Author: Logan Kolb, DO

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Table of Contents

Episode 1 - Intro/Anatomy of , Hair, & Episode 16 - Basal Cell Carcinoma - Pages 30- Nails - Pages 3-6 31

Episode 2 - The Exam - Page 7 Episode 17 - / - Pages 32-33 Episode 3 - Intro to Reaction Patterns/Dr. Gropper Interview - Page 8 Episode 18 & 19 - - Pages 34-36

Episode 4 & 5 - - Pages 9-11 Episode 20 - Diaper - Page 37

Episode 6 - Seborrheic Dermatitis - Page 12 Episode 21 - Multiforme - Page 39

Episode 7 - - Pages 13-14 Episode 22 - SJS/TEN - Pages 40-41

Episode 8 - /Pityriasis Rubra Episode 23 - Viral - Pages 42-43 Pilaris - Pages 15-16 Episode 24 - Toxin-Mediated - Pages Episode 9 - Pityriasiform Disorders - Pages 17- 44-45 18 Episode 26 - Figurate (Gyrate) - Episode 10 - Lichenoid Disorders - Pages 19- Pages 46-47 20 Episode 27 - Urticaria - Pages 48-49 Episode 11 - Annular Disorders - Pages 21-23 Episode 28 - I - Pages 50-52 Episode 12 - - Page 24 Episode 29 - Vasculitis II - Pages 53-55 Episode 13 - - Pages 25-26 Episode 30 - Vasculopathy - Page 56 Episode 14 - /Asteatotic Eczema - Pages 27-28 Episode 31 - Retiform Purpura - Page 57

Episode 15 - - Page 29 Episode 32 - Purpuric Case - Pages 58-61

Episode 33 - Vascular Growths - Pages 62-66

2 - Stratum spinosum 1 – Intro/Anatomy of o Superficial to stratum basale, named for spiny- appearing desmosomes between cells o Keratins 1 and 10 are expressed in this layer and are skin, hair and nails mutated in epidermolytic hyperkeratosis (aka bullous congenital ichthyosiform erythroderma) Vital Functions - Stratum basale o Located just above the basement membrane, is - Sensation, barrier, immune surveillance, UV protection, composed of 10% stem cells thermoregulation o Keratins 5 and 14 are expressed in the basal layer Fun facts and are mutated in patients with epidermolysis bullosa simplex (EBS) - The skin is the largest human organ, 15% of a person’s body weight Major CELL TYPES of the - Skin cancer = most common cancer worldwide; affects 1 in 5 1. Keratinocytes (KC) (“squamous cells”, “epidermal cells”) people o Make up most of epidermis, produce keratin - Our skin is constantly being renewed, with the epidermis 2. Melanocytes (MC) turning over q40-56 days, results in average person shedding o Neural-crest derived 9 lbs of skin yearly o Normally present in ratio of 1 MC : 10 KC’s Skin thickness varies based on…. o Synthesize and secrete pigment granules called melanosomes

- Location: epidermis is thickest on palms/soles at ~ 1.5mm o *** Different races and skin types actually have the (thickness of a penny), thinnest on /postauricular at ~ same amount of melanoCYTES but differ in the 0.05mm (paper) number, size, type, and distribution of

- Age: Skin is relatively thin in children, thickens up until our melanoSOMES, with fairer skin types having more 30’s or 40’s, and then thins out thereafter. lighter-colored pheomelanin and darker skin types

- Sex: Male skin is generally thicker than female skin in all having more of the dark eumelanin. locations 3. Langerhans Cells Overall Anatomy o Consist of 3-5% of the cells in the stratum spinosum, are derived from bone marrow, function as antigen- - Epidermis presenting cells - Dermoepidermal junction (DEJ) o Stain with S-100, CD1a, vimentin, Langerin, peanut - Subcutaneous tissue agglutinin o Contain Birbeck granules, which appear on electron The Epidermis microscopy as tennis racket-shaped organelles Layers o Ultraviolet radiation decreases the number of Langerhans cells, which may explain the mechanism - Stratum corneum (most superficial) of PUVA/narrow-band UVB in decreasing o Serves as a barrier, helping to keep the good stuff in inflammation in psoriasis (such as water) and the bad stuff out such as 4. Merkel Cells bacteria and allergens. o Located just above the basal cell layer of the o Structure is analogous to bricks and mortar epidermis and in the bulge region of hair follicles (corneocytes=bricks which are embedded in the o Believed to function as slow-adapting touch mortar of lipids such as ceramides) receptors o Not present on mucosal sites o Give rise to Merkel cell carcinomas, which are rare, - Stratum lucidum aggressive skin cancers on the head and of o Only present on the palms/soles, appears clear on elderly Caucasian patients H&E - Stratum granulosum The DERMOEPIDERMAL JUNCTION (DEJ) – to be discussed in the o Produces the cornified cell envelope (composed of vesiculobullous podcasts lipids and proteins; helps skin function as a

mechanical and water barrier) o Not present on mucosal sites

3 The where aromatase converts androstenedione to estrone (possible link between obesity and breast cancer) Papillary dermis (superficial) THE ADNEXA (skin appendages) - Appears wavy in 2D on biopsy specimens, as papillary dermis interdigitates with downward projections of epidermis (“rete Eccrine Glands ridges”) - Release sweat to help regulate body temperature by cooling - Contains the sub-papillary plexus, which contains arterioles, the skin when the sweat evaporates. capillaries, venules, lymphatics, and nerves - Located nearly everywhere on the skin except for the lips, - Contains Meissner corpuscles which sense touch and the external auditory canal, the glans penis, and the labia pressure. minora and clitoris. Reticular dermis (deeper) - The total mass of eccrine glands in our body is about the same as one kidney and can make up to 1.8 liters of sweat in - Has its own plexus but contains larger blood vessels. an hour! - Clinical correlation: Clark’s levels for staging - NOT associated with the hair follicle o Level 1 = in situ in the epidermis - Have muscarinic acetylcholine receptors which bind o Level 2 = tumor reaches papillary dermis acetylcholine released from sympathetic nerves, which o Level 3 = tumor fills papillary dermis explains why we sweat when we’re nervous o Level 4 = tumor reaches reticular dermis o Nervous situation → sympathetic nerves are o Level 5 = Tumor invades subcutaneous tissue activated → release acetylcholine → binds Breslow’s depth: measures tumor depth in mm’s from the receptors on our eccrine sweat glands → sweat is granular layer or base of an ulcerated melanoma to the bottom of released → you’re a hot mess the tumor o Explains why botulinum toxin injections, which block acetylcholine release, are effective for hyperhidrosis Dermal Cell Types patients.

- Fibroblasts - produce collagen, elastin, and ground Apocrine Glands substance. o Collagen - 70% of the dry weight of skin, important - Locations (“4 A’s”) - the , areola of the nipple, the in wound healing (Type III fetal collagen → stronger anogenital region, and the auditory canal where they type I collagen) contribute to cerumen (earwax) formation ▪ COLLAGEN 1 AND 3 SYNTHESIS IS o Also make up the Moll’s glands of the (not to DOWNREGULATED BY CORTICOSTEROIDS be confused with Meibomian glands, which are of (→ ATROPHY) AND UV LIGHT sebaceous origin) (→PHOTOAGING). UPREGULATED BY - Secrete odorless variety of proteins, carbohydrates, RETINOIC ACID. ammonia, lipids, and iron → digested by bacteria that create o Elastic fibers – help skin elasticity odorous byproducts → body odor ▪ Decrease in number with aging and are also - Apocrine glands begin to function at puberty and are mainly defective in Marfan’s syndrome due to stimulated by sympathetic adrenergic stimuli. fibrillin-1 mutations. Sebaceous Glands o Ground substance – glycosaminoglycans (GAGs) and mucopolysaccharides - Associated with hair follicles (unlike eccrine glands) ▪ E.g. hyaluronic acid → maintains water - Located everywhere except the palms and soles (which are within the dermis and is often used in hairless) many cosmetic fillers - Secrete sebum (composed mostly of triglycerides, wax - Adnexa – hair follicles, sebaceous and apocrine glands, esters, squalene, and free fatty acids) eccrine glands - Under hormonal influence rather than neurologic influence - Other cells/tissues: blood vessels, lymphatics, and nerves as is seen with eccrine and apocrine glands

THE SUBCUTANEOUS TISSUE (“Sub-Q”) Hair follicles

- is composed of lipocytes and fibrous septa containing - Fun facts collagen and larger blood vessels and nerves. o Humans contain 5 million hairs on average - Functions as an energy store, an insulator that protects o On average, people have 100,000 hairs on the scalp underlying muscles and bones, and as an endocrine organ and lose 100 scalp hairs daily.

4 ▪ Blondes have thicker hair (~120k), red o = early cessation of anagen phase heads have ~80k so that >20% of hairs are in telogen phase. ▪ Hair on the scalp grows roughly 1 - Occurs approximately 3-5 months after a cm/month trigger such as an emotionally stressful o Hair color depends on melanocytes in the hair bulb event, severe illness, or pregnancy transferring melanosomes, which are pigment (prolonged anagen phase until delivery). granules, to the keratinocytes in the bulb matrix. Nails o Darker hair has mostly eumelanin, whereas blonde or red hair has more pheomelanin. - *Add diagram of hair anatomy?

Hair anatomy

- 3 zones: infundibulum, isthmus, and inferior segment - Infundibulum: from surface down to sebaceous gland insertion o Apocrine gland insertion is Above sebaceous gland insertion o Location of inflammation in lichen planopilaris - Isthmus: from sebaceous insertion down to the Hair bulge (location of arrector pili insertion) o Location of inflammation in discoid (Discoid = Deeper) - Inferior segment – everything inferior to hair bulge - Hair bulb o Located in deep dermis or superficial sub-Q for anagen hairs ▪ Want to undermine beneath this plane in , otherwise risk permanent hair loss - Helpful in dermatology because specific changes are (e.g. beard, scalp) caused by a variety of conditions including psoriasis, alopecia - Layers of hair from outside to in… areata, renal disease, and liver disease, amongst others o Glassy membrane (outermost)

o Outer root sheath - Fingernails grow 2-3 mm per month on average and take 4-6 o Inner root sheath – itself has 3 layers… months to regrow its entire length. 1. Henle’s layer (outermost) - Toenails grow approximately 1 mm per month and take 12 to 2. Huxley’s layer (“Henle hugs Huxley”) 18 months to regrow. 3. Cuticle (innermost) - Nail plate – hard part of the nail o Hair shaft – also with 3 layers - Lateral nail fold – the skin abutting the lateral sides of the - Cuticle (outermost) – gives hair its shine nail plate after using conditioner - Proxima nail fold – skin proximal to cuticle - Cortex - Cuticle (eponychium) - cornified epithelium overlying the - Medulla lunula Hair growth - Lunula - white crescent-shaped region under the proximal nail plate - Anagen phase (active growth) - that represents the distal nail matrix. o Normally 85-90% of scalp hairs are in anagen phase; - Nail matrix - underneath the cuticle and proximal nail fold. lasts 2-6 years on average. o The proximal matrix forms the top or dorsal nail o Fractured by chemotherapy in anagen effluvium plate, while the distal matrix forms the bottom or - Catagen phase (involution phase) ventral nail plate. o < 1% of scalp hairs are in catagen phase at any given o Contains melanocytes, therefore can time due to its short length of approximately 2 form in this location. weeks. - Nail bed - underneath the nail plate, is distal to the lunula, - Telogen phase (resting phase) and does not contain melanocytes. o Lasts 3-5 months and thus 10-15% of hairs are in telogen phase in a normal patient.

5 Basic Histology Terminology

- Acanthosis - hyperplasia or thickening of the epidermis and is seen in hyperproliferative conditions such as psoriasis.

- Spongiosis - swelling and of the epidermis. o Spiny desmosomes between cells are visible.

- Parakeratosis - represents thickened stratum corneum with nuclei present - Hyperkeratosis - thickened stratum corneum without nuclei present.

- Hypergranulosis - thickening of the granular layer and may be seen in .

- Papillomatosis refers to multiple finger-like warty projections of the epidermis Atrophy thinning of a layer of skin, such as epidermal atrophy seen in lichen sclerosis.

6 o Location (area of body, flexors/extensors, sun- 2 – The Dermatology exposed, symmetrical, lateralized, dermatomal) o Erythema (pink, red, red-brown, violaceous, near black) Exam o Surface (smooth, rough, warty, crusted, scaly) o Type of lesion (patch, , etc) Important to form good habits for thorough dermatologic H&P o Color – also includes hypopigmented or depigmented Primary lesions o Arrangement – how lesions are arranged in relation - Flat lesions to one another (e.g. grouped, generalized, o Macule (<1cm) – e.g. freckles unilateral, linear) o Patch (>1cm) – e.g. o Border/shape (well circumscribed vs poorly defined, - Raised lesions circular, oval, polycyclic) o Papule (<1cm) – e.g. acne papule o Special sites (mouth, genitalia, nails, hair) o Plaque (flat and >1cm) – e.g. psoriasis Get a good history o Nodule (rounded and >1cm) – e.g. epidermal inclusion cyst - HPI of rash/lesion (OPQRST’s) - Fluid-filled o Onset o Vesicle (<1cm) – e.g. herpes zoster o Previous episodes o Bullae (>1cm) – e.g. o Progression of disease since onset o Nikolsky sign – lateral pressure on unblistered skin o Palliating factors (what makes it better) causes shearing of epidermis o Provoking factors (what makes it worse) o Asboe-Hansen sign – vertical pressure on bullae o Quality of symptoms (itching, burning) causes lateral spread; seen with deep bullae o Radiation of symptoms - Purulent lesions o Severity of symptoms (“how itchy are you on scale o Pustules of 1-10”) o Furuncles (“”) o Treatments tried o Carbuncle – coalescing furuncles - PMH - Wheal () – fleshy plaques 2/2 dermal edema o Atopic triad (atopic dermatitis, asthma, seasonal allergies) Secondary lesions (when primary lesion is traumatized) o Diabetes – predisposed to infection o Excoriations – linear scratch or punctate lesions - PSH o Fissure – crack that reaches dermis - Allergies o Erosion – part of epidermis lost (e.g. ruptured - Medications vesicle) o Rx, OTC, herbals/supplements, when meds were o Ulcers – excavations that reach dermis started, recent dosing changes, changes between o Crusts – dry blood, pus, or serum (“scab”) generics/brand names o Bleeding time affected by: 5 G’s (garlic, ginsing, Vascular lesions ginger, green tea, gingko), fish oil, vitamin E, saw o Telangiectasias – small, discrete bv’s, with palmetto, St. John’s wort pressure - FH o Petechiae – nonblanching red-brown macules - SH <5mm o Occupation, hobbies, pets, recent travel (hiking), o Purpura – nonblanching, >5mm - Physical - If palpable, think about inflammation of o Pick a routine for your FBSE and do it the same each lesions time o Ecchymosis (i.e. bruise) o Head to Toe (scalp, ears, , hands, arms, neck, chest, abdomen, back, top of legs, feet, have pt Other terms stand up to examine buttocks, groin, and back of legs) o Scale – pathology in epidermis o Don’t forget to look in mouth o Reticulate = lacy pattern o Palpate areas where AK’s are common (explain to o Lichenification – accentuated skin lines patient why you do this) Describing rashes (LES T CABS) – adopted from Derm Notes: o Always get permission to examine sensitive areas Dermatology Clinical Pocket Guide by Anatoli Freiman and (breasts, groin) Benjamin Barankin) o Nails/nailfolds if worried for CTDZ

7 5. Vesiculobullous 3 – Intro to Reaction a. Superficial i. Subcorneal pustular dermatosis b. Intraepidermal Patterns i. vulgaris ii. Pemphigus vegetans - Please refer to Dr. Gropper’s paper for further details…. iii. Pemphigus erythematosus o Gropper, C.A., 2001. An approach to clinical iv. H-H dermatologic diagnosis based on morphologic c. Subepidermal reaction patterns. Clinical cornerstone, 4(1), pp.1- i. BP 14. ii. Herpes gestationis 5 Reaction patterns iii. DH 1. Papulosquamous iv. EBA a. Psoriasiform – psoriasis, seborrheic dermatitis, v. Darier’s DZ parapsoriasis, mycosis fungoides vi. Grover’s DZ b. Pityriasiform – , , secondary c. Lichenoid – lichen planus, lichenoid drug eruptions d. Annular – SCLE, EAC, tinea e. Erythroderma – papulosquamous causes (psoriasis, PRP), dermatitis (atopic, ACD, seborrheic, chronic actinic dermatitis), drug reactions, CTCL (Sezary, erythrodermic MF), infections (viral , Norwegian , SSSS), autoimmune (e.g. BP), physical (e.g. burns) 2. Eczematous a. Acute – e.g. contact dermatitis b. Subacute – e.g. stasis dermatitis c. Chronic – e.g. atopic dermatitis 3. Vascular a. b. Toxic erythema – viral exanthems, drug eruptions (SJS/TEN) c. Scarlatiniform – scarlet fever, SSSS, TSS, Kawasaki DZ d. Figurate erythema – EAC, , , e. Urticaria (hives) f. Vasculitis g. Vasculopathy h. Retiform purpura i. Vascular growths 4. Dermal disorders a. Type of inflammatory cells i. Histiocytic – sarcoid, GA, NL, , TB ii. Lymphocytic – leukemia, lymphoma, lupus, PMLE iii. Neutrophilic – Sweet’s, pyoderma gangrenosum, EED iv. Eosinophilic – Well’s syndrome, eosinophilic pustular follicultiis v. Mast cell – urticaria pigmentosa b. Depositional – amyloidosis, calcium, urate, mucin (e.g. myxedema), lipids (e.g. ) 8 o Onycholysis, irregular pitting, oil spots, splinter 4/5 – Psoriasis hemorrhages, subungual hyperkeratosis - Psoriatic arthritis (PsA) Epidemiology/Pathogenesis o More likely if nails and scalp affected; often with am stiffness >30-45 minutes rd th - Bimodal onset (3 and 6 decade; 75% start <40 yo) but may o 5 types present at any age • Oligoarthritis with swelling and - Caused by environmental triggers in genetically predisposed tenosynovitis of hands - 60-70% of cases. pt’s • Asymmetric DIP with nail damage o Triggers SICK LAB • Rheumatoid arthritis-like - Stress/Smoking • Arthritis mutilans - rarest and most severe. - Infection (Group A Step, URI) • Ankylosing spondylitis, which is associated - hypoCalcemia with HLA-B27. - Koebnerization – 25% of pt’s, takes 2-6 o Pearls vs other forms of arthritis on hands weeks • Psoriasis – affects PIP’s, DIP’s, usually - Lithium spares MCP’s - Antimalarials/ACEI/alcohol • RA – affects MCP’s, PIP’s, spares DIP’s - Beta blockers • OA – can affect any joint - Others - Enthesitis – inflammation at tendon insertion sites • CCB’s, NSAIDS, TNF-alpha o Occurs in 20% of patients, classically affects achilles inhibitors - Dactylitis – swelling of finger(s) (“sausage digit”), seen in 15- o Genetic predisposition 30% of patients - PSORS1 - HLA-Cw6 - a/w 90% of early onset, 50% History/ROS late onset cases - HLA-B27 – associated with sacroiliitis-assoc - Get HPI of lesions using OPQRST’s Pso, PsA, pustular Pso - Assess for triggers (SICK LAB) - Remember what HLA types encode…. o Look over patient’s medications!

• HLA A,B,C encode MHC class 1 on - Do you have joint pain? If yes, do you have morning stiffness Nu cells and for how long? - Do you have tendon pain, such as your achilles or elbow? • HLA-DR,DP,DQ encode MHC class - How has your mood been? (depression screen) 2 on APC’s - Discuss diet/exercise - 1 parent affected = 15% risk; both parents - Perform FBSE, look in scalp for unidentified psoriasis = 40% risk - Assess oral mucosa if diagnosis unclear (e.g. Wickham’s Clinical presentation striae of LP) - Assess nails for psoriatic nail changes - Classically presents with erythematous plaques with silvery - Assess finger joints for obvious deformity, point tenderness, scale on extensor elbows/knees, limitations in flexion/extension trunk/scalp/umbilicus/sacrum - Evaluate genitalia if concern for involvement - Variants - Take note of BSA o Guttate psoriasis – raindrop-shaped o Patient’s palm (including fingers) = 1% BSA /plaques in younger patients 2-3 weeks after o Rule of 9’s for burns Strep infxn or URI o Palmoplantar – chronic, thick, painful plaques and Histology: fissures on p/s - Confluent parakeratosis o Inverse – intertriginous areas - Munro’s microabscesses – collections of neutrophils in o Erythrodermic – affects >80-90% BSA stratum corneum, aka “neuts in the horn” o Pustular - Decreased or absent granular layer - herpetiformis (occurs in - Regular acanthosis with thinning over dermal papilla, which pregnancy) contain dilated capillaries - Von Zumbusch (generalized, rapid onset, associated with systemic steroid Immunology overview withdrawal) - Nail psoriasis - APC’s present antigens to naïve T cells in lymph nodes, which o Seen in 10-80% of patients; a/w PsA (psoriatic differentiate into Th1 cells for cell-mediated immunity (CMI) arthritis) or Th2 cells for humoral immunity

9 - Th1 cells: stimulated by IL-12 and promote CD8 T cells to • Liver biopsy at 1.5 – 4g produce IFN-gamma, IL-2, IL-6, IL-8, IL-12 - Cyclosporine (CsA) o IFN-gamma – activates macrophages to secrete o MOA: complexes with cyclophilin to inhibit TNF-α, IL-23, and other inflammatory cytokines calcineurin and reduce IL-2 production o IL-2 – generates CTL’s and NK cells o Dose: usually started 2.5 mg/kg/day (divided in BID o IL-6 – activates acute phase proteins dosing) o IL-8 – recruits neutrophils o Contra: impaired renal function, uncontrolled HTN, - Th17 cells: stimulated by IL-12 and IL-23 and themselves malignancy, serious infections release IL-17, IL-22, and TNF-α o SE: nephrotoxicity, HTN, GI issues, headache, o Ustekinumab (Stelara) blocks p40 subunit common vertigo, hypertrichosis, gingival hyperplasia, lab to IL-12 and IL-23 changes (BULK up; low Mg) o IL-17 and IL-22 are proinflammatory and increase KC • “BULK up” – hyperBilirubinemia, proliferation hyperUricemia (→ gout), hyperLipidemia, o TNF-α - proinflammatory hyperkalemia - Th2 cells: stimulated by IL-4 and produce IL-10 (anti- o Screen: CBC, CMP, hep panel, pregnancy test, quant inflammatory cytokine which inhibits Th1 cells) gold, Mg, uric acid, fasting lipids, urinalysis, blood pressure Treatment o Monitor: CBC, CMP, lipids, UA, Mg, BP monthly x2 Topicals mo then q3mo o If Cr increases 30% over baseline, decrease dose - Topical corticosteroids (TCS) – decrease pro-inflammatory - Acitretin (Soriatane) cytokines like TNF-α and increase IL-10 o Especially useful for pustular, palmoplantar, o Different strengths and formulations (ex. cream, erythrodermic Pso ointment, foams) depending on severity/location o Dose: 25-50mg/d • SE: atrophy, telangiectasias, striae o Contra: pregnant patients, childbearing age not on (permanent) contraception, severe liver or kidney DZ, excess - Calcipotriene – vitamin D analog, decreased KC proliferation ETOH use and blocks IL-2, IL-6, IFN-gamma o SE: dry eyes, decreased night vision, dry lips, - Others: tazarotene, topical calcineurin inhibitors (TCI’s) elevated LFT’s, teratogenicity o Screen: CBC, CMP, lipid panel, pregnancy test

• Monitor: same labs at 1 month then q3 UV treatment month - Apremilast (Otezla) - nb-UVB (“narrow band”, 311-313 nm) o MOA: inhibits phosphodiesterase type 4 (PDE4), o Typically 2-3 tx’s/week, >20 treatments usually leading to increase in cAMP levels which inhibit needed TNF-α, IL-17, and IL-23 - bb-UVB (“broad band”) o No lab monitoring required, however may want to - PUVA (psoralen + UVA) screen for renal disease if suspected (due to renal - Excimer laser (308 nm) – great for scalp dosing) Oral agents – MTX, CsA, Acitretin, apremilast o SE: N/D/weight loss, association with depression

- Methotrexate PASI (psoriasis area and severity index) o MOA: inhibits dihydrofolate reductase (DHFR) → - Score 0-72 based on BSA and 0-4 score for lesion erythema, inhibits purine synthesis in S phase; since T cells induration, and /scale have no purine salvage pathway, they cannot - PASI-75 = 75% reduction in PASI score (e.g. 40 → 10) synthesize DNA/survive o Can calculate easily using Grappa app o Dosed 2.5 – 25mg po once weekly; may divide in 2-3 doses q12 hours o Give folic acid 1mg daily on days not taking MTX o Contra: pregnancy, active infections, liver disease, renal disease, cytopenias o SE: GI issues (N/V/D), infections, bone marrow suppression, rarely interstitial pneumonitis o Screen: CBC, CMP, hep panel, pregnancy test, HIV

(if RF’s) o Monitor: CBC week 2 and 4, LFT’s mo 1 and 2, CBC/CMP q3 mo 10 Biologics IL-17 inhibitors

- Screen patients for hepatitis, TB, malignancy, +/- HIV - Work quickly - Additional screening: IBD, depression (brodalumab) TNF-alpha inhibitors o No increased risk for CHF, neurologic disorders (MS), lymphoma - Ixekizumab (Taltz) – inhibits IL-17a o Dose: 160mg SQ week 0, then 80mg q2 weeks until week 12, then q4 weeks thereafter - Secukinumab (Cosentyx) – inhibits IL-17a o Dose: 300mg SQ weekly x5 weeks then 300mg monthly - Brodalumab (Siliq) – inhibits IL-17 receptor o Dose: 210mg week 0, 1, 2, then q2 weeks thereafter

Biologics affecting IL-23

- Ustekinumab (Stelara) o MOA: blocks p40 subunit common to IL-12 and IL- 23 o Weight based dosing: <100kg patients receive 45mg dose while >100kg patients receive 90mg doses o Dose: SQ injection day 0, month 1, then q-3 mo - Guselkumab (Tremfya) o MOA: blocks p19 subunit on IL-23 only o Dose: 100mg SQ week 0, 4, then q8 weeks - Tildrakizumab (Ilumya) o MOA: blocks p19 subunit on IL-23 only - Additional screening: CHF, demyelinating disease (multiple o Dose: 100mg SQ week 0, 4, then q12 weeks sclerosis, Guillain-Barre syndrome) - Risankizumab (Skyrizi) - Etanercept (Enbrel) o MOA: blocks p19 subunit on IL-23 only o MOA: fully human fusion of TNF receptor linked to o Dose: 150mg SQ week 0, 4, then q12 weeks Fc portion of IgG, binds soluble and membrane- bound TNF o Dose 50mg SQ twice weekly x3 months then weekly thereafter

o Approved for chronic-severe Pso patients age 4+ - Infliximab (Remicade) o MOA: chimeric mouse-human IgG that binds TNF only o Dose: 5 mg/kg IV week 0, 2, 6, then q8 weeks - Adalimumab (Humira) o MOA: fully human monoclonal IgG Ab against transmembrane TNF receptor o Dose: 80mg SQ week 0, 40mg week 1, then 40mg q2 weeks • Note: different from dosing for hidradenitis suppurativa (160mg SQ day 1, 80mg day 15, then 40mg weekly starting day 29) - Certolizumab pegol (Cimzia) o Dose: 400mg week 0, 2, 4, then q4 weeks o Minimal to no placental transfer of drug

11 - Face (Infant) 6-Seborrheic Dermatitis o Atopic Dermatitis: onset later at 1-16 weeks vs seb derm at 1 week. Location on face & flexor surfaces. Epidemiology: Look for family hx of atopic triad (atopic derm, allergic rhinitis, asthma). More pruritic and - All ages, typically post-puberty ages 30-50 y/o inflammatory - On average, 1 in 20 of people affected. o Psoriasis: uncommon and more adherent scales o : look for broken hairs and posterior Background: lymphadenopathy - Lipophilic commensal yeast, malassezia furfur (Pityrosporum Diagnosis: ovale) - Those affected have higher levels of triglycerides and - KOH Prep (“spaghetti & meatballs”; hyphae & spores) cholesterol and low levels of squalene and FAs in their - Biopsy – if diagnosis unclear sebum - HIV testing – if severe/refractory to treatment o Lower levels of P.acnes (converts triglycerides to Free FAs which are antimicrobial to malassezia Histology: species) - Regular acanthosis (regular rete ridge depth + thickened

- Triggers: Stress, Immunosuppression, Sun Exposure, Heat, epidermis), spongiosis, shoulder parakeratosis Fever Treatment: PEARL: If you see severe seborrheic dermatitis in a pt what are some associated disorders? Neurologic dz (e.g. Parkinson’s or - Scalp: Topical anti-inflammatory + Topical antifungals Epilepsy) & HIV/AIDs o Selenium Sulfide (Selsun Blue), Ketoconazole shampoo, ciclopirox, salicylic acid, or tar shampoo Clinical Presentation: • 2-3 x weekly- 5 to 30 minutes - Symmetric erythematous patches with overlying greasy- - Face: Topical Antifungals yellow scale affecting the seborrheic areas (scalp, face, o Ketoconazole vs ciclopirox + 2.5 % hydrocortisone chest, & intertriginous). Itching and burning may be present. - Infants: Conservative approach w/ no tear shampoo → o Adults: M>F, onset in 30s-50s Selenium Sulfide o Infants (“cradle cap”): one week after birth. Classic - Patient Education: erythematous, itchy patches with greasy yellow o Chronic nature of seb derm: control not necessarily scale that resolve by 4 months involving face, post- cure auricular, sternum, & intertriginous areas o Maintenance therapy once flare controlled - Spectrum of dz • Selenium sulfide vs ketoconazole on o Mild: dandruff on the scalp w/out erythema weekend o Moderate: typical clinical picture above with • Calcineurin inhibitor (tacrolimus & thickening plaques (sebopsoriasis) pimecrolimus) o Severe: erythroderma covering 90% of BSA Differential - Scalp (Adult)

o Psoriasis: more circumscribed thick silvery plaques that are less itchy. Additional lesions elsewhere on body! LOOK for NAIL changes! + FH of Pso, + Pso triggers (SICK LAB) o Tinea Capitis: younger population (3-7 y/o). broken hairs to go along with erythema as well as posterior lymphadenopathy o Chronic Contact Dermatitis: >itchy. New hygiene products? Shampoo. - Face (Adult) o o Actinic Keratosis: scale are less yellow/greasy o Lupus: malar rash spares nasolabial folds vs seb derm involving this location o Dermatomyositis: heliotrope rash is more violaceous o : more annular asymmetrically distributed on check

12 (e.g. upper thighs and buttocks) in a 7-Mycosis Fungoides “bathing suit” distribution • Plaque: well-demarcated indurated scaly Epidemiology: plaques that take on a variety of shapes with a violaceous to red-brown color - Most common ~ 50-60 y/o, but may be younger/older • Tumor: rapidly enlarging nodules that - Incidence = 1 in 300,000 develop within patches or within plaques of MF Background: PEARL: What should you think about when you see psoriasis in a - Although lymphoma usually originate in the lymph nodes sun-exposed area? Think Mycosis Fungoides! they can also arise from the skin → primary cutaneous lymphoma (PCL) Diagnosis: - 1) Hodgkin’s vs 2) non-Hodgkin’s o Most common PCL being non-Hodgkin’s cutaneous - Skin biopsy: lymphoma o Will need multiple biopsies to reach definitive • 80% T-cell origin = CTCL diagnosis • 20% B-cell origin = CBCL o If clinical suspicion is high, don’t be afraid to repeat • Note: primary cutaneous Hodgkin’s the biopsy lymphoma is very rare o Broad shave biopsy instead of punch = give o CTCL (Cutaneous T-Cell Lymphoma) pathologist more epidermis to catch • 1) 65% Mycosis fungoides, including epidermotropism variant Sezary Syndrome - Patch & Plaque MF w/out palpable lymphadenopathy does • Other variants: Folliculotropic, NOT need further staging work-up e.g. CT scan, lymph node pagetoid reticulosis, biopsy

granulomatous slack skin - Immunohistochemical Staining: o CD3+, CD4+, CD8-, CD30- • 2) 25% CD30+ Lymphoproliferative • disorders Exception for hypopigmented variant of MF favoring children and darkly pigmented • Lymphomatoid papulosis (LyP) pt: CD4-, CD8+ • Cutaneous anaplastic large cell o Loss of CD7 (most common, least specific) lymphoma (cALCL) o Loss of CD5 & CD2 (less common, more specific) • 3) 10% • Note: CD7, CD5, and CD2 are T cell • 1) Adult T-cell markers leukemia/lymphoma o Ratio of CD4:CD8 increases as MF progresses • 2) Subcutaneous panniculitis-like • Normally 1:1 in other inflammatory dz T-cell lymphoma • <4:1 = less progression = longer survival • 3) Extranodal NK/T-cell lymphoma • <10:1 worse prognosis (seen in Sezary nasal type Syndrome) • 4) Epidermotropic CD8+ CTCL • 5) Cutaneous Gamma-Delta t-cell lymphoma • 6) Cutaneous CD4+ small/medium Histology: t-cell lymphoproliferative disorder - Patch: band-like distribution of atypical lymphocytes @ DEJ • 7) Primary Cutaneous Acral CD8+ o Presence of Epidermotropism: atypical lymphocytes T-cell lymphoma seen in epidermis (where they shouldn’t be) • 8) Peripheral T-cell Lymphoma o Minimal spongiosis o Look for Pautrier’s microabscess, atypical lymphocytes with large hypochromatic nuclei that Clinical Presentation: appear in clusters o Papillary dermal fibrosis - Erythematous, occasionally pruritic, oval scaly patch in sun- - Plaque: similar histo findings to patch stage, but more dense protected “bathing suit” distribution. Classically slow band-like infiltrate in the upper dermis + more progression through 3 stages. Important to note that not all epidermotropism lesions progress in the following manner and can skip this - Tumor: increase in depth and density of atypical order! lymphocytes. Important to note epidermotropism may be o 3 Stages diminished or gone in this stage! • Patch → Plaque→ Tumor • Patch: round or oval patches 1-5 cm in width and may be annular or polycyclic.

Itchy and appear on sun-protected areas

13 Treatment:

- Patch & Plaque Stage MF o Skin Directed therapy • Clobetasol -60% remission • Nitrogen Mustard -60% remission • Narrow band UVB – 75% remission • Psoralen + PUVA • Radiation therapy o Systemic Therapy: (refractory cases) • Interferon-alpha • Oral retinoids (bexarotene… SE = central hypothyroidism) o Systemic Therapy (rapidly progressive or lymph node/visceral involvement) • Chemotherapy: “CHOP” • Cyclophosphamide • Hydroxydaunorubicin (Doxorubicin) • Oncovin (Vincristine) • Prednisone

14 8-Parapsoriasis 8-

Background: Epidemiology: acquired w/ bimodal onset in childhood/adolescence or in patients’ 50’s - Uncommon chronic idiopathic rash mimicking psoriasis

Epidemiology: Clinical Presentation: - Onset ~40 y/o. Males>female (M:F) 3:1 - May begin with scalp erythema with scale→ Red/brown Clinical Presentation: follicular papules with central keratotic plug having a - Small Plaque Parapsoriasis (SPP): “nutmeg grater” appearance affecting the neck, head, trunk, o Scaly patches < 5 cm extensor extremities, and dorsal fingers → Eventually o Wax and wane in course and then either resolve coalescing to scaly plaques w/ a salmon to red orange color spontaneously or w/ treatment after several years that are diffuse and symmetric with islands of sparing o “Bathing suit” distribution (patches of normal skin within affected areas) o NO association w/ cutaneous lymphoma - Look for keratoderma (“PRP sandals”: thick hyperkeratosis o Variant: digitate dermatosis: long finger-like of the skin of palms and soles patches along cleavage lines on the flanks - Thickened yellow brittle nails, NO PITTING (vs. pitting seen in psoriasis) - Large Plaque Parapsoriasis (LPP): PEARL: What are the 6 types of PRP? o Scaly patches > 5cm o “Bathing suit” distribution - Type 1) Classical Adult (55%): o May progress to MF! o Rapid onset of clinical findings w/ good clinical • 10-35% in 6-10 years prognosis. o Variant: retiform parapsoriasis. Wide-spread • 80% cases resolving over 3 years. erythematous scaly patches in a net-like - Type 2) Atypical Adult (5%) distribution. o Chronic course of ichthyotic leg lesions, • Almost all cases progress to MF keratoderma, alopecia - Type 3) Classical Juvenile (10%) Diagnosis: o Clinical picture of classical adult but presenting in < - Biopsy: interstitial infiltrate of CD4+ T-cells 2 y/o - Type 4) Localized/Circumscribed Juvenile (25%) Histology: o Symmetric keratotic follicular papules and erythematous plaques on extensor fingers, elbows, - Both SPP and LPP have parakeratosis, corresponds to the and knee scale seen clinically. o Most common type of PRP in children - Mild acanthosis and spongiosis. - Type 5) Atypical Juvenile (5%) - Mild lymphocytic infiltrate at the DEJ predominantly CD4+ o Chronic follicular hyperkeratosis and erythema + and may have T-cell clonality, especially LPP -like tightening of hands and feet Treatment: - Type 6) HIV associated PRP (1%) o Associated follicular spines, acne conglobata, - Topical corticosteroids & various phototherapies like narrow hidradenitis suppurativa band UVB Diagnosis: - Biopsy Histology:

- “Checkerboard” pattern: alternating orthokeratosis and parakeratosis w/ hyper and hypogranulosis o Looks like a “checkerboard” because you have orthokeratosis (without nuclei) sitting above purple hypergranulosis alternating with parakeratosis (has purple nuclei) sitting above hypogranulosis - Follicular plugging (also seen in lichen sclerosis & discoid lupus) - Shoulder parakeratosis (also seen in seb derm) - Irregular acanthosis

15 Treatment:

- Systemic Retinoids: acitretin or isotretinoin (1mg/kg per day) may clear PRP in 6 months - Methotrexate - TNF-alpha - Cyclosporine - Azathioprine - Phototherapy - Note: topical corticosteroids are typically not that helpful

16 9-Pityriasiform Disorders Secondary Syphilis Background:

Pityriasis Rosea - Gram-Negative Spirochete: Treponema pallidum

Background: - Congenital, Primary, Secondary, and tertiary forms

- Bug or Drugs: Viral associations prior to onset of rash (HHV 6 Clinical Presentation: & 7), bacterial infections (Strep), ACE-i, NSAIDs, beta - Rule of 3s: blockers, gold o ~3 weeks for 1⁰ to develop after Epidemiology: inoculation (painless, indurated w/ associated inguinal lymphadenopathy) - Ages 10-40 y/o • Range: 10-90 days o Chancre lasts ~3 weeks Clinical Presentation: o ~3 weeks (range 3-10 weeks) after 1⁰ chancre - Begins w/ herald patch → hours to weeks later = diffuse appearance, 2⁰ syphilis rash develops, lasting 3-12 eruption of smaller salmon colored oval and slightly scaly weeks = pityriasiform, papulosquamous rash macules, patches and plaques in a “Christmas tree” pattern o If untreated, latency period lasting months to years on the trunk and proximal extremities along lines of skin before tertiary syphilis appears w/ gummas, cleavage cardiovascular, and neurological changes o Look for a trailing scale (scale does not reach the PEARL: Secondary Syphilis vs PR: How to tell the difference? 1) leading edge of the erythematous lesion) and mild Lesions = Darker copper color compared salmon colored of PR 2) itching NO herald patch 3) Can affect palms & soles 4) Prodromal of o Herald patch: present in 70% of cases. fatigue, fever, and arthralgia as well as generalized - Atypical forms: lymphadenopathy, moth eaten alopecia, condyloma lata lesions o Papular Pityriasis rosea: African American children in the mouth and genitals and immunosuppressed. May involve face & scalp. o Inverse Pityriasis rosea: intertriginous areas Diagnosis: o Oral Pityriasis Rosea: aphthous-like ulcers - Screen with + RPR or VDRL → FTA-abs for confirmation PEARL: What other conditions have a trailing scale? Erythema o RPR & VDRL correlate w/ disease activity = helpful annulare centrifugum for assessing tx response. Repeat @ 6 & 12 months. - Biopsy Diagnosis: - Chlamydia, gonorrhea, & HIV testing co-testing

- Biopsy Histology:

Histology: Acanthosis w/ long thin “phallic” rete ridges, vacuolar interface - Thin mounds of parakeratosis, spongiosis, perivascular dermatitis, neutrophils in stratum corneum, plasma cells in lymphohistiocytic infiltrate and extravasated RBCs dermal infiltrate

PEARL: What other disorder shows mounds of parakeratosis? Treatment: (think “PEGS”) – Pityriasis rosea, Erythema annulare centrifugum, - Benzathine Penicillin IM x1 dose @ 2.4 million units Guttate psoriasis, Small plaque Parapsoriasis o If penicillin allergy → Doxycycline 100 mg BID 14 Treatment: days o Adverse effect: Jarisch-Herxheimer rxn-systemic - Self-limited condition & Supportive: Resolves on its own in inflammatory response occurring in first 24 hrs after 3-8 weeks penicillin tx. Presents w/ fever, headache, myalgias o If pruritic → Mild topical steroids, oral anti- due to body’s inflammatory rxn to dead histamines, UVB, oral erythromycin (250 mg x4 daily spirochetes for 2 week duration) o Patient Education: • Safe sex practice • Sexual partners should be assessed and treated as well

17 Tinea Versicolor Background: - Caused by Malassezia furfur & globosa Clinical Presentation: - Scattered, hypopigmented papules and patches on upper trunk and proximal extremities w/ scale - Occurs in sunny more humid climates when patients skin tends to be oilier

PEARL: Why are these lesions hypopigmented? Malassezia yeast digest oils on the skin into azelaic acid which inhibits melanocyte melanin production = no pigment. However, TV isn’t always hypopigmented – it often appears that way because sun exposure tans the surrounding skin! W/o sun exposure, TV will be tan to red macules patches and plaques w/ scale.

Diagnosis:

- KOH Prep: “Spaghetti & Meatballs” = Hyphae and spores

Treatment:

- OTC Selenium Sulfide (Selsun Blue) or zinc pyrithione used as body washes. Keep on skin for >5 minutes prior to rinsing. - Topical Antifungals: Terbinafine, ciclopirox, ketoconazole for 2 week course w/ ~80% cure rate - Oral therapy fluconazole x2 300 mg one week apart - Patient Education: o Recurrent nature of dz o Hypopigmented lesions can take months to repigment after tx o Maintenance therapy, especially during summer months using OTC body wash x1 every 2-4 weeks

18

10-Lichenoid Disorders o Appearance: Classic, Annular, Atrophic, Hypertrophic, Ulcerative, Linear, and Bullous, Lichen Planus Pemphigoids, Pigmentosus • Classic: 6 Ps! Background: • Acute: classic LP w/ rapid onset of diffuse - 1% population lesions that resolve more quickly over - Pt’s usually >20 y/o w/ peak onset in 40-70s course of 3-9 months vs >1 year for classic - Inflammatory disease that affects the skin, mucous LP membranes, hair and nails • Annular: ring-like and typically affect the - Unknown cause: pt may be predisposed to certain HLA penis or axilla subtypes + triggers (meds or virus) → alternate antigens on • Atrophic: depressed or hyperpigmented basal keratinocytes → targeted by T-Cells causing lesions on the legs inflammation and lesions • Ulcerative: affects the palmoplantar surfaces. Chronic ulcers are at > risk for SCC Clinical Presentation: transformation • Hypertrophic: thick scaly plaques on the - Remember the 6 Ps! shins and dorsal feet that are often o Pruritic, purple, polygonal, planar, papules, and symmetric really itchy and can be confused plaques with pickers nodules. SCC or KA develop in o Skin manifestations: anterior forearms and wrists, chronic LP. hands, shins, neck, sacrum, genitals, and generalized o Look for wickham striae (fine grey-white dots or a • Bullous: that arise within chronic LP net-like pattern overlying lesions) lesions o Look for koebnerization = new lesions in the area of • Pemphigoides: blisters arise mostly on trauma (e.g. pt scratching → new lesions in linear uninvolved skin; 2/2 IgG auto-antibodies arrangement) targeting BP antigen 2 of basement membrane (also targeted in bullous PEARL: Most common location to see wickham striae is the oral pemphigoid and herpes gestationis) mucosa. However, only 10% of patients w/ oral lichen planus go • Pigmentosus: grey brown macules w/out on to manifest the stereotypical skin findings. prior erythema on the sun exposed areas of the face and neck w/ darker Fitzpatrick

- LP Variants: Location vs. Appearance vs. Cause skin types 3, 4. o Location: Genital LP, Mucosal LP, Nail LP, Inverse • Typically older age of onset ~30-40 LP, Palmoplantar LP, Lichen Planopilaris y/o (vs ashy dermatosis teens-20s) • Genital: 50% women & 25% men with cutaneous LP o Cause: Actinic, Drug-induced • Mucosal: 50% pts with cutaneous LP. • Actinic: young middle-eastern adults and Reticular wickham striae w/ asymptomatic presents as red/brown plaques on the sun- lacy lines on the inside of the check. Can be exposed areas of the face, neck, and caused by dental fillings, amalgam extremities (mercury). • Drug-induced: 60 y/o w/ generalized • Nail: 10% of pts w/ cutaneous LP. Look for lesions, more eczematous, photo- lateral thinning, longitudinal ridges, distributed, NO wickham striae, spares the pitting, trachyonychia, dorsal pterygium mouth and genitals • Inverse: Intertriginous areas of axilla, • Delayed rxn up to 1 year! inguinal, and inframammary fold • Look for eosinophils on path • Palmoplantar: pain ulcerations on the sole • ACE-I, BB, NSAIDs, gold, HCTZ, • Lichen Planopilaris: erythema and antimalarials, TNF-alpha inhibitors perifollicular scale around the hair follicle on the scalp and can lead to scaring Diagnosis: alopecia. PEARL: LPP vs Discoid Lupus: LPP has more superficial - Biopsy inflammation at the infundibulum vs Discoid Lupus that is Histology: Deeper at the isthmus - Compact hyperkeratosis w/out parakeratosis PEARL: Clinical findings of Graham-Little-Piccardi-Lasseur - Hypergranulosis (opposite to psoriasis which typically has Syndrome? Scarring alopecia of the scalp caused by LPP, hypogranulosis) non-scarring hair loss at the pubic and axillary lesions, - Irregular acanthosis w/ sawtooth rete ridges follicular papules that appear as and classic - Dense lichenoid lymphocytic infiltrate leading to LP lesions of the skin and the mucosa development of civatte bodies (apoptotic keratinocytes) or 19 Max-Joseph spaces (separation between dermis and epidermis) - Eosinophils? Think drug-induced LP

PEARL: Think of classic LP as the strict parent that does not let parakeratosis or eosinophils around!

Treatment:

- Classic LP: topical corticosteroids - Oral or genital LP: topical calcineurin inhibitors (pimecrolimus or tacrolimus) - Hypertrophic lesions: intralesional Kenalog: - Generalized LP: Prednisone 20 mg multiple weeks w/ taper, Intramuscular kenolog, low dose methotrexate, metronidazole 500mg BID, phototherapy (UVB or PUVA) o Acitretin or cyclosporine as last resort

20 Histology:

11-Annular Disorders - Look for hyphae in the stratum corneum - Highlighted by PAS stains

Tinea Treatment:

Background: - : o - Fungi: Can be classified as molds, yeasts, dimorphic fungi Topical Antifungals (terbinafine, ketoconazole, o Molds: filamentous fungi that weave together and clotrimazole, econazole, ciclopirox, tolnaftate, form mycelium naftifine) o o Acquired via direct contact with animals, other Oral Antifungals for extensive lesions and hair infected humans, fomites follicle involvement (terbinafine, fluconazole) o Ex: aspergillus, tinea infections PEARL: Name superficial tinea infections that require oral - Yeast: round, unicellular organisms that reproduce by therapy? Tinea Capitis, Tinea faciei, Majocchi granuloma. Oral budding treatments needed due to the fact that topical tx cannot o Ex: Cryptococcus, Candida, Malassezia furfur penetrate to the hair follicle in the deep dermis! - Dimorphic: “molds in the cold” (outside the body @ 25⁰C) and “yeast in the beast” (in host tissue at 37⁰C) o Ex: Coccidiomycosis, Paracoccidiomycosis, , Blastomycosis Clinical Presentation

- Expanding erythematous annular patches or plaques that classically have an inflamed or scaly leading border - Small vesicles or pustules at the leading edge - Pruritic PEARL: Name tinea infections based on their location! - Scalp, eyebrows, eyelashes: Tinea Capitis o Trichophyton tonsurans (MC cause in U.S.) • Causes an endothrix, within the hair shaft o Microsporum canis (MC cause worldwide) • Causes an ectothrix, outside the hair shaft - Beard: Tinea Barbae - Face: Tinea Faciei - Torso: Tinea Corporis - Arms & Legs: Tinea Corporis - Groin: (*remember if scrotum affected think candida, not tinea*) - Feet: Tinea Pedis - Nails: Tinea unguium or - Hair Follicles outside scalp: Majocchi granuloma Diagnosis: - KOH Prep: o Branching hyphae and mycelium (Candida: yeast and pseudohyphae) - Biopsy

PEARL: What is the difference between hyphae and pseudohyphae? Hyphae are long branching filaments that are partitioned by septa w/out constrictions between the cells. Pseudohyphae are chains or budding cells that can look similar to hyphae but have constrictions between the cells that makes them look like sausage links!

21 Subacute Cutaneous Background:

- Chronic cutaneous lupus: discoid lupus, hypertrophic lupus, lupus panniculitis, tumid lupus, mucosal lupus - Acute cutaneous lupus: strong association w/ SLE presenting with malar rash and photosensitive eruptions - Subacute cutaneous lupus erythematosus (SCLE) → Rule of 50s o Rule of 50s: ~ ½ + ANA, ~ ½ meet criteria for SLE, ~ ½ photosensitive, ~ ½ + Direct immunofluorescent findings Clinical Presentation: - Papulosquamous SCLE: mimics psoriasis but has a photo distribution - Annular SCLE: polycyclic annular plaques occurring on the sun-exposed areas of the face, neck and upper back

Diagnosis:

- Biopsy - Anti-Ro (anti-SSA) & Anti-La (anti-SSB) o + in SCLE, Sjogren syndrome, neonatal Lupus - 50-80% + ANA - Leukopenia on CBC

PEARL: Drug induced SCLE (anti-Ro) vs Drug-induces SLE (anti- histone)

o Drug-induced Systemic LE (SLE): ↓ cutaneous changes, arthralgias, serositis, malar rash; + anti- histone Ab’s • “My HIPP” – Minocycline (+p-ANCA), Hydralazine, Isoniazid, Procainamide, Penicillamine o Drug Induced Subacute LE (SCLE): ↑ cutaneous changes w/ minimal systemic involvement; + anti- Ro (SS-A) • “THANG”: Terbinafine, HCTZ, ACE-I, NSAIDs, Griseofulvin Histology: - Vacuolar interface (degenerate changes at DEJ looking like bubbles) w/ prominent lymphocytic infiltrate, thickening of the basement membrane, mucin deposition, perivascular and peri-adnexal lymphoid aggregates Treatment: - Antimalarials: hydroxychloroquine - Sun Protection - Topical steroids - Stop/switch possible causative medications

22 Erythema annulare centrifugum

Background:

- Type of hypersensitivity due to long list of possible triggers o Infections: Tinea o Medications: penicillin, plaquenil, cimetidine, HCTZ, amitriptyline o Foods: blue cheese, tomatoes o Autoimmune: SLE, hashimotos thyroiditis, o Cancer: leukemia, lymphoma, breast, lung, GI, and prostate cancer

Clinical Presentation:

- Superficial EAC vs Deep EAC o Superficial: Single or multiple annular, erythematous scaling plaques that are slow growing and occasionally pruritic w/ trailing scale o Deep: Dermal process so no scale on lesions

PEARL: Other dz w/ trailing scale? Pityriasis rosea or resolving pustules/furuncles

Diagnosis:

- KOH: negative - Biopsy

Histology:

- Classic “coat-sleeve” infiltrate (densely packed lymphocytes around the blood vessels) w/ diagonal cut

Treatment:

o Address Triggers o Topical steroids, calcineurin inhibitors, UV treatments

23 Clinical Presentation:

12-Erythroderma - Very scaly rash! ↓ Background: - Skin vasodilation = peripheral resistance may lead to tachycardia, high output cardiac failure, and edema - Aka exfoliative dermatitis, pts who have erythema and - Extra blood flow in skin can disrupt thermoregulation scaling affecting > 80-90% BSA regardless of cause leading to hyper or hypothermia. CC: Chills! o At least 50% caused by pre-existing rashes that - ROS: worsen o Severe pruritis: atopic dermatitis or Sezary o Children: May also be 2/2 immunodeficiency (e.g. o Joint pain: psoriasis OMENN syndrome) o Fever: argues against psoriasis - Main Causes (7) o Papulosquamous: psoriasis, pityriasis rubra pilaris - Hints on Physical Exam (suggestive findings): • Psoriasis is the most common cause of o Rash affecting the face = argues against psoriasis erythroderma (~ 20% of cases) o Facial edema = drug rxn or DRESS • Caused by withdrawal of o Mucosal Inflammation = SJS/TEN steroids/cyclosporine/methotrexa o Waxy keratoderma = pityriasis rubra pilaris te vs triggers (“SICK LAB”→ o Nail changes (pitting, onycholysis, oil spotting) = Smoking/Stress, Infections, psoriasis Hypocalcemia, Koebnerization, o Violaceous rash = CTCL Lithium, Anti-malarial/ACE-I, o Salmon rash = pityriasis rubra pilaris BB…also alcohol, obesity, NSAIDs, o Blisters = bullous pemphigoid terbinafine, TNF-alpha inhibitors) o Follicular plugging w/ islands of sparing on dorsal o Dermatitis: atopic, allergic contact, seborrheic, fingers and knees = pityriasis rubra pilaris chronic actinic dermatitis, stasis derm o Larger areas of peeling = acute drug rxn (vs Fine • Atopic Derm: hx of ≥1 features of atopic scale = atopic dermatitis or generalized tinea) triad: atopic derm, hay fever, asthma. o Lymph nodes = malignancy (Sezary) More severe itching. Look for ↑ IgE + • Note: lymphadenopathy is not uncommon eosinophilia on labs in erythroderma regardless of cause • Allergic Contact: (e.g. Parthenian plant in Diagnosis (suggestive findings): India.) • Seborrheic: think of neurologic conditions - CBC: eosinophilia → drug rxn or atopic derm (Parkinson’s) or HIV - CMP: Electrolyte Imbalances & LFT elevations – DRESS • Chronic Actinic: men >50 caused by UVA, syndrome UVB, and visible light. ↑CD8:CD4 . - Blood Culture & Viral Cultures • Stasis derm with profound Id reaction: very - IgE: atopic derm rare cause of erythroderma - ANA: Lupus and dermatomyositis o Drug Rxn: SJS, TEN, DRESS syndrome, drug rash - Peripheral blood smear & Flow Cytometry: Sezary cells Flow; • SJS triggers: Allopurinol, sulfa drugs ↑ CD4:CD8 >10:1 (Bactrim), phenytoin, HIV pt w/ - Multiple Biopsy: may be non-specific in 1/3 of patients; *still antiretroviral therapy a crucial part of workup! o CTCL: erythrodermic MF, Sezary syndrome - KOH study if rash is scaly to r/o generalized tinea • Erythrodermic MF: pre-existing patches or - Lymph node biopsy vs PET CT if lymphadenopathy + concern plaques of MF then progress to for Sezary syndrome erythroderma Treatment: • Sezary Triad: Diffuse lymphadenopathy, malignant T-cells, erythroderma. Also look - Diffuse scaling: Emollients diffusely w/ class IV-XI topical for alopecia, nail changes, leonine facies. steroid • 1000 Sezary cell per microliter or ↑ - If Secondary infection present? Topical antibiotics like CD4:CD8 >10, ↑CD4 (CD7/26-) mupirocin or bleach baths o Infections: Viral exanthems, Norwegian Scabies, - Pruritis: Wet dressings & sedating anti-histamines Staph Scalded Skin syndrome (Benadryl, hydroxyzine), consider prednisone, cyclosporine, o Auto-immune conditions such as Lupus, GVHD, or methotrexate depending on etiology and severity bullous pemphigoid o Physical causes: e.g. Burns

- PEARL: Differential for leonine facies? “PALMS” Paget’s disease of the bone, Amyloidosis, Lepromatous Leprosy, Lymphoma, Leishmaniasis, Mycosis fungoides, Sarcoidosis, Scleromyxedema

24 o Cosmetic Products: Fragrance, Balsam of Peru, 13-Contact Dermatitis para-phenylenediamine (hair dye, henna tattoos)

Background PEARL: Cross Rxn w/ para-phenylenediamine “PASTA”: Paraben, Para-aminobenzoic acid (PABA), Azo dyes, sulfonamides, - Eczematous reaction patterns include thiazides, anesthetics – o Acute: Ex. Irritant vs Allergic Contact Dermatitis o o Subacute: Ex. Stasis Dermatitis Preservatives: formaldehyde o Chronic: Ex. Atopic Dermatitis PEARL: What causes allergic contact dermatitis on baby’s o Note: Any of these forms of dermatitis can present buttocks? Methyl-iso-thiazolinone used in baby wipes in an acute, subacute, or chronic fashion. Above are the more common presentations for each o Adhesives: cyanoacrylates, methacrylate (artificial nails), epoxy resin o Rubber: latex, neoprene in wetsuits, - Irritant (80% of cases): chemical that directly damages the mercaptobenzothiazole (shoe dermatitis) skin barrier with minimal immune system involvement (via PEARL: What does latex cross-react with? “BACK PASSION”: innate immunity) Bananas, Avocados, Chestnuts, Kiwi, Passionfruit o Variants: Acneiform, sensory, airborne, plant- derived Clinical Presentation: • Acneiform: exposure to metal or metal like - Acute: fluids o Inflamed lesions, weeping fluid, w/ vesicles & bulla • Sensory: Burning sensation w/out skin w/in hours to days changes - Subacute: • Airborne: dust or fiberglass o Progressive acute lesions that may have scale • Plant-derived - Chronic: o Can affect anyone with enough contact w/ o Lasting months to years substance o Look for lichenification: thickened skin w/ o Can occur in hours of contact since there is no need accentuated skin lines to recruit memory cells - ROS: o Acid vs Base: Bases are more damaging! Denature o Ask about new personal care products/: proteins in skin and also disrupts lipids in stratum make-up, chap sticks, lotions, laundry-detergents, corneum jewelry, shoes • Bases: Detergents, soaps, bleaches, o If chronic, ask the pt. if the rash gets better on cleaning products vacation • Acids: Sulfuric, hydrochloric, nitric acids - Physical Exam: o Earlobes: Nickel from earrings - Allergic (20%): mediated by immune system, Type IV o Neck: Fragrances, Perfumes such as Balsam of peru hypersensitivity to allergen o Hands: Latex gloves or poison ivy o Only affects small % of pts exposed to allergen o Arms: Poison ivy st o 1 exposure: (APCs + allergen) → sensitization o Wrist: Nickel in watches, chromates in leather on (primed + CD8 T-cells) wristband nd o 2 exposure: Primed Memory CD8 T-cells + allergen o Foot: mercaptobenzothiazole in rubber or → inflammatory response w/in 1-2 days chromates in leather shoe - 7 Main Causes of allergic contact dermatitis (ACD): o Armpits: Fragrance or propylene glycol in o Topical medications: Nitrogen Mustard, triple deodorants antibiotic ointments, Oxybenzone (sunscreen o Abdomen: Nickel in belt buckles or rubber in elastic ingredient), procaine, topical steroids, lanolin, waistbands propylene glycol, ethylenediamine, propolis, o Lower Legs: bacitracin or neomycin used for stasis urushiol oil dermatitis PEARL: Which ingredients in antibiotic ointment cause allergic o Lips: propolis in natural chap sticks or those that contact dermatitis? “BNP”: bacitracin, neomycin, polymyxin B contain sunscreen w/ oxybenzone o Eyelids: tosylamide in nail polish w/ pt rubbing o Plants: urushiol oil (ivy, oak, sumac) → “rhus” eyes, mascara, eyeshadow rubber sponge dermatitis o Penis: latex or rubber, poison ivy o Anus: methylisothiazolinone in wet wipes PEARL: Poison ivy, oak, sumac → toxicodendron, anacardiaceae family Diagnosis:

o Metals: nickel (earrings, belt-buckle), chromates - Patch Testing: TRUE test (most common) (leather, cement, green felt on pool tables), cobalt, o 3 panels w/ 12 test spots for allergens = 35 gold, mercury allergens + 1 control o Location: typically Upper Back 25 o Procedure: Apply TRUE test → return in 2 days for patch removal + 1st reading → return 2-5 days for 2nd reading • Ideally: Apply Monday, Remove Wednesday, Read Friday/Monday • Rules: • Don’t apply to inflamed skin where pt may have acne or sunburns • No topical steroids on site w/in a week or systemic steroids w/in 1-2 weeks • No showering or vigorous exercise for initial 2 days while patches on (may dislodge them)

o Results: • - = no rxn • +/- =doubtful pink rxn • 1+ = weak red rxn • 2+ = vesicular rxn • 3+ = bullous rxn

PEARL: If rxn improves in 2nd reading, it’s likely irritant contact. If rxn, progressively gets worse at 2nd reading, it’s likely allergic contact.

-Biopsy

Histology: Hallmark is “spongiosis” → edema in epidermis

- Acute: swelling can be abrupt, forming vesicles and bulla - Chronic: acanthosis (thickening of epidermis)

PEARL: Allergic vs Irritant? Allergic will have more spongiosis and inflammation in dermis compared w/ irritant. Irritant will also have more “dead-red” keratinocytes

Treatment:

- Avoid irritants and allergens - Topical steroids – mild - Systemic steroids -moderate/severe - Topical Calcineurin inhibitors on face and intertriginous

26 o Erythema improves, think stasis dermatitis 14- Stasis Dermatitis/Red - If thinking , outline erythema on legs o Helps to monitor for improvement w/ antibiotic Leg Differential regimen

Stasis Dermatitis PEARL: Swollen Leg? What do you ask your patient?

Background: - Is the rash painful? Suggests cellulitis - Itchy? Suggests Stasis or Contact Dermatitis - Seen on lower legs of pt w/ chronic venous insufficiency - Extended time on your feet (Trip to Disney)? Stasis - Pathogenesis: Venous insufficiency → venous HTN and Dermatitis extravasation of fluid and RBCs out of vessels into - Significant time immobilized (Plane or Post Surgery)? DVT interstitium → edema, hemosiderin deposition, and - One sided? Cellulitis inflammation in the skin - Bilateral? Stasis Dermatitis - Differential: Lipodermatosclerosis, Contact Dermatitis, - Risk factors for infection (Diabetes, immunosuppressants, Cellulitis, DVT, Necrotizing Fasciitis recently hospitalized)? Cellulitis - Topicals on the rash (Antibiotic ointment)? Allergic Contact Clinical Presentation: Dermatitis - Subacute eczema w/ erythematous slight scaly patches and Diagnosis = CLINICAL! plaques on the lower legs, especially the medial side of the lower leg - Biopsy: May not be helpful; pt already has poor circulation - Associated pitting edema and likely will not heal well - Typically bilateral (can be unilateral if pt has had trauma, prior cellulitis, or surgery e.g. vein harvest for CABG) Histology: - Also can have acute or chronic presentations: - Spongiosis correlating w/ dermatitis seen clinically, increase o Acute: bright red, warm, tender patches or plaques proliferation of capillaries below DEJ (reactive to the relative that may have vesicles or serous weeping fluid anoxia), extravasated RBCs w/ hemosiderin deposits, and PEARL: Ask the patient if they were standing for an extended possibly dermal fibrosis at later stages period of time! (Standing for long periods → acute flare of stasis derm) Treatment: o Chronic: more scale and due to hemosiderin deposition - Compression & Elevation o Compression stockings (>20 mmHg) PEARL: Name other complications that can occur in stasis o Severe: Serial Unna Boots or prednisone dermatitis? o Elevate above level of heart as much as possible 1) Contact sensitization (allergic contact dermatitis): Higher - Topical corticosteroids + Mupirocin for dermatitis rate → due to pts using triple abx ointment on rash since - Patient education they think it is infected, impaired skin barrier, ↑ presence o No cure, only control with above measures; may of inflammatory cells have another case of stasis dermatitis in future 2) Auto-sensitization (id rxn): immune mediated o Empower pt to use compression + elevation eczematous or papulovesicular lesions that occur at

distant sites from primary rash 3) Secondary infections: altered skin barrier + poor circulation = predisposition for super-infection from Staph or Strep Physical Exam: - Unilateral vs bilateral: o Unilateral suggests cellulitis but stasis dermatitis can also be unilateral - Look for an entry for skin infections: o Tinea pedis or skin maceration between toes - Look for scale on rash itself (takes time to develop!) o Argues against cellulitis, suggests stasis dermatitis - Palpate the affected skin o Exquisite pain or crepitus, think necrotizing fasciitis o Unilateral pitting edema + Homans, think DVT - Elevate the leg for 30 seconds 27 Cellulitis Clinical Presentation: - Look for the 4 Cardinal Signs of Inflammation: Red, Hot, Swollen, Tender - Systemic Changes: Fever & Fatigue - +/- Mild ↑ WBC count - Moderate to Severe: +/- Vesicles vs bullae, bruising, petechiae

Asteatotic Eczema

Background: - Extreme form of xerosis affecting pt > 60 y/o - Also known as Eczema Craquele

Clinical Presentation:

- Diffuse xerosis w/ fine scaling that progresses to inflammation and cracking of the skin (resembling cracked porcelain) - Pt experiences pruritis and can be painful when cracking of skin is deep enough to cause fissures - Weeping, crusting, bleeding on occasion

PEARL: What can exacerbate xerosis to cause eczema craquele?

- Low Humidity - Harsh soaps - Prolonged or frequent hot showers - Heating w/ wood stoves - Hypothyroidism, renal failure, liver DZ, malnutrition, HIV, Sjogren’s

Diagnosis:

- Clinical diagnosis typically sufficient w/out biopsy - If no improvement w/ treatment, consider Labs for Thyroid (TSH), Liver & Renal DZ (CMP), HIV, Zinc levels, ANA w/ reflex

Treatment:

- Avoid Triggers - Apply moisturizer o Vanicream, Cetaphil, Cerave, Vaseline w/in 3 minutes after shower while skin is damp to hold moisture - Topical corticosteroids + antihistamines for itching

28 - Adolescent/Adult (12-60 yrs) 15- Atopic Dermatitis o Similar presentation to adolescents w/ ↑ hand eczema Background: - Senile (60+ yrs) o Xerosis triggered by sweating or stress - Form of eczema that is often the first presentation of the “atopic triad” (Atopic Dermatitis, Asthma, & Allergic Diagnosis: Rhinitis) - Clinical Diagnosis consisting of three essential features: 1) o Can occur simultaneously or in succession (the pruritus, 2) eczematous rash, 3) chronic relapsing course atopic march) o Other less common important features include: - 60% rule: 60% begin by age 1; 60% resolve by 12 y/o early age of onset, xerosis, atopy Pathogenesis: o Associated features include: atypical vascular response (facial ), keratosis pilaris, pityriasis - Due to several genetic and environmental factors alba, hyperlinear palms, , periorbital o 1 parent atopic = >50% chance child will be atopic changes (Dennie-Morgan lines), lichenification o Mutations in the filaggrin gene: filament - Allergen specific IgE tests: aggregating protein → natural moisturization factor o RAST Test (“immunoassay”): detect antigen-specific o Deficient in several types of ceramides: IgE in blood to various foods, insect venoms, sphingolipids (“mortar” that holds corneocytes medicine (penicillin), environmental allergen (pollen (“bricks”) together in stratum corneum) or dust mites), & work allergens (latex) o Skin Tests (Skin Prick or patch testing): detect PEARL: What type of inflammatory response is present in acute allergen-specific IgE that activates mast cells in skin atopic derm vs chronic atopic derm? Acute atopic derm has → wheals or contact dermatitis respectively overactive Th2 w/ ↑ IL4, 5, 13 vs chronic atopic derm has Th1 response w/ IFN-g and IL-12 Histology:

PEARL: What are some of the major triggers for atopic dermatitis? - Acute: spongiosis, perivascular lymphocytes and histiocytes Think FADS! w/ occasional eosinophils - Subacute: ↓ spongiosis and ↑ acanthosis F: Fragrances (laundry detergents or perfume), fabrics (wool or - Chronic: ↓↓ spongiosis, ↑↑ acanthosis (mimicking polyester), food allergies (wheat, eggs, milk, peanuts) psoriasiform DZ) dermal fibrosis, hyperkeratosis A: Allergens (pet dander, dust mites) Treatment: D: dry environments, detergents - Avoid Triggers (FADS) S: stress, smoking, sweating, soaps, showering (too long or too - Moisturizing skin daily w/ in few minutes of exiting shower hot) (use bland emollients or petroleum) - First try, low-mid potency topical steroids (e.g. fluocinolone, Clinical Presentation: triamcinolone) or topical Calcineurin inhibitors (pimecrolimus or tacrolimus) - Infantile (2 months – 2 yrs) - Non-sedating antihistamines (loratidine) in morning then o Erythema and scale on the cheeks, scalp, and neck sedating antihistamines (diphenhydramine, hydroxyzine) at along w/ extensor arms and legs night o Very itchy and inflamed - Then systemic therapy if needed, narrow-band UVB, then o Can develop exudative plaques w/ Staph aureus prednisone, cyclosporine, azathioprine, mycophenolate colonization mofetil, methotrexate, dupilumab • Up to 90% of atopic derm pts are colonized with Staph aureus b/c their skin has ↓ antimicrobial peptides (vs psoriatic plaques having ↑ antimicrobial peptides = less likely to get infected) - Childhood (2 -12 yrs) o “The itch that rashes” o Antecubital fossa (flexures) becomes itchy; pt’s tend to scratch leading to classic excoriated lesions and lichenified plaques o Acute flare: ↑ erythema, pruritus, vesicles, and oozing PEARL: What are some other features of atopic dermatitis in children that can help your diagnosis? Eyes: Dennie-Morgan lines & allergic shiners; Face & Neck: & hyperlinear neck folds; Extremities: hyperlinear palms, keratosis pilaris 29 Smoothened inhibitors, Vismodegib and Sonidegib, block smoothened and 16- Basal Cell Carcinoma prevent downstream activation of Gli transcription factors.

Background: PEARL: Mutations that inactivate tumor suppressor, PTCH1, or active SMO can lead to the development of sporadic BCC’s - Most common skin cancer (Incidence ~ 2 Million cases annually in U.S.) - PTCH1 is mutated in Basal Cell Syndrome (Gorlin - Risk Factors Syndrome) o Fair Skin - 2 major or 1 major + 2 minor criteria o Intermittent sun exposure o Sex (Females > males) BCNS Major Criteria: o Old Age o Immunosuppression o >2 BCCs (~20 y/o) - Four Main Clinical Subtypes: o > 3 Palmoplantar pits o Nodular o Calcification of falx cerebri o Superficial o Odontogenic keratocysts of jaw o Morpheaform o Bifid ribs o Fibroepithelial o 1st Degree Relative w/ BCNS

Pathogenesis: Sonic Hedgehog Pathway BCNS Minor Criteria:

o Macrocephaly o Congenital Malformations o Skeletal Abnormalities o Bilateral Ovarian o Medulloblastoma

Clinical Presentation & Histology

- Nodular (50-80% of cases) o Smooth, shiny papule or nodule w/ arborizing vessels and a rolled border o Blue islands of basal cells w/in dermis w/ peripheral palisading, retraction artifact, fibromyxoid stroma - Superficial (10-30% of cases) o Erythematous macule or patch that may have a Figure 1. Under nonproliferative conditions, the PTCH1 receptor, a tumor suppressor, is not bound to its Sonic Hedgehog ligand ad is blocking the subtle crust/scale Smoothed protein. Smoothened is an oncogene that turns on gene o Blue buds of basal cells stemming from the transcription via Gli during proliferative states. epidermis, which do not go any deeper than the papillary dermis - Morpheaform o Indurated, scar-like appearance o Up to 7mm of subclinical spread (Aggressive) o Strands of basal cells cutting into dermis, eventually tapering to one cell thick o Jagged pattern o Pink desmoplastic, scar-like stroma o Lacks peripheral palisading and retraction artifact - Fibroepithelioma o Slow growing, raised, pedunculated, fleshy nodule found on the lower back (can be mistaken for a ) o Thin strands of blue cells interconnecting to form a web-like structure o Fibromyxoid stroma o Less peripheral palisading & retraction Figure 2. a.) A proliferative state occurs after either Sonic Hedgehog binds and turns off the tumor suppressor PTCH1, or PTCH1 is mutated, which BCC HistologicalVariants occurs in around 1/3 of BCC’s. This allows Smoothened to active Gli transcription factors, leading to cell growth and basal cell cancer. b.) - Micronodular

30 o Erythematous macule, papules, or plaque o Can have subclinical extension (Aggressive) o Small blue islands of basal cells w/ subtle - Radiation Therapy palisading and retraction artifact o BCC (Unspecified) - Infundibulocystic • Primary Cure Rate = 92% o Pearly pink papule on the head and neck • Recurrent Cure Rate = 90% o Anastamosing pink strands and blue basal buds - Intralesional or systemic chemotherapies w/ horn cysts intermixed - Basosquamous o Non-specific clinical presentation o

Important Histology Descriptors

*Peripheral Palisading: outer most cells in tumor island line up along the periphery

* Retraction Artifact: clear space between tumor island and surrounding stroma

* Fibromyxoid stroma: blue-grey mucinous background

Diagnosis:

- Biopsy

Treatment:

- o Superficial BCC • Cure Rate = 95% o BCC (unspecified) • Cure Rate = 91-95%

o Reserved for small lesions or pt w/ comorbidities who cannot tolerate surgery - Topical Imiquimod or 5-fluorouracil (5-FU) o Superficial BCC’s • Imiquimod Cure Rate = ~78%

• 5-FU Cure Rate = ~68% o Considerations: Irritation - Electrodessication and Curettage o BCC (unspecified) • Cure Rate = 91-97% o Cannot perform on Scalp. BCC’s can track down into hair follicle. o Considerations: Coin shaped scar + hypopigmentation • Avoid in cosmetic sensitive areas - Wide Local Excision (4mm margins) o BBC (Unspecified) • Primary Cure Rate = 95-99%

• Recurrent Cure Rate = 83% o Considerations: Longer Procedure & physical limitations post-op - Mohs Micrographic Surgery o See Mohs appropriate use criteria and

download the Mohs AUC app • Primary Cure Rate = 99% • Recurrent Cure Rate = 95% o Considerations: Cost & Time

31 PEARL: What is the boiling point of liquid nitrogen? -196⁰ Celsius or -321⁰ Fahrenheit

- Photodynamic therapy Consider these tx - Chemical Peels options w/ diffuse - Topical Chemotherapy AK’s 17- Actinic Keratosis/ Squamous o 5- fluorouracil o Imiquimod Cell Carcinoma o Ingenol Mebutate o Diclofenac Actinic Keratosis - Variance w/ how topical tx is used o 2-4 week of standard continued tx vs 5-10 day Background: intervals w/ healing in between

- Premalignant lesions of SCC PEARL: Recent literature shows 5-FU + calcipotriene = greater o 10% of AK’s will progress to SCC over the course efficacy & tolerability in combo of 10 years - Variants: Squamous Cell Carcinoma o Hypertrophic: thick, adherent scale o : horn-like projection of keratin Background: ½ as tall as lesion’s width - 2nd most common skin cancer (Incidence ~ 700,000 PEARL: About 20% of cutaneous horns can have SCC at the cases annually in U.S.) base, and should be biopsied with a scoop to rule out - More aggressive behavior than BCC malignancy - Main Variants: o Keratoacanthoma o Pigmented: mimic maligna o Bowenoid papulosis o Actinic cheilitis: AK on lip o Bowen’s dz PEARL: Actinic cheilitis will blur the border betwwen the o Erythroplasia of Queyrat vermillion lip and the cutaneous lip. So think of actinic PEARL: Risk factors for SCC? cheilitis when you see scaliness on the lower lip of a patient with extensive sun damage. - Chronic UV exposure - Ionizing Radiation ( E.g. X-rays, CT scans) Clinical Presentation: o SCC arising from radiated skin have 10-30% risk - Erythematous and scaly macules, papules, or plaques on of mets sun-exposed areas - Medications (E.g. Vismodegib, dabrafenib) o Head, neck, dorsal hands, and arms - Immunosuppression - Asymptomatic but may be tender to touch o Transplant pt have 100-250x the likelihood of SCC (vs 5-10x for BCC) Diagnosis: - Older age - Male sex (3:1) - Clinical diagnosis (most common) - Fitzpatrick types I-III - Biopsy taken if wanting to rule out SCC - Chronic scars/burns o Lesions that are hypertrophic or painful and not - HPV responding to treatment - Environmental exposure to arsenic Histology: - Hypertrophic lupus, hypertrophic lichen planus, chronic , exeroderma pigmentosum - Atypia starting in basal layer o Restricted to 1/3 to 2/3 of epidermis PEARL: Risk factors for SCC metastases? - Parakeratosis - Tumor diameter >2cm o Due to rapid cell turnover - Tumor Breslow depth >2mm o Correlates w/ scale we feel clinically o 2-6 mm (4%) - Background of solar elastosis o >6mm (16%) Treatment: - W/in wounds o Radiation scar or discoid lupus (25%) - - Poorly-differentiated tumors o Cure Rate = 40-80% (user dependent) - Perineural invasion >0.1mm - Tumor location on the lip or ear - Recurrent SCC’s

32 - Immunosuppression Treatment:

Pathogenesis: - ED&C o SCC (Unspecified)

- Mutations in tumor suppressor p53 (45-60%) • Cure Rate = 96-100% Clinical Presentation: - 5-FU o SCC (In-situ) - Pink to red papule, plaque, or nodule that may have • Cure Rate = 92% scale, erosion, ulceration or even pigment - Imiquimod - Lesion may be painful or tender o SCC (In-situ) • Cure Rate = 57-80%

- Variants: o SCC (Unspecified) o Keratoacanthoma • Cure Rate = 71% • Dome-shaped nodule w/ a central - Wide Local Excision keratin plug o SCC (Unspecified) • Grow quickly over weeks → involute • Cure Rate = 92% over months - Mohs o SCC (Unspecified) PEARL: Name 2 KA syndromes? • Cure Rate = 97%

1) Ferguson-Smith Syndrome: multiple KA’s that develop in teens and 20’s (localized) 2) Gryzbowski: 1000’s of smaller KA’s in older adults (generalized) 3 G’s = Gryzbowski, grown-ups, generalized

o Bowenoid Papulosis • HPV induced genital in younger pts → SCC in situ (presenting as small papules in anogenital region) • High Risk HPV = 16, 18, 31, 33 o Bowen’s disease • SCC in situ anywhere on body • ↑ Risk of invasion vs Bowenoid o Erythroplasia of Queyrat • SCC in situ on glans penis o Buschke-Lowenstein (HPV 6, 11) • Massive (s) on genital region o Epithelioma cuniculatum (HPV 6, 11) • Slow-growing mass on bottom of foot (destructive) o Oral Florid Papillomatosis (HPV 6, 11) • Multiple wart-like mouth lesions

Diagnosis:

- Biopsy

Histology:

- Nests of squamous epithelial cells arising from epidermis o In-Situ: contained w/in epidermis o Invasive: SCC extending into dermis - Full thickness atypia o Malignant cells w/ abundant eosinophilic cytoplasm o Hyperchromasia - Variable keratinization - Loss of granular layer w/ surface parakeratosis

33 2. Closed comedones (“whiteheads”) 18 & 19 - Acne o White or fleshy bumps that have no obvious follicular opening Background: 3. Inflammatory papules, pustules, nodules 4 Main Contributing Factors 4. Cysts

1. Abnormal keratinization Types of Acne Scars o Keratinocytes proliferate too quickly 1. Icepick o Keratinocytes are more cohesive 2. Boxcar 2. Excess sebum production 3. Rolling o Sebum production under hormonal control 4. Hypertrophic/Keloidal o Androgen receptor on sebaceous glands binds Dihdrotestosterone (DHT) = ↑ sebum Acne Variants production - Acne excoriee PEARL: So why do we give oral contraceptives to female o Often young acne patient w/ anxiety or OCD patients? OCPs inhibit ovarian androgen production via who picks at their lesions negative feedback inhibition = ↓ sebum production. Also, - Acne congloblata OCPs increase sex hormone binding globulin which reduces o Nodulocystic acne w/out systemic changes free androgens in serum. - Acne fulminans o Nodulocystic acne w/ systemic changes 3. Propionibacterium acnes overgrowth o Classically: teenage boys w/ fevers, joint pain, o Thrives in oily environment and even osteolytic bone lesions 4. Inflammation PEARL: SAPHO Syndrome: synovitis, acne conglobata, PEARL: What mechanism does P acnes induce inflammation? pustulosis (including pustular psoriasis), hyperostosis, and P acnes activates toll-like receptor 2, which are receptors on osteitis the surface of keratinocytes and macrophages → causes release of inflammatory mediators like IL-1, IL-8, IL-12, and Pediatric Acne TNF-alpha. - Neonatal Acne (Birth – 1 month) Additional Triggers o 20% of newborns o Usually self-resolves 1. Hormonal or menstrual flares - Infantile Acne (1 month – 1 year) o Look for lesions on the jawline o More comedonal and more resistant than 2. Psychological stress neonatal acne 3. Cosmetic products - Mid-Childhood (1-6 years) o Occlusive foundations, hair spray, pomades o Assess for signs of androgen excess (consider o Consider mineral-based, oil-free endocrine workup) noncomedogenic makeups • Pubic hair, testicle or clitoral 4. Mechanical factors (e.g. sports gear) enlargement, breast development, and 5. Medications increased muscle mass o “A ”: anabolic steroids, prednisone, - Prepubertal Acne (7-11 years) iodides, marijuana (loose association), progesterone-only contraceptives, lithium, Treatment: EGFR inhibitors (e.g. erlotinib) 6. Diet Basic Acne Recommendations o Theory: High Glycemic Load causes ↑ - Counsel to wash face x2 daily and after exercise levels = ↑ androgens o Use gentle cleansers (e.g. Cerave, Cetaphil, • Sweet/Fatty Diet → Plant-based/low Aveeno, Neutrogena, Vanicream) glycemic load may improve acne o Benzoyl peroxide (+ topical antibiotic), salicyclic Clinical Presentation: acid, and sulfur-based washes - Use a daily facial moisturizer w/ > SPF 30 Types of Acne Lesions o Prevents post-inflammatory hyperpigmentation (PIH) 1. Open comedones (“blackheads”) - Refrain from picking → can lead to scarring “Comedone” = plugged hair follicle (“pore”)

Turns black due to air oxidizing oils and debris to

black color

34 rarely, lupus-like syndrome or benign intracranial hypertension (pseudotumor cerebri)

PEARL: College-aged female w/ acne that flares on her Treatment Groups (Severity Stratification) jawline during menses not willing to use oral antibiotics. Dx? 1. Over-the-counter treatments (Listed Above) Hormonal acne Tx? Oral contraceptives and spironolactone

PEARL: If using topical antibiotic, remember to combine with - Oral Contraceptives: BPO wash to ↓ antibiotic resistance, or consider combo o Ortho Tri-Cyclen (norgestimate w/ ethinyl topical like clindamycin/BPO estradiol) o Yaz (drospirenone w/ ethinyl estradiol) 2. Prescription topical antibiotics or retinoids o Estrostep (norethindrone w/ ethinyl estradiol) - Topical Antibiotics: o Remember your ABCDE’s. Azelaic acid, benzoyl PEARL: How do you screen patients to ensure they are safe peroxide, clindamycin, dapsone (Aczone), on the pill? erythromycin, sulfacetamide Risks outweigh benefits in the following: - Topical Retinoids: o Cosmeceuticals (Retinol, Retinal) & 1) >35 yo who smoke >15 more cigarettes per day 2) multiple prescriptions (tretinoin, adapalene, and cardiovascular risk factors such as HTN, diabetes, smoking 3) tazarotene) hx of HTN 4) hx of venous thromboembolism 5) hx of • Tretinoin: inactivated by UV light (use ischemic heart dz 6) hx of stroke 7) current breast cancer, at night) and oxidized/inactivated by hepatocellular adenoma, or malignant hepatoma 8) severe BPO (do not use w/ topical BPO or cirrhosis after BPO wash) - Spironolactone: • Adapalene: 3rd gen. that is light stable o an aldosterone antagonist, inhibiting 5-alpha and often combined w/ BPO (e.g. → Epiduo) reductase (converts testosterone more potent DHT). • Tazarotene: pregnancy category X, o Dosed 50-200 mg daily. strongest topical retinoid o Contraindications include renal insufficiency, PEARL: Topical retinoids are our most important tx for acne! hyperkalemia, pregnancy, and abdominal Target 3 out of 4 components of acne pathogenesis uterine bleeding, and black box warning for (Normalize keratinocyte hyperproliferation, comedolytic, and personal or FHx of breast cancer. anti-inflammatory) o Side effects • Hormonal-related: menstrual PEARL: Use pea-sized amount of topical retinoid and apply irregularities, breast tenderness, and throughout acne prone areas. Remind patients that this is gynecomastia NOT spot tx. If dryness, applying every other night working up • Diuretic-related: urinary frequency, to nightly + moisturizer! orthostatic hypotension, hyperkalemia

PEARL: Retinoids tend to be drying so if the pt has oilier skin PEARL: Hyperkalemia and Spironolactone? and isn’t too sensitive, you can use a higher strength retinoid Recent literature concluded that routine potassium 3. All of the above + oral agents (antibiotics, monitoring in young (18-45 y/o), healthy pts who do not have spironolactone, or oral contraceptives) renal dz, congestive heart failure, or on other RAS - Oral Antibiotics: medications, is not recommended. Otherwise, potassium o Doxycycline (Targadox, Acticlate, Doryx), checked q3-6 months and w/ dosing changes. minocycline (minocin, solodyn), tetracycline • Approved for pts 8 y/o and above 4. Isotretinoin • Patients <8 y/o or tetracycline allergies→ consider erythromycin, - Referred to its old brand name “Accutane”, which is no azithromycin, or bactrim longer available - Daily use for ~ 6 months (Goal: 120-150 mg/kg) PEARL: Doxycycline Side Effect: GI (nausea, vomiting, - Works on all 4 components of acne diarrhea, esophagitis)…↓ w/ large glass of water and meal o May shrink sebaceous glands up to 90% (avoid dairy, calcium decreases absorption), photosensitivity, vaginal , photo-onycholysis.

Minocycline Side Effect: GI (above), hyperpigmentation PEARL: What are the side effects of isotretinoin and how are (scars, shins, sun-exposed), vertigo, teeth discoloration, and they monitored? Birth Defects (Craniofacial & Cardiac abnormalities):

35 • iPledge = ensures 2 forms of contraception + that patients don’t share their medicine or donate blood while on isotretinoin • Monthly negative pregnancy test

Labs: Fasting Lipid panel, LFTs

DRYNESS, including dry skin, lips, eyes (caution pt’s wearing contact lenses), nose bleeds: moisturizer, chapstick, eyedrops, Vaseline

Depression: Screening during visits

Inflammatory Bowel Dz: Screen for personal & FHx

Headache: do NOT combine doxycycline w/ isotretinoin → can cause pseudotumor cerebri

Hair loss, myalgias, arthralgias, slow healing (caution about waxing eyebrows; issues with ingrown nails)

Treatment approaches

MILD amount of comedones and inflammatory lesions

- Treated w/ benzoyl peroxide wash and/or topical retinoid - If compliant, you can escalate treatment if needed by increasing retinoid strength or adding topical antibiotic

MODERATE

- Topical retinoid +/- topical BPO +/- topical antibiotic - Oral antibiotic or OCP/Spironolactone (for female pt) - Consider isotretinoin for moderate pt w/ resistance to previous tx plan above, present w/ scarring, or FHx of scarring acne

SEVERE

- Isotretinoin OR.. - Topical BPO + topical antibiotic + topical retinoid + oral antibiotic

***Always ensure compliance before significantly escalating therapy!

36 20- Diaper Dermatitis Atopic Dermatitis - Uncommon considering occlusive nature of diaper Background maintains moisture - Hyperlinearity, erythema, and excoriations + classic - Affects 25-50% of pediatric patients atopic dermatitis lesions elsewhere - Caused by a combination of mechanical forces and - Personal or FHx of atopy (eczema, hay fever, asthma) alkaline pH of waste material PEARL: Normal skin pH ranges from 4 to 7, which is protective. Under a more alkaline environment, skin is more - Caused by the obstruction of sweat ducts under hot and prone to irritants and Candida. occlusive environments o Feverish + laying in bed all day - Differential Diagnosis (Think SCAMP): o Seborrheic dermatitis PEARL: Miliaria can be subdivided into 3 types: o Candida or Contact dermatitis (irritant or allergic) 1) Miliaria crystallina (most superficial w/ blockage of o Atopic dermatitis (uncommon) or sweat duct in stratum corneum): Clear, pinpoint Acrodermatitis enteropathica vesicles on a sea of scales. o Miliaria 2) Miliaria rubra (sweat duct blockage deeper down in o Psoriasis or Perianal strep the epidermis) erythematous papules - Others: 3) Miliaria pustulosa (even deeper blockage) more o Langerhans cell histiocytosis, granuloma gluteal pustular lesions infantum, Kawasaki dz Psoriasis: History - Sharply-demarcated, red or pink plaques - How often are parents changing the diaper? (should be - Involves the skin folds and will NOT have classic silvery at least 6-7x/day) scale b/c of excessive moisture from occlusive diaper - How do they cleanse the diaper area? Use of wet wipes, - Nail changes (10%) washcloths, soap? Perianal strep - Use of barrier ointment/paste? Using enough? - How is baby feeling? - Bright red, painful, and pruritic - Any recent diarrhea (more irritating) or antibiotic use - Heals w/ desquamation (predisposed to Candida)? - May be hx of strep throat in pt or sibling at home - Diagnosis = Culture Clinical Presentation: Acrodermatitis enteropathica Seborrheic Dermatitis - Inherited or acquired - Often present w/ coexisting cradle cap+ salmon pink o SLC39A4 gene (inherited) dermatitis in diaper area (folds) o Acquired may occur with cessation of breast Candida feeding - Erythema, pustules, and crusted patches or plaques in 3 - Bright red erythema, involvement of skin folds (+/- areas- the diaper area, perioral region, and acral areas scrotum), and satellite papules and pustules at the - Diagnosis = decrease zinc levels or low levels of alkaline periphery of dermatitis phosphatase (zinc-dependent enzyme) - May also have thrush + hx of recent antibiotic use - If severe, pt may also get 2⁰ Id rxn Langerhans Cell Histiocytosis

Contact Dermatitis (Irritant) – more common Four Variants

- Sometimes called “chafing dermatitis” 1) Letterer-Siwe dz: < 2 y/o w/ poor prognosis - Affects convex (outside) areas of the vulva, scrotum, and 2) Hand-Schuller-Christian Syndrome: 2-6 y/o w/ triad buttocks and SPARES the folds of DEB (diabetes insipidus, exopthalamos, and o SPARES folds b/c irritants like urine and stool osteolytic bone lesions) cannot reach these areas where skin is touching 3) Congenital Self-Healing reticulohistiocystosis of skin Hashimoto-Pritzker: skin limited form present at birth Contact Dermatitis (Allergic) 4) Eosinophilic granuloma: >7 y/o w/ localized LCH skin lesions and asymptomatic bone lesions - Rubber in diaper elastic or preservative methylisothiazinone in baby wipes

37 - Yellow-brown crusted papules in the seborrheic distribution of the scalp and diaper areas

PEARL: LCH lesions are more petechial or purpuric, may have lymphadenopathy, lesions respond minimally to tx

Treatment:

Seborrheic dermatitis

- Selenium sulfide - Topical antifungals (Ketoconazole or ciclopirox)

Candida

- Topical nystatin or azoles

Contact Dermatitis (Irritant)

- Diaper hygiene - Hydrocortisone 2.5% 2-3x daily

Contact Dermatitis (Allergic)

- Switch to hypoallergenic products + hydrocortisone 2.5% 2-3 daily

Miliaria

- Avoid overheating and occlusion by removing excess clothing, allowing the diaper area to air out as much as possible - Cooler baths and using fans to cool

Psoriasis

- Hydrocortisone 2.5% 2-3x daily (short-term) - Topical tacrolius (long term use)

Perianal Strep

- Topical mupirocen - Oral amoxicillin

Acrodermatitis enteropathica

- Zinc supplementation o Improves rash in few days

38 21 - Erythema Multiforme 3) EM has specific associations… PEARL: Associations w/ Erythema Multiforme Vascular Rxn Pattern Differential: - 90% are associated w/ infections (SJS 90% caused by 1) Erythema Multiforme medications) 2) Toxic Erythema Group o Most common: HSV and mycoplasma A) Viral Exanthems pneumonia B) Drug Eruptions (SJS, TEN, DIHS, others) o Others: EBV, CMV, HIV, Salmonella, C) Toxin-Mediated Eruptions (SSSS, TSS, KD, Scarlet Fever) Tuberculosis, histoplasmosis, 3) Gyrate/Figurate Erythema - Uncommonly due to medications such as NSAIDs, anticonvulsants, or antibiotics A) Erythema Annulare Centrifigum (EAC) B) Erythema Gyratum Repens (EGR) PEARL: Hx of acute, subacute or discoid lupus + EM = Rowell’s C) Erythema migrans (Lyme disease) Syndrome D) Erythema marginatum (rheumatic fever) Diagnosis: 4) Urticaria - Hx + Physical Exam 5) Vasculitis - Biopsy if diagnosis unclear 6) Vasculopathy Histology: 7) Retiform Purpura - Spongiosis 8) Vascular Growths - Vacuolar interface EM Clinical Presentation: - Scattered epidermal necrotic keratinocytes, “dead reds” - Superficial infiltrate w/ lymphocytes & histocytes - Typically affects young adults - Abrupt-onset, erythematous macules → papules & Treatment: targetoid lesions affecting extremities & face - Classic targetoid lesions have 3 zones - Symptomatic Tx (Self-limiting after 2 weeks) o Pruritis: Anti-histamines (e.g. diphenhydramine 1) Dusky Center that may have vesiculation or necrosis or loratadine) + mild topical steroid 2) Middle pale ring surrounded by o Painful oral lesions: “Magic Mouthwash” 3) Outer erythematous ring (combination of Benadryl, viscous lidocaine, and Maalox w/ or w/o corticosteroids or nystatin) PEARL: Targetoid lesions that are papular or elevated are o If 2/2 recurrent HSV: HSV prophylaxis w/ considered typical targets, whereas those that are acyclovir 400mg daily or valacyclovir 500mg or nonpalpable or macular are considered atypical targets 1g daily up to 6 months or as long as needed

Divided into EM Minor & EM Major: - Both have typical papular target lesions on extremities and face, and neither progress to SJS or TEN EM Minor - NO systemic symptoms (e.g. Fever, arthralgias) - Minimal mucosal involvement EM Major - Systemic symptoms - More severe mucosal involvement (e.g. Erosions of buccal mucosa and lips) PEARL: Other mucosal surfaces that can be affected include: eyes, ears, nose, mouth, vagina, urethra, and anus

PEARL: Erythema multiforme is now considered a separate entity from SJS & TEN! Not considered to be on spectrum.

Three Main Differences between EM & SJS

1) EM = papular targetoid lesions vs SJS = +/- macular targetoid lesions 2) EM favors hands, extremities, and face vs SJS/TEN which relatively spares distal extremities

39 PEARL: How to distinguish SJS from EM? 1) Think about the 22- SJS/TEN distribution of lesions. EM tends to involve the distal extremities, whereas SJS/TEN is much less likely to involve Background: these regions. 2) SJS has atypical macular targets and are not - Rare but potentially fatal drug rashes that lead to raised or palpable as in EM. keratinocyte death, full-thickness necrosis of the PEARL: What’s on your differential for desquamating rashes? epidermis and severe desquamation of the skin and mucosal surfaces SJS, TEN, EM Major, SSSS, toxic-shock syndrome, Mycoplasma - SJS/TEN exist on a spectrum (BSA: body surface area) pneumonia-induced rash and mucositis (MIRM), DRESS o SJS < 10% BSA (DIHS), purpura fulminans, acute graft-versus-host dz, and o TEN > 30% BSA pemphigus vulgaris o SJS/TEN overlap syndrome: 10-30% BSA Pathogenesis: Diagnosis: - Pt w/ predisposition exposed to drug/metabolites → - Hx + Physical Exam activation of FAS death receptor on keratinocytes → - Biopsy secretion of granulysin, granzyme B, and perforin from Histology: immune cells → causing apoptosis of keratinocytes → necrosis and sloughing of skin and mucous membranes - Scattered apoptotic keratinocytes - Onset: typically 1-2 weeks after drug exposure - Unimpressive perivascular lymphohistiocytic infiltrate o Exceptions: w/ eosinophils ▪ Few days if pt has already taken - As lesions progress, there will be full thickness epidermal medication (e.g. Bactrim) necrosis & development of subepidermal blisters ▪ Many weeks in the case of anti- Prognosis: convulsants o Predispositions: slow acetylators of meds, - Calculate SCORTEN (On arrival + 48 hrs later) certain HLA subtypes - Think “TAMEBUG” ▪ HLA- B-1502: Asians & East Indians o Tachycardia >120 BPM exposed to carbamazepine; o Age >40 ▪ HLA-B-5801: Han Chinese exposed to o Hx of malignancy allopurinol) o Epidermal loss >10% ▪ HIV/AIDS patients o Bicarb level >20 mEq/dL o Medications: >100 medication associations o Urea (BUN) >27 mg/dL ▪ Sulfamethoxazole-Trimethoprim o Glucose >250 mg/dL ▪ Allopurinol ▪ Phenytoin, Carbamazepine, Points % Mortality Lamotrigine ▪ Penicillins, Cephalosporins, 0-1 3 Carbapenems, Monobactams ▪ NSAIDs 2 12 ▪ Abacavir, Nevirapine 3 35 Clinical Presentation: 4 58 - Prodrome of fever & flu-like sx 1-2 weeks after initial medication 5+ 90 - 1-3 days later mucocutaneous changes noted. Look for erythema or erosions on mucous membranes. Skin findings typical start on trunk as erythematous macules PEARL: What are some complications of SJS/TEN that we try and targetoid w/ a dusky or purpuric center. to prevent? (Most common: ocular changes: chronic dry eyes, - Lesions will be tender to touch and quickly coalesce in symblepharon, blindness) hours to days Short Term: Fluid loss leading to electrolyte abnormalities, - May progress to flaccid blisters and sheets of skin that hypovolemic shock, multiple organ dysfunction syndrome, start to desquamate. bacterial infections → septic shock, pneumonia, ARDS PEARL: Nearly all pt w/ SJS/TEN will have mucosal Long Term: Poor skin healing, dyspigmentation, scarring → involvement. ALWAYS look in the pt’s eyes, nose, mouth and hair loss & disfiguration (symblepharon, vaginal adhesions) genital mucosa if you are suspecting SJS/TEN!

40

Treatment

- Step 1: Stop the offending drug! - Step 2: Supportive care and Systemic tx

Supportive Care:

- Wound Care o Areas of sloughed skin can be covered in petrolatum-impregnated gauze or nanocrystalline gauze until affected area re- epithelialize - Infection prevention o Antibiotic ointments or petrolatum are applied around mouth and nose - Monitoring fluids and electrolytes o Foley catheter - Nutrition - Consult ophthalmology o Often recommend ophthalmic antibiotic ointments for eyelids and antibiotic or steroid eyedrops to reduce infection and scarring - Consult OB/GYN o Study of female TEN pts: 70% had vulvovaginal lesions → 30% of which had long-term issues ▪ Prophylactic vaginal dilation and topical corticosteroids

Systemic Tx:

- Systemic Corticosteroids o Use advocated early on in dz course, however they also increase risk of infection in these predisposed patients. - IVIG o 0.75 mg/kg/day x 4 days o Check coagulation panel and an IgA level (rule out IgA deficiency) - Cyclosporine - TNF-alpha inhibitors (e.g. infliximab and etanercept)

41 morbilliform eruption on extremities that may take 23 – Viral Exanthems on more of a reticulate, lacy pattern

Background:

- Morbilliform: describes a measles-like rash that 6) Roseola Infantum consists of erythematous macules and papules that - Caused by HHV 6 > HHV 7 coalesce on the trunk, arms, and legs - Infants 6-12 months o Think first of “bugs and drugs” - High fevers <102 degrees Fahrenheit up to 5 days, ▪ Viral/bacterial infections in kids and while child does not appear to be very ill → followed meds in adults by faint, rose-pink morbilliform rash that favors the - In viral exanthems, the virus disseminates to the skin trunk and lasts a few days → not infectious after and mucosa from the blood, and the rash we see rash presents clinically is the pt’s immune response to that virus in o Associated features include febrile seizures, the skin upper respiratory sx, lymphadenopathy, Nagayama’s spots (red macules on soft PEARL: Viruses such as measles or parvovirus B19 cause an palate and uvula) exanthem most of the time, whereas others like RSV cause exanthems <1% of the time. Miscellaneous PEARL: Herpes Viral Infections 1-7 Classic Childhood Exanthems 1-6 o HHV 1,2: 1) Measles (Rubeola) o HHV3: Varicella-Zoster 2) Scarlet Fever o HHV4: Epstein-Barr (EBV) 3) German Measles (Rubella) ▪ Mono, Gianotti-Crosti syndrome, 4) Duke’s disease Oral hairy , Hydroa 5) Erythema Infectiosum (Parvovirus B19) vacciniforme, Burkitt’s lymphoma, 6) Roseola Infantum NK/T cell lymphoma o HHV5: Cytolomegalovirus Clinical Presentation: ▪ Most common (MC) congenital 1) Measles (Rubeola) infection and MC cause of - Highly infectious RNA virus transmitted via respiratory “blueberry muffin baby” droplets (extramedullary hematopoiesis) - Prodrome of Fever & 4 “C’s”: Cough, coryza, o HHV6: Roseola > Pityriasis Rosea conjunctivitis, Koplik spots (white-grey papules on o HHV7: Pityriasis rosea > Roseola buccal mucosa) → few days later a morbilliform rash o HHV8: Kaposi , Castleman’s dz, starts behind the ears and frontal hairline, spreading primary effusion lymphoma (PEL) caudally PEARL: What is a dreaded complication of measles? Subacute PEARL: What is Gianotti-Crosti Syndrome? Aka papular sclerosing panencephalitis, which occurs around 10 years acrodermatitis of childhood, is usually seen in pre-school age after acute infection. Presents w/ devastating neurological sx kids. Present with symmetric, monomorphous, pink-brown like seizures, coma, and death papules on face, buttocks, and extremities w/ relative sparing of the trunk 2) Scarlet Fever (See Episode 24) PEARL: Can you name 3 non-human herpes viruses that can 3) Rubella (German Measles) cause upper respiratory infections and viral exanthems? - Mild/Short 3-day course, Forchheimer spots (palatal Parainfluenza, rhinovirus, influenza type A & B, and ), impressive lymphadenopathy enterovirus such as coxsackie A16. PEARL: Rare complication includes Post-infection encephalitis - Coxsackie A16 aka Hand-foot-and-mouth disease ~ 1 in 6000 cases); Is also a TORCH infection (may have presents with prodrome of fever, upper respiratory, vertical transmission from mother to baby) and may lead to and possibly GI sx → develop vesicular eruption or Hearing, Vision, CV defects, mental retardation erythematous macules on hands, feet, mouth, buttocks, and thighs 5) Erythema Infectiosum (5th/Slapped Check disease) o Self-limited but very contagious → hygiene - Caused by Parvovirus B19 (ssRNA virus) is crucial to prevent spread - Flu-like prodrome of fevers, headaches, myalgias, & small joint arthralgias (10%) → after several days PEARL: Child w/ lesions localized to one armpit or inguinal characteristic erythematous slapped cheeked rash crease? Unilateral laterothoracic exanthem occurs → ~2-3 days later they then develop

42 PEARL: Adult who is sick enough to be in the hospital and you’re suspicious for viral cause? What are some other viruses you should be thinking about? Dengue, Chikungunya, Zika, Mono (EBV), acute HIV

Treatment:

- Supportive

43 24 – Toxin-Mediated Rashes Staph Scalded Skin Syndrome (SSSS)

Background: Toxic Shock Syndrome

- Caused by a specific strain of Staphylococcus (Phage Background: Group 2, Strains 55 & 71) o Produce exfoliatoxins A & B: cleave epidermal - Caused by Staph or Strep protein, desmoglein 1, which is responsible for o Staph: Toxin-1 (TSST-1) keratinocytes adhesion → detachment of ▪ More common, less severe superficial epidermis = skin sloughing ▪ Mortality 3% o Strep (Group A): A, B, C (SPE-A, B, C) PEARL: The same staph exfoliatoxins also cause bullous ▪ Less common, more severe impetigo through the same mechanism, however, in buLLous ▪ Mortality 30-60% impetigo, Staph only grows Locally. SSSS toxins disseminate - Toxins act as superantigens → cytokine storm → systemically. nonspecific T cell activation

Clinical Presentation: Clinical Presentation: - Infants and young kids <6 y/o or adults w/ - Healthy adult w/ foreign body such as immunosuppression or chronic renal failure superabsorbent tampon, surgical packing, or mesh - Look for fevers, skin pain, erythema, superficial - Sudden high fevers, headaches, GI complaints → blistering and desquamation hypotensive shock w/ internal organ involvement 1) Rash classically starts on the face w/ radial fissures (e.g. renal impairment, ARDS, liver failure, DIC) around the mouth, eyes, and nose - Look for scarlatiniform rash (diffuse redness w/ 2) More severe in the intertriginous areas (armpits), pinpoint papules) that classically starts on the trunk considering there is more friction in these areas and then generalizes 3) Lack oral involvement (>desmoglein 3 compensates o Erythematous rash desquamates 1-3 weeks later for loss of desmoglein 1 here) - Strep can cause severe infections leading to extremity pain Diagnosis: PEARL: Unlike SSSS, toxic shock syndrome can involve - Blood culture mucosal surfaces leading to strawberry tongue and inflamed - Skin Culture conjunctiva o Classic sites: umbilical stump or circumcision site Diagnosis: in neonates, the nasopharynx or conjunctiva in kids, and pneumonia or bacteremia in adults - Blood Culture o Commonly skin culture negative, considering - Skin Culture toxin disseminates to skin from distant site Treatment: - Biopsy - Extensive supportive care Histology: - Surgical debridement - Superficial splitting at or just below stratum - Abx granulosum - Full thickness epidermal necrosis ABSENT (If present, think SJS or TEN)

Treatment:

- Abx such as nafcillin, 1st or 2nd gen. cephalosporins, or vancomycin o Clindamycin can be used (shown to decrease

toxin production), however, some studies show resistance in 50% of causative Staph strains - Supportive Care: Electrolytes, IV fluids, gentle woundcare w/ nonadherent dressings - Prognosis: complete recovery w/in weeks

44

Kawasaki Disease Background: Scarlett Fever - Small to medium vessel vasculitis Background: - Incidence ~1 in 5,000 <5 y/o - Most commonly seen in Asian-Americans - 1-10 y/o - Strep (Group A): SPE A, B, C Clinical Presentation: o Via respiratory droplets - Fever of at least 5 days + 4/5 other diagnostic Clinical Presentation: criteria - Think “CRASH & Burn” - Classic strep throat w/ fevers, chills, headache, sore o Conjunctivitis (Nonpurulent): bilateral, spares throat, red and swollen tonsils w/ white exudate, limbus and tender cervical lymph nodes o Rash: polymorphous exanthem w/in 5 days of - Palate petechiae, strawberry tongue fever - No rhinorrhea or cough ▪ Morbilliform, urticarial with sandpapery - Fine sandpapery rash w/ fine macules and papules papules on a background of erythema on the trunk and extremities lasting 4-5 days → ▪ Accentuates w/ friction (groin) healing w/ extensive desquamation o Adenopathy: Cervical lymphadenopathy of at - Look for Pastia’s lines: accentuations of the rash in least 1.5 cm flexural areas w/ linear petechiae o Strawberry Tongue: tongue + other mucosal PEARL: Acute glomerulonephritis & rheumatic fever (JONES) changes (e.g. cracked lips) o Hands + Feet = erythematous & edematous → - JONES Criteria for rheumatic fever o desquamation after 1-2 weeks Joints (Polyarthritis) o o Burn: fevers >39 degrees Celsius >5 days (Pericarditis) o Nodules PEARL: o Erythema Marginatum - Cervical lymphadenopathy is the least common o Sydenham chorea feature (50-75%, often unilateral) Diagnosis: - Fevers usually las at least 1 week and do not respond well to Tylenol - Clinical Presentation - Throat Culture PEARL: Coronary Artery Aneurysms: develop several weeks after symptom onset in around 25% of untreated kids Treatment: Diagnosis: - Amoxicillin o Allergic → Erythromycin, Clindamycin, 1st gen - Clinical Presentation cephalosporins - Lab abnormalities o Think “WATCH” ▪ White count elevation ▪ Anemia ▪ Thrombocytosis vs Thrombocytopenia ▪ CRP ▪ Hypoalbuminemia Treatment:

- 80-100 mg/kg/day Aspirin o Divided into 4 doses o Provide for 2-3 days after fever ends, then given at 3-5mg/kg/day until labs normalize and ECHO negative - 2g/kg infusion IVIG over 12 hrs

45 26- Figurate Erythemas Erythema Migrans Background: Erythema Annulare Centrifigum (EAC) - Caused by spirochete, Borrelia burgdorferi, Background: which is carried by deer tick, Ixodes scapularis - Rash seen in Lyme disease - Triggers: - Tick has to be attached >24hrs for o Infections (e.g. tinea) transmission of Borrelia o Medications (e.g. HCTZ, amitryptyline) o 1-3% transmission rate o Foods (e.g. blue cheese) o Autoimmune conditions Clinical Presentation: o Cancer (rarely) - Erythematous, enlarging targetoid lesion Clinical Presentation: o Appears a few days – 1 month after initial bite - Erythematous annular lesions on the trunk or o Typically on torso, but can have 2⁰ lesions proximal extremities that slowly progress ~ due to spread of spirochete vs additional 2-3 mm/day bites - Classic “trailing scale” (like PR) - Flu-like sx @ onset - Solitary or disseminated - Untreated systemic dz - May itch o Severe arthralgias (60%) Histology: o Bell’s Palsy (10%) Cardiac - AV Block (5%) - Parakeratosis, spongiosis, and o cuffing/coatsleeve perivascular infiltrate Diagnosis: Treatment: - H&P - ELISA + Western Blot: pt w/out hx of bite or - Address Triggers rash but sx of Lyme dz - Topical steroid or Calcineurin inhibitors - UV tx or oral erythromycin Treatment:

Erythema Gyratum Repens (EGR) - Prophylaxis: Single dose 200 mg doxycycline if, Background: o Attached tick = Ixodes scapularis - Paraneoplastic Syndrome: Associated with o Attached > 36 hrs internal cancer in 85% of cases o Med can be started w/in 72 hrs of removal o Majority of rashes occurs ~ 1 year prior to - Removal: grasped w/ forceps as close to the discovery of malignancy skin surface and pull gently w/out twisting or o Lung Cancer most common (Breast/GI Cx puncturing the body of the tick also seen) - Erythema migrans: doxycycline 100 mg BID 2- - 50% of pts have peripheral eosinophilia 3 weeks o Allergy or Pregnant: amoxicillin 500mg q8 Clinical Presentation: hrs 2-3 weeks - Multiple erythematous polycyclic rings w/ wood grain appearance - Trailing scale - Develop rapidly + diffuse ~ 1cm/day Treatment - Find & treat malignancy rash resolves

46 Erythema Marginatum Background: - Rash seen w/in 2-5 weeks following untreated Strep throat or Group A strep skin infections - JONES Criteria – Rheumatic Fever PEARL: Can you name the major & minor Jones Criteria? Major: Joint arthropathy, Carditis, subcutaneous Nodules, Erythema marginatum, Sydenham’s chorea Minor: Arthralgias, fevers, elevated ESR/C-reactive protein, prolonged PR interval Clinical Presentation: - Erythematous macules and patches in an annular or polycyclic arrangement on trunk & proximal extremities - Progress ~ 2-12 mm/day Diagnosis: - CBC, ASO-titer, ESR, CRP - Cardiac Work-up (ECG, Echo) Treatment - Antibiotics: Penicillins, Cephalosporins, Azithromycin, Clarithromycin, or Clindamycin - Anti-inflammatory: Naproxen - Cardiology + Neurology consult

47 ▪ Inducible: a few hours 27- Urticaria ▪ Spontaneous: < 24 hrs ▪ Urticarial vasculitis: >24 hours Background: - Physical Exam: - Commonly known as “hives” o Asses for dermatographism, note size/shape of - Affects 10-20% of population lesions, coexisting lesions (purpura = think urticarial - Presentation at any age vasculitis), lymph nodes (infectious vs malignancy) o Chronic Urticaria: ~20-50 y/o - Other options: allergy testing, CBC, ESR, ANA, TSH, free - Classified into acute, acute intermittent, chronic forms T4, anti-thyroglobulin, possibly stool ova and parasites

PEARL: What are some H&P findings that would make you Acute Urticaria consider urticarial vasculitis? 1) hives lasting >24 hrs 2) painful>pruritic 3) purpura 4) systemic sx Background: Treatment - Lasting < 6 weeks o Does not necessarily occur on a daily basis - Address triggers nd - Triggers: - 2 generation non-sedating antihistamines (Loratadine, o Bugs: insect stings and infections; URIs are most Desloratadine, Fexofenadine, Cetirizine, Levocetirizine) common infectious cause, causing 40% of acute - If minimal improvement, then consider: Increasing dose, nd urticarias (compared to only 5% of chronic urticarias); Adding another 2 gen anti-histamine, H2 receptor st UTIs and GI disease can also be a cause antagonists, leukotriene antagonist, or 1 gen anti- o Drugs: most common are ACE I’s, NSAIDs, opioids histamine ▪ Others: alcohol, vancomycin, polymyxin B, - Other/severe cases: systemic corticosteroids, UV tx, radiocontrast media doxepin, cyclosporine, or Omalizumab o Physical triggers: dermatographism, , delayed pressure, cholinergic, adrenergic, heat, solar, aquagenic, vibrational Contact Urticaria

PEARL: Physical causes of urticaria can present acutely, Background: however we tend to think of them as chronic inducible urticarias! - Immunologic or non-immunologic - Immunologic: type 1 hypersensitivity rxn caused by skin PEARL: How can cold urticaria be dangerous? Pts should be contact with latex, meats, potatoes, etc. counseled against swimming in cold bodies of water, since it - Non-immunologic: triggered by jellyfish stings or stinging → can cause massive histamine release hypotension, nettles syncope, and drowning

o Food: WEMPS mnemonic (wheat, eggs, milk, peanuts, and soy) Clinical Presentation: - Recurrent papular swellings - Can be associated with angioedema typically affecting lips and periorbital areas. Histology: - Limited epidermal change - Superficial dermal edema - Perivascular and interstitial mixed infiltrate with neutrophils - Vascular damage = urticarial vasculitis Diagnosis:

- H&P: o ROS to assess for angioedema, anaphylaxis, triggers (bug, drug, physical, food) ▪ Other: fever, chills, fatigue, rhinorrhea, sore throat, cough, ab pain, N/V/D, dysuria, etc o Key question = duration of lesion

48

Chronic Urticaria

Background:

- Lasting ≥ 6 weeks o Nearly daily or daily episodes - Can be divided into inducible and spontaneous forms - Remember 30% rule: o 30% associated with autoantibodies to mast cells’ IgE receptor or IgE itself o 30% of pt have thyroid auto-ab o 30% exacerbated by aspirin o 30% resolve in 5 yrs PEARL: Thyroid dz is NOT the only associated auto-immune condition. Chronic urticaria can be associated w/ Type I DM, Lupus, RA! PEARL: Strong Association w/ psych: 50% of pts display anxiety, depression, or somatoform dz Clinical Presentation: - Chronic Inducible Urticarias o Dermatographism- ‘skin writing’; wheal that forms within minutes of stroking or scratching skin o Cold urticaria- presents during rewarming phase after cold air/water exposure o Delayed pressure- may be delayed 12 hrs from pressure exposure (e.g. tight waistband) o Cholinergic- sweating and exercise increase core body temp o Adrenergic: blanched vasoconstricted halo occurs after stress-induced release of adrenaline o Heat: w/in minutes of contact w/ heat o Solar: w/in minutes of exposure to all types of light, including visible, UVA, UVB o Aquagenic: contact w/ water of ANY temp o Vibrational: triggered by things like lawnmowers, motorcycles, jackhammer, etc. Histology: - Limited epidermal change - Superficial dermal edema - Perivascular and interstitial mixed infiltrate with neutrophils - ↑ Mast Cells - Vascular damage = urticarial vasculitis Diagnosis:

- See acute urticaria Treatment:

- See acute urticaria - Omalizumab (Xolair)

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49

28- Vasculitis I Vasculitis Purpura - Vasculitis is caused by inflammation of the Background: blood vessel wall o Palpable purpura on dependent areas (e.g. lower legs) - Purpura = visible hemorrhage into the skin or ▪ Inflammation of vessels bring mucosa edema with it → palpable - 6 types: - Vasculopathies refer to blood vessel damage o Petechiae - nonblanchable, pinpoint with minimal or no inflammation of the red macules ≤ 4 mm, think platelets vessel walls o Macular Purpura - nonpalpable and 5- o typically causes macular or 9mm in size, think coagulation nonpalpable purpura o Macular Ecchymosis - aka a bruise, - Typically a type 3 hypersensitivity nonpalpable and is ≥1cm, think o Antibodies to an antigen → immune coagulation complexes form → deposit in vessel o Palpable Purpura - can range in size walls → complement cascade from a few mm’s to many cm’s, activated → inflammation of blood suggests vasculitis and inflammation vessel walls because inflammation brings edema - 4 groups based on vessel size: with it that swells the skin o Small vessel only o Non-inflammatory or Inflammatory ▪ Arterioles, capillaries, and Retiform Purpura - purpura with an postcapillary venules in the angulated or branching pattern, BAD upper and mid dermis SIGN!! ▪ palpable purpura, petechiae, urticarial papules Pathogenesis: ▪ Cutaneous small vessel vasculitis (CSVV), Henoch- - 3 big categories based on location of blood Schonlein purpura (HSP), vessel pathology urticarial vasculitis, acute o problems with the vessel walls hemorrhagic edema of infancy, themselves such as inflammation in erythema elevatum diutinum vasculitis, or other alterations due to (EED), and granuloma faciale diabetes, amyloid deposition, or o small plus medium vessel calcium deposition, as in calciphylaxis ▪ medium vessels include larger o intravascular pathology such as but still small arteries and veins coagulation or platelet abnormalities, in the deep dermis or sub-Q along with embolic conditions ▪ purpura, petechiae, urticarial o problems outside the blood vessel papules, reticularis, wall such as issues ulcers, sub-cutaneous nodules, like scurvy or actinic purpura and even retiform purpura ▪ In both scurvy and actinic ▪ More visceral involvement than purpura, you have problems small vessel only (e.g. kidneys, with collagen in the dermis liver, heart, and mesentery) cushioning the vessels, ▪ group 1: mixed therefore minimal trauma leads cryoglobulinemia types 2 and 3 to easy bruising ▪ group 2: ANCA-associated vasculitides • granulomatosis with polyangiitis (GPA or

50 Wegener’s - May be more severe under areas of pressure granulomatosis) like the sock line • microscopic polyangiitis - May be itchy or painful • eosinophilic - May have systemic symptoms (e.g. fevers and granulomatosis with arthralgia) polyangiitis (EGPA or - Typically resolve over several weeks Churg-Strauss syndrome) Histology: o medium vessel only ▪ Examples: polyarteritis nodosa - LCV: (PAN) and Kawasaki disease - Vessels in the superficial dermis with fibrin o large vessel deposition and expansion of the vessel walls ▪ larger-named arteries like the - RBC extravasation aorta - Perivascular infiltrate containing neutrophils ▪ temporal arteritis (giant cell and karyorrhexis (nuclear debris) arteritis) and Takayasu’s arteritis PEARL: When it comes to terminology for CSVV, some people refer to it as “Leukocytoclastic vasculitis”, but keep in mind that LCV is actually a histology finding and can also be seen in other Cutaneous Small Vessel Vasculitis (CSVV) systemic vasculitic disorders such as GPA.

Background: - leukocytoclastic vasculitis (LCV) that is mostly Henoch-Schonlein Purpura (HSP) confined to the skin - Pathogenesis: an antigen trigger is bound by Background: antibodies and forms big immune complexes that deposit into post-capillary venules → - IgA vasculitis which is THE most common form these lodged immune complexes then of vasculitis in children activate complement, which activates the - Triggers: immune system → causes inflammation that o Infections (e.g. tinea) damages the vessels and allows red cells to o Medications (e.g. HCTZ) leak out → petechiae and palpable purpura in o Foods (e.g. blue cheese) dependent areas o Autoimmune conditions - Triggers: MANIC (same as urticarial vasculitis, o Cancer EED, and Sweet’s syndrome) Clinical Presentation: o Medications (e.g. beta lactam antibiotics, bactrim, thiazides, and oral - Development of the following tetrad 1-2 contraceptives) weeks after a URI or strep infection: o Autoimmune CTD (e.g. lupus, RA or 1. Palpable purpura on the legs and butt Sjogren’s) 2. Arthralgias of knees and ankles o NSAIDs 3. GI issues (e.g. abdominal pain and o Infections (e.g. group A strep, diarrhea with or without melena hepatitis and HIV, and candida) or IBD 4. Renal changes: hematuria, possible o Cancer (<5% of cases, e.g. leukemias nephritis, and renal failure in around 1% and solid organ cancers) of cases - Adults usually have a more aggressive and Clinical Presentation: chronic HSP course - Petechiae and palpable purpura on lower o Associated with solid organ and blood legs that present ~ 1-2 weeks after a trigger cancers (~ 6 months for autoimmune diseases or o 3 Risk factors for renal involvement in cancer) adults: - May become bullous or pustular 1. Fevers

51 2. ↑ ESR Cryoglobulinemias 3. Purpura located ABOVE the waist (“closer to kidneys”) - Cryoglobulins are immunoglobulins that precipitate in the cold Histology: - 3 types: - LCV (see above) o Type 1 Cryoglobulinemia - + DIF with IgA in blood vessel walls ▪ caused by monoclonal IgM > monoclonal IgG → sludging and Treatment/Management: occlusion of blood vessels → - Supportive treatment with or without vasculopathy NOT vasculitis → no prednisone or dapsone LCV on path - Monitor patients with serial UA’s and stool ▪ associated with lymphoproliferative guaiac if they have GI symptoms disorders ▪ Presents with , Raynaud’s phenomenon, Urticarial Vasculitis acrocyanosis, and purpura o Type 2 and Type 3 Mixed - Urticaria clinically, LCV histopathologically Cryoglobulinemia - 4 unique differences than regular urticaria: ▪ Type 2 exhibits monoclonal IgM or o Individual lesions last longer than 24 hours IgG with polyclonal IgG and Type 3 (vs. <24 hours) has polyclonal IgM with polyclonal o More pain and burning than itching IgG (“poly/poly”) o Purpura ▪ Immune complexes activate o Systemic Symptoms complement and cause LCV with - Divided into normocomplementemic and palpable purpura and systemic HYPOcomplementemic changes o ~3/4 of cases have normal complement ▪ Higher association with Hep C levels and are skin-limited ▪ Lab Tests: o ~1/4 of cases are HYPOcomplementemic o ↑ cryoglobulins (sample must ▪ associated with systemic changes be maintained near 98.6◦F (e.g. arthralgias; pulmonary, GI, until it is spun down, renal, and ocular changes; otherwise you get a false- decreased CH50, C3, and C4 levels; negative result) and anti-C1q antibodies) o ↓ C4 complement levels due PEARL: A patient with urticarial vasculitis, IgM to consumption gammopathy, and fevers, bone pain, and arthralgias o + rheumatoid factor (70-90%) has Schnitzler’s syndrome. o + hepatitis B or C test PEARL: Rheumatoid factor by definition is the presence of an antibody that is binding to the Fc portion of IgG. Remember that the Fc portion is the bottom of the antibody’s Y shape. Since types 2 and 3 mixed cryoglobulinemias have polyclonal IgG, it makes sense that you end up with antibodies binding to IgG and thus a positive rheumatoid factor.

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52 29- Vasculitis II Microscopic Polyangiitis Clinical Presentation: ANCA-Associated Vasculitis - Most common cause of pulmonary-renal syndrome Background: o Lower Respiratory (25%) o Glomerulonephritis (80-90%) - Annual incidence of 20 cases/million in North America & Europe PEARL: Simply put, MPA is like GPA (with lower respiratory - ANCA: anti-neutrophilic cytoplasmic ab (IgG) and renal changes) but without the upper resp changes + o C-ANCA: cytoplasmic ANCA target proteinase 3 granulomas o P-ANCA: perinuclear ANCA target myeloperoxidase - Skin Changes: palpable purpura, petechia, & livedo 1. Granulomatosis w/ polyangiitis (Wegener’s reticularis granulomatosis) - Peripheral neuropathy: mononeuritis multiplex 2. Microscopic polyangiitis 3. Eosinophilic granulomatosis w/ polyangiitis (Churg- Labs: Strauss) - P-ANCA

Granulomatosis w/ polyangiitis (GPA) Eosinophilic granulomatosis w/polyangiitis Clinical Presentation: Clinical Presentation: - Triad of upper respiratory, lower respiratory, and renal changes - Presents in 3 stages o Upper respiratory are often initial presentation 1. Adult-onset asthma, allergic rhinitis, nasal polyps ▪ Severe sinusitis 2. Eosinophilia, pneumonia, GI issues ▪ Oral ulcerations 3. Systemic vasculitis w/ palpable purpura, worsening ▪ “Strawberry gums” asthma & allergic rhinitis, and mononeuritis o Lower respiratory changes seen in 70% of patients multiplex & cardiac issues (e.g. cardiomyopathy) ▪ Cough PEARL: EGPA does NOT have renal changes, which ▪ SOB differentiates it from GPA & MPA ▪ Hemoptysis o Renal disease present in 85% of patients Labs: ▪ Severe glomerulonephritis w/ hematuria (80% - + P-ANCA, ↑IgE, ↑WBC mortality in first year w/out tx) ▪ Skin Changes: Palpable purpura, pyoderma- Treatment: gangrenosum-like ulcers, or sub-Q nodules ▪ Peripheral neuropathy & stroke-like sx - Systemic corticosteroid, cyclophosphamide ▪ Systemic fevers, anorexia, & arthralgias

Histology:

- Leukocytoclastic vasculitis along w/ necrotizing palisading granulomas Labs: + C-ANA & elevated sed rate

Treatment:

- Cyclophosphamide, prednisone, & other immunosuppresants (e.g. methotrexate & rituximab)

53

Polyarteritis Nodosa (PAN) Kawasaki Disease

Clinical Presentation: - Children <5 years old - Asian ancestry - Palpable purpura on the lower legs, painful sub-Q - Coronary artery aneurysms develop several weeks nodules, lacy livedo reticularis after sx onset in 25% of untreated pts - Constitutional sx: fevers, malaise, arthralgias - Organ involvement: Clinical Presentation: o Nerves - Fever (5 days duration) + 4/5 criteria PEARL: Neurologic changes affect 75% of PAN pts and include o Think “CRASH & BURN” and motor neuropathies resulting in foot drop! ▪ Conjunctivitis ▪ Rash (Polymorphus exanthem) o Cardiac (e.g. cardiac arrythmias & infarction) ▪ Adenopathy (Cervical lymphadenopathy) o GI: NVD, bowel infarction → hemorrhage ▪ Strawberry Tongue o Renal: renal failure & HTN ▪ Hand & Feet desquamation PEARL: Why do PAN pts not get glomerulonephritis? PAN ▪ Burning Fever (>39⁰Celsius) for 5+ days affects medium-sized vessels that perfuse the kidneys, NOT - Other sx: uveitis, arthralgias, gastroenteritis, irritability, the small vessels w/in the glomeruli = HTN NOT urethritis glomerulonephritis Labs: o GU: male testicular pain o Spares the lungs - Think “WATCH” o ↑ WBC, Anemia, PEARL: Associations include Hep B, Hep C, HIV, CMV, strep, Thrombocytosis/Thrombocytopenia, ↑CRP, IBD Hypoalbuminemia Diagnosis: - Rapid Strep, Blood cultures, UA, ASO titers - Stat ECHO - Criteria: 3 of 10 = Diagnosis 1. Weight loss of 4kg or more Treatment: 2. Livedo reticularis 3. Testicular pain/tenderness - IVIG @ 2g/kg over 12 hrs as a single dose 4. Myalgias or leg weakness or tenderness - Aspirin @ 80-100 mg/kg daily 5. One or more neuropathies. - +/- corticosteroids, cyclophosphamide or cyclosporine 6. Hypertension with diastolic blood pressure >90 7. Elevated BUN >40 or creatinine >1.5 that can’t be explained by dehydration or obstruction. 8. Positive hepatitis B antigen or antibodies. 9. Arteriogram demonstrating aneurysms or occlusion of visceral arteries without another explanation. 10. Biopsy showing small or medium-sized vessel with inflammation (including PMN’s)

- Other work-up: Hep B+C ab titers, BMP, UA, BCB, ESR, CRp, C&P-ANCAs, ASO titers - Renal Angiogram: Look for aneurysms or renal artery stenosis Histology: - Leukocytoclastic vasculitis w/in medium-sized arteries in the deep dermis or sub-Q +/- lobular panniculitis next to the involved vessels Treatment

- Immunosuppresants (e.g. systemic corticosteroids for 6 months) + methotrexate or cyclophosphamide - Consult nephro & cardio

54

Temporal Arteritis (Giant Cell Arteritis) Septic Vasculitis

- Onset: >50 y/o (~70’s) - Systemic infection that damages the vessels by either - Develop granulomatous vasculitis of the temporal 1) invading the vessels directly or 2) causing immune- artery mediated damage Clinical Presentation: - Causes: Subacute bacterial endocarditis, - Tenderness along temporal artery, loss of pulses, Staphylococcal or Pseudomonas septicemia, Neisserial headache, jaw claudication gonococcemia and meningococcemia, Vibrio vulnificus, - Skin Changes: erythema, , purpura, or tender rickettsialpox and Rocky Mountain Spotted fever nodules - Systemic Changes: fevers, associated polymyalgia Clinical Presentation: rheumatica, visual changes - Presentation of septic vasculitis can vary widely, from Labs: hemorrhagic pustules of staph septicemia to large ulcerating bullae caused by pseudomonas in cases of - ESR, CRP, temporal artery biopsy ecthyma gangrenosum

Treatment: Histology:

- Aspirin & systemic steroids - Small vessel vasculitis with neutrophils and thrombi

Takayasu’s Arteritis PEARL: Septic Vasculitis histology differs from the vasculopathies in that vasculopathies like DIC and TTP have - Onset: <40 y/o - Granulomatous vasculitis affecting the aorta or its minimal or no inflammatory infiltrate to go with their thrombi main branches on path, while septic vasculitis does have inflammation with thrombi! Clinical Presentation:

- ↓ radial pulses and a difference in blood pressure >10 mmHg between each arm - Constitutional sx: fevers, night sweats, and weight loss, claudication of the extremities - Skin changes: erythematous papules, purpura,

, and Raynaud’s phenomenon

Labs:

- Elevated ESR

Treatment:

- Systemic Corticosteroids

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55 -Renal disease: chronic renal failure and may present with 30 - Vasculopathy bruising, petechiae, and GI bleeding. Use of dialysis improves platelet function! Background: Embolic Disorders -Conditions with blood vessel damage in the absence of vasculitis -Cholesterol emboli: cholesterol fragments that dislodge from a -Often due to problems with clotting, typically an inherited or plaque and travel downstream to plug arterioles in the skin. Can acquired issue with platelets or the coagulation pathway occur spontaneously or after cardiac procedures . Associated with peripheral eosinophilia! Inherited coagulopathies -Oxalate emboli o Factor 5 Leiden: Factor V that is resistant to degradation by protein C → coagulation cascade activated Miscellaneous o Protein C/S deficiency: incapable of deactivating factors V & VIII = “broken brakes” →coagulation cascade -Pigmented purpuras activated o Schambergs disease: affects the lower legs of middle o Antithrombin III mutation: Blocks factors II & X = broken aged adults appears as petechiae with golden-brown brakes! hemosiderin staining o Hyperhomocyteinemia: 2-4x risk of thrombosis o Lichenoid purpura of Gougerot and Blum: rust-colored to o Sickle cell disease: Acidosis or low O2 → sticky sickle cells violaceous lichenoid papules on the legs and trunk of → clotting older men Acquired coagulopathies o Purpura annularis telangiectodes; 1-3 cm annular patches with petechiae on the legs of younger women -Anti-phospholipid syndrome: patients are more prone to forming o Lichen Aureus: solid golden to rust colored macules or clots, therefore look for a hx of stroke, MI, DVT, PE, miscarriages. papules Cutaneous changes are related to occlusion, including livedo o Eczematous Dermatitis of Doucas and Kapetanakis: mix reticularis, splinter hemorrhages, or retiform purpura. of eczema and petechiae showing up on older men

o Anti-cardiolipin Diagnosis: o Lupus anticoagulant o Anti-beta2 glycoprotein Biopsy will show fibrin thrombi with minimal inflammation and no leukocytoclastic vasculitis -Liver disease: not only affects coagulation production but also has an impact on platelet function Screening labs: PT, PTT, INR, Protein C/S, Factor V Leiden, Antithrombin III, Prothombin 22-10 gene mutations, anti- -Type I cryoglobulinemias: lymphoproliferative disorder making prothrombin antibodies, homocysteine levels monoclonal IgM = clogging up vessels → vasculopathy Treatment: -Purpura fulminans: acutely sick patient with disseminated intravascular coagulation (DIC) Targets underlying disease, often in conjunction with a hematologist. PEARL: Risk factors for acquired coagulation: immobilization, obesity, cancer, pregnancy, smoking, oral contraceptives Pigmented purpuras: Topical steroids + vitamin C 500mg BID + rutoside 50mg BID Increased platelet destruction

- ITP (Idiopathic ): autoimmune destruction of platelets due to IgG autoantibodies coating platelets and leading to macrophage destruction in the spleen

- TTP (Thrombotic Thrombocytopenic Purpura): caused by a deficiency in ADAMS TS13, an enzyme that cleaves VW factor multimers. Since these multimers build up you get platelet aggregation and thrombosis. THINK “FAT RN”: Fevers, Anemia, Thrombocytopenia, Renal, Neurologic

-DIC: massive activation of coagulation, leading to ischemia and diffuse thrombosis.

-HIT (Heparin Induced Thrombocytopenia)

Abnormal platelet function -Medications (aspirin, NSAIDs)

-Myeloproliferative disorders 56 - H&P: 31- Retiform Purpura o Are lesions inflamed or palpable? ▪ Inflammatory Retiform Purpura, leaning toward Background: vasculitis - Due to complete blockage of dermal & sub-Q vessels → o Distributed Symmetrically on UE & LE? skin infarction → hemorrhage ▪ DIC - Clinical sign hinting toward an underlying medical o Focused on the fatty areas (e.g thighs or lower condition abdomen)? ▪ Calciphylaxis or coumadin necrosis PEARL: Important to remember that retiform purpura is a o Located on cooler areas (e.g. ears or digits)? clinical sign, NOT the diagnosis! ▪ Cryoglobulinemia or levamisole-tainted cocaine - Differential Diagnosis: Think “ADVICE” o Atrophie blanche (white, angulated scarred plaque o Anti-phospholipid syndrome w/ surrounding inflammation on LE) present? o Drugs ▪ Anti-phospholipid ab syndrome ▪ Heparin & coumadin o Recent heart cath? o Vasculitis or Vasculopathies ▪ Cholesterol Emboli o Infections o Elderly pt w/ recent broken hip? ▪ Meningococcemia (N.meningitides) ▪ Fat emboli ▪ Echthyma gangrenosum (Pseudomonas) - Labs: ▪ Necrotizing fasciitis (Group A Strep or o CBC w/ diff, CMP, Coagulation Profile, Sed Rate, CRP, Clostridum) UA, Drug Tox Screen ▪ Angioinvasive fungi (Aspergillus) - Biopsy: Very Important! ▪ Disseminated strongyloidiasis o Excisional vs double-punch ▪ Brown recluse spider bites o 1) Center of lesion & 2) Edge of lesion o Calciphylaxis or Cocaine tainted w/ levamisole Treatment: o Emboli (cholesterol or fat) - Anti-phospholipid ab syndrome

o Anticoagulation Clinical Presentation: - Drugs o Heparin Necrosis = Stop Heparin + alternative - Pt present acutely/very sick in hospital anticoagulant (e.g. argatroban) - Purpura that are angulated in shape o Coumadin Necrosis = Stop Coumadin + alternative o Sometimes referred to as “branching purpura” anticoagulation + Vitamin K or Fresh Frozen Plasma o Hot Neon Pink → dark black-purple in color - Vasculitis o Tender to touch o Systemic anti-inflammatory medications (e.g. o Occurs anywhere on body but favors dependent prednisone) or steroid-sparring agent (e.g. areas (e.g. lower legs) methotrexate) o Associated w/ hemorrhagic bullae or ulcers w/in distribution - Vasculopathy o Consult Hematology - Infectious Low Occlusive Spectrum High o Bacteria: antibiotics o Fungal: anti-fungals

o Parasite: anthelmintics Livedo Reticularis Livedo Racemosa Retiform Purpura o Brown recluse: supportive + wound care - Calciphylaxis Livedo Reticularis/Livedo Racemosa o IV sodium thiosulfate + correction of serum calcium, phosphate, parathyroid hormone levels - Due to vasospasm, vascular wall inflammation, or early - Cocaine obstruction o Stop drug use - Emboli Clinical Presentation: o Cholesterol: Supportive CV measures + surgical - Erythema in a completely-connected netlike pattern, intervention usually on the extremities o Fat: Repair long bone fx +/- IVC filter or o Livedo Racemosa: Similar appearance to livedo corticosteroids reticularis w/out complete netlike connection © 2019-2020 Pearl Podcasting LLC, All Rights Reserved Diagnosis:

57 Purpuric Rash Case Study

Subjective

HPI:

Patient is a 68-year-old male who is otherwise healthy besides being obese and having a new diagnosis of hypertension in the last year. His rash has been going on for a few weeks, this is the first time he’s had it, it started on the legs and has since spread to her torso and arms in the last 2 days which prompted her ED visit, he hasn’t tried any treatments and can’t pinpoint anything that makes it better or worse. He’s otherwise had a cold recently with fatigue, sinus congestion, rhinorrhea, and a cough, but this has been improving since it started a few weeks ago. Medications include HCTZ and ibuprofen prn for sinus headaches.

ROS:

Constitutional: Fevers, chills, fatigue, night sweats, loss of appetite, and unintended weight loss

- Fevers: cutaneous small vessel vasculitis, or a septic vasculitis - Weight loss of 4kg ≥ is one of the ACR criteria for polyarteritis nodosa - B Symptoms (Fevers, chills, night sweats): ↑ suspicion of malignancy (e.g. LCV or a lymphoproliferative disorder triggering a type 1 cryoglobulinemia)

Eyes: Eye pain, vision changes, erythema

- Both eye pain + vision changes: granulomatosis with polyangiitis - Young child + ocular changes (conjunctivitis) think Kawasaki dz - Elderly + vision changes/blindness = temporal arteritis

Ears, Nose, & Throat: runny nose, nose bleeds, sinus pain; ear pain or hearing loss

- Runny nose, nose bleeds, sinus pain = granulomatosis with polyangiitis - URI/sore throat could be a sign of Strep pharyngitis = infectious trigger of CSVV

Respiratory: shortness of breath, cough (+/- productive)

- Infection/pneumonia as a CSVV trigger, but also remember that sick pts w/ purpura, pulmonary involvement may hint to any of the 3 ANCA vasculitides

Cardiac: chest pain, palpitations, and orthopnea

- CHF is the #1 killer of pts w/ Eosinophilic granulomatosis with polyarteritis

Gastrointestinal: N/V/D, abdominal pain, and hematochezia

- Gi sx can hint Henoch schonlein purpura, or maybe inflammatory bowel disease as an underlying association for a cSVV pt - Kawasaki disease pts may experience abdominal pain and diarrhea

Genitourinary: urinary frequency, urgency, dysuria, hematuria, tenderness

- UTI as trigger for cSVV - Gross hematuria = HSP or granulomatosis with polyangiitis - Testicular tenderness or pain = polyarteritis nodosa in male pts

58

Musculoskeletal: joint pain, muscle pain, or muscle weakness

- Arthralgias can be nonspecific but are seen with cSVV, urticarial vasculitis, or 75% of Henoch-Schoenlein purpura cases - Joint pain may be a sign of associated autoimmune disease or can occur in the cryoglobulinemias w/out associated autoimmune disorders as well - Muscle pain, tenderness, or weakness can be seen in polyarteritis nodosa pts

Neurological: peripheral neuropathy, numbness, tingling, or motor weakness

- Neuro changes are present in over half of PAN, GPA, and EGPA pts

Hematology: easy bruising, bleeding gums, epistaxis, lymphadenopathy

- Easy bruising, bleeding gums, or epistaxis = coagulation or platelet abnormalities - While swollen glands or lymph nodes → think malignancy or infection

Skin: pruritis, pain, and location of new lesions Objective

Physical Exam:

Vital Signs: HTN can be a sign of polyarteritis nodosa or EGPA

Ears, Nose, Throat: examine mucosa of the nose and mouth for ulcerations or the pathognomonic strawberry gums of granulomatosis with polyangiitis

Genitourinary: testicular tenderness = polyarteritis nodosa in male pts

MSK: peripheral (UE + LE) motor strength

Neuro: sensation, gait

Skin: Crucial features: 1) size of purpura 2) +/- palpable 3) +/- livedoid pattern

Other: Look for urticarial lesions = urticarial vasculitis. Also take note of whether lesions appear on areas susceptible to the cold, such as the ears.

Labs:

*There is no protocol for workup (patient dependent). Should be guided by your PE and ROS.*

Tier 1: CBC, CMP, UA as general screening.

Tier 2: If unresolved, consider LFT’s, stool guiac, coagulation profile, Sed Rate, CRP, ANA, rheumatoid factor, ASO titers, HIV, Hepatitis serologies

Tier 3: C or P ANCA, cryoglobulins, anti-phospholipid ab, C3 & C4 complement levels, SPEP, UPEP, Peripheral Blood Smear

Other work-up: Chest X-ray, punch biopsy

59

Clinical Reasoning

CBC:

- Platelet count: elevated in essential thrombocytosis or low in a variety of inherited or acquired platelet disorders (e.g. ITP) - Anemia: polyarteritis nodosa or Kawasaki disease patients, or abnormalities suggestive of a lymphoma (e.g. impressive lymphocytosis or pancytopenia) - Eosinophilia: cholesterol emboli or EGPA

CMP:

- Renal involvement w/ elevated creatinine → Henoch-Schoenlein purpura, polyarteritis nodosa, granulomatosis with polyangiitis, and microscopic polyangiitis

UA:

- Hematuria in Henoch-Schoenlein purpura, granulomatosis with polyangiitis, microscopic polyangiitis, and polyarteritis nodosa - Detects glomerulonephritis by detecting red cells, red cell casts, and protein in the urine

Coagulation Profile:

- ↑ in PT, PTT, or INR = info on coagulation status

ESR & CRP:

- Clue for systemic involvement, but they are especially helpful for Kawasaki disease and temporal arteritis

Complement Levels:

- Helpful w/ cryoglobulinemia → low in 90% of those pts - Helpful w/ urticarial vasculitis and systemic lupus, since low complement levels are associated with systemic involvement

Rheumatoid Factor:

- Positive in over 70% of cryoglobulinemia cases → cryoglobulinemia types 2 and 3 are caused by a mix of antibodies in a patient’s system

Hepatitis Panel:

- Hep B & C can be associated with polyarteritis nodosa and cryoglobulinemia

Tox Screen:

- If considering, cocaine (levamisole-induced vascular lesions) → tox screen can help clinch the diagnosis

Biopsy:

- You perform two lesional punch biopsies, one for H&E and the other for DIF - Biopsy shows vasculitis present or not. If +, categorized based on the vessel size involved. If -, then consider vasculopathy → hematology referral

DIF

- IgA deposition in and around small blood vessels = Henoch-Schoenlein

60 - DIF will also be positive in ~ 70-80% of several other types of vasculitis, including cSVV, urticarial vasculitis, and Polyarteritis nodosa = perivascular C3 and IgM, IgA, or IgG Assessment

1) Cutaneous Small Vessel Vasculitis Plan

1) Supportive Care - Treat any underlying infections, stop or switch any meds you suspect are playing a role, and then tell patient elevate and compress their legs, which is often the most severely affected area for cSVV pts - If your cSVV patients are itchy, you can add on antihistamines, topical steroids, or other topical treatments for pruritus such as calamine lotion - If patients aren’t getting better with supportive measures or they are severely affected, that’s when you reach for systemic medications such as colchicine, dapsone, prednisone, or other systemic immunosuppressants

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61 o Median age of 33- Vascular Lesions involution is 3 years old and lesions are more Pre-Quiz: persistent if they’re present after 4 years of 1. What is the difference between a vascular age tumor and malformation, and what is an 3. What does PHACES syndrome stand for? example of each? • Posterior fossae malformations - • Vascular tumors (either benign or e.g. Dandy Walker malformations malignant) represent a • - extensive on the proliferation of normal-appearing face and often segmental cells or structures • Arterial anomalies - e.g. aneurysms o e.g. hemangiomas or or anomalous branches of internal pyogenic granuloma carotids or cerebral arteries • Vascular malformations involve an • Cardiac anomalies - e.g. atrial or error in the development of blood ventricular septal defects or vessels coarctation of the aorta o Tend to be present at • Eye abnormalities - e.g. cataracts birth and persist for a or retinal vascular changes patient’s lifetime • Sternal clefting or Supraumbilical o e.g. capillary raphe malformations (port wine stains), New Vascular Reaction Pattern Order for lymphangiomas Easier Memorization 2. How do we categorize hemangiomas, and how do you counsel parents on what to 1. Urticaria expect? 2. Erythema multiforme – 2 forms (EM Major, • Two categories: EM minor) o Congenital - present at 3. The toxic erythema group with the three birth subclasses ▪ rapidly involuting a. Drug - drug eruptions like SJS congenital b. Bug - viral exanthems hemangiomas c. Toxin - toxin-mediated eruptions (RICH) or including staph scalded skin noninvoluting syndrome, Toxic shock syndrome, congenital scarlet fever, and Kawasaki disease hemangiomas 4. The four figurate erythemas (NICH) a. erythema annulare centrifigum o Infantile - develop after b. erythema gyratum repens birth, usually within the c. erythema migrans first few weeks of life d. erythema marginatum • We expect them to eventually go 5. Vasculitis - inflammation of the blood vessel away wall o They resolve at a rate of 6. Vasculopathy - vascular damage in the 10% per year, with 50% absence of vasculitis of lesions gone by age 7. Retiform purpura 5, 70% by age 7, 90% by 8. Vascular growths - including and 9 years old vascular malformations.

62 Infantile Hemangiomas

Background: - Pediatric neurology/cardiology + ophthalmology consults - Extremely common, affect between 2-12% of infants PEARL: Neonates with a red patch in V1 need to be followed closely on a weekly basis, since - Risk Factors: early hemangiomas can look exactly like a port o Female sex wine stain one day and then develop the classic o Premature birth elevation of hemangiomas within days to weeks o Advanced maternal age o Placental abnormalities - e.g. placenta previa Nevus Flammeus (aka Port Wine Stain) o Pre-eclampsia Background: Clinical Presentation: - Congenital capillary malformations that are - Up to 50% start with a precursor lesion present at birth such as a red patch or telangiectasias - Associated with Sturge-Weber Syndrome - Typically superficial and have a bright red o Infants with an extensive port wine color, but can have deeper components stain in a V1 nerve distribution on that take on a blue hue the forehead are at risk of Sturge- o 25% of cases can be a mix of Weber syndrome superficial and deep components - Grow rapidly during the first 5 months of Clinical Presentation: life, plateau between 9-12 months, slowly involute thereafter - Start as a pink to red patch - Well-demarcated Diagnosis: - DO NOT rapidly proliferate and simply grow slowly with the patient - Reasons for aggressive treatment/workup - DO NOT SELF RESOLVE and actually can o Ulceration - more aggressive become thickened and bumpy or papular treatment needed later in life o Threaten function by involving the - Sturge-Weber syndrome has a triad of a periocular area, nose, ears, lips, or port wine stain in a V1 distribution, genitals leptomeningeal angiomatosis (usually o Extensive in the beard area - 60% presents with seizures), and glaucoma risk of airway involvement o Large/segmental in a V1 nerve Treatment: distribution on the face - ↑ risk of PHACES syndrome - Pediatric neurology + ophthalmology + ▪ Brain MRI and radiology consults echocardiogram o Large/segmental in the PEARL: Do NOT mix up the association between V1 lumbosacral area - ↑ risk of LUMBAR/SACRAL syndrome port wine stains with Sturge-Weber syndrome and the V1 ’s association with PHACES syndrome. Treatment:

- Topical timolol or Oral Propranolol: rule out arterial and cardiac anomalies first if PHACES concern

63 Nevus Simplex Pyogenic Granuloma

Background: Background:

- the most common vascular malformation - Typically affect children and young adults affecting ~1/3 of newborns - Triggers: - aka salmon patch, stork bite, or angel kiss o minor trauma in about 1/3 of cases o pregnancy Clinical Presentation: o medications - e.g. systemic retinoids like isotretinoin and oral - Presents as a pink, blanchable patch that is contraceptive pills often located in the midline of the occiput more so than the face or low back Clinical Presentation: - Compared to a port wine stain, a nevus simplex is lighter in color, is less well- - Start as a friable, red papule that grows demarcated, and usually resolves if it is on relatively quickly over the course of weeks the face to a few months - Tend to appear on the trauma-prone sites of the gingiva, lips, fingers, or face - Typically solitary, but there can be multiple lesions at times

PEARL: Use the full name pyogenic granuloma and do not call it a PG, because people often use PG to describe pyoderma gangrenosum, which is a completely different condition. Abbreviations are helpful in dermatology, but pyogenic granulomas and pyoderma gangrenosum are two conditions where you will probably want to avoid using the abbreviation PG.

64 Angiokeratomas Tufted Angioma

Background: - Classically pink-red plaques on the neck of children less than 1 year of age - Angio = superficial vascular nature, - Can be associated with the Kassabach- keratoma = hyperkeratotic look Merritt phenomenon (KMP) o Refers to when platelets are trapped and destroyed in vascular Clinical Presentation: lesions, leading to rapid lesion growth and coagulopathies - 5 types: o Solitary or multiple PEARL: KMP is classically seen in tufted angiomas or angiokeratomas kaposiform hemangioendotheliomas (KHE). ▪ Tend to favor the lower Remember that these two lesions TAKHE away extremities platelets, with TAKHE spelled T-A-K-H-E and standing o Angiokeratomas of Fordyce for Tufted Angioma and Kaposiform ▪ Classically appear on the HemangioEndothelioma. scrotum or vulva of older patients Glomus Tumor o Angiokeratoma corporis diffusum ▪ Often clustered in a

bathing suit distribution - Classically present as solitary painful red and is associated with papule on the finger

Fabry’s disease - Can cause significant nail dystrophy o Angiokeratoma circumscriptum ▪ Appears as coalescing Angiolymphoid Hyperplasia with angiokeratomas Eosinophilia (ALHE) developing into a plaque in children Background: o Angiokeratoma of Mibelli ▪ Occurs in teenagers most - Occur in young to middle-aged adults often on the hands and feet Clinical Presentation:

Histology: - Presents as grouped, pink to red-brown - Dilated vessels in the papillary dermis dome-shaped papules classically by the ear - Acanthotic or thickened epidermis but can be anywhere on the head and neck

PEARL: At first glance, angiokeratomas basically look Histology: like a bloody on path. - Proliferation of vessels in the dermis with large epithelioid endothelial cells - Background of lymphocytic and eosinophilic inflammation

Treatment:

- Variety of treatments: o Excisional surgery - most common o Cryotherapy o Intralesional Kenalog o Imiquimod

65 Kaposi’s Sarcoma (KS) Angiosarcoma

Background: - High-grade malignant vascular tumor - Classically presents in an elderly Caucasian - Low-grade vascular tumor man with a bruise-like patch, plaque, or nodule on their face or scalp that is Clinical Presentation: progressively enlarging - 5 year survival of <20% - 4 types: o Classic KS PEARL: You have a patient with history of mastectomy and chronic lymphedema of their arm ▪ Consists of slow from the axillary lymph node dissection, and they enlargement of macules start to develop purpuric papules and plaques of into vascular plaques and that limb. What do you they have? This vignette nodules on the legs of describes Stewart-Treves syndrome, which describes older men with a the development of angiosarcoma in an area of Mediterranean chronic lymphedema. It usually takes at least 4 background years of problems with lymphedema before the o African endemic KS angiosarcoma develops in the affected area. ▪ Affects young African males in endemic areas

▪ Can be fatal o Iatrogenically

immunocompromised KS ▪ Typically skin-limited

▪ Occurs in patients on immunosuppressive medications for organ transplants or autoimmune disease o AIDS-associated KS ▪ Caused by HIV

Histology: - Stain for Human Herpes Virus-8 (HHV-8) on

path to confirm diagnosis because it is present in 100% of lesions

Treatment:

- Variety of treatments: o Cryotherapy o Alitretinoin - topical retinoid o Systemic chemo for progressive cases with internal organ involvement

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