REVIEW OF ANATOMY AND PHYSIOLOGY I. LAYERS OF THE SKIN a. Epidermis b. Dermis c. Subcutaneous tissue 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

II.

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 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

IV.

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 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 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 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 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

VI.

VII.

VIII.

IX.

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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 weeks B. Chronic urticaria: beyond 6 weeks I. A. B. C. D. E. Pathogenesis mast cell: major effector cells in urticaria and angioedema cutaneous mast cells adhere to fibronectin, laminin and vitronectin Substance P, VIP and somatostatin activate mast cells Vascular permeability produced by H1 receptors 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 Pressure urticaria: often painful 0.5 to 6 hrs after sustained pressure 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 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 Contact urticaria a. b. c. d. e. f.

E. F.

G.

H.

IgE-mediated or non-immunologic Passive transfer Proteins from latex products Proteins may retained be in glove powder Cross-reactivity to bananas, avocado and kiwi Rhinitis, conjunctivitis, dyspnea, shock

I.

Papular urticaria a. symmetric, hypersensitivity reaction to insect bites b. mainly in children c. extensors, exposed areas Idiopathic Urticaria/Angioedema : 70% a. H. pylori possibly implicated

J.

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

L.

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 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

III.

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 ________________________________________________________________________

IV.

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) st 1 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)

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.

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

Internal organ involvement Duration Complications Mortality rate Healing

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 10-30% BSA >30% BSA

SJS SJS-TEN overlap 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 st Burning sensation on mucosa 1 , 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