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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5192_Библиотеки_им_академика_М_И_Перельмана.pdf
• Average age of onset 5 30 to 40 yo, but children and
elderly may also be affected
• M . F
• Over 97% of DH and celiac disease (CD) patients have
one or both of the following HLA II alleles:
■
HLA-DQ2 (90%)
■
HLA-DQ8 (7%)
• Strongly a/w other autoimmune diseases: Hashimoto
thyroiditis (most common; .50%) . insulin-dependent
diabetes mellitus (IDDM) . pernicious anemia »
Addison’s, alopecia areata (AA), myasthenia gravis,
vitiligo, and SLE
Pathogenesis
• Gluten is a grain protein found in wheat, rye, and barley
■
NOT in oats, rice, or corn
• Gliadin (antigenic component of gluten): soluble by-
product of gluten
• TTG2: transglutaminase protein present in GI lamina
propria; anti-TTG2 IgA antibodies responsible only for gut
involvement (not skin) in DH and CD
• TTG3 (epidermal transglutaminase): present in epidermis
and dermal papillae; anti-TTG3 IgA antibodies responsible
for skin involvement in DH
• Pathogenesis: ingestion of gluten-containing grains
→ gluten broken down into gliadin inside GI lumen
→ gliadin transported across GI mucosa to lamina
propria → TTG2 in lamina propria deamidates gliadin
→ deamidated gliadin forms a covalent bond w/ TTG2
→ TTG2-gliadin complex is a neoantigen recognized
by HLA-DQ2 (or HLA-DQ8) on APCs → specic Th
and B cells activated → production of IgA autoantibodies
against TTG2 or TTG2-gliadin complex → IgA
antibodies bind to TTG2 complexes in lamina propria
→ neutrophil recruitment, damage to intestinal villi
→ enteropathy and villous atrophy → later, epitope
spreading results in IgA autoantibodies against
epidermal transglutaminase (TTG3) → circulating antiTTG3 IgA binds locally to TTG3 within dermal
papillae → neutrophils recruited to dermal papillae
(“neutrophilic papillitis”) → release elastase and
MMPs → subepidermal blister most prominent above
papillae
Clinical features
• Extremely itchy herpetiform vesicles arising on urticarial
plaques
■
Vesicles rupture easily → excoriations usually the only
nding on exam
• Classic distribution (most helpful clue): symmetric
extensor extremities, buttocks, knees, and back/neck
(. face/scalp) (Fig. 3.23)
■
Hemorrhagic/petechial palmoplantar lesions (useful
clue)
• Only 20% of patients w/ DH have symptomatic GI
disease, but .90% have some degree of gluten-sensitive
enteropathy on GI biopsy
Histopathology
• Ideally, biopsy an early blister for H&E: subepidermal
bulla (most pronounced above dermal papillae),
3.4 Blistering Diseases
Fig. 3.23 Erosions on an urticarial base on the elbow of a patient with dermatitis
herpetiformis. (Courtesy of Julia S. Lehman, MD.)
neutrophilic papillitis (neutrophils “stufng” dermal
papillae).
• In reality, often indistinguishable from LABD, but for
Boards purposes, DH has less conuent dermal
neutrophilic inammation, and blisters are more localized
to dermal papillae.
Laboratory testing
• DIF: granular IgA deposits in dermal papillae (90%)
■
Other pattern (10%): granular IgA deposition along
BMZ
■
Ideal biopsy site for DIF: 1 cm away from blister
• Serologic tests:
■
Tissue transglutaminase antibodies (ELISA) are often
positive
■
Antiendomysial antibodies (IIF on monkey esophagus
with IgA) may be positive in DH (80%) and CD (.95%)
■
Anti-gliadin antibodies may also be positive, but have
high false (1) rates
Treatment
• Dapsone (ToC): controls skin disease very rapidly
(,48–72 hours); no effect on GI disease/lymphoma
risk; check for G6PD deciency before initiating
■
If dapsone not tolerated, use sulfapyridine (good
second-line agent w/ ↓ risk of hemolysis)
• Gluten-free diet: controls both skin and GI disease; is
only way to ↓ risk of GI lymphoma (mucosa-associated
lymphoid tissue [MALT]-lymphoma)
• Avoid iodide (ingestion or topically) since may → DH
exacerbation
Prognosis/clinical course
• Lifelong (90%), waxing and waning
Comparative DIF images
• PV (Fig. 3.24)—epidermis stained in chicken-wire pattern;
strongest in lower epidermis (vs. PF)
• PF (Fig. 3.25)—chicken-wire pattern evident diffusely in
epidermis (upper epidermis . lower epidermis)
• BP versus EBA (Figs. 3.26 and 3.27)
115
CHAPTER 3 • General Dermatology
Fig. 3.24 DIF of pemphigus vulgaris with IgG deposition predominantly in the
lower epidermis. (Courtesy of Kerith Spicknall, MD.)
Fig. 3.25 DIF of pemphigus foliaceus with C3 deposition throughout the epidermis, but more intensely in the supercial layers. (Courtesy of Dr. Derek Marsee,
Diagnostic Pathology Medical Group.)
Fig. 3.27 IgG autoantibodies from patients with epidermolysis bullosa acquisita,
anti-p200 pemphigoid, and certain types of mucous membrane pemphigoid
(e.g., antibodies against laminin 5/332) bind to the dermal side (oor) of the blister.
Fig. 3.28 Direct immunouorescence specimen of a patient with paraneoplastic
pemphigus, showing both cell-surface deposition on keratinocytes and basement membrane zone deposition with IgG. (Courtesy of Julia S. Lehman, MD.)
• PNP—pemphigus erythematosus looks similar
(Fig. 3.28)
• DH (Fig. 3.29) versus LABD (Fig. 3.30)
• Porphyria cutanea tarda (PCT; Fig. 3.31)
Fig. 3.26 Circulating IgG autoantibodies from bullous pemphigoid patients bind
to the epidermal side (roof) of the salt-induced split.
116
Inherited blistering diseases
Epidermolysis bullosa (see Chapter 4)
Darier disease (Keratosis follicularis)
• Autosomal dominant; complete penetrance, variable
expressivity
• Peak age of onset 5 puberty (70% prior to 20 yo)
• Chronic course, without spontaneous remission
• Mutation: ATP2A2 (encodes SERCA2 5 calcium ATPase
of endoplasmic reticulum) → defective Ca
sequestration into ER → impaired synthesis and folding
21
Fig. 3.29 Dermatitis herpetiformis. Granular IgA deposition along the dermal–epidermal junction, with stippling in the dermal papillae. (Courtesy of Julia S. Lehman, MD.)
3.4 Blistering Diseases
Fig. 3.30 Linear IgA bullous dermatosis—direct immunouorescence. A linear
pattern of IgA deposition is present within perilesional skin. (Courtesy of Julia S.
Lehman, MD.)
Fig. 3.31 Homogeneous staining of C5b-9, accompanied by concomitant
granular deposition within the microvasculature of this patient with underlying
porphyria cutanea tarda. (Direct immunouorescence; original magnication:
1000). (From Vasil KE, Magro CM. Cutaneous vascular deposition of C5b-9
3
and its role as a diagnostic adjunct in the setting of diabetes mellitus and porphyria cutanea tarda. J Am Acad Dermatol . 2007;56[1]:96–104.)
Fig. 3.32 Darier disease. Typical seborrheic distribution of brown, keratotic papules.
(Courtesy of Dr. Lawrence Lieblich, MD.)
of cell adhesion proteins → keratinocyte acantholysis
and apoptosis
• Malodorous, warty, crusted, and red-brown papules/
plaques in seborrheic distribution (Fig. 3.32); often see
keratotic palmar papules/pits; longitudinal red and white
alternating nail streaks w/ distal “V-shaped” notching;
50% have oral cobblestoning (hard palate most common)
• Segmental Darier disease
■
Type 1 (most common): Blaschkoid streaks of Darier
lesions; post-zygotic ATP2A2 mutation
■
Type 2: generalized Darier w/ focal areas of severe
involvement; heterozygous germline mutation 1
postzygotic loss of other allele
• Prone to secondary infections (Kaposi varicelliform
eruption can be particularly serious)
• ↑ Incidence of epilepsy, intellectual impairment, bipolar
disorder, and depression
• Histopathology: papillomatous epidermal hyperplasia w/
epidermal acantholysis and dyskeratosis (corps ronds
and grains)
■
Corps ronds: large, round, acantholytic keratinocytes
w/ dark nuclei surrounded by a bright pink rim of
condensed keratin; located mostly in spinous layer
■
Corps grains: attened cells composed of bright pink
condensed keratin and a very thin dark nuclear
remnant (looks like parakeratotic nucleus); located
mostly in stratum corneum
• Rx: systemic retinoids (.90% effective), topical
steroids and retinoids, and topical antimicrobials to
↓ odor
117
CHAPTER 3 • General Dermatology
Hailey-Hailey disease (Familial benign
chronic pemphigus)
• Autosomal dominant; complete penetrance, variable
expressivity
• Wider range of onset age than Darier (teens to 20 yo
mostly, but may arise later)
• Mutation: ATP2C1 (encodes hSPCA1, a Ca
the Golgi apparatus) → defective Ca
golgi → impaired processing of proteins involved in cell-
cell adhesion → acantholysis
• Most commonly affects intertriginous sites (lateral neck,
inframammary, axillae, groin, and perianal)
• Subtle, accid vesicle on normal or inamed skin → ruptures
to give macerated, eroded plaques (Fig. 3.33), often w/
circinate shape
• No mucosal involvement (unlike Darier)
• Prone to secondary infections (Kaposi varicelliform
eruption can be most serious)
• Histopathology: psoriasiform hyperplasia (differentiates
from pemphigus) w/ diffuse acantholysis (resembling a
“dilapidated brick wall”); fewer dyskeratotic keratinocytes
than Darier
• Rx: topical steroids; procedural intervention (e.g., CO
laser ablation) is very effective
■
Retinoids not nearly as effective as in Darier
21
21
ATPase of
sequestration into
2
Fig. 3.33 A 47-year-old patient with axillary Hailey-Hailey disease. (From
Pretel-Irazabal M, Lera-Imbuluzqueta JM, España-Alonso A. Carbon dioxide
laser treatment in Hailey-Hailey disease: a series of 8 patients. Actas Dermosiliogr
2013;104[4]:325–333.)
Other blistering diseases
• Multiple non-immunobullous and non-inherited diseases
may cause blistering
• Clinicopathologic correlation is often needed for accurate
diagnosis
• See Tables 3.9 and 3.10
Table 3.9 Other Blistering Disorders
Disease Clinical Setting Clinical Presentation Blister Location
Bullous
diabeticorum
Coma blister Coma due to meds
Friction blisters New pair of ill-fitting shoes;
Bullous small
vessel vasculitis
Bullous drug
eruptions
Bullous arthropod
assault
Delayed postburn/
postgraft blisters
Edema blisters Anasarca or acute exacerbation
PUVA-induced acrobullous dermatosis is the rapid occurence of tense bullae on distal extremities due to PUVA damage to the epidermodermal cohesion 1
friction/trauma.
Modied from Mascaró JM Jr. Other vesiculobullous diseases. In: Bolognia JL, Jorizzo JL, Schaffer JV. Dermatology. 3rd ed. Philadelphia: Elsevier; 2012:515–522.
Longstanding diabetics w/
peripheral neuropathy,
retinopathy, or nephropathy
(barbiturates . benzos,
alcohol, opioids), or non–druginduced coma
sports or military involvement
Pts w/ small vessel vasculitis
(cutaneous or systemic), often
IgA vasculitis
Pts receiving meds, often with
polypharmacy
Most common in children or pts
with hematologic malignancy
(CLL . mantle cell lymphoma,
NK/T-cell lymphoma)
Blisters at sites of prior trauma
(burns, graft site)
of chronic edema
p/w sudden eruption of tense, non-inflammatory, clear fluid-filled vesicles/
bullae, 0.5 to several cm, on feet (.lower legs . hands . forearms);
histopathology: cell-poor subepidermal blister; DIF negative; Rx:
spontaneous resolution in 2–6 weeks; may aspirate if uncomfortable
Tense blisters arising on sites of pressure 48–72 hours after loss of
consciousness; blisters due to pressure-induced necrosis; histopathology: cellpoor subepidermal blister w/ basophilic sweat gland necrosis 1/– epidermal
necrosis; DIF negative; Rx: heals spontaneously in 1–2 weeks
Very common in young, physically active, repetitive friction; initially red
macules at site of friction → painful intraepidermal blisters w/ blood-tinged
fluid; histopathology: pauci-inflammatory blister just under granular layer ;
DIF negative; Rx: heals spontaneously; may drain to relieve pressure
LCV w/superimposed hemorrhagic vesicles and bullae, usually on distal
extremities → may ulcerate; histopathology: LCV or IgA vasculitis w/
subepidermal edema/bullae and often epidermal necrosis
See Table 3.10 See Table 3.10
Grouped pruritic papules w/ central blistering; may have persistent
papulonodules (persistent arthropod assault); pts w/ lymphoma may have
reaction in absence of definitive insect bite (“bug bite-like reactions”) ;
histopathology: eosinophilic spongiosis, superficial and deep perivascular/
periadnexal lympho-eosinophilic inflammation (1/– flame figures ),
superficial dermal edema; Rx: topical steroids, oral antihistamines
Tense vesicles/bullae appearing weeks to months (avg. 37 days) after original
wound has completely healed; due to fragility of new DEJ ; histopathology:
cell-poor subepidermal blister with dermal fibrosis and angioplasia; negative
DIF; Rx: spontaneous resolution
Tense blisters in edematous dependent sites (distal LE, feet most common);
histopathology: cell-poor subepidermal bullae with massive dermal edema and
epidermal spongiosis; Rx: treat underlying edema, compression wraps
Subepidermal
Subepidermal
Intraepidermal
Subepidermal
Intraepidermal
. subepidermal
blister (may
occur if dermal
edema severe)
Subepidermal
Subepidermal
118
3.5 Connective Tissue Disease (CTD) and Sclerosing Dermopathies
Table 3.10 Bullous Drug Eruptions
Disease Characteristic Features Commonly Implicated Drugs
Fixed drug eruption Sharply circumscribed erythematous to dusky
Stevens–Johnson syndrome (SJS),
toxic epidermal necrolysis (TEN)
Drug-induced autoimmune
blistering diseases
Drug-induced pseudoporphyria Eruption resembles porphyria cutanea tarda clinically
Acute generalized exanthematous
pustulosis
Phototoxic drug eruptions Limited to sun-exposed areas
Bromoderma and iododerma Acneiform lesions , papulopustules, nodules, or
Palmoplantar erythrodysesthesia
(acral variant of toxic erythema of
chemotherapy)
Occasionally, eczematous drug reactions (e.g., secondary to warfarin, calcium channel blockers) and systemic contact dermatitis can be papulovesicular;
patients with drug reaction eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS) can also develop vesicles.
Modied from Mascaró JM Jr. Other vesiculobullous diseases. In: Bolognia JL, Schaffer JV, Cerroni L. Dermatology. 4th ed. Philadelphia: Elsevier; 2018:554–561.
violaceous patches
Central blisters or erosions may appear
Often resolves with postinammatory hyperpigmen-
tation
Recurrence at same location(s) following drug reexpo-
sure
Prodrome of fever and painful skin
Areas of dusky erythema associated with epidermal
detachment (varying from ,10% [SJS] to .30%
[TEN])
Mucosal involvement
Primarily linear IgA bullous dermatosis, pemphigus, bul-
lous pemphigoid
Diagnosis based on histologic ndings, immunouores-
cence studies, and drug history
and microscopically
Porphyrin determinations are within normal limits
Acute onset, usually occurring within 2 days of drug
exposure
Areas of erythema studded with pustules; occasionally
vesicles
Fever, malaise, leukocytosis
Resembles exaggerated sunburn
Necrotic keratinocytes are seen on biopsy
even vegetative lesions simulating pemphigus
vegetans
Clear or hemorrhagic blisters can develop (more com-
mon in iododerma)
Painful erythema develops primarily on the palms, soles
and digits following chemotherapy administration
The skin becomes edematous, its color changes to
dark red or violet, and blisters and erosions may
develop
Sulfonamides, NSAIDs, tetracyclines, barbiturates,
aspirin, acetaminophen (paracetamol), metronidazole,
phenolphthalein
NSAIDs, antibiotics (sulfonamides and b-lactams),
anticonvulsants, allopurinol
Linear IgA bullous dermatosis: vancomycin . b-lactams,
captopril, NSAIDs
Pemphigus: penicillamine, captopril , b-lactams, gold
Bullous pemphigoid: diuretics (especially furosemide),
antibiotics, dipeptidyl peptidase 4 inhibitors, checkpoint
inhibitors; PUVA can rarely induce BP
NSAIDs (especially naproxen), nalidixic acid, thiazides,
furosemide, tetracyclines
b-Lactams, macrolides, pristinamycin, terbinafine,
calcium channel blockers (diltiazem), hydroxychloroquine,
carbamazepine, acetaminophen, metronidazole
Tetracyclines (especially doxycycline), quinolones,
psoralens, NSAIDs, diuretics
Bromides, iodine-containing drugs (e.g., amiodarone),
radiographic contrast media
Cytarabine, doxorubicin, capecitabine, 5-fluorouracil
(especially prolonged infusions), multi-kinase inhibitors
(e.g., sorafenib, sunitinib), busulfan, taxanes, clofarabine,
pralatrexate
3.5 CONNECTIVE TISSUE DISEASE
(CTD) AND SCLEROSING
DERMOPATHIES
Connective tissue disease laboratory
studies
Antinuclear antibodies (ANA)
• ANAs are autoantibodies that target various nuclear antigens:
■
Extractable nuclear antigens (ENAs):
Ro/SSA: most strongly a/w Sjögren’s syndrome (SjS;
70%) and neonatal lupus (100%), but also present
in subacute cutaneous lupus erythematosus (SCLE;
75%–90%) and SLE (50%)
La/SSB: most strongly a/w SjS (40%), but also in SCLE
Scl-70 (DNA topoisomerase I): most strongly a/w
diffuse systemic sclerosis (SSc; 60%)
Jo-1 (histidyl tRNA synthetase): Dermatomyositis/
polymyositis (DM/PM) with antisynthetase
syndrome
Smith (Sm): highly specic for SLE (only 10%–30%
sensitive)
RNP (U1 RNP): very high titers correlate with
mixed connective tissue disease (MCTD; 100%);
lower titers in SLE
■
Non-ENA targets:
Double-stranded DNA (dsDNA): highly specic
for SLE (60% sensitive), a/w lupus nephritis,
correlates with lupus band test (LBT) from sunprotected skin
Histone: most a/w drug-induced SLE (95%)
Centromere: a/w CREST (80%)
119
CHAPTER 3 • General Dermatology
• ANAs may be detected by ELISA (newer, cheaper method)
or IIF (older but more sensitive method; substrate is Hep2
cancer cell line)
■
Despite its limitations, the classic IIF ANA test still remains
the most efcient screening test for systemic AICTD
■
ELISA studies useful for identifying specic antigenic
targets → helpful in serologically narrowing the
diagnosis between CTDs
• ANA titer 5 highest dilution of patient’s serum that still
produces uorescence (considered positive if . 1:40)
• Range of ANAs in “healthy” individuals
■
$1:40 (20% 30%)
■
$1:80 (10% 12%)
■
$1:160 (5%)
■
$1:320 (3%)
• Rates of ANA positivity:
■
SLE: 99%
Less than 1% of SLE patients have negative ANA by
IIF → highly unlikely to get false (–) result by
current testing methods!
■
SSc: 90%
■
SjS: 70%
■
DM/PM: 40%–65%
• Common ANA IIF patterns (and corresponding antigenic
targets by ELISA):
■
Homogenous (aka “diffuse”): anti-dsDNA and antihistone antibodies
A/w SLE and drug-induced SLE
■
Peripheral (aka “rim”): dsDNA
A/w SLE
■
Speckled (aka “particulate”): Ro/SSA, La/SSB, U1RNP,
Smith, RNA polymerases, and Scl-70
Non-specic but may be a/w SjS and MCTD
■
Nucleolar: RNA processing molecules (brillarin/
U3RNP), anti-PM/Scl
A/w SSc, PM-SSc overlap
■
Centromere (aka “discrete speckled”): anti-centromere
antibodies
Specic for CREST
• Know the autoantibody associations for each AI-CTD
(Table 3.11)
Lupus band test (LBT)
• Granular continuous band of immunoglobulin
deposits (IgM . IgG . IgA) and complement (C3) at
DEJ in lesioned and non-lesioned skin of sun-exposed
or sun-protected sites in patients w/ SLE visualized
via DIF
Table 3.11 High-Yield Autoantibodies in Connective Tissue Diseases
Target Prevalence (%) Molecular Specificity Key Association
Lupus erythematosus (listed prevalence is for SLE)
ANA 99 N/A
ssDNA 70 Denatured DNA Risk for developing SLE in DLE patients ; also seen in linear morphea
C1q 60 C1q component of complement Severe SLE, hypocomplementemic urticarial vasculitis syndrome
dsDNA 60 Double-stranded (native) DNA
U1RNP 50 (low titers) Splicesome RNP Overlapping features with other AI-CTDs; high titers in MCTD (100%)
Ro/SSA 50 hYRNP Neonatal LE/congenital heart block (99%) ; SCLE (75%–90%);
La/SSB 20 hYRNP SCLE (30%–40%); SjS (40%); occurs in conjunction with SSA/Ro
Cardiolipin 50 Cardiolipin (phospholipid) Antiphospholipid syndrome in SLE : recurrent abortions,
Histone 40 Histones Drug-induced SLE
Smith (Sm) 10–30 Splicesome RNP Highly specific for SLE; higher prevalence in African Americans and
b2 glycoprotein 1
rRNP 7–15 (40% in
Ku 10 DNA repair complex Overlap syndromes with DM/PM and SSc
PCNA 50 Component of multiprotein
DM/PM
ANA 40 N/A Most common IIF patterns: speckled, nucleolar
p155 (TIF1-g)
25 Cofactor for cardiolipin High risk of thrombosis in SLE; primary antiphospholipid syndrome
Asians)
18–23 (adults)
18–35 (juvenile DM)
Ribosomal P proteins Highly specific for SLE; a/w neuropsychiatric LE
complexes involved in cellular
prolifertion
Transcriptional intermediary factor
1-g (tumor suppressor protein)
Most sensitive serologic test for SLE → most common IIF pattern in
SLE5 homogenous, peripheral
SCLE positive in 60%–80% (speckled/particulate IIF)
DLE positive in 5%–25%
Highly specific test for SLE; a/w LE nephritis → useful for monitoring
nephritis activity
primary SjS (70%); a/w photosensitivity
thrombocytopenia, hypercoagulable state, livedo reticularis, leg ulcers,
acral infarction, hemorrhagic cutaneous necrosis
Asians (30%–40%)
Clinically amyopathic/hypomyopathic DM ; cancer-associated
classic DM (adults only); GI involvement; severe cutaneous disease
w/ heliotrope rash/V sign/Gottron papules, psoriasiform plaques,
ovoid palatal patches, palmar hyperkeratosis, “red on white patches”
(atrophic hypopigmented patches w/ telangiectasias)
Younger age of onset in kids
120
3.5 Connective Tissue Disease (CTD) and Sclerosing Dermopathies
Table 3.11 High-Yield Autoantibodies in Connective Tissue Diseases—cont'd
Target Prevalence (%) Molecular Specificity Key Association
p140 (NXP-2) 15 (adults)
Aminoacyl tRNA
synthetases
Anti-Jo1 Jo1 (20)
Anti-PL7 PL7 (5)
Anti-PL12 PL12 (3)
EJ/OJ
Mi-2 4–35 (adults)
MDA5/ CADM-140 10–30 (adults)
SRP 5 Signal recognition particle Fulminant DM/PM (severe muscle weakness) with cardiac involvement,
Ku 3 DNA repair complex DM overlap syndromes with SLE, Sjögren’s, or SSc
SAE 8 Post-translational modification Adults: strong HLA associations, severe skin disease, progressive muscle
Systemic sclerosis
ANA 95 N/A Most common patterns: speckled, nucleolar, centromere (CREST)
Centromere 30 (PSSc)
DNA topoisomerase
I (formerly Scl-70)
RNA polymerases
(I and III)
Fibrillarin (U3RNP) 5 (overall) U3RNP a/w internal organ involvement
MMP1 and MMP3 50 (overall)
Calpastatin 25 (overall) Endogenous inhibitor of calcium-
Morphea
ANA 40 NA N/A
Topoisomerase IIa
ssDNA 50 NA Most prevalent in linear morphea, correlates w/ disease severity/activity
Histones 35 Histones Most prevalent in linear and generalized morphea, correlates w/
Fibrillin-1 30 Fibrillin-1 (component of ECM) Rarely positive in PSSc or CREST
Rheumatoid arthritis
Rheumatoid factor 80 Fc portion of IgG Low levels: very non-specic, may be seen in other AI-CTDs, infections,
Cyclic citrullinated
proteins
Sjögren’s syndrome
a-Fodrin
Ro/SSA 60–70 hyRNP
La/SSB 20–40 hyRNP Seen in same contexts as Ro/SSA; almost never positive if Ro/SSA is negative
Mixed connective tissue disease (MCTD)
U1RNP 100 (by definition) Splicesome RNP Low titer positivity can be seen in SLE
LE, lupus erythematosus; SCLE, subacute lupus erythematosus; RA, rheumatoid arthritis; SjS, Sjogren syndrome; AI-CTDs, autoimmune connective tissue, diseases;
PSSc, progressive systemic sclerosus; ECm, extracellular membrane; HTN, hypertension; DM, dermatomyositis; PM, polymyositis; SSc, systemic sclerosus.
Modied from Dutz JP, Jacobe HT, Sontheimer RD, Saxton-Daniels S. Autoimmune connective tissue diseases. In: Bolognia JL, Schaffer JV, Cerroni L. Dermatology.
4th ed. Philadelphia: Elsevier; 2018:649–661.
20–25 (juvenile DM)
Up to 20 tRNA synthetases Anti-synthetase syndrome (myositis, mechanic’s hands, arthritis,
EJ/OJ (,1)
4–10 (juvenile DM)
7–50 (juvenile DM)
80 (CREST)
60 (PSSc)
15 (CREST)
45 (PSSc)
6 (CREST)
70 (PSSc)
33% (CREST)
75
70 CCP proteins in skin (filaggrin)
70 Actin-binding protein (involved in
Nuclear matrix protein (MORC
family CW-type zinc finger 3
[MORC3])
Helicase Classic DM skin findings (e.g., shawl sign, Gottron papules, etc.), mild
MDA5 CADM w/rapidly progressive ILD (adults and kids); distinctive skin
CENP-B Most specific for CREST, a/w pulmonary HTN
DNA topoisomerase I Most strongly a/w progressive systemic sclerosus ( PSSc) with pulmonary
RNA polymerase I/ III High levels correlate w/ severe skin involvement (diffuse) and renal
Degrade ECM proteins
dependent protease, calpain
Topo Iia
and joints
secretion)
Adults: a/w malignancy, subcutaneous edema and calcinosis; 80% of
all cancer-related DM has autoantibodies to NXP-2 or TIF1-g
Juvenile: severe muscle disease, GI bleeding (vasculopathy), calcinosis
Raynaud phenomenon, severe ILD [worse with non-Jo1 antibodies])
muscle disease; good response to treatment
findings (skin ulcers [MCP/IP joints, elbows, knees, nail folds] , oral
ulcers, painful palmar papules, lateral digit hyperkeratosis/scaling,
nonscarring diffuse alopecia, panniculitis); arthritis, fever, hand swelling
poor prognosis
disease, a/w hydroxychloroquine drug eruptions
Juvenile: severe skin disease BUT minimal muscle disease
fibrosis and poorer prognosis
crisis in PSSc; a/w internal malignancy (breast cancer #1)
Not used clinically
disease severity/activity
liver dz, sarcoid, systemic vasculitides
High levels: a/w severe, crippling, erosive RA and extra-articular mani-
festations of RA (systemic vasculitis, neuropathy); may also have high
levels in mixed cryoglobulinemia (types II and III) secondary to Hep
C infection
a/w Severe RA; also a predictor for development of RA
Most specific antibody for SjS
Also important in neonatal LE (99%) and SCLE (may be a/w
photosensitivity)
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CHAPTER 3 • General Dermatology
• Three different types of LBTs exist:
■
Lesional LBT
High sensitivity in patients w/ SLE
LBT may also be positive in patients with chronic
cutaneous lupus erythematosus (CCLE; 60%–
80%)
Helpful in differentiating from other rashes in nonSLE patients
♦ Can see false (1) LBT in rosacea, telangiectasias,
and polymorphous light eruption (PMLE) →
band is usually weaker in intensity and more
focal/interrupted
Positive LBT seen in , 5% of DM
↑ # of immunoreactants → ↑ specicity for
SLE
■
Sun-exposed, non-lesional skin (shoulder, proximal
extensor forearm)
Positive in 70% 80% of SLE
Useful in making diagnosis of SLE in patients
without skin lesions
25% of people without SLE will demonstrate a
weak interrupted linear and granular DEJ deposition
of IgM and Clq (less frequently IgG, IgA, and C3),
which usually does not meet criteria for a positive
LBT
■
Sun-protected, non-lesional skin (medial exor
forearm, medial upper arm, and buttocks)
Positive in 35% 55% of SLE
Useful for measuring disease activity and assessing
prognosis
Correlates with anti-dsDNA autoantibodies →
a/w severe extracutaneous disease including renal
disease
Lupus erythematosus
• There are three major “specic” cutaneous manifestations
of lupus: acute (ACLE), subacute (SCLE), and chronic
(CCLE) (Fig. 3.34)
■
These three cutaneous manifestations are not mutually
exclusive→ patients may have more than one
cutaneous morphology at any given time
■
Every form of cutaneous lupus may be seen in the
setting of SLE or as an isolated cutaneous disease
■
Degree of association with SLE varies by cutaneous
subtype (Table 3.12)
• All patients with “specic” cutaneous lesions of lupus
should be evaluated for systemic disease (SLE) via
clinical exam, H&E, DIF, and serologic studies
• In addition, multiple “non-specic” cutaneous lesions
may be seen in lupus (discussed in SLE section)
Chronic cutaneous lupus erythematosus (CCLE)
Epidemiology
• Female predominance
• DLE accounts for the majority of CCLE
■
40%–70% of SLE patients will have discoid lesions
■
However, only 5%–20% of patients with DLE
progress to SLE
5% for patients w/ head-only involvement
20% for patients w/ diffuse involvement
Majority of DLE patients who progress to SLE do so
within rst 5 years; younger age, high ANA titer, skin
type V/VI may also increase progression risk
■
African Americans more commonly affected w/ DLE
CHARACTERISTIC SITES OF INVOLVEMENT FOR THE THREE MAJOR SUBTYPES OF CUTANEOUS LUPUS ERYTHEMATOSUS
Acute cutaneous LE Subacute cutaneous LE Chronic cutaneous LE
Alopecia
"Butterfly"
rash
Fig. 3.34 Characteristic sites of involvement for the three major forms of cutaneous lupus erythematosus (LE). (From Lee LA, Werth VP. Lupus erythematosus. In:
Bolognia JL, Schaffer JV, Cerroni L. Dermatology. 4th ed. Philadelphia: Elsevier; 2018:662–680.)
within lesions
LE tumidus
Lupus panniculitis
Discoid LE
Chilblain lupus
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3.5 Connective Tissue Disease (CTD) and Sclerosing Dermopathies
Table 3.12 Different Forms of Cutaneous Lupus and Their Association
With Systemic Lupus Erythematosus (SLE)
Type of Cutaneous Lupus Association With SLE
• Acute cutaneous lupus erythematosus
(ACLE)
• Subacute cutaneous lupus erythematosus
(SCLE)
• Chronic cutaneous lupus erythematosus
(CCLE)
Localized DLE (head and neck)
Widespread/disseminated DLE
Hypertrophic DLE
Lupus erythematosus tumidus (LET)
Lupus panniculitis
Chilblain lupus
• Other variants
Bullous eruption of SLE
Rowell’s syndrome
Modied from Lee LA, Werth VP. Lupus erythematosus. In: Bolognia JL,
Jorizzo JL, Schaffer JV. Dermatology. 4th ed. Philadelphia: Elsevier;
2017:615–629.
1111
11
1
11
1
1/–
1
11
1111
11 to 111
Pathogenesis
• UVR (UVB . UVA) has role in lesional development
• Type I IFN signature w/ CD41 T-helper 1 (Th1) cells and
CD81 cytotoxic T-cell recruitment and activation
• Tobacco:
■
Smoking is a risk factor for DLE
■
Stopping may help resolve recalcitrant lesions
• Genetic predisposition (multiple genes—e.g., TYK2, IRF5,
CTLA4); TREX1 mutations a/w familial chilblain lupus
CCLE clinical subtypes
1. Discoid LE
• Most common form of CCLE
• Begin w/ red macules or plaques → later develop scale,
atrophy, and scarring, w/ central hypopigmentation and
peripheral hyperpigmentation (more apparent in darker-
skinned patients) (Fig. 3.35)
• Langue du chat (cat’s tongue): carpet “tack-like” spines
on undersurface of scale
• Typical locations: face, scalp (cicatricial alopecia), and
ears (esp. conchal bowl)
■
Occasionally occurs in photoprotected sites, but rare to
see discoid lesions below the neck unless lesions above
the neck are also present
■
25% have mucosal involvement (lips, conjunctiva,
nasal mucosa, genitals)
• ANA (1) in 5%–25%
• DLE variants:
■
Localized DLE
Above neck only
■
Widespread DLE
Above and below neck
Stronger association w/ SLE, more likely to have
serologic abnormalities
■
Childhood DLE
Higher rate of progression to SLE
Fig. 3.35 Extensive scarring from discoid lupus erythematosus. (From James
WD, Elston DM, Treat JR, Rosenbach MA, Neuhaus IM. Connective tissue diseases. In: Andrews’ Diseases of the Skin. 13th ed. Philadelphia: Elsevier;
2020:157–183.)
2. Hypertrophic (verrucous) LE
• Thick, hyperkeratotic and verrucous scaling plaques w/
indurated border
• ↑ Risk SCC (akin to hypertrophic LP)
• Typical locations: extensor forearms . face, and upper
trunk (sun-exposed sites)
■
Favors upper half of body (vs. hypertrophic LP 5
lower half)
• Usually accompanies typical discoid lesions
3. Chilblain LE
• Red or dusky purple papules/plaques on ngertips, rims
of ears, calves, and heels
• Chronic relapsing course
• Precipitated by cold, but often persists year-round (vs.
non-lupus-associated chilblains)
4. Tumid lupus erythematosus
• Edematous, indurated, erythematous, often annular
plaques without epidermal involvement (Fig. 3.36),
lesions resolve without scarring or atrophy
■
Plaques may have central clearing
• Typical locations: face and trunk
• Responds well to antimalarials
• Considered to be on a clinical spectrum w/ Jessner’s and
reticular erythematous mucinosis (REM), with similar
ndings on histology
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CHAPTER 3 • General Dermatology
• Most commonly seen in conjunction w/ cutaneous DLE
• Lesions:
■
Classic plaque with central erythema and surrounding
white keratotic border, usually on hard palate
■
Discoid lesions most commonly on the lip
• Typical locations: buccal mucosa, hard palate, and
vermillion lip (lower . upper)
• ↑ Risk SCC
• Presence of ulceration → a/w ↑ risk for systemic
involvement
Fig. 3.36 Lupus erythematosus tumidus. Annular pink plaques on the back.
(Courtesy Dr. Heather Holahan, University of North Carolina, Department of
Dermatology.)
• Differentiating tumid LE versus Jessner’s versus REM:
■
Jessner’s: similar clinical appearance, but has CD81
predominant inltrate w/ ↓ mucin
■
REM is histologically identical to tumid LE, but is
morphologically distinctive (erythematous macules and
papules or plaques on mid back/chest in a reticular
pattern)
5. LE panniculitis/profundus
• Indurated, non-tender, subcutaneous nodules or plaques
that heal w/ atrophy (depressed scarring of fatty areas)
• Overlying skin often normal, but may have discoid
changes (if DLE lesions above panniculitis plaques 5
lupus profundus)
• Typical locations: face, upper arms, upper trunk, breasts,
buttocks, and thighs
• Antimalarials effective
• 15% a/w SLE (panniculitis may be rst sign)
6. DLE-LP overlap
• Coexisting DLE and LP w/ overlap lesions
• Palmoplantar involvement is characteristic
• DDx: LP-like rash can also occur in SLE patients on
antimalarials
7. Mucosal LE
• Does not include non-lupus specic mucosal ulcers a/w SLE
Laboratory testing
• (1/–) ANA, leukopenia, and ↑ ESR
■
Serologic abnormalities more common in patients
w/ widespread DLE
Histopathology
• DLE
■
H&E: compact othrohyperkeratosis, vacuolar interface
dermatitis w/ necrotic keratinocytes and pigment
incontinence, epidermal atrophy, BMZ thickening,
follicular plugging, supercial and deep perivascular/
periadnexal lymphohistiocytic inammation with
plasma cells, CD1231 plasmacytoid dendritic cells
(helpful in distinguishing lupus from most lymphomas
and other inammatory diseases), and mucin
deposition (Fig. 3.37)
Lacks eosinophils
■
DIF
LBT(1) on lesional skin in 75%; ideal to choose
lesion that has been present for a few months or more
♦ More likely to be positive on head/neck and
extremities compared with trunk
• Hypertrophic (verrucous) LE
■
Similar histologic features as DLE but w/ greater
orthohyperkeratosis and endophytic buds of
hyperplastic follicular epithelium (. interfollicular
epidermal hyperplasia)
Pseudoepitheliomatous hyperplasia is often
mistaken for SCC
A B
Fig. 3.37 (A) and (B) Discoid lupus erythematosus histology. Note focal interface dermatitis, dense perivascular/periadnexal lymphoid inltrates, and thickened basement membrane zone (BMZ). (From Elston DM: Interface dermatitis. In: Elston DM, Ferringer T, eds. Dermatopathology. 3rd ed. Philadelphia: Elsevier, 2019:132–152.)
124