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ETAS_04 general

ETAS_04 general


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    ETAS_04 general ETAS_04 general Document Transcript

    • 4  General Dermatology Priya Swamy Zeikus, MD Bruce E. Strober, MD, PhD Katherine L. White, MDC o n t e n t s4.1 Acne Vulgaris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 764.2 Rosacea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794.3 Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 814.4 Psoriatic Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 864.5 Reiter’s Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 864.6 SAPHO Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 874.7 Sneddon-Wilkinson Disease . . . . . . . . . . . . . . . . . . . . . 884.8 Lichen Planus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 884.9 Atopic Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 924.10 Alopecia Areata . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 954.11 Alopecia: Other Forms . . . . . . . . . . . . . . . . . . . . . . . . . . 964.12 Vitiligo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 984.13 Pityriasis Rubra Pilaris . . . . . . . . . . . . . . . . . . . . . . . . . . . 994.14 Lichen Sclerosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 994.15 Granuloma Annulare . . . . . . . . . . . . . . . . . . . . . . . . . . . 1004.16 Hirsutism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1014.17 Amyloidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1024.18 Calciphylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1044.19 Angioedema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 Carcinoid Syndrome and Flushing Disorders . . . . . 1064.20 4.21 Lupus Erythematosus . . . . . . . . . . . . . . . . . . . . . . . . . . 1074.22 Scleroderma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 (Continued on next page) General Dermatology  73
    • 4.23 Dermatomyositis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 4.24 Sjogren’s Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 4.25 Connective Tissue Disease: Serology . . . . . . . . . . . . . 115 4.26 Relapsing Polychondritis . . . . . . . . . . . . . . . . . . . . . . . . 117 4.27 Behçet’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 4.28 Livedo Reticularis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 4.29 Leukocytoclastic Vasculitis . . . . . . . . . . . . . . . . . . . . . . 119 Cryoglobulinemia and Cryofibrinogenemia . . . . . . . 122 4.30 4.31 Acanthosis Nigricans . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 4.32 Lipodystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 4.33 Hyperlipoproteinemias . . . . . . . . . . . . . . . . . . . . . . . . . . 125 4.34 Xanthomatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 4.35 Vitamin Deficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 4.36 Diabetes and Skin Disease . . . . . . . . . . . . . . . . . . . . . . 130 4.37 Langerhans Cell Histiocytosis . . . . . . . . . . . . . . . . . . . . 132 4.38 Cutaneous T-cell Lymphoma . . . . . . . . . . . . . . . . . . . . 133 4.39 Pyoderma Gangrenosum . . . . . . . . . . . . . . . . . . . . . . . . 136 4.40 Sweet’s Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 4.41 Erythema Annulare Centrifugum . . . . . . . . . . . . . . . . . 138 4.42 Erythema Elevatum Diutinum . . . . . . . . . . . . . . . . . . . . 138 4.43 Erythema Nodosum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 4.44 Mastocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140 4.45 Cutaneous Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . . 142 4.46 Perforating Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 144 4.47 Elastosis Perforans Serpiginosa . . . . . . . . . . . . . . . . . 144 4.48 Reactive Perforating Collagenosis . . . . . . . . . . . . . . . 145 Cutaneous Features and Disorders of Pregnancy . . 145 4.49 4.50 Pruritus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 4.51 Scleredema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 4.52 Nephrogenic Fibrosing Dermopathy/ Nephrogenic Systemic Fibrosis . . . . . . . . . . . . . . . . . 14974  2011/2012 Dermatology In-Review l Committed to Your Future
    • Committed to Your Future For practice exam questions and interactive study tools, visit the Dermatology In-Review Online Practice Exam and Study System at DermatologyInReview.com/GaldermaSponsored by
    • 4.1 ACNE VULGARISKey Pathogenic Factors • Abnormal keratinization (follicular retention hyperkeratosis) • Inflammation • Presence of Propionibacterium Acnes (P. acnes) in sebum • Sebum production, under hormonal control, starting at adrenarchePathogenesis Overview • Precursor lesion of comedonal and inflammatory acne is the microcomedo • Human sebum is rich in triglycerides.1 P. acnes makes an enzymatic lipase which cleaves triglycerides into free fatty acids • Inflammation is triggered by follicular wall rupture and subsequent immune response. P. acnes itself is pro-inflammatory; it can activate complement, and neutrophil chemotaxis and activity • IL-1, a pro-inflammatory cytokine, may promote follicular plugging and microcomedo formation2 • Toll-like receptors (TLR’s) → a large group of receptors that recognize certain bacterial patterns. TLR-2 activation by P. acnes leads to intracellular signal transduction and upregulation of the immune response by stimulating pro-inflammatory cytokines.3 Certain topical retinoids have been shown to downregulate TLR-2 expression4Clinical Variants Acne Vulgaris • Noninflammatory lesions are the microcomedo and the comedo (open and closed) • Inflammatory lesions are papules, pustules and nodules Acne Conglobata • A severe variant characterized by large, often multiple comedones, abscesses with sinus formation, and inflammatory nodules • Seen most frequently in young male patients • Follicular occlusion triad consists of acne conglobata, hidradenitis suppurativa, and dissecting cellulitis of the scalp. Treatment is with high dose isotretinoin Acne Fulminans • A rare, explosive form of severe cystic acne affecting young males • Marked by acute, suppurating nodules and plaques that ulcerate and form blackish eschar • The trunk is affected more severely than the face  • Patients may be systemically ill, with leukocytosis, fever, arthralgias, and myalgias. Lytic changes, indicative of a sterile osteomyelitis, can be seen on x-ray and bone scans. The sternoclavicular joint and the chest wall are most frequently affected • Treatment is with oral prednisone, intralesional steroids, antibiotics, and isotretinoin Miscellaneous Acne Variants Industrial Acne  • Chloracne is a form of industrial acne triggered by workplace exposure to chlorinated compounds •  he malar cheeks and postauricular scalp, as well as the scrotum, are affected. The lesions  T  are characterized by large comedones as well as inflammatory papules, pustules, and cysts • Insoluble cutting oils are the most frequent cause of industrial acne76  2011/2012 Dermatology In-Review l Committed to Your Future
    • • Dioxin (2,3,7,8 tetrachlorobenzodioxin) is a well-known, potent trigger of acneiform eruptions5 Acneiform Eruptions • Numerous oral agents have been associated with acneiform eruptions, including the halogens bromide and iodide, androgenetic hormones such as testosterone, ACTH, corticosteroids, isoniazid (INH), lithium, erbitux, phenytoin, cyclosporine, and Vitamins B2, B6, and B126Treatment of Acne Vulgaris Topical Retinoids • Tretinoin (all trans-retinoic acid), adapalene, and tazarotene are effective comedolytic agents which normalize follicular epithelial differentiation • Retinoid activity is mediated by retinoid receptors. Two groups exist: RA receptors (RAR) and RX receptors (RXR). Each has three receptor subtypes: α, β, γ. RAR-γ is the most important mediator of retinoid activity in the skin • Tretinoin and adapalene are pregnancy category C drugs; tazarotene is category X. Tretinion activates RAR receptors α, β, γ. Bexarotene selectively binds retinoid X receptors. Adapalene activates RAR β and γ. Tazorac binds RAR α, β, γ but shows selectively for RAR β and RAR γ Topical Antibiotics (Erythromycin and clindamycin)  • Decrease the population of P. acnes on the skin • Increasing antibiotic resistance has discouraged their use as monotherapy Benzoyl Peroxide (BPO) • Bactericidal agent with direct oxidizing effects, and thus no potential for resistance • Irritation, dryness, and bleaching of clothing or hair may occur Combination Products (Clindamycin or Erythromycin and BPO) • Synergistic efficacy and decreased potential for antibacterial resistance • May cause irritation Azelaic Acid • Dicarboxylic acid that has weak activity against P. acnes • Inhibits tyrosinase, and can be helpful in reducing post-inflammatory pigment alteration. Itching, burning or dryness at the initiation of treatment is not uncommon • Pregnancy category B Oral Antibiotics Tetracyclines • Tetracycline, doxycycline, and minocycline • Inhibit RNA-dependent protein synthesis by binding the bacterial 30s ribosomal subunit • Tetracycline is best absorbed on an empty stomach, and its absorption is inhibited by chelation with bi- and trivalent cations (e.g., calcium, bismuth, iron) • Tetracycline can cause permanent brown discoloration of the teeth in children, and is not used routinely for children under the age of eight • Risk of photosensitivity Demecycline > Doxycycline > Tetracycline > Minocyline • Photo-onycholysis has been reported with Tetracycline  • Unlike other tetracyclines, doxycycline is excreted via the GI tract rather than the kidneys, and thus is the tetracycline of choice in renally compromised patients 8 General Dermatology  77
    • • Minocycline has been associated with CNS symptoms, including vertigo and headache, autoimmune hepatitis, drug-induced anti-histone Ab positive SLE-like syndrome, and hyperpigmentation • Minocycline can cause hyperpigmentation of the skin. Three types are generally  described: - Blue-Black Discoloration: Appearing in areas of prior skin injury, such as acne scars - Blue-Gray Discoloration: Often at the lower anterior legs and forearms - Muddy Brown Discoloration: Found on sun-exposed areas. The least common type of hyperpigmentation • The first two types show staining for both iron and melanin [Fontana Masson stains melanin black; Perls stain stains iron (hemosiderin) blue]. The third type shows increased melanin at the basal layer and within macrophages • Doses of tetracyclines below the minimum inhibitory concentration (MIC) can inhibit neutrophil chemotaxis, pro-inflammatory cytokine cascades, and reduce P. acnes production of lipase Macrolides • Include erythromycin and azithromycin • Inhibit RNA-dependent protein synthesis by binding the 50s ribosomal subunit • Erythromycin can cause gastrointestinal distress and potentially significant drug interactions • Erythromycin inhibits the hepatic cytochrome P450 system and can increase serum levels and potential toxicities of carbamazepine, theophylline, warfarin, digoxin, methylprednisolone Trimethoprim-sulfamethoxazole (TMP-SMX) • Considered second-line therapy for acne, due to increased risk of serious adverse reactions, including hypersensitivity reactions • TMP-SMX inhibits bacterial folic acid synthesis • Drug hypersensitivity syndrome is characterized by fever, skin eruption and internal organ involvement Isotretinoin • Gold standard for treating nodular acne and recalcitrant acne • Reduces sebum production by reducing sebaceous gland size, normalizes follicular keratinization, and indirectly reduces P. acnes and its inflammatory sequelae • A potent teratogen • Half-life of isotretinoin is 10-20 hours13 • Doses range from 0.5-2.0 mg/kg/day for 4 to 6 months (or 120-150 mg/kg total dose) • Patients are monitored monthly for changes in the plasma lipids, liver function tests and complete blood counts. Monthly pregnancy tests for women are also required. The most common laboratory abnormalities are increased triglycerides, followed by elevation of ALT and AST; decreased blood counts are rare; increased exercise can cause elevation of creatinine phosphokinase • Almost all patients experience cheilitis, xerosis, dry nasal mucosa, dry eyes • Other, less common side effects: hair thinning (usually reversible), skin infection, petechiae, abdominal pain, corneal opacities, bone and joint pain, headache, diffuse idiopathic skeletal hyperostosis (DISH)78  2011/2012 Dermatology In-Review l Committed to Your Future
    • • Screen for papilledema if headache, nausea, and vomiting u TIP occurs aseudotumor cerebri occurs P more often with co-adminis- • Recent reports of serious psychiatric events possibly related tration of a tetracycline to isotretinoin have drawn considerable attention. A large population based study with control groups failed to show an increased risk of depression, suicide attempt and suicide among isotretinoin treated patients14 Hormonal Therapies • May be an important component of acne treatment in the female patient, especially for adult women with a predominance of acne at the lower face • Most common endocrinopathy associated with acne is polycystic ovary syndrome (PCOS), characterized by acne, obesity, hirsutism, amenorrhea and glucose intolerance • Congenital adrenal hyperplasia (CAH) is also associated with acne • Although rare, very high levels of DHEA-S may suggest an adrenal androgen-secreting tumor • A patient whose acne fails to respond to conventional therapy, whose acne flares cyclically, with hirsutism, alopecia or irregular menses warrants an endocrine work-up, including free and total testosterone, LH, FSH, and DHEA-S • Benefit from hormonally-based therapies, such as oral contraceptives (OCPs) • Usually ethinyl estradiol. OCP’s lead to a decrease in free testosterone levels by increasing the adrenal production of sex hormone binding globulin (SHBG) • Spironolactone, commonly dosed between 50 to 200 mg/day → blocks androgen receptors and adrenal androgen synthesis. Side effects include menstrual irregularities, breast tenderness, and intestinal symptoms, which can be mitigated by concomitant OCP use. Hyperkalemia is more likely in the setting of renal failure. Spironolactone is not FDA- approved for the treatment of acne. It is pregnancy category X4.2 Rosacea • Papules and papulopustules in central region of face against a vivid background of telangiectases. Later, diffuse hyperplasia of connective tissue with enlarged sebaceous glands • Localized to nose, cheeks, chin, forehead, glabella; less commonly affected areas include the retroauricular, V-shaped chest area, neck, back, scalp • Flushing and blushing evoked by UV, heat, cold, chemical irritation, strong emotions, alcoholic beverages, hot drinks, and spicesVariants of Rosacea Persistent Edema of Rosacea (Rosacea Lymphedema or Morbihan’s Disease) • Hard, nonpitting edema • Often misdiagnosed as cellulitis Ophthalmic Rosacea • Blepharitis, conjunctivitis, iritis, keratitis (inflammation of cornea) • The treatment of choice for ocular rosacea is oral antibiotics General Dermatology  79
    • Granulomatous Rosacea • Dozens of brown-red papules or nodules on diffusely reddened skin, frequently involving lower eyelids • Histopathology: perifollicular and perivascular noncaseating epithelioid granulomas • Chronic and unremitting Steroid Rosacea • Rosacea resulting from steroid use • Steroid atrophy with resultant telangiectases • Flaming red, scaling, papule-covered face • Severe pain, discomfort • Withdrawal of steroid accompanied by exacerbation of disease • Slow tapering of steroid over months is required Rosacea Fulminans (Pyoderma Faciale) • Occurs almost exclusively in post-adolescent women; lots of flushing and blushing • Large coalescent nodules and confluent draining sinus occupy most of the face • Prognosis is excellent, and recurrences rare Perioral Dermatitis • May be triggered or exacerbated by topical steroid use • Generally responds well to topical and/or oral antibiotic treatmentTreatment Topical • Antibiotics – often effective – Topical clindamycin and erythromycin – Topical metronidazole active against papules and pustules, but not telangiectasia and flushing – Topical sulfur-based preparations • Azelaic acid • Sunscreens • Green-tinted makeup concealer can neutralize redness Systemic • Antibiotics – generally responds well – Tetracyclines – Erythromycin • Isotretinoin – indicated in phymas; but rosacea often rapidly recurs after discontinuation of isotretinoin Treatment for Rosacea Fulminans • Oral glucocorticoids, 1.0 mg/kg per day for 7-10 days, add isotretinoin, with slow tapering of steroid, for 3-4 months until all inflammatory lesions disappear • Do not incise draining abscesses • Topical steroids (potent) for first two weeks80  2011/2012 Dermatology In-Review l Committed to Your Future
    • Phymas Rhinophyma • Occurs almost exclusively in men 1.) Gnathophyma – chin swelling 2.) Metophyma – forehead and nose saddle 3.) Otophyma – earlobes 4.) Blepharophyma – eyelids4.3 Psoriasis Psoriasis is an immune dysregulatory disease resulting from persistent T-cell activation andthe resultant release of TH1-based cytokines such as TNF-α and IL-2. These cytokines cause kera-tinocytic proliferation (acanthosis), and increased recruitment of inflammatory cells into the psori-atic skin.Epidemiology • Affects approximately 2% of population of U.S. • Usually begins in 3rd decade of life. Bimodal incidence: peaks at ages 29 and 55 • An early onset predicts more severe disease. Also, early onset more likely with positive family historyInheritance • Increased incidence in offspring of parents in which one or both affected • Monozygotic twin concordance HLA association with • HLA-B13 • HLA-B17 (earlier onset and more serious disease) • HLA-Bw57 • HLA-Cw6 (most definitive associated HLA type) – relative risk 9-15 times normal • Psoriatic arthritis in disequilibrium with HLA-B27, especially if spondylitis presentClinical Features Skin Lesions • Sharply demarcated papules and plaques • Non-coherent silvery scales • Auspitz sign → bleeding upon removal of scale • Koebnerization seen in 20% • Woronoff Ring: Area of blanching around psoriatic plaques secondary to decrease in prostaglandin, PGE2Clinical Patterns Chronic Stationary/Psoriasis Vulgaris • Most frequent • Red, scaly lesions persist for years • Little alteration in shape/distribution of plaques • Areas of predilection: elbows, knees, scalp, retroauricular region, lumbar, umbilicus • When localized in the major skin folds, scaling is absent General Dermatology  81
    • Guttate (Eruptive) Psoriasis • Small (0.5 to 1.5 cm) lesions over upper trunk and proximal extremities • Early age of onset/young adults  • Streptococcal throat infection frequently precedes eruption Psoriatic Erythroderma • Affects all body sites • Erythema is most prominent feature, scaling less prominent Generalized Pustular Psoriasis  • Von Zumbusch type; acute variant • Usually no other forms on skin at same time  • Fever, lasting several days, with eruption of sterile pustules 2-3 mm diameter paralleling the fever • Distribution: Trunk, extremities including nail beds, palms, and soles • Pustules arise on highly erythematous skin • Fingertips may become anonychic and atrophic  • Hypocalcemia, hypoalbuminemia, leukocytosis Localized Pustular Psoriasis • Systemic symptoms absent • Two distinct conditions 1.) Pustulosis palmaris et plantaris 2.) Acrodermatitis continua of Hallopeau Psoriatic Nail Disease • May be of nail matrix or nail bed origin • Fingernails involved in 50%, toenails in 35% • Nail changes more frequent (80-90%) in patients with arthritis  • Psoriatic nail changes of matrix → pits (the most common nail change of psoriasis and representing focal psoriasis of the proximal matrix) and leuconychia • Pits in psoriasis are generally more randomly distributed than the regular rows of pits seen in alopecia areata • Psoriatic nails changes of nail bed origin include: salmon spots, “oil spots,” onycholysis, subungual hyperkeratosis, and splinter hemorrhages16 Psoriatic Arthritis • Asymmetric oligoarthritis, small joints of hands • Associated onycholysis Trigger Factors • Warmer weather and sunlight reported to be u TIP beneficial a rugs D • Physical trauma – Koebner reaction –  teroids – withdrawal of systemic and S • Infection possibly topical) corticosteroids can result in severe flares – 50% of children exacerbate existing psoriasis – Lithium during 2-3 week interval after URI – Beta-blockers –  cute guttate psoriasis frequently follows an A – Interferons  – ACE inhibitors acute streptococcal infection by 1-2 weeks (56- – Granulocyte-colony stimulating factors17 85%) and streptococcal infections may play a role a ntimalarials and NSAIDS are not elieved to A in exacerbating other forms of psoriasis truly exacerbate psoriasis in most patients82  2011/2012 Dermatology In-Review l Committed to Your Future
    •  – Infection with HIV may represent another trigger factor • Stress – psoriasis made worse by stress in 30-40% of casesSystemic Associations • Psoriatic arthritis • Crohn’s disease and ulcerative colitis • HTN, obesity, diabetes, and chronic oropharyngeal infections found more frequently in psoriatic patients • Pustular psoriasis associated with HLA-B27, and arthropathy is common • Increased risk of lymphomaKeratinocyte Proliferation • 8-fold shortening of epidermal cell cycle (36 hrs vs. 311 hrs for normal)Treatment Anthralin (topical) • Advantage: lacks long-term side effects • Possesses antiproliferative activity on human keratinocytes • Also, strong anti-inflammatory effects by inhibiting PMNs and monocytes • Irritant reactions, especially after increasing concentration too fast • Can stain hair to purple • Brownish discoloration of surrounding skin—reversible Vitamin D3 Analogues • Calcipotriol, tacalciol, calcitriol • Inhibit keratinocyte proliferation and induce terminal differentiation • Anti-inflammatory • Used for plaque-type psoriasis QD or BID • Calcipotriol inactivated by salicylic acid or lactic acid (Lac-hydrin) • Should be used after UV-light (calcipotriol absorbs UV) • Local irritation Tazarotene • Retinoid • Reduces scaling and plaque thickness, with little effectiveness on erythema • May be beneficial in combination with phototherapy Tar • Unknown activity • 2-5% tar in various bases effective in chronic plaque-type psoriasis Topical Glucocorticoids PUVA • Oral ingestion of a potent photosensitizer such as 8-methoxypsoralen (8-MOP) or trimethoxypsoralen (0.6 mg/kg) and variable doses of UVA, 2 hours after ingestion • Treatments given TIW or QIW • Clearing usually occurs after 19 to 25 treatments • Overdosing results in sunburn, 24-48 hour post-treatment • Psoralens → intercalate with DNA, with energy of UVA covalently cross-link nucleic acids between opposing strands of duplex regions, leads to irreversible photo-inhibition of DNA synthesis and mitosis General Dermatology  83
    • • Nausea, dizziness, headache • Photosensitivity during the 8-12 h after ingestion of psoralen, protective eyewear needed  • Higher frequency of squamous cell carcinomas, and perhaps malignant melanoma risk, increases after 250 treatments Methotrexate  • Synthetic analog of folic acid that competitively inhibits dihydrofolate reductase • Inhibits S phase of cell cycle (like hydroxyurea) • 10-30 mg once per week PO or IM • Nausea, anorexia, fatigue, headaches, alopecia, stomatitis • Leukopenia and thrombocytopenia indicate overdose → leucovorin rescue required • Careful in kidney dysfunction → renal excretion • Acute interstitial pneumonitis (rare) • Hepatotoxicity; exclude those with liver disease or alcohol abuse; above a cumulative dose of 1.5 g, liver biopsy is often recommended before continuing with therapy • Also effective in treating psoriatic arthritis Cyclosporine  • Inhibits release of cytokines, specifically IL-2, by binding and deactivating calcineurin • Effective in erythrodermic and generalized pustular psoriasis • Start at 2.5 to 4 mg/kg per day, and can go as high as 5.5 mg/kg per day • Renal impairment (often reversible) → reduce dosage by 25% if creatinine increases to 30% or greater of baseline • Hypertension (Treat with ACE-inhibitors) • Elevated triglycerides • Hyperkalemia • Hypomagnesemia • Hepatotoxicity • Hypertrichosis (common), gingival hyperplasia, trichomegaly, nausea, vomiting, diarrhea, arthralgia, myalgia, tremor, acne, sebaceous hyperplasia, and fatigue may occur • Long-term risk of malignancy • Metabolized by P450, thus erythromycin or ketoconazole will increase drug levels Retinoids → Acitretin • Vitamin A derivatives • Effective in pustular and palmoplantar forms of psoriasis • Acitretin is most commonly used, given at 25 mg per day initially • Restrict use in women of childbearing age • Regulate growth and terminal differentiation of keratinocytes; modulate transcription of specific genes through retinoid response elements • Show lower response rates than other systemic modalities for treatment of plaque-type psoriasis → often ineffective as monotherapy for plaque-type psoriasis  • Effective when combined with ultraviolet phototherapy (either UVB or PUVA) • Treatment over 3-4 months necessary • Dose related adverse effects: cheilitis, sicca symptoms of eyes and mouth, generalized pruritus, dry skin, loss of stratum corneum of palms and soles, hair loss • Muscle and joint pain • Elevation in serum lipids, and also LFTs • Monitor liver and kidney function, blood glucose, lipid profile84  2011/2012 Dermatology In-Review l Committed to Your Future
    • Biologic Agents (see Table 4.1) • Etanercept • Efalizumab • Alefacept • Infliximab • Adalimumab • Ustekinumab Table 4-1. BiologicsDrug Mechanism Labs Pregnancy Other ClassEtanercept Recombinant fusion protein to TNF 50 mg SC injections B receptor; binds soluble TNF-alpha twice weeklyEfaluzimab Humanized antibody that binds CD11a Weekly SC C component of LFA1 which binds to injections ICAM1 on APC and endothelial cellsAdalumimab Antibody towards human TNF-alpha Self administered IM B injection qoweekAlefacept Protein that blocks the interaction of IM injections once CD4 B LFA3 and Fc human IgG, LFA3 is the weekly or once counts receptor for CD2 and increased in weekly IV bolus CD45 Ro T cellsInfliximab Monoclonal antibodies which inhibit IV injections, first B Contraindicated TNF-alpha dose followed by in CHF, may dose at weeks 2, 6, cause drug then dosed 8 weeks induced SLEUstekinumab Human antibody that blocks IL-12 and SC injections once, PPD B IL-23 then in 4 weeks then in 12 weeks Systemic Glucocorticoids • Systemic steroids are very rarely used in the treatment of psoriasis as many better alternative therapies exist • Severe rebound psoriasis can occur after discontinuation • Chronic use leads to well-characterized side effects of systemic corticosteroid use Combination Therapies • Often desirable, as combinations can limit the toxicities of individual therapies; examples: – Topical steroids with UVB or PUVA – Retinoids with PUVA or narrow band UVB – Vitamin D analogues with UVB – Ingram method: coal tar baths, UVB, anthralin – Methotrexate with UVB – Methotrexate with cyclosporine – Etanercept with methotrexate Phototherapy, conventional systemic agents, and biologic agents treating psoriasis are dis-cussed elsewhere in this text. General Dermatology  85
    • 4.4 Psoriatic ArthritisFeatures • 20-40% of psoriatic patients; higher frequency found in moderate to severe psoriasis patients • Age of onset: 18–50 years • Usually (80%) rheumatoid factor negative (seronegative) • Synovial, serum and lesional levels of TNF-α are increased in psoriasis and psoriatic arthritis18Types of Psoriatic Arthritis • Asymmetric oligoarthritis or polyarthritis (most common) • Symmetric polyarthritis (RA-like) • Spondylitis (axial) • Distal interphalangeal joint (DIP) disease • Arthritis mutilans (least common) • Enthesopathy (inflammation of ligaments and tendons at insertion point on bones)19Clinical • Morning stiffness of joints lasting more than 60 minutes • Inflammation of DIP joints → often with nail involvement (~80%) • Dactylitis: “sausage digits” • Enthesitis/Enthesopathy → Inflammation of tendons or ligaments or at sites of tendon insertion into bone • Spondylitis/sacroiliitis and axial disease • Reduced range of motion of shoulders, neck, and lower back • 80% of patients present with skin disease firstRadiographic Features of Psoriatic Arthritis • “Sausage digits” • Large eccentric erosions • Pencil-in-cup deformities—erosive changes of the joint: phalangeal distral tip is pencil on an eroded cuplike joint space • Tuft resorption: (acroostcolysis) • Periostitis: inflammation of the periosteum • SacroileitisTherapy for Psoriatic Arthritis • NSAIDs • Sulfasalazine • Methotrexate • Etanercept (FDA-approved therapy) • Ustekinumab (awaiting FDA approval)4.5 Reiter’s Syndrome Chronic inflammatory disease similar to psoriasis with psoriatic arthritis. • Urethritis • Conjunctivitis • Arthritis86  2011/2012 Dermatology In-Review l Committed to Your Future
    • Few patients present with classic triad, thus can be diagnosed with • Peripheral arthritis > 1 month duration • Associated urethritis (or cervicitis) Occurs in young men of HLA-B27 genotype. Rarely occurs in women.Clinical • Any one of triad • Fever, weakness, and weight loss • Nonbacterial urethritis with painful and bloody urination and pyuria • May involve gastroenteritis • Cystitis, prostatitis, seminal vesiculitis • Keratitis may lead to corneal ulceration • Iritis common • Arthritis is asymmetric • Endocarditis, pericarditis, myocarditis, aortic insufficiency • Erythema nodosumSkin Lesions • Multiple small, yellowish vesicles that break, become confluent, and form superficial erosions → frequently on genitals and palms • Crusted, hyperkeratotic papules and plaques on plantar surfaces → keratoderma blennorrhagicum • Penile lesions: Perimeatal balanitis; circinate lesions; similar lesions seen on vaginal mucosa of affected women • Buccal, palatal, and lingual mucosa may show painless, shallow, red erosions, and severe stomatitis • Nails become thick and brittle with heavy subungual hyperkeratotic depositsEtiology • Chlamydia trachomatis associated with cases involving infection of GU tract • HLA-B27 in 80% of cases u TIPTreatment a • Topical steroids Shigella flexneri (most common) of nonurethral form of Reiters, • NSAIDs Salmonella spp., Yersinia spp., • Methotrexate Ureaplasma urealyticum, Borrelia • Acitretin burgdorferi, Cryptosporidia, Campylobacter fetus • Cyclosporine • TNF-inhibiting biologics such as etanercept • Course of disease marked by exacerbation and remission. A chronic deforming arthritis occurs in 20%4.6 SAPHO Syndrome • Synovitis • Acne (Acne fulminans or conglobata) • Pustulosis (pustular psoriasis) • Hyperostosis • Osteomyelitis General Dermatology  87
    • 4.7 Sneddon-Wilkinson Disease u TIP a ssociation with IgA monoclonal A • Subcorneal pustular dermatosis gammopathy • Middle-aged women • Superficial pustules in annular and serpiginous patterns • Abdomen, axillae, groin • Pustules are sterileHistology • Pustules form below stratum corneum without acantholysis • Contains many neutrophilsTreatment • Dapsone • Acitretin • Narrow band UVB Chronic condition, possibly related to psoriasis, with remissions of variable duration.4.8 Lichen Planus Inflammatory disorder that affects the skin, mucous membranes, nails, and hair. • Purple, polygonal, pruritic, papule, planar • Scaling is not as prominent as other papulosquamous diseases • Prevalence: <1%, no racial preference • 2/3 cases between ages of 30 and 60Etiology and Pathogenesis Classification Scheme • Idiopathic (classic) • Drug associated • Associated with other diseases (Ulcerative Colitis, Alopecia Areata, Vitiligo, Dermatomyositis, Myasthenia Gravis)Role of Infection • Hepatitis C implicated in triggering LP • Association with syphilis, HSV2, HIV, amebiasis and chronic bladder infectionsClinical Manfiestations • Erythematous to violaceous, flat-topped, polygonal papule, with occasional small central umbilication • Thin, transparent, adherent scale atop the lesion • Wickham’s striae – fine, whitish reticulated networks on surface of well-developed plaques • LP begins as erythematous macules that evolve over weeks; initial lesions always appear on the extremities • Generalized eruption develops over one to four months • Symmetrically involves flexural areas of wrists, arms, legs; also, oral mucosa and genitalia • Inverse LP: Axillae, groin, inframammary areas • LP is usually pruritic; oral involvement generally asymptomatic, unless erosive → extremely painful • Koebnerization (isomorphic response) occurs88  2011/2012 Dermatology In-Review l Committed to Your Future
    • Clinical Variants Configuration Annular LP • Blacks more commonly affected • On penis and scrotum • Also, larger lesions reach 2-3 cm in diameter and become hyperpigmented with raised outer rim Linear LP • Secondary to trauma, often Hypertrophic LP • Shins, interphalangeal joints • Most pruritic • Heals with scar formation and hyper/hypopigmentation Atrophic LP • Rare • White, bluish papules or plaques with central superficial atrophy • Most common lower extremities and trunk • Resembles lichen sclerosus et atrophicus Vesiculobullous LP • Rare • Vesicles and bullae within lesions of LP • Bullae arise from papules of LP, not normal skin • Subepidermal separation Erosive Ulcerative LP • Chronic and painful bullae and ulcerations on feet • Usually associated with more typical LP lesions of nails, mucosal surfaces and skin • Loss of toenails and alopecia common u TIP  • SCC may develop in lesions of ulcerative LP, a therefore biopsy may be indicated Erosive mucous membrane disease more • In oral LP, oral mucosa, gingiva and tongue may be common in patients with Hepatitis C infection affected. Desquamative gingivitis may occur • Histology of mucosal LP differs from LP of the skin in that parakeratosis rather than orthokeratosis is seen, secondary to the lack of granular layer on mucosal surfaces21 Follicular LP (lichen planopilaris) • Individual keratotic and follicular papules and studded plaques • Trunk and medial aspects of proximal extremities • Affects scalp – cicatricial alopecia  • Graham-Little-Piccardi-Lassueur syndrome: triad of 1.) Follicular LP of skin and/or scalp 2.) ultifocal cicatricial alopecia of scalp M 3.) onscarring alopecia of axillary and pubic areas N Lichen Planus Pigmentosus • Uncommon • Hyperpigmented, dark brown macules in sun-exposed areas and flexural folds • Occurs in darker-pigmented people • Similar to erythema dyschromicum perstans General Dermatology  89
    • Actinic LP • More common in Middle Eastern countries in spring/summer • Affects sun-exposed areas • Typical LP may be seen over extremities • Pruritus and scaling minimalSites of Involvement LP of the Scalp • Lichen planopilaris or follicular LP: individual keratotic papules that coalesce and merge to form patches • Women > men • Uni- or multifocal hair loss • End-stage: scarring alopecia • Pseudopelade of Brocq: scarring alopecia and fibrosis; end stage of follicular fibrosis caused by primary inflammatory dermatosis such as LP, LE, pustular scarring forms of folliculitis, favus, scleroderma, and sarcoidosis Mucosal LP • Affects mouth, vagina, esophagus, conjunctiva, urethra, anus, nose, and larynx • 60-70% patients with LP • Only manifestation of LP in 20-30% • Forms: reticular, plaque-like, atrophic, papular, erosive-ulcerative, and bullous forms • Male genitalia: 25% of cases, glans penis most common site (annular lesions, frequently) • Female genitalia: leukoplakia/erythroplakia, erosive, or generalized desquamative vaginitis • Vulvar and gingival LP can exist together – erythema and erosions of gingivae and tongue and white reticulated plaques • Conjunctival LP: cicatricial conjunctivitis LP of the Nails • 10-15% of cases • Usually in combination with other LP lesions on skin • 20-nail dystrophy (trachyonychia) can be seen, but trachyonychia is not diagnostic of LP • Thinning, longitudinal ridging, and distal splitting of nail plate (onychoschizia) • Also, oncholysis, longitudinal striation (onychorrhexis), subungual hyperkeratosis, or anonychia • Classic finding: dorsal pterygium or forward growth of the eponychium with adherence of proximal nail plate; also “tenting” sign as nail plate elevated with longitudinal splitting • Pits common Inverse LP • Rare • Occurs in flexural areas such as axilla, under breast, groin • Reddish-brown, discrete papules Palmoplantar LP • Yellowish, compact keratotic papules and papulonodules on lateral margins of fingers and hand surfaces90  2011/2012 Dermatology In-Review l Committed to Your Future
    • Special Forms of LP/Lichenoid Eruption Drug-induced LP • May be typical or atypical for classic LP, localized or generalized • Typically manifest postinflammatory hyperpigmentation, alopecia, without Wickham’s striae • Symmetric eruption on trunk and extremities—photodistribution common with these drugs: 5-FU, carbamazepine, chlorpromazine, diazoxide, ethambutol, quinine/quinidine, tetracyclines, thiazides and furosemide • Mucous membrane involvement often associated with specific drugs and chemicals— amalgam containing mercury; gold more common LP–Lupus Overlap • Classic lesions of LP not usually seen • Photosensitivity, pruritus, follicular plugging also uncommon • Lesions on extremities, commonly: atrophic plaques and patches with hypopigmentation and a livid red-to-blue violet color with telangiectasia and minimal scaling; bullae may develop • May progress to SLE • Prolonged course • Histo: Lichenoid reaction and histologic features of LE seen in same biopsy Lichen Planus Pemphigoides u TIP • Tense blisters atop lesions of LP, or development of vesicle a ichenoid drug eruptions have L de novo on uninvolved skin been associated with β-blockers, antimalarials, captopril, gold, peni- • Differentiate from bullous LP, where blisters in lesions cillamine, HCTZ, NSAIDs of longstanding LP as a result of intense lichenoid inflammation and extensive liquefaction degeneration of u TIP basal keratinocytes a ichenoid contact dermatitis L • Histologically like LP, with linear deposition of IgG and C3 at – color film developers, dental restorative materials, musk DE junction ambrette, nickel, aminoglyco- • Circulating IgG autoantibodies react to 180/200 kDa antigen sides, gold within BM zone Keratosis Lichenoides Chronica (Nekam Disease) • Violaceous papular and nodular lesions; hyperpigmented and hyperkeratotic, covered with gray scales • Often, linear and reticulate pattern on the dorsal hands and feet, extremities and buttocks • Very refractory to treatment LP and Malignant Transformation • Risk is very low to none at all • Risk increased by longstanding disease, erosive or atrophic types of LP, and tobacco use • Most common sites for malignant transformation are tongue, gingiva and buccal mucosa • Most patients developing SCC in cutaneous LP had a history of either arsenic or X-ray exposure Lichenoid Keratosis (Lichen Planus-like Keratosis) • Brown to red scaling papule or plaque found on sun-exposed skin of extremities • Histological features of LP with additional finding of parakeratosis • Frequently occur with solar lentigo, seborrheic keratosis, and actinic keratosis General Dermatology  91
    • Associated Conditions • Autoimmune chronic active hepatitis • Primary biliary cirrhosis • Postviral chronic active hepatitis • HCV in some populationsTreatment • Spontaneous remissions and exacerbations • Oral/Mucosal LP– replacement of gold or amalgam dental restorations • Topical high potency steroids for mucosal and limited cutaneous disease • Topical immunomodulators such as tacrolimus ointment for oral/genital disease • Topical anesthetics for oral pain • Intralesional TAC • Systemic steroids for refractory cases • PUVA photochemotherapy successful in generalized LP • Oral retinoidsCourse and Prognosis • Typically persists 1-2 years • May follow chronic, relapsing course • Spontaneous remission on average after 15 months • Lichen planopilaris most chronic and progressive with little potential for hair regrowth • Hypertrophic LP follows protracted unremitting course • Oral LP does not usually spontaneously regress4.9 ATOPIC DERMATITISClinical Features Major • Pruritus • Facial and extensor involvement in infants and children • Flexural lichenification in adults • Chronic or relapsing dermatitis • Personal/family history of atopy Associated Features • Xerosis • Cutaneous infection • Nonspecific dermatitis of hands/feet • Ichthyosis, palmar hyperlinearity, keratosis pilaris • Pityriasis alba • Nipple eczema • White dermatographism and delayed blanch response • Anterior subcapsular cataracts, keratoconus • Elevated serum IgE levels • Positive immediate-type allergy skin tests • Early age of onset • Dennie-Morgan infraorbital folds92  2011/2012 Dermatology In-Review l Committed to Your Future
    • • Orbital darkening • Facial erythema or pallor • Perifollicular accentuation • Course influenced by environmental and/or emotional factorsGenetics • Stronger correlation between siblings than between siblings and parents • Exposure to environmental factors during childhood is likely to be the major factor • Seen in families with atopic dermatitis, asthma, and allergic rhinitis • Filaggrin gene mutations are known risk factorClinical Manifestations • Typically begins in infancy → 50% in first year of life, and an additional 30% between 1 and 5 years • Most children with AD eventually develop allergic rhinitis or asthma later in childhood Infancy • AD generally more acute and primarily involves the face, scalp, and the extensor surfaces of the extremities • Diaper area spared Older Children • Patient develops the chronic form of AD with lichenification and localization of the rash to the flexural folds of the extremities • Subsides as patient grows older, leaving adult with skin that is prone to itching and inflammation • Chronic hand eczema may be the primary manifestation of adults with ADComplications Ocular Problems • Eyelid dermatitis and blepharitis • Atopic keratoconjunctivitis • Keratoconus: conical deformity of cornea • Cataracts Infections • Frequently complicated by recurrent skin infections: u TIP – Kaposi’s varicelliform eruption → herpes simplex → results in annate antimicrobial peptides I eczema herpeticum → incubation of 5-12 days, multiple, itchy, include human β-defensin (HBD) and cathelicidins, such vesiculopustular lesions erupt in a disseminated pattern → as LL 37. Ong et al found a often become hemorrhagic and crusted deficiency of HBD-2 and LL – Molluscum contagiosum 37 in lesions from patients with atopic dermatitis com- – HPV pared to those with psoriasis. – Superficial fungal infections—Trichophyton rubrum and This decreased expression of Pityrosporum ovale innate antimicrobial peptides – S. aureus – found in over 90% of AD skin lesions. Honey may explain the increased sus-  ceptibility to colonization and colored crusting, folliculitis, and pyoderma are indicators of skin infection with S. aureus in secondary bacterial skin infection. Regional lymphadenopathy patients with atopic dermatitis4 common. Deep-seated S. aureus infections may indicate hyper-IgE syndrome General Dermatology  93
    • Foods • Food allergens exacerbate skin rashes in at least a subset of patients with AD, particularly infants and young children • Eggs, milk, peanuts, soybeans, tree nuts, fish, and wheat are the most common allergens implicated in AD • Following positive oral food challenges in children with AD, histamine concentration increases in the plasma  • Most AD patients do NOT have food allergyImmunohistochemistry • Lymphocytes are CD3+, CD4+, and CD45RO+ memory T helper cells • Langerhans cells and macrophages infiltrating into AD skin lesions have surface-bound IgE • Activated eosinophils are present in significantly greater numbers in chronic as compared to acute AD lesions Immunologic Abnormalities in AD • Increased synthesis of IgE • Increased expression of CD23 (low affinity IgE receptor) on B cells and monocytes • Increased basophil histamine release • Impaired DTH response • Decreased CD8 suppressor/cytotoxic T-cell number and function • Increased secretion of IL-4 and IL-5 by TH2 cells • Decreased secretion IFN-gamma by TH1 cells An Immunologic Aside • TH1 cells → produce IL-2, IFN-γ, and TNF-β, associated with cell-mediated immunity • TH2 cells → produce IL-4, IL-5, IL-6, IL-10, and IL-13, associated with antibody mediated immune responsesManagement Allergens • Dust mites, molds, animal dander, pollens • Avoidance of triggering foods • Infants and young children more likely to have food allergies; older children and adults sensitive to environmental aeroallergens Infectious Agents • Anti-staphylococcal antibiotics helpful in those colonized • HSV: Antiviral treatment very important to prevent disseminated disease; IV treatment may be necessary for disseminated eczema herpeticum • Molluscum contagiosum → topical imiquimod, liquid nitrogen, topical salicylic acid, or no therapy Pruritus • Antihistamines → use sedating antihistamine at night Systemic Glucocorticoids • Rarely indicated, and risk of rebound flare after discontinuation • Short courses can be done while other modalities are started, and tapering dosage is critical94  2011/2012 Dermatology In-Review l Committed to Your Future
    • UV Phototherapy • UVB useful adjunct to treatment of chronic recalcitrant AD • High intensity UVA can be fast-acting and effective with acute exacerbations of AD Systemic Cyclosporine or Tacrolimus • Oral cyclosporine or tacrolimus can help severe AD that is refractory to topical steroids • Discontinuation of treatment may result in rapid relapse of skin disease Probiotics • The utility of probiotics in primary prevention of atopic dermatitis has been studied • Lactobacillus GG cultures were given to pregnant women with a history of atopy to assess the effect of potentially beneficial gut flora on the prevention of atopic disease in their children • Frequency of atopic dermatitis in the probiotic group was half that in the placebo group at two years of lifePrognosis • Disease more severe and persistent in young children • Periods of remission grow longer as patient ages • Mild disease at infancy: Spontaneous resolution occurs in 40% of patients after age 5 • Poor prognostic factors – Widespread AD in childhood – Associated allergic rhinitis or asthma – Family history of AD – Early age of onset4.10 Alopecia AreataGenetics • High frequency of family history, especially in patients with early onset (37%) • Twin concordance = 55% (identical twins)Immunologic Factors • Major associations: Vitiligo and thyroid disease (10%), with increased prevalence of antithyroid antibodies and thyroid microsomal antibodies in AA • Other autoimmune diseases shown to be associated: pernicious anemia, diabetes, LE, myasthenia gravis, RA, polymyalgia rheumatica, ulcerative colitisEmotional Stress • May be precipitating factor in some casesClinical Features u TIP a ATTERNS of alopecia areata: patchy (most common); • Prevalence: 0.1-0.2%, with lifetime risk of 1.7% P reticulated; ophiasis (parietal/temporal/occipital); • Affects men and women equally ophiasis inversus (sisapho – bandlike pattern in fronto • 60% present before age 20 parietotemporal scalp); diffuse • Pull test may be positive at margins, indicating early disease • Usually asymptomatic, but some patients perceive pruritus, tenderness, burning, or pain preceding hair loss • Areata – partial loss of scalp hair General Dermatology  95
    • • Totalis – total loss of scalp hair • Universalis – 100% loss on scalp, eyebrows, eyelashes, and rest of body • Initial regrowth is white, followed by repigmentation • Nail dystrophy (10-66%), seen in one, some, or all nails, preceding, coinciding, or occurring after hair disease → pitting with irregular pattern or in organized rows; trachyonychia: longitudinal striations resulting in sandpaper appearance; Beau’s lines; onychorrhexis; thinning or thickening; koilonychia; red-spotted lunula; punctate or transverse leukonychiaPrognosis • Unpredictable course and pattern • Most patients see complete regrowth within one year without treatment • 10% develop severe chronic form • Predictors for poor prognosis: atopic dermatitis, childhood onset, widespread involvement, ophiasis, duration for longer than five years, onychodystrophyTreatment • All local treatments help treated areas, but do not prevent further spread • Spontaneous recovery is extremely common, with most showing regrowth within 1 year • First line: IL steroids concentration of 5 mg/cc maximum of 3 cc per visit → 0.1 cc per site, approximately 1 cm apart; after 6 months and no response, d/c • Topical steroids as monotherapy generally ineffective • Minoxidil 5%: stimulates follicular DNA synthesis and regulates hair physiology independently of blood flow influences; effective with alopecia areata involving 20-99% involvement in 25-50% of patients → initial hair regrowth in 12 weeks • Anthralin 0.25-1.0% • Squaric acid dibutyl or DNCB or DPCP (diphenylcyclopropenone) – aim is to maintain low- grade tolerable erythema, scaling, and pruritus, with weekly applications • PUVA, with either topical or systemic psoralen therapy; relapse after discontinuation occurs • Cyclosporine works, but systemic use associated with adverse effects and high recurrence rate4.11 Alopecia: Other Forms u TIPTrichotillomania a iopsy shows high B • Practice of plucking or breaking hair from the scalp or eyelashes number of catagen • Areas of alopecia characteristically contain hairs of varying length hairs, pigmentary defects and casts, • Girls under age of 10 trichomalacia, and • Treat with psychotherapy and antidepressant hemorrhageHot Comb Alopecia • African American women who straightened their hair with hot combs • Characteristically on the crown and spreads peripherally to form a large oval area of partial hair loss • Thermal damage to follicle by hot petrolatum, leading to destruction of hair follicle and follicular scar • May be same as follicular degeneration syndrome/central centrifugal scarring alopecia96  2011/2012 Dermatology In-Review l Committed to Your Future
    • Pseudopelade of Brocq • Scarring alopecia where destruction of the hair follicle produces multiple round, oval, or irregularly shaped cicatricial patches of varying sizes • No pustules, crusts, or broken-off hairs are present • Onset is insidious • Female:male = 3:1 • Alopecia permanent • No inflammation with decreased or absent sebaceous glands, normal or atrophic epidermisTraction Alopecia • Prolonged tension on the hair from braiding, ponytails, rolling curlers, twisting with fingersPressure Alopecia • Occipital areas of babies lying on their backs • In adults, prolonged pressure on the scalp during general anesthesia or after prolonged bedrest • People with chronic illness after prolonged bed rest in one position • Likely related to pressure-induced ischemiaLoose Anagen Syndrome • Anagen hairs pulled from the scalp with little effort • Blonde girls • Usually improves with ageFollicular Mucinosis • Deposition of mucin in the outer root sheath and sebaceous glands • Most commonly on scalp and beard area • Secondary type associated with CTCL with widespread and chronic lesions, and patients are olderMeralgia Paresthetica • May have alopecia of the anesthetic area of the outer thighHypothyroidism • Hair coarse, dry, brittle, and sparse • Telogen hairs 3x more prevalentHyperthyroidism • Hair becomes extremely fine and sparseAlopecia Neoplastica • Hair loss from metastatic tumors • Usually breast carcinoma General Dermatology  97
    • 4.12 Vitiligo • Half of all cases begin before age 20 • Depigmented white patches surrounded by normal or hyperpigmented border • Trichrome vitiligo: intermediate tan zones halfway between the normal skin color and the depigmentation • Hairs in vitiliginous areas become whiteFour Types 1.) Localized or focal (includes segmental) 2.) Generalized (most common) 3.) Universal 4.) AcrofacialGeneralized • Symmetrical • Face, upper chest, dorsal hands, axillae, groin • Skin around all orifices • Areas of trauma (knees and elbows)Focal • Asymmetric • Treatment resistant • 5% of adult, 20% of childhood cases of vitiligoUniversal • Entire body surface depigmentedAssociations • Insulin-dependent diabetes • Pernicious anemia • Hashimoto’s thyroiditis • Grave’s disease • Addison’s disease • Alopecia areataGenetics • Multifactorial • 30% of vitiligo patients have an affected relativeTreatment • Topical corticosteroids • Ultraviolet phototherapy (Narrow band UVB and Psoralen with UVA) • Laser (308 nm excimer) • Topical tacrolimus • Re-pigmented surgery with punch minigrafts, dermoscopic dermal grafts98  2011/2012 Dermatology In-Review l Committed to Your Future
    • 4.13 Pityriasis rubra pilaris • Small follicular papules → salmon-orange to reddish-brown color, pinhead size, and topped with scaly plug • Yellowish pink scaling patches, often begins on scalp • Solid confluent palmoplantar hyperkeratosisProgresses to: • Sides of the neck and trunk • Extensor surfaces of the extremities • Any portion of the body can be affectedClinical Features • Involvement generally symmetrical and diffuse, with characteristic small islands of normal skin within the affected areas • Palms and soles will be hyperkeratotic with fissuring • Nails: dull, rough, thickened, brittle, and striated; may crack and break; no pittingTreatment • Topical keratolytics • Systemic retinoids • Vitamin A 500,000 units daily • Systemic steroids for short term management • Methotrexate • Azathioprine • Cyclosporine4.14 Lichen sclerosus • Presents from childhood to old age, and occurs in all races • Females predominate at all agesClinical • White, polygonal, and flat-topped papules or plaques surrounded by erythematous to violaceous halo • Later, lesions coalesce into large atrophic patches, becoming smooth, slightly wrinkled, and white • Bullae may arise in patches • Pruritus can be severe, especially in anogenital area, where erosions and fissuring can occur • In women, normal anatomic structures may be obliterated • Balanitis xerotica obliterans → male involvement of the glans penis; hemorrhage is common in the glans • Extragenital lesions most frequent on the upper back, chest, and breasts, and are usually asymptomatic • + KoebnerizationCancer Risk • Increased risk of genital SCC in both men and women • Lifetime risk for women less than 5% General Dermatology  99
    • Etiology • Autoimmune phenomenon, likely • 20% of both men and women have at least one autoimmune disease (vitiligo, alopecia areata, or thyroid disease), and a larger proportion have circulating antibodies • Trauma can induce lesions, and boys do better after circumcisionChildhood LS • Onset in childhood in 10-15% of cases • Girls outnumber boys 10:1 • Genital disease represents 90% of childhood LS • In girls: Symptoms include difficulty with defecation, dysuria, perineal pruritus, and perineal skin lesions • In boys: Phimosis is most common presenting sign • May resolve spontaneously, especially around puberty (50% of girls, after circumcision in boys)Treatment • Superpotent topical steroids twice daily to be tapered in either strength or frequency over time • Topical tacrolimus ointment or pimecrolimus cream, sometimes effective • Oral retinoids may work with anogenital lichen sclerosus in both men and women4.15 Granuloma annulareLocalized GA • Young adults • Lateral or dorsal surfaces of fingers, hands, elbows, feet, ankles • White, pink, flat-topped papules that spread peripherally • Never ulcerate and heal without scarring • 75% clear within 2 yearsGeneralized GA • Diabetes in 20% • Diffuse papules • May be pruritic or asymptomatic • Lasts three months to four yearsMacular GA • Flat or slightly palpable lesions over feet, ankles, and upper medial thighs • Small papules can be felt in some casesSubcutaneous GA • Most common in children • Often a history of trauma to area • Multiple lesions may be present • Generally asymptomaticPerforating GA • Dorsum of hands100  2011/2012 Dermatology In-Review l Committed to Your Future
    • • Papules with central keratotic core representing transepidermal elimination of the degenerated material in the center of GA lesions4.16 Hirsutism u TIPAndrogens in Women a rugs → Hirsutism without D Virilization/Defeminization • Dehydroepiandrosterone (DHEA), adrenal • Androstenedione–adrenal, ovary •  Phenytoin •  Minoxidil • Testosterone–ovary, adrenal, extraglandular conversion of •  Diazoxide androstenedione and dehydroepiandrosterone •  Cyclosporine – Adrenal androgen regulated by adrenocorticotropin •  Hexachlorobenzene – Ovarian androgen regulated by luteinizing hormone – The hair follicle requires conversion of testosterone to dihydrotestosterone for expression of androgen actionTumors → Rapid Onset of Hair Growth with or without Accompanying Virilization • Adrenal adenomas and carcinomas • Arrhenoblastoma • Kruckenberg tumors of ovaryPolycystic Ovarian Disease • Most common cause of ovarian hyperandrogenism • Manifestations: Hirsutism, amenorrhea, virilizationCongenital Adrenal Hyperplasia Congenital adrenal hyperplasia (defects in adrenal steroidogenesis) can occur at any point in life. • 21-hydroxylase deficiency • 11β-hydroxylase deficiency • 3β-hydroxysteroid dehydrogenase isomerase deficiency (3β-hsd)Idiopathic Hirsutism • Women with evidence of androgen excess but with normal menses, normal-sized ovaries, no evidence of tumors of adrenal or ovary, and normal adrenal function • Slight elevations of plasma androstenedione and testosterone commonSigns of Virilization Signs of virilization → correlates with androgen overproduction • Deepening of the voice • Temporal balding • Clitoromegaly • Increased muscle mass in the limb girdlesSigns of Cortisol Excess • Plethora • Central obesity • Striae • Dorsocervical/supraclavicular fat pads General Dermatology  101
    • Work-up • Pelvic exam: Search for palpable ovarian masses • Radiographic imaging of the pelvis/adrenal glands • Laboratory exam: DHEA > 8000 ng/ml or serum testosterone > 2 ng/ml suggest neoplasm • Plasma testosterone levels in the normal range are difficult to interpret → does not necessarily reflect the free or unbound levels of hormone under conditions when testosterone-binding globulin levels are either increased or decreased • Cushing syndrome, if suspected, should be evaluated with an overnight dexamethasone suppression test • Polycystic ovarian disease: Diagnosis from history and physical exam • Delayed onset adrenal hyperplasia: Short ACTH stimulation test and measurement of plasma 17-hydroxy-progesterone4.17 Amyloidosis • Beta-pleated sheet forms of various host-synthesized moleculesClassification 1.) Primary (often has skin findings) 2.) Secondary (rare skin manifestations) 3.) Primary localized 4.) Secondary cutaneous or tumor associated 5.) Familial syndromesPathology • PAS positive and diastase resistant • Congo-red positive • Purple with crystal violet • Positive with thioflavin T • Secondary systemic amyloid (aa) loses its birefringence after treatment with potassium permanganate, but primary and localized forms do not u TIPPrimary Systemic Amyloidosis arotein AL → derived from Ig P • Involves tongue, heart, GI tract, and skin light chains (lambda subtype); • Involves skin in 40% AL also found in nodular amyloidosis produced by a • Includes myeloma-associated amyloidosis plasmacytomaClinical • Shiny, smooth, firm, flat-topped papules of waxy color that coalesce into nodules or plaques • Commonly around nose, eyes, mouth, and mucocutaneous junctions •  Purpuric lesions result from amyloid infiltration of blood vessels; occurs after trauma (pinch purpura) • Glossitis → may lead to dysphagia; lateral aspects of tongue shows indentations from teeth • Bullous amyloidosis → subepidermal hemorrhagic bullae at areas of trauma • Carpal tunnel syndrome • RA-like arthropathy • Shoulder pad sign → enlarged deltoids • Cardiac arrythmias and chf cause death • Prognosis poor102  2011/2012 Dermatology In-Review l Committed to Your Future
    • Secondary Systemic Amyloidosis • Amyloid in the adrenals, liver, spleen, and kidney as a result of some chronic disease, such as TB, leprosy, Hodgkin’s, Behçet’s, rheumatoid arthritis, ulcerative colitis, schistosomiasis, or syphilis • Skin not involved u TIPPrimary Cutaneous Amyloidosis a A amyloid fibrils → derived from SAA protein, an A • Keratin is the protein component acute phase reactant • No amyloid around the blood vessels a A also seen in Muckle-Wells (renal amyloidosis, rti- A Macular Amyloidosis caria, fevers, limb pains, and deafness) and familial • Moderately pruritic, brown, rippled Mediterranean fever macules in interscapular region of the a ialysis-related amyloidosis: beta 2-microglobulin is the D back protein component altered by uremia → carpal tunnel • May have associated notalgia paresthetica syndrome, bone cysts, and spondyloarthropathy Lichen Amyloidosis • Bilateral shins • Type IIa MEN • Small, brown, discrete, scaly papules • Treat by reducing friction, occlusion, il steroidsNodular Amyloidosis • Single or multiple nodules on extremities, trunk, genitals, or face • Overlying epidermis may appear atrophic • Numerous plasma cells • AL typeSecondary Cutaneous Amyloidosis • Seen following PUVA therapy and in benign and malignant neoplasms: nonmelanoma skin cancers, seborrheic keratoses, trichoepitheliomas • Also, keratin-derived amyloidFamilial Syndromes Associated with Amyloidosis • Familial Mediterranean fever and Muckel-Wells syndrome → show AA protein • MEN IIa → keratin-derived amyloidFamilial Amyloidotic Polyneuropathy (fap) • Fap I and fap II → mutations in transthyretin • Fap III → apolipoprotein a-1 • Fap IV → gelsolin mutation General Dermatology  103
    • Table 4-2. AmyloidosisTypes Fibril Protein Other FeaturesSystemicPrimary AL (lambda λ chain) Involves tongue, heart, GI tract, and skin. Petechiae, purpura, waxy skin colored papules, alopecia, car- pal tunnel syndrome, neuropathy, arthropathSecondary AA Result of chronic disease: TB, leprosy, Hodgkin’s, RA, Reiter’s, syphilis No Skin involement Amyloid in the adrenals, liver, spleen, and kidneyLocalizedCutaneousMacular Altered Keratin Rippled brown macules in interscapular region on back, notalgia parestheticaLichen Altered Keratin Brown, scaly papules on bilateral shinsNodular AL chains Single or multiple nodules on extremities, genitals, trunk, or faceHereditaryFamilial AA AR, intermittent fevers, renal amyloidosis,Mediterranean peritonitis, pleurisyFever MEFV gene; marenostrin/pyrin proteinMuckle Wells AA AD, periodic attacks of urticaria, fever, deafness, renal amyloidosisHemodialysis β2 microglobulinAssoicationSenile B amyloid protein Senile or neuritic plaques, Alzheimer’s disease4.18 Calciphylaxis • Painful violaceous eschar-like plaques associated with soft tissue necrosis • Metastatic cutaneous calcification from increased parathyroid hormone (and increased calcium phosphate product) secondary to renal failure • Treatment: Phosphate binding agents, parathyroidectomy104  2011/2012 Dermatology In-Review l Committed to Your Future
    • 4.19 AngioedemaReview of the Complement System Classic Pathway • C1 binds to Fc fragment of IgM or IgG in immune complexes • C1q does the binding to immunoglobulin • C1s fragment digests C4 and C2, activating them into a C4b, 2a complex, creating C3 convertase, that activates C5 convertase → membrane attack complex Alternative Aathway • Less clear, but C3 activated by a C3-convertase complex consisting of C3b, bb • During inflammation, low levels of C3b bind factor b, that undergoes cleavage by factor d to generate C3b, bb → acts as a C3 convertase C1 Esterase Inhibitor • Protease inhibitor • Inhibits the catalytic subunits of first components of classical pathway (C1r and C1s), kallikrein, plasmin • In absence of C1 esterase inhibitor, activated C1 and plasmin generate activated C2 kinin • C2 kinin mediates angioedema Angioedema u TIP Type I: anherited (Quincke’s edema) (Normal C1q levels) I  • Occurs in setting of lymphoproliferative disease life • Detected in the first or second decade of (low-grade lymphoma, CLL, monoclonal gammo • Autosomal dominant pattern of inheriance pathy of undetermined significance, systemic • Serum C1q normal in inherited form amyloidosis) or rheumatologic illness, where idio • efect in synthesis and/or function of C1 D esterase inhibitor type/anti-idiotype immune complexes consume • ype I: Low amounts of normal C1 sterase T available C1q, and functionally and quantitatively inhibitor lower the amounts of C1 esterase inhibitor • ype II: Normal amounts of dysfuncional C1 T • Can also occur in setting of autoimmunity esterase inhibor directed against the C1 esterase protein aAcquired (Low C1q) • Important point: in both the inherited and • ffects adult or elderly with no family history A acquired forms levels of C2 and C4 are decreased • erum C1q decreased in acquired form S because of the uncontrolled actions of C1sClinical Presentation • Swelling of head, neck, and extremities • Abdominal symptoms • Upper airway symptoms • Recurrent symptoms, with intervening time of weeks to monthsTreatment • Androgen therapy: danazol or stanozolol → bring about dramatic decreases in frequency and severity of attacks • Glucocorticoids, but tapering results in relapse of symptoms • Therapy for underlying disease • Pretreatment with androgens prior to surgical procedures General Dermatology  105
    • Diagnosis • Screen with C3 and C4 levels → C4 low, C3 normal in angioedema • C1q level low in acquired, but normal in hereditary4.20 Carcinoid Syndrome and Flushing DisordersMenopausal Flushing • Perimenstrual flushing when estrogen levels low • Hot beverages and emotion can exacerbate • Pharmocologic menopause caused by drugs: danazol, tamoxifen, clomophene citrate, decapeptyl, leuprolide, and 4-hydroxyandrostenedione • Tubal ligation or any surgical loss of ovarian function • Clinical manifestations include drenching perspiration, waking episodes during the night, prodromal sensation of overheating before the onset of flushing and sweating • Treat with oral estrogen replacement or clonidine hydrochloride 0.05 mg bidEmotional Flushing • Can treat with biofeedback, hypnosis, and nadolol (40-80 mg qd)Foods • Monosodium glutamate • Scombroid group of fish (tuna and mackerel) • Spicy foodsMastocytosis • See separate section later in this chapterMedications • Nicotinamide, disulfiram, metronidazoleCarcinoid Syndrome • <4% with abdominal carcinoid tumors have the carcinoid syndrome • Presence of syndrome implies hepatic metastases, extraabdominal carcinoid tumor, or large enough tumor burden such that the liver cannot degrade the increased level of hormone • Tumors derived from enterochromaffin (Kulchitsky) cells • Appendix is most common site, followed by the ileum • Ileal tumors are the most common source of the classic carcinoid syndrome, and these tumors metastasize most frequently Clinical • Pellagra-like lesions caused by excessive utilization of tryptophan → hyperkeratosis, xerosis, scaling of legs, forearms, and trunk, angular cheilitis, and glossitis • Rosacea stigmata • Yellow-brown or brown-gray patches on the forehead, back, and wrists • Pruritus • Chronic watery diarrhea in 85% • Abdominal pain, constipation, nausea, vomiting, malabsorption, anorexia, weight loss, small bowel obstruction, and rectal bleeding • Respiratory symptoms of wheezing, stridor, dyspnea, coughing, and bronchospasm106  2011/2012 Dermatology In-Review l Committed to Your Future
    • • Arthritis, psychiatric symptoms, osteoblastic bone lesions • Fibrotic reactions affecting the valves of the heart Diagnosis • Serotonin overproduction  • Elevated urinary 5-HIAA • Foods and drugs can affect the urinary excretion of 5-HIAA4.21 Lupus ErythematosusClassification Chronic Cutaneous LE • Discoid • Verrucous (hypertrophic) • LE-LP overlap • Chilblain • Lupus Panniculitis Subacute Cutaneous LE • Papulosquamous • Annular • Neonatal • Complement deficiency syndromes Acute Cutaneous LE • Systemic LE with skin lesions → localized or generalized erythema with bullaeDiscoid Lupus • Young adults, women:men 2:1 • Dull red macules with adherent scales extending into patulous follicles • Plugged follicles • Patches heal with atrophy, scarring, dyspigmentation, and telangiectasia Localized • Above neck: scalp, nose, malar, lips, ears • Pruritus and tenderness common • Mucosal involvement of mouth, nose, eyes, vulva common Generalized • Less common than localized • Thorax and upper extremities, in addition to usual sites above the neck • Elevated ESR, positive ANA, or leukopenia more common Course • 95% of cases confined to the skin at outset will remain so • Abnormal labs such as ANA, leukopenia, hematuria, or albuminuria identify those who progress; also, rash above and below the neck • Relapses are common • BCC or SCC occur in scars, and a favored site is the lower lip General Dermatology  107
    • Treatment • Sun avoidance • Avoid exposure to heat, cold, trauma • Topical corticosteroids (potent) with or without occlusion • IL steroids Antimalarials • First hydroxychloroquine (Plaquenil), then chloroquine, or add quinacrine • Side effects: erythema multiforme, purpura, urticaria, ocular risks are very small, nausea, vomiting, tinnitus, abducens nerve paralysis, toxic psychoses, leukopenia, and thrombocytopenia • Exacerbate PCT • Bleach hair • Quinacrine yellows hair and conjunctivae become yellowOther Forms of Cutaneous LE Verrucous LE (Hypertrophic) • Non-pruritic, papulo-nodular lesions on arms and hands • Resembles KA’s or LP • Treat with IL TAC LE-LP Overlap Syndrome • See LP section Chilblain Lupus Erythematosus • Chronic, unremitting form with lesions on fingertips, ears, calves, and heels • Lesions are due to cold • Treatment is the same as LE LE Panniculitis • Deep dermal and subcutaneous nodules, rubbery-firm, sharply defined, and nontender • Head, face, upper arms, chest, buttocks, thighs • Chronic, in women 20-45 years old • DLE at other sites, commonly • Heals with atrophy and deep depressions • Treat with antimalarials for many months Subacute Cutaneous Lupus • Scaly papules that evolve into either psoriasiform or polycyclic annular lesions (more commonly) • Telangiectasia and dyspigmentation always present • No follicular involvement • No scarring • Occurs on sun-exposed surfaces of face and neck, inner arms, axillae and flanks • Spares knuckles • Photosensitivity in 40% u TIP • Hard palate involved in 40% a ajority positive for anti-Ro M • Concomitant DLE in 20% a rugs that may induce: HCTZ, D • At least half of the patients meet ARA criteria of SLE enicillamine, glyburide, griseofulvin, piroxicam, spironolactone, diltiazem, (usually have arthralgia, arthritis, leukopenia, positive ANA) ACE inhibitors, terbinafine • Disease runs a mild course108  2011/2012 Dermatology In-Review l Committed to Your Future
    • Neonatal LE • Annular scaling erythematous macules and plaques on head and extremities within the first few months of life in babies born to mothers with LE, rheumatic disease, or other connective tissue disorders • 50% mothers asymptomatic at delivery • Lesions resolve spontaneously by 6 months, healing without scarring • Photosensitivity may be prominent u TIP • 75% of cases involve girls a 0% have congenital heart 5 • Thrombocytopenia and hepatic disease as frequent as cardiac block, which is permanent (this may be the only manifestation disease of disease)Complement Deficiency Syndromes • Most commonly C2 and C4 • Photosensitivity • Annular scle lesions • Ro antibody formationSystemic LE Criteria: 4 Needed • Malar erythema • Discoid LE • Photosensitivity • Oral ulcers • Nonerosive arthritis • Serositis (carditis or pleurisy) • Nephropathy • CNS disorder (seizure or psychosis) • Hematologic disorder • Immunologic disorder (positive LE cell preparation, anti-DNA or Sm, false-positive RPR) • Positive ANA Cutaneous manifestations • Butterfly facial erythema, may be associated with edema → lasts days to weeks and heals without scarring • Bullous lesions, sun-exposed areas → histologically like EBA with antibodies against collagen Type VII, but responds to dapsone (EBA does not) • Fingertips and toetips show puffy erythema, telangiectasias • Periungual telangiectasias • Red lunulae • Erythematous to purplish palms and soles • Telangiectasias on face or elsewhere • Diffuse nonscarring hair loss with short, broken-off hairs in frontal region • Multiple (>15) dermatofibromas • Vasculitis secondary to antiphospholipid antibody • Cryoglobulinemia, livedo reticularis, thrombophlebitis, cutaneous infarction • Erythema multiforme-like lesions (Rowell’s syndrome) • Calcinosis cutis • Plaque-like depositions of mucin General Dermatology  109
    • Pregnancy and SLE • Miscarriages occur with greater frequency • LE may worsen, or go into remission during pregnancy • Fetal death risk increased with anti-cardiolipin or anti-Ro antibodies • Postpartum period shows the highest risk to the patientDrug-induced LE • Usually benign course u TIP • Hydralazine → 14%, with slow acetylators (HLA-DR4) a Hydralazine, procainamide, sulfon- more prone amides, penicillin, anticonvulsants, • Procainamide → 50% of treated patients minocycline, and INH • Anti-histone antibody closely associated with symptomatic a rug-induced LE not usually D disease associated with skin, renal, and CNS manifestations • Penicillamine induces native disease, with anti-dsDNA Ab’s • HCTZ induces SCLE4.22 Scleroderma Chronic disease of unknown etiology affecting the microvasculature and loose connective tissue.Classification Localized Scleroderma • Morphea → most common type • Generalized morphea → morphea, symmetric and bilateral lesions; but absence of Raynaud’s, acrosclerosis, and organ involvement differentiates from SSc • Guttate morphea (LS&A) • Nodular morphea • Subcutaneous morphea (morphea profunda) • Linear scleroderma → bandlike lesions that may involve the deeper layers of the skin Systemic Sclerosis • Limited (lSSc): 60%, includes CREST syndrome; 70-80% have anti-centromere antibodies and systemic involvement may not appear for years; patients are older than dSSc and many outlive the disease; better survival rate (50% at 12 years) • Diffuse (dSSc): Abrupt onset of swelling of the hands and feet with Raynaud’s and hidebound changes in the skin; polyarticular symmetric synovitis, tenosynovitis and tendon friction rubs often present; nail fold capillary dilatation and destruction  • arly onset of internal organ involvement; anti-topoisomerase 1 antibodies (SCL-  E 70) in 30%; worse survival rate (15% at 12 years)Epidemiology Localized Scleroderma • Women:men 3:1 • More common in whites Systemic Sclerosis • Women:men 4:1 • More common in black women, with diffuse disease more likely to affect black women • 7-year survival 75%110  2011/2012 Dermatology In-Review l Committed to Your Future
    • Scleroderma-like Disorders u TIP • leomycin: Pulmonary Fibrosis, Raynaud’s, and cutaneous a olyvinyl chloride → scleroderma B P with hepatic and pulmonary fibrosis changes indistinguishable from SSc (reversible upon discontinuation of drug) • Scleroderma-like skin changes seen in scleromyxedema, PCT, GVHDClinical Localized Morphea • Circumscribed sclerotic plaques with ivory-colored centers and violaceous borders (if disease active) • Plaques may be elevated or depressed, are indurated but not bound to the deeper structures • May occur after radiation therapy • All forms of localized morphea have good prognosis with disease becoming inactive in three to five years Generalized Morphea • Widespread involvement • Multiple indurated plaques and hyperpigmentation • Upper trunk, abdomen, buttocks, and legs • Not associated with systemic disease Guttate Morphea (LS&A) • Multiple small chalk-white lesions that lack the firm character of morphea Nodular Morphea • Lesions resemble keloids • May coexist with more typical lesions of morphea Morphea Profunda (Subcutaneous Morphea) • Deep, bound-down, sclerotic plaques Atrophoderma Pierini and Pasini • Idiopathic atrophy of the skin characterized by single or several depressed areas of skin • Lesions are well-defined with a “cliff drop” border Linear Scleroderma • Single, unilateral linear band • Lower extremities are most frequent site • Upper extremities, frontal head (coup de sabre), thorax also involved • Differentiate from morphea by involvement of deeper layers of skin with fixation to underlying structures • May cause severe deformity • May be associated with spina bifida occulta Melorheostosis • Linear, dense, cortical hyperostosis • Affects an involved limb usually, but may be widespread Parry-Romberg Syndrome • Facial hemiatrophy; may be form of linear scleroderma • Hyperpigmentation followed by atrophy of the dermis, subcutaneous fat, muscle, and sometimes the bone General Dermatology  111
    • Systemic Sclerosis • Initial complaints related to Raynauld’s or chronic nonpitting edema of the hands and fingers • Pain and stiffness of the fingers and knees • First manifestation may be migratory polyarthritis • Usually, skin changes precede visceral involvement by several years • Disease extends to upper extremities, trunk, face, and finally the lower extremities • Periorbital edema may occur in the early edematous phase • Face becomes mask-like • Lips thin, and opening of the mouth becomes constricted (microstomia) • Painful induration of the gums and tongue • Matlike telangiectases • Thinning or complete loss of hair and anhidrosis • Generalized hyperpigmentation without adrenal insufficiency • Focal hyper/hypopigmentation • Periungual telangiectasia occurs like in SLE and DM; 75% of those with ssc have enlarged, dilated nail fold capillaries forming giant loops • Recurrent painful ulceration of the fingertips and slow-healing ulcers of the knuckles • Bone resorption causing dissolution of the terminal phalanges • Cutaneous calcification over fingertips and over bony prominences → may ulcerateSystemic Involvement in SSC • Esophageal dysfunction is most common (>90%) • Dysphagia from decreased peristalsis, and may occur before skin findings seen • Heartburn • Small intestine involvement gives rise to constipation, diarrhea, bloating, and malabsorption • Pulmonary Fibrosis • Early pulmonary involvement with lowered diffusing capacity of the alveolocapillary membrane correlates with changes of the nail fold capillaries • Cardiac conduction defects, heart failure, pericarditis with effusion; myocardial fibrosis seen in 50-70% of SSc • Renal disease with slowly progressive uremia CREST Syndrome • Telangiectasias on face, upper trunk, hands • Develops later in life • Esophageal dysfunction is identical to that of the more severe forms of the disease • Anti-centromere antibodies in 50-96%, but only 12-25% in those with dSSc • Mixed connective tissue disease: combined features of scleroderma, LE, and myositis → high titers to ribonucleoproteinPathogenesis Three processes occur • Damage to vascular endothelium • Immunologic and inflammatory activation • Dysregulated extracellular matrix metabolismCourse • Morphea and linear scleroderma → few months to many years • 50% of patients with lesions that disappear are left with areas of hypo- or depigmentation112  2011/2012 Dermatology In-Review l Committed to Your Future
    • • Coup de sabre lesions may remain unchanged or become more extensive • Limited SSc rarely progresses to dSSc • Visceral involvement ultimately develops in dSSc • 5 year mortality for dSSc is about 50% → pulmonary fibrosis and renal hypertensive crisis in dSSc; pulmonary hypertension in lSScManagement Localized Scleroderma • Generally self-limited, so no treatment necessary • High potency topical steroids to lesions augmented by IL steroids • Antimalarials, phenytoin, colchicine, and systemic steroids have little benefit in generalized morphea • D-penicillamine may soften skin, allow the resumption of skin growth, and the cessation of new lesions • High dose UVA1 (340-450 nm) for morphea Systemic Sclerosis • Azathioprine, chlorambucil, methotrexate, cyclophosphamide variably successful • Systemic steroids do not alter the overall disease course • Cyclosporine may result in decrease in skin thickness, but pulmonary function remains unchanged and renal function may worsen • Extracorporeal photophoresis very controversial • D-penicillamine may be effective if used in early disease, with improved survival curves in patients because of lower incidence of renal disease; side effects limit long-term use: autoimmune lupus/polymyositis, pemphigus, nephrotic syndrome, myasthenia gravis, and Goodpasture syndrome • ACE-inhibitors markedly improve survival by treating renal disease • Peripheral vasospasm treated with diltiazem • Calcinosis treated with calcium channel blockers • Reflux esophagitis with proton-pump inhibitors • Physical therapy • Cessation of smoking decreases morbidity in those patients with documented Raynaud’s4.23 Dermatomyositis With or without skin lesions, weakness of proximal muscle groups is the prominent feature.Cutaneous Findings • Heliotrope rash: Violaceous erythema and swelling of periorbital skin • Gottron’s papules: Flat-topped, violaceous papules over MCP, PIP, DIP joints • Periungual telangiectasias with frayed cuticles • Erythematous or urticarial patches and plaques on upper portion of face and extremities • Photosensitivity • Hyperkeratosis, scaling, fissuring, and hyperpigmentation over the fingertips, sides of thumb, and fingers • “Mechanic’s hands” • Raynaud’s phenomenon • Poikiloderma of chest or back (Shawl sing), Oron lateral thighs (Holster sign) • Calcinosis cutis: More often in kids with Dermatomyositis General Dermatology  113
    • Muscle Changes • Symmetric weakness with swelling and pain, involving shoulder • Difficulty swallowing, talking, or breathing • Cardiac disease late in disease • Skin eruption precedes muscle symptoms by two to three months • Amyopathic dermatomyositis: lack of muscle inflammation after a year or longerAssociated Diseases • Sclerodermatous changes → sclerodermatomyositis (anti-KU antibodies) • Other collagen vascular diseases • Presence of anti-Jo-1 antibody, as well as anti-PL-7, anti-PL-12 (anti-synthetase antibodies) correlates well with pulmonary diseaseNeoplastic Risk • Cancer can precede, occur simultaneously as, or follow DM u TIP • Malignancy usually in 5th or 6th decade of life, and more aOvarian cancer is overrepresented common in womenIncidence u TIp • Twice as prevalent in women aChildhood DM • Bimodal peak: Small peak in children and large peak in •  runsting Type: more common, slow B adults between 40 and 65 course, progressive weakness, calcinosis, teroid responsiveLaboratory Findings •  anker Type: vasculitis of muscles and GI B • Creatinine kinase, aldolase, LDH, and transaminase tract, rapid onset of severe weakness, elevations (AST>ALT) steroid unresponsive, and death • Perform EMG and MRI to find disease activity • Pulmonary function tests • Barium swallow for esophageal dysmotilityMyositis Specific Antibodies (MSAS) • Positive ANA in 60-80% of patients • Anti-Mi-2 • Anti-p-155 (linked to cancer associated myositis and amyopathic dermatomyositis) • Anti-Jo-1 • Anti-CADM-140 (in patients with amyopathic DM) • Anti-Ku, Anti-Srp u TIpTreatment a nti-Mi-2 AB’s correlate with shawl A • Systemic corticosteroids sign, cuticular changes, and good prognosis • Azathioprine • Methotrexate a nti-Jo-1 AB’s correlate with A • Sunscreens pulmonary fibrosis, Raynaud’s, polyarthritis • Antimalarials • Mycophenolate mofehl a nti-SRP AB’s correlate with A cardiac disease and poor rognosis • Cyclophosphamide • Treat calcinosis with aluminum hydroxide, diphosphonates, a nti-Ku AB’s correlate with A sclerodermatomyositis diltiazem, colchicine, low dose warfarin114  2011/2012 Dermatology In-Review l Committed to Your Future
    • Course • Major causes of death are cancer, ischemic heart disease, and lung disease4.24 Sjogren’s syndromeTriad • Keratoconjunctivitis sicca • Xerostomia • Rheumatoid arthritis • More than 90% women • Vasculitis → palpable purpura • Patients develop lymphoreticular malignancy such as NHLLaboratory • Labial salivary gland biopsy • Schirmer Test for xerostomia detects diminished glandular secretion • RF positive • Positive cryoglobulins • Anti-Ro • Anti-La • Antibodies to fodrin (93% specific)4.25 Connective tissue disease: serologyDouble-Stranded DNA Antibodies (dsDNA) • ELISA used more than IF • Performed on Crithidiae Luciliae → possesses giant mitochondrion with no ssDNA • Positivity highly characteristic of SLE → highly correlative with positive DIF in patient’s normal skin (lupus band), low complement levels, renal disease, and poor prognosis • Highly positive levels confirm diagnosis of SLE; low levels found in RA, Hashimoto’s, Grave’s, Waldenstrom’s, MCTD, SSc, Sjogren’s, autoimmune liver disease • Negative test does not exclude SLE (50-83% sensitive)Single-stranded Antibodies • Very low diagnostic value → detected in LE and other CTD’s (DM, morphea, Sjogren’s, and linear morphea of children) u TIPRNP Antibodies aHistone Antibodies • Small ribonucleoproteins (SRNP) •   haracteristic of drug-induced C • SS-A (Ro), SS-B (La), SM, and U1RNP SLE → >90% of patients Anti-Ro Antibodies •   0% of patients with idiopathic 3 SLE have anti-histone Ab’s • Found in LE (varying percentages based on subset of LE) and Sjogren’s (50%) • Strongly associated with photosensitivity (especially in SCLE) Anti-La Antibodies • More than 90% with positive anti-La also positive for anti-Ro u TIP • Associated diseases similar to those associated with anti-Ro a 100% of patients with MCTD General Dermatology  115
    • Ro and La Helpful in Workup of Photosensitivity • Confirm clinical diagnosis of SCLE, Sjogren’s, or neonatal LE • Patients with chronic idiopathic vasculitis • Useful in testing ANA negative patients with clinical manifestations of sle or scle Anti-U1RNP • 30% of patients with SLE; patients with SLE and anti-U1RNP also have other positive serologies • Majority of patients with positive U1RNP have SLE rather than MCTD • Presence associated with sclerodactyly, Raynaud’s, esophageal dysmotility Anti-Sm • Diagnostic of SLE, and not reported in patients with other ctd’s • Found in 15-40% of patients with sle • Most patients with anti-sm also have u TIP antibodies to u1rnp (converse is not aOther Antibodies true) •  cl-70 (anti-topoisomerase) → characteristic of SSc, S ANA substrate → human Hep-2 cells; a serum and defines presence of systemic involvementnegative on animal substrate may be positive •  nti-centromere → marker for crest syndrome Aon human cells Titer → negative or low in young •  nti–jo-1 (histidyl trna synthetase) seen in minority Aand healthy persons; high in those with systemic of patients with dm and polymyositis → associated with pulmonary involvement and mechanic’s hand skinCTD; less than 1:80 has no diagnostic value. lesionsPatterns – Peripheral → sle → staining native DNA (most specific pattern for SLE) – Homogeneous → sle → staining native DNA, histones – Nucleolar → SSc, sle → staining nucleolar RNA – Centromere → crest → staining kinetochore – Speckled → mctd, sle, ssc, sjogren’s → staining ribonucleoproteins • ANA-negative sle → determined often on animal substrates, yet later found to be positive on human cells, or if patient only makes antibodies to ssdna (not detected by most tests) • Almost all patients with SLE have positive ANAs • Ana: high negative predictive value, low positive predictive valueAntiphospholipid Antibodies • Also called the lupus anticoagulant and anticardiolipin antibodies • Associated with thrombosis (not bleeding) • Most prevalent in sle patients • Seen in patients taking certain drugs (cocaine, ifn-α, procainamide, hydralazine, quinine, quinidine, phenytoin, fansidar, phenothiazines), chronic infections • Indications for testing – Livedo reticularis – Purpura and necrosis – Ulcers – Internal organ thrombosis – Recurrent miscarriages – Screening in patients with SLE116  2011/2012 Dermatology In-Review l Committed to Your Future
    • Table 4-3. Antinuclear Antibody PatternsPattern Associated Antibody Associated DisorderHomogenous anti-histone SLE false +, Drug induced LE, SLERim (peripheral) anti-ds DNA SLE nephritisSpeckled (fine speckled) anti-Sm SLE anti Ro and La (SSA/B) SLE, Sjogrens syndrome anti-U1RNP SLE, MCTD anti-Ku SLE, scleroderma, myositis anti-topoisomerase (Scl-70) Scleroderma, SLECentromere (discrete speckled) anti-kinetochore CRESTNucleolar anti-U1RNP Scleroderma, SLEanti-RNA polymeraseanti-PM-Scl4.26 Relapsing Polychondritis • Intermittent episodes of inflammation of the articular and nonarticular cartilage • Results in chondrolysis, dystrophy, and atrophy of the cartilage • Both sexes equally affected • Onset in 4th to 5th decadeClinical • Beefy red involvement of the ears confined to the cartilaginous portion • Often unilateral • Acute flare of inflammation lasts 1-2 weeks • 85-90% of patients develop auricular chondritis • Conductive deafness because of swollen cartilage • Recurrent episodes of chondritis result in destruction of normal cartilaginous structures and their fibrotic replacement → floppy or cauliflower ears • Nasal septal cartilage inflamed (50-70%) → rhinitis, crusting, bleeding, and saddle-nose deformity • Involvement of bronchi results in hoarseness, coughing, and dyspnea • Migratory arthralgia seen in 50-80% • Ocular disease: conjunctivitis, scleritis, iritis (any part of the eye may be affected) • Cardiovascular: aortic regurgitation and aortic aneurysm • 1/3 have associated rheumatic or autoimmune disease and many have LCVLaboratory • Elevated ESRMAGIC Syndrome • Behçet’s and relapsing polychondritis simultaneously (mouth and genital ulcers with inflamed cartilage) General Dermatology  117
    • Pathophysiology • Autoimmunity: IgG anti-type II collagen antibodies with titers corresponding to disease activity → found in up to 50% of patients with relapsing polychondritis (in only 15% in those with RA) • Antibodies directed against native and not denatured collagen II • Type II collagen restricted to cartilageCourse • Unpredictable; chronic and variable with episodic flares (usually 1-4 weeks) and spontaneous remissions • Peripheral arthritis predicts a worse course • Causes death in 1/3 of patients secondary to airway collapse, cardiovascular complications, and infection (secondary to systemic steroids)Treatment • Dapsone 100 mg QD to BID with maintenance dose for 4-6 months → but may be ineffective in controlling scleral inflammation • Systemic steroids • Cyclosporine • NSAIDs • TNF-alpha inhibitors4.27 BehCet’s diseaseRecurrent Oral Ulceration • Recurred at least 3 times in 12 month periodPlus 2 of the Following: • Recurrent genital ulceration • Eye lesions (posterior uveitis) • Skin lesions (erythema nodosum, pseudofolliculitis, papulopustular lesions, or acneiform nodules) • Positive pathergy testClinical Features • Lesions are painful • CNS lesions occur and give picture of multiple sclerosis • Thrombophlebitis • Thrombosis of the superior vena cava • Asymmetric, non-erosive polyarthritis • Associated with hla-b51Treatment • Sucralfate • Colchicine • Dapsone • Thalidomide • Tnf-inhibiting agents such as infliximab and etanercept118  2011/2012 Dermatology In-Review l Committed to Your Future
    • 4.28 Livedo ReticularisPhysiologic • Cutis marmorataIntravascular Obstruction • Stasis • Cardiac failure • Emboli • Cryoglobulinemia • Anticardiolipin syndrome • Hyperoxaluria • Arteriosclerosis • Hyperparathyroidism • Arteritis (pan, rheumatoid arteritis, le, dm, syphilis, tb, pancreatitis)Drugs • Amantadine, quinine, quinidine4.29 Leukocytoclastic Vasculitis Diverse group of disorders: combine segmental inflammation with necrosis of blood vessels.May be primary, a feature of a systemic disorder, or idiopathic.Pathogenesis • Postulated that circulating immune complexes are locally deposited. The complexes activate complement, and thus attract neutrophils, which release lysosomal enzymes and damage tissue • ANCAs, antineutrophilic autoantibodies – C-ANCAs (cytoplasmic)—specific for proteinase 3 – P-ANCAs (perinuclear)—specific for myeloperoxidase • Seen with hepatitis C infection. ANCAs produce necrotizing vasculitis by activating circulating pmns and monocytes, which then adhere to blood vessels, degranulate, and release toxic oxygen metabolites to cause vascular injuryClinical Manifestations • Palpable purpura – non-blanching erythematous papules • Papules, urticaria, angioedema, pustules, vesicles, ulcers, necrosis, and livedo reticularis • Usually occurs on lower extremities or over dependent areas such as the back and gluteal regions. Uncommon on face, palms, soles, and mucous membranes • Palpable purpura persists 1-4 weeks, resolving often with transient hyperpigmentation and/ or atrophy • Symptoms: pruritus, burning, and pain less commonly. Episode associated with fever, malaise, arthralgias, and myalgiasAssociated Chronic Disorders • Rheumatoid arthritis • Sjogren’s syndrome • Sle General Dermatology  119
    • • Dermatomyositis • Hypergammaglobulinemic purpura • Mixed connective tissue disease, relapsing polychondritis, and scleroderma • Paraneoplastic vasculitis • Associated malignancies such as Hodgkin’s, lymphosarcoma, adult T-cell leukemia, mycosis fungoides, myelofibrosis, aml, cml, iga myeloma, diffuse large cell leukemia, hairy cell leukemia, squamous cell bronchiogenic carcinoma, prostate cancer, renal cell carcinoma, and colon carcinoma • Cryoglobulinemia • Particularly mixed types II and III • Occur in idiopathic LCV • Associated with hepatitis A, B, and C • Cystic fibrosis • IBD of the colon • Behçet’s diseaseANCA’s • Seen with hepatitis C infection • Palpable purpuraAntiphospholipid Antibodies • Livedo reticularis is most common findingPrecipitating Infections • Group A β hemolytic streptococci • Staphylococcus aureus • Mycobacterium leprae – erythema nodosum leprosum, cutaneous nodular lesions of leprosy, involves capillaries, venules, arterioles, veins, and small to medium sized arteries • Hepatitis B • HIV • N. meningitidis • Rocky Mountain spotted fever • Catheter infectionsPrecipitating Drugs • Penicillin • Sulfonamides • Thiazides • Allopurinol • Phenytoins • Nsaids • Ptu and hydralazine in association with ancas • Streptokinase • Radiocontrast media • Monoclonal antibodies • G-CSF120  2011/2012 Dermatology In-Review l Committed to Your Future
    • Idiopathic Disorders Henoch-Schonlein Syndrome • Most widely recognized subgroup • Mostly children • Recent URI in 75% • Involves skin, synovia, GI tract, kidneys • Skin lesions of adults show blisters and necrosis • Long-term morbidity from kidney disease, which is predicted by the spread of purpura to the upper trunk Acute Hemorrhagic Edema of Childhood • Affects children and infants < 2 years of age • Painful, edematous petechiae and ecchymoses on head and distal extremities • Triggering factors: Infection, drugs, immunization • Lacks systemic features of HSP, and resolves within 1-3 weeks without sequelae Urticarial Vasculitis • Episodes of recurrent urticaria and angioedema • Occurs with serum sickness, connective tissue disorders, infections (Hep B and C, infectious mononucleosis), physical urticarias, colon carcinoma, administration of potassium iodide, fluoxetine, NSAIDs, and as an idiopathic disorder • Lesions often persist from 3-5 days, and usually heal without residua. Episodes are chronic, range in duration from months to years • 70% afflicted are women • General features: Fever, malaise, and myalgia, with possible lymphadenopathy and hepatosplenomegaly • Episodic arthralgias u TIP • Renal: Diffuse GN or glomerulitis a Schnitzler’s syndrome: episodes of urticarial vasculitis that • GI: Diarrhea, nausea, vomiting occur in association with monoclonal IgM M component. • Pulm: Laryngeal edema Fever, lymphadenopathy, hepatosplenomegaly, bone pain, • Eye: Conjunctivitis, uveitis, episcleritis and sensorimotor neuropathy • CNS: Headaches, pseudotumor cerebri Nodular Vasculitis • Recurrent, tender, red, subcutaneous nodules over lower extremities, especially the calves; lesions can occur on thighs, buttocks, trunk, and arms • No systemic manifestations • Women between 30 and 40 • Erythema induratum: form of nodular vasculitis associated with M. tuberculosis Livedoid Vasculitis (Atrophie Blanche) • Recurrent painful ulcers of lower extremities in association with persistent livedo reticularis; often deep purple in color • Atrophie blanche: Healed lesions result in sclerotic pale areas surrounded by telangiectases • Associated with arteriosclerosis or stasis • Pathogenesis may be secondary to fibrin thrombi in lumens of superficial vessels • Sneddon’s syndrome: Livedo reticularis and livedoid vasculitis associated with ischemic cerebrovascular lesions, hypotension, and extracerebral arterial and venous thromboses General Dermatology  121
    • Genetic Domplement Deficiencies • C2, C4a and C4b seen in some patientsEosinophilic Vasculitis • Idiopathic syndrome with recurrent pruritic, purpuric, papular skin lesions with angioedema • Also, urticarial plaques and palpable purpura present • Infiltrate of eosinophilsLCV Treatment • H1 antihistamines used with palpable purpura to alleviate lesional symptoms • H1 blockers with NSAIDs • Colchicine or hydroxychloroquine can be added to or substituted for these agents; no benefit, then use dapsone • Systemic steroids, azathioprine, cyclophosphamide, plasmapheresis, cyclosporine • IFN-alpha clears lesions in Hep CUrticarial Vasculitis • H1 blockers, indomethacin, colchicine • Systemic steroids alleviates urticaria and systemic problemsErythema Elevatum Diutinum • DapsoneNodular Vasculitis • NSAIDs, colchicine, systemic steroidsErythema Nodosum Leprosum • ThalidomideLivedoid Vasculitis • Aspirin, dipyridamole, colchicine, low-dose heparin, systemic glucocorticoids, and low molecular weight dextran, nifedipine, pentoxyfylline4.30 Cryoglobulinemia and cryofibrinogenemiaCryoglobulinemia Circulating immunoglobulins complexed with other immunoglobulins or proteins that revers-ibly precipitate in the cold. Type I  • Single monoclonal immunoglobulin, usually IgG or IgM • Usually an underlying β-cell malignancy such as myeloma or lymphoma • Associated also with CLL and Waldenstrom’s macroglobulinemia • Purpura, acrocyanosis, retinal hemorrhage, Raynaud’s phenomenon, and arterial thrombosis Type II (Mixed Cryoglobulinemia)  • Monoclonal IgM rheumatoid factor complexed with polyclonal IgG • Multiple myeloma, Waldenstrom’s, CLL, rheumatoid arthritis, Sjogren’s, Hepatitis C • Lcv with palpable purpura, arthritis/arthralgias, and vascular purpura122  2011/2012 Dermatology In-Review l Committed to Your Future
    • Type III (Mixed Cryoglobulinemia)  • Rheumatoid factors that are polyclonal IgM and IgG, complexed with each other or with another protein • Often complement activated and complement levels are lower • Sle, ra, sjogren’s, infectious mononucleosis, CMV infection, primary biliary cirrhosis, Hepatitis B, Hepatitis C • LCv with palpable purpura, arthritis/arthralgias, and vascular purpura Essential Mixed Cryoglobulinemia • Cryoglobulins and the manifestation of symptoms without an identifiable connective tissue, neoplastic, or infectious process • Often HCV infection coincides Clinical Features • Purpura, livedo, Raynaud’s, distal ulcerations • Affected organs are skin, kidneys, liver, musculoskeletal, and nervous systemsCryofibrinogenemia • Cryoproteins in anticoagulated blood or plasma that reversibly precipitate in the cold • Composed of fibrinogen • Cutaneous manifestations: purpura, ecchymoses, gangrene, ulcers • Associated with malignancy, thromoembolic disease, diabetes, pregnancy, oral contraception, and pseudotumor cerebri4.31 Acanthosis nigricans Cutaneous marker of either insulin resistance, malignancy or obesity.Clinical • Grayish-brown, velvety plaques, hyperpigmentation, papillomatous • Most common to least common areas: axillae, neck, external genitalia, groin, face, inner thighs, antecubital and popliteal fossae, umbilicus, perianal area • Achrochordons • Tylosis: Palmoplantar hyperkeratosis with acanthosis palmaris or pachydermatoglyphy (exaggeration of fingerprints, or tripe palms) • Mucosal involvement consisting of thickening and papillomatosis with minimal hyperpigmentationAssociated Conditions • Insulin resistance, associated with obesity, with positive correlation between degree of AN and severity of obesity • Lipodystrophies (Lawrence-Seip syndrome) • Leprechaunism – elfin appearance of face, thickened skin, absence of subcutaneous fat, and hirsutism • Type A syndrome: Severe acanthosis nigricans, hirsutism, clitoromegaly, and masculine habitus • Type B syndrome: AN after teenage years with less extensive involvement, with often underlying SLE (anti-insulin receptor auto-antibodies) • Malignancy: More extensive and involves mucosal surfaces; usually adenocarcinomas (gastric) • Drugs: testosterone, nicotinic acid, diethylstilbestrol, oral contraceptives, triazinate, glucocorticoids, topical application of fusidic acid General Dermatology  123
    • 4.32 LipodystrophyPartial Lipodystrophy • Etiology unknown • Loss of subcutaneous fat in clearly demarcated, generally symmetric areas • Begins on face, spreads downward, stopping at any level → face become cachectic, with disappearance of buccal fat pads; premature aged expression; sunken eyes; easy visualization of veins • Lower part of body may be affected without upper part being affected • Excess fat deposition over hips and thighs frequently in women • 80% female, and usually begins before age 15Laboratory • Hypertriglyceridemia and insulin resistance • Clinically apparent diabetes in 20% • Decreased serum complement (C3) • Increased C3 nephritic factor → immunoglobulin that binds Factor H, an inhibitor of C3, allowing uncontrolled C3 activation • Glomerulonephritis (unknown frequency)Treatment • No effective therapyGeneralized Lipodystrophy • Etiology unknown • Lack both subcutaneous fat and extracutaneous adipose tissue • Congenital (Seip-Lawrence syndrome) • Acquired (Berardinelli-Seip syndrome) • Often, acanthosis nigricans, hypertrichosis, generalized hyperpigmentation, and thick, curly scalp hair • Patients have voracious appetites, perspire excessively, and may be heat-intolerant despite normal thyroid function (elevated basic metabolic rate) • Muscles, genitalia appear hypertrophic • Mental retardation is commonLaboratory and Internal Disease • Glucose intolerance (lipoatrophic diabetes); insulin resistance detected earlier than diabetes • Hepatomegaly resulting from increased fat; cirrhosis may develop • Renal, retinal, and neuropathic diabetic changes • CT and ultrasound show reduced fat around viscera • Eruptive xanthomas may appearTreatment • No effective treatment124  2011/2012 Dermatology In-Review l Committed to Your Future
    • 4.33 HyperlipoproteinemiasType I • Familial lipoprotein lipase deficiency (AR) or apoprotein CII deficiency • Increased chylomicrons • Eruptive xanthomas, lipemia retinalis • Associated with hepatomegaly, pancreatitis, abdominal pain (“horrible, screaming pain”)Type IIa • Familial hypercholesterolemia, common hypercholesterolemia (AD) • Increased LDL • Tendinous, tuberous, xanthelasma, arcus juvenilis, planar, eruptive • econdarily caused by hepatoma, obstructive biliary disease, porphyria, hypothyroidism, S anorexia, nephrotic syndrome, Cushing’s • AtherosclerosisType IIb • Familial hypercholesterolemia (AD) • Increased LDL and VLDL • Tendinous, tuberous, xanthelasma, arcus juvinilis, planar • Secondarily caused by nephrotic syndrome and Cushing’s syndrome • AtherosclerosisType III • Familial Dysbetalipoproteinemia (AR) • Increased IDL • Palmar, planar, tendinous, tuberous, eruptive, intertriginous xanthomas • Secondarily caused by paraproteinemia • Atherosclerosis • Associated with diabetes, gout, and obesityType IV • Familial hypertriglyceridemia (AD) • Increased VLDL • Eruptive, tendinous, tuberous • Secondarily caused by diabetes, uremia, paraproteinemia, alcoholism, lipodystrophy, obesity • AtherosclerosisType V • Familial type V hyperlipoproteinemia, familial lipoprotein lipase deficiency (AD) • Increased chylomicrons and VLDL • Eruptive, lipemia retinalis • Secondarily caused by diabetes, obesity, and pancreatitis • Associated with hepatomegaly General Dermatology  125
    • 4.34 XanthomatosisClinical Types and Associations Tuberous Xanthoma • Flat or elevated, rounded, grouped, yellowish, or orange nodules over joints (particularly elbows and knees) • Types II, III, and IV • Biliary cirrhosis Tendinous Xanthoma • Papules or nodules over tendons (extensor tendons on dorsum of hands, feet, and achilles) • Types II, III Eruptive Xanthoma • Small yellow/orange/red papules appearing in crops over entire body → buttocks, flexor surfaces, arms, thighs, knees, oral mucosa and may koebnerize • Associated with markedly elevated or abrupt increase in triglycerides (elevated chylomicrons) • Types i, iii, iv, and v • Diabetes, obesity, pancreatitis, chronic renal failure, hypothyroidism, estrogen therapy, corticosteroids, isotretinoin, acitretin Planar Xanthoma • Flat macules or slightly elevated plaques with yellow/tan color, spread diffusely over large areas • Frequently associated with biliary cirrhosis, biliary atresia, myeloma, HDL-deficiency, monoclonal gammopathy, lymphoma, leukemia, serum lipoprotein deficiency, xanthomas following erythroderma, ra, acquired c1 esterase deficiency • Characteristically around eyelids, neck, trunk, shoulders, or axillae • Types ii, iii Palmar Xanthoma • Nodules and irregular plaques on palms and flexural surfaces of fingers • Type III u TIP Xanthelasma a anthoma striata palmaris: diagnostic of type III X • Most common type of xanthoma dysbetalipoprotinemia (broad beta disease) • Eyelids, 2-30 mm in length • Frequent symmetry • Usually present without any other disease, but may occur concomitantly with other xanthomas; can occur in types II and III, particularly • Common among women with hepatic or biliary disorders, also seen in myxedema, diabetes, and phytosterolemia • Best treated with surgical excision4.35 Vitamin Deficiencies Alcoholism is the main cause of nutritional disease in developed nations. Other conditions: • Postoperative patients • Psychiatric patients • Unusual diets • Inflammatory bowel disease126  2011/2012 Dermatology In-Review l Committed to Your Future
    • • Cystic fibrosis • Surgical bowel dysfunction • Inborn errors of metabolismVitamin A Phrynoderma (Hypovitaminosis A) • Diseases of fat malabsorption: Crohn’s, celiac disease, CF, cholestatic liver disease • Required for normal keratinization • Deficiency leads to inflammatory disease of gut and lung • Supplementation required in rubeola (200,000 IU/day for 2 d) Clinical • Phrynoderma → toadskin, keratotic papules over extremities and shoulders surrounding pilosebaceous follicles • Spreads to involve abdomen, back, buttocks • Whole skin dryness and fine scaling • Night blindness • Xerophthalmia • Keratomalacia Hypervitaminosis A • Similar to side effects of synthetic retinoid therapy • Prone individuals: Children, hepatic disease, dialysis patients • All Vitamin A supplementation should be stopped if patient taking a retinoid Clinical Children • Loss of hair and coarseness of remaining hair • Loss of eyebrows • Exfoliative cheilitis • Generalized exfoliation and pigmentation of skin • Clubbing of fingers • Bone growth retardation • Pseudotumor cerebri (bulging fontanelles in infants) Adults • Dryness of lips • Anorexia • Joint and bone pains • Follicular hyperkeratosis • Desquamation of skin • Fissuring of corners of mouth and nostrils • Loss of scalp hair and eyebrows • Nail dystrophyVitamin D • Deficiency: Alopecia only skin manifestation • Elderly: Results from decreased sun exposure and poor intake • Those taking anticonvulsants • Fat malabsorption • Extensive sun protection and sunscreen does not lead to Vitamin D deficiency • Excess: Hypercalcemia and generalized calcinosis General Dermatology  127
    • Vitamin K • Does not occur in adults (synthesized by bacteria in gut) • Deficiencies occur because of malabsorption caused by biliary disease, malabsorption syndromes, CF, anorexia nervosa, liver disease of all causes • Drugs such as coumadin, salicylates, cholestyramine, cephalosporins • Cutaneous manifestations: purpura, hemorrhage, ecchymosisVitamin B2 Deficiency (Riboflavin) • Most often in alcoholics • Oral-ocular-genital syndrome • Angular cheilitis • Atrophic tongue that is magenta • Seborrheic-like dermatitis around nose • Genital dermatitis → scrotal dermatitis sparing midline and extending to thighs • Photophobia and blepharitisVitamin B6 Deficiency (Pyridoxine) • Caused by uremia and cirrhosis; pharmacologic agents • Seborrheic dermatitis-like eruption • Atrophic glossitis with ulceration • Angular cheilitis • Conjunctivitis • Intertrigo • Neurologic symptoms: somnolence, confusion, neuropathyVitamin B12 Deficiency • Deficiency of intrinsic factor, achlorhydria, ileal disease, congenital absence of transcobalamin II • Occurs 3-6 years after GI abnormalities • Glossitis → bright red, atrophic tongue • Hyperpigmentation → resembles Addison’s disease • Canities • Neurologic findingsFolic Acid Deficiency • Hyperpigmentation, glossitis, cheilitis, and megaloblastic anemia, identical to Vitamin B12 deficiencyVitamin C Deficiency (Scurvy) • Male alcoholics and psychiatric patients • Hemorrhagic signs, hyperkeratosis of the hair follicles, hypochondriasis, and hematologic abnormalities • Perifollicular petechiae • Subperiosteal hemorrhage leading to pseudoparalysis • Subungual, subconjunctival, intramuscular, and intraarticular hemorrhage • Hemorrhagic gingivitis • Epistaxis • Delayed wound healing128  2011/2012 Dermatology In-Review l Committed to Your Future
    • Niacin Deficiency (Pellagra) • Can result from deficiency in niacin (Vitamin B3 or nicotinic acid) or its precursor tryptophan • Alcoholics • Carcinoid tumors • Hartnup disease (impaired absorption of tryptophan) • GI disorders • Prolonged IV supplementation • Anorexia nervosa • Medications: INH, azathioprine, 5-FU Clinical  • Photosensitive eruption on face, neck, and upper chest (Casal’s necklace); may be vesiculobullous • Thickening and pigmentation over bony prominences • Seborrheic dermatitis-like eruption on the face • Diarrhea, depression, abdominal pain, dementia, coma • Patients die in four to five years if untreated Pathology • Most characteristic → pallor and vacuolar changes of keratinocytes in the upper layers of the stratum malphighii, just below the granular layer; a cleft may develop in upper epidermisBiotin Deficiency • Patients with short gut or malabsorption • Ingestion of avidin (raw egg whites) binds biotin causing deficiency • Multiple carboxylase deficiency • Holocarboxylase synthetase deficiency Clinical • Dermatitis is similar to zinc deficiency → periorificial and marked by patchy, red, eroded lesions of face and groin • Conjunctivitis • AlopeciaZinc Deficiency • Inherited abnormality, or acquired • Presentation in infancy most common → especially premature infants • Human breast milk has adequate zinc, and weaning precipitates deficiency in premature infants and those with acrodermatitis enteropathica • Low maternal breast milk zinc levels or higher infant requirements can precipitate deficiency in full-term infants • Zinc requirements increase during metabolic stress (infection) Clinical • Pustular and bullous lesions in an acral and periorificial distribution • Patchy, red, dry scaling with exudation and crusting • Angular cheilitis and stomatitis • Periungual erythema, scaling, and pustules • Patients are irritable and emotionally labile General Dermatology  129
    • Labs • Low serum zinc levels • Low alkaline phosphatase (a zinc-dependent enzyme)Essential Fatty Acid Deficiency • Infants with low birth weight • GI anomalies • Inflammatory bowel disease • Intestinal surgery • Parenteral nutrition (prolonged) Clinical • Similar dermatitis to that of zinc and biotin deficiency • Widespread erythema and intertriginous weeping eruption • Diffuse alopecia • Ratio of eicosatrienoic acid to arachidonic more than 0.4 diagnostic of EFA deficiencyIron Deficiency • Koilonychia, glossitis, angular cheilitis, pruritus, and telogen effluvium • Plummer-Vinson: Microcytic anemia, dysphagia, and glossitis seen nearly entirely in middle- aged women; lips are thin and opening of mouth is small and inelasticMarasmus u TIP aKwashiorkor • Prolonged deficiency of both protein and calories • Children 60% of their ideal body weight •   rotein deficiency but adequate P caloric intake • No edema or hypoproteinemia •  Edema and potbelly • Skin is dry, wrinkled, and loose •   ypopigmented hair → reddish H yellow to gray or whiteCarotenemia •   Flag sign” → hair grown during “ • Excessive ingestion of carrots, oranges, squash, spinach, periods of poor nutrition is pale yellow corn and beans, butter, eggs, rutabagas, pumpkins, yellow turnips, sweet potatoes, or papaya leading to yellowish discoloration of skin • Prominent on palms, soles, and central faceLycopenemia • Excessive ingestion of red foods like tomatoes, beets, chili beans, and various fruits leads to reddish discoloration of skin4.36 Diabetes and skin diseaseInfections • Staph pyodermas • Candidiasis • Erythrasma • EpidermophytosisXanthomatosis • Chylomicronemia with xanthomas • Regression when diabetes brought under control130  2011/2012 Dermatology In-Review l Committed to Your Future
    • • Xanthelasma: Occurs in hyperlipidemic states (including diabetes) and may occur without demonstrable abnormality of plasma lipidsDiabetic Dermopathy • Asymptomatic, irregularly shaped patches over anterior lower legs • Depressed and brown surfaces • Often accompanied by significant microangiopathy elsewhere in bodyBullous Lesions/Bullous Diabeticorum • Spontaneous bullae on extremities, especially of the feet • Heal without scarring within weeks • Bullae occur in plane of basement membrane above basal laminaThickened Skin and Stiff Joints • 1/3 of patients have tight, thickened and waxy skin over dorsa of the hands • Multiple, minute, flesh-colored papules on dorsum of fingers, knuckle pads, and periungual areas • Contractures of hands • Scleredema adultorumCutaneous Neuropathy • Autonomic disturbances that accompany neuropathy including anhidrosisNecrobiosis Lipoidica • 0.3% of diabetics • 3:1 female:male • Only a minority of those with NLD actually have diabetes • Anterior and lateral surfaces of lower legs, usually (also face, arms, and trunk) • Begins as small, dusky-red elevated nodule with sharply circumscribed border, enlarging to an atrophic plaque • Brownish-yellow center, red border • Extremely chronic and indolent • Diabetes may precede (80%) or occur subsequent to development of lesions (10%); rest have no glucose intolerance; most have abnormal glucose tolerance in response to glucocorticoidsGranuloma Annulare • Generalized form more common in DMVitiligo • Greater than expected incidence in patients with DM Type 1 • May precede clinically evident diabetesAcanthosis Nigricans • See separate discussion General Dermatology  131
    • 4.37 Langerhans Cell HistiocytosisHistiocytosis X • Proliferation of dendritic or Langerhans histiocytesMorphology • Rose-colored papules, some scaling, crusting, and ulceration • Merging of lesions on scalp gives seborrheic dermatitis appearance • Nail changes: Paronychia, nail fold destruction, onycholysis, subungual hyperkeratosis (poor prognostic signs)Systemic Manifestations • Extremely variable • Pulmonary involvement in >50% → lungs show honeycomb appearance; dyspnea, cyanosis, and pneumothorax • Hepatosplenomegaly: Never the initial sign of disease • Bone lesions (60%) • Hematopoietic involvement (rare) • FeverClassification Letterer-Siwe Disease • Acute, disseminated LCH • First year of life • Cutaneous disease more common in this entity (80%), and usually initial sign • Fever, anemia, thrombocytopenia, enlargement of liver and spleen (never presenting sign) • Potentially fatal visceral involvement • Only osteolytic lesion is in mastoid bone (looks like otitis media) Hand-Schuller-Christian Disease • Early childhood • Less extensive visceral involvement • Chronic, multifocal disease • Cutaneous disease in only 30% • Osseous lesions, especially of cranium (80%) • Exophthalmos (10-30%) • Can cause diabetes insipidus (50%), caused by granulomatous infiltration of posterior pituitary gland Eosinophilic Granuloma • Older children and adults • Benign • One or a few bone lesions • Affects skull, ribs, and vertebrae most frequently • Can affect mucosa Hashimoto-Pritzker Disease (Congenital, Self-healing Reticulohistiocytosis) • Present at birth, usually • No mucous membrane lesions • Systemic signs absent • Rapid spontaneous regression132  2011/2012 Dermatology In-Review l Committed to Your Future
    • Course and Prognosis • Skin and bone involvement good signs, and organ involvement bad • 10% with multifocal disease die, 60% have chronic course, 30% show complete remissionManagement Treatment based on age, extent of disease, and location of lesions Children • Nonaggressive management • Observation • Topical nitrogen mustard for persistent lesions Adults • Topical nitrogen mustard • PUVA • CO2 laser • Thalidomide • Isotretinoin Bone Involvement • Surgical excision • Glucocorticoid injections • Radiotherapy in adults • Monochemotherapy for multiple bone lesions4.38 Cutaneous T-Cell LymphomaClinical Types Patch and Plaque Stage • Flat lesions associated with inflammation and pruritus, that can persist for years or resolve spontaneously • Patch stage can last for months to years before progressing • Plaques can arise de novo Hypopigmented MF • Darker-skinned patients • Patients respond to therapy by regaining pigment Pigmented Purpura • Capillaritis Granulomatous CTCL and Slack Skin • Primarily in females • Large regions of slack skin accompanied by fibrotic bands Pagetoid Reticulosis (Woringer-Kolopp Disease or Acral MF) • Typically presents as a solitary plaque (localized) • Long duration, slow growing • Benign; long duration without progression • Pronounced epidermotropism • Follicular MF General Dermatology  133
    • Alopecia Mucinosa • Follicular mucinosis • Grouped follicular papules or red, raised, boggy, occasionally nodular plaques • Alopecia may be presenting sign • Histology: Sebaceous glands and outer root sheaths disrupted with increased mucin deposition • CTCL may be present before development of alopecia mucinosa Erythrodermas • De novo or as a progression from pre-existing CTCL lesions • May lead to leonine facies • Alopecia, ectropion, nail dystrophy, ankle edema • Sezary syndrome may cause Tumor Stage MF • Predilection for face and body folds • May occur in pre-existing plaques and patches of CTCL • Neoplastic cells more malignant biologically • Nodules may ulcerate • May spontaneously resolve, but prognosis is poor • Infiltrate denser than plaque stage, and extends to subcutaneous fat • Epidermotropism is not a prominent feature, and grenz zone may appearDiagnosis • Diagnosis made by biopsy • Multiple punch biopsies at 3 month intervals may be needed • Any patient with chronic, refractory dermatosis (acd, ad, psoriasis, prp) should be biopsied to rule out ctcl • Clonality assists in diagnosis, but is not pathognomonicPeripheral Blood • Malignant clonal T-cell populations recirculate from skin to lymph nodes, and then to blood, even in patch stage disease, CD4+/CD7- • Elevated CD4/CD8 ratio indicates disease expansion into blood • Flow cytometry must be a component in the staging process (CD4/CD8), CD3, CD45RO • Memory cell marker CD45RO is elevated often in cases of peripheral blood involvement by CTCLSezary Cells • Hyperchromatic and hyperconvoluted nuclei • Represent an activated T-cell • Can be seen in inflammatory dermatoses, and in Dilantin (phenytoin) hypersensitivity syndrome • 100 cells counted to assess percentage, and >5% associated with poor prognosisPrognosis • Involvement of 10% or less with patch disease: median survival of 12 years • Tumors, erythroderma, or node involvement: median survival 2-3 years • Sezary syndrome: 2-3 years134  2011/2012 Dermatology In-Review l Committed to Your Future
    • Topical Chemotherapy • Nitrogen mustard (bis-chloro nitrosurea, BCNU); mechlorethamine (10 mg in 50 ml tap water as initial dose) • Ointment-based mechlorethamine has longer shelf life • Side effects: Hypersensitivity, primary irritation, second cutaneous malignancies, hypo and hyperpigmentation • Daily whole-body application required until remission, after which frequent maintenance therapy usedRadiotherapy • Electrons penetrate only to upper dermis • Whole body irradiation induces complete remission in >80%; with relapse rate higher in later stages of CTCL • Most relapses occur within first year after cessation of treatment • Local side effects: Alopecia, atrophy of sweat glands and skin, radiodermatitis, and edema; fractionating dose reduces side effects • SCC incidence increased • 2nd and 3rd courses acceptable if neededPhotochemotherapy • PUVA • Induces remission even in tumor stages Extracorporeal Photochemotherapy • Photoinactivation of a portion of the patient’s lymphocyte compartment with 8-methoxypsoralen + UVA, followed by reinfusion • Two consecutive days every four weeks • Effective for erythroderma • Requires 4-12 months for response Alpha and Gamma Interferon • 10-27% complete response within 6 months using monotherapy • 3 million units 3x/week, and can be increased to 20 million units per day as tolerated • Maintenance dose of 1 million units daily • Toxicities: Flu-like symptoms first week. Side effects: chronic fatigue; long-term neurologic toxicity may occur, and autoimmune phenomena such as proteinuria, thrombocytopenia, and anemia DAB-IL-2 Toxin/Denileukin Diftitox • Diphtheria toxin fused to IL-2, binding to receptor, killing cells • Infiltrates must contain high levels of IL-2 receptor-positive cells • May cause fluid retention, diffuse erythema, and liver abnormalities, which are all reversible Systemic High-Dose Chemo • Palliative • Glucocorticoids, adriamycin, CHOP therapy General Dermatology  135
    • 4.39 Pyoderma gangrenosumFour Types Ulcerative • Inflammatory pustule with surrounding halo • Enlarges over days and ulcerates • Many lesions begin at sites of trauma (pathergy) • Distinct rolled edges and show satellite violaceous papules that break down and fuse with central ulcer • Painful • Adults 40-60 years old on lower extremities and trunk • Heal with thin, atrophic scars Pustular • Describes the primary pustular lesions that may or may not progress on to ulcerative lesions • Often seen associated with IBD • Associated with pyostomatitis vegetans and subcorneal pustular dermatosis Bullous • Less destructive, more superficial • Overlap with atypical Sweet’s • Patients with leukemia or polycythemia vera • Red inflammatory plaques that become dusky and develop superficial erosion of the epidermis • Less painful than ulcerative Vegetative • Least aggressive form • Cribiform chronic superficial ulcerations on the trunk, usually • Not painful • Not often associated with systemic disease u TIPClinical Associations a50% have associated disease, most commonly is IBD (UC > Crohn’s) • 1.5-5% of patients with IBD develop PG • Diseases run separate courses • Associated with leukemia, myeloma, monoclonal gammopathy (IgA), polycythemia, chronic active hepatitis, hcv, hiv, sle, pregnancy, and Takayasu’s Arteritis • Associated with PAPA syndrome → pyogenic arthritis, pyoderma gangrenosum, severe cystic acne • 33% have arthritis → asymmetrical, seronegative, monoarticular arthritis of the large joints • Children with congenital deficiency of leukocyte-adherence glycoproteinsHistology • Massive dermal edema with epidermal neutrophilic abscesses at the violaceous undermined borderTreatment • If lesions pustular, seek and treat for underlying IBD • Aggressiveness of treatment determined by severity of disease136  2011/2012 Dermatology In-Review l Committed to Your Future
    • • Local treatment: Compresses or whirlpool baths with use of ointment occlusive dressings • Potent topical steroids or IL steroids • Topical tacrolimus • Systemic steroids, and if not responding, pulse methylprednisolone • Sulfapyridine, sulfasalzine, and dapsone • Clofazamine 200-400 mg qd • Cyclosporine is the next choice, with 85% of reported cases responding dramatically: start at 5 mg/kg • Infliximab • Other agents: thalidomide, SSKI, azathioprine, cyclophosphamide, chlorambucil4.40 Sweet’s syndromeAcute Febrile Neutrophilic Dermatosis • Recurrent painful plaque-forming inflammatory papules, fever, peripheral leukocytosis, a diffuse dermal infiltrate, and prompt resolution of symptoms and lesions with glucocorticoid therapyClinical Skin • Sudden eruption of tender red or bluish red papules or nodules uTIP over face, neck, upper extremities a ace, upper extremities, and F neck, most commonly • Coalesce to form irregular sharply bordered plaques (“relief of a mountain range”) • Transparent vesicular appearance, though solid (“illusion of vesiculation”) • Eventually resolve without scarring after weeks or months Systemic • Fever, leukocytosis, with patients appearing dramatically ill • Headache, arthralgia, myalgia, and general malaise, conjunctivitis, and episcleritis • Bone: Sterile osteomyelitis • Neuro: Aseptic meningitis, neurologic and psychiatric symptoms, with neutrophils in the CSF • Renal: Proteinuria, hematuria, glomerulonephritis • Hepatic: Infiltration of portal triad and tracts with elevated LFT’s • Pulmonary: Culture-negative infiltratesLaboratory • Elevated ESR • Peripheral leukocytosis with neutrophilia • Malignancy-associated Sweet’s: anemia, normal or low neutrophil count and abnormal platelet count • Proteinuria if renal involvementEtiology • No known cause. Thought to be a hypersensitivity reaction u TIP • Majority of patients have a febrile upper respiratory tract aCan be drug-induced (GCSF) infection, tonsillitis, or influenza-like illness that precedes their skin lesions by 1-3 weeks • Can be associated with intestinal infection with Yersinia enterocolitica General Dermatology  137
    • Pathology • Edema of the dermal papillae and dense infiltrate composed largely of neutrophils, with some lymphocytes and histiocytes, and occasional eosinophils • Infiltrate is bandlike in papillary dermis (“Sea of neutrophils”) • Leukocytoclasia commonAssociated Diseases Probable Association • Infection: Usually upper respiratory tract and GI tract u TIP • Inflammatory bowel disease a Malignancy, most commonly • Medications: G-CSF – anemia commonly associated, and hematologic (AML); lesions tmp-sfx may precede diagnosis of • Pregnancy leukemia Treatment • Corticosteroids • Potassium Iodide4.41 Erythema Annulare Centrifugum • Polycyclic erythematous lesions that grow eccentrically and slowly • Often recurrent • Characteristic trailing scale at inner border • Characteristic lymphocytic coat sleeving of vascular/adnexae on pathologyAssociations • Idiopathic • Malignancy • Dermatophyte (feet and groin) But no extensive workup necessary4.42 Erythema Elevatum DiutinumClinical Features and Course Morphology • Multiple lesions: Papules plaques or nodules • Early lesions often pink or yellow. Older lesions are red or purple and harder. Lesions may be round or oval, and surface is smooth with occasional scale. Also, freely movable from underlying tissues Distribution • Symmetric on extensor surfaces, especially skin overlying joints, especially on hands and knees. Also involve the buttocks and skin overlying the achilles tendon Symptoms • Asymptomatic to very painful Associated Symptoms and Conditions • Arthralgia (most common) • Recurrent pharyngeal and sinopulmonary infection, usually streptococcal • Inflammatory bowel disease138  2011/2012 Dermatology In-Review l Committed to Your Future
    • Course • Variable, but often progressive over 5-10 years, with long-term remission possible • Periods of waxing and waning u TIPLaboratory Findings aIgA (mainly) or IgG or IgM monoclonal • Elevation in ESR gammopathies or even myelomaTreatment • Dapsone or sulfapyridine – with exacerbation after the drug’s withdrawal • Glucocorticoids not effective systemically, but intralesional and topical high potency steroids may decrease the size of lesions4.43 Erythema Nodosum Extensor surfaces, lower extremities: inflammatory, spontaneously M NEM ON I Cregressing, tender, nodular lesions. Erythema Nodosum SHOUT BCGClinical Sarcoid, Sulfa, Strep • Erythematous, tender nodules on anterior shins; also seen on Histoplasmosis thighs, lateral aspects of lower legs, arms, and face Oral contraceptives Ulcerative colitis • Onset of new lesions often accompanied by fever, chills, malaise, TB and leukocytosis Bechet’s • Often progresses into a violaceous blue color Crohns • 70% have associated arthropathy that may persist after GI (Yersinia) disappearance of eruption • Occurs at any age, but most prevalent between 20 and 30 years of age • Results from immunologic reaction triggered by drugs, benign and malignant systemic illness, bacterial, viral, and fungal infectionsInfections • Streptococcal, beta hemolytic: cutaneous lesions develop within three weeks of infection • Tuberculosis: Associated with primary infection • Yersinia • Blastomycosis, coccidioidomycois, histoplasmosis; dermatophytes, particularly those causing tinea capitis with kerion formation • Often occurs after acute respiratory illness that is nonstreptococcal for which no agent identified • Viruses: paravaccinia, infectious mononucleosis, lymphogranuloma venereum, cat-scratch disease, psittacosis, Hepatitis BSarcoidosis • May be presenting sign along with hilar adenopathy • Lofgren’s syndrome: sarcoidosis, erythema nodosum (good prognosis)Drugs • Sulfonamides • Bromides • Oral contraceptives General Dermatology  139
    • Enteropathies • Ulcerative colitis more frequently than Crohn’s diseaseMiscellaneous Causes • Behçet’s syndrome • Malignancy: Lymphoma, leukemia, cervical cancer • Onset of radiation therapy for cancerTreatment • Spontaneous resolution usually occurs within three to six weeks without scarring • NSAIDs such as indomethacin or naproxen • Systemic steroids effective in severe cases and can be dangerous if infection is etiology • Potassium iodide 400 to 900 mg daily4.44 Mastocytosis • Mast cell hyperplasia in the bone marrow, liver, spleen, lymph nodes, GI tract, and skin • Clinical: Pruritus, flushing, urtication, abdominal pain, nausea, vomiting, diarrhea, bone pain, vascular instability, headache, and neuropsychiatric difficultiesEtiology and Pathogenesis • Originate from pluripotent (CD34+) bone marrow cells → circulate through blood → mature into fully granulated cells • Mutations in c-kit → associated with enhanced receptor function • Increased production of mast cell mediators: – Histamine – Heparin – Tryptase – Leukotrienes – Prostaglandin D2 – Platelet activating factor – Cytokines – growth enhancing and proinflammatorClinical • Features are due to excess production of mast cell-dependent mediators • Patients in every category of mastocytosis sometimes experience flushing or vascular collapse → provoked by alcohol, aspirin, narcotics, contrast agents (iodinated), insect stings, exercise, or infections Major Types of Mastocytosis • Urticaria pigmentosa – Most common skin manifestation in children and adults – 90% of those with indolent mastocytosis – Small, yellow-tan to reddish-brown macules or slightly raised papules – Darier’s sign: Trauma/rubbing of lesions causes urtication and erythema – Associated with pruritus exacerbated by changes in temperature, friction on skin, ingestion of hot beverages or spicy foods, ethanol, and certain drugs • Diffuse cutaneous mastocytosis – Diffuse mast cell infiltration without discrete lesions140  2011/2012 Dermatology In-Review l Committed to Your Future
    • – Usually occurs before age of three – Entire skin involved – Skin normal to yellow-brown and thickened • Solitary mastocytomas – Rare – Onset before six months of age – Involute spontaneously, usually • Bullous eruptions with hemorrhage – Neonates – Blisters may erupt spontaneously • Telangiectasia macularis eruptiva perstans – <1% of patients – Tan-to-brown macules and patchy erythema – Telangiectasias observed – Exclusively in adultsSystemic Features Gastrointestinal Disease • Gastric hypersecretion secondary to elevated histamine → gastritis with peptic ulcer disease • Diarrhea and abdominal pain • Malabsorption • LFT’s abnormal in half of patients → alkaline phosphatase elevated Splenomegaly • 50% of patients • Mast cell infiltrates with fibrosis • Extramedullary hematopoiesis Bone Marrow • Radiographically detectable lesions in majority of patients → proximal long bones most often affected; pathologic fractures may occur • Anemia, leukopenia, thrombocytopenia and eosinophilia may occur Neuropsychiatric • Decreased attention span • Memory impairment • Irritability Mastocytic Leukemia • Rarest form and has most fulminant behavior; peripheral blood shows numerous immature mast cellsWork Up 1.) Skin exam – gross and microscopic 2.) Bone marrow biopsy 3.) 24 hour urine • Suspicion should prompt a bone marrow biopsy and aspirate for diagnosis and categorization of the type of mastocytosis • Obtain 24 hour urine for 5-hydroxyindoleacetic acid (5-HIAA) and urinary metanephrines to rule out carcinoid tumor or pheochromocytoma General Dermatology  141
    • Treatment • H1 blockers reduce pruritus, flushing, tachycardia • H2 blockers added • Cromolyn sodium, particularly for GI complaints • Ketotifen and azelastine, antihistamines that stabilize mast cells • Epinephrine for vascular collapse (patients should be prepared to self-administer) • PUVA (with methoxsalen) relieves pruritus and whealing after 1-2 months, but recurs after 3-6 months • Topical glucocorticoids under occlusion for 8 hours per day over 8-12 weeks can be used for extensive UP; lesions recur after discontinuation • Radiotherapy for bone painSurvival • 50% of children with UP resolve by adulthood • Adults with UP usually progress gradually to systemic disease and rarely develop hematologic disease • Diffuse cutaneous mastocytosis is usually associated with indolent systemic disease • Mast cell leukemia: survival less than six months • Lymphadenopathic mastocytosis with eosinophilia: two to four years without therapy4.45 Cutaneous Sarcoidosis • Skin lesions occur in 25% of patients with sarcoidosisLupus Pernio • Middle aged females, increased in African Americans • Chronic, violaceous, indurated plaques • Predilection for nose, ears, lips, and face • Persistent sarcoidosis characterized by extensive pulmonary infiltration and fibrosis, chronic uveitis, and bone lesions • Nose lesion accompanied by granulomatous infiltration of nasal mucosa and upper respiratory tract, and bony nasal septum may be destroyed • Bulbous or sausage-shaped finger in a patient with lupus pernio indicates presence of underlying bone lesionPlaques • Violaceous, elevated, indurated • Limbs, face, back, and buttocks • Distribution is symmetric • In African Americans, hypopigmented appearance: “hypomelanotic umbrella” • Sarcoid lesions may appear psoriaticPapular Eruptions • Most common skin manifestations in African Americans • Waxy, translucent, flat top, 2-6 mm • Occur on face, lids, around orbits, neck, upper back142  2011/2012 Dermatology In-Review l Committed to Your Future
    • Subcutaneous Nodules/Darier Roussy Sarcoidosis • Oval, firm, painless • Arise deep in dermis and subcutis • Found on trunk and extremities • Rarely, ulcerateErythema Nodosum • Most common nonspecific cutaneous manifestation of sarcoidosis (Lofgren’s syndrome) • Hallmark of acute sarcoidosis, predominantly of women of childbearing age • May be associated with fever, malaise, polyarthralgia • Associated with good prognosis in sarcoidosisLaboratory Investigations • Hypercalcemia: due to increased intestinal absorption secondary to active form of Vitamin D3 overproduction (in lungs) • ACE level: raised in 60%, higher in patients with hilar adenopathy and pulmonary infiltration (stage II) and positive in patients with extrathoracic sarcoidosis; ACE derived from epithelioid cells of granulomas and thus reflects granuloma load in the body • ACE used for monitoring clinical course, not for diagnosis (60% sensitive, and 90% specific)Immunology Cutaneous Anergy • Depression of DTH reactions; negative PPD in 66% • Anergy does not correlate with disease activity—persists even during recovery Humoral Responses • Exaggerated circulating antibody • Hypergammaglobulinemia occurs in half the patients Kveim Test • Intradermal injection of homogenized tissue from sarcoidosis patient • Requires four to six weeks for nodule to developTreatment Glucocorticoids • Prednisone, 20-40 mg qd, is treatment of choice • Dose is reduced gradually to 10 mg daily • After 4-6 weeks of daily treatment, dose can be reduced to 10-20 mg every other day • IL triamcinolone to disfiguring lesions • Topical glucocorticoids to individual lesions Antimalarials • Chloroquine • Hydroxychloroquine Immunosuppressive Drugs • Methotrexate • Infliximab Surgery • Excision of small lesions • Grafting of extensive sarcoid ulcers General Dermatology  143
    • 4.46 Perforating DisordersPerforating Folliculitis Pathogenesis • Lesions may be related to superficial trauma Clinical • Keratotic follicular papules over extensor surfaces • Association with chronic renal failureReactive Perforating Collagenosis Pathogenesis • Lesions precipitated by superficial trauma altering collagen in the dermal papillae Clinical • Pinhead keratotic papules that grow to 6-10 mm in diameter • Center of lesion becomes umbilicated containing tightly adherent plug • First lesions usually appear in infancy after minor trauma or arthropod biteKyrle’s Disease (Hyperkeratosis folliculitis) Pathogenesis • Absence of collagen • Follicular plug in an epidermal invagination Clinical • Scaly folliculo-centric papulesElastosis Perforans Serpiginosum (EPS) MNEMONIC Pathogenesis MAD PORES • Altered elastic fibers in dermis and concomitant alteration of Marfan’s collagen fibers Acrogeria Down’s • Elastic fibers act as a foreign body and are eliminated through transepidermal channels Penicillamine Clinical Osteogenesis Imperfecta Rothmund-Thomson • Patients with MADPORES: Marfans, Acrogeria, Down syndrome, Ehlers Danlos Penicillamine, Osteogenesis Imperfecta, Ehlers Danlos Scleroderma • Flesh colored to erythematous umbilicated papules 2-3 mm arranged in arcuate serpiginous or grounded fashion • Nape and sides of neck, upper extremities Treatment • Cryotherapy4.47 Elastosis perforans serpiginosaPathogenesis • Altered elastic fibers in dermis and concomitant alterations of collagen fibers • Elastic fibers act as a foreign body and are eliminated through transepidermal channels144  2011/2012 Dermatology In-Review l Committed to Your Future
    • Patients • Idiopathic • Patients with Down’s syndrome, heritable connective tissue disorders (Ehlers-Danlos Type IV, osteogenesis imperfecta, Marfan’s syndrome, Rothmund-Thomson, scleroderma, and acrogeria), penicillamineClinical • 2nd decade of life • Flesh-colored to erythematous umbilicated papule 2-3 mm, with central, tightly adhering plug that bleeds when removed • Nape and sides of neck, upper extremities • Arcuate, serpiginous, grouped, scattered, discrete • Regression leaves atrophic, wrinkled, and hypopigmented scarsTreatment • Cryotherapy • Avoid electrocautery, dermabrasion, and surgery4.48 Reactive Perforating CollagenosisPathogenesis • Perhaps genetic predisposition • Development of lesions likely precipitated by minor superficial trauma altering collagen in the dermal papillae • No associated metabolic disordersClinical • Lesions start as pinhead-sized keratotic papules and grow to 6-10 mm in diameter over one month • Center of lesion becomes umbilicated containing a tightly adherent leathery plug that if removed leaves a bleeding crater • Heals with a minor scar of hypopigmented macule • First lesions usually appear in infancy after minor trauma or arthropod bite • AsymptomaticTreatment • No consistently successful therapy • Maybe phototherapy4.49 Cutaneous features and disorders of PregnancyPemphigoid Gestationis • Seen only in pregnancy or with trophoblastic tumors • Begins in 2nd or 3rd trimester • Urticarial or papulovesicular lesions on trunk; spreads rapidly and may involve face and palms/soles, evolving into bulla • Pruritus may precede lesions • May remit prior to delivery, but 75% flare post-partum • Recurs with pregnancy, OCP’s, or menses General Dermatology  145
    • Laboratory • Severity may correlate with eosinophilia • Increased anti-thyroid antibodies Immunofluorescence • Direct: C3 in homogeneous, linear band at BMZ (perilesional and lesional skin); IgG in 30-40% • Indirect: Complement fixation at BMZ; HG factor = complement fixing IgG antibody; almost all patients show IgG1 against BMZ Pathophysiology • IgG against 180 kd BP antigen; → extracellular domain • Theory: Cross reaction of antibodies directed against amniotic BMZ • Pregnancies can skip disease Treatment and Course • Prednisone 0.5 mg/kg/day (topical steroids often ineffective) • Increased risk for small for gestational age infant and prematurity • Mother: Increased lifetime risk of Grave’s diseaseCholestasis of Pregnancy • The same as prurigo gravidarum +/- jaundice • Cholestatic jaundice of pregnancy = abnormal LFT’s • Prurigo gravidarum = pruritus and abnormal bile acids without jaundice Clinical • Usually 3rd trimester • 50% associated with UTI • <50% develop jaundice • Intense pruritus without lesions • Resolves within 2 days post-partum Laboratory • Bile acids elevated 3-1000x normal • Direct bilirubin not more than 2-5 mg/dl • Hepatic ultrasound is normal Course and Prognosis • Mother: Low Vitamin K → post-partum hemorrhage • May recur with future pregnancy • Increased risk of cholelithiasis • Fetus: Premature labor (common), fetal distress, perinatal death Treatment • UVB phototherapy for symptoms • Cholestyramine given with Vitamin K • Rest and low fat diet • Ursodeoxycholic acid or UDCA (16 mg/kg/day) → reduces risk of premature delivery and pruritus • Dexamethasone 12 mg/day x 7 days → decreases lab abnormalities and pruritus, used in conjunction with UDCA • Deliver at 38 weeks or earlier146  2011/2012 Dermatology In-Review l Committed to Your Future
    • Polymorphous Eruption of Pregnancy (or PUPPP) Clinical u TIP • Papules begin in striae and spread to trunk and a rimigravidas, increased with maternal P obesity and twin gestation extremities • Usually in 3rd trimester • Resolves 15 days post-partum, sometimes prior to delivery Laboratory • Normal Treatment and Course • Topical steroids • Antihistamines • Systemic steroids • No maternal or fetal morbidityPustular Psoriasis of Pregnancy • Also called “impetigo herpetiformis” Clinical • Late 1st trimester to 3rd trimester • Often begins in intertriginous regions and spreads to trunk and extremities • Spares face, palms, and soles • Erythematous plaque with ring of pustules, that enlarges at periphery and erodes or crusts at periphery • Mucosa can be involved • Onycholysis • No pruritus • Malaise, anorexia, fever, chills, nausea, vomiting, diarrhea Course • Remits quickly post-partum • Recurs with subsequent pregnancies, menses and OCP’s • Fetus at risk for placental insufficiency Laboratory • Hypocalcemia • Leukocytosis • Elevated ESR • Pustule culture negative Treatment • Prednisolone 80 mg/d → decreases mortality risk for mother • Treat hypocalcemia • May require early delivery4.50 PruritusPathophysiology • The only peripheral tissue from which itch evoked is skin, with the exception of the cornea • The C and A delta fibers in the uppermost skin unique in their ability to produce itch • Histamine produces itch via the H1 receptor General Dermatology  147
    • • Other substances that produce itch: papain, trypsin, serotonin, bradykinin, kallidin, kallikrein, substance P and VIP • Prostaglandins exaggerate existing itch • Opiates have both central and peripheral itch-producing actionConditions that Cause Pruritis Chronic Renal Disease • Affects 80% of those on dialysis • Dialysis causes temporary relief • Emollients, antihistamines ineffective • Antihistamines rarely work • Secondary hyperparathyroidism is an occasional cause of uremic pruritus • Increased population of mast cells in skin • UV phototherapy may benefit Cholestasis • High level of bile salts, and cholestyramine causes symptomatic improvement Endocrine Disease • Thyrotoxicosis – often due to increased skin blood flow which raises skin temperature • Hypothyroidism – pruritus secondary to the dry skin of myxedema • Postmenopausal pruritus may be generalized or localized, usually in anogenital area Malignancy • Most common association: Hodgkin’s disease and polycythemia vera Polycythemia Vera  •  50% have water-induced pruritus; referred to as “bath itch” or aquagenic pruritus • May precede development of PV by years • Itch is independent of temperature of water HIV Infection • Increased itching secondary to scabies, pediculosis, candidiasis, or seborrheic dermatitis, or renal/hepatic dysfunction • Eosinophilic folliculitis • Pruritus of HIV • May respond to UVB, PUVA, or dapsone Workup of Generalized Pruritus • Physical exam, including pelvic and rectal • CBC • Stool for O&P, occult blood  • CXR • Thyroid, renal, and liver function tests • Drug history4.51 SCLEREDEMAClinical Manifestations • Skin involvement may be preceded by prodrome of low-grade fever, malaise, myalgia, arthralgia • 65% develop infection usually of streptococcal origin a few days to 6 weeks before onset148  2011/2012 Dermatology In-Review l Committed to Your Future
    • • Marked, nonpitting, symmetric induration of the skin • Affects posterior and lateral aspects of neck, spreads to face, shoulders, back, arms, and thorax • Induration is waxy white or shiny, and diffuse without sharp demarcation between involved and uninvolved areas Laboratory Findings • Increase in ASO titer in some patients • Glucose tolerance test may be warranted • Hyperinsulinemia may be present Pathogenesis • Unknown  • Syndrome of long duration, obesity, adult onset, and latent or overt diabetes associated with cardiovascular disease noted • Dermis markedly increased in size with increase in hydroxyproline and hexosamines • Association with monoclonal gammopathy, IgG type Treatment • None Course and Prognosis • Spontaneously resolves in 6 months to 2 years • 25% show no resolution, especially in those with DM Table 4-4. Monoclonal Gammopathy and Disease Associations Type Disease IgA EED, pyoderma ganrenosum, subcorneal pustular dermatosis, IgA pemphigus, POEMS, Sweet’s syndrome IgM Schnitzler syndrome, Waldenstrom macroglobulinemia IgG NXG (IgG κ), scleredema (IgG κ > λ), scleromyxedema (IgG λ > κ) 4.52 Nephrogenic fibrosing dermopathy (Nfd)/ nephrogenic systemic fibrosis (nsf) Pathogenesis • Occurs in patients with renal insufficiency who have had imaging studies with gadolinium Clinical Manifestations • Induration, thickening, hardening of skin with brawny hyperpigmenting • Flexion contractures, stiffening of the hands • Pain, pruritus common • Extremities most commonly involved, then trunk • Affected skin is shiny, with peau d’orange appearance Treatment • Extracorporeal pholophoresis • Limited options • Increased morbidily/mortality because of contractures, mobility problems, falls, and fractures • Prognosis General Dermatology  149
    • References1. Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s dermatology in general medicine. 5th ed. New York: McGraw-Hill, Health Professions Division, 1999.2. Ingham E et al. Proinflammatory levels of interleukin-1 alpha-like bioactivity are present in the majority of open comedones in acne vulgaris. J Invest Dermatol. 1992; 98: 895-901.3. Kim J et al. Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses. J Immunol. 2002; 169:1535-1541.4. Wolf JE. Potential anti-inflammatory effects of topical retinoids and retinoid analogues. Adv Ther 2002; 19:109-118.5. Odom, RB. Andrews’ diseases of the skin, 9th ed. Philadelphia: WB Saunders, 2000; 96.6. Goldstein SM and Wintroub BU, Adverse cutaneous reactions to medications. Baltimore: Williams and Wilkins, 1996; 55-57.7. Wolverton, SE. Comprehensive dermatologic drug therapy. Philadelphia: WB Saunders, 2001; 277.8. Wolverton, SE. Comprehensive dermatologic drug therapy. Philadelphia: WB Saunders, 2001; 41.9. Elder D et al. Lever’s histopathology of the skin, 8th ed. Philadelphia: Lipincott Raven, 2001; 295.10. Webster GF et al. Suppression of polymorphonuclear leukocyte chemoactic factor production in Propionibacterium acnes by subminimal inhibitory concentrations of tetracycline, ampicillin, minocycline and erythromycin. Antimicrob agents chemother. 1982; 21:770-772.11. Wolverton, SE. Comprehensive dermatologic drug therapy. Philadelphia: WB Saunders, 2001; 872.12. Archer JS, Archer DF. Oral contraceptive efficacy and antibiotic interaction: a myth debunked. J Amer Acad Dermatol. 2002 June; 46 (6): 917-23.13. Wolverton, SE. Comprehensive dermatologic drug therapy. Philadelphia: WB Saunders, 2001; 277.14. Jick SS et al. Isotretinoin use and risk of depression, psychotic symptoms and attempted suicide. Arch Dermatol 2000; 136: 1231-1236.15. Wolverton, SE. Comprehensive dermatologic drug therapy. Philadelphia: WB Saunders, 2001: 396.16. Baran R and Tosti A. Nails. Dermatology in General Medicine, 5th Edition. New York, McGraw-Hill, 1999, p ­ 757-759.17. Kavanaugh A. Flare of psoriasis and psoriatic arthritis following treatment with granulocyte colony stimulat- ing factor. Am J Med 1996; 101(5): 567-8.18. Partsch G et al. Highly increased levels of tumor necrosis factor alpha and other proinflammatory cytokines in psoriatic arthritis synovial fluid. J Rheumatol 1197; 24(3): 518-23.19. Odom, RB. Andrews’ diseases of the skin, 9th Edition. Philadelphia: WB Saunders, 2000; 220.20. Rapp SR et al. Psoriasis causes as much disability as other major medical diseases. J Am Acad Dermatol. 1999; 41: 401-407.21. Elder D et al. Lever’s Histopathology of the Skin, 8th ed. Philadelphia: Lipincott Raven, 1997; 169.22. Bach JF, The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 2002; 347 (12); 911-920.23. Boner A, Valetta E, Bellanti JA. Improvement of atopic dermatitis following nature measles virus infection: Four case reports. Ann Allerg 1985; 55:605-608.24. Ong PY et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 2002; 347 (15); 1151-1159.25. Kalliomaki M et al. Probotics in primary prevention of atopic disease: A randomized placebo controlled trial. Lancet. 2001; 357: 1076-9.26. Cerroni L, Kerl H. B cell lymphomas of the skin. In Bolognia JL, et al., Eds. Dermatology. Mosby: London, 2003: 1497.27. Fairley J. Cacifying and ossifying diseases of the skin. In Bolognia JL. et al., Eds. Dermatology. Mosby: London. 2003: 692-3.28. Callen JP, Wortman RL. Dermatomyositis. Clinical Dermatolo. Sept-Oct 2006; 24(5) 363-73.29. Cowper SE, Kuo PH, Bucala R. Nephrogenic systemic fibrosis and gadolinium exposure: association and les- sons for idiopathic fibrosing disorders. Arthritis Rheun. Oct 2007; 56(10):3173-5.150  2011/2012 Dermatology In-Review l Committed to Your Future
    • NOTES General Dermatology  151
    • NOTES152  2011/2012 Dermatology In-Review l Committed to Your Future