REVIEW OF ANATOMY AND PHYSIOLOGY

I. LAYERS OF THE SKINa. Epidermisb. Dermisc. Subcutaneous tissue

II. EPIDERMISa. outermost layer of the skinb. 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, &

desmosomesf. 3 basic cell types

i. Keratinocytes 1. squamous cell2. ectodermal origin3. production of keratin

a. surface coat of the epidermisb. 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 cytoplasm3. 1 melanocyte:4 basal keratinocytes (cheeks) to 1:10 (limbs) →

forming with them an ”epidermal melanin unit”4. production of melanin5. Key Implications: Vitiligo, Melanoma, Hyperpigmentation

iii. Langerhans cells1. clear, dendritic cells just above the middle of the spinous zone of

the epidermis2. striking cytoplasmic vacuolation 3. electron microscopy: lobulated nucleus and Birbeck granules

(rod/racquet inclusions4. potent stimulators of T-cell mediated immunoreactions5. Key Implications: Inflammatory skin diseases

III. DERMISa. 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 TISSUEa. deepest layerb. derived from mesenchyme c. consists of adipose tissue, blood vessels & nervesd. also contains sweat glands & bases of hair folliclese. Key Implications: Panniculitis such as Erythema nodosum

V. SEBACEOUS GLANDSa. holocrine glandsb. usually develop as lateral protrusions from the outer root sheath of hair folliclesc. found everywhere on the body except the palms and solesd. more abundant in the scalp, face, midline of the back, perineum and orifices of

the bodye. in eyelids: glands of Zeis and meibomian glandf. buccal mucosa & vermilion of lip: Fordyce’s spotsg. areola of women: Montgomery’s tuberclesh. labia minora & glans: Tyson’s glandsi. Key Implications: Acne

VI. ECCRINE SWEAT GLANDSa. only true sweat gland in humansb. found everywhere on the skin except the lips, clitoris, labia minora, external

auditory canalsc. maximum distribution: palms, soles, axillae, foreheadd. normally between the reticular dermis & subQ e. Key Implications: Hyperhidrosis

VII. APOCRINE GLANDSa. tubular glandsb. axillae, areola, periumbilical region, perineal & circumanal areas, prepuce,

scrotum, mons pubis, labia minora, external auditory canals (ceruminous glands), eyelids (Moll’s glands)

c. small & non-functional until pubertyd. apocrine (decapitation) secretion – apical portion of glandular cells appear

“pinched-off” & released into lumen of gland during secretion e. Key Implications: Bromhidrosis

VIII. BLOOD SUPPLYa. from perforating vessels w/in the skeletal muscle and subcutaneous fatb. 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

fatd. Key Implications: Erythema, Necrosis

IX. NERVESa. 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 nucleusd. Key Implications: Neural tumors, Leprosy

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

I. URTICARIA AND ANGIOEDEMA

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

I. PathogenesisA. mast cell: major effector cells in urticaria and angioedemaB. cutaneous mast cells adhere to fibronectin, laminin and vitronectinC. Substance P, VIP and somatostatin activate mast cellsD. Vascular permeability produced by H1 receptorsE. Release of mast cell products----alteration in vasopermeability----appearance of adhesion

molecules on endothelial cells----attachment of blood leukocytes

II. Clinical manifestationsA. Urticaria: superficial dermis; rarely persist more than 24 to 48 hrsB. Angioedema: deep dermis, subcutaneous and submucosalC. 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 pressureF. Cholinergic urticaria

a. increase in core body temperatureb. warm bath or shower, exercise, or feverc. small wheals surrounded by erythema, which may be confluentd. increased prevalence of atopye. injection of metacholine produces lesion

G. Adrenergic urticariaa. wheals surrounded by white halo during emotional stressb. simulated by intracutaneous injection of epinephrinec. eruption similar to cholinergic urticariad. elderly, polycythemia, Hodgkin’s, myelodysplastic syndrome and

hypereosinophilic syndromee. mast cell degranulation present in biopsies

H. Contact urticariaa. IgE-mediated or non-immunologicb. Passive transferc. Proteins from latex productsd. Proteins may retained be in glove powdere. Cross-reactivity to bananas, avocado and kiwif. Rhinitis, conjunctivitis, dyspnea, shock

I. Papular urticariaa. symmetric, hypersensitivity reaction to insect bitesb. mainly in childrenc. 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 degranulationa. 8% receiving intravenous radiographic contrast mediab. opiate analgesics, polymyxin B, curare and D-tubocurarine

L. Urticaria/Angioedema relating to Abnormalities of Arachidonic Acid Metabolisma. intolerance to aspirin and NSAIDSb. inhibition of inducible PGHS-2 (cyclooxiginase 2)

M. Reaction to administration of blood productsa. immune complex formation and complement activationb. lead directly to vascular and smooth muscle alterations via

anaphylatoxins

N. Other forms of Urticaria:1. Cold Urticaria2. Local heat urticaria3. Solar urticaria4. Exercise-induced anaphylaxis

a. Autoimmune urticaria

III. Laboratory findings1. In all patients

a. history and PEb. provocative tests for physical urticaria

2. In selected patientsa. CBC with differentialb. ESRc. Urinalysisd. Blood chemistry profilee. Stool examination for ova and parasitesf. Hep B virus surface antigen and Hep B and C antibodiesg. Thyroid microsomal and peroxidase antibodiesh. Antinuclear antibodyi. Cryoproteins: for suspected acquired cold urticariaj. Skin tests for IgE-mediated reactionsk. RAST for specific IgEl. Skin biopsy

IV. Approach to the managementa. Identification and removal of precipitating causeb. Administration of H1 antihistaminesc. Combination of H1 antihistamines, use a different class. d. Administration of H1 and H2e. Addition of B-adrenergic agonist to an H1 antihistaminef. Avoidance of epinephrine except in respiratory or cardiovascular

collapseg. Alternate day systemic steroids in refractory disease

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II. CUTANEOUS REACTIONS TO DRUGS

1) Pathogenesis of Drug Eruptionsa) variation in drug-metabolizing enzymesb) variations in HLA associationc) Reactive drug products

2) Morphological approach to Drug eruptionsi) 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) 1st 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 eruptions1. 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,ACE2. papulosquamous or annular cutaneous lesions3. photosensitive4. absent or mild systemic involvement5. circulating anti-Ro (SSA)

III. Clinical features that warn of a potentially severe drug reaction1. Systemic

a. fever, pharyngitis, malaise, arthralgia, cough and meningismb. lymphadenopathy

2. Cutaneousa. evolution to erythrodermab. prominent facial involvement with or without edema or swellingc. mucous membrane involvementd. skin tenderness, blistering or sheddinge. purpura

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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-TENEtiology HSV (majority) Drugs (80-95%)Course Acute, self-limited, recurrent Acute, self-limited, episodicProdromes Absent to moderate Intensive, skin-tendernessTypical lesions Fixed plaques, target lesion,

blisters, no NikolskyMacules, 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 moreComplications None Septicemia, pneumonia, GIT

hemorrhage, renal failure, heart failureMortality 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-γ 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 Nikolsky’s, 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 1st, 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:

Fitzpatrick’s Dermatology in General Medicine, 2008

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