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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5192_Библиотеки_им_академика_М_И_Перельмана.pdf
3.5 Connective Tissue Disease (CTD) and Sclerosing Dermopathies
• Chilblain LE
■
Demonstrates features of both chilblains (papillary
edema, perivascular and dermal lymphohistiocytic
inltration) and DLE
■
DIF: (1) LBT
• Tumid LE
■
No signicant epidermal changes (e.g., lacks
follicular plugging, vacuolar interface, and BMZ
thickening)
■
Shares characteristic dermal features of DLE:
Perivascular and periadnexal lymphoid aggregates in
upper and lower dermis, with clusters of CD1231
plasmacytoid dendritic cells
Massive mucin deposition (more than classic DLE;
amount rivals that seen in DM)
■
Histologically similar to REM and Jessner’s, except Jessner’s
has CD81 predominant inltrate and lacks mucin
■
DIF: (1) LBT in 50%
• LE panniculitis
■
May have histologic ndings of overlying DLE (if DLE
epidermal and dermal changes present 5 lupus
profundus)
■
Dermal mucin deposition
■
Subcutaneous ndings:
Lymphocytic lobular panniculitis
Hyaline (“waxy pink”) fat necrosis
Nodular lymphoid aggregates, with clusters of
CD1231 plasmacytoid dendritic cells
Fat lobules may be rimmed by lymphocytes
♦ Important to differentiate from subcutaneous
T-cell lymphoma: atypical cells, lacks dermal
lymphoid nodules, lacks CD1231 plasmacytoid
dendritic cells (helpful IHC stain), lacks mucin
■
DIF: (1) LBT in 35%–70%
• DLE-LP overlap
■
Typical lesions of LE or LP will demonstrate H&E and
DIF ndings for that condition
■
Overlap lesions may show features typical for both
• Mucosal LE
■
Hyperkeratosis, atrophy of rete pegs, vacuolar-tolichenoid interface dermatitis; supercial and deep
perivascular lymphocytic inltrate
■
DIF: (1) LBT
Treatment
• Treatment algorithm: (Fig. 3.38)
Good response
7
Maintain
7
Maintain
Quinacrine discontinued
Good response
7
Maintain
Local disease
Topical treatment
Retinoids
Good response
Reduce and
discontiue
No response
HCQ or CQ
3
Prevention: e.g., sunscreens
1
No responseGood response
Add Quinacrine
No response
Partial response
Add MTX
No response
Thalidomide
4
Severe and widespread skin
manifestations
Topical treatment (CS and/or CI)
systemic CS (active disease)
No response Good response
2
+
HCQ or CQ
+
Good response
Good response
Good response
MMF/EC-MPS
1
Dapsone
6
Maintain
7
Maintain
7
Maintain
7
Maintain
Good response
5
7
Maintain
7
No response
Fig. 3.38 Cutaneous lupus erythematosus (CLE): update of therapeutic options. Algorithm of treatment for CLE. Topical agents include topical steroids, calcineurin
inhibitors, and retinoids. Consider retinoids earlier for discoid lupus-lichen planus overlap. Thalidomide is used at 50 to 100 mg daily for clearing and 25 to 50 mg
daily-twice weekly for maintenance; lenalidomide works similarly but without the peripheral neuropathy of thalidomide. CI, Calcineurin inhibitor; CQ, chloroquine; CS,
corticosteroids; EC-MPS, mycophenolate sodium; HCQ, hydroxychloroquine; MMF, mycophenolate mofetil; MTX, methotrexate. (From Kuhn A, Ruland V, Bonsmann
G. Cutaneous lupus erythematosus: update of therapeutic options part I. J Am Acad Dermatol. 2011;65[6]:e179–e193.)
Other systemic agents
or experimental therapy
No response
125
CHAPTER 3 • General Dermatology
Prognosis/clinical course
• 5%–20% progress to SLE (typically within rst 5 years
after diagnosis)
• ↑ Risk of progression w/ widespread DLE and
childhood DLE
Subacute cutaneous lupus erythematosus
Epidemiology
• Female predominance (4:1)
• More common in whites (vs. DLE)
• 30%–50% of patients w/ SCLE lesions will eventually
meet criteria for SLE, but most usually only have mild
disease
Pathogenesis
• Proposed mechanism: UVR-induced apoptosis → apoptotic
bodies containing high levels of nuclear antigens (e.g.,
Ro, La, DNA) 1 reduced clearance of apoptotic cells
(particularly in complement deciency-related LE) → loss
of immune tolerance → release of proinammatory
cytokines and production of ANAs, most importantly
anti-Ro/SSA autoantibodies
• Genetic associations:
■
HLA-B8 (strongest association), HLA-DR3, and others
■
Hereditary C2 and C4 deciencies
• Antibodies
■
Anti-Ro/SSA (75%–90%)—of note, SSA plays role in
cell survival after ultraviolet radation and regulates
inammation
Thought to be pathogenic in SCLE
May cause clinical overlap w/ SjS
• Complement
■
SCLE is a/w complement deciencies, especially
deciencies in the early intrinsic pathway (C1q/r/s,
C2, and C4)
Clinical features
• Often has a chronic, relapsing course
• Photosensitivity prominent in 50%
• Two clinical variants:
■
Papulosquamous SCLE: psoriasiform plaques
(Fig. 3.39)
■
Annular SCLE: scaly polycyclic annular plaques with
central clearing
• Typical locations: sun-exposed areas of lateral face
(central face spared), neck, V-chest, and upper back/
extremities
• Often heals w/ hypopigmentation, but no scarring
• May have clinical overlap w/ SjS (both have Ro/SSA
autoantibodies)
• Systemic manifestations are common, but only 30%–50%
fully meet criteria for SLE
■
Arthritis/arthralgias 5 most common systemic nding
(up to 70%)
Laboratory testing
• Antibodies
■
Anti-Ro/SSA (75%–90%)
Fig. 3.39 Subacute cutaneous lupus erythematosus, papulosquamous. Psoriasiform lesions coalesce to form retiform arrays. (From Okon LG, Werth VP. Cutaneous lupus erythematosus: diagnosis and treatment. Best Pract Res Clin
Rheumatol. 2013;27[3]:391–404.)
■
Anti-La (30%–40%)
■
ANA (60%–80%; usually in a speckled/particulate
pattern)
• Other
■
Leukopenia (20%)
Histopathology
• Compact hyperkeratosis, prominent epidermal atrophy,
vacuolar interface dermatitis w/ pigment incontinence,
BMZ thickening, PV/PA lymphoid aggregates (limited to
supercial dermis) w/ scattered plasma cells, clusters of
CD1231 plasmacytoid dendritic cells, and mucin
deposition
■
Lacks eosinophils and follicular plugging
• DIF:
■
Granular particulate IgG/IgM within the epidermis
■
(1) LBT in 60%–85% (usually not as thick or intensely
stained as in DLE)
Treatments
• First line: antimalarials and sun protection
• Recalcitrant: may require other immunosuppressive meds
Drug-induced SCLE (DI-SCLE)
• Skin always involved!
• Rare to have systemic involvement
• Photosensitive papulosquamous eruption (often
psoriasiform to lichenoid) w/ annular plaques on upper
body and extensor upper extremities
• Antibodies: anti-Ro/SSA (80%), anti-La/SSB
• Hundreds of drugs have now been implicated in
DI-SCLE:
■
Most common: HCTZ, terbinane, TNF-a inhibitors
(may also cause drug-induced SLE), proton pump
inhibitors (PPI), calcium channel blockers (CCBs),
anti-epileptic agents, taxanes, griseofulvin
■
Less common: ACE inhibitors, b-blockers, statins,
antihistamines, IFN-a and IFN-b, NSAIDs
126
3.5 Connective Tissue Disease (CTD) and Sclerosing Dermopathies
SCLE-like syndromes
Neonatal lupus erythematosus (NLE)
• Epidemiology
■
Female predominance for NLE of skin (3:1) and
cardiac NLE (2:1)
• Pathogenesis
■
Result of transplacental passage of maternal
autoantibodies, most importantly anti-Ro/SSA (99%)
Autoantibodies can result in heart block requiring
pacemaker
Unselected women w/ anti-Ro/SSA antibodies →
1%–2% risk of having child w/ NLE
Women w/ SLE or another dened CTD with
anti-Ro/SSA antibodies → 15% risk having a child
w/ NLE
Women who have a prior child w/ NLE → 25% risk
of NLE in subsequent children
• Clinical features
■
Cutaneous ndings:
Lesions arise within rst weeks of life but usually
not present at birth
Skin lesions (similar to adults w/ SCLE but more
prominent facial involvement):
♦ Photosensitivity
♦ Periorbital erythema 5 “raccoon eyes”
♦ Annular, polycyclic erythematous plaques w/
central clearing and raised red border, ne scale,
typically located on scalp, neck, or face
♦ Non-scarring
♦ Resolves w/ dyspigmentation and
telangiectasias
■
Systemic ndings:
Cardiac (70% overall have some cardiac
abnormality; 30–40% have congenital third-degree
heart block)
♦ Heart block is almost always present by birth,
developing in utero between 16 and 24 weeks
gestation
♦ Usually p/w bradycardia and irreversible
complete heart block (third degree)
Occasionally p/w rst- or second-degree heart
block → may progress to complete heart
block
Hepatobiliary disease (50%)
♦ P/w transient conjugated hyperbilirubinemia in
rst weeks of life, or transient elevations of
aminotransferases
Hematologic abnormalities
♦ Thrombocytopenia
♦ Neutropenia, lymphopenia, and hemolytic
anemia
■
Mother
50% of women with a child w/ NLE are
asymptomatic at time of child’s birth
♦ Half of mothers who are initially asymptomatic
later develop SjS or SLE
• Histology
■
Same as SCLE
■
DIF: (1) LBT in 50%
• Laboratory testing
■
Autoantibodies
Anti-Ro/SSA antibodies (99%)
Anti-La/SSB and anti-U1RNP antibodies may be
found in combination with anti-Ro/SSA antibodies
(rarely present alone)
■
↑ LFTs
■
Hematologic cytopenias (mainly thrombocytopenia)
• Treatment
■
Skin disease
Sun protection 1 topical CS
■
Cardiac disease
In utero:
♦ Prenatal systemic CS may ↓ risk of developing
congenital heart block
Does not decrease rate of cutaneous NLE,
however
♦ Hydroxychloroquine throughout pregnancy
→ ↓ risk of a child w/ cardiac NLE for women w/
SLE and anti-Ro/SSA (1) women with a previous
child affected by NLE
Neonatal:
♦ Once complete heart block occurs, it is
irreversible
♦ Pacemaker required for heart block in two thirds
of patients w/ cardiac NLE
■
Hematologic and LFT abnormalities
Usually no treatment needed
• Prognosis/clinical course
■
Children with NLE may be at ↑ risk of developing SLE
or autoimmunity later in life
■
Skin disease
Lesions resolve without scarring by 6 months
(as maternal antibodies clear from neonatal
circulation)
Residual atrophy, dyspigmentation, and
telangiectasias persist for months to years
■
Cardiac disease
Low-grade AV blocks are reversible and sometimes
normalize without therapy
Complete (third-degree) heart block is irreversible
Cardiac NLE has 20%–30% mortality rate
■
Hematologic and LFT abnormalities
Transient with spontaneous resolution within 4 to
6 months
Complement deciencies
• Epidemiology
■
Primary C2 deciency
Most common hereditary complement disorder
Only 10%–20% with homozygous C2 deciency
will develop SLE (low risk)
♦ Since C2 deciency is more common than other
early complement deciencies, it is the most
common cause of complement deciencyassociated SLE
■
Primary C1q and C4 deciencies
Homozygous deciencies are very rare, but are
associated with a very high risk of developing
autoimmune disease
SLE risk with homozygous mutations: C1q (90%)
. C1r/s . C4 . C2 (10%–20%)
127
CHAPTER 3 • General Dermatology
• Pathogenesis
■
UV-damaged apoptotic keratinocytes express
autoantigens (esp. Ro/SSA) on cell surface
■
Early components of complement normally help clear
out these apoptotic keratinocytes
■
Deciencies in early components (C1, C4, C2) of
classic complement pathway → impaired phagocytic
clearance of apoptotic bodies containing high levels of
autoantigens → loss of immune tolerance and
autoantibody-mediated inammation
• Clinical
■
Deciency of any early classical complement
component (C1, C2, C4) a/w ↑ risk for SLE and
infections w/ encapsulated bacteria
■
C2 deciency-associated SLE (most common but least
severe):
Adult onset (average 30 yo)
F . M
SLE w/ less severe systemic disease (e.g., mild or
absent renal disease)
Prominent photosensitivity and SCLE lesions
↑ Bacterial infections w/ encapsulated bacteria,
especially Streptococcus pneumonia
■
C1q/r/s and C4 deciency-associated SLE (less
common but more severe)
Childhood onset
Severe, recalcitrant renal disease
Photosensitivity with CCLE or SCLE
Palmoplantar keratoses (C4 deciency only)
↑ Risk of infection with encapsulated bacteria and
candida
■
Anti-C1q autoantibodies (acquired)
Arise in 30%–50% of SLE patients, a/w lupus nephritis
Seen in 100% of patients w/
hypocomplementemic urticarial vasculitis (HUV)
• Laboratory ndings
■
Low or absent ANA titers
■
Anti-Ro/SSA antibodies in majority
■
↓ Complement levels (screening test is CH50, which
is markedly decreased)
Acute cutaneous lupus erythematosus (ACLE)
• 60% of SLE patients develop a malar rash
• Of the three major cutaneous lupus subtypes, ACLE is
most strongly a/w SLE
• Classically p/w localized (malar) erythema 5 “buttery
rash” (Fig. 3.40); a transient eruption following sun
exposure lasting hours to weeks
■
Classically involves the nasal bridge and bilateral malar
eminence, sparing the melolabial folds (in contrast to
facial erythema of DM), but may also involve the
forehead, periorbital areas, and sides of neck
■
Morphology ranges from mild erythema to edematous
lesions
■
Lesions may develop scaling, papules, erosions,
poikiloderma, atrophy, or dyspigmentation that can
help distinguish it from other facial rashes
■
Malar discoid lesions do not count as a “buttery rash”
• Buttery rash may occasionally be accompanied by a
more generalized photodistributed eruption involving the
Fig. 3.40 Patient with severe acute lupus erythematosus, with marked erythema
in a photodistribution. (From the William Weston Collection, Aurora, CO. In:
Fitzpatrick JE, High WA, Kyle WL. Urgent Care Dermatology: Symptom-Based
Diagnosis. Philadelphia: Elsevier; 2018.)
V-neck, upper back, extremities, and dorsal hands,
classically sparing the knuckles (in contrast to the
conuent macular violaceous erythema [CMVE] of DM)
• Histopathology: vacuolar interface dermatitis, dermal
edema, and sparse perivascular lymphocytic inltrate
limited to upper dermis
■
Lacks follicular plugging and other dermal changes
• DIF: (1) LBT
• Laboratory tests: ACLE is highly a/w SLE → perform same
lab studies as in SLE to search for end-organ damage
• Treatment: skin lesions of ACLE respond to treatment for
systemic symptoms; for recalcitrant skin disease, refer to
treatment algorithm presented in DLE section
■
Cutaneous ares tend to correlate w/ systemic disease
activity
Other rare cutaneous lupus variants
Bullous SLE
• Epidemiology
■
Female predominance
■
Predominately African Americans
• Pathogenesis
■
Antibodies against NC1 and NC2 domains of type VII
collagen (same as EBA)
■
a/w HLA-DR2
• Clinical
■
By denition, patients must meet American College
of Rheumatology criteria for diagnosis of SLE in
order to term it “bullous SLE”
■
Widespread, symmetric eruption of tense,
subepidermal bullae on erythematous-to-urticarial
base (Fig. 3.41)
■
Involves both sun-exposed and non-exposed areas
■
Typical locations: face, neck, upper trunk, and proximal
extremities
Mucosal involvement is common
■
Systemic symptoms same as SLE
128
3.5 Connective Tissue Disease (CTD) and Sclerosing Dermopathies
Fig. 3.41 Bullous lupus erythematosus. (From James WD, Elston DM, Treat JR,
Rosenbach MA, Neuhaus IM. Connective tissue diseases. In: Andrews’ Dis-
eases of the Skin . 13th ed. Philadelphia: Elsevier; 2020:157–183.)
• Histopathology
■
Subepidermal bulla with neutrophils at DEJ and in
dermal papillae
■
DIF: multiple immunoreactants (IgG, C3, IgA, IgM)
present in granular pattern along BMZ, along with
linear deposition of IgG and/or C3
• Laboratory testing
■
Salt-split skin IIF: dermal deposition with IgG
■
ELISA: autoantibodies to collagen VII
■
ANA (1) in 100%
Frequently positive for dsDNA, Sm, Ro/SSA, and La/
SSB
■
end-organ damage; 50% of cases a/w lupus nephritis
• Treatment
■
Dapsone (ToC) → dramatic response within 1 to 2 days
Differentiates bullous SLE from EBA!
■
Immunosuppressant meds may be needed for
recalcitrant disease
• Prognosis/clinical course
■
Often a/w systemic lupus are
■
Lesions of bullous LE respond dramatically to dapsone
with cessation of new lesions and healing over a few days
Rowell’s syndrome
• Targetoid lesions clinically resembling EM, arising in
setting of ACLE, SCLE, or DLE; typically Ro/SSA (1)
Toxic epidermal necrolysis-like lupus
erythematosus
• Triggered by excessive UV exposure in patients with
preexisting ACLE or SCLE
Systemic lupus erythematosus (SLE)
Epidemiology
• 80% of SLE patients will have skin ndings
■
ACLE is the cutaneous phenotype most strongly a/w
systemic lupus (71%; 60% with malar rash), but patients
with any form of cutaneous lupus may develop SLE
■
Also, patients with SLE may have any combination of
the various forms of cutaneous lupus
• Female predominance
• African Americans have a 43 ↑ incidence, earlier age of
onset, and higher mortality
Pathogenesis
• UV n h IL-1, IFN-γ, TNF-a, and AMPs, as well as NETosis;
other major cytokines: B-lymphocyte stimulator (BLyS),
IL-6, IL-17, IL-18
■
UV n CCL5 and CXCL8 n hWBC and adhesion
molecules/endothelial cell activation
• h IFN in lupus for various reasons n hCXCL9 and
CXCL10 and dendritic cells (may present keratinocytederived antigens to CD81 T cells; produce more IFN)
• CXCL9 and CXCL10 n hCXCR3(1) CD41 and CD81 T
cells and immature plasmacytoid dendritic cells 5 interface
lichenoid reaction
• Genetics
■
Strong genetic component
■
Susceptibility loci conferring the highest risk for SLE:
Genes encoding early complement components—
C1Q, C2, C4B, C4A; ITGAM (cellular adhesion,
immune complex clearance)
Innate immunity (TREX1, TYK2, IRF5, STAT4 [also
apoptosis])
B- and T-cell function (HLA-DR, CTLA4, PTPN22,
STAT4)
• Environmental triggers: sunlight (UVB . UVA),
cigarettes, infections, vitamin D deciency, estrogen
Clinical
• SLE diagnostic criteria (ACR criteria for SLE)
■
Need to satisfy four items (at least one clinical and one
immunologic item) OR have biopsy-proven nephritis
compatible w/ SLE in the presence of ANA or antidsDNA antibodies (Fig. 3.42)
• Cutaneous manifestations of SLE
■
Lupus-specic skin ndings:
ACLE
SCLE
CCLE (11%)
Rowell’s syndrome
TEN-like LE
Bullous SLE
■
Non-specic skin ndings suggestive of SLE:
Diffuse non-scarring alopecia (31%)
Periungal telangiectasias and erythema
♦ Dermoscopy: “wandering” dilated glomeruloid
loops (in contrast, DM and SSc both have
symmetric dilation and dropout of vessels; OslerWeber-Rendu has ectasia of half of the capillary
loop)
Non-specic mucosal ulcers (26%)
Vasculitis:
♦ Leukocytoclastic vasculitis (LCV; most common)
♦ Urticarial vasculitis (especially HUV)
♦ Polyarteritis nodosa (PAN)-like lesions
♦ Palisaded neutrophilic granulomatous
dermatitis (PNGD)/interstitial granulomatous
dermatitis and arthritis (IGDA)
Cutaneous signs of antiphospholipid syndrome
(APLS):
♦ Livedo reticularis (10%); LR 1 ischemic strokes
5 Sneddon syndrome
129
CHAPTER 3 • General Dermatology
Antinuclear antibodies (ANA) at a titer of 1:80 on HEp-2 cells or an equivalent positive test (ever)
Entry criterion
If absent, do not classify as SLE
If present, apply additive criteria
Additive criteria
Do not count a criterion if there is a more likely explanation than SLE.
Occurrence of a criterion on at least one occasion is sufficient.
SLE classification requires at least one clinical criterion and 10 points.
Criteria need not occur simultaneously.
Within each domain, only the highest weighted criterion is counted toward the total score
Clinical domains and criteria Weight
Constitutional
Fever 2
lmmunology domains and criteria Weight
Antiphospholipid antibodies
Anti-cardiolipin antibodies OR
Anti–2GP1 antibodies OR
Hematologic
Leukopenia
Thrombocytopenia
Autoimmune hemolysis
Neuropsychiatric
Delirium
Psychosis
Seizure
3
4
4
2
3
5
Lupus anticoagulant 2
Complement proteins
Low C3 OR low C4
Low C3 AND low C4
SLE-specific antibodies
Anti-dsDNA antibody* OR
Anti-Smith antibody 6
Mucocutaneous
Non-scarring alopecia
Oral ulcers
Subacute cutaneous OR discoid lupus
Acute cutaneous lupus
2
2
4
6
Serosal
Pleural or pericardial effusion
Acute pericarditis
5
6
§
.
3
4
Musculoskeletal
Joint involvement 6
Renal
Proteinuria 0.5g/24h
Renal biopsy Class II or V lupus nephritis
Renal biopsy Class Ill or IV lupus nephritis
4
8
10
Total score:
Classify as systemic lupus erythematosus with a score of 10 or more if entry criterion fulfilled.
Fig. 3.42 Classication criteria for systemic lupus erythematosus (SLE). Of note, neurological disease occurs in 18% of SLE patients, serositis in 19%, leukopenia in
35%, thrombocytopenia in 16%, APLS in 10%, lymphadenopathy in 9%, autoimmune hemolytic anemia in 3%, fever in 31%, and arthritis in 85%. Anti-b2GPI, Anti-β2
glycoprotein I; anti-dsDNA, anti-double-stranded DNA. *, In an assay with ≥ 90% specicity against relevant disease controls. §, additional criteria items within the same
domain will not be counted. (From Aringer M, Costenbader K, Daikh D, et al. 2019 European League against Rheumatism/American College of Rheumatology classication criteria for systemic lupus erythematosus. Arthritis Rheumatol . 2019;71[9]:1400–1412.)
♦ Atrophie blanche-like lesions
♦ Degos-like lesions
♦ Ulcerations
♦ Purpura fulminans and retiform purpura due to
catastrophic APLS
Papulonodular mucinosis
♦ Highly a/w SLE (75% of cases)!
♦ Asymptomatic skin-colored to red papules w/
central depression and pigmentation; favors
V-neck, upper chest/back, and upper extremities
130
3.5 Connective Tissue Disease (CTD) and Sclerosing Dermopathies
Others:
♦ Secondary Raynaud phenomenon (37%), multiple
eruptive dermatobromas, palmar erythema,
Sweet-like neutrophilic dermatosis, calcinosis cutis
• SLE and pregnancy
■
Course may be stable, worsen, or improve
■
Patients w/ lupus nephritis are at ↑ risk of
complications
■
Postpartum period is highest risk
■
Fetal complications
Preterm birth
Preeclampsia, especially w/ lupus nephritis
Anti-cardiolipin antibodies → ↑ risk of fetal
loss
NLE in patients w/ anti-Ro/SSA and anti-La/SSB
■
Management in pregnancy
Continuation of hydroxychloroquine and low-dose
steroids
Consider AZA
Anticoagulation for APLS
Histopathology
• Please refer to sections on types of lupus-specic skin
lesions
Laboratory testing
• Routine labs: ↑ inammatory markers (ESR and CRP),
hemolytic anemia (Coombs positive), leukopenia or
lymphopenia, thrombocytopenia, proteinuria, and
hematuria
• Complement abnormalities: ↓ total complement levels
(CH50), autoantibodies against C1q (a/w severe SLE
nephritis and HUV)
• Serologies:
■
ANA (99%)
■
Anti-ssDNA antibodies
Neither sensitive nor specic for SLE
■
Anti-dsDNA (60%)
Not sensitive, but highly specic (95%) for SLE
Useful in monitoring disease activity (esp. lupus
nephritis)
Correlates strongly w/ LBT from sun-protected skin
Likely contribute to pathogenesis of disease
■
Anti-Smith antibodies (10%–30%)
Not sensitive, but highly specic for SLE
■
Anti-U1RNP (50%)
Lower titers in SLE than in MCTD (most important
association)
■
Anti-Ro/SSA antibodies (50%)
■
Anti-histone antibodies
Drug-induced SLE (.95%)
■
Anti-RNP (ribosomal P) antibodies
High specicity but low sensitivity for SLE
a/w Neuropsychiatric SLE
Not currently used in clinical practice
■
Antiphospholipid antibodies
Anti-b2-glycoprotein IgM/IgG/IgA
Anti-anticardiolipin IgM/IgG/IgA
Lupus anticoagulant activity
Treatment
• Photoprotection in all patients
• Mild active disease (no life-threatening visceral organ
involvement): hydroxychloroquine (#5 mg/kg/day actual
body weight) 1/2 NSAIDs; chloroquine if not working;
can add quinacrine to either
• Moderate-severe active disease lacking renal involvement:
prednisone 1 steroid-sparing agent (AZA, MTX, MMF,
belimumab [monoclonal human antibody that inactivates
BLyS causing apoptosis and inhibition of B-cell
maturation], anifrolumab)
• Severe active disease w/ renal (or other organ) involvement:
prednisone (high dose) versus IV solumedrol 1
cyclophosphamide or MMF (depending on nephritis class)
• Moderate-severe recalcitrant disease: rituximab,
belimumab, volvosporin
Prognosis/clinical course
• Childhood onset has a higher risk of lupus nephritis and
mortality
• 10-year survival: 90%
• Most common causes of death:
■
First 5 years: inammatory lesions of SLE and infection
■
Beyond 5 years: arterial (e.g., MI) and venous (i.e., deep
venous thrombosis/pulmonary embolism) thromboses
↑ Risk of thrombosis w/ anticardiolipin antibodies
and OCPs
Drug-induced SLE (DI-SLE)
• Lupus-like syndrome related to continuous drug exposure
(usually . 1 year after drug initiation) that typically
resolves within 4 to 6 weeks of discontinuation of
offending drug
• Serologically characterized by (1) anti-histone
antibodies (.95%) and (–) dsDNA autoantibodies
■
Positivity for ANAs may persist for up to 12 months,
even in absence of clinical symptoms!
• Patients generally do not meet ACR criteria for SLE
• DI-SLE typically lacks skin ndings and has milder
systemic involvement (lacks renal and CNS ndings)
than idiopathic SLE
• Most common clinical ndings:
■
Arthritis/arthralgia (90%)
■
Myalgia (50%)
■
Serositis (pericarditis, pleuritic)
■
Fever and weight loss
• Most important implicated drugs:
■
High risk: procainamide, hydralazine
a/w slow acetylators
■
Medium and low risk: quinidine, methyldopa, INH,
chlorpromazine, D-penicillamine, propylthiouracil,
PUVA, minocycline, TNF-a inhibitors (iniximab and
etanercept . adalimumab), interferon
D-penicillamine may “unmask” true SLE
Minocycline differs from classic DI-SLE:
♦ Often negative for anti-histone antibodies
♦ (1) antineutrophil cytoplasmic antibody (ANCA)
against myeloperoxidase (MPO) or elastase
TNF-a inhibitors differ from classic DI-SLE:
♦ Anti-dsDNA antibodies frequently positive
(. anti-histone)
♦ ↑↑↑ Skin involvement (malar rash,
photosensitivity, SCLE and DLE lesions)
131
CHAPTER 3 • General Dermatology
Lupus-related diseases
Jessner’s lymphocytic inltrate of skin
• Epidemiology
■
Primarily middle-aged adults with no sex predilection
• Pathogenesis
■
Photosensitive eruption
■
Possibly a variant of LE, on a spectrum w/ tumid LE
and REM
• Clinical
■
Red papules or plaques (often annular w/ central
clearing) (Fig. 3.43)
■
Absent epidermal changes
■
Typical locations: head, neck, and upper back
■
Duration: weeks to months
■
No systemic manifestations
• Histopathology
■
Similar to tumid LE and REM, but with a
predominance of suppressor CD81 T cells and
↓ mucin
■
Absent interface dermatitis
■
Supercial and deep dense PV/PA lymphocytic
inltrate
■
DIF: negative
• Laboratory testing
■
No associated laboratory abnormalities
• Treatment: sun protection, antimalarials
• Prognosis/clinical course: resolves spontaneously without
sequelae
Reticular erythematous mucinosis
• Middle-aged females often w/ history of tanning bed use
• Likely variant of LE, on spectrum w/ tumid LE
• P/w persistent, photoaggravated (UVA and UVB) eruption
consisting of erythematous papules or plaques on middle
of chest/back, typically in a reticular conguration
• Exacerbating factors: OCPs, menses, pregnancy, heat, and
sweating
• Histopathology: same as tumid lupus; DIF negative (most
cases)
• Laboratory testing: no associated laboratory abnormalities
• Treatment: sun protection, resolution within 4 to 8 weeks
w/ antimalarials
Other autoimmune connective tissue diseases and sclerosing dermopathies
Dermatomyositis (DM)
Epidemiology
• Female predominance (2:1); African Americans .
Caucasians
• Bimodal peaks: childhood (4–14 years) and adulthood
(40–60 years)
■
25% of adult-onset patients have underlying malignancy
■
Juvenile dermatomyositis (JDM) is not associated with
malignancy
Pathogenesis
• Evidence of issues with humoral immunity (B-cell
autoantibody; e.g., myositis-specic autoantibodies) and
cellular immunity/apoptosis (e.g., CD81 lymphocytes in
skin and muscle); both environmental and genetic factors
contribute to development of disease
• Genetic predisposition:
■
Polymorphisms in various HLA alleles (e.g., HLA-DR3 and
HLA-B8 with JDM, HLA-DR52 with anti-Jo-1 antibodies)
■
TNF-a308A polymorphism (a/w JDM) → ↑
thrombospondin-1 (a potent anti-angiogenic
factor) → ↑ occlusion of capillaries
• Environmental factors (e.g., malignancy, UV, viral
infections, drugs) trigger a humoral autoimmune process
in genetically susceptible individuals → differences in the
specic autoantibodies account for the different clinical
manifestations
■
80% of patients with cancer-associated DM have
antibodies against TIF-1g (p155) or NXP-2
(p140)
■
Drug-induced dermatomyositis: hydroxyurea (most
common, .50%), statins, TNF-a inhibitors,
checkpoint inhibitors (ipilimumab), D-penicillamine,
cyclophosphamide, BCG vaccine, NSAIDs
Drug-induced DM is separated into two groups:
♦ Hydroxyurea-induced DM: much longer latency
period (average 60 months) after drug initiation;
myositis never seen (0%); only 16% have (1)
ANA
♦ Non-hydroxyurea–induced DM: occurs within
2 months after drug initiation; 80% have muscle
weakness/myositis; ANA usually (1) (54%)
♦ Both groups have pathognomonic skin lesions of
DM (heliotrope rash, Gottron’s papules), and
may have (1) ANA
♦ Both forms resolve within 1 to 2 months of
discontinuation
Fig. 3.43 Lymphocytic inltrate of Jessner. Annular erythematous plaque on the
trunk. (From James WD, Elston DM, McMahon PJ. Cutaneous lymphoid hyperplasia, cutaneous T-cell lymphoma, other malignant lymphomas, and allied diseases. In: Andrews’ Diseases of the Skin Clinical Atlas . Philadelphia: Elsevier;
2018:501–516.)
132
Clinical features
• Muscle disease (no longer required for diagnosis!):
■
Slowly progressive, symmetric proximal muscle
weakness (extensors . exors)
Biopsies 5 perifascicular atrophy
3.5 Connective Tissue Disease (CTD) and Sclerosing Dermopathies
■
Generally lacks muscle pain (myalgias)
■
Typically affects quadraceps, triceps, shoulders, hip
girdle, and neck exors → difculty walking up stairs,
standing up from sitting position, or brushing hair
■
Esophageal/oropharyngeal muscles → dysphagia,
aspiration pneumonia
■
Cardiac disease (common)
Mostly subclinical EKG abnormalities
Clinically overt disease (congestive heart failure,
complete heart block, myocarditis, dangerous
arrhythmias, and coronary artery disease) is rare but
life-threating
■
Diaphragm weakness (rare but life-threatening)
• Classic skin ndings:
■
Gottron’s papules (pathognomonic)
Lichenoid papules overlying knuckles (. other
extensor joints) (Fig. 3.44)
Less common than Gottron’s sign (macular
erythema overlying joints)
■
Symmetric conuent macular violaceous erythema (CMVE)
Facial erythema w/ malar involvement, usually
involving the melolabial folds (vs. nasolabial
sparing in lupus)
Eyelids 5 heliotrope sign 1/– periorbital edema
♦ Arises as a result of inammation of underlying
orbicularis oculi muscle, NOT the skin!
Overlying joints 5 Gottron’s sign
♦ Elbows, knees, DIP, PIP, and MCP joints
Overlying extensor tendons of hands and forearms
5 linear extensor erythema
Fig. 3.45 “Mechanic’s hands” in dermatomyositis. (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.)
Photodistributed CMVE or poikiloderma
(hyperpigmentation, hypopigmentation,
telangiectasias, and atrophy)
Chest (“V-neck sign”), upper back (“Shawl sign”),
lateral thigh (“Holster sign”)
• Other common skin ndings:
■
Mechanic’s hands
Rough, hyperkeratosis and ssuring of the lateral
and palmar side of ngers, usually more radial digits
involved (Fig. 3.45)
Strongly a/w anti-MDA5 antibodies and anti-
synthetase syndrome
■
Nail changes
“Ragged” cuticles
Proximal nailfold w/ dilated capillary loops
alternating with areas of vessel dropout (Fig. 3.46)
Periungual erythema
■
Pruritus—often severe (especially on scalp)
■
Psoriasiform scalp dermatitis and non-scarring alopecia
• Less common skin ndings:
■
Calcinosis cutis
Fig. 3.44 Gottron’s papules of dermatomyositis. Classic skin lesions over the
distal and proximal interphalangeal joints with coalescence of pink–violet lichenoid papules. (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.)
Fig. 3.46 Cuticular hypertrophy, splinter hemorrhages, and periungual telangiectasias in a patient with dermatomyositis. (From Vleugels RA, Callen JP. Dermatomyositis. In: Callen JP, Jorizzo JL, Bolognia JL, Piette WW, Zone JJ. Dermato-
logical Signs of Internal Disease. 4th ed. Philadelphia: Elsevier; 2009:11–19.)
133
CHAPTER 3 • General Dermatology
Much more common in JDM (25%–70%) than
adults (,20%)
♦ a/w anti-p140 (NXP-2) autoantibodies in JDM
Favors elbows, knees, and buttocks
a/w ngertip ulcers, pain, loss of function, and
prolonged course
■
Palmar papules
Erythematous palmar papules or macules 1/–
overlying hyperkeratosis/ulceration; painful (unlike
Gottron’s papules)
a/w anti-CADM-140/MDA-5 antibodies
■
Clinical features overlapping w/ PRP (Wong-type
dermatomyositis, more common in Asians, follicular
hyperkeratosis)
■
Vasculitis (never a good sign!): more common in JDM
In adults → a/w malignancy
JDM w/ severe systemic vasculitis 5 Banker variant
JDM
♦ Cutaneous ulcerations, muscle infarction, GI
involvement (hemorrhage, ulceration,
perforation), widespread calcinosis, and a severe
course w/ poor response to therapy
■
Others: agellate erythema (a/w anti-Mi2 antibodies),
panniculitis (a/w anti-MDA5 antibodies),
lipodystrophy, hypertrichosis, Raynaud phenomenon
(a/w antisynthetase syndrome), oral mucosal changes
(a/w anti-TIF1 antibodies), necrotic/ulcerative lesions
(due to cutaneous vasculopathy; anti-MDA5
antibodies), and erythroderma (a/w malignancy)
• Other common (non-muscular) systemic ndings:
■
Pulmonary disease (15%–65%)
p/w diffuse interstitial lung disease (ILD) of
varying severity
Rapidly progressive ILD → a/w anti-synthetase and
anti-CADM-140/MDA5 autoantibodies
■
GI involvement (up to 37% of JDM cases): dysphagia,
dysmotility, GI infraction
■
Arthralgia and/or non-erosive arthritis
Classication (Box 3.6)
• Adult-onset DM
■
Classic DM
Slowly progressive symmetric, proximal muscle
weakness w/ classic skin ndings
■
CADM (amyopathic or hypomyopathic)
Classic skin ndings without clinical muscle disease
Box 3.6 Dermatomyositis (DM) Classication
Adult-onset DM
• Classic DM
• Cancer-associated myositis (CAM)
• DM overlap syndrome
• Clinically amyopathic DM (CADM)
• Amyopathic DM
• Hypomyopathic DM
Juvenile DM
• Classic DM
• Clinically amyopathic DM (CADM)
• Amyopathic DM
• Hypomyopathic DM
a/w CADM-140 (MDA5) and TIF1-g (p155)
autoantibodies
♦ When a/w CADM-140 → rapidly progressive
ILD
■
Cancer-associated myositis (CAM)
May p/w classic DM or CADM
Associated with: ↑ age (fth to sixth decades most
common), rapid disease onset, skin necrosis,
periungal erythema, markedly elevated ESR or CK,
lack of antisynthetase syndrome features, and lack
of Raynaud phenomenon
Boards Fodder: TIF1-g (p155) or NXP-2 (p140)
autoantibodies are present in 80% of all cancerassociated DM!
Most common cancers:
♦ Ovarian (classic exam answer!) and GI (colon .
other) cancer are overrepresented
♦ Nasopharyngeal carcinoma overrepresented in
Asians
♦ Others: breast, lung, pancreatic, and non-
Hodgkin’s lymphoma
Timing:
♦ Malignancy may be discovered before, after, or at
the same time as the diagnosis of DM
♦ Cancers diagnosed before DM precede diagnosis
by # 2 years
♦ Most cancers are detected within 1–2 years of
DM diagnosis
♦ Risk for most cancers returns to normal 3 years
after diagnosis (exceptions 5 pancreatic and
colorectal cancers → risk remains elevated
beyond 5 years)
■
Antisynthetase syndrome
Antisynthetase autoantibodies (Jo-1, PL-7, PL-12,
OJ, EJ)
Acute disease onset
Constitutional symptoms
Raynaud phenomenon
Mechanics hands
Non-erosive arthritis
ILD
■
DM overlap syndromes
Denition: DM 1 other CTD
Autoantibodies suggestive of overlap
♦ Anti-U1-RNP 5 mixed CTD
♦ Anti-Ku 5 PM overlapping with either SLE, SjS,
or scleroderma
♦ Anti-PM/Scl (PM-1) 5 DM/PM 1 scleroderma
(“sclerodermatomyositis”)
• Juvenile DM
■
DM in patients , 16 yo (average 7 yo); F . M (2–5:1)
■
JDM is not a/w ↑risk malignancy!
■
Important autoantibodies in JDM (some antibodies
may have different associations in kids vs. adults):
Anti-CADM-140 (MDA5) → a/w ILD in kids
Anti-p140 (NXP-2) → a/w calcinosis and
contractures in kids but NO increase in malignancy
■
Variants:
Classic JDM (Brunsting variant):
♦ Most common (90%)
♦ Gradual onset of classic skin and muscle disease
134