlamydia, Neisseria,
Mycobacterium
Viral: hepatitis C . B » A, HIV
Fungal/yeast: Candida
Autoimmune CTD including: SLE, Sjögren’s, RA .
dermatomyositis, scleroderma, polychondritis
IBD
Behçet’s disease
Most common:
Antibiotics: b-lactams (penicillin, cephalospo-
rins), sulfonamides, minocycline,
quinolones
Anti-inammatory: NSAIDs, COX-2 inhibitors
Other culprits:
Leukotriene inhibitors
Anti-thyroid: propylthiouracil
Anti-hypertensives: thiazides, hydralazine
Biologics: TNF-a inhibitors, MTX, Rituximab
Hormonal: OCPs
G-CSF
Retinoid: isotretinoin
Levamisole-tainted cocaine
Allopurinol
Radiocontrast media
Most common:
Hematologic malignancy (Multiple myeloma
Monoclonal gammopathies T-cell leukemia, MF,
AML, CML Diffuse large cell leukemia Hairy cell
leukemia)
Less common:
Solid organ
(GU: prostate cancer, renal cancer GI: colon
cancer)
Embolic
Cyroglobulinemia
Table 3.36 Evaluating for Systemic Vasculitis
General
Workup If There Is No Concern for Systemic Involvement:
CBC [eosinophilia in EGPA], BMP [↑ Cr], ↑ ESR
(.40mm/hr), ↑ LFTs, UA [hematuria/proteinuria]
Extensive
Workup
GI
Renal Serial UAs [hematuria, proteinuria]
Infectious Hepatitis B and C
Inflammatory
Neoplastic
Other
CBC, complete blood count; BMP, basic metabolic panel; LFTs, liver func-
tion tests; UA, urinalysis; HSP, Henoch-Schonlein purpura; ASO, antistreptolysin; HIV, human immunodeciency virus; CXR, chest xray; TTE,
transthoracic echocardiogram; ESR, estimated sedimentation rate; CRP,
C-reactive protein; ANA, anti-neutrophil antibody; RF, rheumatoid factor;
WNL, within normal limits; HUV, hypocomplementemic urticarial vasculitis;
SLE, systemic lupus erythematosus; ANCA, anti-neutrophil cytoplasmic
antibody; GPA, granulomatous polyangitis; PAN, polyarteritis nodosa;
EGPA, eosinophilic granulomatous polyangitis; APLS, antiphospholipid an-
tibody syndrome; SPEP, serum protein electrophoresis; UPEP, urine protein electrophoresis.
If There Is Concern for Systemic Involvement
Consider General Workup Plus:
Stool guaiac [1/– melena in HSP]
HIV
ASO titer (if (1), consider streptococcal infection)
Abnormal CXR (inltrates, opacities)
Consider TTE and blood cultures in a patient with high
fever or heart murmurs
Consider other cultures based on history
↑ ESR
↑ CRP (↑ in infection and autoimmune disease)
ANA
RF (if (1) consider Sjögren’s, rheumatoid arthritis, cryo-
globulinemia)
C3, C4, CH50, C1q (WNL in NUV; ↓ C3/C4/C1q in
HUV, SLE, other autoimmune vasculitides, atheroem-
bolization)
ANCA ((1)c-ANCA in GPA; (1)p-ANCA in MPA, EGPA, PAN)
Antiphospholipid antibodies ((1) in APLS)
SPEP/UPEP (if (1) consider hematologic malignancy)
CXR (nodules or masses suggestive of malignancy)
Abnormal peripheral blood smear
Cryoglobulins (if (1), consider cryoglobulinemia)
Immunoglobulins (IgA(1) in HSP, IgE(1) in EGPA)
■
If any are present → consider systemic vasculitis!
■
Paresthesia and lack of painful lesions associated with
systemic involvement
• Prognosis: 10% will have chronic and relapsing course
with mean duration 2 years
Pathology
• H&E biopsy best within 18 to 48 hours; DIF best even
earlier (within 8–24 hours)
■
After 48 hours, pathology is non-specic and may show
mononuclear cells rather than neutrophils
• Perivascular neutrophilic inltrate (w/ leukocytoclasis)
centered around post-capillary venules w/ brinoid
necrosis of vessel walls and endothelial swelling, and
RBC extravasation
■
Concomitant involvement of the deeper larger vessels
→ suggests systemic vasculitis
• DIF: 80% w/ perivascular C3 and IgM in rst 48 hours;
after 72 hours, only C3 in minority
Laboratory testing
• ↑ ESR suggestive of systemic disease
• Signicant complement consumption is suggestive of
more extensive or systemic disease
• If systemic disease is suspected, evaluate as per Table 3.36
Treatment
• Depends on severity of disease (Table 3.37)
Subtypes of cutaneous small vessel vasculitis
Henoch-Schonlein purpura (HSP)
Epidemiology
• Most common pediatric vasculitis
• 90% of cases occur in children , 10 yo with male
predominance
• Seasonal variation, with winter predominance
197
CHAPTER 3 • General Dermatology
Table 3.37 Treatment Approach for Cutaneous Small Vessel Vasculitis
Severity of disease
Mild Supportive measures: 90% will have spontaneous reso-
Chronic or
severe
Severe
ulcerating
lution, 10% will have a chronic course
Remove suspected meds
Leg elevation and compression stockings
NSAIDs for arthralgias is controversial
H1 blockers, H2 blockers
Topical steroids
Colchicine (0.6 mg, 2–3×/day)
Dapsone (100–200 mg/day)
Combination of colchicine 1 dapsone or colchicine 1
pentoxifylline is more efcacious than monotherapy
Oral prednisone (0.5–1 mg/kg with a 4–6 week taper)
Can add immunosuppressive agents including:
Azathioprine (1–2 mg/kg/day)
Mycophenylate mofetil (up to 2 g daily)
Cyclophosphamide (1–2 mg/kg/day)
Cyclosporine (2.5–5 mg/kg/day)
IVIG (in an immunodecient patient)
Plasmapheresis (in refractory cases)
Pathophysiology
• IgA vascular deposition in small blood vessels results in:
■
Activation of several cytokines
■
Neutrophil activation of nitric oxide and ROS
• Triggers:
■
Occurs 1 to 2 weeks after a URI; ASO titers elevated in
20%–50%, but causal role of Streptococcus unclear
■
Other infections: Bartonella henselae, parvovirus B19, S.
aureus, H. pylori, and coxsackievirus
■
Drug exposure reported in a minority of patients
Clinical presentation
• Tetrad:
■
Skin: palpable purpura on the buttocks and lower
extremities (100%)
■
Musculoskeletal: arthralgias (75%); arthritis of the
knees and ankles
■
GI: colicky abdominal pain (65%), diarrhea, 1/–
melena; hematochezia (20%)
■
Renal (40%–50%): hematuria w/ risk of nephritis,
end-stage renal disease (1%–3%)
Treatment
• First line: supportive measures (self-limited disease and
resolves in weeks to months)
■
Add prednisone 1/– AZA or cyclosporine if abdominal
pain, arthritis, or severe nephritis
Controversial if prednisone is preventative of renal
disease (Cochrane review did not show benet)
■
Dapsone shortens duration and helps with skin ndings
■
Ranitidine decreases duration and severity of
abdominal pain
■
IVIG considered if rapidly progressive glomerulonephritis
Laboratory testing: see CSVV section
• DIF shows IgA in blood vessel walls
• Renal f/u (serial blood pressure, urinalysis [UA;
hematuria, proteinuria], BUN, CRE, GFR) for at least
5 years in adults and 6 months in children!
• Guaiac if abdominal pain or suspect GI bleed
Pathology
• LCV
• DIF with IgA deposits, C3, and brin in dermal small
blood vessels
• Rate of renal disease is greater if there are no eosinophils
on skin biopsy
Acute hemorrhagic edema of infancy (Fig 3.86)
Epidemiology
• Occurs in children , 3 years
• 70% are boys
Pathophysiology
• Immune complex deposition in small blood vessels
• Triggers: (Table 3.37)
Clinical presentation
• Large annular or targetoid/cockade, edematous, hemorrhagic
plaques on the head (cheeks and ears) and upper extremities
Key features of adult HSP
• More likely to have aggressive course with diarrhea and
chronic renal insufciency (30%)
• Risk factors for chronic renal sequelae: preexisting renal
disease, DM2, HTN, abnormalities in renal testing at time
of vasculitis diagnosis (even very small anomalies)
• Adults who p/w fever, ↑ ESR, and purpura above the
waist are more likely to have IgA glomerulonephritis
• A/w solid organ neoplasms (especially lung cancer) .
hematologic neoplasms
• More frequent vesiculobullous lesions and cutaneous
necrosis (60%)
• Prognosis: recurs in up to 40%
Key features of childhood HSP
• Severe renal disease in 5%–7%; more common over 8 yo
• Abdominal pain is a signicant predictor of nephritis
• Orchitis and pulmonary hemorrhage are rare manifestations
198
Fig. 3.86 Acute hemorrhagic edema; typical large annular hemorrhagic plaques.
(From James WD, Elston DM, Treat JR, Rosenbach MA, Neuhaus IM. Cutaneous
vascular diseases. In: Andrews’ Diseases of the Skin, 13th Ed. Philadelphia:
Elsevier; 2020, pp 813-861.e5.)
3.22 Vasculitides, Vasculopathies, and Other Vascular Disorders
Table 3.38 Triggers for Acute Hemorrhagic Edema of Infancy
Triggers
Infection: viral or
bacterial
Drug
URI: adenovirus, coxsackievirus, EBV
Diarrheal illness: hepatitis A, campylobacter, rotavirus
UTI: Escherichia coli
Other: HSV, VZV
Antibiotics: b-lactams, TMP-SMX
Analgesic: NSAIDs, acetaminophen
Vaccination
• Tender non-pitting acrofacial edema
• Not ill-appearing, but may be febrile
• Prognosis: resolves in 1–3 weeks
Pathology
• LCV
• DIF can have IgA deposits
Treatment
• Supportive with anti-histamines; resolves spontaneously
in 1 to 3 weeks
Urticarial vasculitis
• NUV (70%–80%): normocomplementemic urticarial
vasculitis
■
Skin-limited and idiopathic
• HUV (20%–30%): hypocomplementemic vasculitis
■
Highly a/w systemic disease
Epidemiology
• Females . 50 years most commonly affected, especially
in HUV (same demographics as AICTDs)
Table 3.40 Systemic Involvement in Urticarial Vasculitis
System Associated Symptoms or Disease
Musculoskeletal (50%) Arthralgias, myalgias
Gastrointestinal (15%–30%) Recurrent abdominal pain, diarrhea,
Pulmonary (20%) SOB, severe COPD, laryngeal edema
Renal (20%–30%) Glomerulonephritis or interstitial nephritis
Ocular (50%) Uveitis, conjunctivitis, episcleritis
Constitutional symptoms Fever, malaise, arthralgias, myalgias
nausea/vomiting
• Recurrent episodes lasting months to years
• Systemic ndings (more common in HUV) are highlighted
in Table 3.40
Pathology
• LCV (often subtle in degree)
• Diffuse interstitial neutrophils seen more commonly in
HUV and may be a/w SLE
• DIF: 70% have perivascular Igs and C3, but a lupus band
(granular Ig or C3 along the BMZ) increases the risk for
SLE and renal disease in HUV patients
Laboratory testing
• NUV: same as CSVV
• HUV: ↓ CH50, C3 and C4; anti-C1q Ab (100% of HUV
patients) and ↑ ESR
■
Check ANA given strong association of HUV with SLE
(up to 50%)
• Schnitzler’s syndrome: urticarial vasculitis 1 IgM
gammopathy 1 two of the following: fever, arthralgia,
bone pain, ↑ ESR, or ↑ WBC
Pathophysiology
• Complement and immune complex deposition in blood
vessel wall and activation of the complement cascade
■
Hypocomplementemic form: IgG antibodies bind C1q
→ reduced serum levels of C1q
• Causative agents: often idiopathic, but multiple triggers
may play role (Table 3.39)
Clinical presentation
• Painful/burning urticarial lesions lasting . 24 hours (vs.
,24 hours for normal urticaria) on trunk and LE; resolves
w/ hyperpigmentation or purpura; may have
concomitant angioedema
Table 3.39 Causes of Urticarial Vasculitis
Idiopathic
Autoimmune disease SLE (associated w/ HUV)
Infection—viral Hepatitis B/C, EBV
Medications NSAIDs
Malignancy Leukemia/lymphoma
Other Serum sickness
Sjögren’s
MTX, TNF-a inhibitors
Cimetidine
Fluoxetine
Potassium iodide
Gammopathies (IgM, IgG)
Treatment (Table 3.41)
Erythema elevatum diutinum
Epidemiology
• Rare and chronic condition of middle-aged and older patients
• A/w HIV
Pathophysiology
• Immune complex deposition with repeat inammation
and partial healing → perivascular brosis
• May be a/w multiple systemic diseases (Table 3.42)
Clinical presentation
• Early lesions: red-brown violaceous papulonodules and
plaques on extensor surfaces and near joints
Table 3.41 Treatment Approach for Urticarial Vasculitis
Primary Antihistamines
Alternatives Dapsone
Severe
Oral steroids
Indomethacin
Colchicine
Hydroxychloroquine
Prednisone1 mycophenolate mofetil
Rituximab
Intravenous immunoglobulin
azathioprine
199
CHAPTER 3 • General Dermatology
Table 3.42 Triggers of Erythema Elevatum Diutinum (EED)
Infection
Autoimmune disease IBD, celiac disease, SLE, RA
Hematologic malignancy IgA paraproteinemia/monoclonal
b-Hemolytic Streptococci
HIV
HBV
TB
Syphilis
gammopathy
Myelodysplasia
• Later lesions: rm nodules and masses at previously
inamed sites
• Systemic associations: ocular (scleritis/uveitis) and arthralgias
Pathology
• Early: LCV with interstitial neutrophils resembling
neutrophilic dermatoses
• Late: perivascular storiform brosis (“onion skin
brosis” around dermal vessels) with neutrophils
Treatment
• Dapsone is the ToC
• Other treatments: NSAIDs, tetracyclines, and colchicine
• Most resolve spontaneously in 5–10 years
Mixed cryoglobulinemia (see Cryoglobulinemia section)
Granuloma faciale
Epidemiology
• Adults (Caucasian . African American) and M . F
Clinical features
• Single or multiple discrete red-brown papules, plaques,
and nodules on the face, especially the nose, malar
prominence, forehead, and ear
■
Some consider granuloma faciale and erythema
elevatum diutinum to be the same entity with different
anatomic predilections
• May have follicular prominence, telangiectasias, or a
“peau d’orange” appearance
Pathology
• LCV (ndings may be difcult to identify)
• Grenz zone
• Dense mixed dermal inltrate consisting of eosinophils,
neutrophils, lymphocytes and plasma cells (Fig. 3.87)
Treatment
• Intralesional triamcinolone (2.5–5 mg/mL)
• Cryotherapy 1 intralesional triamcinolone
• Topical steroids
• Topical tacrolimus
• If unresponsive, consider dapsone (50–100 mg/day),
colchicine, or plaquenil
• PDL
Small to medium vessel vasculitis
• General features:
■
Mixture of signs of CSVV and medium vessel disease
Livedo, retiform purpura, ulcers, and subcutaneous
nodules
Consider especially if there is pulmonary and/or
renal involvement
• Types:
■
ANCA (1): granulomatosis with polyangiitis (GPA,
formerly Wegener granulomatosis), microscopic
polyangiitis (MPA), eosinophilic granulomatosis with
polyangiitis (EGPA, formerly Churg-Strauss syndrome)
■
CTD (SLE and RA)
■
Mixed cryoglobulinemia (type II and III)
ANCA-positive vasculitis
(Tables 3.42 and 3.43)
• General pathophysiology:
■
ANCA-mediated vascular injury is caused by
neutrophils and monocytes that produce toxic oxygen
metabolites
Important ANCA associations (boards tip: if you
cannot remember the specic ANCA associations
during the exam, just guess p-ANCA because it is the
less specic autoantibody and is therefore associated
w/ most of the diseases):
■
GPA (Wegener): c-ANCA
■
Levamisole-induced vasculitis: p-ANCA
Fig. 3.87 Granuloma faciale (low magnication). (From
Rapini RP. Vasculitis and other purpuric diseases. In:
Practical Dermatopathology. 2nd ed. Philadelphia:
Elsevier; 2012:73–86.)
200
Normal epidermis
Grenz zone
Diffuse inflammation
3.22 Vasculitides, Vasculopathies, and Other Vascular Disorders
Table 3.43 Features of ANCA Autoantibodies
p-ANCA (less specific) Myeloperoxidase Perinuclear staining
c-ANCA (highly specific) Serine protease 3 Granular cytoplasmic staining
ANCA, Anti-neutrophil cytoplasmic antibody; EGPA, eosinophilic granulomatosis with polyangiitis; MPA, microscopic polyangiitis; PAN, polyarteritis nodosa.
Table 3.44 ANCA(1) Vasculitides
Disorder ANCA Type Systemic Findings and Symptoms Cutaneous Findings Other Defining Features
Granulomatosis with
polyangiitis (Wegener’s)
Microscopic polyangiitis
Eosinophilic
granulomatosis
with polyangiitis
(Churg-Strauss)
c-ANCA Nasal/sinus: sinusitis
p-ANCA . c-ANCA
p-ANCA Nasal/sinus
rhinorrhea
Pulmonary
Cough
Hemoptysis
Renal: Glomerulonephritis with hematuria
CNS: peripheral neuropathy, CVA
Nasal/sinus
None
Pulmonary
Alveolar hemorrhage
Renal
Glomerulonephritis with hematuria
CNS
Neuropathy, mononeuritis multiplex
Nasal polyps
Allergic rhinitis
Pulmonary
Asthma (adult-onset)
Renal: less common
CNS: mononeuritis multiplex, symmetric
polyneuropathy
Cardiac: cardiomyopathy, pericarditis,
valvular disease
GI: N/V, abdominal pain
Palpable purpura
PG-like nodules
Strawberry gums
Palpable purpura
Livedo reticularis
Retiform purpura
Ulcers
Palpable purpura
Painful subcutaneous nodules
EGPA, MPA . PAN
Other autoimmune disease
Chronic infection
GPA (Wegener's) . MPA
Granulomatous
Non-granulomatous
Granulomatous
eosinophilia
■
EGPA: p-ANCA . c-ANCA
■
MPA: p-ANCA . c-ANCA
■
Minocycline-induced lupus erythematosus: p-ANCA
Granulomatosis with polyangiitis (Wegener)
Epidemiology
• Middle-aged adults 1 children
Pathophysiology
• c-ANCA-mediated (anti-PR3) Th1 immune response
→ granuloma formation
• PR3 expression on apoptotic neutrophils stimulates APCs
→ Th1-induced granulomas—this process is “neutrophil
priming”
• Genetic predisposition; nasal S. aureus carriage may
trigger are that improves with antibiotics
Clinical presentation
• Triad of:
■
Necrotizing granulomas of the upper and lower
respiratory tract
Respiratory: cough, hemoptysis, and shortness of breath
Nasal/sinus inammation: rhinorrhea, sinusitis,
and purulent or bloody nasal discharge
■
Systemic vasculitis
Musculoskeletal: arthralgias
Ocular: conjunctivitis, proptosis, and keratitis
CNS: peripheral neuropathy and cerebrovascular
accident
■
Glomerulonephritis
Death from renal disease if left untreated (.80%
1-year mortality)
• Cutaneous ndings: 10%–21% at initial presentation,
15%–46% throughout course of the disease
■
Palpable purpura in dependent areas
■
Oral ulcers are common—gingival hyperplasia with
“strawberry gums” (Fig. 3.88) is rare, but
pathognomonic
■
Painful PG-like nodules or necrotic ulcers
■
Cutaneous disease a/w earlier onset and more
widespread vasculitis
• Limited form: cutaneous or pulmonary subtype
• Constitutional symptoms: fever, weight loss, anorexia, and
malaise
Pathology
• LCV 1 extravascular necrotizing palisading granulomas
with basophilic debris (“blue granulomas”)
201
CHAPTER 3 • General Dermatology
Fig. 3.88 Wegener granulomatosis; strawberry gingiva. (From James WD, Elston
DM, Treat JR, Rosenbach MA, Neuhaus IM. Cutaneous vascular disorders. In:
Andrews’ Diseases of the Skin. 13th ed. Philadelphia: Elsevier; 2020:813–861.)
Laboratory testing
• ↑ ESR and ↑ WBC
• (1) c-ANCA
■
Sensitivity (up to 90%) and specicity (80%–100%)
■
May be absent in patients with localized GPA
■
May have a role in disease monitoring
• Abnormal UA: microscopic hematuria or RBC casts
• Abnormal CXR: nodules, inltrates, and cavities often found
• Sinus involvement: abnormal sinus X-ray, CT sinus, or
nasal biopsy
Treatment
• Induction: cyclophosphamide (2 mg/kg/day) 1 steroids
(Prednisone 1 mg/kg/day); other options include MTX 1
steroids, rituximab (4 infusions of 375 mg/m
1 steroids, plasma exchange (with cyclophosphamide 1
steroids)
2
weekly)
• Maintenance:
■
MTX (20–25 mg/wk) 1 oral steroids
■
AZA (2 mg/kg/day) 1 oral steroids
■
Other options include: rituximab, MMF 2 g daily, IVIG,
iniximab
■
Rituximab . AZA . MMF for preventing relapses
■
Consider adding TMP-SMX to treat nasal Staphylococcus
carriage
• Prognosis:
■
Relapse rate: 50% within 5 years
Microscopic polyangiitis (MPA)
Epidemiology
• M . F; peaks at 65 to 75 years
Pathophysiology
• Unclear, may be ANCA-mediated
• a/w Infective endocarditis, meds, and malignancy
Table 3.45 Comparison of Microscopic Polyangiitis (MPA) and Polyarteritis
Nodosa (PAN)
PAN MPA
Renal: glomerulonephritis –
Hypertension and
microaneurysms
Pulmonary symptoms –
ANCA(1)
Hepatitis B or C association
Table 3.46 Systemic Involvement in Microscopic Polyangiitis (MPA)
Renal (79%–90%) Focal segmental necrotizing
Pulmonary (25%–50%) Pulmonary capillaritis, pulmonary hemorrhage
Neurological (up to 33%) Mononeuritis multiplex, peripheral neuropathy
1
– (less likely)
1
glomerulonephritis
1
1
1 (more likely)
• Constitutional symptoms may be present for months to years
• Systemic symptoms (Table 3.45):
■
Most common cause of pulmonary-renal syndrome
(Table 3.46)
Pathology
• LCV with segmental small . medium vessel vasculitis
• No granuloma formation, unlike GPA or EGPA
Laboratory testing: see CSVV, especially:
• p-ANCA (anti-MPO, 60%) . c-ANCA (anti-PR3, 30%)
• Abnormal UA (proteinuria or hematuria)
• Abnormal CXR or CT (chest)
• Other: abnormal EMG or lung/nerve/kidney biopsy
Treatment
• Induction:
■
Cyclophosphamide (2 mg/kg/day) 1 oral steroids
(1 mg/kg/day)
■
Other options: rituximab 1 steroids, MTX 1 steroids,
plasma exchange (with cyclophosphamide 1 steroids)
• Remission:
■
MTX/AZA 1 steroids (similar to GPA); other options:
MMF, rituximab, IVIG, iniximab
■
Rituximab . AZA . MMF for preventing relapses
• Localized
■
TMP-SMX 1 oral steroids
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)
Epidemiology
• Peaks in middle age
Pathophysiology
• Mixed inammatory and ANCA-mediated tissue damage
with granuloma formation and neutrophilic vasculitis
with eosinophils
• Possible triggers: rapid steroid taper, vaccination, leukotriene
inhibitors, and anti-IgE antibody (omalizumab)
Clinical presentation
• 20%–70% have skin ndings: cutaneous palpable purpura,
petechiae . livedo racemosa, retiform purpura, ulcers, and
splinter hemorrhages, acral erythematous macules
202
Clinical presentation: three classic stages (Table 3.47)
• Cutaneous: presenting sign in 14%, but vast majority will
develop at some point in disease course:
■
Palpable purpura on the lower extremities
3.22 Vasculitides, Vasculopathies, and Other Vascular Disorders
Table 3.47 Stages of Churg-Strauss Syndrome
Stage Presentation
1 (prodromal
atopic
phase)
2 (eosinophilic
phase)
3 (vasculitis
phase)
■
Painful symmetric subcutaneous nodules of the extremities
Adult-onset asthma (nearly 100% patients)
Nasal polyps
Allergic rhinitis
Eosinophilia
Pneumonia
GI: N/V, abdominal pain
Systemic necrotizing vasculitis
Pulmonary: asthma, sinusitis, allergic rhinitis
Neurologic: mononeuritis multiplex, symmetric poly-
neuropathy, sensorineural hearing loss, episcleritis,
facial nerve palsy
Cardiac: pericarditis, valvular disease, endocardiomy-
opathy (leading cause of death)
and scalp; urticaria and erythema can occur also
• Systemic ndings: see Table 3.47
■
Limited renal involvement unlike GPA and MPA
Pathology
• LCV w/ mixed inltrate of eosinophils, neutrophils,
lymphocytes, and macrophages
• Palisading neutrophilic and eosinophilic extravascular
granulomas with degenerated collagen bers (“red
granulomas”)
Laboratory testing
• (1) ANCA: patients more likely to have neurologic and
renal disease
• (–) ANCA linked to cardiac disease
• p-ANCA . c-ANCA in leukotriene-associated Churg-Strauss
• Eosinophilia (eosinophils . 1500/mm
3
)
• Leukocytosis
• ↑ IgE
• CXR: patchy inltrates, interstitial disease, and nodular
masses; CT: bronchial wall thickening and ground glass
opacities peripherally
• a/w Hepatitis B (5%–7%) and hepatitis C
• Cutaneous form:
■
A/w Streptococcal infection in children
■
Has been a/w minocycline
Clinical presentation
• Two forms:
■
Classic subtype with multi-system vasculitis
Rare pulmonary involvement, unlike ANCAassociated vasculitides
■
Cutaneous (Fig. 3.89) subtype with limited systemic
involvement (Table 3.48)
Pathology
• LCV
• Necrotizing arteritis of medium-sized arteries
■
In skin, these vessels are located in subcutis and at the
dermopannicular junction
• Microaneurysms → thrombosis, ischemia, and necrosis
■
Microaneurysms seen on angiography of mediumsized vessels (coronary, renal, celiac, and mesenteric
arteries)
• Later course dened by brosis
• DIF: IgM and/or C3 in the walls of cutaneous blood
vessels
Laboratory testing: see CSVV
• CBC: anemia and leukocytosis
• UA for hematuria and RBC casts
• Hepatitis B and C
• ANCA (p-ANCA , 20% positive)
• Consider angiography if suspect microaneurysm or
stenosis
• In children, consider ASO
Treatment
• TOC: Oral steroids (1 mg/kg/day)
• Severe multiorgan involvement:
■
Cyclophosphamide (2 mg/kg/day) 1 oral steroids
• AZA, MTX or MMF can be used for maintenance
■
Meplizumab (IL-5 MAB) approved for adults with
EGPA w/ severe asthma
Medium vessel vasculitis
Subtypes: PAN and Kawasaki’s disease
Polyarteritis nodosa
Epidemiology
• M . F; peaks 40 to 60 years
• 10% of cases overall are cutaneous form, but it is the most
common form in children
Pathophysiology
• Possible triggers: medications, infections, inammatory
disease (IBD, SLE), hairy cell leukemia; may be immune
complex-mediated
Fig. 3.89 Polyarteritis nodosa. Subcutaneous, tender, purpuric plaques and reticulated purpura on the legs. (Courtesy of Christopher Sayed, MD.)
203
CHAPTER 3 • General Dermatology
Table 3.48 Features of Classic and Cutaneous Polyarteritis Nodosa (PAN)
Key Cutaneous
Features Systemic Features
Classic subtype
(PAN)
Cutaneous
subtype
(C-PAN)
Palpable purpura on
lower extremities
Painful single/multiple
subcutaneous
nodule(s) on lower
extremities that may
ulcerate
Nodules may follow
course of supercial
blood vessels, especially in the lower
extremities
Livedo reticularis
Rare digital or penile
infarction
Pink to purple-red
nodules on lower
extremities near the
malleoli and may extend proximally
Atrophie blanche: atro-
phic, ivory, stellate
scars
Livedo reticularis
Digital gangrene
Constitutional symptoms:
fever, weight loss, arthralgias, malaise
Multi-organ involvement:
Renal: HTN and renal
failure (most common
cause of death)
Cardiac: cardiomyopathy,
MI, arrhythmias
Nervous system: paresthe-
sias, motor or polyneuropathies (foot drop)
GI: N/V, bowel infarction,
hemorrhage, mesenteric
ischemia
GU: orchitis
Multi-organ infarcts from
aneurysms
Constitutional symptoms:
fever, myalgias
Minimal organ involvement:
Nervous: peripheral neu-
ropathy
Musculoskeletal: arthral-
gias, myalgias
Treatment
• Cutaneous subtype:
■
Oral steroids for 3–6 months or longer; may need to
add colchicine, azathioprine, methotrexate or dapsone
if ineffective
■
Children: consider penicillin or tonsillectomy, given
the association with streptococcal infection
• Severe systemic disease:
■
Cyclophosphamide (2 mg/kg/day) 1 oral steroids for
12 months
■
Iniximab or rituximab
■
IVIG
• Hepatitis B (1):
■
IFN-a 1/– vidarabine/lamivudine 1/– plasma
exchange
Clinical presentation (Fig. 3.90)
• Fever for at least 5 days followed by:
■
Conjunctival injection (usually non-exudative)
■
Mucous membrane: lip/oral mucosa erythema, ssured
lips, strawberry tongue, and injected oral and
pharyngeal mucosa
■
Cutaneous: polymorphous eruption including
psoriasiform, morbilliform, scarlatiniform (particularly
perineal with desquamation), and EM-like lesions on
hands/feet
■
Cervical lymphadenopathy
■
Extremity changes: peripheral edema/erythema of
hands/feet, or periungual desquamation
• For diagnosis, need fever $ 5 days 1 four out of ve of
the above
• May get orange-brown or white transverse nail
discoloration
• Systemic complications:
■
Cardiac: coronary artery aneurysms/ectasia (secondary
to vasculitis) and myocarditis
■
Musculoskeletal: arthritis/arthralgias
■
Pulmonary: pneumonitis
■
CNS: aseptic meningitis and facial nerve palsies
■
Ophthalmology: anterior uveitis
■
GI: gastroenteritis, hepatomegaly, bile duct
inammation/hepatitis, jaundice, and pancreatitis
Laboratory testing
• ↑ CRP and ESR
• CBC (anemia, leukocytosis, ↑ neutrophil/eosinophils,
and thrombocytosis)
• ↓ Albumin, sodium, potassium, and HDL
Kawasaki disease (acute febrile mucocutaneous lymph node syndrome)
Epidemiology
• 80% of cases in kids , 5 years; M . F
• ↑ Incidence in Japanese
Pathophysiology
• Unclear etiology, but likely due to infection by unknown
agent
• Genetic and ethnic factors → ↑ susceptibility
• Inammation, scarring, stenosis, and aneurysm formation
in the small, medium, and large musculoelastic arteries
including the coronary artery
204
Fig. 3.90 Lip erythema, ssuring, and bleeding in a patient with Kawasaki disease. Oropharyngeal ndings occur in 80% to 90% of patients, including redness of the lips, tongue, and throat. Lip ssuring and dryness are also common.
(From Bayers S, Shulman ST, Paller AS. Kawasaki disease: part I. Diagnosis,
clinical features, and pathogenesis. J Am Acad Dermatol. 2013;69[4];501.
e1–e11, quiz 511–512.)