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3.5 Connective Tissue Disease (CTD) and Sclerosing Dermopathies
+
Topical (bid,
occluded)
Calcipotriene
Tacrolimus
Superficial
Phototherapy
Localized or where body
NB UVB, BB UVA, UVA-1
Continued
progression
New lesions 6 months’s duration, disease extension,
Active
inflammation (erythema, edema), sclerotic or indurated periphery
Generalized Localized GeneralizedLocalized
Phototherapy
(wholebody)
NB UVB,
BB UVA, UVA-1
Progression with
local phototherapy
Continued
progression/deep
involvement
*Inactive/damage
Pigmentary changes, static size, atrophy, central sclerosis
Deep
Functional/
cosmetic threat
Systemic
MTX
PCMT
Functional impairment:
Cosmetic impairment
PT/OT
Orthotics
Podiatry
Rheumatology
Confirmed long-term disease inactivity
Oral maxillofacial surgery
plastic surgery
Work-up negative for deep muscle,
fascia, bone involvement
Local excision Inject fillers (face)
Fig. 3.55 Therapeutic algorithm for morphea based on existing evidence. Supercial involvement is dened by histologic evidence of papillary dermal involvement.
Deep involvement is dened as sclerosis or inammation of reticular dermis, subcutis, fascia, or muscle. Histologic examination and/or magnetic resonance imaging
are encouraged to evaluate lesions for depth of involvement and, likewise, determine appropriate treatment and evaluation of therapeutic efcacy. BB, Broadband;
MTX, methotrexate; NB, narrowband; OT, occupational therapy; PCMT, pulsed intravenous corticosteroids plus methotrexate; PT, physical therapy; UV, ultraviolet.
*There is very little evidence for any therapy addressing disease damage in morphea. There is minimal evidence for efcacy of these measures. Risk of disease reactivation is also unknown, but surgical measures should only be undertaken in long-standing, inactive disease. 1Topical therapies should not be used as monotherapy
in the presence of active and progressively functional impairment (e.g., decreased range of motion, contracture, and limb length discrepancy). Systemic manifestations
most commonly reported to occur in morphea include arthritis, seizures/headaches (en coupe de sabre), and ocular manifestations. All patients with morphea should
be assessed for their presence and appropriate referrals made. (From Zwischenberger BA, Jacobe HT. A systematic review of morphea treatments and therapeutic
algorithm. J Am Acad Dermatol. 2011;65[5]:925–941.)
Indurated phase: edematous ngers harden and
become tight and shiny
Late (atrophic) phase: skin atrophy with exion
contractures
■
Skin thickening of ngers (only count higher score)
Puffy ngers with diffuse, non-pitting increase in
soft tissue (2 points)
Scler odactyly of the ngers (distal to the four
MCP joints, but proximal to the PIP joints)
(4 points)
■
Fingertip lesions with loss of substance from nger pad
(only count higher score)
Digital tip ulcers (2 points)
♦ Thought to be due to trauma
145
CHAPTER 3 • General Dermatology
Fingertip pitting scars (3 points)
♦ Thought to be due to ischemia
■
Telangiectasia (2 points)
Matted telangiectasias of face/lips/palms (more
common in limited SSc/CREST):
♦ Telangiectasias have smooth/“mat-like” squared-
off edges
♦ In contrast, hereditary hemorrhagic telangiectasia
has irregular telangiectasias w/ radiating vessels
■
Abnormal nail fold capillaries (2 points)
Dilated capillary loops alternating w/ capillary
drop out
■
Pulmonary arterial hypertension (PAH) and/or ILD
(maximum score is 2)
PAH (2 points)
ILD (2 points)
■
Raynaud phenomenon (3 points)
Leading cause of secondary Raynaud phenomenon
Initial presenting sign in 50% of SSc
■
Any SSc-related autoantibodies: anti-centromere, antitopoisomerase I (Scl-70), or anti-RNA polymerase III)
(3 points)
• SSc subtypes:
■
Limited SSc
Denition: limited involvement of distal
extremities (distal to MCP/MTP joints) and face
Lacks severe renal/pulmonary involvement →
improved overall mortality
♦ Commonly see isolated PAH
Variants:
♦ CREST syndrome
Calcinosis cutis (40%)
Raynaud phenomenon (99%)
Esophageal dysmotility (90%)
Sclerodactyly
Telangiectasias (mat telangiectasias; 90%)
♦ SSc sine scleroderma:
Raynaud phenomenon and positive serology,
but no cutaneous involvement
■
Diffuse SSc (“progressive systemic brosis,” PSS)
A/w severe visceral disease and worse
prognosis
Sclerosis involving distal and proximal extremities
as well as the face and trunk
• Other cutaneous ndings
■
Raynaud phenomenon and hand edema are the two
earliest and most common presenting features of SSc
■
Beaked nose, microstomia, and loss of wrinkles
■
Calcinosis cutis, usually over joints, may ulcerate
■
Xerotic itchy skin
■
Dyspigmentation: two types
Diffuse hyperpigmentation in sun-exposed or
pressure-related areas
Hypopigmentation of the upper trunk/face with
perifollicular sparing (“salt-and-pepper” sign)
(Fig. 3.56)
■
Pterygium inversum unguis: extension of
hyponychium on undersurface of nail plate
• Extracutaneous ndings ranging from asymptomatic to
severe
Fig. 3.56 Scleroderma-associated depigmentation with preserved perifollicular
pigmentation. The salt-and-pepper appearance resembles repigmented vitiligo.
(From Wigley FM, Boin F. Clinical features and treatment of scleroderma. In:
Firestein GS, Budd RC, Gabriel SE, Koretzky GA, McInnes IB, O’Dell JR, eds.
Firestein & Kelly’s Textbook of Rheumatology. 11th ed. Philadelphia: Elsevier;
2021:1499–1538.)
■
Pulmonary (70%)
Most common cause of mortality
ILD (more common in diffuse SSc/PSS)
Pulmonary hypertension (more common in limited
SSc/CREST)
■
Cardiovascular
↑ Risk of atherosclerosis, MI, and stroke
Myocardial brosis → restrictive cardiomyopathy
and arrhythmias
■
GI (90%)
Most common site of visceral disease
A/w (↑) morbidity but no ↑ risk of mortality
Lower esophageal dysphagia/dysmotility (90%)
→ aspiration and esophagitis
Gastroparesis
Gastric antral vascular ectasia (aka watermelon
stomach) (1%–20%)
Small and large bowel dysmotility
Weak rectal tone → stool incontinence
■
Renal
Scleroderma renal crisis (SRC)
♦ p/w rapid rise in creatinine
♦ Affects 20% of diffuse SSc patients (PSS)
♦ Almost never seen in limited SSc
♦ ACE-I will decrease risk
■
Musculoskeletal
Arthralgias/arthritis
Palpable tendon friction rubs
Histopathology
• Same as morphea
Laboratory testing
• (1) ANA (.90%)
• Anti-centromere
■
a/w Limited SSc . diffuse SSc
■
↑ Risk of PAH and digital ulcers
146
3.5 Connective Tissue Disease (CTD) and Sclerosing Dermopathies
• Anti-topoisomerase I (anti-Scl-70)
■
a/w Diffuse SSc . limited SSc
■
↑ Risk of ILD, digital ulcers, synovitis, joint
contractures, and cardiac involvement
• Others: see Table 3.11
• CXCL4 is a biomarker for skin and lung brosis
and PAH
Treatment
• Most important goal 5 control internal organ
involvement!
■
Renal disease: ACE inhibitors for SRC and HTN
■
Pulmonary disease:
ILD: cyclophosphamide, rituximab, MMF, HSCT,
and adjuvant N-acetylcysteine
PAH: endothelin receptor antagonists (e.g.,
bosentan), PDE-5 inhibitors, prostacyclin analogs
(e.g., iloprost), lung transplant
■
GI involvement: PPIs for GERD symptoms, promotility
agents
■
Cardiac involvement: ACE inhibitors
• Specic skin-directed treatments (often ineffective):
■
Raynaud phenomenon: tobacco cessation, cold
temperature avoidance, and vasodilators (CCBs
[nifedipine], angiotensin II receptor blockers
[losartan], PDE-5 inhibitors, endothelin receptor
antagonists, prostaglandins, selective serotonin
reuptake inhibitors [SSRIs])
■
Digital ulcers: same measures as Raynaud
phenomenon; IV iloprost, ASA/clopidogrel
■
Cutaneous sclerosis: phototherapy (PUVA, UVA1), ECP,
glucocorticoids, immunosuppressives (MMF [w/ ILD],
MTX [w/o ILD], rituximab), HSCT
■
Calcinosis cutis: surgical excision (can recur), CCBs
(questionable efcacy), warfarin and extracorporeal
shock-wave lithotripsy
Prognosis/clinical course
• Mortality (10-year survival):
■
Diffuse SSc (PSS): 50%
■
Limited SSc: 70%
• Due to the efcacy of ACE inhibitors for SRC, ILD is now
the #1 cause of death
■
Screen for lung disease w/ high-resolution CT and
PFTs
• Indicators of poor survival
■
Older age, male, African Americans, poor
socioeconomic status
■
↑ ESR and anemia
■
Major organ involvement: myositis, extensive
cutaneous disease, heart involvement, ILD,
and PAH
■
Presence of palpable tendon friction rubs
Additional boards factoids
Eosinophilic fasciitis (Shulman syndrome)
Epidemiology
• Female and Caucasian predominance
• Most present in fourth to sixth decades
Pathogenesis
• Pathogenesis unknown, but TGF-b levels markedly
elevated
• A/w recent history of strenuous activity (30%)
■
Other potential triggers: trauma, borreliosis, and
statin use
Clinical features
• Key feature 5 rapid onset of symmetric edema/
induration and pain in extremities in a/w peripheral
eosinophilia
■
Spares hands, feet, and face
■
Progresses to woody induration and brosis with a
peau d’orange (“pseudocellulite” appearance)
■
“Dry river bed” or “groove sign” 5 linear depressions
of veins within indurated skin
■
Lacks Raynaud phenomenon
• Disease associations (not very common): inammatory
arthritis, joint contractures, carpal tunnel syndrome,
hemolytic anemia, myelodysplastic disorder, lymphoma/
leukemia, MGUS, and multiple myeloma
• DDx:
■
SSc:
EF spares hands, feet, and face
EF lacks Raynaud phenomenon and visceral
involvement
■
Eosinophilia-myalgia syndrome (L-tryptophan),
Spanish toxic oil syndrome (rapeseed oil)
EF lacks prominent systemic symptoms (fever,
myalgias, and pulmonary involvement)
Histopathology
• Massive thickening and brosis of deep fascia (10–50x
the normal width); lymphoplasmacytic inltrate 1/2
eosinophils
■
Must obtain deep biopsy (to fascia)
■
Eosinophils occasionally present in biopsy, but tissue
eosinophilia is NOT essential to diagnosis
→ peripheral eosinophilia is more typical!
Laboratory testing
• Peripheral eosinophilia (80%), ↑ ESR,
hypergammaglobulinemia
• Metalloproteinase inhibitor-1 (TIMP-1) 5 serologic
marker of disease activity
• MRI or CT scan demonstrates fascial thickening → may
eliminate need for biopsy in some cases
Treatment
• Excellent response to systemic steroids (vs. deep
morphea)
• Steroid-sparing agents: hydroxychloroquine, cyclosporine,
dapsone, MTX, PUVA, UVA1 1/– acitretin, and TNF-a
inhibitors
• Physical therapy to prevent joint contractures
Prognosis/clinical course
• Up to one third may resolve spontaneously, but some
degree of induration usually persists
• Response to steroids can be appreciated after a few weeks
147
CHAPTER 3 • General Dermatology
• Features a/w refractory disease:
■
Concomitant morphea-like skin lesions
■
Truncal involvement
■
Younger age of onset
■
Dermal brosis on histopathology
Nephrogenic systemic brosis
(Nephrogenic brosing dermopathy
NSF/NFD)
Epidemiology
• Typically presents in fth decade
• No sex or race predilection
Pathogenesis
• Fibrosis of skin and internal organs occurs as a result of
gadolinium-containing contrast exposure in the setting
of acute kidney injury or severe chronic kidney disease
(CKD)
■
Theory: gadolinium leaks into tissues → engulfed by
macrophages → release probrotic cytokines and
growth factors → “circulating brocytes” (CD341,
ProCollagen I1 cells) recruited to skin → excess
collagen and ECM production
• Onset: typically 2 to 4 weeks after gadolinium exposure,
but can occur after several years
Fig. 3.57 Hyperpigmented sclerotic plaques of nephrogenic brosing dermopathy. (From James WD, Berger TG, Elston DM, Neuhaus IM. Connective tissue
diseases. In: Andrews’ Diseases of the Skin . 12th ed. Philadelphia: Elsevier;
2016:153–178.)
Clinical features
• Cutaneous ndings
■
Insidious onset of symmetrically distributed, painless,
hyperpigmented and indurated “patterned plaques”
(reticular or polygonal morphology) (Fig. 3.57 and
Fig. 3.58)
Extremities . trunk
■
Deep induration of proximal extremities resulting in a
“pseudocellulite” or cobblestone appearance
■
Marked woody induration with peau d’orange changes
■
Puckering or linear banding due to focal areas of
bound-down skin on proximal extremities
■
Dermal papules: brawny to skin-colored papules or
nodules with absent epidermal change
• Scleral plaque (exam favorite!): white-yellow plaques w/
dilated capillaries in patients , 45 yo (above this age,
scleral plaques are less specic because of the clinical
overlap w/ pinguecula) (Fig. 3.58)
• Extracutaneous involvement (very rare)
■
Fibrosis and calcication of rete testis, dura mater,
diaphragm, renal tubules, heart, and lungs
Histopathology
• Very similar to scleromyxedema, but brosis usually
extends more deeply (into fat and fascia)
■
Diagnostic ndings are most prominent in subcutaneous
fat septae → must obtain deep biopsy (to fascia)
■
↑ Collagen (bundles only slightly thickened)
■
↑ Spindled brocytes (positive staining for CD34 and
procollagen I) extending deeply into SQ brous septae
■
In contrast, morphea and scleroderma have loss/↓
CD341 cells in dermis
• ↑ Mucin (stains with Prussian blue)
Fig. 3.58 Nephrogenic systemic brosis of the arm. (From Kribben A, Witzke O,
Hillen U, Barkhausen J, Daul AE, Erbel R. Nephrogenic systemic brosis: pathogenesis, diagnosis, and therapy. J Am Coll Cardiol. 2009;53[18]:1621–1628.)
Laboratory testing
• ↑ Cr/BUN
• Calcium and/or phosphorus abnormalities
Treatment
• Refractory to treatment w/ CS and other
immunosuppressives
• Treatment of kidney disease is most important → may
slow or improve NSF
• Physical therapy for all patients to prevent joint
contractures
• Anecdotal reports of improvement w/ imatinib,
rapamycin, photodynamic therapy (PDT), UVA1, IVIG,
plasmapheresis, extracorpeal photopheresis, and
discontinuation of erythropoietin
Prognosis/clinical course
• Chronic, progressive course
• 2-year mortality rate 50%
148
3.6 Granulomatous/Histiocytic Disorders
Additional boards factoids
• Know the differences between the major sclerosing/
brosing dermopathies (Table 3.13)
Other sclerosing/brosing skin disorders
(Table 3.14)
Abnormalities of dermal brous
• Treatment
■
EPS/RPC generally mild; treat w/ local therapies,
avoid trauma
■
Acquired perforating dermatosis: difcult to treat;
BB- or NB-UVB is most effective
Abnormalities of connective tissue
• Discussed in Table 3.16
and elastic tissue
Perforating diseases (Elastosis
perforans serpiginosa [EPS], reactive
perforating collagenosis [RPC],
acquired perforating dermatosis,
and perforating calcic elastosis)
• Discussed in Table 3.15
• All are characterized by transepidermal elimination
of dermal connective tissue
• All p/w papules and nodules with keratotic plugs
Table 3.13 Major Clinical and Laboratory Manifestations of Systemic Sclerosis and Other Selected Conditions Characterized by Cutaneous Induration
Systemic
Sclerosis Morphea
Major clinical
variants
Raynaud
phenomenon
Symmetric
induration
Sclerodactyly
Facial involvement
Systemic
involvement
Antinuclear
antibodies
Anti-centromere
antibodies
Anti-topoisomerase I
(Scl-70) antibodies
Anti-RNA
polymerase III
Monoclonal
gammopathy
Spontaneous
remission
a
May be preceded by edematous phase.
b
With improved renal function.
GVHD, Graft-versus-host disease; NSF, nephrogenic systemic brosis; 11 almost always; 1 common; 6 sometimes; –, rare or unusual.
Courtesy of Vincent Falanga, MD. From Connolly MK. Systemic sclerosis (scleroderma) and related disorders. In: Bolognia JL, Schaffer JV, Cerroni L.
Dermatology. 4th ed. Philadelphia: Elsevier; 2018:693–706.
Limited
Diffuse
11
a
11
11
1
11
11 6generalized and
1 limited
1 diffuse
1 diffuse
– –
Plaque-type
morphea
Linear morphea
Generalized
morphea
– – – – – –
– plaque-type and
linear
6 generalized
– – – – –
– plaque-type and
generalized
1 linear (en coup
de sabre)
– for plaque-type
but 6 for linear
involving head
(ocular, CNS)
linear
– plaque-type
– – – – – –
– – – – – –
– – – – – –
11plaque-type
1 generalized
6 linear
Eosinophilic
Fasciitis Scleredema Scleromyxedema NSF Chronic GVHD
a
11
1 11 1 1
– – – –
6
11 11type I
3.6 GRANULOMATOUS/HISTIOCYTIC
DISORDERS
Non-infectious granulomas
Granuloma annulare (GA)
Epidemiology
• Children and young adults most commonly affected
(2/3 arise before 30 yo)
• F . M (2:1)
Post-infectious (type I)
Monoclonal gammopa-
thy-associated (type II)
Diabetes mellitus-
associated (type III)
11 11 1 1
6types I and II
– type III
1 type II 11
6 types II and III
1 6
– –
b
6
Lichen sclerosis-like
Morphea-like
Scleroderma-like
Fasciitis
6
149
CHAPTER 3 • General Dermatology
Table 3.14 Other Sclerosing/Fibrosing Skin Disorders
Disease Clinical Other
Mucinoses
Scleredema Erythema and woody induration of skin with a peau d’orange appear-
Scleromyxedema Progressive condition, characterized by widespread, symmetric, linearly
Pretibial myxedema Waxy indurated nodules or plaques with a peau d’orange appearance on
Immunologic
Chronic GVHD Morpheaform plaques on trunk, which may become generalized Usually still see some degree of interface
Paraneoplastic/neoplastic
POEMS syndromes
(polyneuropathy, organomegaly,
endocrinopathy, M-protein, and
skin changes)
Amyloidosis (primary systemic form) Diffuse induration of face, distal extremities, and trunk N/A
Carcinoid syndrome Sclerotic skin on legs N/A
Carcinoma en cuirasse Sclerodermoid induration of chest wall due to infiltration by cancerous cells Breast cancer most commonly
Metabolic
Diabetic cheiroarthropathy Symmetric, painless loss of joint mobility, and stiffness of the small joints
Porphyria cutanea tarda Morpheaform plaques in sun-exposed areas, hyperpigmentation, and
Diffuse sclerodermoid conditions due to exogenous substances
Toxic oil syndrome p/w morbilliform eruption, flu-like symptoms, peripheral eosinophilia,
Eosinophilia-myalgia syndrome Presents initially with fever, fatigue, weakness, severe myalgias,
Polyvinyl chloride Workers exposed can develop skin findings that mimic scleroderma
Bleomycin Pulmonary fibrosis, Raynaud phenomenon, and cutaneous changes
Taxanes (docetaxel, paclitaxel)
Nephrogenic systemic fibrosis Discussed in NSF section a/w Gadolinium-based contrast agents
Localized sclerodermoid conditions due to exogenous substances
Radiation-induced morphea Morphea-like plaques in radiation field (sometimes extend beyond
Sclerosis at injection sites Vitamin K (Texier’s disease) , silicone or paraffin implants/injections,
ance; visceral involvement rare
Type 1 (55%): usually preceded by URI, especially Strep pharyngitis; typi-
cally affects middle-aged women, involving the face (expressionless
face w/open mouth), neck, trunk, proximal upper extremities; usually resolves after 6–24 months
Type 2 (25%): same clinical presentation as type 1, but with associated
IgG monoclonal gammopathy
Type 3 (20%, aka scleredema diabeticorum): a/w IDDM; typically in
obese middle-aged men, involving posterior neck and upper back
distributed waxy papules, typically involving face/neck, dorsal hands,
extensor forearms, elbows, and upper trunk; diffuse infiltration can
mimic scleroderma and result in leonine facies; histologically similar
to NSF, but fibrosis does not extend as deeply into subcutis and fascia;
extracutaneous involvement common (GI: dysphagia; MSK: arthritis,
proximal muscle weakness, carpal tunnel; neuro: peripheral neuropathy)
the shins
Sclerotic skin changes favoring extremities, hyperpigmentation ,
hypertrichosis, hyperhidrosis, digital clubbing, leukonychia
of the hand with scleroderma-like skin thickening of the dorsal aspects of
the hands and feet; “prayer sign”
hypertrichosis
and pulmonary edema; swelling and thickening of the skin occurs initially
→ followed by skin atrophy/fibrosis, dermal sclerosis, joint contractures,
sicca symptoms, and Raynaud phenomenon
peripheral eosinophilia, and a non-specific erythematous macular
eruption; half develop sclerodermatous skin changes including
eosinophilic fasciitis (30%), morphea, and diffuse/localized scleroderma
including diffuse sclerosis of the skin, sclerodactyly, Raynaud
phenomenon, and hepatic/pulmonary fibrosis
indistinguishable from progressive systemic sclerosis
Diffuse edema (legs #1 site) → slowly becomes sclerotic; may result in
flexion contractures
irradiated area); chest wall most common site
intralesional bleomycin, opioids (methadone, pentazocine)
Histologically shows wide spaces between
collagen bundles filled with mucin
a/w IgG paraproteinemia and HIV
Due to deposition of hyaluronic acid, most
commonly in Graves’ disease, but may
also be seen with hypothyroidism and
rarely euthyroid patients
dermatitis histologically
Glomeruloid hemangiomas are strongly
associated (only present in a minority of
patients)
30%–50% of chronic DM2 patients;
correlates w/ microvascular disease
Pseudoporphyria lacks sclerodermoid
changes, hyperpigmentation, and
hypertrichosis
Due to ingestion of aniline-degraded
rapeseed cooking oil; seen in Spain
in 1981
Due to ingestion of contaminated
L-tryptophan, seen in 1989
Absent autoantibodies
Absent autoantibodies
Absent autoantibodies; can occur after
one or several courses of chemotherapy
in setting of kidney disease
Most common in breast CA pts with
history of XRT
Bleomycin may cause SSc-like diffuse
eruption if used systemically
150
3.6 Granulomatous/Histiocytic Disorders
Table 3.15 Major Perforating Diseases
Clinical Histopathology High-Yield Facts/Associations
Familial reactive perforating
collagenosis (RPC)
Acquired perforating
dermatosis (includes acquired
RPC, Kyrle disease)
Elastosis perforans serpiginosa
(EPS)
Perforating calcific elastosis Very rare; adulthood; mostly black
Data from Rapini RP. Perforating diseases. In: Bolognia JL, Schaffer JV, Cerroni L. Dermatology. 4th ed. Philadelphia: Elsevier; 2018:1690–1696.
Rare, childhood onset; M 5 F; upper
extremities; keratotic papules develop
at sites of trauma (3–4 week latency);
spontaneous resolution (6–10 weeks)
Common; adult onset; M 5 F;
diabetes/renal failure; intense pruritus;
legs or generalized; koebnerize; central
keratotic plug
Rare; childhood or early adulthood;
M . F (4:1); annular/serpiginous
plaques w/ keratotic papules along
rim; most commonly on lateral neck
. face, arms, flexural areas
women; plaques on abdomen
(periumbilical) with peripheral
keratotic papules
Hyper-/parakeratotic
crusted plug; COLLAGEN
fibers extend through
epidermis into plug
Resembles RPC most
commonly (may also
resemble perforating
folliculitis or less
commonly EPS)
Keratotic crusted plug
surrounding epithelial
hyperplasia (“crab-claw”)
grabbing pink elastic fibers
in superficial dermis (VVG
stain: elastic fibers stain
black vs. collagen pink)
Transepidermal elimination
of calcified elastic fibers
(PXE-like)
Sites of minor trauma
Collagen perforates
Upper extremities
Almost always a/w diabetes or renal failure
(10% of dialysis patients)
Lower extremities (extensor)
MAD PORES
Marfan’s Penicillamine, PXE
Acrogeria Osteogenesis imperfecta
Down’s Rothmund-Thomson
Ehlers-Danlos
Scleroderma
May occur in Wilson’s dz and cystinuria patients
on D-penicillamine
Obese hypertensive multiparous black
women
Abdomen (especially periumbilical)
Table 3.16 Abnormalities of Connective Tissue
Clinical Features Histopathology High-Yield Facts/Associations
Mid-dermal elastolysis Uncommon; circumscribed areas
Anetoderma 1–2 cm areas of flaccid/
Follicular atrophoderma Dimple-like follicular-based
Atrophoderma
vermiculatum
Striae Atrophic linear lesions along
Hypertrophic scar/keloids Darker skin, often familial tendency;
of fine wrinkling; symmetric on
trunk, lateral neck, extremities;
Caucasian middle-aged females
wrinkled skin, usually elevated
(.depressed or flat); neck, trunk,
upper extremities; primary form
F . M, 15–25 yo
“ice-pick” depressions; dorsal
hands/feet and cheeks; onset
birth to early childhood
Variant of follicular atrophoderma
that is on face/cheeks
exclusively; may be (1) sporadic,
(2) inherited as a sole finding
(autosomal dominant), (3) part
of a syndrome, or (4) presenting
feature of KP atrophicans
cleavage lines violaceous in color,
Caucasians; F . M
10–30 yo;
Hypertrophic scar conned to
wound borders and raised; keloids delayed in onset, extend
beyond wound borders
Normal H&E, elastic tissue stains
demonstrate selective loss of
elastic fibers in the mid dermis
only
Normal H&E, elastic tissue stain
shows near complete loss of
elastic fibers in papillary and
reticular dermis; fragmented
elastic fiber remnants visible
Dilated follicles w/plugging,
inflammation and dermal collagen
sclerosis
Same as above Associated with:
Clinical diagnosis
Hypertrophic scar: ↑ broblasts/
collagen (type I >III) oriented
both parallel to skin surface like
normal scar and in whorled
nodules; vertically oriented vessels
Keloids: haphazardly-arrayed thick
bundles of hyalinized collagen
UV light may have role in pathogenesis
Primary (idiopathic)
Jadassohn-Pellizzari (inammatory)
Schweninger-Buzzi (non-inammatory)
Secondary
Infection, penicillamine, inammatory dermatosis,
autoimmune (lupus, Sjögren’s, Graves’ dz),
cutaneous tumors
Associated with:
Bazex-Dupre-Christol syndrome (follicular
atrophoderma, BCCs of face, milia, localized
hypohidrosis above neck, hypotrichosis)
Rombo syndrome (atrophoderma vermicula-
tum, milia, acral erythema, peripheral vasodilation with cyanosis, multiple BCCs)
Nicolau-Balus syndrome (generalized eruptive
syringomas, atrophoderma vermiculata and
milia)
Others: Tuzun (scrotal tongue), and Braun-
Falco-Marghescu (PPK and KP)
Puberty, pregnancy; ↑ in Marfan’s syndrome
Hypertrophic scars spontaneously resolve
Keloids persist in absence of treatment; Rx:
IL-steroids (rst line), excision, XRT, topical
imiquimod, lasers, IL 5-FU
151
CHAPTER 3 • General Dermatology
Pathogenesis
• Unknown etiology; most likely Th1-type delayed
hypersensitivity reaction to a variety of triggers (trauma/
isomorphic Koebner response, insect bites, tuberculin skin
test, mycobacterial/viral infection, drugs, or UV radiation)
■
Trigger → Th1 reaction → monocyte accumulation in
dermis → release of lysosomal enzymes → degradation
of elastic bers
• Majority of affected patients are healthy (especially
localized GA)
■
Generalized GA more commonly a/w hyperlipidemia
(up to 45%), type I diabetes, HIV, thyroid disease,
malignancy (clinical pattern atypical—e.g., palms and
soles)
Clinical features
• Benign, self-resolving condition that p/w asymptomatic
annular/arciform plaques comprising multiple small,
non-scaly, esh-colored to pink or violaceous papules
■
Solitary umbilicated papules are common presentation
on ngers/hands
■
Previously involved skin in center of the annulus often
has red-brown color
• Distribution: isolated hands/arms most common (60%;
particularly dorsal hands/ngers and elbows) . isolated
legs/feet (20%; particularly dorsal feet and ankles) .
combined upper and lower extremities (7%)
■
Less commonly: isolated truncal lesions (7%) or trunk
1 other sites (5%)
• Variants:
■
Patch GA: symmetric erythematous patches commonly
on bilateral dorsal feet (or trunk and extremities); often
lacks annular conguration; histology shows
interstitial GA most commonly
■
Subcutaneous or deep dermal GA (“pseudorheumatoid
nodule”): most common in children , 6 yo; large,
asymptomatic rheumatoid-like nodules on dorsal foot
(#1 site), palms, shins, buttocks, and scalp; often a/w
trauma; 50% also have classic GA lesions
■
Generalized (disseminated) GA: occurs in minority of
patients; later age of onset (40–50s); composed of
innumerable small red-violaceous papules coalescing
into small annular plaques especially on upper trunk/
proximal upper extremities (Fig. 3.59); poor response
to treatment; usually self-resolves over 3 to 4 years;
lipid abnormalities in 45%; diabetes in 21% (vs. only
10% in localized GA); ↑ prevalence of HLA-Bw35
■
Perforating GA: 5% of GA cases; most commonly on
dorsal hands and ngers; small papules with central
keratotic plug, umbilication, or ulceration;
transepidermal elimination of degenerated collagen
seen histologically
■
GA-like eruptions: may be seen in association with solid
organ tumors, B- and T-cell lymphomas, HIV (p/w
generalized GA . localized), at sites of prior herpes
zoster scars, or drug-induced (TNF-a inhibitors .
amlodipine, allopurinol, diclofenac, gold)
Histopathology
• All forms are characterized by granulomatous dermal
inammation with foci of collagen/elastic ber
degeneration, ↑ mucin, and scattered eosinophils
• If LCV, granulomatous vasculitis, or thrombosis is present,
there is ↑ risk of systemic disease (probably represents
PNGD variant)
• Three common histologic patterns:
■
Interstitial (most common; 70% of cases): most subtle
pattern; singly-arrayed histiocytes between collagen
bers; minimal collagen/elastic ber degradation; key
to diagnosis is ↑ dermal mucin between collagen
bers (best appreciated w/ colloidal iron or Alcian
blue) and perivascular eosinophils
■
Palisaded granulomas (25%): best visualized at low
power; consist of one or more palisaded granulomas
w/ central degeneration of collagen/elastic bers and
↑ dermal mucin
■
Sarcoidal pattern (5%): rare histologic presentation
comprising well-formed epithelioid histiocytic nodules
A B
Fig. 3.59 (A) and (B) Disseminated granuloma annulare consisting of erythematous annular plaques. (From Solano-López G, Concha-Garzón MJ, de Argila D, Daudén
E. Successful treatment of disseminated granuloma annulare with narrowband UV-B phototherapy. Actas Dermosiliogr. 2015;106[3]:240–241.)
152
3.6 Granulomatous/Histiocytic Disorders
• Deep GA: palisaded granulomas w/ central blue-colored
mucin (vs. pink brin in RA) in deep dermis/SQ
• Perforating GA: typical GA ndings, plus transepidermal
elimination of degenerated collagen and granulomatous
debris
Treatment
• Localized/asymptomatic: reassurance, high-potency topical
or intralesional steroids, TCIs, lasers, and light cryotherapy
■
In some cases, biopsy of lesion → resolution
• Severe disease: phototherapy, antimalarials, nicotinamide,
isotretinoin, dapsone, pentoxiphylline, PDT, triple
antibiotic regimens (minocycline, ooxacin, and
rifampin), and TNF-a inhibitors
Prognosis/clinical course
• Spontaneous resolution in 2 years for half of patients
• 40% recurrence rate, but recurrent episodes clear faster
Annular elastolytic giant cell granuloma (actinic granuloma of O’Brien
• GA variant affecting chronically sun-exposed skin (face,
neck, upper trunk, and arms)
• Possibly caused by inammatory response to UV; most
commonly middle-aged women
• Start as esh-colored to pink papules → coalesce into
annular plaques 1 to 10 cm in diameter; normally , 10
total lesions
• Histopathology: interstitial (. well-formed palisaded)
granulomatous inltrate w/ more multinucleated
foreign body GCs than are typically seen in GA;
phagocytosed elastic bers within histiocytes and GCs
(“elastophagocytosis”); no collagen alteration or lipid
deposition, lacks mucin; Verhoeff-Van Gieson (VVG)
stain shows absence of elastic bers and loss of solar
elastosis in affected areas
• Rx: typically persistent (vs. GA); poor response to standard
GA treatments
Interstitial granulomatous dermatitis and arthritis (IGDA) and palisaded neutrophilic granulomatous dermatitis (PNGD)
• F . M
• These two granulomatous dermatitides exist on a
spectrum (Table 3.17)
• Both are a/w systemic diseases:
■
SLE and ANCA vasculitides (PNGD . IGDA)
■
RA (both)
■
Other autoimmune diseases (both)
• Pathogenesis: autoimmune condition → immune
complex deposition in/around dermal vessel walls →
chronic, low-intensity vasculitis (more brisk and
neutrophil-rich in PNGD) → gradual impairment of
blood ow to dermal collagen → collagen degeneration
→ palisaded granulomatous inammation in reaction to
degenerated collagen
Table 3.17 Interstitial Granulomatous Dermatitis and Arthritis (IGDA)/
Palisaded Neutrophilic Granulomatous Dermatitis (PNGD)
IGDA PNGD
Annular plaques or linear red to
skin-colored cords (aka “rope
sign ” usually in axilla)
Trunk, buttocks, and intertriginous
areas (symmetric)
Histology: small rosettes of
palisading histiocytes (w/ giant
cells) in mid/deep reticular dermis
(“bottom heavy”) around small foci
(smaller than GA) of degenerated
collagen; interstitial lymphocytes;
no mucin; 1/–neutrophils; no
obvious vasculitis
Most common associations:
RA, seronegative arthritis,
autoimmune thyroiditis, SLE, IBD
Arthralgias or arthritis (50%)
Red to violaceous tender
papules/plaques 1/–
umbilication 1/– perforation/
ulceration
Symmetric involvement of extensor
digits (including palms), elbows,
and other extensors
Histology: small vessel LCV
w/basophilic collagen
degeneration and neutrophilic
infiltrates (early) → palisaded
granulomas with basophilic
collagen degeneration 1/
perforating collagen (late)
Most common associations: RA,
SLE, ANCA (1) vasculitides
(Wegener’s/Churg-Strauss
. others), malignancy
(lymphoproliferative)
• ANA(1) in 50%
• No specic treatment exists other than treating underlying
disease, 1/– topical or IL-steroids
• 66% of patients achieve complete remission (months
to years); 33% have persistent, chronic, relapsing
course
Interstitial granulomatous drug eruption
• Clinically may resemble interstitial GA, IGDA, or PNGD
■
Annular, red, non-scaly papules and plaques w/
indurated border; favors creases and often
photodistributed; spares mucous membranes
• Most commonly caused by CCBs, statins, TNF-a
inhibitors (months to years after drug initiation)
■
Others: ACE inhibitors, furosemide, b-blockers,
antihistamines, HCTZ, anakinra, thalidomide
• Histology: may resemble interstitial GA, IGDA, or PNGD
but frequently has deeper dermal involvement (bottom
two thirds of dermis), interface dermatitis, atypical
lymphocytes, and lacks mucin
• Typically resolves months after drug discontinuation
Necrobiosis lipoidica (Necrobiosis lipoidica diabeticorum, NLD)
Epidemiology
• F . M (3:1)
• Only 0.03% of diabetics have NLD, but 22% of patients
with NLD have or will develop diabetes/glucose
intolerance
■
Diabetics w/ NLD have ↑ risk of peripheral neuropathy,
retinopathy, and joint immobility
• May be a/w smoking
153
CHAPTER 3 • General Dermatology
Pathogenesis
• Vascular compromise from immunodeposition in vessel
walls or diabetes-related microangiopathic changes →
subacute dermal ischemia → dermal collagen
degeneration → secondary granulomatous inammatory
response
Clinical features
• Early lesions manifest as rm, reddish papules → expand
into atrophic plaques (usually multiple) on bilateral shins
w/ a peripheral violaceous to erythematous rim and
atrophic central yellow-brown discoloration w/
telangiectasias (Fig. 3.60)
■
Dermoscopy: comma-shaped vessels (early lesions),
and irregular arborizing vessels (older lesions)
■
Minor trauma results in ulceration (30%)
• Adnexae and neural elements frequently lost within NLD
plaques → ↓ pinprick/ne touch sensation, hypohidrosis,
and localized alopecia
Histopathology
• “Square biopsy” sign
• Horizontally arranged (“layered”) palisaded
granulomatous inammation w/ horizontal tiers of
degenerated collagen bers (irregular size and shape) and
dermal sclerosis
• Process diffusely involves entire dermis and subcutaneous
fat septae (vs. GA, which tends to have patchy dermal
involvement with areas of normal intervening dermis)
• Lacks mucin
• Plasma cells and multinucleated GCs are abundant (both
uncommon in GA)
• 1/– epidermal atrophy; 1/– vascular hyalinization
(Fig. 3.61)
Treatment
• First line: potent topical and/or intralesional steroids
(injected into inammatory rim); TCIs (early lesions)
• Systemic steroids, colchicine, cyclosporine, TNF-a
inhibitors, CO2 laser, stanozolol, pentoxyfylline in
chronic/recalcitrant cases
• Surgical excision to fascia w/ skin grafting may be
necessary in severe ulcerative cases
Prognosis/clinical course
• Rarely undergoes spontaneous remission (17% at
8–12 years)
• Control of blood glucose levels does not affect disease
course
• No treatment has demonstrated efcacy in large double-
blind studies
• SCC may arise in chronic ulcerative lesions
Necrobiotic xanthogranuloma (NXG)
• Peak in sixth decade; M 5 F
• Multisystem histiocytic disease that p/w rm yellow
xanthomatous plaques and nodules, most commonly in
periorbital region (Fig. 3.62) (. trunk, proximal
extremities)
■
Often ulcerates and leads to scarring
• 50% have ophthalmic manifestations (ectropion, keratitis,
uveitis, and proptosis); majority also have endocardial
involvement; hepatosplenomegaly common
• Strongly a/w IgG monoclonal gammopathy (due to
plasma cell dyscrasia or multiple myeloma)
■
Skin ndings precede diagnosis of malignancy by
2–20 years
• Histopathology: diffuse (pandermal and into subcutis),
palisading xanthogranulomas w/ necrobiotic collagen,
foamy histiocytes, “dirty dermis” (scattered inammatory
cell debris), abundant cholesterol clefts, and multiple
Touton and bizarre foreign body GCs (HUGE
multinucleated cells w/ “horse-shoe” arrangement of 25
to 50 nuclei → these cells are not seen in NLD or GA)
• Rx: none effective; treat underlying malignancy or
paraproteinemia
Fig. 3.60 Necrobiosis lipoidica with red-yellow atrophic plaques on anterior shin.
(From James WD, Elston DM, McMahon PJ. Errors in metabolism. In: Andrews’
Diseases of the Skin: Clinical Atlas . Philadelphia: Elsevier; 2018:361–378.)
154
Cutaneous Crohn’s disease
Epidemiology
• 20%–45% of Crohn’s patients have skin or mucosal
ndings
• Crohn’s specic (uncommon): contiguous perianal/
genital/oral Crohn’s, distant (“metastatic”) Crohn’s
• Non-specic/reactive (more common): EN, PG (ulcerative
colitis [UC] . Crohn’s), pyostomatitis vegetans (UC .
Crohn’s), pathergy (pustular response to trauma), EB
acquisita (IBD is the most common cause of EBA), and
acrodermatitis enteropathica-like syndrome due to zinc
deciency
• F . M; average age 5 35 yo
• Cutaneous Crohn’s is more frequently a/w colorectal
rather than small intestinal disease
• Skin ndings may precede GI diagnosis of Crohn’s (20%
of cases)