REVIEW OF ANATOMY AND PHYSIOLOGY

I. LAYERS OF THE SKIN

a. Epidermis
b. Dermis
c. Subcutaneous tissue

II. EPIDERMIS
a. outermost layer of the skin
b. 0.04 mm on the eyelids to 1.6 mm on the palms (thickest)
c. Primary role: cornification (formation of the outermost dead layer of the skin
stratum corneum)
d. synthesis of lamellar granules & distinctive proteins (keratins, fillagrin, involucrin)
e. alterations of nuclei, cytoplasmic organelles, plasma membranes, &
desmosomes
f. 3 basic cell types
i. Keratinocytes
1. squamous cell
2. ectodermal origin
3. production of keratin
a. surface coat of the epidermis
b. structural protein of hair & nails
4. Key Implications: Atopic dermatitis, Squamous cell carcinoma

ii. Melanocytes
1. neural crest origin
2. nucleus smaller & more deeply basophilic than basal
keratinocyte , dendritic cytoplasm
3. 1 melanocyte:4 basal keratinocytes (cheeks) to 1:10 (limbs)
forming with them an epidermal melanin unit
4. production of melanin
5. Key Implications: Vitiligo, Melanoma, Hyperpigmentation

iii. Langerhans cells
1. clear, dendritic cells just above the middle of the spinous zone of
the epidermis
2. striking cytoplasmic vacuolation
3. electron microscopy: lobulated nucleus and Birbeck granules
(rod/racquet inclusions
4. potent stimulators of T-cell mediated immunoreactions
5. Key Implications: Inflammatory skin diseases

III. DERMIS
a. derived from mesenchyme
b. composed of:
i. collagen (70%)
ii. elastin (1-3%)
iii. ground substance (proteoglycans)
c. Implications: Dermal tumors, Scars and keloids, Scleroderma

IV. SUBCUTANEOUS TISSUE
a. deepest layer
b. derived from mesenchyme
c. consists of adipose tissue, blood vessels & nerves
d. also contains sweat glands & bases of hair follicles
e. Key Implications: Panniculitis such as Erythema nodosum

V. SEBACEOUS GLANDS
a. holocrine glands
b. usually develop as lateral protrusions from the outer root sheath of hair follicles
c. found everywhere on the body except the palms and soles
d. more abundant in the scalp, face, midline of the back, perineum and orifices of
the body
e. in eyelids: glands of Zeis and meibomian gland
f. buccal mucosa & vermilion of lip: Fordyces spots
g. areola of women: Montgomerys tubercles
h. labia minora & glans: Tysons glands
i. Key Implications: Acne

VI. ECCRINE SWEAT GLANDS
a. only true sweat gland in humans
b. found everywhere on the skin except the lips, clitoris, labia minora, external
auditory canals
c. maximum distribution: palms, soles, axillae, forehead
d. normally between the reticular dermis & subQ
e. Key Implications: Hyperhidrosis

VII. APOCRINE GLANDS
a. tubular glands
b. axillae, areola, periumbilical region, perineal & circumanal areas, prepuce,
scrotum, mons pubis, labia minora, external auditory canals (ceruminous glands),
eyelids (Molls glands)
c. small & non-functional until puberty
d. apocrine (decapitation) secretion apical portion of glandular cells appear
pinched-off & released into lumen of gland during secretion
e. Key Implications: Bromhidrosis

VIII. BLOOD SUPPLY
a. from perforating vessels w/in the skeletal muscle and subcutaneous fat
b. Superficial vascular plexus
i. positioned in the upper part of the reticular dermis, just beneath the
papillary dermis
c. Deep vascular plexus
i. lower part of the reticular dermis, & separates it from the subcutaneous
fat
d. Key Implications: Erythema, Necrosis

IX. NERVES
a. both somatic sensory (pain, itch, temperature, light tough, pressure, vibration,
proprioception) & autonomic motor nerves (cutaneous vascular tone, pilomotor
response, sweating)
b. travel along the course of superficial & deep vascular plexus neurovascular
plexus
c. wavy, spindle-shaped, or S-shaped nucleus
d. Key Implications: Neural tumors, Leprosy
________________________________________________________________




Urticaria and Angioedema, Reactions to Drugs, Stevens Johnsons Syndrome- Toxic
Epidermal Necrolysis

I. URTICARIA AND ANGIOEDEMA

A. Acute urticaria: less than 6 weeks
B. Chronic urticaria: beyond 6 weeks

I. Pathogenesis
A. mast cell: major effector cells in urticaria and angioedema
B. cutaneous mast cells adhere to fibronectin, laminin and vitronectin
C. Substance P, VIP and somatostatin activate mast cells
D. Vascular permeability produced by H1 receptors
E. Release of mast cell products----alteration in vasopermeability----appearance of adhesion
molecules on endothelial cells----attachment of blood leukocytes

II. Clinical manifestations
A. Urticaria: superficial dermis; rarely persist more than 24 to 48 hrs
B. Angioedema: deep dermis, subcutaneous and submucosal
C. Specific antigen sensitivity (shellfish, nuts, chocolate, drugs, Penicillin, aeroallergens and
hymenoptera, helminths)

D. Dermographism: most common form of physical urticaria; transient wheal which appears
rapidly and fades within 30 minutes

E. Pressure urticaria: often painful 0.5 to 6 hrs after sustained pressure
F. Cholinergic urticaria
a. increase in core body temperature
b. warm bath or shower, exercise, or fever
c. small wheals surrounded by erythema, which may be confluent
d. increased prevalence of atopy
e. injection of metacholine produces lesion
G. Adrenergic urticaria
a. wheals surrounded by white halo during emotional stress
b. simulated by intracutaneous injection of epinephrine
c. eruption similar to cholinergic urticaria
d. elderly, polycythemia, Hodgkins, myelodysplastic syndrome and
hypereosinophilic syndrome
e. mast cell degranulation present in biopsies

H. Contact urticaria
a. IgE-mediated or non-immunologic
b. Passive transfer
c. Proteins from latex products
d. Proteins may retained be in glove powder
e. Cross-reactivity to bananas, avocado and kiwi
f. Rhinitis, conjunctivitis, dyspnea, shock

I. Papular urticaria
a. symmetric, hypersensitivity reaction to insect bites
b. mainly in children
c. extensors, exposed areas

J. Idiopathic Urticaria/Angioedema : 70%
a. H. pylori possibly implicated
b. Recurrent, fever, weight gain, absence of internal organ damage,
benign, peripheral blood eosinophilia

K. Urticaria after direct mast cell degranulation
a. 8% receiving intravenous radiographic contrast media
b. opiate analgesics, polymyxin B, curare and D-tubocurarine

L. Urticaria/Angioedema relating to Abnormalities of Arachidonic Acid Metabolism
a. intolerance to aspirin and NSAIDS
b. inhibition of inducible PGHS-2 (cyclooxiginase 2)

M. Reaction to administration of blood products
a. immune complex formation and complement activation
b. lead directly to vascular and smooth muscle alterations via
anaphylatoxins



N. Other forms of Urticaria:
1. Cold Urticaria
2. Local heat urticaria
3. Solar urticaria
4. Exercise-induced anaphylaxis
a. Autoimmune urticaria

III. Laboratory findings
1. In all patients
a. history and PE
b. provocative tests for physical urticaria

2. In selected patients
a. CBC with differential
b. ESR
c. Urinalysis
d. Blood chemistry profile
e. Stool examination for ova and parasites
f. Hep B virus surface antigen and Hep B and C antibodies
g. Thyroid microsomal and peroxidase antibodies
h. Antinuclear antibody
i. Cryoproteins: for suspected acquired cold urticaria
j. Skin tests for IgE-mediated reactions
k. RAST for specific IgE
l. Skin biopsy

IV. Approach to the management
a. Identification and removal of precipitating cause
b. Administration of H1 antihistamines
c. Combination of H1 antihistamines, use a different class.
d. Administration of H1 and H2
e. Addition of B-adrenergic agonist to an H1 antihistamine
f. Avoidance of epinephrine except in respiratory or cardiovascular
collapse
g. Alternate day systemic steroids in refractory disease
________________________________________________________________________


II. CUTANEOUS REACTIONS TO DRUGS

1) Pathogenesis of Drug Eruptions
a) variation in drug-metabolizing enzymes
b) variations in HLA association
c) Reactive drug products


2) Morphological approach to Drug eruptions
i) Exanthematous eruptions
- most common (95%)
- starts on trunk and spreads peripherally
- pruritus almost always present
- starts 1 week after therapy and resolve within 7 to 14 days
- bright red to brownish-red then scaling and desquamation
- PCN, Sulfonamides, NNRT (Nevirapine), antiepileptics
- Exanthem with fever and internal organ involvement= HSR (Hypersensitivity
Syndrome Reaction)
1
st
exposure effect or 1 to 6 weeks after exposure
fever and malaise
toxic metabolites by aromatic anticonvulsants
hydroxylamines and nitrosol from Sulfonamides

ii) Urticarial
- pruritic wheals
- lasts less than 24 hrs
- angioedema unilateral and non-pruritic, lasts for 1 to 2 hrs, may persist for 2
to 5 days
- with drug use, IgE mediated hypersensitivity
- Narcotics cause release of histamine independent of IgE
- ACE inhibitors frequent cause of angioedma
- Serum sickness-like reactions: fever+ rash + arthralgia 1 to 3 weeks after
initiation of drugs

iii) Pustular
- Acneiform eruptions
iodides, bromides, ACTH, Steroids, Isoniazid, androgens, lithium,
actinomycin D, phenytoin
arms and legs, monomorphous
comedones are absent

- Acute Generalized Exanthematous pustulosis
Fever + leukocytosis
1- 3 weeks after intake of drugs or 2 to 3 days when previously sensitized
starts on face and main skin creases
generalized desquamation 2 weeks later
spongiform subcorneal pustules and edema of the upper dermis

iv) Bullous drug eruptions
1. Drug induced Pemphigus
- penicillamine and thiol drugs
- remit spontaneously in 35 to 50% of cases
- presents as pemphigus foliaceous
- average interval to onset of 1 year
- associated with ANA in 25% of patients
- non-thiol pemphigus with mucosal involvement 15% spontaneous recovery
2. Drug-induced bullous pemphigoid
- younger patients
- Furosemide
- few eos and neuts on biopsy
- thrombi in dermal vessels and necrotic keratinocytes
3. Erythema mulfiforme major, SJS, TEN
- more severe presentation most likely drug related
- EM with no mucous membrane involvement vs SJS-TEN
- anticonvulsants , allopurinol, NSAIDS
- use of steroids controversial
- IVIg 0.2 to 0.75 g/kg for 4 consecutive days

v) Fixed drug eruption
- solitary, bright red
- genitalia and perianal area
- 30 minutes or 8 to 16 hrs after ingestion of the medication
- burning, fever, malaise, abdominal symptoms
- Ibuprofen, Sulfonamides and Tetracyclines
- Histologically resembles EM


vi) Drug-induced Vasculitis
- 10% of acute cutaneous vasculitis
- Allopurinol, Penicillins and thiazide diuretics
- Interval 7 to 21 days
- Palpable purpura on lower extremities
- May manifest as urticaria
- Presence of p-ANCA against myeloperoxidase

vii) Drug-Induced lupus
- frequent musculoskeletal complaints + fever + weight loss + systemic
symptoms
- Minocycline induced after 2 yrs; symmetric polyarthritis and hepatitis + livedo
- Antihistone antibody rarely present
- Drug induced Subacute Cutaneous Lupus Erythematosus
1. thiazide, CCB,ACE
2. papulosquamous or annular cutaneous lesions
3. photosensitive
4. absent or mild systemic involvement
5. circulating anti-Ro (SSA)


III. Clinical features that warn of a potentially severe drug reaction
1. Systemic
a. fever, pharyngitis, malaise, arthralgia, cough and meningism
b. lymphadenopathy
2. Cutaneous
a. evolution to erythroderma
b. prominent facial involvement with or without edema or swelling
c. mucous membrane involvement
d. skin tenderness, blistering or shedding
e. purpura
________________________________________________________________________


III. ERYTHEMA MULTIFORME, SJS-TEN

Self-limited exanthem
At least 2 salient features
Target lesions clinically
Satellite cell necrosis of the epidermis histologically (necrotic keratinocyte + adjacent
lymphocyte
2 main subsets recognized
EM
Mild and relapsing
Most often triggered by recurrent HSV
Stevens-Johnson Syndrome-TEN complex
Severe mucocutaneous reaction
Most often elicited by drugs

Table 1: Comparison of Clinical Features of Erythema Multiforme (EM) and SJS-TEN

Feature EM SJS-TEN
Etiology HSV (majority) Drugs (80-95%)
Course Acute, self-limited, recurrent Acute, self-limited, episodic
Prodromes Absent to moderate Intensive, skin-tenderness
Typical lesions Fixed plaques, target lesion,
blisters, no Nikolsky
Macules, flat atypical target lesions,
central necrosis; Nikolsky
Mucosal
involvement
Frequent but mostly mild, usually
oral mucosa
Prominent, severe, 2-3 mucosal sites
Body surface
affected
<10% <10 to 30%
Constitutional
symptoms
Absent to moderate Prominent to severe
Pathology Satellite cell necrosis of
keratinocytes, DEJ blister formation,
prominent lymphocytic infiltrate,
edema of papillary dermis
Massive keratinocytes necrosis,
sloughing of epidermis, paucity of
lymphocytic infiltrates
Internal organ
involvement
Absent Not infrequent
Duration 1-3 weeks 2-6 weeks or more
Complications None Septicemia, pneumonia, GIT
hemorrhage, renal failure, heart failure
Mortality rate 0 1-50%
Healing Heals without scarring Sequelae due to mucosal scarring


ERYTHEMA MULTIFORME


DEFINITION
Self-limited , relapsing
Target-shaped urticarial plaques
Mucous membrane lesions

INCIDENCE AND EPIDEMIOLOGY
HSV- dominant cause in both children and adults
HSV 1 and 2
Clinical lesion of recurrent HSV precede an outbreak of EM in 80% of cases
Other factors circumstantial
Hep B and C
Other viral infections
Progesterone
Drugs: rare

PATHOGENESIS OF EM
Cell-mediated Immune-reaction
Destruction of HSV antigen-expressing keratinocytes (expression of viral polymerase) by
CD8+ cells
Induction of apoptosis leads to satellite cell necrosis
Exocytosis facilitated by ICAM 1 (probably stimulated by interferon- from CD4 cells)
Dermal inflammation mediated by CD4+ T-cells (responsible for the wheal-like configuration)

CLINICAL MANIFESTATIONS
Prodrome usually absent (URTI)
All lesions appear within 3 days
Symmetric acral, on extensors (dorsa of the hands, feet, elbows and knees)
Less often on palms and soles, thighs and buttocks and trunk
Centripetal progression
Usually symptomless, may have burning or itching
THE RASH
Monomorphous
Wheal-like erythematous papule or plaque
Periphery erythematous and edematous, center violaceous and dark- indicating that
inflammatory activity may regress or relapse in the center
Often the center turns purpuric or necrotic
THE TARGET LESION
Dusky central disk or blister
Ring of pale edema peripherally
Erythematous halo
May present as central bulla and a marginal ring of vesicles (herpes iris of Bateman)
MUCOSAL LESIONS
Present in up to 70% of patients
Almost exclusively limited to the oral cavity
Lips, palate, gingivae
Cervical lymphadenopathy usually present
< 10% body surface area

COURSE AND PROGNOSIS
mild course
subsides within 1 to 4 weeks
recovery is complete, no sequelae
does not progress to SJS-TEN

RELATIONSHIP TO RECURRENT HSV INFECTION
In more than 70% of recurrent EM, HSV precedes rash
Herpes labialis more common (9:1)
Interval of 8 days (HSV to EM)
Not all episodes of EM preceeded by clinically evident HSV, not all HSV followed by EM


LABS
Usually normal
Elevated ESR, moderate leukocytosis, acute phase proteins and mildly elevated liver
transaminase


TREATMENT
Regression in 2 weeks
Symptomatic treatment
Systemic steroids unnecessary
Oral acyclovir 200 mg 5x a day
Recurrent EM: Antiviral medications
Attacks recur after withdrawal of antiviral but becomes less frequent and less severe
Dapsone, antimalarials, AZA, thalidomide
________________________________________________________________________

SJS-TEN

Aka Lyell syndrome
Severe, episodic, mucocutaneous intolerance reaction
More often induced by drugs, less by infections
Macular rash (atypical target lesion) + one or more mucosal site (oral, conjunctival and
anogenital)
In TEN, resembles scalding
Constitutional symptoms and internal organ involvement occur often and may be severe
Self-limited
Significant mortality rate
Sequelae due to mucosal scarring may develop

CLASSIFICATION
<10% BSA SJS
10-30% BSA SJS-TEN overlap
>30% BSA TEN

INCIDENCE AND EPIDEMIOLOGY
no ethnic preponderance
females 2x as males
most often in adults
incidence dramatically increased in HIV

ETIOLOGY
polyetiologic
drugs causative in 80 to 95% of patients with TEN; >50% with SJS
3 major groups of commonly implicated drugs
Sulfa drugs: long acting sulfonamide and Co-trimoxazole as the most common causes
Anticonvulsants: Phenytoin, Carbamazaepine and Phenobarbital
Carbamazepine: highest incidence of SJS-TEN per user
Hydantoins as the main cause of TEN in children
Valproic acid with high relative risk
NSAIDS: butazone and oxicam derivatives
Mycoplasma pneumoniae inciting factor

PATHOGENESIS
Cytotoxic immune reaction which destroys keratinocytes expressing foreign antigens
CD8+ cells in epidermis, CD4+ cells in dermis
Defects of detoxification systems in liver and skin leads to formation of reactive
hydroxylamines from sulfonamides or arene oxides from aromatic anticonvulsants
Antibodies to desmoplakin I and II

CLINICAL FEATURES
Prodrome of 1 to 14 days in at least 50% of cases
Fever, malaise, headache, rhinitis, cough, sore throat, chest pain, vomiting, diarrehea,
myalgias and arthralgia
Patients often have received antimicrobial and anti-inflammatory treatment
Starts as a macular rash on face, neck chin and central trunk
Spreads to extremities
Irregularly shaped pale livid macules
Positive Nikolskys, often tender
Maximum disease expression n 4 to 5 days
Limited confluence in SJS, widespread to total in TEN
Necrosis of the epidermis on pressure points
Denudations may involve 10 to 90% BSA
Shedding of skin appendages: finger, toenails, eyebrows and cilia
Rash simultaneous or preceeded by mucous membrane lesions
Buccal mucosa, palate and vermilion border of lips always affected
Bulbar conjunctiva and anogenital mucosa less often involved
All 3 sites involved in 40% of cases
Burning sensation on mucosa 1
st
, then blisters which rupture to form ulcers with gray-white
pseudomembranes
Lips covered with crusts
Painful oral lesions
Otitis media may be seen
Eye findings include chimosis, vesiculation and painful erosions and bilateral lacrimation
Less common: purulent conjunctivitis with photophobia, pseudomembranes, corneal
ulcerations, anterior uveitis an panophthalmitis
Genital involvement: purulent lesions of the fossa navicularis and glans in males, vulva and
vagina in females
Anal erosions less frequent

EXTRACUTANEOUS INVOLVEMENT
Fever, arthralgias, weakness, prostration
Internal involvement rare in SJS, severe in TEN
Resp and GIT
Dehydration and electrolyte imbalance may proceed to shock
Myocarditis and MI frequently seen in fatal cases
Renal abnormalities rare except for microalbuminuria
ATN, membranous GN and ARF have been described

LATE COMPLICATIONS
Transient hypo- and hyperpigmentation
Scarring not usual except in extensive cases
Scarring (30%) most serious in the eyes: symblepharon, synechiae, entropion and ectropion,
trichiasis, corneal opacities or pannus formation
Sjogren like (dry eye) syndrome

EXTRACUTANEOUS PATHOLOGY
Extensive fibrinoid necrosis, including stomach, spleen, trachea and bronchi

LABORATORY INVESTIGATIONS
Elevated ESR
Moderate leukocytosis
Microalbuminuria
Hypoproteinemia
Elevated liver transaminase and anemia
Transient decrease of peripheral CD4+ T lymphocyte counts
Neutropenia regarded as an unfavorable prognostic sign
Proteinuria an elevated BUN occur in 5% of cases


TREATMENT
Specialized center
Should not be ambulatory
Referral to an intensive care unit or to a burn center not mandatory
No accepted treatment guidelines nor any controlled therapeutic trials
Cornerstones of therapy
Withdrawal of the offending agent
May reduce death risk to 30%
Does not immediately halt disease progression
Most likely offending drug: introduced in the past 4 weeks and is a known risk drug
for SJS-TEN
Active suppression of disease progression
Glucocorticoids
Mainstay of the treatment of SJS-TEN
If given longer, increases risk for infection
In principle, no effect on disease progression
Mortality rates differ in published series (0-50%), with or without steroids
Do not shorten peak and regression phases
If given, high doses are required (1-2 mg/kg methylprednisolone/day)
Rapid tapering indicated
Immunoglobulins
Promising strategy to block progression
Antibodies against the Fas ligand which prevents apoptosis
0.2 to 0.75 /kg/day for 4 consecutive days
rapid decrease of disease progression
nephropathy is rare, but frightening
Plasmapharesis and hemodialysis
Not recommended at present time
Supportive measures
Fluid, protein and electrolyte balance
Control of infection
BP, Hct, ABG and electrolytes must be monitored
CVP not routine
Skin
Early aggressive debridement not indicated
Spontaneous re-epithelialization rapid
Avoid Sulfonamide-containing topicals
Eyes
Lubricants, steroids, antibiotic drops
Respiratory tract
Alimentation
High calorie, high protein
Anesthetic mouthwash
Antimicrobial treatment
Infections most important threat
Bacterial and fungal cultures 2 to 3x a week from skin and mucosa
Watch out for HSV and Candida on genital lesions
Prophylaxis: PCN 2 X 10 millions units per day in the beginning (mortality less 10%)


COURSE AND PROGNOSIS
1% mortality rate for SJS
5 to 50% mortality for TEN
unfavorable prognostic signs
old age
extensive skin lesions
neutropenia
impaired renal function
intake of multiple drugs
Serum glucose level greater than 14 mmol/L
Bicarbonate level less than 20 mmol/L
major complications leading to death
Septicemia (Staph, Pseudomonas, Candida)
GI hemorrhage
Pneumonia
Fluid and electrolyte imbalance leading to renal insufficiency
MI, Cardiac insufficiency
recovery is slow an depends on adequate treatment
healing may require from 3 to 6 weeks
recurrences exception rather than the rule


References:

Fitzpatricks Dermatology in General Medicine, 2008

Prepared by: Johannes F. Dayrit MD, FPDS
Dermatology/Dermatopathology
yohannmdderm@gmail.com