General Dermatology

and Milind G. Parikh3, 2



(1)
University of Florida, College of Medicine, Gainesville, FL, USA

(2)
Private Practice:, Orlando, FL, USA

(3)
Department of Internal Medicine/Cardiology, University of Central Florida College of Medicine, Orlando, FL, USA

 



Keywords
AcnePsoriasisDermatitisHairPhotodermatosesPregnancy dermatosesRosaceaLichen planusAllergensANA



3.1 Acne and Related Conditions



A. Acne Vulgaris and Special Forms (Tables 3-1, 3-2)



Acne Vulgaris





  • Inflammation of the pilosebaceous unit (PSU) causing comedones, papulopustules and nodules


  • Four key pathogenic factors



    • Abnormal follicular keratinization



      • ↑ Corneocyte cohesiveness and proliferation


    • Propionibacterium acnes ( P. acnes ) in sebum



      • Gram + anaerobic rod, resident flora in follicle but acne patients with higher concentration


      • Naturally produces porphyrins (coproporphyrin III), which is the target of light-based acne therapy


      • Secretes lipases which cleave lipids in sebum into pro-inflammatory free fatty acids (FFAs), which are both comedogenic and chemotactic


      • Binds/activate toll-like receptor 2 (TLR2)


    • Inflammation



      • IL-1, IL-8, and TNF-α through TLR-2 pathway


    • Hormonal effect on sebum due to androgens



      • ↑ Sebum production due to androgen-stimulated sebaceous glands


      • Androgen receptors present on basal layer of sebaceous gland and ORS of hair follicle; respond to most potent androgen, dihydrotestosterone (DHT), and testosterone (latter produced by gonads and can be converted to DHT via 5α reductase)


      • Dehydroepiandrosterone sulfate (DHEA-S): weak androgen produced by adrenal glands


  • Microscopic precursor lesion: microcomedo


  • May present with non-inflammatory comedones (open/closed), inflammatory papules, pustules, ± nodules


  • Histology: follicular distension often with ruptured PSU and accompanying brisk inflammatory response, ± foreign body reaction with multinucleated giant cells


  • Treatment:


















Topical therapy

Benzoyl peroxide, retinoids (tretinoin, adapalene, tazarotene), azelaic acid, dapsone, clindamycin, sodium sulfacetamide/sulfur and salicylic acid

Topical retinoids: comedolytic and downregulate TLR-2

Other therapies

Oral antibiotic, isotretinoin, oral contraceptive pill, spironolactone; photodynamic therapy or blue light alone

Cannot combine isotretinoin and tetracycline due to risk of pseudotumor cerebri


A327767_2_En_3_Fig1_HTML.gif


Figure 3.1:
A: Acne conglobataB: Acne excoriéeC: Acne in PCOS



Table 3-1:
Acne Variants





































Type

Clinical Features

Acne fulminans

– Severe form of nodulocystic acne in young males (13-16 years old)

– Presents with sudden-onset suppurative nodular acne with ulceration, eschars and systemic symptoms (may include myalgias, arthralgias, fever, ↑ ESR, ↑ WBCs, ± sterile osteolytic bone lesions typically over clavicle or sternum)

– Treat with low-dose isotretinoin and prednisone or prednisone alone initially,

followed by isotretinoin to prevent flare and formation of granulation tissue

Acne conglobata

(Figure 3.1A)

– Acute-onset nodulocystic acne without systemic manifestations

– Part of the follicular occlusion triad (dissecting cellulitis of scalp, pilonidal cyst and hidradenitis suppurativa)

Acne excoriée

(Figure 3.1B)

– Mainly seen in young women with emotional or psychological disorders (such as obsessive-compulsive disorder) who repeatedly pick at lesions

– Presents as mild acne with several excoriations, crusted erosions and sometimes ulcerations with subsequent scarring

– Antidepressants may be warranted

Acne with underlying endocrinologic abnormality

(Figure 3.1C)

– If acne with accompanying hirsutism ± irregular menses, check lab work for hormonal abnormality (check LH, FSH, DHEA-S, free and total testosterone)

– Source of androgens:  ovarian androgens: testosterone

           adrenal androgens: DHEA-S, 17-hydroxyprogesterone

Polycystic ovarian syndrome (PCOS):

– Seen in 5-10% of women of reproductive age

– Androgen excess causing hirsutism, irregular menses, ± polycystic ovaries, ± obesity, insulin resistance, ↑ LH/FSH ratio, ↓ fertility, ↑ testosterone

– Acne lesions typically nodular; involve lower ½ of face (especially jawline)

– Treatment: oral contraceptive pill (resulting in ↑ SHBG, ↓ free testosterone), spironolactone (off-label, blocks androgen receptor)

Late congenital adrenal hyperplasia

– ↑ DHEA-S or 17-hydroxyprogesterone due to partial deficiency of

adrenal enzymes (commonly 21-hydroxylase or 11-hydroxylase)

Industrial acne

– Due to exposure to insoluble cutting oils or chlorinated aromatic hydrocarbons (such as chlorinated dioxins and dibenzofurans)

– Chloracne (form of industrial acne): presents with comedones, pustules and cysts over malar cheeks, retroauricular region, and scrotum

Acne mechanica

– Due to repeated obstruction of the pilosebaceous unit through friction/pressure

Neonatal acne (Cephalic neonatal pustulosis)

– Begins around 2 weeks of age and often resolves by 3rd month of age

– Presents with erythematous small papules on cheeks

Infantile acne

– Typically begins around 3-6 months of age, resolves within 1-2 years

Drug-induced acne

(Acneiform eruption)

– Due to corticosteroid, phenytoin, lithium, isoniazid, iodides, epidermal growth factor receptor inhibitors (EGFRI: cetuximab, erlotinib, gefitinib), anabolic steroids

– Presents with abrupt-onset monomorphic-appearing papules and pustules; comedones typically not seen



Table 3-2:
Syndromes Associated with Acne



















Syndrome

Clinical Features

PAPA syndrome

Pyogenic Arthritis (sterile), Pyoderma gangrenosum, Acne

– Inherited (AD), CD2 binding protein 1 (CD2BP1) mutation; CD2BP1 is a pyrin-interacting protein, which is part of inflammatory pathway associated with familial Mediterranean fever, Muckle-Wells syndrome, and familial cold urticaria

– Skin changes typically present near or at puberty

HAIR-AN

HyperAndrogenism, Insulin Resistance, Acanthosis Nigricans

SAPHO(Chronic recurrent multifocal osteomyelitis)

Synovitis, Acne (conglobata), Pustulosis (palmoplantar), Hyperostosis, Osteitis

– Inflammatory bone changes (commonly involving sternoclavicular joint, spine {spondyloarthropathy} and long bones); peripheral arthritis also common

– 1st line treatment: bisphosphonates suggested in many case reports and series; other treatments include mainstay therapies for psoriatic arthritis (methotrexate, anti-TNFα agents, etc)


B. Acneiform Conditions



Gram-Negative Folliculitis





  • Exacerbation of acne after long-term antibiotic use


  • Presents with centrofacial pustules, especially perinasal


  • Treat with isotretinoin if severe or recurrent


Acne Keloidalis Nuchae (Figure 3.2A)





  • Chronic folliculitis of occipital scalp and posterior neck in men of African, Hispanic or Asian descent


  • Presents initially as inflammatory follicular papules and pustules which over time evolve into firm, dome-shaped papules with fibrosis, ± coalesce into keloidal plaques


  • Treatment: avoid mechanical irritation; mixture of tretinoin and potent corticosteroid gel (if noninflamed), topical and/or systemic antibiotics, punch excision or intralesional corticosteroid injection for papules/keloids, laser epilation


Pseudofolliculitis Barbae (Figure 3.2B)





  • Inflammatory condition typically in men of African descent, especially with tightly curled hair


  • Distal end of curved hair penetrates epidermis and dermis after being shaved → subsequent foreign-body inflammatory reaction


  • Inflammatory papules, pustules and sometimes abscesses in beard region and anterolateral neck; may form hypertrophic scars and keloids


  • Treatment: topical or systemic antibiotics, topical corticosteroid, topical clindamycin/benzoyl peroxide; prevention with clippers, chemical depilatories and glycolic acid lotion



A327767_2_En_3_Fig2_HTML.gif


Figure 3.2:
A: Acne conglobata, shoulderB: Acne keloidalis nuchae


Perioral Dermatitis (Periorificial Dermatitis) (Figure 3.3A)





  • Distinctive dermatitis with discrete papules and pustules with erythematous, sometimes scaly, base around the mouth, nose, and possibly periorbital area


  • Previous use of fluorinated topical steroid may cause or exacerbate condition


  • Treatment: oral tetracycline, topical metronidazole, azelaic acid, and/or sodium sulfacetamide/sulfur


Acne Inversa (Hidradenitis Suppurativa) (Figure 3.3B)





  • Chronic inflammatory and scarring disease of apocrine gland-bearing skin sites (axillae and anogenital area)


  • Initially thought to be due to obstruction of apocrine glands, but now thought to be from occlusion of follicular infundibula with subsequent rupture of the follicle and surrounding inflammation


  • Presents with double-ended comedones, tender nodules and sterile abscesses in groin, axillae, perianal and/or inframammary region; sequelae include sinus tracts, chronic drainage, and scarring (hypertrophic scars, rope-like elevation of skin, dermal contractures)


  • Histology: follicular hyperkeratosis, rupture of follicular epithelium, heavy inflammatory infiltrate (lymphocytes, neutrophils, plasma cells) around hair follicles ± sweat glands (sometimes extending to apocrine glands), abscess formation, foreign body-type granulomas, fibrosis in late stages


  • Treatment: weight reduction, smoking cessation, antiseptic soap, absorbent powder, topical aluminum chloride, intralesional corticosteroid injection into early inflammatory lesions, adalimumab, systemic corticosteroids (but typically flare when discontinued), isotretinoin (results often disappointing), acitretin, surgical excision and grafting; avoid incision and drainage (can result in scarring and chronic sinus tract formation)


Fox-Fordyce Disease (Figure 3.3C)





  • Chronic pruritic disorder of the apocrine glands due to obstruction and dilation


  • Intensely pruritic, dome-shaped flesh-colored follicular papules in axillae, ± anogenital and periareolar skin


  • Treatment (difficult): topical and intralesional corticosteroids, topical tretinoin, cleocin lotion



A327767_2_En_3_Fig3_HTML.gif


Figure 3.3:
A: Perioral dermatitisB: Hidradenitis suppurativa(Courtesy of Dr. Sima Jain)C: Fox-Fordyce disease(Courtesy of Dr. Sophie M. Worobec)


C. Rosacea (Figure 3.4A-C)






  • Chronic inflammatory condition of facial pilosebaceous units with increased vascular hyperreactivity; common in fair-skinned patients with peak in the 3rd to 5th decade


  • Presents with easy flushing and gradual reddening of complexion; exacerbating factors may include particular foods (especially spicy), alcoholic beverages, UV exposure, hot weather, warm beverages, and exercise























Type

Clinical Findings

Erythematotelangiectatic

(Type 1)

Prolonged flushing (>10min), persistent central facial erythema, ± telangiectasias, ± burning/stinging sensation, easy irritation

Papulopustular

(Type 2)

Persistent central facial erythema with acneiform pustules and papules (no comedones)

Phymatous

(Type 3)

Indurated erythematous to yellow-brown papules/nodules with persistent edema; almost exclusively in men; rhinophyma (subtype) over distal half of nose; less common sites include forehead, chin, philtrum, ears and eyelids

Ocular

(Type 4)

Xerophthalmia, tearing, pain, blurry vision, blepharitis, conjunctivitis, recurrent chalazion, keratitis, iritis, scleritis





  • Steroid rosacea: use of oral/topical corticosteroid results in exacerbation of disease after initial improvement


  • Granulomatous rosacea: red-brown papules/nodules with underlying granulomatous inflammation


  • Histology: early lesions with dilated blood and lymphatic vessels; later lesions show lymphectasia, perivascular and perifollicular lymphohistiocytic infiltrate, ± poorly organized granulomas, dermal fibrosis, sebaceous gland hyperplasia, ± Demodex folliculorum mites within infundibula


  • Treatment:



    • Sun protection and avoidance of triggers, green-tinted makeup (conceals redness)


    • Topical therapy: metronidazole or azelaic acid best for inflammatory lesions, sodium sulfacetamide/sulfur, topical brimonidine (best for erythema)


    • Oral therapy: tetracyclines, macrolides, isotretinoin


    • Other: pulsed-dye laser or intense pulsed light for erythema/telangiectasias, CO2 laser for phymatous rosacea


A327767_2_En_3_Fig4_HTML.jpg


Figure 3.4:
A: Rosacea, papulopustular(Courtesy of Dr. Paul Getz)B: Rosacea, granulomatous(Courtesy of Dr. Iris K. Aronson)C: Rhinophyma


D. Rosacea Variants



Lupus Miliaris Disseminatus Faciei (Figure 3.5A)





  • Yellow-brown to red small monomorphic smooth papules on malar cheeks and periorifically


  • Lack history of flushing and lack telangiectasias


  • Histology: prominent small granulomas, ± central necrosis or caseation


  • Treatment: long term therapy with minocycline or isotretinoin


Pyoderma Faciale (Rosacea Fulminans) (Figure 3.5B)





  • Mainly seen in postadolescent females; may be rare variant of rosacea


  • Presents with acute onset of erythematous papules, pustules, nodules and abscesses in centrofacial region with background of dull cyanotic erythema, ± draining sinuses; ± mild systemic symptoms (myalgias, fever,↑ ESR, ↑ WBC)


  • Treatment: initial use of oral corticosteroid followed by low-dose isotretinoin and slow taper of corticosteroid


Morbihan’s Disease (Solid Facial Edema)





  • Presents with woody, nonscaling edema involving midline face and cheeks


  • Treatment: isotretinoin ± ketotifen × 4-5 months


3.2 Papulosquamous, Lichenoid and Eczematous Dermatoses



A. Papulosquamous Dermatoses



Psoriasis Vulgaris with Subtypes (Figure 3.5C, 3.6A-C)





  • Polygenic inflammatory disease with chronic, recurrent course; affects 2% of population


  • Bimodal onset with 3rd or 6th decade; earlier onset associated with more severe disease


  • Pathogenetic factors



    • Abnormal T cell activation



      • Thought to be mediated by new distinct type of T helper cell, Th17 cells; T cell-mediated autoimmunity toward poorly defined antigens


      • Cytokine profile:



        • ↑ IL-2, IFNγ (Th1 cytokines)


        • ↑ IL-1, IL-6, TNFα (innate cytokines)


        • ↑ IL-12 (stimulates Th1 cells)


        • ↑ IL-23 (stimulates Th17 cells)


        • ↑ IL-22, IL-17, TNFα (Th17 cytokines)


        • IL-22 correlates with disease severity


        • T cell disease supported by response to T cell inhibitors like cyclosporine; worsening through IFNγ

IL-12 and IL-23 have common subunit p40: target of ustekinumab



A327767_2_En_3_Fig5_HTML.gif


Figure 3.5:
A: Lupus miliaris disseminata(Courtesy of Dr. Iris K. Aronson)B: Pyoderma faciale(Courtesy of Dr. Paul Getz)C: Plaque psoriasis





  • Abnormal keratinocytes



    • ↑ Mitotic activity and leukocyte recruitment; keratinocytes move to upper layer in 3–5 days (vs. normal 28 days)


    • ↑ Human β-defensin-2 (hBD2), secretory leukocyte protease inhibitor (SLPI), and skin-derived anti-leukoproteinase (SKALP): antimicrobial peptides resulting in ↓ risk of secondary infection


    • ↑ Involucrin in all layers (except basal)


    • Shed without loss of nucleus (parakeratotic scales)


    • Epidermal expression of STAT-3, which induces upregulation of TGFα and ICAM-1


    • Secrete IL-1, TNFα, IL-6, IL-8 (chemoattractant)


  • Genetics (polygenic and multifactorial)



    • HLA associations:


    • Cw6 (strongest) associated with early onset


    • B13, DR7, B17, B57 associated with earlier onset


    • B27 associated with psoriatic arthritis


    • A2 and Cw2 (weaker association)

B13, B17, Cw6: guttate psoriasis





  • In moderate to severe psoriasis, ↑ risk of cardiovascular disease; other comorbidities may include hypertension, obesity, dyslipidemia, diabetes mellitus; may also have ↑ risk of developing cancer particularly nonmelanoma skin cancer, lymphoma and lung cancer (according to recent study); common genetic factors (B27) may also cause ↑ incidence of inflammatory bowel disease


  • Triggering factors: physical trauma (Köebner phenomenon), infection (especially streptococcal pharyngitis), stress and medications (lithium, β-blocker, antimalarial, IFN, ACEI, NSAID, withdrawal of systemic corticosteroid, G-CSF)


  • Chronic plaque psoriasis presents with erythematous, scaly sharply-bordered macules, papules and plaques covered with silvery scale over extensor surfaces (knees, elbows), scalp, gluteal cleft, ± genitalia, ± intertriginous areas; chronic course with flares


A327767_2_En_3_Fig6_HTML.jpg


Figure 3.6:
A: Plaque psoriasisB: Plaque psoriasis(Courtesy of Dr. Paul Getz)C: Guttate psoriasis





  • Guttate psoriasis (Figure 3.7A) presents with acute-onset rain drop-like scaly papules on the trunk and extremities often in young patients; frequently preceded by streptococcal infection and eruption usually resolves completely within few months (may turn into chronic plaque psoriasis in adults)


  • Special locations:



    • Palms and soles (palmoplantar psoriasis)


    • Intertriginous areas (inverse psoriasis)


  • Psoriatic nails (Figure 3.7BC): may affect nail matrix, bed or plate; may be sole involvement or part of extensive disease



    • Pitting (nail matrix → focal parakeratosis in nail plate)


    • Leukonychia (nail matrix)


    • Onychodystrophy (nail matrix ± bed → subungual hyperkeratosis)


    • Oil spots (nail bed → yellow brown spots)


    • Onycholysis (nail bed → separation of plate from bed)


    • Splinter hemorrhages (↑ capillary fragility in nail bed)


  • Erythroderma (Figure 3.7C)



    • Generalized erythema and scaling (>90% skin surface affected), ± leukocytosis, ↑ ESR, lymphadenopathy; may develop suddenly from guttate or stable psoriasis but typically due to inappropriate treatment of disease


  • Histology: confluent parakeratosis (focal in guttate), hyperkeratosis, collection of neutrophils in s. corneum (Munro microabscesses) and spinous layer (spongiform pustules of Kogoj), hypogranulosis, acanthosis with clubbed rete ridges, suprapillary thinning, dilated blood vessels in papillary dermis, perivascular lymphocytes


  • Treatment:



    • Topicals



      • Vitamin D3 analogues (ie. calcipotriol, calcipotriene)


      • Corticosteroids


      • Calcineurin inhibitors (pimecrolimus/tacrolimus for intertriginous areas)


      • Tazarotene


      • Coal tar


      • Anthralin


      • Fixed combination betamethasone dipropionate/calcipotriol


    • Oral



      • Apremilast


      • Acitretin


      • Methotrexate


      • Cyclosporine


    • Other:



      • TNFα inhibitors, IL-17 inhibitor and p40 (IL-12/IL-23) inhibitor


      • Phototherapy (PUVA, NBUVB)

        Excimer laser

Topical calcipotriene may be inactivated in acidic environment (ie. salicylic acid)



A327767_2_En_3_Fig7_HTML.gif


Figure 3.7:
A: Guttate psoriasisB: Psoriasis involving nailC: Erythrodermic psoriasis(Courtesy of Dr. Paul Getz)


Pustular Psoriasis (Figure 3.8A-C)





  • Distinct from psoriasis vulgaris in both features and clinical course


  • ↑ HLA-B27 incidence


  • Two types: generalized and localized (palmoplantar pustulosis, acrodermatitis continua suppurativa)


  • Generalized (von Zumbusch)



    • Presents initially with malaise and fever, subsequent onset of erythematous macules studded with sterile pustules; initially in intertriginous areas but quickly spreads to trunk, extremities and nails (skin feels painful), ↑ risk for infection


    • Risk factors: tapering oral corticosteroid, infection, hypocalcemia, pregnancy (impetigo herpetiformis)


    • Labs: leukocytosis, hypoalbuminemia


    • Treatment: correct electrolyte and protein imbalance, methotrexate or cyclosporine (avoid systemic corticosteroid), later treatment can include photherapy or biologic treatment


  • Palmoplantar pustulosis



    • Tense, sterile pustules over palmoplantar surface with yellow-brown macules; may be associated with SAPHO syndrome (so prudent to inquire about any sternoclavicular tenderness and/or back pain)


    • Treatment: acitretin, topical corticosteroid


  • Acrodermatitis continua of Hallopeau



    • Variant of pustular psoriasis limited to finger tip or digit; HLA-B27 association


    • Presents with sterile pustules on erythematous base at tip of finger (less likely on toe) forming lakes of pus, associated pain and impaired use of digit; if pustules within nail bed, nail will typically be shed; may have loss of bony structures


    • Treatment: topical calcipotriene, topical corticosteroid, acitretin


Psoriatic Arthritis (Table 3-3)





  • Up to 30% of patients with psoriasis have arthritis; associated with moderate to severe psoriasis and typically occurs several years after appearance of skin lesions


  • Rheumatoid factor negative (seronegative) arthritis; HLA-B27 association


  • Tendons and ligaments often involved (enthesopathy or enthesitis) in addition to bone and cartilage


  • ↑ TNFα level in synovium and serum in patients with psoriasis and psoriatic arthritis


  • Almost all patients with psoriatic arthritis have nail changes (up to 20% may have no skin findings)


  • Common features include pain at tendon insertion sites, digital involvement and sacroiliac disease, asymmetric joint involvement, negative rheumatoid factor, morning stiffness lasting more than 1 hour


  • Treatment: TNFα antagonists, IL-17 inhibitor, p40 (IL-12/IL-23) inhibitor, oral apremilast, methotrexate, NSAIDs, cyclosporine, sulfasalazine



A327767_2_En_3_Fig8_HTML.gif


Figure 3.8:
A: Pustular psoriasisB: Palmoplantar psoriasis(Courtesy of Dr. Paul Getz)C: Palmoplantar psoriasis(Courtesy of Dr. Paul Getz)



Table 3-3:
Forms of Psoriatic Arthritis
































Type of Arthritis

%

Salient Features

Asymmetric oligoarthritis

70%

Single or multiple distal joints in hands or feet involved; synovitis and joint swelling, ± swelling of digit (dactylitis or ‘sausage finger’); knees, ankles and sometimes axial involvement (if HLA-B27 positive) may also occur

Asymmetrical DIP arthritis

5-10%

Single or multiple DIP joint involvement; periarticular swelling with concomitant nail involvement

Symmetrical polyarthritis (RA-like)

15%

Involvement of small and medium-sized joints (PIP, MCP, wrists, elbows); difficult to distinguish from rheumatoid arthritis (RA); usually seronegative

Spondylitis and sacroiliitis

5%

Typically in men and resembles ankylosing spondylitis, with addition of knee and sacroiliac involvement, ± peripheral joint involvement, ± inflammatory bowel disease or uveitis, often positive for HLA-B27

Arthritis mutilans

5%

Digits become shorter, wider, softer due to osteolysis of phalanges and metacarpals; results in telescoping motion of digits

X-ray findings: ‘pencil in cup’ deformity (distal head of bone apearing sharpened like a point) fusiform tissue swelling (‘sausage digit’), tuft resorption, eccentric erosions


Reactive Arthritis (Reiter’s Disease) (Figure 3.9)





  • Autoimmune condition that develops in response to infection in another part of the body (cross reactivity)


  • Linked to two factors



    • Genetic factor: HLA-B27


    • Exposure to pathogen



      • May follow urethritis after exposure to GU pathogens (likely Chlamydia trachomatis)


      • May follow GI infection after exposure to enteric pathogens such as Campylobacter spp., Shigella flexneri, Ureaplasma urealyticum, Salmonella spp., or Yersinia spp.


  • Bacterial antigen mimics portion of HLA molecule with subsequent dysregulation of immune control mechanism


  • More common and severe in HIV patients; may be presenting sign of HIV


  • Presentation



    • Peripheral arthritis > 1 month duration, with


    • Associated urethritis or cervicitis


    • Other findings: urethritis, conjunctivitis, fever weakness, weight loss, erythema nodosum


A327767_2_En_3_Fig9_HTML.jpg


Figure 3.9:
Circinate balanitis(Reprint from Burgdorf WH, Plewig G, Wolff HH, Landthaler M, eds. Braun-Falco’s Dermatology. 3rd ed. Heidelberg: Springer; 2009.)





  • Skin findings in 5% patients: psoriasiform lesions similar to psoriasis



    • Keratoderma blenorrhagicum: thick plaques with pustules and erythema on plantar surfaces


    • Circinate balanitis: circinate erythematous lesions on glans penis (almost pathognomonic)




  • Classic triad: urethritis, arthritis, conjunctivitis


  • Treatment: treatment of any triggering infection (doxycycline 100mg bid × 14 days); arthritic symptoms may treat with biologic agent, methotrexate, cyclosporine, acitretin or NSAID; cutaneous lesions with high-potency topical corticosteroid


Pityriasis Rubra Pilaris (PRP)





  • Disorder of keratinization with bimodal distribution involving children and adults, nearly always acquired (occasional familial cases described)


  • Presents with follicular hyperkeratotic papules on erythematous base, which coalesce into large orange-red to red patches with characteristic ‘islands of sparing’; palms and soles with waxy orange-red keratoderma; may rapidly evolve into erythroderma; nail changes include subungual hyperkeratosis and nail plate thickening


  • 5 types: Type I and II in adults, Type III-V in children (see Chapter 2 for pediatric types)


  • Type I (classic): over half of all cases; sudden onset of symptoms with duration of 2-5 years


  • Type II (atypical): about 5% cases, slow onset with alopecia, localized lesions and chronic course


  • Histology: acanthosis, thickened granular layer, ‘checkerboard parakeratosis’ (orthokeratosis alternating with parakeratosis both vertically and horizontally), ‘shoulder parakeratosis’ adjacent to follicular plugs, perivascular lymphocytic infiltrate


  • Treatment: high potency topical corticosteroid, systemic retinoid, methotrexate, ± phototherapy, azathioprine, infliximab


B. Lichenoid Dermatoses



Lichen Planus (Figure 3.10A-C, 3.11A-C, Table 3-4)





  • Pruritic papular disease of skin and mucous membranes


  • Due to cell-mediated autoimmune reaction toward basal layer keratinocytes; may be idiopathic, drug-related or infection-related (HCV)


  • 4P’s: papular, pruritic, polygonal, purple


  • Often lasts 1-2 years (except oral and hypertrophic forms, which typically have protracted courses)



A327767_2_En_3_Fig10_HTML.jpg


Figure 3.10:
A: Annular lichen planus(Courtesy of Dr. Paul Getz)B: Blaschkoid lichen planus(Courtesy of Dr. Iris K. Aronson)C: Oral lichen planus(Reprint from Norman R, ed. Diagnosis of aging skin diseases. London: Springer; 2008.)



Table 3-4:
Types of Lichen Planus


































































Type

Description

Acute LP

Eruptive lichenoid papules with wide distribution, heals with hyperpigmentation; self-limited (typically resolves within 9 months)

Actinic LP

Photosensitive variant of LP with melasma-like appearance or lichenoid papules over face, neck and dorsal hands; typically in children and young adults with spring or summer onset (some consider entity as lichenoid form of PMLE)

Annular LP

Annular papules and plaques with central clearing (commonly over penis)

Atrophic LP

Lichenoid papules replaced with depressed atrophic areas typically over lower legs, ± residual hyperpigmentation; resembles lichen sclerosus clinically

Bullous LP

Vesicles and bullae arising within existing LP lesions (intense inflammatory reaction at dermoepidermal junction causes subepidermal bullae)

Drug-induced LP

Distribution typically generalized or sun-exposed sites; Wickham’s striae uncommon; ± eosinophils and parakeratosis on histology; medication typically taken for several months before eruption appears

Common meds: β-blockers, captopril, penicillamine, HCTZ, antimalarials, furosemide, quinidine, NSAID, tetracycline, quinacrine, gold, sulfonylureas, hydroxyurea, methyldopa

Erosive or ulcerative LP

Painful, chronic, recalcitrant erosive lesions especially on oral mucosa and palmoplantar surface; small ↑ risk of SCC within longstanding lesions; erosive oral LP associated with liver disease (HCV)

Genital LP

Seen in up to 20% of LP patients; glans penis common site for men (annular lesions, small grouped papules, or larger plaques); vulvar LP commonly erosive and may coexist with gingival involvment (‘vulvovaginal gingival syndrome’)

Hypertrophic LP

Thick, hyperkeratotic intensely pruritic plaques commonly found over shins or dorsal feet; also known as LP verrucosus

Inverse LP

LP lesions in groin, axillae and inframammary regions

Linear LP

Linear groups of lichenoid papules following lines of Blaschko

Mucosal LP

Up to 50% patients with skin disease may have oral mucosal changes; ranges from reticular, atrophic, erosive, bullous, papular to pigmented; reticular type most common with lacy white hyperkeratosis on buccal mucosa, lips, tongue and gingiva; typically asymptomatic unless erosive; rarely may see esophageal, laryngeal or conjunctival involvement

Nail LP

10% of LP patients; may be isolated finding; typically lateral nail thinning, longitudinal ridging, dorsal pterygium, splitting, ± twenty nail dystrophy

LP/LE overlap

Clinical and histologic features of both LE and LP

Palmoplantar LP

Painful hyperkeratotic yellow to erythematous plaques on palms and soles (lateral borders and pressure points), ± ulceration, erosions; recalcitrant to therapy

LP Pemphigoides

DIF: linear IgG/C3 at BMZ  IIF: IgG at roof of blister (salt-split skin)

Tense vesicles and bullae arise in normal, uninvolved skin; typically blisters occur weeks to months after appearance of typical LP lesions; overlap between bullous pemphigoid and LP; + IgG antibody to BP180 (NC16A)

LP Pigmentosus

Gray-brown macules in sun-exposed areas ± flexural folds in darker-skinned patients; similar to erythema dyschromicum perstans

Lichen planopilaris

Keratotic follicular papules with violaceous rim leading to cicatricial alopecia

Graham-Little-Piccardi-Lasseur syndrome : typical skin/mucous membrane LP, scarring alopecia of scalp, nonscarring loss of pubic/axillary hairs





  • Presents with intense pruritus and violaceous, smooth flat-topped papules and plaques with fine scale (Wickham’s striae) over flexor wrists, forearms, legs, presacrum and other areas, + Köebner phenomenon


  • No conclusive evidence to support association with autoimmune disease (per Bolognia); difficult to determine if true HLA association


  • Histology



    • Hyperkeratosis (without parakeratosis)


    • ↑ Granular layer


    • Partially effaced rete ridges with widened papillae (‘sawtooth’ appearance)


    • Vacuolar change of basal layer with colloid bodies


    • Band-like lymphocytic infiltrate at dermoepidemal junction


    • Dermal melanophages


  • Treatment: superpotent topical corticosteroids, topical calcineurin inhibitors, intralesional or systemic corticosteroid, phototherapy, methotrexate, acitretin, metronidazole (latter for erosive oral form)


Lichenoid Keratosis





  • Likely due to inflammation of lentigo, actinic keratosis or seborrheic keratosis


  • Brown to red scaly papule on sun-exposed extremity


  • Solitary lesion mimicking lichen planus histologically


Graft-Versus-Host Disease (GVHD) (Figure 3.12A-C)





  • Clinical syndrome resulting from the transfer of immunologically competent cells to an immunosuppressed host


  • Donor lymphocytes recognize the recipient as ‘foreign’ and mount an immunological attack primarily against the skin, mucosa, gastrointestinal tract and liver


  • Histocompatibility (both major and minor complexes) between the donor and host is the most important factor in the development of GVHD



A327767_2_En_3_Fig11_HTML.gif


Figure 3.11:
A: Lichen planus, lips*B: Lichen planus, palmoplantar*C: Lichen planus, genital* *Courtesy of Dr. Paul Getz





  • One of the major complications of allogeneic hematopoietic stem cell transplantation (can also occur after transfusion of unirradiated blood products or donor lymphocytes in setting of solid organ transplantation)


  • Two forms (acute and chronic GVHD) based on time of presentation since transplant date (part of same spectrum)


  • Acute GVHD:



    • Occurs within first 100 days following transplantation (typically within 1-3 weeks after transplantation)


    • Presents with a maculopapular eruption which may coalesce into confluent erythema (± evolve into erythroderma or bullae resembling toxic epidermal necrolysis); acral erythema with violaceous discoloration of pinna of ear suggestive


    • Triad of dermatitis, enteritis with diarrhea, and hepatitis with abnormal LFTs, ± high fever, conjunctival erythema


    • Histology: vacuolization of basal layer, necrotic keratinocytes, sparse perivascular or interface dermatitis, ± complete epidermal necrosis (severe cases)


    • Course: 30-50% of patients with moderate to severe acute GVHD die


    • Treatment: systemic corticosteroid


  • Chronic GVHD:



    • Occurs after mean of 4 months (as early as 40 days)


    • Evolves from acute GVHD in approximately 50% surviving patients, otherwise de novo


    • Divided into early lichenoid and late sclerodermoid



      • Lichenoid GVHD: violaceous to erythematous lichenoid papules over dorsal hands, forearms, trunk and may become widespread, ± mucous membrane involvement (lacy white plaques or erosions in mouth, salivary gland involvement with Sjögren-like syndrome)


      • Sclerodermoid GVHD: sclerotic plaques similar to morphea, ± hyperpigmentation, ± sicca symptoms, may also involve the gastrointestinal tract, lungs, liver and musculoskeletal system


    • Main cause of death of chronic GVHD: infection due to immuno-suppression


    • Histology: chronic lichenoid GVHD similar to lichen planus; sclerodermoid GVHD with epidermal atrophy and dermal fibrosis


    • Treatment: topical calcineurin inhibitor, PUVA, UVB, prednisone, hydroxychloroquine, cyclosporine, mycophenolate mofetil, azathioprine, photopheresis


A327767_2_En_3_Fig12_HTML.jpg


Figure 3.12:
A: GVHD, acute*B: GVHD, acute* *Reprint from Morgan MB, Smoller BR, Somach SC, Deadly Dermatologic Diseases. New York, NY: Springer; 2007.C: GVHD, chronic(Reprint from Burgdorf WH, Plewig G, Landthaler M, Wolff HH, eds. Braun-Falco’s Dermatology. 3rd ed. Heidelberg: Springer; 2009.)


C. Eczematous Dermatoses



Atopic Dermatitis:

See Chap. 2


Contact Dermatitis (CD) (Figure 3.13A-B, Tables 3-5 to 3-8)





  • Acute or chronic inflammatory reaction to a substance in contact with the skin; divided into irritant and allergic


  • Irritant contact dermatitis (ICD)



    • Accounts for 80% of CD


    • Due to direct local cytotoxic effect of irritant on skin


    • Acute ICD: acute exposure to toxic agent; presents with pruritus and sharply-localized erythema with vesicles, edematous papules or hemorrhagic blisters, ± scaling or crusting; no distant spread


    • Chronic ICD: repeated exposure to mild irritants (low-grade irritation); presents with diffuse or localized but ill-defined scaly patches and plaques


  • Allergic contact dermatitis (ACD)



    • Accounts for 20% of all CD


    • Type IV delayed hypersensitivity to contactant (to which already sensitized), onset may be delayed as long as 24 to 96 hours after allergen exposure


    • Nickel and poison ivy most common


    • Patch testing (Figure 3.13C) is the gold standard for diagnosing ACD; grading system:



















Reaction

Description

+

Weak reaction with erythema, infiltration, ± papules

++

Strong reaction: vesicles, erythema, infiltration, papules

+++

Spreading bullous reaction





  • Poral reaction: non-allergic reaction of erythem- atous dots (cobalt residing in acrosyringium)





  • Acute ACD: typically presents 24-48 hours after exposure and presents with pruritus, vesicles, weeping and erythema, ± dissemination of lesions


  • Subacute ACD: presents with eczematous scaly plaques or lichenification correlating to areas of contact with allergen





  • Histology: spongiosis, intraepidermal vesicles and superficial perivascular infiltrate in acute setting; acanthosis, hyperkeratosis and mild superficial infiltrate in chronic setting


  • Treatment: avoid exposure irritants/allergens; topical corticosteroid, patch testing (for ACD), if severe may use short-term systemic corticosteroid



A327767_2_En_3_Fig13_HTML.jpg


Figure 3.13:
A: Allergic contact dermatitis(Courtesy of Dr. Paul Getz)B: Subacute contact dermatitisC: Patch testing, 2+ reaction(Courtesy of Dr. Sophie M. Worobec)

































Factors

ACD

ICD

Previous exposure required

Yes

No

Immunologic reaction

Yes

No

Distant spread

Yes

No

Dose-related response

No

Yes

Similar reaction in others w/ exposure

No

Yes



Table 3-5:
Table of Contact Allergens






















































































































































































Formaldehyde-Releasing Preservatives

Quaternium-15

Most common cosmetic preservative to cause ACD; personal care products

2-Bromo-2-nitropropane-

1,3-diol (Bronopol)

Formaldehyde-releasing preservative in personal care products and variety of industrial applications

Diazolidinyl urea

(Germall II)

Formaldehyde-releasing preservative; personal care products especially bubble baths, baby wipes and household detergents

Imidazolidinyl urea

(Germall 115)

Formaldehyde-releasing antimicrobial preservative used in cosmetics

DMDM hydantoin

Formaldehyde-releasing antimicrobial preservative used in cosmetics like shampoo, hair conditioners and skin care products

Rubber accelerators

Thiuram

Thiuram cross reacts w/ disulfiram

Rubber in shoes, rubber gloves, elastic, fungicides, paints, barrier contraceptives

Mercaptobenzothiazole

(MBT)

Most common cause of allergic shoe dermatitis

Rubber products, tires, antifreeze, anticorrosive agents, cutting oils, electrical cords, fungicides, rubber shoes (sneakers, tennis shoes, etc)

Carba mix

Leather shoes, tires, fungicides, cosmetic applicators, gloves, adhesives, elastic, barrier contraceptives; may cross react with thiuram derivatives

Mercapto mix

Tires, elastic, rubber gloves, electrical cords, rubber soles of shoes, etc

Black rubber mix

Heavy use rubber products such as tires, hoses, cables and belts

Mixed dialkyl thioureas

Neoprene rubber (wetsuit), goggles, elastic, paint remover, shoe insoles

Textiles

Disperse blue 106

Clothing dye (bed linens, blue dye, clothing, tights, garment lining)

Ethylene urea melamine formaldehyde mix

Permanent press clothing (wrinkle-resistant)

Textile dermatitis typically occurs where clothing fits tightly (posterior neck, upper back, lateral thorax, axillae, waistband, flexor surfaces); ± purpuric contact dermatitis

Adhesives

Epoxy resin (bisphenol A)

Glues, plastics, electrical insulation, paint and primer

Colophony (rosin, abietic acid)

Paper, cosmetics, paint, adhesives, waxes, chewing gum, used in baseball/ballet/musical instruments to ↑ friction

Cyanoacrylate (methyl or ethyl)

Fast-acting adhesive (Super or Krazy Glue), liquid bandages, Dermabond

Ethyl acrylate

Artificial nail (adhesive)

Methacrylate (methyl or ethyl)

Adhesive, artificial nails, dental fillings/sealants, hearing aids, hard contact lenses, glue (bone cement) for artificial joints, acrylic denture material

p-tert-butylphenol formaldehyde resin

Leather/rubber adhesive

Sunscreen components

Benzophenone-3

PABA ± cross react w/ sulfonamides, azo dyes, benzocaine, PPD

Sunscreens, rubber products, cosmetics

PABA (Padimate O)

Sunscreen (UVB)

Oxybenzone

Oxybenzone: most common sunscreen agent to cause photoallergic contact dermatitis

Sunscreen (UVA)

Corticosteroids

Tixocortol-21-pivalate

Group A (hydrocortisone acetate, prednisone, methylprednisolone)

Budesonide

Budesonide also marker for some Gr. D steroids

Group B (triamcinolone acetonide, desonide, fluocinolone acetonide, fluocinonide, halcinonide)

Hydrocortisone-17-butyrate

Group D (hydrocortisone-17-valerate/butyrate, clobetasone-17-butyrate clobetasol proprionate, betamethasone valerate/diproprionate)

Hair preparations

Paraphenylenediamine (PPD)

Permanent hair dye, ‘black henna’ (not natural henna from plant), photographic developer, printing inks, black rubber, temporary tattoos;

ACD typically on eyelids/ear helices/hairline or hands

May cross react with: PABA, sulfonamides (including thiazide and furosemide), para-aminosalicylic acid, benzocaine and procaine (ester anesthetics), azo dyes (temporary/semi-permanent hair dye, pen ink, coloring agent)

Monothioglycolate

Permanent wave preparations; typically in glycerol monothioglycolate

Ammonium persulfate

Hair bleach, bleaching agent in flour

Others

Bacitracin

Topical antibiotic ointment, otic and ophthalmic preparations

Balsam of Peru

Naturally occurring fragrance material, found in topical medications

Benzalkonium chloride

Skin disinfectant (ophthalmic solutions), cosmetics

Benzocaine, tetracaine

May cross-react with PABA, PPD, and sulfonamides

Local anesthetic (ester)

Cobalt

Added to other metals to ↑ hardness; found in jewelry, buttons, cosmetics, hair dye, joint replacements, ceramics, enamel, cement, paint, and pottery

Dimethyl fumarate

Furniture, shoes, and car seats; added for antifungal property to prevent mold growth

Cocamidopropyl betaine

Hair and bath products like shampoo (surfactant)

Ethylenediamine

Medical creams, antifreeze, paint

Cross-reacts with hydroxyzine and aminophylline

Euxyl K400

Cosmetic and household products (preservative)

Fragrance mix

Several components (cinnamic aldehyde), detects 70% fragrance allergies

Formaldehyde

Textile resins (wrinkle-free clothing), cosmetics, tissue fixative, embalming solution, paints, disinfectants, and medications

Gold

Jewelry, dentistry, electronics, treatment of certain diseases (RA, SLE, etc)

Glutaraldehyde

Cold sterilization (medical/dental equipment), disinfectant, tan shoe leather

Lanolin (wool alcohol)

Cosmetics and some topical creams

Methylchloroiso-thiazolinone (Kathon CG)

Preservative in cosmetics and shampoos (antibacterial properties)

Neomycin sulfate

Antibiotic ointment, hemorrhoidal cream, otic and ophthalmic preparations

Co-sensitivity often between neomycin and bacitracin

Nickel sulfate

Costume jewelry, buckles, and snaps; dimethylglyoxime test detects nickel (positive if turns pink); ± co-sensitivity seen with nickel and cobalt

Paraben mix

Cosmetics, topical medications, food, textiles, antiperspirants

Potassium dichromate

Cement, leather (footwear), plaster, wood finishes, green felt of card tables

Propylene glycol

Cosmetics, topical medications (vehicle), antifreeze

Thimerosal

Preservative in contact lens solution, vaccines, otic/ophthalmic solution, antiseptic

↑ photosensitivity with piroxicam if patient with positive reaction to thimerosal

Tocopherol acetate

Vitamin E

Toluene sulfonamide

Nail polish (typically appears eyelid dermatitis or periungual dermatitis)



Table 3-6:
Plant Allergens
























































Allergen

Plant (common name)

Scientific name

Urushiol

(includes pentadecacatechol in oleoresin)

Poison ivy, poison sumac, poison oak

Family: Anacardiaceae

Genus: Toxicodendron; Species: Rhus

May cross react with Japanese lacquer tree (sap), cashew tree, mango tree, Indian marking nut (black juice), Brazilian Pepper tree (sap), gingko (seed pulp)

Sesquiterpene lactone

Dermatitis may be airborne (face, neck) or direct contact (hands)

Chrysanthemum, ragweed, sunflower, artichoke, arnica, daisy, marigold, arnica

May cross react with permethrin

Family: Asteraceae or Compositae

Primin

Primrose

Family: Primulaceae

Species: Primula obconica

Diallyl disulfide, allylpropyl disulfide

Garlic, onion, chives

Family: Alliaceae

Genus: Allium

Allicin

Garlic, onion, chives

Family: Alliaceae

Genus: Allium

Tuliposide A

Peruvian lily

Family: Alstroemeriaceae
 
Tulip, hyacinth

Family: Liliaceae

d-usnic acid

Lichens

Several genera including Parmelia

Colophony

(Abietic acid, rosin)

Pine tree (resin)

Family: Pinaceae

Species: Pinus species

Tea tree oil

(Limonene)

Ti or tea tree

Family: Myrtace ae

Species: Melaleuca alternifolia

3-carene

Turpentine

Family: Pinaceae



Table 3-7:
Plant irritants (ICD)




























Irritant

plant

Bromelin

Pineapple (Ananas comosus)

Calcium oxalate

Dumb cane (Araceae), daffodils (Narcissus spp.), hyacinth (Liliaceae), pineapple

Phorbol esters(in milky latex)

Poinsettias, spurges, crotons (Euphorbiaceae)

May cause temporary blindness if latex contacts eye

Capsaicin

Chili peppers (Solanaceae)

Thiocyanates

(Allyl isothiocyanate)

Garlic (Alliaceae)

Black mustard and radish (Brassicaceae)

Ranunculin converts to protoanemonin after plant injury

Protoanemonin(Ranunculin)

Buttercups (Ranunculaceae)

Causes intense linear vesiculation



Table 3-8:
Pigment Reactions from Tattoos


































Tattoo Color

Chemical

Black

Carbon, iron oxide

Blue

Cobalt

Brown

Ferric oxide

Green

Chromic oxide

Most common allergic reaction seen from red tattoo pigment

Purple

Manganese

Red

Cinnabar (mercury sulfide), cadmium red

White

Titanium dioxide

Yellow

Cadmium sulfide


3.3 Granulomatous, Metabolic and Depositional Diseases



A. Granulomatous Diseases



Granuloma Annulare (GA) (Figure 3.14A-C)





  • Asymptomatic, benign and self-limited granulomatous disease of the dermis seen in both adults and children


  • Unknown etiology; may include trauma and sun exposure


  • Presents as skin-colored to pink non-scaly papules coalescing into annular or arciform plaque typically over dorsal hand or foot; variants listed below:























GA Variant

Description

Patch GA (Macular)

Patches of erythema typically over extremities ± trunk

Generalized GA (Disseminated)

Flesh-colored pink papules over trunk/extremities; poor response to treatment; association with diabetes

Perforating GA

Small papules with central umbilication and crusting (discharging necrotic collagen) typically over dorsal hands

Subcutaneous GA

Deep dermal nodules similar to rheumatoid nodules; typically asymptomatic





  • Histology: necrobiotic foci in dermis surrounded by histiocytes (palisading granulomas) or histiocytes splayed between collagen bundles (interstitial type), mucin accumulation, ± perivascular lymphocytes/eosinophils


  • Treatment: clinical observation as typically self-limited (50-75% in 2 years) in localized GA, potent topical corticosteroid, topical calcineurin inhibitor or intralesional corticosteroid; systemic therapy can be considered for disseminated GA but none consistently proven effective


Necrobiosis Lipoidica ± Diabeticorum (NLD) (Figure 3.15A-B)





  • Uncommon necrobiotic disease associated with diabetes mellitus (DM): 30-40% patients with NLD have DM, but only 0.03-3% of patients with DM manifest with NLD


  • Presents with yellow to red-brown atrophic to indurated plaques typically over pretibial areas; prominent telangiectasias, ± ulceration


  • Histology: normal to atrophic epidermis, histiocytes often encircling necrobiotic collagen in dermis in layered fashion (tier-like, parallel to epidermis), ± sclerosis, interstitial lymphocytes, plasma cells, histiocytes, and multinucleated giant cells (granulomatous inflammation)



A327767_2_En_3_Fig14_HTML.gif


Figure 3.14:
a: Granuloma annulareb: Granuloma annulare(Courtesy of Dr. Paul Getz)c: Subcutaneous GA(Courtesy of Dr. Paul Getz)
Horizontal palisading and plasma cells on histology (unlike GA)





  • Treatment: high potency topical corticosteroid (1st line) or IL injection into active border; aspirin + dipyridamole (to ↓ plt aggregation), niacinamide, and if severe refractory ulcerations consider excision with graft


Annular Elastolytic Giant Cell Granuloma (Actinic Granuloma)





  • Unclear if distinct disease or variant of GA


  • ± Related to inflammation triggered by actinic damage


  • Presents as annular erythematous plaque with slightly atrophic center in sun-exposed areas of older adults; tendency for slow spread


  • Histology: solar elastosis, absence of elastic fibers in center of lesion, elastic fibers adjacent to/within giant cells (elastophagocytosis), granulomatous inflammation


  • Treatment: topical corticosteroids (inconsistent response)


Necrobiotic Xanthogranuloma (NXG) (Figure 3.15C)





  • Rare, multisystem histiocytic disease


  • Presents as red-orange to yellow papules, nodules or plaques on face (periorbital), tendency toward ulceration


  • 80% with IgG monoclonal gammopathy (↑ risk of plasma cell dyscrasias and lymphoproliferative disorders)


  • Histology: mid-dermal palisading xanthogranuloma (mid-dermis extending to fat consisting of histiocytes, foamy cells, plasma cells, giant cells (Touton and bizarre foreign body), cholesterol clefts in areas of necrobiosis


Cutaneous Crohn’s Disease





  • Skin changes related to Crohn’s disease


  • Genital: labial or scrotal erythema with swelling


  • Nongenital: erythematous indurated plaque or ulcerations with drainage (typically perianal)


  • Oral: cobblestoning (buccal mucosa), small aphthae-like ulcers or linear ulcers, pyostomatitis vegetans, cheilitis glandularis, indurated fissuring of lower lip


  • Histology: non-caseating granulomas (sarcoidal or diffuse)


  • Treatment: topical/IL/oral corticosteroid, oral antibiotic (ie. metronidazole), azathioprine, sulfasalazine, adalimumab; of note, treatment of intestinal manifestations usually improves skin lesions


Foreign Body Granuloma (Tables 3-9, 3-10)





  • Immune response to exogenous or endogenous material that has wounded skin


  • Histology: ranges from sarcoid-like granulomatous reaction, necrobiotic reaction, suppurative reaction to reaction consisting of mild fibrosis



A327767_2_En_3_Fig15_HTML.gif


Figure 3.15:
a: Necrobiosis lipoidica(Courtesy of Dr. Sophie M. Worobec)b: Necrobiosis lipoidica(Courtesy of Dr. Paul Getz)c: Necrobiotic xanthogranuloma (Reprint from Morgan MB, Smoller BR, Somach SC. Deadly Dermatologic Diseases. New York, NY: Springer; 2007.)



Table 3-9:
Properties of Foreign Bodies

























Doubly refractile with polarized light (Birefringent)

PAS Positive

Silica (dirt or glass)

Talc (deodorant/powdered gloves)

Starch

Wood splinter

Sutures (nylon)

Plant material

Starch

Keratin (hair shafts)

Spines of sea urchins

Cholesterol esters



Table 3-10:
Common Foreign Body Reactions
























































Foreign Body

Clinical Findings

Histological Reaction

Intralesional corticosteroid

Yellowish to skin-colored nodule at site of injection

Foreign body granuloma with pale blue (mucin-like) acellular material in center

Keratin

Erythematous follicular papules (ie. acne keloidalis nuchae)

Foreign body granuloma, ± fragments of keratin (section of hair shafts, birefringent)

Suture material

Erythematous papule or papules

Birefringent basophilic suture fibers in dermis with surrounding foreign body granuloma

Tattoo pigment

Lichenoid papules, eczematous dermatitis, erythema or induration

Extracellular pigment (typically black) with foreign body reaction (only if allergic reaction)

Wood splinter

Induration, erythema or papule

Brownish color with prominent cell walls (honeycomb appearance) surrounded by granulomatous inflammation; birefringent

Silica, zirconium, beryllium

Erythema, induration or papule

Foreign body granuloma, sarcoidal granuloma or caseating granuloma; doubly refractile spicules

Silicone

Nodule, indurated plaque or ulceration

‘Swiss cheese’ appearance due to presence of silicone filled cavities surrounded by histiocytes (may be multinucleated or foamy)

Hyaluronic acid

Erythema, induration, papule or nodule

Basophlic amorphous material, stains with Alcian blue

Paraffin

Firm indurated nodule or plaque, ± ulceration

‘Swiss cheese’ appearance (stains with oil red O)

Starch

Indurated nodule typically

Maltese cross configuration with polarized light

Monsel’s solution

Clinically consistent with nevus or tattoo

Brown black deposits (containing iron) in dermis due to ferrous subsulfate


Sarcoidosis (Figure 3.16A-D)





  • Chronic multisystem inflammatory disease characterized by non-caseating granulomas of unknown etiology


  • Related to ↑ activity of cell mediated immune system


  • ↑ Frequency and severity in African American patients


  • Presents with cutaneous findings in approximately 30-40% patients, may be sole or initial manifestation


  • Presents typically with non-scaly, skin-colored to red-brown circinate or annular infiltrated papules/plaques on face, lips, neck, trunk, extremities; cutaneous sarcoidosis may develop within pre-existing scars



    • Hypopigmented lesions not uncommon in African-American patients


    • Sarcoidal plaques may appear psoriasiform


    • Less common presentations include ichthyosis over lower legs, hypopigmentation, scarring alopecia, and ulcerations


    • Variants (listed below)


  • Histology: superficial and deep sharply defined naked epithelioid granulomas with minimal lymphocytes, giant cells, eosinophilic stellate inclusion bodies (asteroid bodies) or round basophilic laminated inclusions (Schaumann bodies) seen in giant cells


  • Diagnosis (of exclusion): ↑ ACE, ↑ calcium, ↑ ESR


  • Treatment: topical, IL or systemic corticosteroid, hydroxychloroquine, methotrexate or other immunosuppressant



A327767_2_En_3_Fig16_HTML.gif


Figure 3.16:
A: SarcoidosisB: Sarcoidosis, hypopigmented (Courtesy of Dr. Iris K. Aronson)C: Sarcoidosis*D: Sarcoidosis**Reprint from Lipsker D. Clinical examination and differential diagnosis of skin lesions. Paris, France: Springer;2013.










































Sarcoidosis Variant

Clinical Findings

Lupus pernio

Violaceous doughy infiltration on nose, cheeks or earlobes; often associated with chronic sarcoidosis of lungs, chronic uveitis and bone cysts; chronic course

Darier-Roussy disease

Also known as sarcoidal panniculitis; painless subcutaneous mobile nodules without epidermal change

Löfgren’s syndrome

Acute sarcoidosis; erythema nodosum, hilar adenopathy, acute iritis, migrating polyarthritis, and fever

Mikulicz syndrome

Complex of symptoms caused by a variety of systemic disorders (ie. Sjögren syndrome, lymphoma and sometimes sarcoidosis)

Parotid and lacrimal enlargement with swelling, ± sicca symptoms

Parinaud oculoglandular syndrome

Conjunctivitis with ipsilateral lymphadenopathy

Also caused by infection (cat-scratch fever and tularemia)

Heerfordt’s syndrome

‘Uveoparotid fever’; fever, parotid gland enlargement, anterior uveitis, facial nerve palsy

Erythema nodosum

Seen in acute or subacute sarcoidosis; good prognostic sign, associated with transient sarcoidosis that resolves spontaneously

Oral sarcoidosis

May involve mucosa, tongue, major salivary glands, hard palate and gingival tissue

Ocular sarcoidosis

Seen in 15-25%: anterior uveitis (common), lacrimal gland involvement, chronic uveitis leading to adhesions, glaucoma, and blindness

Non-mucocutaneous findings

Lung disease (alveolitis, fibrosis, hilar adenopathy), liver, spleen, bone, kidney, heart, GI involvement; hypercalcemia


B. Metabolic and Depositional Diseases



Amyloidosis (Figure 3.17)





  • Refers to several diseases sharing common feature of abnormal deposition of eosinophilic amyloid protein in various tissues


  • Amyloid properties: insoluble fibril protein aggregates with β-pleated sheet configuration





  • Classified into systemic and organ-limited amyloidosis, with the former being associated with ↑ morbidity and mortality (unlike the cutaneous counterpart)

    Histology: deposits of eosinophilic, homogenous and amorphous material limited to papillary dermis with melanin incontinence in lichen/macular amyloidosis; waxy eosinophilic fissured nodules involving dermis in nodular amyloidosis; characteristic staining pattern showing green birefringence under polarized light with Congo red stain; other stains include methyl violet, crystal violet, PAS + (diastase resistant), Sirius red, pagoda red 9, scarlet red (RIT), and thioflavin T


A327767_2_En_3_Fig17_HTML.gif


Figure 3.17:
Lichen amyloidosis(Courtesy of Dr. Paul Getz)



Table 3-11:
Types of Cutaneous Amyloidosis
































Type

Description

Protein

Macular amyloidosis

Presents with hyperpigmented small firm papules in rippled appearance coalescing into thin plaque typically over interscapular region; asymptomatic or moderately pruritic; ± associated notalgia paresthetica

Treatment: potent topical corticosteroid, topical capsaicin

Keratinocyte-derived

Seen in MEN type 2A

Lichen amyloidosis

(Figure 3.17)

Presents with small, flat-topped shiny papules typically over shins, highly pruritic

Treatment: reduce friction, potent topical corticosteroid ± occlusion or IL corticosteroid, phototherapy

Keratinocyte-derived

Seen in MEN type 2A

Nodular amyloidosis

(Figure 3.18c)

Presents with single or multiple waxy nodules ± purpura on limbs or trunk

Can progress to systemic involvement in about 7% cases → long term follow up needed

Treatment: excision or laser ablation if few lesions

AL (immunoglobulin light chains, typically λ)

Secondary amyloidosis

Amyloid deposits seen both in benign and malignant cutaneous tumors

Keratinocyte-derived

Multiple endocrine neoplasia (MEN) type 2A (Sipple syndrome): RET gene, AD

Medullary thyroid carcinoma, pheochromocytoma, hyperparathyroidism, ± lichen or macular amyloidosis

Of note, MEN type 1 (Wermer syndrome) associated with facial angiofibromas, collagenomas and lipomas

Type 2B (aka type 3) associated with mucosal neuromas




Table 3-12:
Types of Systemic Amyloidosis

TTR transports thyroxine & retinol
































Type

Description/treatment

Protein

Primary systemic

amyloidosis

Usually associated with underlying plasma cell dyscrasia; up to 50% may have mucocutaneous lesions including macroglossia (± indentation of teeth), difficulty swallowing, ecchymosis and ‘pinch’ purpura due to vessel fragility from perivascular amyloid deposition (‘raccoon eyes’), waxy nodules and plaques, bullous lesions (especially hemorrhagic); hoarseness; other non-cutaneous involvement include carpal tunnel syndrome, RA-like arthropathy, shoulder pad sign (amyloid infiltration around periarticular soft tissue), cardiac arrhythmias, heart failure, restrictive cardiomyopathy; may be associated with multiple myeloma; confirmation of diagnosis in absence of cutaneous findings aspiration of abdominal fat to detect amyloid deposits

AL (light chain)

Secondary systemic amyloidosis

Amyloid deposition in organs due to underlying chronic inflammatory or infectious process (ie. rheumatoid arthritis, tuberculosis, chronic abscess, periodic fever syndromes such as familial Mediterranean fever, TRAPS and Muckle-Wells syndrome – see below); skin typically not involved

AA (non-immunoglobulin protein: amyloid-associated)

Hemodialysis-associated amyloidosis

Due to ↓ excretion of β2-microglobulin in patients with long-term hemodialysis; deposition in synovial membranes resulting in carpal tunnel syndrome and spondyloarthropathy

2 M

(β2-microglobulin)

Familial amyloidosis

Includes familial amyloidotic polyneuropathy, AD inheritance; findings include peripheral and autonomic neuropathy; treatment: orthotopic liver transplantation (remove major source of TTR)

ATTR (TTR or transthyretin)

Senile systemic amyloidosis

Late-onset disease seen in elderly due to deposition of TTR-derived amyloid fibrils in heart causing CHF, cardiomyopathy

ATTR (transthyretin or TTR)

Muckle-Wells syndrome (MWS): CIAS1 mutation (encodes cryopyrin), AD → urticaria, deafness, renal amyloidosis, acute attacks of fever, abdominal pain, myalgias, arthralgias, and conjunctivitis; treat w/ glucocorticoids or anakinra (recombinant human IL-1 receptor antagonist)

Familial Mediterranean fever (FMF): MEFV mutation (encodes pyrin, also known as marenostrin), AR → recurrent episodes of polyserositis, fever, erysipelas-like erythema (legs); treat w/ colchicine (prophylaxis)

TNF receptor associated periodic syndrome (TRAPS): TNFR1 mutation, AD → high fever, erythematous annular or serpiginous patches/plaques on extremities, abdominal pain, arthralgias/myalgias; treat w/ TNF inhibitors or glucocorticoids


Mucinoses





  • Heterogenous group of skin disorders involving abnormal accumulation of mucin


  • Mucin



    • Mixture of acid glycosaminoglycans normally produced in small amounts by fibroblasts


    • Routine H&E shows blue-staining material between collagen bundles or empty space

Special stains for mucin: Alcian blue, colloidal iron or toluidine blue




Table 3-13:
Forms of mucinoses






















Type

Description/treatment

Scleromyxedema

(Figure 3.18D)

Presents with generalized symmetric eruption of several waxy firm papules accompanied by induration and thickening of the skin (sclerodermoid) with ↓ mobility; typically involves hands, forearms, face (‘leonine facies’), neck, thighs and upper trunk; associated with monoclonal gammopathy (paraproteinemia) IgG λ (lambda light chain); due to fibroblast proliferation and mucin deposition in dermis; non-cutaneous manifestations include myopathy, arthropathy, neuropathy, dysphagia, lung and renal disease; poor prognosis

Treatment: disappointing; stem cell transplant, oral immunosuppressants (including thalidomide), electron beam therapy; of note, monthly melphalan used in past but associated with ↑ mortality

Lichen myxedematosus

(Papular mucinosis)

Localized form of scleromyxedema (spectrum) with small, flat-topped shiny papules mainly over extensor extremities; does not progress to scleromyxedema but shows little tendency for spontaneous resolution

Treatment: observation or topical corticosteroid

Scleredema

(Scleredema of Buschke)

(Scleredema diabeticorum)

(Figure 3.18E)

Three forms:

– Infection-related: preceding fever, malaise and infection (typically streptococcal) in children and women; presents with induration of cervicofacial area with extension to proximal extremities and trunk; typically self-limited

– Gammopathy-related: similar to above but with insidious onset and without preceding infection; typically associated with monoclonal gammopathy

– Diabetes-related: subtle onset erythema and induration of neck and back(± peau d’orange appearance) in obese men with IDDM; persistent involvement

All three may have some form of systemic involvement: dysphagia, cardiac abnormalities, serositis

Treatment (for latter 2 types): phothotherapy, cyclophosphamide, oral glucocorticoid, cyclosporine

Reticular erythematous mucinosis (REM)

Erythematous macules and papules in reticulated pattern over midline chest and back; may be induced by UV light

Treatment: antimalarials, sun protection


Porphyria (Figure 3.18D)





  • Inherited or acquired disorders due to enzyme deficiency causing ↑ production of porphyrins (photosensitizing) or their precursors during heme synthesis

Porphyrins (uroporphyrin, coproporphyrin, protoporphyrin) absorb light intensely in the Soret band (400-410 nm) → reactive oxygen species with subsequent damage to skin, liver, and/or rbcs




Table 3-14:
Types of Porphyria































































Inheritance/Defect

Labs

Description

Treatment

Congenital Erythropoietic Porphyria (CEP) (Gunther’s disease)

AR

Uroporphyrinogen III cosynthase

Urine: ++ uro/coproStool: ++ copro

RBC: + uroPlasma: + fluoresce

CEP: Colorless (anemia), Erythrodontia, PhotosensitivityUTC (uro three cosynthase): Ur Teeth r Colored

Extreme photosensitivity (bullae with subsequent mutilated scarring), hypertrichosis, erythrodontia (red fluorescent teeth), hemolysis, red urine (stains diapers), ↑ risk skin CA

Light avoidance, transfusions for anemia, ± bone marrow transplantation (BMT), ± splenectomy

Erythropoietic Protoporphyria (EPP)

AD

Ferrochelatase

EPP: enzyme starts w/F

Urine: normal levelsStool: ++ proto

RBC: ++ protoPlasma: ± fluoresce

Photosensitivity with burning, heals with waxy scars, porphyrin gallstones, hepatic damage

Light avoidance, oral β-carotene, monitor liver

Porphyria Cutanea Tarda (PCT)

AD (familial form) or acquired

Uroporphyrinogen decarboxylase (UD)

PCT – UD: Urine Dazzles pink (fluoresce with Wood’s light)

Urine: ++ uro >copro

Stool: + isocopro

RBC: normal levels

Tense bullae, erosions, milia and scarring on sun-exposed skin, hypertrichosis (temples), iron overload, scleroderma-like changes, facial hyperpigmentation

Phlebotomy every 2 weeks, oral antimalarial agent

Triggers: alcohol, HCV, estrogen, polychlorinated hydrocarbons iron overload (hemochromatosis, C282Y gene), HIV

Acute Intermittent Porphyria (AIP)

AD

Porphobilinogen deaminase (PBD)

AIP-PBD: Abdomen Is Painful, Please Barbiturates D/C

Urine: + ALA, PBG,

Stool/RBC/plasma: all normal levels

NO skin findings; neurologic and psychiatric findings w/↑ abdominal pain

Remove trigger, glucose loading, hematin infusion

Triggers: drugs (barbiturates, sulfonamides, griseofulvin), stress, fasting, alcohol, hormonal changes (progesterone) and infection

Variegate Porphyria (VP)

AD

Protoporphyrinogen oxidase (PPO)

Urine: + ALA/PBG

Stool: + proto, copro

Plasma: + fluoresce

Overlap between AIP and PCT

Same treatment for AIP during acute attacks

VP-PPO: ViPs have Pink Plasma Optimized at 626 nm (fluoresces)

Hereditary Coproporphyria

AD

Coproporphyrinogen oxidase (CPO)

Urine: ALA, PBG,

Stool: + copro, proto

RBC: normal level

Acute attacks similar to mild version of AIP, may have skin findings (mimics PCT)

Same a variegate prophyria

Hepatoerythropoietic Porphyria

AR

Uroporphyrinogen decarboxylase

Urine: + uro

Stool: + uro, coproRBC: + proto

Overlap between PCT and CEP

Photoprotection (phlebotomy NOT effective)


Uro: uroporphyrinogen Copro: coproporphyrinogen Isocopro: isocoproporphyrinogen Proto: protoporphyrinogen ALA: aminolevulinic acid PBG: porphobilinogen


A327767_2_En_3_Fig18_HTML.gif


Figure 3.18:
A: Cutaneous Crohn’s disease* B: Cutaneous Crohn’s disease*C: Nodular amyloidosis** D: Scleromyxedema***E: Scleredema*** F: Porphyria cutanea tarda*****Reprint from Wu, Selsky, Grant-Kels (eds). Atlas of Dermatological Manifestations of Gastrointestinal Disease. New York, NY: Springer; 2013.**Reprint from Lipsker D. Clinical Examination and Differential Diagnosis of Skin Lesions. Paris, France: Springer; 2013.***Reprint from Smoller BR, Rongioletti F (eds).Clinical and Pathological Aspects of Skin Diseases in Endocrine, Metabolic, Nutritional and Deposition Disease. New York, NY: Springer; 2010.****Reprint from Maddrey WC (ed). Atlas of the Liver. New York, NY: Springer; 2004.


Calcific Uremic Arteriolopathy (Calciphylaxis) (Figure 3.19)





  • Rare condition of systemic calcification involving small and medium-sized vessels with ischemic necrosis of the skin and soft tissue; high mortality


  • Presents initially as painful violaceous mottling (reticulated) typically on lower extremities → stellate purpura with central necrosis, ± central bulla, followed by necrosis and ulceration; death due to gangrene and sepsis


  • Most commonly in patients with end-stage renal disease on hemodialysis or after renal transplant with elevated calcium-phosphate product


  • Treatment



    • Normalization of calcium-phosphate product (by low calcium dialysis)


    • Sodium thiosulfate (↑ solubility of calcium deposits)


    • Bisphosphonates (pamidronate, etidronate)


    • Calcimimetics (cinacalcet)


    • Parathyroidectomy


    • Wound therapy


Familial Hyperlipidemias







Table 3-15:
Types of Familial Hyperlipidemia




























































Type

Defect

↑ CAD

Risk

Serum

Serum levels

Clinical findings

Type I

Familial LPL deficiencyFamilial hyperchylomicronemia

↓ Lipoprotein lipase (LPL) or apoprotein CII defect

No

Creamy top layer

↑↑ TG (chylomicrons)

Eruptive xanthomas, acute pancreatitis abdominal pain, lipemia retinalis

Type IIa

Familial hypercholesterolemiaFamilial defective apo B100

LDL receptor defect (mutation of LDLR or apo B)

Yes

Clear

↑↑ Cholesterol (LDL)

Tendinous and tuberous xanthomas, xanthelasma

Type IIb

Familial combined hypercholesterolemia

LDL receptor defect

Yes

Clear or cloudy

Cholesterol

TG

(LDL, VLDL)

Tendinous and tuberous xanthomas, xanthelasma

Type III

Familial dysbetalipoproteinemia

Apoprotein E defect

Yes

Turbid

Cholesterol

TG

(IDL, VLDL)

Xanthoma striatum palmare,

tuberous xanthomas

pathognomonic

Type IV

Familial hypertriglyceridemia

↑ Production of VLDL

±

Turbid

↑ TG

(VLDL, IDL)

Eruptive xanthomas;

associated with DM, obesity, alcoholism

Type V

Apolipoprotein C-II defect

±

Creamy top layer

↑↑ TG

Cholesterol

(VLDL, chylo)

Eruptive xanthomas, acute pancreatitis abdominal pain


A327767_2_En_3_Fig19_HTML.gif


Figure 3.19:
Calciphylaxis(Reprint from Morgan MB, Smoller BR, Somach SC. Deadly Dermatologic Diseases. New York, NY: Springer; 2007.)



Table 3-16:
Types of Xanthomas (Figure 3.20A-C)









Type of Xanthoma

Description

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Aug 7, 2017 | Posted by in Dermatology | Comments Off on General Dermatology
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